Novel peptide-polysaccharide conjugates

Abstract

The present invention provides novel peptide conjugates, uses of such peptides in human medicine, and pharmaceutical compositions containing them. [Solution] Provided are conjugates formed between one or more linear polysaccharide chains and peptides selected from specific amino acid sequences, as well as positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of said conjugates, which are particularly useful in the treatment of wounds, burns, and conditions characterized by inflammation, including mucosal disorders such as anorectal diseases, inflammatory bowel diseases, gynecological diseases, and dental diseases. Hyaluronic acid is a preferred linear polysaccharide.

Description

[Technical Field]

[0001] This invention relates to novel peptide conjugates, the use of such peptides in human medicine, and pharmaceutical compositions containing them. Specifically, this invention relates to the use of these conjugates and compositions, for example, in the treatment of inflammation. [Background technology]

[0002] Inflammation is typically characterized as a local tissue response to the invasion of, for example, microorganisms, specific antigens, damaging cells, or physical and / or chemical factors. The inflammatory response is usually a protective mechanism that destroys, weakens, or isolates both the harmful substance and the damaged tissue, initiating tissue healing.

[0003] Inflammation can result from physical trauma, infection, certain chronic diseases (e.g., autoimmune diseases such as psoriasis and rheumatoid arthritis), and / or chemical and / or physiological responses to external stimuli (e.g., part of an allergic response). A complex series of events may be involved, in which inflammatory mediators increase blood flow and local vasodilation, leading to redness and heat, fluid exudation, and often local swelling, leukocyte migration to the inflamed area, and pain.

[0004] Many conditions / disorders are characterized by and / or caused by abnormal tissue damage and inflammation. Such conditions typically feature activation of immune defense mechanisms, resulting in effects that are more detrimental than beneficial to the host, and are generally associated with varying degrees of tissue redness or congestion, swelling, hyperthermia, pain, itching, cell death, tissue destruction, cell proliferation, and / or loss of function. Examples include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, glomerulonephritis, and transplant rejection.

[0005] Typically, a series of complex events lead to inflammatory changes such as increased blood flow due to local vasodilation resulting in redness and heat, extravasation of leukocytes and plasma often resulting in local swelling, activation of sensory nerves (causing pain in some tissues), and loss of function. These inflammatory changes are triggered by a cascade of cellular and biochemical events involving cells such as neutrophils, monocytes, macrophages, and lymphocytes, along with inflammatory mediators such as vasoactive amines, cytokines, complement factors, and reactive oxygen species.

[0006] In particular, inflammation plays a crucial role in the wound healing process. Therefore, wounds and burns can be classified as conditions associated with inflammation. The conventional view in this field is that anti-inflammatory drugs should not be directly applied to open wounds because they are detrimental to the progression of wound healing.

[0007] Fibrosis is defined as the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM), such as collagen and fibronectin), within and around inflamed or damaged tissue. While collagen deposition is typically a reversible part of wound healing, in cases of severe tissue damage or when the wound healing response itself becomes unregulated, it can often develop into an increasingly irreversible fibrotic response. Furthermore, fibrosis is known to be a major cause of morbidity and death in many chronic inflammatory diseases, as well as in end-stage liver disease, kidney disease, idiopathic pulmonary fibrosis (IPF), and heart failure. It is also a pathological feature of many chronic autoimmune diseases, including scleroderma, rheumatoid arthritis, Crohn's disease, ulcerative colitis, myelofibrosis, and systemic lupus erythematosus. In addition, fibrosis can influence the pathogenesis of many progressive myopathies, metastases, and graft rejection.

[0008] Mussel adhesion proteins (MAPs), also known as the foot proteins of Mytilus edulis (MEFPs), are proteins secreted by marine mollusks such as Mytilus edulis, Mytilus coruscus, and Perna viridis. Eleven individual adhesion protein subtypes derived from mussels have been identified, including collagen pre-COL-P, pre-COL-D, and pre-COL-NG; mussel foot matrix proteins PTMP (proximal filament matrix protein) and DTMP (distal filament matrix protein); and mfp proteins mfp-2 (sometimes called "MEFP-2" and used interchangeably below), mfp-3 / MEFP-3, mfp-4 / MEFP-4, mfp-5 / MEFP-5, mfp-6 / MEFP-6, most preferably mfp-1 / MEFP-1 (e.g., Zhu et al. This includes (see al., Advances in Marine Science, 2014, 32, 560-568 and Gao et al., Journal of Anhui Agr.Sci., 2011, 39, 19860-19862).

[0009] The majority of mefp-1 consists of 70-90 tandem repeats of the decapeptide: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (see SEQ ID NO: 1, Waite, Int. J. Adhesion and Adhesives, 1987, 7, 9-14). This decapeptide sequence may be isolated as a low molecular weight derivative of naturally occurring MAP, or, for example, Yamamoto i It may also be synthesized as described in J.Chem.Soc., Perkin Trans., 1987, 1, 613-618. See also Dalsin et al., J.Am.Chem.Soc., 2003, 125, 4253-4258.

[0010] Decapeptide analogs, particularly Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2), are also disclosed. See, for example, US5,616,311 and WO96 / 39128.

[0011] The use of lysine amino acid residues for preparing multi-antigen peptides is, for example, seen in Tam, Proc. Natl. Acad., Sci. USA, 1988, 85, 5409-541. 3. Disclosed in Rao et al., J.Am.Chem.Soc., 1994, 116, 6975-6976, US5,229,490 and WO2010 / 038220.

[0012] The use of peptide-based scaffolds as drug delivery vehicles is disclosed. For example, Br See okx et al., J.Control.Release, 2002, 78, 115-123.

[0013] Hyaluronic acid (HA) and sodium hyaluronate are widely used to prepare biomaterials for tissue engineering (e.g., Khunmanee et al., J.Ti). (See ssue Eng., 2017, 8, 1-16). HA is a naturally occurring polysaccharide widely distributed throughout the human body in connective tissue, epithelial tissue, and nerve tissue. It is a major component of synovial fluid and one of the main lubricating components of fluids. It is also an important component of articular cartilage and is involved in the resistance of cartilage to compression. As a major component of skin, it is involved in tissue repair and contributes to tissue hydrodynamics, cell migration, and proliferation. As a major component of the extracellular matrix, it plays an important role in tissue regeneration, inflammatory responses, and angiogenesis (the stage of skin wound repair).

[0014] HA can form a gel with water. This is useful in osteoarthritis as an intra-articular injection, and in skin treatments as a dermal filler to treat facial wrinkles in cosmetic surgery. HA is approved by the U.S. Food and Drug Administration (FDA) for this purpose, and treatment involves repeated injections at 6-12 month intervals using either a subcutaneous needle or a microcannula.

[0015] Cross-linking of HA is necessary to prevent biodegradation by free radicals and enzymes, and to extend the duration of HA fillers. Currently, chemical cross-linking agents such as 1,4-butanediol diglycidyl ether (BDDE) are used, but it is known that problems arise when these cross-linking agents are present in cross-linked HA products. For example, BDDE has been reported to be mutagenic in Drosophila model organisms (Foureman et al., Environ. Mol. Mutagen., 1994, 23, 51-63). Furthermore, BDDE is suspected of being carcinogenic (WO2017 / 076495).

[0016] There is a clear need for new and / or improved drugs that can be used to treat inflammation and inflammation-characterized conditions. [Overview of the Initiative]

[0017] According to a first aspect of the present invention, one or more linear polysaccharide chains and preferably peptide components (a), (b), (c) or (d) defined below: (a) peptide component of formula I AQB I (In the formula, A and B are independently Z or A 1 -Q 1 -B 1 This represents Q, where Q represents the structural fragment of equation II. [ka] In the formula, the dashed line represents the connection point of Q to A and / or B, m represents an integer from 1 to 4, and A 1 and B 1represents, independently, Z or A 2 -Q 2 -B 2 where A 2 and B 2 each represent, independently, Z or Z-Q 3 -Z, and Q 1 Q 2 and Q 3 each represent, independently, a structural fragment of formula III,

Chemical formula

[0018] Preferably, one or more linear polysaccharide chains contain hyaluronic acid (HA).

[0019] The conjugates of the present invention that may be referred to include the following: a peptide component selected from one or more of (a), (b), and / or (c), where W represents a sequence of one or two amino acids, where the amino acids are selected from one or more of the group Lys, Ala, and DOPA, and X 1 This represents Pro, X 2 represents Ser, Pro, or Hyp, and Y represents a single bond or a sequence of 1 to 5 (e.g., 1 to 4) amino acids, the amino acids being selected from one or more of the groups Lys, Ala, Pro, Hyp, Thr, DOPA, and Tyr.

[0020] Preferred compounds of the present invention include the following: X 1 X stands for Hyp, or more preferably Pro. 2 is represented by Pro, or more preferably Hyp, W is represented by HCA, HCA-Ala-, preferably Ala or Lys-Ala, or more preferably DOPA or DOPA-Ala-, and / or Y is represented by a sequence of 5, preferably 3, or more preferably 4 amino acids, the amino acids being selected from one or more of the group Lys, Ala, Hyp, Thr, DOPA, and Tyr.

[0021] More preferably, the conjugate of the present invention is based on Y-Pro-Y1-Y 2 -Lys-, or more preferably -Hyp-Y 1 -Y 2 -Lys- and -Thr-Y 1 -Y 2 One example is a sequence of four amino acids selected from -Lys-, Y 1 and Y 2 Each of these is independently selected from Base Pro or, more preferably, Ala, Hyp, Thr, DOPA, and Tyr.

[0022] When Y represents a sequence of four amino acids, preferred conjugates of the present invention include those in which the amino acid sequence defined by Y is selected from the following groups: -Pro-Thr-DOPA-Lys-, -Pro-Thr-Tyr-Lys-, -Thr-Tyr-Pro-Lys-, and -Thr-DOPA-Pro-Lys-, And, more preferably, -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys-, and -Thr-Ala-Hyp-Lys-.

[0023] When Y represents a sequence of two amino acids, preferred conjugates of the present invention include those in which the amino acid sequence defined by Y is selected from the groups -Hyp-Thr-, -Thr-Tyr-, -Pro-Thr-, and -Thr-DOPA-.

[0024] Other preferred conjugates of the present invention that may be mentioned include those in which the amino acid sequence defined by Y is selected from -Thr-Tyr-Lys-, -Tyr-Pro-Lys-, -DOPA-Pro-Lys-, -Hyp-Thr-Tyr-, -Hyp-Thr-Tyr-Hyp-Lys-, and more preferably from the groups -Thr-Tyr-Hyp-Lys-DOPA- and -Hyp-Thr-DOPA-.

[0025] When the conjugate of the present invention contains a peptide component of formula I (as defined in (a) above), those that may be referred to are those in which m represents 1, 3, or more preferably 4, and Q, Q 1 Q 2 and Q 3 One or more of these must be a Lys or more precisely a "Lys fragment" that conforms to what is defined above as the "structural fragments of Formulas II and III" (if applicable).

[0026] Each time it appears in the formula, Q, Q 1 Q 2 , and Q 3 These can each be combined into 0, 1, or 2 Z groups.

[0027] In this regard, preferred conjugates of the present invention include those in which the peptide component of formula I is as follows: Either A or B represents Z, and the other represents A. 1 -Q 1 -B 1 It represents, or more preferably, both A and B represent Z, or both A 1 -Q 1 -B 1 It represents Q each time it appears in the expression. 1 preferably represents a Lys fragment, and Z is defined as described above.

[0028] Further preferred conjugates of the present invention also include: A 1 and B 1 One side represents Z, and the other side represents A 2-Q 2 -B 2 represents, or more preferably, A 1 and B 1 both represent Z, or both represent A 2 -Q 2 -B 2 represents, and each time it appears in the formula, Q 2 preferably represents a Lys fragment, and Z is defined as described above.

[0029] Even more preferred conjugates of the present invention include the following: A 2 and B 2 One of them represents Z, and the other represents Z-Q 3 -Z, or more preferably, A 2 and B 2 both represent Z, or both represent Z-Q 3 -Z, and each time it appears in the formula, Q 3 preferably represents a Lys fragment, and Z is defined as described above.

[0030] Even more preferred conjugates of the present invention include those in which 2 both A 2 and B represent Z.

[0031] The peptide components of the conjugates of the present invention that may be mentioned include those in which n is 0, 1 or 4, or more preferably, n is 0.

[0032] When the conjugate of the present invention contains the peptide component defined in (b) or (c) above, the terms "dopamine" and "dopamine fragment" that may be defined by the substituent G refer to the structural fragment of formula IV

Chemical formula

[0033] The preferred values ​​of p in the peptide components defined in (b) above are in ascending order of priority: 2, 3, 1, and 4.

[0034] A particular conjugate of the present invention comprising the peptide component defined in (b) above is one in which G is absent, and in this respect, preferred peptide components include those with the following amino acid sequences: Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID NO: 7), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp -Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 8), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 9) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 10), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 11), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala- Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 13), and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp -Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 14).

[0035] Compounds of the present invention that may be mentioned include: U represents Tyr and / or W represents Ala, and in this regard, the conjugate of the present invention includes: as peptide components of formula I as defined in (a) above, Z is selected from the following group: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA---(SEQ ID NO: 17), Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-- (SEQ ID NO: 18), and Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp -Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 19), and Examples of peptide components defined in (c) above that may be mentioned include those with the following amino acid sequences: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 20), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID NO: 21) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Dopamine (SEQ ID NO: 22) Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (Sequence ID 23) Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 24), Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (Sequence ID 25) Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID NO: 26), Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (Sequence ID 27) Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID NO: 28), Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (Sequence ID 29) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 30), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 31) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 32), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID NO: 33) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Dopamine (SEQ ID NO: 34) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID NO: 35), and Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-Dopamine (SEQ ID NO: 36).

[0036] The compounds of the present invention that may be mentioned include the following: U represents Tyr and / or W represents Lys-Ala-, and in this respect the conjugate of the present invention includes: as peptide components of formula I defined in (a) above which may be mentioned, Z is selected from the following group: Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr---(SEQ ID NO: 37), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(SEQ ID NO: 38), and more preferably, Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(SEQ ID NO: 39), and Examples of peptide components defined in (c) above that may be mentioned include those with the following amino acid sequences: Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 40) Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Dopamine (SEQ ID NO: 41) Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 42) Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 43), and Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 44).

[0037] Further conjugates of the present invention that may be mentioned include: U represents Tyr and / or W represents HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-, and in this respect the conjugates of the present invention include: as peptide components of formula I as defined in (a) above, Z is selected from the following group: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 45), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 46), HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 47) HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 48) And, more preferably, In the formula, Z is selected from the following group: DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 49) DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 50) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), and DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 52), and Examples of peptide components defined in (c) above that may be mentioned include those with the following amino acid sequences: DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 53) DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 54) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 55), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 56), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 57) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 58) HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (Sequence ID 59) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 60), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 61) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 62), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 63) and HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 64).

[0038] Other conjugates of the present invention that may be mentioned include: U represents DOPA and / or W represents Ala or Lys-Ala-, and in this regard, conjugates of the present invention that include the peptide component of formula I as defined in (a) above include those in which Z is selected from the following group: Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 67) Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 68) And, more preferably, Z is selected from the following group: Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 69) and Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-H yp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-- (SEQ ID NO: 70), and Peptide components defined in (c) above that may be mentioned include those with the following amino acid sequence: Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-dopamine (SEQ ID NO: 71), Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 72) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 73) Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (Sequence ID 74) Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys (Sequence ID 75) Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (Sequence ID 76) Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys (Sequence ID 77) Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (Sequence ID 78) Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys (Sequence ID 79) Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys (Sequence ID 80) Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys (Sequence ID 81) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 82) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 83) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (Sequence ID 84) Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (Sequence ID 85) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 86) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID NO: 87) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-Dopamine (SEQ ID NO: 88) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Dopamine (SEQ ID NO: 89) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 90) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID NO: 91) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID NO: 92) and Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-Dopamine (SEQ ID NO: 93).

[0039] Further conjugates of the present invention that may be mentioned include: U represents DOPA and / or W represents HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-, and in this regard, certain conjugates of the present invention that include the peptide component of formula I as defined in (a) above that may be mentioned include Z selected from the following group: HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 94) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 95) HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 96) HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 97) Furthermore, Z is selected from the following group: DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 98) DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 99) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 100) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 101), and DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 102) And as peptide components defined in (c) above that may be mentioned, the following amino acid sequence is included: DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 103), DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 104) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 105) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 106) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 107). HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 108) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 109) HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 110) HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (Sequence ID 111) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 112) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 113) and HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 114).

[0040] When the conjugate of the present invention includes a peptide component of formula I as defined in (a) above, those that may be referred to include the peptide component of formula I that is: A and B both represent Z, and one or preferably both Z groups represent: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 45), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 48) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(SEQ ID NO: 67)HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(SEQ ID NO: 94) DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 99) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 100) Alternatively, more preferably, one or both Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Or Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16), Or, more preferably, one or both Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), Or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), And Q represents a Lys fragment.

[0041] Further conjugates of the present invention that include the peptide component of formula I as defined in (a) above may be mentioned include the peptide component of formula I that is: A and B are both A 1 -Q 1 -B 1 This represents A 1 and B 1 Both of these represent Z, and one, or preferably both, Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16) Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 39) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 45), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 46), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66) Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 38) HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 96) DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 98) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 100) Alternatively, more preferably, one or both Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 2) or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), and Q 1 This represents a Lys fragment.

[0042] Further conjugates of the present invention that include the peptide component of formula I as defined in (a) above may be mentioned include the peptide component of formula I that is: A and B are both A 1 -Q 1 -B 1 This represents A 1 and B 1 Both are A 2 -Q 2 -B 2This represents A 2 and B 2 Both of these represent Z, and one, or preferably both, Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 45), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 100) Alternatively, more preferably, one or both Z groups represent: DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 52), Or, more preferably, one or both Z groups represent: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), and Q 1 and Q 2 Both of these represent Lys fragments.

[0043] Further conjugates of the present invention that include the peptide component of formula I as defined in (a) above may be mentioned include the peptide component of formula I that is: A and B are both A 1-Q 1 -B 1 This represents A 1 and B 1 Both are A 2 -Q 2 -B 2 This represents A 2 and B 2 Both are ZQ 3 -Z represents one or preferably both Z groups, and each Z group represents: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 2), Or Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), and Q 1 Q 2 and Q 3 These all represent Lys fragments.

[0044] When the conjugate of the present invention includes the peptide component defined in (d) above, those that may be referred to include: W 1 This represents either Ala or Ser, or is absent (in which case Lys is the N-terminal amino acid). X 2 represents Pro, Hyp, or diHyp, and / or if K is not present, W 1 represents Ala or does not exist, J represents Lys, and I represents Pro, Hyp, diHyp, or Thr (i.e., I does not represent DOPA or Tyr).

[0045] Preferred conjugates of the present invention that include the peptide component defined above (d) include: U 1 This represents DOPA, or moreTyr, and X 1 This represents Hyp, or more preferably Pro, and X 2 This represents diHyp, or more preferablyHyp, and Y 1represents an amino acid sequence of 1 to 4, for example, 3, 1, or preferably 2, and the amino acid sequence is selected from the group Pro, Hyp, Thr, DOPA, and Tyr.

[0046] The peptide components defined in (d) above that may be mentioned include W 1 This includes elements that represent Ser.

[0047] However, the more preferred peptide component defined in (d) above is W 1 Those in which W does not exist, or more preferably, 1 This includes things that represent Ala.

[0048] The preferred peptide components defined in (d) above also include those in which J represents Lys.

[0049] More preferably, the peptide components defined in (d) above also include those in which I represents DOPA or Tyr, more preferably Pro or in particular Hyp.

[0050] The preferred peptide components defined in (d) above also include those in which J represents Lys and Z represents DOPA or Tyr, more preferably Pro or especially Hyp.

[0051] The preferred peptide components defined in (d) above include Y 1 The amino acids in the sequence defined by include compounds selected from Pro, preferably DOPA, more preferably Hyp, Thr, and Tyr.

[0052] The particularly preferred peptide component defined in (d) above is Y 1 In a sequence defined by: the amino acid DOPA, preferably Thr, or more preferably Tyr, is linked to I, and / or the amino acid Pro, or more preferably Hyp or Thr, is linked to X. 2 This includes items that connect to it.

[0053] Y in the particularly preferred peptide component defined in (d) above 1 The preferred values ​​include -Hyp-Thr-Tyr, or more preferably -Hyp-Thr-DOPA-, when it is a three-membered amino acid sequence, and -Thr-Tyr-, or more preferably -Thr-DOPA-, or -Pro-Thr-, or more preferably -Hyp-Thr-, when it is a two-membered amino acid sequence.

[0054] The specific conjugates of the present invention that include the peptide components defined in (d) above include those that do not contain K.

[0055] In this regard, the peptide components defined in (d) above include those containing the following amino acid sequences: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 115) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 116) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 117) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 118) Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 119) Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 120) Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 121) Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 122).

[0056] A more preferred conjugate of the present invention, comprising the peptide component defined above (d), includes the following amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 123) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 124), More preferably, containing the following amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 125) and especially those containing the following amino acid sequences: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 126) It includes.

[0057] Further conjugates of the present invention that include the peptide component defined in (d) above may be mentioned, the absence of J, and having the following amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 127) Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence No. 128) Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 129) Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 130) Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 131) Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 132) Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 133) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 134) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence No. 135) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 136) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 137) And in particular, those containing the following amino acid sequences: Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 138) It includes.

[0058] Further conjugates of the present invention comprising the peptide component defined in (d) above include those in which K is an N-terminal HCA group and which have the following amino acid sequence: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 139), More preferably, the amino acid sequence defined as follows: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 140) It includes.

[0059] A more preferred conjugate of the present invention, comprising the peptide component defined in (d) above, may be mentioned, is W 1 The one where J is Ala, J is Lys, and contains the following amino acid sequence: Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 141) Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (Sequence ID 142) Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 143), Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 144) And in particular, those defined by the following amino acid sequences: Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 145) It includes.

[0060] Further preferred conjugates of the present invention, comprising the peptide components defined in (d) above which may be mentioned, are those that do not contain J and include the following amino acid sequence: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 146), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 147), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp (Sequence ID 148) Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (Sequence ID 149), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 150) Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (Sequence ID 151) and Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 152) It includes.

[0061] Those skilled in the art will understand that a conjugate is a compound formed by electrostatically bonding and / or covalently bonding one compound to another.

[0062] The term "electrostatic crosslinking" will be understood by those skilled in the art to include the association of disordered molecules into an ordered state due to its properties or electrostatic interactions (the primary mechanism of gelation, also called "self-assembly," observed in amphiphilic peptide molecules (Hauser et al., Biomed. Mat. 2015, 11, 014103)).

[0063] In this case, the conjugate of the present invention is preferably formed by covalently bonding one or more linear polysaccharide chains to one or more peptide components defined by the above formulas (a), (b), (c) and / or (d).

[0064] In this regard, the conjugate of the present invention may comprise one or more (and preferably at least two) linear polysaccharides, such as HA chains. In other words, such linear polysaccharide chains (e.g., HA) can be crosslinked by linking to one or more peptide components defined by one or more of the above formulas (a), (b), (c) and / or (d).

[0065] For example, the conjugate of the present invention is characterized by at least one covalent bond (e.g., an amide bond) formed by a reaction between an amine (i.e., -NH2) group present in the peptide component defined in (a), (b), (c) and / or (d) above and a carboxylic acid (i.e., -CO2H) moiety present in one or more HA chains. For example, an amide bond may be formed between one amine group of a Lys residue in the peptide component of formula I and one carboxylic acid group of a glucuronic acid residue of HA.

[0066] Preferably, in the conjugate of the present invention, at least about 0.1 (e.g., at least about 1%) of the carboxylic acid groups in the HA chain form amide bonds with the amine groups of the peptide component.

[0067] Other conjugates of the present invention that may be mentioned are those in which up to about 25% (e.g., up to about 5%) of the carboxylic acid groups in the HA chain form amide bonds with the amine groups of such peptide components.

[0068] In particular conjugates of the present invention that may be mentioned, about 0.1% to about 25% (e.g., about 1% to about 5%) of the carboxylic acid groups in the HA chain form amide bonds with the amine groups of such peptide components.

[0069] Those skilled in the art will understand that crosslinking is the linking of one polymer chain (e.g., a polysaccharide chain such as HA) to another polymer chain. In the context of the present invention, one or more peptide components as defined in (a), (b), (c) and / or (d) above may be chemically bonded to each of two or more, for example, HA chains, thereby forming the conjugate of the present invention via crosslinking between HA chains.

[0070] A particular conjugate of the present invention is formed between one or more specific peptide components defined in (a), (b), (c) and / or (d) above, in particular between the peptide components of formula I of (a) above as defined below, where: A and B are both Z or A 1 -Q 1 -B 1 This represents A 1 and B 1 Both are Z or A 2 -Q 2 -B 2 This represents A 2 and B 2 Both are ZQ 3 -Z represents Q 1 Q 2 , and Q 3 Each of these represents a "Lys fragment" as defined above, and W represents DOPA or DOPA-Ala-, and / or U represents DOPA, and the conjugate contains one or more and two or more hyaluronic acid molecules.

[0071] A more specific conjugate of the present invention is a conjugate formed between peptide components of formula I as defined in (a) above, where A and B both represent Z, W represents DOPA or DOPA-Ala-, and / or U represents DOPA, and the conjugate comprises one or more and two or more hyaluronic acid molecules.

[0072] As used herein, Pro represents proline, Ala represents alanine, Ser represents serine, Tyr represents tyrosine, Hyp represents hydroxyproline (including 3-hydroxyproline (3Hyp) and 4-hydroxyproline (4Hyp)), diHyp represents dihydroxyproline (including 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp)), Thr represents threonine, Lys represents lysine, Ala represents alanine, and DOPA represents 3,4-dihydroxyphenylalanine. The 3,4-dihydrocinnamic acid (HCA) residue is essentially a DOPA residue, but it lacks an -NH2 group at the 2- or α-position relative to the carboxylic acid bonded to the N-terminal amino acid (Lys or Ala).

[0073] The conjugates of the present invention include positional isomers within the amino acids of a peptide (e.g., diHyp, Hyp, and Tyr moieties), whether in salt form or not, as well as mixtures of such positional isomers. For example, the definition of Tyr includes not only tyrosine (4-hydroxyphenylalanine) but also 2- and 3-hydroxyphenylalanine. The definition of Hyp includes 4-hydroxyproline (4Hyp), 3-hydroxyproline (3Hyp), and 5-hydroxyproline (5Hyp). It is more preferable that the Hyp residue is 4-hydroxyproline. Similarly, the definition of diHyp includes 3,4-dihydroxyproline (3,4diHyp), 3,5-dihydroxyproline (3,5diHyp), and 4,5-dihydroxyproline (4,5diHyp). It is more preferable that the diHyp residue is 3,4-dihydroxyproline (3,4diHyp).

[0074] Furthermore, in addition to the standard central carbon atoms of the amino acids in the conjugates of the present invention (which are not exclusive but are usually in an L-configuration), certain amino acids in the sequence contain additional chiral carbon atoms. All such stereoisomers and mixtures thereof (including racemic mixtures) are within the scope of the present invention. In this regard, the definition of Hyp includes trans-4-hydroxy-L-proline, cis-4-hydroxy-L-proline, trans-3-hydroxy-L-proline, cis-3-hydroxy-L-proline, trans-5-hydroxy-L-proline, and cis-5-hydroxy-L-proline, but the Hyp used in the conjugates of the present invention is preferably 4-hydroxy-L-proline. Similarly, the corresponding definition may also apply to diHyp, where the two hydroxyl groups may be cis or trans relative to each other. In any case, individual enantiomers of the peptide components defined by the above formulas (a), (b), (c), or (d) that may form part of the conjugates of the present invention are within the scope of the present invention.

[0075] The conjugate of the present invention may also be in the form of a salt. Salts that may be mentioned include pharmaceutically acceptable salts and / or cosmetically acceptable salts, such as pharmaceutically acceptable acid addition salts and base addition salts. Such salts may be formed by conventional means, for example, by reacting the conjugate of the present invention with one equivalent or more of a suitable acid or base in an optionally chosen solvent or in a medium in which the salt is insoluble, and then removing the solvent or medium using standard techniques (e.g., by vacuum, freeze-drying or filtration). Salts may also be prepared by exchanging the counterion of the conjugate of the present invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0076] Preferred salts include, for example, acetates, hydrochlorides, bisulfates, maleates, mesylates, tosylates, alkaline earth metal salts such as calcium and magnesium, or alkali metal salts such as sodium and potassium salts. Most preferably, the conjugate of the present invention may be in the form of an acetate.

[0077] The conjugates of the present invention can be prepared by conventional techniques, for example by standard amino acid coupling techniques, using standard coupling reagents and solvents, as described below. The conjugates of the present invention can also be synthesized from available starting materials using appropriate reagents and reaction conditions. Those skilled in the art may, in this regard, refer in particular to “Comprehensive Organic Synthesis” by BMTrost and I. Fleming, Pergamon Press, 1991. Further references that may be used include “Heterocyclic Chemistry” by JA Joule, K. Mills and GFS. mith,3 rd This includes the edition, published by Chapman & Hall, “Comprehensive Heterocyclic Chemistry II” by ARKatritzky, CWRees and EFVScriven, Pergamon Press, 1996, and “Science of Synthesis”, Volumes 9-17 (Hetarenes and Related Ring Systems), Georg Thieme Verlag, 2006.

[0078] The conjugates of the present invention can be isolated from their reaction mixtures and, if necessary, purified using prior art, such as that known to those skilled in the art. Accordingly, the preparation process of the conjugates of the present invention described herein may include, as a final step, isolation and optional purification of the conjugates of the present invention.

[0079] Those skilled in the art will understand that in the processes described above and below, it may be necessary to protect the functional groups of the intermediate compound with protecting groups. Protection and deprotection of functional groups may be carried out before or after the reaction.

[0080] Protecting groups are well known to those skilled in the art and can be applied and removed according to techniques such as those described below. For example, the protected compounds / intermediates described herein can be chemically converted to unprotected compounds using standard deprotection techniques. The type of chemistry involved will determine the need and type of protecting group, as well as the sequence for achieving the synthesis. The use of protecting groups is well described in "Protective Groups in Organic Synthesis," 5th edition, TW Greene & P. ​​G.M. Wutz, Wiley-Interscience (2014), the contents of which are incorporated herein by reference.

[0081] Therefore, the conjugates of the present invention are useful as pharmaceuticals for humans and animals. Thus, although they are indicated as pharmaceuticals (and / or in veterinary medicine), they can also be used as part of cosmetics and / or medical devices.

[0082] The conjugates of the present invention may be pharmacologically active on their own, or they may exist or be prepared as specific pharmaceutically acceptable (e.g., “protected”) derivatives of the conjugates of the present invention that do not have such activity, but which can be administered orally and subsequently metabolized or chemically converted in the body to form the conjugates of the present invention. Such compounds may therefore be described as “prodrugs” of the conjugates of the present invention (which may have some pharmacological activity, provided that such activity is recognizably lower than the activity of the active compound to which they are metabolized / converted).

[0083] As used herein, when a prodrug is described, it will include a compound that forms an experimentally detectable amount of the conjugate of the present invention within a predetermined time after administration. All prodrugs of the conjugate of the present invention are included within the scope of the present invention.

[0084] If the conjugates of the present invention have pharmacological activity, they are particularly useful in the treatment of inflammation.

[0085] "Treatment of inflammation" includes the treatment of inflammation in any organ of the body (including soft tissues, joints, nerves, vascular system, internal organs, especially mucosal surfaces, and specifically the skin), regardless of the cause, and also includes all such inflammatory disorders or conditions, and / or disorders or conditions characterized by inflammation (e.g., as a symptom).

[0086] Inflammatory disorders and / or conditions may (and typically) be characterized by the activation of immune defense mechanisms that produce effects that are more detrimental than beneficial to the host. Such conditions are generally associated with varying degrees of tissue redness or congestion, swelling, edema, hyperthermia, pain (including numbness), fluid exudation, itching (pruritus), cell death, and tissue destruction, cell proliferation, and / or loss of function.

[0087] Inflammatory conditions that may be mentioned include arteritis, diabetes, metabolic syndrome, rosacea, asthma and allergies, ankylosing spondylitis, chronic obstructive pulmonary disease, gouty arthritis, inflammatory bowel disease (such as Crohn's disease and ulcerative colitis), multiple sclerosis, osteoarthritis, pancreatitis, prostatitis, psoriatic arthritis, rheumatoid arthritis, tendinitis, bursitis, Sjögren's syndrome, systemic lupus erythematosus, uveitis, urticaria, vasculitis, mastocytosis, diabetic vascular complications, migraine, atherosclerosis, and related cardiovascular disorders. A condition characterized by inflammation that may be mentioned is chronic obstructive pulmonary disease (COPD). Further conditions characterized by inflammation that may be mentioned are inflammatory bowel diseases, including Crohn's disease and, in particular, ulcerative colitis. Other conditions characterized by inflammation that may be mentioned are gynecological conditions such as cervicitis, vaginal inflammation, and colpitis. Diseases affecting the gastrointestinal tract, such as gastric ulcer formation (e.g., gastritis, gastric ulcers, stomach cancer, and other gastric mucosal diseases), as well as inflammation associated with gastroesophageal reflux disease (GERD), constipation, and gastritis, cancer, and infections (e.g., viral infections such as the common cold or influenza).

[0088] Further inflammatory conditions that may be specifically mentioned include inflammation of the skin or mucous membranes (including the mucous membranes of the oral cavity, nose, eyes, vagina, cervix, and / or anorectum, more specifically including the mucous membranes of the oral cavity or nose), such as inflammation resulting from infection (such as viral and / or bacterial infections) or allergic / atopic conditions (such as rhinitis (e.g., allergic rhinitis), pharyngitis, periodontitis, gingivitis, xerosis, conjunctivitis (e.g., allergic conjunctivitis), dermatitis, urticaria (hives), and food allergies), as well as other inflammatory conditions such as herpes, drug eruptions, photoerectomy, sunburn, early signs of skin cancer (erythematous skin lesions), pathological alopecia (including post-skin grafting), chemical rashes, psoriasis, erythema multiforme, folliculitis, eczema, and otitis externa. Photoerectomy is a condition that may be specifically mentioned.

[0089] More specifically, the conjugates of the present invention may be used to treat certain medical conditions characterized by and / or associated with inflammation. Such conditions may include wounds (including abrasions (scratches), incisions (including surgical incisions), lacerations, punctures, avulsions, bruises, and scars), burns (including inflammation resulting from post-burn surgery such as skin grafts), and other conditions such as hemorrhoids. Wounds may be acute or chronic and / or result from one or more inflammatory disorders as defined herein.

[0090] Wounds of the skin or mucous membranes may result from physical injury inside or outside the membrane surface, or they may be caused by (i.e., symptoms of) an underlying physiological disorder.

[0091] Physical (e.g., "open") wounds can be caused by sharp objects (cuts, incisions, punctures) or blunt / mechanical forces (lacerations, abrasions, avulsions), physical impacts (bruises), heat or chemicals (burns and blisters), ultraviolet radiation (sunburn), or cold (chilblains or frostbite). Wounds can be superficial (damage to the epidermis and / or dermis only) or full-thickness (damage to the epidermis and / or below the dermis). In severe cases, subcutaneous and / or submucosal tissues such as muscles, bones, joints, and even internal organs may be damaged.

[0092] The conjugate of the present invention can be used to alleviate pain (including numbness) associated with inflammation and / or wounds. Specifically, the conjugate of the present invention can be used to alleviate procedural pain and / or non-procedural pain. Those skilled in the art will understand that the term “procedural pain” (i.e., surgical pain) refers to acute pain associated with medical investigations and treatments performed for medical purposes. The term “non-procedural” refers to general pain associated with inflammation and / or wounds (e.g., pain associated with dental ulcers, burns, and / or scars) that is not the result of a specific medical intervention.

[0093] The conjugates of the present invention can be used not only to treat inflammation, pain (including numbness), and / or pruritus (itching) associated with the wound itself and the healing process, but also to prevent the exudation of bodily fluids from the wound, the risk of infection, and physiological reactions resulting from inflammation and / or the wound healing process, such as scarring and melanin pigmentation.

[0094] A scar is the result of inflammation and / or wound healing, and is a general term for the formation of fibrous tissue that is a consequence of such inflammation / healing.

[0095] The conjugate of the present invention may also be useful in suppressing the production of melanin pigmentation, whether it is caused by inflammation and / or wound healing or not. The conjugate of the present invention may also be useful in suppressing melanin pigmentation-related disorders such as melasma, freckles, melanin deposition, butterfly rash, and other pigmentation, skin cancer with melanoma, and pigmentation caused by sun exposure or skin diseases such as acne.

[0096] Wounds can also arise as a result of disease or disorder (e.g., inflammation). Such wounds may include blisters, as well as / or ulcers of the skin and mucous membranes. These are common conditions that are often long-lasting and difficult to treat. Skin tissue can often be damaged, removed, liquefied, infected, and / or necrotic. Ulcers, especially if infected, can have secondary health consequences, are difficult to heal, and are costly to treat. They can also cause significant psychological stress and financial loss to the patient, potentially affecting both overall well-being and quality of life.

[0097] Alternatively, inflammatory skin conditions or diseases in which the conjugate of the present invention is particularly useful include the treatment of psoriasis, acne, eczema and dermatitis, especially allergic / atopic dermatitis, as well as rhinitis, especially allergic rhinitis, hemorrhoids, chronic obstructive pulmonary disease, and mucositis characterized by ulcerative colitis.

[0098] Psoriasis is a chronic inflammatory skin disease that tends to recur (some patients never recover). Clinical symptoms of psoriasis primarily include erythema and scaling, which can occur anywhere on the body but are more commonly seen on the scalp and hands and feet.

[0099] Acne is a follicular (hair follicle-sebaceous gland) chronic inflammatory skin disease whose development is closely related to major factors such as excessive sebum, obstruction of the hair follicle-sebaceous gland ducts (including closed and open comedones), bacterial infection, and inflammatory response. It tends to develop in adolescence and is characterized by pleomorphic skin lesions on the face. Therefore, the term acne includes both common acne and rosacea (i.e., red nose).

[0100] Eczema is an inflammatory skin reaction characterized by intense itching, triggered by various internal and external factors. It has three stages: acute, subacute, and chronic. The acute phase tends to produce exudate, while the chronic phase involves infiltration and hypertrophy. Skin lesions are itchy and frequently recur.

[0101] Dermatitis is a common skin condition characterized by roughness, redness, itching, eczema, and dryness. Small nodules, refractory ulcers, and pigmented spots caused by dermatitis can develop into basal cell carcinoma, squamous cell carcinoma, and malignant melanoma if left untreated. Dermatitis can be caused by a variety of internal and external infectious or non-infectious factors, including substances (contact dermatitis) or allergies (allergic / atopic dermatitis). Furthermore, seborrheic dermatitis (seborrheic eczema) and all forms of steroid-dependent dermatitis (photosensitive seborrhea, perioral dermatitis, rosacea-like dermatitis, steroid rosacea, steroid-induced rosacea, iatrosacea, steroid dermatitis-like rosacea, topical corticosteroid-induced rosacea-like dermatitis, and, more specifically, facial corticosteroid-addicted dermatitis (FCAD) or facial corticosteroid-dependent dermatitis (FCDD) characterized by flushing, erythema, telangiectasia, atrophy, papules, and / or pustules of the facial area after long-term treatment with topical corticosteroids (including uncontrolled use, abuse, or misuse) (see, e.g., Xiao et al, J. Dermatol., 2015, 42, 697-702 and Lu et al, Clin. Exp. Dermatol., 2009, 35, 618-621).

[0102] Rhinitis is irritation and inflammation of the mucous membrane inside the nose. Common symptoms of rhinitis include nasal congestion, runny nose, sneezing, and postnasal drip. The most common type of rhinitis is allergic rhinitis, caused by allergens such as pollen, dust, mold, or flakes of skin from certain animals. Surprisingly, it has been found that patients with allergic rhinitis treated with the conjugate of the present invention experienced relief of itchy eyes, even when the conjugate of the present invention was administered intranasally (i.e., into the nasal mucosa).

[0103] Hemorrhoids are swellings caused by large inflammation of hemorrhoidal blood vessels found inside or around the rectum and anus. Symptoms include bleeding after stool passage (i.e., sores), hemorrhoid prolapse, mucus discharge and itching, burning, redness, and swelling in the anal area. Hemorrhoids are thought to be a result of increased abdominal pressure, for example, as a consequence of constipation or diarrhea.

[0104] Chronic obstructive pulmonary disease (COPD) is the name given to a group of lung conditions that cause difficulty breathing, including emphysema (damage to the alveoli) and chronic bronchitis (long-term airway inflammation). COPD occurs when the lungs become inflamed, damaged, and narrowed. The damage to the lungs is usually irreversible and results in impaired airflow in and out of the lungs. Symptoms of COPD include shortness of breath, a wet cough, frequent chest infections, and persistent wheezing. The most common cause of this disease is smoking, but other risk factors include high levels of air pollution, as well as occupational exposure to dust, chemicals, and smoke.

[0105] The conjugate of the present invention may exert a positive effect in reducing erythema, redness and swelling, edema, blisters, and bullous pemphigoid caused by various pathological conditions, including those generally and specifically mentioned herein, and may also inhibit the exudation of subcutaneous fluid and suppress itching and pain caused by such inflammatory conditions.

[0106] Other inflammatory conditions that may be mentioned include: (a) inflammation caused by oral mucositis, aphthous ulcers, otitis media, laryngitis, tracheitis, esophagitis, gastritis, enteritis, and enterocolitis (including bacterial dysentery, chronic amebic dysentery, schistosomiasis, nonspecific ulcerative colitis, and regional enteritis), cervicitis and endometritis, endometritis, inhalation injury, etc., as well as inflammation of the mucosa associated with cancer, and inflammation of the mucosa such as infections (e.g., viral infections such as the common cold or influenza) that affect the mucosal surface of the oral cavity, nasopharynx, ears, throat, trachea, gastrointestinal tract, cervix, etc.

[0107] (b) For example, fractures, suppurative infections of bone and joints, inflammation due to rheumatic bone disease, and suppurative osteomyelitis (acute, chronic, localized, sclerosing, post-traumatic), suppurative arthritis, bone tumors (osteoma, osteoid osteoma, chondroma), bone cysts, osteoclastoma, primary osteosarcoma (osteosarcoma, chondrosarcoma, osteofibrosarcoma, Ewing's sarcoma, non-Hodgkin lymphoma, myeloma, chordoma), metastatic bone tumors, neoplastic lesions of bone (bone cysts, aneurysmal bone cysts, eosinophilic granulomas, fibrous dysplasias), and orthopedic inflammation associated with rheumatoid arthritis.

[0108] (c) Neuroinflammation such as peripheral polyneuritis, facial neuritis, peripheral neuritis, subcutaneous neuritis, ulnar neuritis, and intercostal neuritis.

[0109] (d) Inflammation of subcutaneous and submucosal soft tissues, such as myositis, ligamentitis, tendinitis, cystitis, lymphadenitis, fodderitis, tonsillitis, synovitis, and fasciitis, as well as inflammation of soft tissues caused by injury, contusion, or laceration of muscles, ligaments, fascia, tendons, synovial membrane, fat, joint capsules, and lymphatic tissues.

[0110] (e) Vascular inflammation such as allergic leukocytoclastic vasculitis, allergic cutaneous vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis, as well as vascular inflammation associated with vascular cancer caused by allergic leukocytoclastic vasculitis, polyarteritis nodosa, thromboangiitis, granulomatous vasculitis, lymphocytic vasculitis, vasculitis with abnormal blood composition, and rheumatic vasculitis.

[0111] (f) Inflammation of internal organs such as the heart, stomach, intestines, lungs, liver, spleen, kidneys, pancreas, bladder, ovaries, and prostate, including but not limited to pericarditis, myocarditis, endocarditis, pneumonia, hepatitis, spleenitis, nephritis, pancreatitis, cystitis, oophoritis, prostatitis, and gastric ulcers.

[0112] (g) Inflammation of the eye and surrounding areas, such as conjunctivitis, keratitis (e.g., acute superficial keratitis, nummular keratitis, interstitial keratitis, discoid keratitis, neurotrophic keratitis, mucosal maculitis, herpetic keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, Acanthamoeba keratitis, rotifera keratitis, punctate superficial keratitis, ulcerative keratitis, lagophthalmos, actinic keratitis, and acute conjunctivitis during contact lens wear), and optic neuritis.

[0113] (h) Inflammation of the gums and oral cavity, such as periodontitis, gingivitis, and odontogenic ulcers.

[0114] (i) Rheumatoid arthritis, rheumatoid arthritis, rheumatic bone disease, ankylosing spondylitis, bursitis, Crohn's disease, gout, infectious arthritis, juvenile idiopathic arthritis, osteoarthritis, osteoporosis, polymyalgia rheumatica, polymyositis, psoriatic arthritis, scleroderma, Sjögren's syndrome, spondyloarthritis, systemic lupus erythematosus, tendinitis, and other rheumatoid arthritis-related inflammations.

[0115] The conjugates of the present invention may also be used to treat certain specific diseases of the digestive system, such as gastroesophageal reflux disease (GERD), which may be characterized by sourness in the mouth, reflux, heartburn, dysphagia and / or sore throat, increased salivation (heartburn), nausea, chest pain, and cough. GERD can cause injuries to the esophagus, including reflux esophagitis (i.e., inflammation of the esophageal epithelium that can cause ulcers at or around the junction of the stomach and esophagus), esophageal stricture (i.e., persistent narrowing of the esophagus caused by reflux-induced inflammation), Barrett's esophagus (i.e., intestinal metaplasia (i.e., changes in epithelial cells from squamous epithelium to intestinal columnar epithelium in the distal esophagus), and / or esophageal adenocarcinoma (a form of cancer).

[0116] The conjugate of the present invention may also be used to treat certain specific respiratory diseases such as cystic fibrosis, typical interstitial pneumonia, allergic pneumonia, asbestosis, emphysema, cor pulmonale, and pulmonary embolism. A specific disease condition that may be mentioned is idiopathic pulmonary fibrosis (IPF).

[0117] IPF is a diffuse and fatal interstitial lung disease characterized by pathological features including alveolar epithelial damage, widespread proliferation of lung fibroblasts, and excessive deposition of extracellular matrix, ultimately leading to irreversible lung tissue damage. In the later stages of the disease, subjects with IPF experience respiratory failure and death. The conjugate of the present invention has been found to be useful in the treatment of IPF and / or in the alleviation of pathological conditions associated with this disease.

[0118] The conjugates of the present invention are particularly useful in the treatment of the following pulmonary and / or fibrotic conditions (whether otherwise stated herein): pulmonary fibrosis, renal fibrosis, hepatic fibrosis, silicosis, acute bronchitis, chronic bronchitis, tracheobronchitis, bronchial asthma, severe asthma, bronchiectasis, upper respiratory tract infections including the common cold and influenza), allergic airway inflammation, bacterial pneumonia, viral pneumonia, mycoplasma pneumonia, reckettsia, radioactive pneumonia, pneumococcal pneumonia (including staphylococcus, streptococcus, and gram-negative bacilli), pulmonary candidiasis (including aspergillosis, mucormycosis, histoplasmosis, actinomycosis, and nocardiosis), pulmonary mycosis, cryptococcosis, lung abscess, and anaphylactic pneumonia (Leoffler's syndrome). Syndrome)) Exogenous allergic alveolitis, pulmonary eosinophilia (eosinophilia), obstructive emphysema, pulmonary edema, pulmonary tuberculosis, respiratory alkalinity (acidosis), acute lung injury, interstitial lung disease, empyema, pulmonary fibroma, and cor pulmonale.

[0119] Specific mucosal disorders and diseases in which the conjugate of the present invention is deemed useful include anorectal diseases such as diarrhea, hemorrhoids, abscesses, fistulas, anal fissures, anal pruritus, anal sinusitis, warts, and rectal prolapse; inflammatory bowel diseases, particularly ulcerative colitis, Crohn's disease; gynecological diseases such as cervicitis, vaginitis, pelvic pain and disorders; and dental diseases such as paraodontitis.

[0120] The conjugate of the present invention may further possess antioxidant effects by increasing SOD (superoxide dismutase) production and reducing lipid oxidation. Therefore, the conjugate of the present invention is considered to have antioxidant properties.

[0121] The conjugates of the present invention may also have antipyretic properties, for example, by lowering the body temperature of the subject and reducing fever, thereby enabling the treatment of fever and / or alleviating its pathological condition. Therefore, the conjugates of the present invention and formulations containing them are considered to be antipyretics.

[0122] A further aspect of the present invention provides a method for treating inflammation, inflammatory disorders, and / or disorders / conditions characterized by inflammation (e.g., as a symptom), comprising administering a conjugate or salt thereof of the present invention to a patient in need of such treatment.

[0123] To avoid misunderstanding, in the context of this invention, the terms “treatment,” “therapy,” and “treatment” include therapeutic or palliative treatment for patients in need of treatment, as well as prophylactic treatment and / or diagnosis for patients susceptible to inflammation and / or inflammatory disorders.

[0124] The conjugate of the present invention may further possess antiviral properties that enable the treatment of viral infection or viral disease by interfering with viral replication within a host, as opposed to the treatment of any viral infection or any pathological condition of a viral infection, such as pain and / or inflammation. Such antiviral properties may also enable the prevention of the development of such infection or disease, the protection of cells within a host from (e.g., further) viral infection, the prevention or cessation of the spread of viral infection or disease (within a single host or from one host to a new host), or the prevention of viral reactivation after a waiting period in a host.

[0125] A further aspect of the present invention provides a method for treating a viral infection, comprising administering a conjugate or a salt thereof to a patient in need of such treatment.

[0126] Viral infections that may be mentioned include adenoviridae (e.g., adenovirus), papillomaviridae (e.g., human papillomavirus), polyomaviridae (e.g., BK virus, JC virus), herpesviridae (e.g., herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, Epstein-Barr virus, human cytomegalovirus, human herpesvirus type 8), poxviridae (e.g., smallpox), hepadnaviridae (e.g., B Hepatitis viruses, parvoviridae (e.g., parvovirus B19), astroviridae (e.g., human astrovirus), caliciviridae (e.g., norovirus, Norwalk virus), picoraviridae (e.g., coxsackievirus, hepatitis A virus, poliovirus, rhinovirus), coronaviridae (e.g., severe acute respiratory syndrome virus), flaviviridae (e.g., hepatitis C virus, yellow fever virus, dengue virus, West Nile virus) (e.g., tick-borne encephalitis virus), retroviridae (e.g., human immunodeficiency virus, HIV), togaviridae (e.g., rubella virus), arenaviridae (e.g., Lassa virus), bunyaviridae (e.g., hantavirus, Crimean-Congo hemorrhagic fever virus, Hantan virus), filoviridae (e.g., Ebola virus, Marburg virus, Ravn virus), orthomyxoviridae (e.g., influenza A virus (e.g., H1N1 and H3N2 viruses)) This category includes influenza viruses (including influenza B virus or influenza C virus), paramyxoviridae (e.g., measles virus, mumps virus, parainfluenza virus, respiratory syncytial virus), rhabdoviridae (e.g., rabies virus), hepeviridae (e.g., hepatitis E virus), reoviridae (e.g., rotavirus, orbivirus, cortivirus, vannavirus), and viruses not assigned to a family such as hepatitis D virus.

[0127] Viruses that may be mentioned more specifically include herpes simplex virus, type 1 and type 2, human papillomavirus, influenza virus, and parainfluenza virus.

[0128] The conjugate of the present invention may further possess antibacterial and / or bacteriostatic properties, which may enable the treatment of bacterial infection or disease by inhibiting the growth or proliferation of bacteria within the host, as opposed to treating any pathological condition of any bacterial infection or disease, such as pain and / or inflammation. Therefore, the conjugate of the present invention is considered to be a bactericide and / or preferably a bacteriostatic agent.

[0129] Such antimicrobial properties may also enable the prevention of the development of such infections or diseases, the protection of cells within a host from (e.g., further) bacterial infections, the prevention or cessation of the spread of bacterial infections or diseases (within a single host or from one host to a new host), or the prevention of bacterial reactivation after a waiting period in the host.

[0130] A further aspect of the present invention provides a method for treating a bacterial infection, comprising administering the conjugate or a salt thereof of the present invention to a patient in need of such treatment.

[0131] The conjugates of the present invention may further possess anti-cancer properties that enable the treatment of cancer itself, i.e., by interfering with cancer, as opposed to the treatment of any pathological condition of cancer, such as pain and / or inflammation. Such anti-cancer properties may also include the prevention of the development of such diseases, for example, by treating inflammation and thereby preventing such development.

[0132] According to another aspect of the present invention, a method for treating cancer is provided, comprising administering the conjugate or a salt thereof of the present invention to a patient in need of such treatment.

[0133] Specific cancers that may be mentioned include oral cancer, nasopharyngeal cancer, middle ear cancer, conjunctival cancer, throat cancer, tracheal cancer, esophageal cancer, stomach cancer, intestinal cancer, cervical cancer, endometrial cancer, oral mucositis, rhinitis, otitis media, conjunctivitis, pharyngitis, laryngitis, tracheitis, esophagitis, gastritis, enterocolitis, cervixitis, endometritis, and skin cancers caused by erythematous skin lesions, etc. A specific skin cancer that may be mentioned is basal cell carcinoma.

[0134] "Patients" include reptiles, birds, and preferably mammals (especially humans).

[0135] According to the present invention, the conjugate of the present invention is administered in the form of a pharmaceutical preparation comprising a compound in a pharmaceutically acceptable dosage form, preferably topically or systemically, for example, orally, intravenously, or intra-arterial (including intravascular and other perivascular devices / dosage forms (e.g., stents)), intramuscularly, cutaneously, subcutaneously, transmucosally (e.g., sublingually or buccally), rectally, intravaginally, intradermally, transdermally, transnasally, pulmonaryly (e.g., trachea or bronchi), preferably topically, or by any other parenteral route.

[0136] Inhalation (e.g., intranasal administration) is particularly useful when the condition being treated is inflammation resulting from rhinitis or a viral infection of the respiratory tract (e.g., upper respiratory tract infections such as the common cold and influenza).

[0137] Lung administration is particularly useful when the condition being treated is COPD or IPF. Topical administration can be enhanced by creating a spray containing the active ingredient, for example, by using a powder aerosol or by using an aqueous mist with appropriate atomization technology or equipment such as a nebulizer.

[0138] Anorectal administration, using appropriate delivery methods such as an injectable foam solution or suppositories, is particularly useful when the condition being treated is hemorrhoids or ulcerative colitis.

[0139] Administration to the lower gastrointestinal tract can also be achieved by parenteral, and especially by oral, delivery using standard delayed-release or sustained-release coating techniques known to those skilled in the art. In particular, distinct portions of the upper or lower intestine may be targeted. For example, colonic administration can also be achieved by colon-targeted drug delivery means that are initially administered orally or parenterally.

[0140] The conjugate of the present invention may, alternatively, be administered by direct, systemic parenteral administration. Such administration may be useful in methods for treating inflammatory and / or fibrotic disorders or conditions in one or more organs of a patient.

[0141] The organs that may be mentioned include the stomach, intestines, pancreas, liver, spleen, bladder, vascular system, ovaries, prostate, preferably the heart and kidneys, more preferably the lungs.

[0142] Visceral fibrotic conditions that may be mentioned include acute and / or severe internal fibrotic conditions characterized by an excessive accumulation of fibrous connective tissue (as described above) in and around inflamed or damaged tissue. For this reason, the formulations of the present invention may be useful in the treatment or prevention of fibrosis (as described above) and the morbidity and death that may be associated therewith. For this reason, visceral (e.g., acute and / or severe) fibrotic conditions that can be treated with the formulations of the present invention include fibrosis of the liver, kidneys, lungs, cardiovascular system including the heart and vascular system, pancreas, spleen, central nervous system (neurofibrosis), myelofibrosis, eyes, vagina, cervix, and other organs.

[0143] Visceral inflammatory conditions include any severe condition (i.e., a condition requiring intensive medical treatment) or a condition that may develop into one; conditions in which certain inflammatory elements are evident that may be characterized by detectable inflammation; and conditions in which the disease is evident (or anticipated) and / or life-threatening.

[0144] Inflammatory conditions that may be mentioned include one or more acute disorders or conditions of one or more viscera (including any of the organs mentioned above) characterized by inflammation (e.g., as a symptom), such as acute visceral injury (i.e., one or more conditions that require immediate medical intervention, or that may develop into a condition requiring immediate medical intervention). By treating such acute inflammatory disorders, the formulations of the present invention may prevent or inhibit the onset of symptoms (acute or chronic) associated with such conditions, and may inhibit the progression of morbidity and / or death associated with such conditions.

[0145] Therefore, acute inflammatory conditions that may be mentioned include conditions such as peritonitis, pancreatitis, colitis, proctitis, gastritis, duodenitis, pharyngitis, GERD, periodontitis, and stomatitis. Specific acute inflammatory conditions that may be mentioned include acute lung injury, airway injury (such as burns), acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), and acute injury to one or more organs (including any of those mentioned above), such as inflammation, injury, and / or failure of multiple organs.

[0146] Such conditions can be caused by internal or external trauma (e.g., injury or burns), or by infections such as viruses, bacteria, or fungi.

[0147] For example, proctitis (including eosinophilic, adenitis, and / or ulcerative proctitis) can be caused by inflammatory bowel disease, infections, radiation (e.g., cancer), drugs such as antibiotics, surgery, or allergic reactions such as food intolerance.

[0148] For example, multi-organ inflammation, injury, and / or failure may result from extensive and / or traumatic external injury, including traumatic and / or extensive burns. Traumatic external burns are understood to include second-degree burns, more specifically third-degree and fourth-degree burns. Extensive external burns are understood to include burns affecting at least about 10% of the patient's body surface area, such as at least about 20% or at least about 15%. External (and internal) burns may result from exposure to heat, chemicals, etc.

[0149] Acute inflammatory and / or fibrotic conditions may also result from sepsis or septic shock, which can be caused by viral, bacterial, or fungal infections. Furthermore, acute lung injury, ARDS, and SARS in particular can be caused by viruses such as coronaviruses, including the novel SARS coronavirus 2 (SARS-CoV-2).

[0150] Therefore, one or more of the aforementioned (e.g., acute) inflammatory conditions can (in fact, in some cases, likely) result in some form of internal tissue damage and / or dysfunction of associated internal tissues. As such, associated tissues include (e.g., mucosal) tissues such as airway epithelium. Such tissue damage can also lead to one or more of the fibrotic conditions described above. For example, SARS disease, caused by the novel coronavirus SARS-CoV-2 (coronavirus disease 2019 or COVID-19), is known to often result in fibrosis arising from one or more of a number of factors, including inflammation.

[0151] In this regard, the conjugates and salts of the present invention exhibit particular utility in the treatment of related inflammatory and / or fibrous conditions, given that such conditions are often characterized by one or more comorbidities. A condition “characterized by comorbidities” includes the fact that the primary condition in question simultaneously causes (or is caused by) another further medical condition, which (preferably) includes those described above, and these conditions may interact with and / or overlap with each other in some way.

[0152] Therefore, the following is provided: A method for treating at least one inflammatory and / or fibrous disorder or condition in one or more internal organs of a patient, comprising administering a direct, systemic, parenteral administration of the conjugate of the present invention or a pharmaceutically acceptable salt thereof to a patient requiring such treatment. A method for treating two or more inflammatory and / or fibrous disorders or conditions of one or more internal organs of a patient, comprising administering a direct, systemic, parenteral administration of the conjugate of the present invention or a pharmaceutically acceptable salt thereof to a patient requiring such treatment. A method for reducing the incidence of morbidity and / or death associated with or potentially associated with one or more inflammatory and / or fibrous disorders or conditions of one or more internal organs of a patient, comprising direct systemic parenteral administration of the conjugate of the present invention or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

[0153] When the conjugates / salts of the present invention are administered directly and parenterally, they may be administered intravenously, intra-arterially, intravascularly, perivascularly, intramuscularly, skinly, and / or subcutaneously, for example by direct injection, or by any other parenteral route, in the form of the conjugates or salts of the present invention, in the form of a pharmaceutically acceptable dosage form.

[0154] For this reason, pharmaceutically acceptable formulations for use in such administration may include the conjugate of the present invention mixed with pharmaceutically acceptable adjuvants, diluents, or carriers that can be selected with due consideration for the intended parenteral administration route and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate release or modified release of the conjugate of the present invention.

[0155] For this reason, injectable formulations may be in the form of aqueous formulations such as suspensions and / or, more preferably, solutions (e.g., formulations containing physiological saline (e.g., solutions), formulations containing phosphoric acid (e.g., solutions), formulations containing acetate (e.g., solutions), or formulations containing borate (e.g., solutions), such as (optional) buffered aqueous formulations (e.g., solutions), or lyophilized powders that can be reconstituted with a vehicle such as an aqueous vehicle prior to use (e.g., injection).

[0156] Injectable formulations may include other suitable excipients known to those skilled in the art, such as solvents (e.g., water), co-solvents, solubilizing agents (e.g., cyclodextrin), wetting agents, suspending agents, emulsifying agents, thickening agents, chelating agents, antioxidants, reducing agents, antibacterial preservatives, bulking agents, and / or protecting agents.

[0157] Injectable formulations are preferably buffered to a physiologically acceptable pH value (e.g., a pH between about 4.5 and about 9.5, e.g., about 6 to about 9, e.g., between about 6.5 and about 8.5) using buffers and / or pH adjusters as described herein by standard techniques and may further include tonicity modifiers (such as sodium chloride).

[0158] Notwithstanding the above, preferred delivery modes of the conjugates of the present invention include suitable (e.g., pharmaceutically and topically acceptable) vehicles suitable for application to the skin and / or appropriate mucosal surfaces, and / or the inflammatory site in a commercial preparation (e.g., mucosa including oral and / or nasal mucosa, lung, anorectal and / or colon), or more preferably, the skin), but oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, or pulmonary delivery may also be included.

[0159] Administration by injection is particularly useful for administering the conjugate of the present invention in the form of a solution of a suspension, for example, to the dermis (e.g., intradermal injection), joint cavity, or eye.

[0160] Administration by intradermal injection (e.g., intradermal) is particularly useful for administering the conjugate of the present invention to the dermis in the form of a solution or suspension (e.g., a skin filler). This is particularly useful as an administration means for the aforementioned melanin pigmentation therapy or for the use of the conjugate of the present invention, for example, in the treatment of wrinkles.

[0161] Administration by injection is particularly useful, for example, for filling the surgical site of the nasal cavity, fistula, the space between the gum and the tooth root, or the paranasal space. This is particularly useful for shaping and / or lubricating the support.

[0162] The conjugates of the present invention will generally be administered in the form of one or more, for example, pharmaceutical preparations, mixed with (e.g., pharmaceutically acceptable) adjuvants, diluents, or carriers, which can be selected with due consideration of the intended route of administration (e.g., topical administration to the relevant mucosa (including the lung) or preferably the skin) and standard pharmaceutical or other (e.g., cosmetic) practices. Such pharmaceutically acceptable carriers may be chemically inert to the active compound and may have no harmful side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers may also impart immediate or modified release of the conjugate of the present invention.

[0163] Suitable pharmaceutical formulations are either commercially available or described in literature, e.g., Remington, The Science and Practice of Pharmacy, 22 nd edition, Pharmaceutical Press (2012), and Martindale - The Complete Drug Reference, 38 th The preparation can be carried out in accordance with the techniques described in Edition, Pharmaceutical Press (2014) and the documents referenced herein, and the relevant disclosures of all such documents are incorporated herein by reference. Otherwise, the preparation of a suitable formulation containing the conjugate of the present invention can be achieved by a person skilled in the art using conventional techniques in a manner not of the present invention.

[0164] The conjugate of the present invention may be in the form of an aqueous formulation such as an emulsion, suspension, and / or solution (optionally) buffered aqueous formulation (e.g., solution) such as a physiological saline-containing formulation (e.g., solution), a phosphate-containing formulation (e.g., solution), an acetate-containing formulation (e.g., solution), or a borate-containing formulation (e.g., solution), or in the form of a lyophilized powder.

[0165] The conjugate of the present invention may be further and / or alternatively combined with a suitable excipient. • Gel formulations (suitable gel matrix materials include cellulose derivatives, carbomers and alginates, tragacanth gum, gelatin, pectin, carrageenan, gellan gum, starch, xanthan gum, cationic guar gum, agar, noncellulose polysaccharides, sugars such as glucose, glycerin, propanediol, vinyl polymers, acrylic resins, polyvinyl alcohol, carboxyvinyl polymers, and especially hyaluronic acid), • Lotions (suitable matrix materials include cellulose derivatives, glycerin, noncellulose polysaccharides, polyethylene glycol of different molecular weights, and propanediol), • Pastes or ointments (suitable paste matrix materials include glycerin, petrolatum, paraffin, polyethylene glycol of different molecular weights, etc.), • Creams or foams (suitable excipients (e.g., foaming agents) include hydroxypropyl methylcellulose, gelatin, polyethylene glycol of different molecular weights, sodium dodecyl sulfate, fatty alcohol polyoxyethylene · Powdered aerosol (containing sodium telsulfonate, corn gluten powder, and acrylamide), · Powdered aerosol (suitable excipients include mannitol, glycine, dextrin, dextrose, sucrose, lactose, sorbitol, and polysorbate, e.g., dry powder inhalant), · Liquid for oral or inhalation, e.g., water, (aerosol) spray (suitable excipients include viscosity modifiers such as hyaluronic acid, sugars such as glucose and lactose, emulsifiers, buffers, alcohol, water, preservatives, sweeteners) A variety of injectable solutions or suspensions (which may be aqueous or otherwise, and which may contain solvents and co-solvents, solubilizers, wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffers, and / or pH adjusters, volume expanders, protective agents, and tonic modifiers) can be prepared, and certain injectable solutions or suspensions that may be mentioned include skin fillers (e.g., injectable fillers or soft tissue fillers), especially when the conjugate of the present invention is combined with hyaluronic acid.

[0166] Moisturizers such as glycerol, glycerin, polyethylene glycol, trehalose, glycerol, petrolatum, paraffin oil, silicone oil, hyaluronic acid and its salts (e.g., sodium and potassium salts), octanoic acid / capric triglyceride, and / or antioxidants such as vitamins and glutathione, and / or pH adjusters such as acids, bases, and pH buffers may also be included in such formulations as needed. Furthermore, hexadecanol (cetyl alcohol), fatty acids (e.g., stearic acid), sodium dodecyl sulfate (sodium lauryl sulfate), sorbitan esters (e.g., sorbitan stearate, sorbitan oleate, etc.), monoacylglycerides (e.g., glyceryl monostearate), polyethoxylated alcohols, polyvinyl alcohols, polyol esters, polyoxyethylene alkyl ethers (e.g., polyoxyethylene sorbitan monooleate), polyoxyethylene castor oil derivatives, and ethoxylated fatty acid esters may also be included in such formulations as needed. This may include surfactants / emulsifiers such as polyoxylglycerides, lauryldimethylamine oxide, bile salts (e.g., sodium deoxycholate, sodium cholate), phospholipids, N,N-dimethyldodecylamine-N-oxide, hexadecyltrimethylammonium bromide, poloxamer, lecithin, sterols (e.g., cholesterol), sugar esters, and polysorbates; preservatives such as phenoxyethanol and ethylhexylglycerin; and thickeners such as acryloyldimethyltaurate / VP copolymer. In particular, stearic acid, glyceryl monostearate, hexadecanol, sorbitan stearate, cetyl alcohol, and octanoic acid / capric acid glyceride may be included, especially in cream formulations.

[0167] The conjugates of the present invention, and (e.g., pharmaceutical) formulations containing them (e.g., solutions, gels, creams, ointments, lotions, foams, pastes, and / or dry powders as described above), can be further combined with a suitable matrix material to prepare bandages or therapeutic patches for application to biological surfaces such as skin or mucous membranes. Thus, such formulations may be used to impregnate matrix materials such as gauze, nonwoven fabric, or silk paper. Alternatively, the therapeutic patch may be, for example, a band-aid, face mask, eye mask, hand mask, foot mask, etc.

[0168] While petroleum jelly may be used when applying such bandages to wounds, we have also found that bandages can be prepared without the need for petroleum jelly by combining a PEG (e.g., PEG400)-based ointment with the matrix material.

[0169] The conjugate of the present invention may also be used in combination with a solid support (e.g., a nasal dressing to stop nosebleeds), a skin scaffold (e.g., in wound healing), or artificial bone (e.g., in the case of bone grafts / implants).

[0170] The conjugate of the present invention may be administered by inhalation as a suspension, dry powder, or solution. Suitable inhalation devices include pressurized metered-dose inhalers (pMDIs) that are manually or exhaled and can be used with or without a standard spacer device, dry powder inhalers (DPIs) which may be single-dose or multi-dose power-assisted, and soft mist inhalers (SMIs) or nebulizers in which the aerosol drug in a fine mist is delivered at a slower rate than a spray supplied using, for example, a pMDI.

[0171] In pMDI, the conjugate of the present invention can be administered as a pressurized suspension of finely ground particles dispersed in a propellant (e.g., together with excipients such as HFA, mannitol, lactose, sorbitol) or as an ethanol solution to deliver one or more metered doses of about 20 to about 100 μL in each action. Action can be performed by hand (e.g., by pressing) or by inhalation (respiratory action) and is accompanied by a spring-driven flow trigger system.

[0172] In a DPI, the conjugate of the present invention may be administered alone or in combination with a larger particle-size inert excipient (e.g., mannitol) in a capsule that can be pre-filled in the device or manually filled, in the form of finely ground drug particles (approximately 1 to 5 μm in size). Inhalation from a DPI may break down the drug particles and disperse them into the airways.

[0173] In SMI, the conjugate of the present invention can be stored as a solution in a cartridge filled with the device. A spring can release the dose to a micropump so that when a button is pressed, the dose is released and a jet stream of the drug solution is released.

[0174] Furthermore, the conjugate of the present invention can be administered in the form of a fine mist of aerosolized solution using various nebulizers. Nebulizers may include exhalation-enhanced jet nebulizers (where an airflow moves through a jet with the help of a compressor to aerosolize the drug), exhalation-activated jet nebulizers (where, after the patient inhales, an airflow moves through a tube with the help of a compressor to aerosolize the drug), ultrasonic nebulizers (where a piezoelectric crystal vibrates and heats to induce aerosolization and atomization), and vibrating mesh nebulizers (where a piezoelectric crystal vibrates a mesh plate to induce aerosolization and produce very fine droplets without significantly changing the temperature of the solution during atomization).

[0175] A further aspect of the present invention provides a process for preparing a pharmaceutical composition / formulation as defined herein, comprising combining the conjugate of the present invention as defined above with one or more pharmaceutically acceptable excipients as defined above.

[0176] The conjugate of the present invention may also be combined in therapy with one or more growth factors selected from platelet-type growth factors (including platelet-derived growth factor, PDGF), osteosarcoma-derived growth factor (ODGF), epidermal growth factor (EGF), transforming growth factors (TGFα and TGFβ), fibroblast growth factors (αFGF, βFGF), insulin-like growth factors (IGF-I, IGF-II), nerve growth factor (NGF), interleukin-type growth factors (IL-1, IL-1, IL-3), erythropoietin (EPO), and colony-stimulating factor (CSF).

[0177] A further aspect of the present invention provides a (e.g., pharmaceutical) composition comprising the conjugate of the present invention and one or more pharmaceutically acceptable excipients such as adjuvants, diluents, or carriers. Preferred formulations are suitable for topical application to mucous membranes (including oral and / or nasal mucosa, lungs, anorectal and / or colon), or more preferably to the skin, and thus comprise a topically acceptable adjuvant, diluent, or carrier.

[0178] Accordingly, pharmaceutical compositions comprising the conjugate of the present invention, which are suitable for topical administration (e.g., to the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin), are presented, as well as the use of such formulations in the treatment of inflammation, inflammatory disorders, and / or disorders including conditions characterized by inflammation (e.g., as a symptom) by direct topical administration (e.g., to mucous membranes including the oral and / or nasal mucosa, lungs, anorectal region and / or colon, or preferably to the skin).

[0179] With respect to this aspect of the invention, for the avoidance of doubt, topical formulations comprising the conjugates of the invention can be used in any and all of the conditions described herein, including the treatment of inflammation, in the treatment of any and all inflammatory disorders, and / or in the treatment of any and all conditions characterized by inflammation as referred to, defined or described above herein. Similarly, topical formulations comprising the conjugates of the invention that may be referred to include any and all of those referred to, defined or described above. Any and all of the relevant disclosures herein are incorporated herein by reference in combination with this aspect of the invention.

[0180] Topical formulations (e.g., based on a liquid or (e.g., aqueous) solution) comprising the conjugates of the invention can be particularly useful for wound healing and can relieve pain (including pain) and, in particular, itching / pruritus associated with the wound itself and the wound healing process. Such topical formulations comprising the conjugates of the invention can be particularly useful for preventing and / or suppressing the exudation of body fluids from a wound, particularly during the acute inflammatory phase, e.g., in the first 48 hours, after a burn or wound has been sustained. This prevents the risk of infection and other physiological reactions. Such topical formulations comprising the conjugates of the invention can also be particularly useful in preventing and / or suppressing scars and melanin pigmentation (see above), whether or not associated with a wound.

[0181] Administration of the conjugates of the invention can be continuous or intermittent. The mode of administration can also be determined by the timing and frequency of administration, but in the case of a therapeutic treatment of inflammation, it is also determined by the severity of the condition.

[0182] Depending on the disorder being treated, the patient, and the route of administration, the conjugates of the invention can be administered to patients in need of treatment at different therapeutically effective amounts.

[0183] Similarly, the amount of the active ingredient in the formulation is determined by the severity of the condition being treated and the patient, but can be determined by a person skilled in the art.

[0184] In any case, practitioners or other persons skilled in the art can routinely determine the most appropriate actual dosage for individual patients, depending on the severity of the condition and the route of administration. The dosages referred to herein are examples of average cases, and naturally, there may be individual cases for which higher or lower dosage ranges are appropriate, and these are also within the scope of the present invention.

[0185] The dosage can be administered once to four times a day (for example, three times).

[0186] The appropriate concentration of the conjugate of the present invention in an aqueous solution product may be approximately 0.01 (e.g., approximately 0.1) to approximately 15.0 mg / mL in all cases, calculated as a free (non-salt) peptide.

[0187] The appropriate topical dose of the conjugate of the present invention is, in all cases, approximately 5 μg / cm³, calculated as the free (non-salt) compound. 2 In therapeutic areas, etc., approximately 1 to 10 μg / cm³ 2 Approximately 0.1 (e.g., approximately 0.5) to approximately 20 μg / cm³, including the therapeutic area. 2 Treatment area, etc., approximately 0.05 to approximately 50 μg / cm³ 2 It falls within the scope of treatment.

[0188] Appropriate doses of the conjugate of the present invention for intranasal administration (e.g., by inhalation) range from about 0.01 μg to about 2000 mg, for example, about 0.1 μg to about 500 mg, or 1 μg to about 100 mg. Specific doses for intranasal administration that may be mentioned include about 10 μg to about 1 mg, particularly the dose of about 0.1 mg (i.e., about 100 μg). Intranasal administration of about 0.1 mg per day of the conjugate of the present invention has been found to be particularly effective in treating conditions associated with inflammation of the nasal cavity and mucosa, such as rhinitis (e.g., allergic rhinitis).

[0189] Appropriate doses of the conjugate of the present invention for pulmonary administration (e.g., by inhalation) are in the range of about 0.01 μg to about 2000 mg, for example, between about 0.1 μg and about 500 mg, or 1 μg to about 100 mg. Specific doses for pulmonary administration that may be mentioned include doses of about 10 μg to about 10 mg, particularly about 0.6 mg (i.e., 60 μg) to 6 mg (for use in the treatment of COPD or IPF).

[0190] The pH value of the formulation containing the conjugate of the present invention is preferably in the range of about 1.0 to about 9.0 (for example, about 3.0 to about 8.0).

[0191] In any case, the dose administered to mammals, particularly humans, must be sufficient in the context of the present invention to produce a therapeutic response in the mammal over a reasonable time frame (as described above). Those skilled in the art will recognize that the precise dose and composition, as well as the selection of the most appropriate delivery regimen, are also influenced, among other things, by the pharmacological properties of the formulation, the nature and severity of the condition being treated, the physical and mental state of the recipient, as well as the age, condition, weight, sex and response of the patient being treated, the stage / severity of the disease, and genetic differences among patients.

[0192] The conjugates of the present invention are useful in human and veterinary medicine. In this regard, the conjugates of the present invention, having an appropriate degree of relevant pharmaceutically (or biological) activity as described above, can be used as pharmaceuticals for humans and / or animals.

[0193] A specific conjugate of the present invention comprising the peptide component defined in (a), (b), (c), or (d) above, preferably W / W. 1 Whatever represents HCA, HCA-Ala, or more preferably DOPA or DOPA-Ala, and / or U / U 1 Those representing DOPA may, in addition to possessing the above-mentioned biological activity, and / or alternatively, possess adhesive properties.

[0194] These adhesive properties are related to the W / W ratio. 1 and / or U / U 1 This stems from the fact that the elements can bridge each other to form a three-dimensional network.

[0195] Such conjugates of the present invention can adhere to many substrates, including inorganic substrates such as glass and metal, and organic substrates such as biological tissue.

[0196] In this regard, such conjugates of the present invention may also be used as wound surface repair products, wound surface protection products, medical biological adhesive products, medical coating products, industrial coating products (for example, in corrosion prevention in ships, electronic equipment, pipelines, etc.), biochemical reagents, medical products, sterilization products, culture vessels for cell culture, and the like.

[0197] Such conjugates of the present invention can form films on various skin and mucous membrane wound surfaces, such as burns, ulcers, frostbite, and pressure ulcers, to promote healing. Such conjugates of the present invention can also be used in surgical procedures, such as closing surgical incisions, bonding fractured bones, bonding mucous membranes, and coating human implants such as artificial bones, cartilage brackets, periosteum, artificial joints, dental implants, occlusion stents, spinal fixation devices, spinal spacers, and organ patches.

[0198] According to a further aspect of the present invention, the invention comprises one or more peptide components defined in any of (a), (b), (c), and / or (d) above, preferably W / W. 1 represents HCA, HCA-Ala-, or more preferably DOPA or DOPA-Ala-, U / U 1 The present invention provides a conjugate as an adhesive or film-forming material in which DOPA is represented.

[0199] As mentioned above, naturally occurring MAPs are known for their adhesive properties, but it is important to understand that such adhesive properties may arise from the fact that they are high molecular weight linear peptides that can exist in multiple conformations, enabling intermolecular and intramolecular DOPA residue reactions / crosslinking and thus adhesion. The conjugates of the present invention (made from both linear polypeptides and / or proteins or multiple branched low molecular weight residues) have been shown to have similar (adhesive or biological) properties to naturally occurring MAPs.

[0200] In addition to these properties, such conjugates of the present invention, which can be used as pharmaceutical excipients, can be mixed with suitable active ingredients before or after crosslinking and / or at least partial crosslinking, in which case the conjugates of the present invention serve as excipients such as carriers for forming a stable pharmaceutical composition.

[0201] Such crosslinking can be carried out by various chemicals (egiodin vapor, glutaraldehyde, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide (EDC / NHS), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), or other water-soluble condensing agents) or by enzymatic means (ethirosinase, or as described below). Nevertheless, regardless of the level of pharmacological activity that the conjugates of the present invention may have, they can be combined with pharmaceutically active ingredients in any case, either in combination therapy (described below), or as or as part of a pharmaceutically acceptable excipient (e.g., adjuvant, diluent, or carrier), as part of a medical device, and / or as part of a drug-medical device combination.

[0202] Therefore, in this regard, certain conjugates of the present invention can be considered novel, multifunctional excipients that can be used in a variety of applications in the pharmaceutical field. In this regard, the conjugates of the present invention can be used as adhesives or film-forming agents (for example, as described below) and / or as release-delay polymers, binders, suspending agents, gelling agents, coating agents, or as diluents or carriers for drugs of varying solubility.

[0203] In this regard, the conjugate of the present invention can be combined with a number of known pharmaceutically active ingredients, including any agents or drugs that can produce certain physiological effects (as therapeutic or prophylactic abilities against a particular disease or condition) in living subjects, particularly mammals and especially humans (including patients). This applies regardless of whether the conjugate of the present invention is used as: · as a separate pharmaceutically active ingredient in combination therapy, · as a medical device or as part thereof, · as a combination of a drug and a medical device or as part thereof, or · as a pharmaceutically acceptable excipient.

[0204] Therefore, such patients may also receive (and / or have already received) therapy based on the administration of one or more of the other active ingredients, meaning that they receive one or more prescribed doses of the active ingredients referred to herein before, in addition to, and / or after, treatment with the conjugate of the present invention.

[0205] The pharmaceutical active agents that can be administered simultaneously with the conjugate of the present invention include any agents or drugs that can produce certain physiological effects (in terms of therapeutic or prophylactic ability for a particular disease or condition) in a living subject, particularly mammals and particularly human subjects (including patients).

[0206] The pharmaceutically active agents may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics and wound healing agents (e.g., growth factors).

[0207] In this regard, the conjugate of the present invention can be combined with a number of known pharmaceutically active components, including any agents or drugs that can produce certain physiological effects (as therapeutic or prophylactic abilities against a particular disease or condition) in living subjects, particularly mammals and especially human subjects (including patients).

[0208] The biological activators may be selected from, for example, anti-inflammatory agents, pro-inflammatory agents, antibiotics, antibacterial agents and / or antiparasitic agents, antiviral agents (e.g., protease inhibitors), anesthetics and wound healing agents (e.g., growth factors).

[0209] Non-limiting examples of anti-inflammatory drugs that can be used include rheumatic diseases and / or arthritis (e.g., cataphram, betamethasone, naproxen, cyclosporine, chondroitin, celecoxib, etodolac, meclofename, salsalate, methylprednisolone, and piroxicam), osteoarthritis (e.g., sulindac, meloxicam, fenoprofen, etoricoxib, and nabumetone), inflammation and its symptoms (e.g., fever, pain, itchiness, and / or swelling) (for example) (e.g., mefenamic acid, indomethacin, aspirin, ketrolac, fluorometholone, loteprednol, hydrocortisone, fluorometholone, bromfenac, prednisolone acetate, indomethacin and ibuprofen), allergies and their symptoms (e.g., pheniramine, diphenhydramine, naphazoline, antazoline, prednisolone, rhodoxamide, pemirolast, oxymetazoline, ketotifen, naphazoline, emestine fumarate, oro Patadine, azelastine, tranilast, levocabastine, cortisone, ephedrine, cetirizine, levocetirizine, pseudofedrine, fexofenadine, terfenadine, loratadine and Alexis), respiratory diseases (asthma and / or COPD) (e.g., budesonide, ciclesonide, nedocromil, dexamethasone, ambroxol and pranlukast), skin diseases (e.g., mometasone, triamcinolone, desonide, sulfacetamide, This includes tacrolimus, allantoin, and triamcinolone; mastocytosis (e.g., cromolyn); gout (e.g., diclofenac and febuxostat); conjunctivitis (e.g., hydrobenzone, pranoprofen, and zinc sulfate); eye diseases (e.g., dextran 70, thyroxine / liothyronine, and eye extracts); known or commercially available pharmaceutically acceptable salts of any of the above; and any combination of any of the above compounds and / or salts.

[0210] Anti-inflammatory agents that may be mentioned include endogenous (and / or exogenous) lipid-based pro-resolving, anti-inflammatory molecules or mediators such as lipoxins, resolvins, and protectins. Anti-inflammatory agents that may be mentioned include prostaglandins (eglatanoprost, prostaglandin E1, and prostaglandin E2) and leukotrienes (e.g., leukotriene B4).

[0211] Non-limiting examples of antibiotics that may be used include chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomycin, gentamicin, cetylpyridinium, neomycin, roxithromycin, silver sulfadiazine, clarithromycin, clindamycin, metronidazole, azithromycin, mafenide, sulfamethoxazole, paracetamol, chloramphenicol, pseudoephedrine, mupirocin, amoxicillin, amoxicillin / clavulanate, trimethoprim / sulfamethoxazole, cephalexin, moxifloxacin, any known or commercially available pharmaceutically acceptable salts of the above, as well as any combination of the above compounds and / or salts.

[0212] Non-limited examples of antiviral drugs that can be used include tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, idoxuridine, trifluridine, brivudine, vidarabine, entecavir, terbivudine, foscarnet, zidovudine, didanosine, zalcitabine, stabudine, lamivudine, abacavir, emtricitabine, nevirapine, delavirdin, efavirenz, etravirine, rilpivirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, ritonavir, atazanavir, fosamprenavir, tipranavir, darunavir, telaprevir, boceprevir, and simeprevir. This includes vir, asunaprevir, raltegravir, elvitegravir, dolutegravir, rsv-igiv, palivizumab, docosanol, enfuvirtide, maraviroc, vzig, varizig, acyclovir, ganciclovir, famciclovir, valacyclovir, penciclovir, valganciclovir, cidofovir, tenofovir disoproxil fumarate, adefovir dipivoxil, homivirsen, podophyllox, imiquimod, synecatechin, interferon-α2b (recombinant, human), any known or commercially available pharmaceutically acceptable salt of any of the above, as well as any combination of any of the above compounds and / or salts.

[0213] Non-limiting examples of anesthetics that may be used include articaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, any known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0214] Non-limiting examples of usable wound regenerative agents include basic fibroblast growth factor (recombinant, human; recombinant, bovine), epidermal growth factor (recombinant, human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant, human), granulocyte-macrophage-stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, etaclizine, retinoids, calf blood deproteinized extract, carrageenan, amiotide, known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0215] Such pharmaceutically active ingredients include those that can be administered topically, for example, to the skin or mucous membrane surface, together with the conjugate of the present invention.In this regard, preferred active ingredients from the above list include cyclosporine, chondroitin, loteprednol, fluorometholone, bromfenac, prednisolone acetate, indomethacin, oxymetazoline, ketotifen, naphazoline, emestine fumarate, olopatadine, azelastine, tranilast, levofloxacin, cortisone, ephedrine, cetirizine, pseudoephedrine, levocetirizine, fexofenadine, terfenadine, loratadine, Alexis, dexamethasone, ambroxol), sulf Acetamide, tacrolimus, allantoin, triamcinolone, cromolyn, nedocromil, diclofenac, hydrobenzoyl, pranoprofen, zinc sulfate, dextran 70, thyroxine / liothyronine, eye extract, chloramphenicol, ofloxacin, levofloxacin, tobramycin, norfloxacin, ciprofloxacin, lomefloxacin, lincomycin, fluconazole, enoxacin, furazolidone, nitrofurazone, rifampicin, micronomisomycin, gentamicin, cetylpyridinium, ne Omycin, roxithromycin, silver sulfadiazine, clarithromycin, sulfamethoxazole, chloramphenicol, tobramycin ribavirin, acyclovir, moloxidine, foscarnet, ganciclovir, interferon-α2b (recombinant, human), articaine, dextropropoxifen, sevoflurane, cophenylcaine, lidocaine, prilocaine, pramoxin, benzocaine, dibucaine, diclonin, tetracaine, bupivacaine, basic fibroblast growth factor (recombinant, human; recombinant) This includes, , bovine, epidermal growth factor (recombinant, human; yeast), rhEFG(I), acid fibroblast growth factor (recombinant, human), granulocyte-macrophage-stimulating factor (recombinant, human), silver sulfadiazine, zinc sulfadiazine, fusidic acid, bacitracin, chlorhexidine, silver nitrate, triethanolamine, etaclizine, retinoids, calf blood deproteinized extract, carrageenan, amiotide, known or commercially available pharmaceutically acceptable salts of any of the above, as well as any combination of any of the above compounds and / or salts.

[0216] Other pharmaceutically active components that may be administered concurrently with the conjugate of the present invention include those that may be administered to treat one or more of the aforementioned gastrointestinal disorders.

[0217] Non-specific examples of gastrointestinal medications include oxalazine (orthalazine), sulfasalazine, domperidone, erythromycin, berberine, dexamethasone, cefuroxime axetil, levofloxacin, mesalazine, belladonna, sulfobenzidine, azathioprine, sulfasalazine, and live bacillus (e.g., clostridium). Butyricum licheniformis, Cereus), probiotics (such as Bifidobacterium), Tegaflu, Nifuratel, Amoxicillin, Ampicillin, Nistatin, Allicin, Cefadroxyl, Diclonin, Carmoflu, Fluorouracil, Mosapride, Carbosulfan sodium, Thrombin, Pantoprazole, Cimetidine, Cisapride, Ethylenediamineaminocaproic acid, Roxatidine acetate, Vincristine, Azasetron, Lentinan, Bismuth salts (Egalminate, Potassium citrate) and magnesium salts such as magnesium trisilicate, Bicarbonate, Vitamin U, Aluminum hydroxide, Belladonna extract, Famotidine and calcium carbonate, Magnesium hydroxide, Hydrotalcite, Proton pump inhibitors (Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole) This includes, but is not limited to, dexlansoprazole or esomeprazole, glycine, trypsin, allantoin aluminum hydroxide, L-glutamin sodium allenate, levanpet, rotandine, cuxipatite, lafutidine, thymic protein, Elysium erinaceus, ylsogladine maleate, nizatidine, L-glutamine and sodium azulene sulfonate (or trim guarenate), ranitidine, bismuth citrate, lactobacillin, bisacorzine, dimethylsiloxane, Clostridium butyrate, loperamide hydrochloride, dibazole, secnidazole, zinc acetate, montmorillonite, tegaflu / gimeracil / oteracil, famotidine, oteracil, doxifluridine, capecitabine, any known or commercially available pharmaceutically acceptable salts of the above, as well as any combination of the above compounds and / or salts.

[0218] Pharmaceutical active ingredients that may be mentioned for use in combination with the conjugate of the present invention include active ingredients useful for treating inflammation and / or inflammatory disorders (other anti-inflammatory agents).

[0219] Such anti-inflammatory agents that can be used in combination with the conjugate of the present invention in the treatment of inflammation include therapeutic agents useful for treating inflammation and / or diseases characterized by inflammation as one of its pathological conditions. Depending on the pathological condition being treated, such anti-inflammatory agents include, for example, NSAIDs (e.g., aspirin), aminosalysates (e.g., 5-aminosalicyclic acids), and 5-aminosalicyclic acids, as described below. The conjugates of the present invention may also include alicyclic acid (mesalazine), leukotriene receptor antagonists (e.g., montelukast, pranlukast, and zafirlukast), corticosteroids, analgesics, and certain enzymes such as trypsin, as described below. The conjugates of the present invention may also be combined with leukotrienes (cysteinylleukotrienes and leukotriene B4).

[0220] Other preferred agents that can be combined with the conjugate of the present invention include LTB4 (for the treatment of wounds and burns), NSAIDs (e.g., aspirin), montelukast (for the treatment of general inflammation), and trypsin (e.g., for the treatment of mucosal inflammation associated with viral infections).

[0221] The conjugate of the present invention can also be combined with other therapeutic agents known to cause inflammation as a side effect when administered.

[0222] The conjugates of the present invention can be combined with stem cells (e.g., totipotent (totipotent cells), pluripotent (e.g., embryonic or induced pluripotent stem cells), multipotent (e.g., mesenchymal stem cells), oligopotent (e.g., hematopoietic stem cells), or unipotent (e.g., muscle stem cells)).

[0223] Other known pharmaceutically active ingredients can also be administered in combination with the conjugate of the present invention in many ways.

[0224] For example, the conjugate of the present invention may be administered together with (or other) pharmaceutically active ingredients (or "therapeutic agents") in the same (e.g., pharmaceutical) formulation, or separately (simultaneously or sequentially) in different (e.g., pharmaceutical) formulations.

[0225] Such combination products provide an administration of the conjugate of the present invention in combination with other therapeutic agents, and may be provided as separate formulations (at least one of which contains the conjugate of the present invention and at least one of which contains the other therapeutic agent) or as a combination preparation (i.e., a single formulation containing the conjugate of the present invention and the other therapeutic agent) (i.e., formulated).

[0226] Accordingly, the following are also provided: (1) a (e.g., pharmaceutical) formulation comprising the conjugate of the present invention, another pharmaceutically active ingredient, and optionally a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent, or carrier), the formulation being hereinafter referred to as the “combination preparation”; (2) a parts kit comprising the following components: (A) the conjugate of the present invention in the form of a (e.g., pharmaceutical) formulation, optionally mixed with a pharmaceutically acceptable inert excipient (e.g., an adjuvant, diluent, or carrier); and (B) another pharmaceutically active ingredient in the form of a (e.g., pharmaceutical) formulation, optionally mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier; (A) and (B) are each provided in a form suitable for administration when combined with the other component.

[0227] In a further aspect of the present invention, a process is provided for preparing a combination preparation (1) as defined herein, comprising combining the conjugate of the present invention with other pharmaceutically active ingredients and at least one (e.g., pharmaceutically acceptable) excipient.

[0228] In a further aspect of the present invention, a process is provided for preparing a parts kit (2) as defined herein, the process comprising combining components (A) and (B). As used herein, reference to relating means that the two components are suitable for administration in combination with each other.

[0229] Therefore, with respect to the process for preparing the parts kit as defined above, by “associating” the two components with respect to each other, we include the possibility that the two components of the parts kit may (i) be provided as separate formulations (i.e., independently of each other) and then be brought together for use in combination therapy, or (ii) be packaged and presented together as separate components of a “combination pack” for use in combination therapy.

[0230] Accordingly, parts kits are further provided that include (I) one of the components (A) and (B) as defined herein, along with (II) instructions for using that component in combination with the other of the two components.

[0231] In relation to the parts kit described above, the conjugate of the present invention may be provided in the form of a (e.g., pharmaceutical) formulation mixed with one or more further pharmaceutically acceptable excipients (e.g., adjuvants, diluents, or carriers), however, when the compound of the present invention is provided primarily for the function of a medical device or as an excipient, it may not be provided with such further pharmaceutically acceptable excipients. In any case, it is preferable that the (other) pharmaceutically active ingredients of the parts kit be provided in the form of a formulation mixed with a pharmaceutically acceptable adjuvant, diluent, or carrier.

[0232] The parts kit described herein may comprise two or more formulations comprising two or more formulations containing an appropriate amount / dose of the conjugate of the present invention, and / or another therapeutic agent, in order to provide repeated doses. If two or more formulations of appropriate amounts / dose (containing any of the active compounds) exist, such formulations may be the same or different in terms of the dose, chemical composition, and / or physical form(s) of any of the compounds.

[0233] When the Parts Kit described herein is referred to as “administered in combination with ~”, it includes the administration of each component sequentially, separately, and / or simultaneously during the treatment period for the relevant medical condition.

[0234] Accordingly, with respect to the combination products of the present invention, the term "administration in combination with ~" means that, during the treatment period of the relevant medical condition, the two components of the combination product (the conjugate of the present invention and other anti-inflammatory agents) are administered (optionally repeatedly) together or separately in sufficiently close time intervals, resulting in a greater beneficial effect on the patient than if either the formulation containing the conjugate of the present invention or the formulation containing the other agent were administered alone or without the other component (optionally repeated) over the same treatment period. The determination of whether the combination provides a greater beneficial effect with respect to the treatment of a particular medical condition and over the course of that treatment will depend on the medical condition being treated or prevented, but can be conventionally achieved by those skilled in the art.

[0235] Furthermore, in the context of the parts kit according to the present invention, the term “combined with ~” includes the fact that one or the other of the two components may be administered before, after, and / or simultaneously with (optionally and repeatedly) the administration of the other component. When used in this context, the terms “conjugates” and “administered simultaneously with ~” include the fact that individual doses of the relevant conjugates and other anti-inflammatory agents of the present invention are administered within 48 hours (e.g., 24 hours) of each other.

[0236] Depending on the disorder being treated, the patient, and the route of administration, the conjugate of the present invention may be administered to patients requiring treatment at different therapeutically effective doses.

[0237] In relation to the above-mentioned combination preparations and parts kits, the other pharmaceutically active ingredients are preferably anti-inflammatory agents as described above, or drugs known to cause inflammation as a side effect.

[0238] Whenever the term "approximately" is used herein in the context of quantities such as the concentration and / or dose of an active ingredient, molecular weight, or pH, it will be understood that such variables are approximations and can therefore vary by ±10%, for example, ±5%, and preferably ±2% (for example, ±1%) from the numerical values ​​specified herein. In this regard, the term "approximately 10%" means, for example, ±10% for the numerical value 10, i.e., 9% to 11%.

[0239] The conjugates of the present invention have the advantage of having a wide variety of applications, including: As a biological activator in various pathological conditions characterized by inflammation (whether the condition itself is an organic inflammatory disease, whether it is related to inflammation or is characterized by inflammation (e.g., wounds or burns)), and / or in the aforementioned surgical and / or cosmetic uses, • In combination therapy, or as one or part thereof, it exhibits a more inactive function, and therefore, when combined with the active pharmaceutical ingredient, - pharmaceutically acceptable excipients (e.g., adjuvants, diluents or carriers), - Medical devices, and / or - The medical device portion in a combination of pharmaceuticals and medical devices.

[0240] The uses and methods described herein may also have the advantage of being more convenient for physicians and / or patients, more effective, less toxic, having a broad range of activity, being potent, having fewer side effects, or having other useful pharmaceutical properties that surpass similar methods (treatments) known in the prior art, in the treatment of the conditions mentioned above, whether for use in the treatment of inflammation, inflammatory disorders, or disorders characterized by inflammation as a sign (including wounds), or for other purposes.

[0241] The present invention is illustrated by the following examples, but is not limited thereto. [Examples]

[0242] Exemplary Example 1 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2 (Sequence ID 11) Fmoc-Lys(Boc)-Wang resin (9.15 g, GLS180322-41301, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0243] Methylene chloride (DCM, 200 mL, Shandong Jinling Chemical Industry Co. Ltd., Shandong, China) was added to the column, and the resin was immersed for approximately 30 minutes. Next, the DCM was removed by vacuum filtration.

[0244] The resin was washed three times with N,N-dimethylformamide (DMF, 200 mL; Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong, China).

[0245] A 20% piperidine solution in DMF (200 mL, Shandong Shitaifeng Fertilizer Industry Co. Ltd., Shandong Province, China) was added as a deprotection solution and the reaction was allowed to proceed for 20 minutes. The solution was then removed by vacuum filtration, and the column was washed six times with DMF.

[0246] Fmoc-DOPA(Acetonide)-OH (4.14 g, GLS190219-21003, GL Biochem, Shanghai, China) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU, 2.89 g, GLS170805-00705, GL Biochem, Shanghai, China) were added to the resin. DMF (150 mL) was added to the reaction column, followed by the addition of N,N-diisopropylethylamine (DIPEA, 2.33 g, Suzhou Highfine Biotech Co.Ltd., Jiangsu, China). After 30 minutes of reaction, a Kiaser test was performed using a small amount of resin. A color reaction was detected in the resin after 30 minutes, indicating that the reaction was complete. The solvent was removed by vacuum filtration.

[0247] The above coupling process was repeated to couple the remaining amino acids in the same amounts (molars): Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0248] After coupling Fmoc-Ala-OH to the resin, the above coupling steps were repeated, starting with Fmoc-Lys(Boc)-OH, followed by Fmoc-DOPA(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH.

[0249] In an alternative procedure, after bonding Fmoc-Ala-OH to the resin, a deprotection step was performed to remove the Fmoc protection of Dopa. The resin was washed three times with DMF (200 mL each time). A 20% piperidine solution in DMF (200 mL) was added as a deprotection solution and reacted for 20 minutes. The resin was then subjected to the following solvents: DMF (200 mL each time), DCM (200 mL each time), and methanol (200 mL each time; Xilong Scien The resin was washed three times at Tific Co., Ltd. (Guangdong, China). The resin was dried under vacuum for approximately two hours.

[0250] 160.0 mL (i.e., 10 mL per gram of dry resin) of lysate consisting of 95% trifluoroacetic acid (TFA), 2.5% water, and 2.5% triisopropylsilane (Tis) was added, and the peptide-containing compound bound to the resin was immersed. After cutting for approximately 2 hours, the solid support was removed by filtration, and the filtrate was collected under reduced pressure. 1600 mL (i.e., 10 mL per 1 ml of filtrate) of diethyl ether (Xilong Sci) was added to the filtrate. The compound was precipitated at entific Co., Ltd. (Guangdong, China), and the precipitate was recovered by filtration. The precipitate was vacuum-dried for approximately 2 hours to obtain 7.53 g of the crude title compound.

[0251] The crude product was first analyzed as a 1 mg / mL sample in pure water and detected using a Shimadzu LCMS-8050 system. The analytical column was an Agilent ZORBAX Eclipse SB-C18 (4.6 × 250 mm, 5 μm column, detection: 220 nm UV, solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 5% to 90% over 50 minutes, flow rate 1.0 mL / min, sample volume: 10 μL).

[0252] The target peak was eluted at 11.926 mins with the expected molecular weight, and the purity was 60.345%. MS: m / z 2380.6

[0253] Next, 7.5 g of the crude product was dissolved in 80 mL of pure water and purified using an LC3000 preparative apparatus. The preparative column model was the Dubhe-C18 model (Hanbon Sci.&Tech.Co.,Ltd., Jiangsu, China) (50 × 250 mm, 100A column, detection: 220 nm UV). A suitable gradient for elution was calculated from the LCMS detection step (solvent A: 0.1% TFA in MeCN, solvent B: 0.1% TFA in water, linear gradient of solvent A concentration from 5% to 20% over 30 minutes; flow rate 60.0 mL / min). The fraction was collected and analyzed using a Shimadzu LC-20 HPLC system (using the same column except that a linear gradient of solvent A concentration from 5% to 30% over 25 minutes was used).

[0254] Next, for the anion exchange step, the fraction with a purity of 98% was mixed. This was achieved using an LC3000 preparative apparatus (preparative column model: Dubhe-C18 model (above)). The fraction was diluted once with pure water and loaded directly onto the column. The column was then washed with 0.37% ammonium acetate in pure water for approximately 20 minutes, followed by pure water for another 20 minutes at a flow rate of 60 mL / min, and then eluted with the following gradient (solvent A: 0.1% HAc in MeCN, solvent B: 0.1% HAc in water, linear gradient of solvent A concentration from 5% to 20% over 30 minutes, flow rate 60.0 mL / min). The fraction was collected and analyzed using a Shimadzu LC-20 HPLC system (column and conditions as above). The fraction with a purity of 98% was mixed and lyophilized to obtain 3.06 g of the purified title compound.

[0255] Exemplary Example 2 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Lys (Sequence ID 153) Fmoc-Lys(fmoc)-Wang resin (9.9g, GLS191010-41303, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0256] The method was the same as described in Exemplary Example 1, except that Fmoc-Lys(Boc)-OH was first coupled to the resin, followed by Fmoc-Dopa(acetonide)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, and Fmoc-Ala-OH, and the amounts of amino acids, TBTU, and DIPEA were doubled (in moles) compared to Exemplary Example 1. MS: m / z 2508.8

[0257] The same procedure was repeated to obtain a further batch of the crude title compound (yield 7.89 g). Analysis showed that the target peak eluted at 11.376 min with the expected molecular weight (MS: m / z 2508.8). The purity was 68.985%.

[0258] Next, 7.8 g of the crude product was purified as described in Exemplary Example 1 above, and after lyophilization, 2.57 g of the pure title compound was obtained. MS: m / z 2508.8

[0259] Exemplary Example 3 {[(Dopa-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 154) Fmoc-Lys(fmoc)-Wang resin (9.9g, GLS191010-41303, GL Biochem, Shanghai, China) was loaded into a glass reaction column.

[0260] The method involved first coupling with a resin, followed by coupling with Fmoc-Lys(Fmoc)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-4-Hyp(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Pro-OH, Fmoc-Lys(Boc)-OH, Fmoc-Ala-OH, and Fmoc-Dopa(acetonide)-OH. Except for Fmoc-Lys(Fmoc)-OH, the amounts of amino acids, TBTU, and DIPEA were four times (in moles) compared to Exemplary Example 2, except that the method was the same as described in Exemplary Example 2. MS: m / z 11671.1

[0261] The same procedure was repeated to obtain a further batch of the crude title compound (yield 28.89 g). Analysis showed that the target peak eluted at 11.896 min with the expected molecular weight (MS: m / z 11671.1). The purity was 29.985%.

[0262] Next, 28.8 g of the crude product was purified as described in Exemplary Example 1 above, and after freeze-drying, 5.57 g of the pure title compound was obtained.

[0263] Exemplary Example 4 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2) The title peptide was synthesized using substantially the same procedure as described in Exemplary Example 1 above, except that appropriate amino acids were used in the appropriate peptide coupling sequence. MS: m / z 1183.3

[0264] Example 1 (Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys)2-Lys(SEQ ID NO: 153)HA Conjugate HA-EP2 (1g, 19072911, Furida Biotech, Shandong, China) was dissolved in 100 mL of pure water for 8 hours to prepare a 1% HA solution (50 mM carboxyl groups).

[0265] DMTMM (275 mg, Sigma) and the product from Example 2 (22 mg) were dissolved in 20 mL of pure water to prepare DMTMM (50 mM) and peptide (2.5 mM amino group) solutions. 20 mL of 1% HA solution was added to 20 mL of the DMTMM and peptide solution and stirred at room temperature for 1 day.

[0266] One day later, 0.1 g of the reacted gel was collected and thoroughly mixed with 0.4 mL of 96% ethanol. The sample was then centrifuged at 15,000 rpm for 15 minutes. The supernatant was collected and detected using a Shimadzu LC-20 HPLC system (Shimadzu, Japan) equipped with an LC-20AT binary pump, DGU-20A5 degasser, SIL-20AC autosampler, CTO-20AC column oven, and SPD-M20A photodiode array detector.

[0267] The samples were analyzed using an Agilent SB-C18 column (5 μm, 4.6 x 250 mm, Agilent, USA) under the following conditions. Mobile phase: 0.1% TFA in acetonitrile (solvent A) and 0.1% TFA in water (solvent B) • Linear gradient program: 0-25 minutes, 10%-35% solvent A ·Flow rate: 1.0mL / min, Column temperature: 30°C • The PDA detector records the UV spectrum in the range of 190nm to 400nm. • Monitor the HPLC chromatogram at 220nm.

[0268] The concentration of the product of Example 2 (unbound free peptide) in the supernatant was calculated to be 0.052 mg / mL according to its standard curve. Therefore, approximately 0.29 mg / mL (=22 / 40 - 0.052 × 5) of peptide was bound to HA-EP2, which corresponds to approximately 11.6 mg (=0.29 × 40) of peptide per 200 mg (0.2 g = 20 × 1%) of HA-EP2.

[0269] The product is isolated by adding 100 mL of 96% ethanol dropwise to the reaction mixture and allowing it to precipitate. A white powder is obtained and thoroughly washed with water:ethanol = 1:4, 96% ethanol, and finally anhydrous ethanol. The product is vacuum-dried at 38°C for 3 days.

[0270] Example 2 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(Sequence ID 2)HA Conjugate HA (200 mg, HA-EP2, Bloomage Biotechnology Co. Ltd., Jinan, China) was placed in a test tube, and 2 mL of 0.2 M NaOH was added to dissolve the HA powder, and it was thoroughly mixed.

[0271] Peptide (SEQ ID NO: 2) (220 mg, P200921, USUN Pharmaceutical Co. Ltd., Jiangyin, China) was placed in a separate test tube. The peptide powder was dissolved in 1 mL of 0.4 M HCl, then DMTMM (275 mg, Aladdin, Shanghai, China) was added and dissolved, and thoroughly mixed.

[0272] Next, the mixture was transferred to a test tube containing the HA solution and mixed thoroughly. Then the test tube was covered and heated at 35°C for approximately 16 hours to allow the reaction to occur.

[0273] After 16 hours, the solution had hardened into a colorless gel. The gel was removed and cut once through a 20-mesh screen. Next, the cut gel was immersed for 1 hour in 100 mL of HA buffer (containing 9.0 g of NaCl, 30 mg of KH2PO4, and 140 mg of Na2HPO4·12H2O in a total volume of 1 L of pure water). The gel swelled after immersion. The HA buffer was removed by filtration, and the gel was cut three times through a 200-mesh screen to produce small, uniform particles.

[0274] Next, the small particles were immersed in 100 mL of HA buffer for 1 hour to remove the condensant (DMTMM) (a step similar to dialysis), and then the HA buffer was removed by filtration. This step was repeated seven more times to completely remove the DMTMM. Even smaller particles were obtained at a concentration of approximately 30 mg / g.

[0275] HA (10 mg, HA-EP2, Bloomage Biotechnology Co. Ltd., Jinan, China) was dissolved in 1 mL of HA buffer, and 1 g of the prepared small particles was added and thoroughly mixed. The final product was obtained at a concentration of 20 mg / g.

[0276] The obtained product was filled into the final packing material and sterilized with moist heat.

[0277] The resulting product can be used to fill in wrinkles and folds.

[0278] Example 3 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID NO: 2) HA conjugate in combination with celecoxib The HA conjugate is obtained as described in Example 2.

[0279] Mix HA conjugate and celecoxib in a 10:1 mass ratio and stir until homogeneous. The resulting product can be used for intra-articular injection to alleviate the symptoms and relieve pain associated with osteoarthritis.

[0280] Example 4 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID NO: 2)HA conjugate combined with diclofenac sodium. The HA conjugate is obtained as described in Example 2.

[0281] Mix HA conjugate and diclofenac sodium in a 5:1 mass ratio and stir until homogeneous. The resulting product can be used for intra-articular injection as an analgesic and / or anti-inflammatory agent.

[0282] Example 5 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID NO: 2) HA conjugate combined with rifampicin. The HA conjugate is obtained as described in Example 2.

[0283] Mix HA conjugate and rifampicin in a mass ratio of 20:1 and stir until homogeneous. The resulting product can be used in ophthalmic surgery as an anti-inflammatory, anti-inflammatory, and / or analgesic agent.

[0284] Example 6 Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID NO: 2) HA conjugate for bleeding A 49-year-old woman had suffered from allergic rhinitis for approximately five years. She experienced seasonal allergies every spring and fall. She was prescribed fluticasone propionate nasal spray to control her condition, but her nose began to dry out the previous winter. As a result of continued use of fluticasone propionate nasal spray, she suffered from nosebleeds. When she experienced another allergic attack in the spring, in addition to her prescribed medication, she used a spray (0.5 mg) of Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 2) HA conjugate dissolved in 1 mL of HA buffer, as described in Example 2 above. She used the conjugate spray 4-5 times during the day. The bleeding stopped, and her dry nose improved significantly. This demonstrated that the compound in the title can be used to alleviate the condition of a dry nose.

[0285] Example 7 {[(Dopa-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 154) HA gel An appropriate amount of peptide component, methylcellulose (2.2g; Shandong Gua Mix with ngda Technology Development Co., Ltd., Shan Dong, China and purified water (75.3 g), and stir until a homogeneous colloidal suspension is formed to prepare a gel containing {[(Dopa-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys)2-Lys]2-Lys}2-Lys (SEQ ID NO: 154). Next, 0.5 g of HA powder (HA-EP2, Blo) was added. Sinopharm Biotechnology Co. Ltd., Jinan, China, glycerin (11g) and propanediol 11g (both from Sinopharm Chemical Reagent Co. Ltd. was added to a methylcellulose / water mixture, and the resulting mixture was rapidly stirred for 5 minutes to obtain the title product.

[0286] Hereinafter, the product of Example 7 will be referred to as "HA gel".

[0287] Example 8 Mouse ear swelling model Twenty healthy male BALB / c mice, 6-8 weeks old and with an average weight of 18-25g, supplied by Changzhou Cvens Experimental Animal Co. Ltd., were isolated in cages for approximately one week prior to the experiment. The cage temperature was maintained at 25-27°C, humidity at 74%, with alternating 12-hour light / dark cycles, and the mice were given free access to food and water. The mice were randomly divided into four groups of five, as shown in Table 1 below.

[0288] The left ear of each mouse was used as an autocontrol. The right ear of each mouse was treated with various different methods, as summarized in Table 1 below. 20 μL of xylene (Shanghai A Laddin Bio-Chem Technology Co., Ltd. (Shanghai, China) was applied to both the inner and outer surfaces of the right ear of each mouse. The ear began to swell after approximately 4 minutes. Next, 40 μL of the treatment agent or vehicle was applied to the right ear of each group. The mice were returned to their cages.

[0289] Dexamethasone Acetate Cream (DEX, Tianjin Jinyao Pharma) Ceutical Co., Ltd. was used as a positive control. The HA gel was synthesized as described in Example 7 above. [Table 1]

[0290] The mice were sacrificed by neck dislocation after 40 minutes. Both ears were amputated. Using an 8mm diameter skin pouch (Electron Microscopy Sciences, Hatfield, PA, USA), a portion of the ear was taken from the same area on both ears. The weight was recorded, and the swelling rate was calculated as follows: Swelling rate = (Weight of right ear - Weight of left ear) / Weight of left ear × 100%. The results are shown in Table 2 below. [Table 2]

[0291] The results above indicate that HA gel can reduce xylene-induced swelling.

Claims

1. A conjugate formed between one or more linear polysaccharide chains and a peptide, wherein the peptide component is defined as (a), (b), (c), or (d) below: (a) Peptide component of formula I A-Q-B I (In the formula, A and B independently determine Z or A １ -Q １ -B １ This represents, Q represents the structural fragment of equation II, 【Chemistry 1】 During the ceremony, The wavy line represents the connection point of Q to A and / or B. m represents an integer from 1 to 4. A １ and B １ However, independently, Z or A ２ -Q ２ -B ２ This represents, A ２ and B ２ are, independently, Z or Z-Q ３ -Z, where Q １ Q ２ and Q ３ However, independently, it represents the structural fragment of formula III, 【Chemistry 2】 During the ceremony, The dashed line adjacent to the NH element is Q １ Q ２ and Q ３ A １ and / or B １ A ２ and / or B ２ The lines represent the bonding points to Z and Q, respectively, and the wavy line adjacent to the O atom indicates Q １ Q ２ and Q ３ Q, Q １ and Q ２ These represent the connection points to and respectively, where m is as defined above. Each time Z appears in the formula, it represents a peptide component of the following amino acid sequence: [W-Lys-X １ -Ser-U-X ２ -Y] ｎ -W-Lys-X １ -Ser-U-X ２ -Y--- (Sequence No. 3) During the ceremony, The dashed lines represent the Z bond points to the rest of the molecule. n represents 0 or an integer from 1 to 4. Each time it appears in the formula, W is either absent or represents a sequence of one or two amino acids, wherein the amino acids are selected from one or more of the group consisting of Lys, Ala, DOPA, and 3,4-dihydrocinnamic acid (HCA) residues, provided that if present, the HCA residue is located at the N-terminus of peptide sequence Z. X １ However, it represents Pro, Hyp, or diHyp, U represents Tyr, DOPA, or a single bond. X ２ , represents Ser, Pro, Hyp, or diHyp, Y represents a single bond or a sequence of 1 to 5 amino acids, wherein the amino acids are selected from one or more of the following groups: Lys, Ala, Pro, Hyp, diHyp, Thr, DOPA, and Tyr), or (b) Peptide component with the following amino acid sequence [Ala-Lys-X １ -Ser-U-X ２ -Y] ｐ -Ala-Lys-X １ -Ser-U-X ２ -Y-G (Sequence No. 4) (In the formula, p represents an integer from 1 to 4, G is either absent or represents DOPA or dopamine. X １ , U, X ２ , and Y is as defined above), or (c) Peptide components with the following amino acid sequence W-Lys-X １ -Ser-U-X ２ -Y-G (Sequence No. 5) (In the formula, W, １ , U, X ２ Y and G are as defined above), or (d) Peptide component K-W with the following amino acid sequence １ -Lys-X １ -Ser-U １ -X ２ -Y １ -I-J (Sequence No. 6) (In the formula, K represents an optional N-terminal HCA group, W １ However, it may not be present, or it may represent a sequence of one or two amino acids, wherein the amino acids are selected from one or more of the groups Ser, Lys, Ala, and DOPA. U １ However, it represents Tyr, DOPA, or a single bond. Y １ However, it represents a single bond, or represents Y, I represents Pro, Hyp, diHyp, Thr, DOPA, or Tyr. J either represents Lys or does not exist. X １ , X ２ A conjugate selected from one or more of the following (where Y is as defined above): Furthermore, positional isomers, stereoisomers, and pharmaceutically or cosmetically acceptable salts of the conjugate.

2. The conjugate according to claim 1, wherein the polysaccharide chain is hyaluronic acid.

3. X １ The conjugate according to claim 1 or 2, wherein Pro is represented.

4. X ２ A conjugate according to any one of the prior claims, wherein the conjugate represents Pro or Hyp.

5. A conjugate according to any one of the prior claims, wherein W represents HCA, HCA-Ala-, Ala, DOPA, Lys-Ala, or DOPA-Ala-.

6. The conjugate according to claim 5, wherein W represents HCA, HCA-Ala-, DOPA, or DOPA-Ala-.

7. The conjugate according to any one of the prior claims, wherein Y represents a sequence of four amino acids, and the amino acids are selected from one or more of the group consisting of Lys, Ala, Hyp, Thr, DOPA, and Tyr.

8. Y is -Hyp-Y １ -Y ２ -Lys- and -Thr-Y １ -Y ２ This represents an amino acid sequence selected from the group -Lys-, where Y １ and Y ２ The conjugate according to claim 7, wherein each is independently selected from the group Ala, Hyp, Thr, DOPA, and Tyr.

9. The amino acid sequences defined by Y are -Pro-Thr-DOPA-Lys-, -Pro-Thr-Tyr-Lys-, -Thr-Tyr-Pro-Lys-, -Thr-DOPA-Pro-Lys-, -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-Tyr-Lys-, -Hyp-Thr-DOPA-Lys-, -Hyp-Thr-Ala-Lys-, -Thr-Tyr-Hyp-Lys-, -Thr-DOPA-Hyp-Lys- The conjugate according to claim 7, selected from the group consisting of -Thr-Ala-Hyp-Lys-, -Hyp-Thr-, -Thr-Tyr-, -Pro-Thr-, -Thr-DOPA-, -Thr-Tyr-Lys-, -Tyr-Pro-Lys-, -DOPA-Pro-Lys, -Hyp-Thr-Tyr-, -Thr-Tyr-Hyp-Lys-DOPA-, -Hyp-Thr-Tyr-Hyp-Lys and -Hyp-Thr-DOPA.

10. A conjugate according to any one of the prior claims, wherein m represents 4.

11. A and B both represent Z, or both represent A １ -Q １ -B １ A conjugate according to any one of the prior claims, representing the above.

12. A １ and B １ However, both could represent Z, or both could represent A ２ -Q ２ -B ２ A conjugate according to any one of the prior claims, representing the above.

13. A ２ and B ２ However, both represent Z, or both represent Z-Q ３ A conjugate representing -Z as described in any one of the prior claims.

14. A conjugate according to any one of the prior claims, wherein n is 0.

15. A conjugate according to any one of the prior claims, wherein G does not exist.

16. (b) The peptide component defined in (b) has the amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys (SEQ ID NO: 7), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp -Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 8), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 9), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 10), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 11), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp- Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 12), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-L ys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 13), or The conjugate according to claim 15, comprising Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 14).

17. The conjugate according to any one of claims 1 to 15, wherein U represents Tyr and / or W represents Ala-.

18. (a) The Z in the peptide component defined in (a) Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA---(SEQ ID NO: 17), Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Ser-Hyp-Thr-Tyr-Lys-- (SEQ ID NO: 18), and A conjugate according to claim 17, selected from the group Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 19).

19. The conjugate according to any one of claims 1 to 15, wherein U represents Tyr and / or W represents Lys-Ala-.

20. (a) The Z in the peptide component defined in (a) Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr --- (SEQ ID NO: 37), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 38), and The conjugate according to claim 19, selected from the group Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 39).

21. The conjugate according to any one of claims 1 to 15, wherein U represents Tyr and / or W represents HCA-, HCA-Ala-, DOPA-, or DOPA-Ala-.

22. (a) The Z in the peptide component defined in (a) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys --- (SEQ ID NO: 45), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 46), HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence No. 47), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 48), DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 49), DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 50), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(Sequence ID 51), and The conjugate according to claim 21, selected from the group DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 52).

23. The conjugate according to any one of claims 1 to 15, wherein U represents DOPA and / or W represents Ala or Lys-Ala-.

24. (a) The Z in the peptide component defined in (a) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66), Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 67), Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 68), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 69), and A conjugate according to claim 23, selected from the group Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 70).

25. The conjugate according to any one of claims 1 to 15, wherein U represents DOPA and / or W represents HCA-, HCA-Ala-, DOPA-, or DOPA-Ala-.

26. Z is HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 94), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 95), HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 96), HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 96), DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 98), DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 99), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 100), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys---(Sequence ID 101), and The conjugate according to claim 25, selected from the group DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(SEQ ID NO: 102).

27. In the peptide component defined in (a), A and B both represent Z, and one or both Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys --- (SEQ ID NO: 45), HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 48), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65), Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA---(Sequence ID 67), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 94), DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys---(Sequence ID 99), or This represents DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys--- (Sequence ID 100), A conjugate according to any one of the prior claims, wherein Q represents a Lys fragment.

28. In the peptide component defined in (a), A and B are both A １ -Q １ -B １ This represents A １ and B １ However, both represent Z, and one or both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 38), Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA---(Sequence ID 39), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys --- (SEQ ID NO: 45), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 46), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 65), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66), HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 96), DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys---(Sequence ID 98), or This represents DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys--- (Sequence ID 100), Q １ A conjugate according to any one of claims 1 to 26, wherein the conjugate represents a Lys fragment.

29. In the peptide component defined in (a), both A and B are A １ -Q １ -B １ This represents A １ and B １ However, both are A ２ -Q ２ -B ２ This represents A ２ and B ２ However, both represent Z, and one or both Z groups, Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys --- (SEQ ID NO: 2), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 15), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys---(Sequence ID 16), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys --- (SEQ ID NO: 45), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys---(SEQ ID NO: 51), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys---(SEQ ID NO: 52), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 66), or This represents DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys--- (Sequence ID 100), Q １ and Q ２ The conjugate according to any one of claims 1 to 26, wherein both represent Lys fragments.

30. In the peptide component defined by (a), both A and B are A １ -Q １ -B １ represents, A １ and B １ both are A ２ -Q ２ -B ２ represents, A ２ and B ２ both are Z-Q ３ -Z represents, and one or both of the Z groups are Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys---(Sequence ID 1), or This represents Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 2), Q １ Q ２ and Q ３ The conjugate according to any one of claims 1 to 26, wherein each represents a Lys fragment.

31. The peptide component defined in (c) has the amino acid sequence: Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 20), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID NO: 21), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-Dopamine (SEQ ID NO: 22), Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys (Sequence ID 23), Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys (SEQ ID NO: 24), Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys (Sequence ID 25), Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys (SEQ ID NO: 26), Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys (Sequence ID 27), Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys (SEQ ID NO: 28), Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys (Sequence ID 29), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 30), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 31), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 32), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA (Sequence ID 33), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-Dopamine (SEQ ID NO: 34) Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID NO: 35), or The conjugate according to claim 17, comprising Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-dopamine (SEQ ID NO: 36).

32. The peptide component defined in (c) has the amino acid sequence: Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 40) Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-dopamine (SEQ ID NO: 41), and Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 42), Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 43), or The conjugate according to claim 19, comprising Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 44).

33. The peptide component defined in (c) has the amino acid sequence: DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 53) DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 54) DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 55), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 56), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 57), DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 58) HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys (Sequence ID 59), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 60), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 61), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 62), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 63), or The conjugate according to claim 21, comprising HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 64).

34. The peptide component defined in (c) has the amino acid sequence: Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Dopamine (SEQ ID NO: 71), Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 72) Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 73) Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys (Sequence ID 74), Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys (Sequence ID 75), Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys (Sequence ID 76), Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys (Sequence ID 77), Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys (Sequence ID 78), Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys (Sequence ID 79), Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys (Sequence ID 80), Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys (Sequence ID 81), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 82), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 83), Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr (Sequence ID 84), Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr (Sequence ID 85), Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA (SEQ ID NO: 86); Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA (SEQ ID NO: 87) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-Dopamine (SEQ ID NO: 88) Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-Dopamine (SEQ ID NO: 89) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA (SEQ ID NO: 90) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA (SEQ ID NO: 91) Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-Dopamine (SEQ ID NO: 92), or The conjugate according to claim 23, comprising Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-dopamine (SEQ ID NO: 93).

35. The peptide component defined in (c) has the amino acid sequence: DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 103) DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (SEQ ID NO: 104) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 105) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 106) DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (SEQ ID NO: 107) HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 108), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 109), HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys (SEQ ID NO: 110) HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys (Sequence ID 111), DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 112), HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 113), or The conjugate according to claim 25, comprising HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys (SEQ ID NO: 114).

36. In the peptide component defined in (d), W １ The conjugate according to any one of claims 1 to 4 or 7 to 9, wherein Ala or Ser is represented or not present.

37. In the peptide component defined in (d), X ２ The conjugate according to any one of claims 1 to 4, 7 to 9, or 36, wherein the conjugate represents Pro, Hyp, or diHyp.

38. In the peptide component defined in (d), K is absent, and W １ The conjugate according to any one of claims 1 to 4 or 7 to 9, 36 or 37, wherein when J represents Lys, I represents Pro, Hyp, diHyp or Thr.

39. In the peptide component defined in (d), Y １ In the array defined by, The amino acids DOPA, Thr, or Tyr are linked to I, and / or Amino acids Pro, Hyp, or Thr are X ２ A conjugate according to any one of claims 1 to 4 or 7 to 9, 36 to 38, which is connected to the

40. The conjugate according to any one of claims 1 to 4, 7 to 9, or 36 to 39, wherein K is absent in the peptide component defined in (d).

41. The peptide component defined in (d) has the amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 115), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 116), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 117), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 118), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys (Sequence ID 119), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 120), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 121), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (Sequence ID 122), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 123), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 124), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 125), or The conjugate according to claim 40, comprising Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 126).

42. The conjugate according to any one of claims 1 to 4, 7 to 9, 36, 37, 39, or 40, wherein J is absent in the peptide component defined in (d).

43. The peptide component defined in (d) has the amino acid sequence: Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 127), Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence ID 128), Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 129), Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 130), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (Sequence ID 131), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 132), Ser-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 133), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Hyp (Sequence ID 134), Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Hyp (Sequence ID 135), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp (Sequence ID 136), Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 137), Ser-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA (SEQ ID NO: 138) HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr (SEQ ID NO: 146), HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp (SEQ ID NO: 147), Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp (Sequence ID 148), Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro (Sequence ID 149), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp (Sequence ID 150), Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 151), or The conjugate according to claim 42, comprising Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp (SEQ ID NO: 152).

44. The conjugate according to any one of claims 1 to 4, 7 to 9, 36 to 39, or 42, wherein K is an N-terminal HCA group in the peptide component defined in (d).

45. The peptide component defined in (d) has the amino acid sequence: HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys (Sequence ID 139), or The conjugate according to claim 44, comprising HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 140).

46. In the peptide component defined in (d), W １ The conjugate according to any one of claims 1 to 4, 7 to 9, 36 to 40, or 44, wherein A is Lys.

47. The peptide component defined in (d) is: Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 141), Ala-Lys-Pro-Ser-Pro-Thr-Tyr-Pro-Lys (Sequence ID 142), Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys (SEQ ID NO: 143), Ala-Lys-Hyp-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys (Sequence ID 144), or The conjugate according to claim 46, comprising the amino acid sequence Ala-Lys-Hyp-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys (SEQ ID NO: 145).

48. A conjugate according to any one of the prior claims, for use in human or animal medicine.

49. A conjugate according to any one of claims 1 to 47, for use as a pharmaceutical product.

50. A pharmaceutical formulation comprising a conjugate according to any one of claims 1 to 47 and a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

51. The pharmaceutical formulation according to claim 50, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier is suitable for topical administration, is adapted, and / or presented in packaging, and is a topical adjuvant, diluent, or carrier.

52. A pharmaceutical formulation according to claim 50 or 51, in the form of a gel, spray, cream, ointment, or dry powder.

53. The pharmaceutical formulation according to claim 50, which is suitable for administration by injection, is adapted, and / or presented in packaging.

54. A pharmaceutical formulation according to claim 51 or 53, for use in the treatment of melanin pigmentation, wrinkles and / or arthritis.

55. A pharmaceutical formulation according to any one of claims 50 to 54, further comprising one or more pharmaceutically active ingredients.

56. It is a parts kit, and the components are: (A) A conjugate according to any one of claims 1 to 47, or a pharmaceutical preparation according to any one of claims 50 to 54, (B) A pharmaceutical formulation comprising one or more pharmaceutically active ingredients mixed with a pharmaceutically acceptable adjuvant, diluent or carrier, A parts kit in which components (A) and (B) are provided in a form suitable for administration in combination with the other.

57. The pharmaceutical formulation according to claim 55, or the parts kit according to claim 56, wherein the pharmaceutically active ingredient is an anti-inflammatory agent, an anti-inflammatory agent, an antibiotic, an antibacterial agent and / or an antigenic animal agent, an antiviral agent, an anesthetic and / or a wound healing agent.

58. The pharmaceutical formulation or parts kit according to claim 57, wherein the pharmaceutically active ingredient is an anti-inflammatory agent.

59. A conjugate according to any one of claims 1 to 47, a formulation according to any one of claims 50 to 55, 57 or 58, or a parts kit according to claim 56, for use in the treatment of inflammation, inflammatory disorders and / or disorders characterized by inflammation.

60. Use of a conjugate according to any one of claims 1 to 47, a formulation according to any one of claims 50 to 55, 57 or 58, or a parts kit according to claim 56 for the manufacture of a drug for the treatment of inflammation, inflammatory disorders and / or disorders characterized by inflammation.

61. A method for treating inflammation, inflammatory disorders, and / or disorders characterized by inflammation, comprising administering to a patient in need of such treatment a conjugate according to any one of claims 1 to 47, a formulation according to any one of claims 50 to 55, 57, or 58, or a parts kit according to claim 56.

62. The use according to claim 59, the use according to claim 60, or the method according to claim 61, wherein the inflammation, inflammatory disorder, and / or disorder characterized by inflammation is selected from the group of radiation vaginitis, vaginal fibrosis, and / or rhinosinusitis.

63. The conjugate, formulation, or parts kit for use according to claim 59, the use according to claim 60, or the method according to claim 61, wherein the injury characterized by inflammation is a wound or burn, or causes such a wound or burn.

64. The conjugate, formulation, or parts kit for use, use, or method according to claim 63, wherein the disorder causing the wound is hemorrhoids or ulcerative colitis.

65. The conjugate, formulation, or parts kit, use, or method for use according to any one of claims 48 to 64 (as necessary), wherein the conjugate or a salt thereof is administered topically in the form of a topical formulation.

66. A conjugate, formulation, or parts kit, use, or method for use according to claim 65, wherein the associated pathological condition is treated by direct topical administration to the skin.

67. The conjugate, formulation, or parts kit, use, or method for use according to claim 65, wherein the aforementioned related pathological condition is treated by direct local administration to the mucosal surface.

68. A conjugate, formulation, or parts kit, use, or method for use according to any one of claims 48 to 68 (as necessary), wherein the conjugate is administered by oral, intravenous, cutaneous or subcutaneous, nasal, intramuscular, intraperitoneal, intrapulmonary, or anorectal delivery.

69. A conjugate, formulation, or parts kit, use or method for use according to any one of claims 48 to 69 (as needed), wherein the conjugate according to any one of claims 1 to 47 functions as an excipient, a medical device, or a medical device component of a drug-medical device combination.

70. A conjugate, formulation, or parts kit, use or method for use according to any one of claims 48 to 67 (as needed), wherein the conjugate according to any one of claims 1 to 47 is crosslinked before or after administration to a subject.

71. The conjugate according to claim 70 for use as an adhesive or film-forming material.

72. The conjugate for use according to claim 71, wherein the use is as a wound surface repair product, a wound surface protection product, a medical biological adhesive product, a medical coating product, an industrial coating product, a biochemical reagent, a medical product, a sterilization product, or as a culture vessel for cell culture.

73. A conjugate for use according to claim 71 or 72, wherein a film is formed on the wound surface of the skin or mucous membrane, thereby promoting healing.

74. A conjugate for use according to any one of claims 71 to 73, wherein the use is in closing a surgical incision, bonding fractured bone, bonding mucous membranes, or coating a human implant.

75. A pharmaceutical formulation comprising the conjugate described in claim 71 and a pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier.

76. The pharmaceutical formulation according to claim 75, wherein the pharmaceutically or cosmetically acceptable adjuvant, diluent, or carrier is suitable for topical administration, adapted, and / or presented in packaging, and is a topical adjuvant, diluent, or carrier.

77. A pharmaceutical formulation according to claim 75 or 76, in the form of a gel, spray, cream, ointment, or dry powder.

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