Cyclic oligopeptides that bind interleukin-13 and methods of use thereof

Abstract

The present disclosure relates to cyclic oligopeptides that bind to interleukin-13 (IL-13), which have therapeutic effects in methods of treating or preventing IL-13 related skin disorders or conditions. The present disclosure also provides methods of treating or preventing IL-13 related skin disorders or conditions using the IL-13 binding cyclic oligopeptides. The present disclosure further provides methods of producing cyclic oligopeptides that bind to IL-13.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a PCT international application claiming priority to U.S. Provisional Application No. 63 / 351,712 filed on June 13, 2022 and U.S. Provisional Application No. 63 / 418,715 filed on October 24, 2022. The contents and disclosures of each of the foregoing applications are incorporated herein by reference in their entirety. Sequence Listing The present disclosure contains a sequence listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on June 13, 2023, is named "000388-0004-WO1.xml", and is 25,927 bytes in size. BACKGROUND OF THE DISCLOSURE

[0001] Interleukin-13 (IL-13) is one of the key cytokines involved in the type 2 (T2) immune response. A recent study suggests that it plays an important role in driving peripheral inflammation. IL-13 is secreted by T lymphocytes and mast cells and has been identified as the main cytokine involved in atopic dermatitis (AD) inflammation, as evidenced by local overexpression of IL-13. IL-13 affects skin biology by recruiting inflammatory cells, altering the skin microbiome, and reducing epidermal barrier function. Alopecia areata (AA) is an autoimmune disorder that has phenotypic similarities to AD, such as itch, elevated IgE levels, and filaggrin mutations. A genomic study of AA patients identified IL-13 genetic susceptibility. In addition, lesional scalp from AA patients showed elevated IL-13 mRNA compared to non-lesional scalp. In addition, studies have shown that IL-13 levels in the serum of AA patients are significantly elevated compared to healthy controls.

[0002] IL-13 has a significant impact on the immune response and barrier function of the skin, in part through its ability to activate STAT6, resulting in decreased expression of key structural proteins of the skin such as filaggrin, filaggrin 2, loricrin, involucrin, keratin 1, keratin 10, hornerin, desmoglein 1, and desmocollin, as well as lipid components. These changes lead to increased transepidermal water loss (TEWL), a hallmark of AD. IL-13 has also been reported to reduce AMP production by keratinocytes, thereby playing a role in skin dysbiosis, which is characterized by heavy colonization by Staphylococcus aureus, which has been shown to precede the appearance of AD lesions.

[0003] Given the role of IL-13 in the generation and maintenance of inflammatory responses and its significant impact on epidermal barrier function, pharmacological approaches targeting IL-13-induced pathways are being developed. Such approaches include the use of small molecules that interfere with the interaction between IL-13 and its receptor; small molecules that interfere with intracellular signaling pathways, such as kinase inhibitors; and biologics that block the binding of IL-13 to its receptor sites, such as monoclonal antibodies. For example, tralokinumab is a fully human IgG4 antibody that binds to IL-13 at an epitope that overlaps with the IL-13Rα receptor binding site, thereby preventing IL-13 from binding to both IL-13Rα1 and IL-13Rα2.

[0004] However, each of these methods has significant limitations in its application to the treatment of inflammatory conditions and diseases of the skin, such as AD and AA. For example, the current use of topical corticosteroids to treat atopic dermatitis may result in unwanted side effects, such as skin atrophy or thinning, striae or stretch marks, easy bruising, and telangiectasia. Continuous use of topical steroid treatments may also result in withdrawal effects or rebound effects once treatment is abandoned, with symptoms including, for example, burning, itching, and flaking of the skin. In addition, existing antibody treatments for AD, such as troloxetine, are administered by injection. Therefore, there is still a need for therapeutic agents targeting IL-13 to treat skin diseases and conditions, particularly therapeutic agents suitable for topical application. Summary of the Disclosure

[0005] The present disclosure provides cyclic oligopeptides that bind IL-13 and methods of using such cyclic oligopeptides to treat IL-13-associated skin disorders or conditions.

[0006] The first aspect of the present disclosure provides a cyclic oligopeptide that binds to IL-13. In some embodiments, the cyclic oligopeptide comprises 2 to 22 amino acid residues. In some embodiments, the cyclic oligopeptide comprises 6 to 8 amino acid residues. In some embodiments, the cyclic oligopeptide comprises an L-proline residue or a D-proline residue.

[0007] In some embodiments, the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 1-11. In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of D-ARG D-PHE D-VAL TYR GLU PRO (SEQ ID NO: 1). Optionally, the cyclic oligopeptide comprises the amino acid sequence of ARG THR D-VAL GLU D-PHE D-PRO (SEQ ID NO: 2). The cyclic oligopeptide may comprise the amino acid sequence of GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of ARG GLU D-VAL TRP D-PRO D-PRO (SEQ ID NO: 4). Optionally, the cyclic oligopeptide comprises the amino acid sequence of TRP VAL ARG GLU D-PRO D-PRO (SEQ ID NO: 5). The cyclic oligopeptide may comprise the amino acid sequence of TYR ARG GLU D-THR D-VAL D-PRO (SEQ ID NO: 6). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7). Optionally, the cyclic oligopeptide comprises the amino acid sequence of D-LEU ARG GLU PRO TRP MET PRO (SEQ ID NO: 8). The cyclic oligopeptide may comprise the amino acid sequence of D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQ ID NO: 9). In some embodiments, the cyclic oligopeptide comprises the amino acid sequence of ARG ASP TYR CYSD-PRO D-TRP D-PRO (SEQ ID NO: 10). Optionally, the cyclic oligopeptide comprises the amino acid sequence of VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11).

[0008] In some embodiments, the cyclic oligopeptide has the structure of any one of compounds 1-11 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of compound 1 as defined herein. Optionally, the cyclic oligopeptide has the structure of compound 2 as defined herein. The cyclic oligopeptide may have the structure of compound 3 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of compound 4 as defined herein. Optionally, the cyclic oligopeptide has the structure of compound 5 as defined herein. The cyclic oligopeptide may have the structure of compound 6 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of compound 7 as defined herein. Optionally, the cyclic oligopeptide has the structure of compound 8 as defined herein. The cyclic oligopeptide may have the structure of compound 9 as defined herein. In some embodiments, the cyclic oligopeptide has the structure of compound 10 as defined herein. Optionally, the cyclic oligopeptide has the structure of compound 11 as defined herein.

[0009] In some embodiments, the cyclic oligopeptide is lipidated. In some embodiments, the cyclic oligopeptide is PEGylated.

[0010] A second aspect of the present disclosure provides a pharmaceutical preparation comprising the cyclic oligopeptide disclosed herein and a pharmaceutically acceptable carrier.

[0011] A third aspect of the present disclosure provides a method for treating or preventing an IL-13-related skin disorder or condition in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of any one or a combination of the cyclic oligopeptides disclosed herein. In some embodiments, the subject is a human.

[0012] In some embodiments, the skin disorder or condition associated with IL-13 is an inflammatory, allergic or autoimmune disorder or condition. In some embodiments, the skin disorder or condition associated with IL-13 is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata, prurigo and molluscum contagiosum. Optionally, the skin disorder or condition associated with IL-13 is atopic dermatitis. The skin disorder or condition associated with IL-13 can be allergic contact dermatitis. In some embodiments, the skin disorder or condition associated with IL-13 is urticaria. Optionally, the skin disorder or condition associated with IL-13 is eczema. The skin disorder or condition associated with IL-13 can be chronic hand eczema. In some embodiments, the skin disorder or condition associated with IL-13 is a bullous disease (bullous pemphigoid). Optionally, the skin disorder or condition associated with IL-13 is alopecia areata. The IL-13 associated skin disorder or condition may be prurigo. In some embodiments, the IL-13 associated skin disorder or condition is molluscum contagiosum.

[0013] In some embodiments, the cyclic oligopeptide or a combination thereof binds to IL-13 and reduces the biological activity of IL-13 and / or IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or a combination thereof binds to IL-13. In some embodiments, the cyclic oligopeptide or a combination thereof reduces the biological activity of IL-13 and / or IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or a combination thereof reduces the biological activity of IL-13. In some embodiments, the cyclic oligopeptide or a combination thereof reduces the biological activity of IL-13. In some embodiments, the cyclic oligopeptide or a combination thereof reduces the biological activity of IL-13 receptor (IL-13R). In some embodiments, the cyclic oligopeptide or a combination thereof reduces the biological activity of IL-13 and IL-13 receptor (IL-13R).

[0014] In some embodiments, the cyclic oligopeptide or a combination thereof is administered topically. Optionally, the cyclic oligopeptide or a combination thereof is administered transdermally. In some embodiments, the cyclic oligopeptide or a combination thereof is administered subcutaneously. Optionally, the cyclic oligopeptide or a combination thereof is administered intravenously. In some embodiments, the cyclic oligopeptide or a combination thereof is administered orally.

[0015] The fourth aspect of the present disclosure provides a method for producing a cyclic oligopeptide that binds to IL-13. In some embodiments, the method comprises the following steps: (1) contacting FMOC (9-fluorenylmethoxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue under conditions suitable for forming a peptide bond between the first amino acid residue and the resin-bound D-Pro or Pro to form a resin-bound oligopeptide; (2) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (3) contacting the resin-bound oligopeptide with another amino acid residue under conditions suitable for forming a peptide bond between the other amino acid residue and the resin-bound oligopeptide; (4) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) cyclizing the oligopeptide.

[0016] In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). Optionally, the conditions suitable for forming a peptide bond in steps (1) and (3) also include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA).

[0017] In some embodiments, steps (3) and (4) are repeated 1 to 20 times before removing the resin from the oligopeptide.

[0018] In some embodiments, the cyclization step includes forming a covalent bond between the carboxyl group of the D-Pro or Pro residue and one or more amino groups of the linear oligopeptide. In some embodiments, the cyclization step includes adding DMF, PyBOP (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole) and DIEA to the linear oligopeptide and incubating the mixture at room temperature.

[0019] In some embodiments, the cyclic oligopeptide that binds to IL-13 is a cyclic oligopeptide disclosed herein.

[0020] Specific embodiments of the present disclosure are set forth in the following numbered paragraphs: 1. A cyclic oligopeptide that binds to IL-13. 2. The cyclic oligopeptide of embodiment 1, wherein the cyclic oligopeptide comprises 2 to 22 amino acid residues. 3. The cyclic oligopeptide of embodiment 2, wherein the cyclic oligopeptide comprises 6 to 8 amino acid residues. 4. The cyclic oligopeptide of any one of embodiments 1-3, wherein the cyclic oligopeptide comprises an L-proline residue or a D-proline residue. 5. The cyclic oligopeptide of any one of embodiments 1-4, wherein the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. 6. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence D-ARG D-PHED-VAL TYR GLU PRO (SEQ ID NO: 1). 7. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence ARG THR D-VALGLU D-PHE D-PRO (SEQ ID NO: 2). 8. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3). 9. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence ARG GLU D-VALTRP D-PRO D-PRO (SEQ ID NO: 4). 10. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence TRP VAL ARGGLU D-PRO D-PRO (SEQ ID NO: 5). 11. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence TYR ARG GLUD-THR D-VAL D-PRO (SEQ ID NO: 6). 12. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7). 13. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence D-LEU ARGGLU PRO TRP MET PRO (SEQ ID NO: 8). 14. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQ ID NO: 9). 15. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence ARG ASP TYRCYSD-PRO D-TRP D-PRO (SEQ ID NO: 10). 16. The cyclic oligopeptide of embodiment 5, wherein the cyclic oligopeptide comprises the amino acid sequence VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11). 17. The cyclic oligopeptide of embodiment 1, wherein the cyclic oligopeptide has the structure of any one of compounds 1-11 as defined herein. 18. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of Compound 1 as defined herein. 19. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 2 as defined herein. 20. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 3 as defined herein. 21. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 4 as defined herein. 22. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 5 as defined herein. 23. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 6 as defined herein. 24. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 7 as defined herein. 25. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 8 as defined herein. 26. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 9 as defined herein. 27. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 10 as defined herein. 28. The cyclic oligopeptide of embodiment 17, wherein the cyclic oligopeptide has the structure of compound 11 as defined herein. 29. The cyclic oligopeptide of any one of embodiments 1-28, wherein the cyclic oligopeptide is lipidated. 30. The cyclic oligopeptide of any one of embodiments 1-28, wherein the cyclic oligopeptide is PEGylated. 31. A pharmaceutical preparation comprising the cyclic oligopeptide according to any one of embodiments 1-30 and a pharmaceutically acceptable carrier. 32. A method of treating or preventing an IL-13-related skin disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one or a combination of the cyclic oligopeptides of embodiments 1-30. 33. The method of embodiment 32, wherein the subject is human. 34. The method of embodiment 32 or 33, wherein the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. 35. The method according to embodiments 32-34, wherein the cyclic oligopeptide has the structure of any one of compounds 1-11. 36. The method of any one of embodiments 32-35, wherein the IL-13-related skin disorder or condition is an inflammatory, allergic, or autoimmune disorder or condition. 37. The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata, prurigo, and molluscum contagiosum. 38. The method of any one of embodiments 32-35, wherein the IL-13-related skin disorder or condition is atopic dermatitis. 39. The method of any one of embodiments 32-35, wherein the IL-13-related skin disorder or condition is allergic contact dermatitis. 40. The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is urticaria. 41. The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is eczema. 42. The method of any one of embodiments 32-35, wherein the IL-13-related skin disorder or condition is chronic hand eczema. 43. The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is a bullous disease (bullous pemphigoid). 44. The method of any one of embodiments 32-35, wherein the IL-13-related skin disorder or condition is alopecia areata. 45. The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is prurigo. 46. ​​The method of any one of embodiments 32-35, wherein the IL-13-associated skin disorder or condition is molluscum contagiosum. 47. The method of any one of embodiments 32-46, wherein the cyclic oligopeptide or combination thereof binds to IL-13 and reduces the biological activity of IL-13 and / or IL-13 receptor (IL-13R). 48. The method of any one of embodiments 32-47, wherein the cyclic oligopeptide or combination thereof is administered topically. 49. The method of any one of embodiments 32-47, wherein the cyclic oligopeptide or combination thereof is administered transdermally. 50. The method of any one of embodiments 32-47, wherein the cyclic oligopeptide or combination thereof is administered subcutaneously. 51. The method of any one of embodiments 32-47, wherein the cyclic oligopeptide or combination thereof is administered intravenously. 52. A method for producing a cyclic oligopeptide that binds to IL-13, comprising the following steps: (1) contacting FMOC (9-fluorenylmethoxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue under conditions suitable for forming a peptide bond between the first amino acid residue and the resin-bound D-Pro or Pro to form a resin-bound oligopeptide; (2) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (3) contacting the resin-bound oligopeptide with another amino acid residue under conditions suitable for forming a peptide bond between the other amino acid residue and the resin-bound oligopeptide; (4) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) Cyclizing the oligopeptide. 53. The method of embodiment 52, wherein the conditions suitable for forming peptide bonds in steps (1) and (3) include adding O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). 54. The method according to embodiment 53, wherein the conditions suitable for forming peptide bonds in steps (1) and (3) further include adding N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA). 55. The method of any one of embodiments 52-54, wherein steps (3) and (4) are repeated 1 to 20 times before removing the resin from the oligopeptide. 56. The method of any one of embodiments 52-55, wherein the cyclization step comprises forming a covalent bond between the carboxyl group of the D-Pro or Pro residue and one or more amino groups of the linear oligopeptide. 57. The method of embodiment 52, wherein the cyclization step comprises adding DMF, PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole) and DIEA to the linear oligopeptide and incubating the mixture at room temperature. 58. The method of any one of embodiments 52-57, wherein the cyclic oligopeptide that binds to IL-13 is a cyclic oligopeptide according to any one of embodiments 1-30. 59. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 25% after 24 hours. 60. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 30% after 24 hours. 61. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 35% after 24 hours. 62. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 40% after 24 hours. 63. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 45% after 24 hours. 64. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 50% after 24 hours. 65. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 55% after 24 hours. 66. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 60% after 24 hours. 67. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 10% after 1 hour. 68. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 15% after 1 hour. 69. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 20% after 1 hour. 70. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a skin penetration rate of at least 25% after 1 hour. 71. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 1.0 x 10 -5 Average skin permeability coefficient in cm / hr. 72. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 2.0 x 10 -5 Average skin permeability coefficient in cm / hr. 73. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 5.0 x 10 -5 Average skin permeability coefficient in cm / hr. 74. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 1.0 x 10 -4 Average skin permeability coefficient in cm / hr. 75. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 1.0 x 10 -2 Average skin permeability coefficient in cm / hr. 76. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 2.0 x 10 -2 Average skin permeability coefficient in cm / hr. 77. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 3.0 x 10 -2 Average skin permeability coefficient in cm / hr. 78. The cyclic oligopeptide of any one of embodiments 1-30, wherein the cyclic oligopeptide has a molecular weight of at least 4.0 x 10 -2Average skin permeability coefficient in cm / hr. 79. The cyclic oligopeptide of any one of embodiments 1-30 and 59-78, wherein the cyclic oligopeptide has a rapid onset of action after topical application. 80. The cyclic oligopeptide of any one of embodiments 1-30 and 59-78, wherein the cyclic oligopeptide is suitable for long-term delivery after topical application. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figures 1A-1K The chemical structures of exemplary cyclic oligopeptides of the present disclosure, Compounds 1-11, are depicted respectively.

[0022] Figure 2A The mass spectrum (MS) of Compound 1 is provided. Figure 2B A high performance liquid chromatography (HPLC) chromatogram of Compound 1 is provided. Figure 2C Provided is a surface plasmon resonance (SPR) assay curve showing the binding affinity of Compound 1 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Figure 2D Shown is the skin permeation rate of Compound 1 over a period of up to 24 hours. Figure 2E The average permeability coefficient (Kp) of Compound 1 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0023] Figure 3A The MS spectrum of compound 2 is provided. Figure 3B The HPLC chromatogram of Compound 2 is provided. Figure 3C Provided is an SPR assay curve showing the binding affinity of Compound 2 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Figure 3D Skin permeation of Compound 2 up to 24 hours is shown. Figure 3E The average permeability coefficient (Kp) of Compound 2 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0024] Figure 4A The MS spectrum of compound 3 is provided. Figure 4B The HPLC chromatogram of compound 3 is provided. Figure 4C Provided is an SPR assay curve showing the binding affinity of Compound 3 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Figure 4D The skin permeation rate of Compound 3 up to 24 hours is shown. Figure 4E The average permeability coefficient (Kp) of Compound 3 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0025] Figure 5AThe MS spectrum of compound 4 is provided. Figure 5B The HPLC chromatogram of compound 4 is provided. Figure 5C Provided is an SPR assay curve showing the binding affinity of Compound 4 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Figure 5D Shown is the skin permeation rate of Compound 4 up to 24 hours. Figure 5E The average permeability coefficient (Kp) of Compound 4 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0026] Fig. 6A The MS spectrum of compound 5 is provided. Figure 6B The HPLC chromatogram of Compound 5 is provided. Figure 6C Provided is an SPR assay curve showing the binding affinity of Compound 5 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.6D The skin permeation rate of Compound 5 up to 24 hours is shown. Fig. 6E The average permeability coefficient (Kp) of Compound 5 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0027] Fig. 7A The MS spectrum of compound 6 is provided. Figure 7B The HPLC chromatogram of compound 6 is provided. Figure 7C Provided is an SPR assay curve showing the binding affinity of Compound 6 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.7D The skin permeation rate of Compound 6 up to 24 hours is shown. Fig. 7E The average permeability coefficient (Kp) of Compound 6 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0028] Fig. 8A The MS spectrum of compound 7 is provided. Figure 8B The HPLC chromatogram of compound 7 is provided. Figure 8C Provided is an SPR assay curve showing the binding affinity of compound 7 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.8D The skin permeation rate of Compound 7 up to 24 hours is shown. Fig. 8E The average permeability coefficient (Kp) of Compound 7 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0029] Fig.9A The MS spectrum of compound 8 is provided. Fig. 9B The HPLC chromatogram of Compound 8 is provided. Fig. 9CProvided is an SPR assay curve showing the binding affinity of Compound 8 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.9D The skin permeation rate of Compound 8 up to 24 hours is shown. Fig.9E The average permeability coefficient (Kp) of Compound 8 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0030] Fig. 10A The MS spectrum of compound 9 is provided. Fig. 10B The HPLC chromatogram of compound 9 is provided. Fig. 10C Provided is an SPR assay curve showing the binding affinity of compound 9 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig. 10D The skin permeation rate of Compound 9 up to 24 hours is shown. Fig.10E The average permeability coefficient (Kp) of compound 9 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0031] Fig.11A The MS spectrum of compound 10 is provided. Fig. 11B The HPLC chromatogram of compound 10 is provided. Fig. 11C Provided is an SPR assay curve showing the binding affinity of Compound 10 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.11D Skin permeation of Compound 10 up to 24 hours is shown. Fig.11E The average permeability coefficient (Kp) of Compound 10 over 1, 2, 4, 8, 12 and 24 hours is shown.

[0032] Fig. 12A The MS spectrum of compound 11 is provided. Fig. 12B The HPLC chromatogram of compound 11 is provided. Fig. 12C Provided is an SPR assay curve showing the binding affinity of Compound 11 to IL-13, with the x-axis representing the reaction time and the y-axis representing the response height (response units). Fig.12D The skin permeation rate of Compound 11 is shown up to 24 hours. Fig.12E The average permeability coefficient (Kp) of Compound 11 over 1, 2, 4, 8, 12 and 24 hours is shown. DETAILED DESCRIPTION OF THE DISCLOSURE

[0033] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those of ordinary skill in the art. In the event of a conflict, the present specification, including definitions, will control.

[0034] It should be understood that any embodiment described herein, including embodiments described under different aspects of the disclosure and different parts of this specification (including embodiments described only in the examples), can be combined with one or more other embodiments of the disclosure unless expressly denied or inappropriate. The combination of embodiments is not limited to those specific combinations claimed through multiple dependent claims.

[0035] All publications, patents, and published patent applications mentioned in this application are expressly incorporated by reference in their entirety. In the event of a conflict, the present specification, including its specific definitions, will control.

[0036] Where aspects or embodiments are described in terms of Markush groups or other alternative groupings, this application encompasses not only the entire group listed as a whole, but also each member of the individual group and all possible subgroups of the main group, as well as the main group lacking one or more of the group members.

[0037] Throughout this specification, the word "comprise" or some variations such as "comprises" or "comprising" will be understood to mean the inclusion of a specified integer (or component) or group of integers (or components) but not the exclusion of any other integer (or component) or group of integers (or components).

[0038] Throughout this specification, where a composition is described as having, including or comprising (or variations thereof) a particular component, it may be considered that such a composition may also consist essentially of or consist of the enumerated components. Similarly, where a method or process is described as having, including or comprising a particular process step, these processes may also consist essentially of or consist of the process steps. In addition, it should be understood that the order of steps or the order in which certain actions are performed is unimportant, as long as the compositions and methods described herein remain operable. Moreover, two or more steps or actions may be performed simultaneously.

[0039] As used herein, the term "comprising" means "including but not limited to". "Comprising" and "including but not limited to" are used interchangeably. Therefore, these terms will be understood to mean the inclusion of the specified integers (or components) or groups of integers (or components), but not the exclusion of any other integers (or components) or groups of integers (or components).

[0040] The term "for example" or any examples following "such as" are not meant to be exhaustive or limiting.

[0041] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0042] The articles “a,” “an,” and “the” are used herein to refer to one or to more than one (ie, to at least one) of the grammatical object of the article.

[0043] Although the disclosed numerical ranges and parameters are approximate, the numerical values ​​listed in the specific examples are reported as accurately as possible. However, any numerical value essentially contains certain errors, which inevitably come from the standard deviations present in their respective test measurements. Therefore, as used herein, the term "about" allows a variation of ±10%. As used herein, the term "about" refers to a value or parameter that includes (and describes) the embodiment for the value or parameter itself. Moreover, all ranges disclosed herein should be understood to cover any and all subranges contained therein. For example, the specified range "1 to 10" should be deemed to include any and all subranges and single numbers between the minimum value 1 and the maximum value 10 (and including 1 and 10); that is, all subranges starting with a minimum value of 1 or greater, such as 1 to 6.1, and all subranges ending with a maximum value of 10 or less, such as 5.5 to 10, or a single number in a specified range or subrange, such as 2, 5, 8 or 10.

[0044] As used herein, amino acids having the L-configuration are represented using the standard three-letter code, e.g., Ala for alanine, Gly for glycine, Val for valine, Leu for leucine, Ile for isoleucine, Pro for proline, Ser for serine, Thr for threonine, Asn for asparagine, Gln for glutamine, Cys for cysteine, Met for methionine, Phe for phenylalanine, Tyr for tyrosine, Trp for tryptophan, Asp for aspartic acid, Glu for glutamic acid, His for histidine, Lys for lysine, and Arg for arginine. As used herein, amino acids having the D-configuration are indicated by adding "D-" before the standard three-letter code, e.g., D-Ala for D-alanine, D-Gly for D-glycine, D-Val for D-valine, D-Leu for D-leucine, D-Ile for D-isoleucine, D-Pro for D-proline, D-Ser for D-serine, D-Thr for D-threonine, D-Asn for D-asparagine, D-Gln for D-glutamine, D-Cys for D-cysteine, D-Met for D-methionine, D-Phe for D-phenylalanine, D-Tyr for D-tyrosine, D-Trp for D-tryptophan, D-Asp for D-aspartic acid, D-Glu for D-glutamate, D-His for D-histidine, D-Lys for D-lysine, and D-Arg for arginine. definition

[0045] In order to make the present disclosure more easily understood, certain terms are first defined. These definitions should be interpreted in conjunction with the remainder of the present disclosure as understood by those of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art.

[0046] As used herein, the terms "administer" and "administer" include any suitable route for providing a subject with a cyclic oligopeptide or pharmaceutical composition of the present disclosure to treat a skin disorder or condition, such as an IL-13-related skin disorder or condition. For example, the cyclic oligopeptide or pharmaceutical composition can be administered topically, transdermally, subcutaneously, intravenously or orally. The dosage forms that can be used for the methods of the present disclosure may include films, dispersants, suspensions, solutions, ointments, lotions, creams, powders, drops (e.g., eye drops or ear drops), sprays, patches, etc. Administration can also be performed, for example, once, multiple times, and / or over one or more longer time periods. In some embodiments, administration includes direct administration (including self-administration) and indirect administration (including the act of prescribing a prescription). For example, as used herein, a physician instructs a patient to self-administer a drug, or instructs a patient to have another person administer the drug and / or provide a drug prescription to the patient, i.e., administering the drug to the patient. When a method is part of a treatment regimen involving more than one pharmaceutical composition or treatment modality, the disclosure contemplates that the pharmaceutical compositions may be administered at the same or different times and by the same or different routes of administration.

[0047] As used herein, the terms "bind" and "binding" refer to the molecular binding of two or more molecules, such as IL-13 and a cyclic oligopeptide, which is an attractive interaction between two or more molecules resulting in a stable association of the molecules in close proximity to each other. In the present disclosure, the strength of molecular binding or the affinity between the bound molecules can be quantified by, for example, surface plasmon resonance (SPR) assays.

[0048] As used herein, the term "cyclic oligopeptide" refers to an oligopeptide chain containing a cyclic bond sequence.Cyclic oligopeptides are usually first generated in the form of linear oligopeptides, and then cyclized, for example, by chemical or enzymatic means.Cyclic bond sequences can be formed in the following ways, for example, the connection between the amino terminus and the carboxyl terminus of a linear oligopeptide, the connection between the amino terminus of a linear oligopeptide and the side chain of one of the amino acid residues in the oligopeptide, the connection between the carboxyl terminus of a linear oligopeptide and the side chain of one of the amino acid residues in the oligopeptide and / or the connection between the side chains of two different amino acid residues in the oligopeptide.The length range of the cyclic oligopeptide of the present disclosure is two amino acid residues to twenty amino acid residues.In some embodiments, the length range of the cyclic oligopeptide of the present disclosure is four amino acid residues to ten amino acid residues.In some embodiments, the length range of the cyclic oligopeptide of the present disclosure is six amino acid residues to ten amino acid residues.

[0049] The term "dosage unit form" as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.

[0050] As used herein, the terms "interleukin-13" and "IL-13" refer to a protein encoded by the IL13 gene in humans or a protein encoded by a homologous gene of the human IL13 gene in a non-human species.

[0051] As used herein, the term "IL-13-associated skin disorder or condition" refers to a skin disease, skin disorder, or skin condition associated with an IL-13-related immune regulatory dysfunction. An IL-13-associated skin disorder or condition may be an inflammatory, allergic, or autoimmune disorder or condition. Non-limiting examples of IL-13-associated skin disorders or conditions include atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata, prurigo, and molluscum contagiosum.

[0052] The term "oligopeptide" refers to a polymer of amino acid residues. The term also applies to amino acid polymers in which one or more amino acids are chemical analogs or modified derivatives of corresponding naturally occurring amino acids.

[0053] As used herein, "pharmaceutically acceptable carrier" and "pharmaceutically acceptable excipient" are used interchangeably and refer to any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. Pharmaceutically acceptable carriers are well known in the art. See, for example, Remington's Pharmaceutical Sciences and the United States Pharmacopoeia: National Formulary, Mack Publishing Company, Easton, PA (1984), which are incorporated herein by reference. Some examples of pharmaceutically acceptable carriers are water, saline, phosphate buffered saline, glucose, glycerol, ethanol, etc., and combinations thereof. In many cases, it is preferred to include isotonic agents, such as sugars, polyols such as mannitol, sorbitol, or sodium chloride in the composition. Other examples of pharmaceutically acceptable substances are wetting agents or small amounts of auxiliary substances, such as wetting agents or emulsifiers, preservatives, or buffers, which extend the shelf life of the antibody or enhance the effectiveness of the antibody. Pharmaceutical compositions can be prepared by mixing an antibody disclosed herein with an acceptable carrier, excipient or stabilizer in the form of, for example, a lyophilized powder, a slurry, an aqueous solution or a suspension (see, e.g., Brunton et al. (eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th ed., (2018) McGraw-Hill, New York, NY; Adejare, A. (ed.), Remington: The Science and Practice of Pharmacy, 23rd ed., (2020) Academic Press, New York, NY; Nema et al. (eds.), Pharmaceutical Dosage Forms: Parenteral Medications, 3rd ed., (2010) Informa Healthcare, NY, Augsburger et al. (eds.), Pharmaceutical Dosage Forms: Tablets, 3rd ed. (2008) CRC Press, NY; Lieberman et al. (eds.), Pharmaceutical Dosage Forms: Disperse Systems, 2nd ed., (2010) Informa Helathcare, NY; Weiner and Kotkoskie, Excipient Toxicity and Safety, (2007) Informa Healthcare, New York, NY; each of which is incorporated herein by reference).

[0054] As used herein, the term "pharmaceutically acceptable salt" refers to those salts suitable for pharmaceutical use, for example, salts that are used in humans and lower animals without causing excessive stimulation, allergic reactions, etc. Pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 66: 1-19 (1977), which is incorporated herein by reference. Salts can be prepared on-site during the final separation and purification of the cyclic oligopeptides disclosed herein, or separately prepared by reacting the free base or free acid functional group with a suitable reagent, as generally described below. For example, the free base functional group can be reacted with a suitable acid. Suitable pharmaceutically acceptable salts can include metal salts, such as alkali metal salts, such as sodium, potassium and lithium salts; and alkaline earth metal salts, such as calcium salts or magnesium salts. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentylpropionate, digluconate, dodecylsulfate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, decanoate, valerate, and the like.

[0055] As used herein, the term "residue" refers to a position in an oligopeptide and its associated amino acid entity.

[0056] The terms "subject", "patient" and "individual" are used interchangeably and refer to mammals, including but not limited to human patients and non-human primates, as well as experimental animals such as rabbits, dogs, cats, rats, mice and other animals. Therefore, the terms "subject" or "patient" as used herein mean any mammalian patient or subject to which the cyclic oligopeptides or related compositions of the present disclosure can be administered. In some embodiments, the subject is a human patient. The subjects of the present invention include subjects suffering from IL-13 related disorders or conditions.

[0057] The term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount of the cyclic oligopeptide of the present disclosure that will alleviate one or more symptoms of an IL-13-related skin disease or condition in a patient to some extent, for example, to achieve a beneficial and / or desired change in the overall health of a patient suffering from an IL-13-related skin disorder or condition, as described herein. The full therapeutic effect does not necessarily occur by administering a single dose, and may only occur after a series of doses are administered. Therefore, a therapeutically effective amount can be administered in one or more administrations. The precise effective amount required for a subject will depend on, for example, the size, health status and age of the subject, the nature and extent of the disease, the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. The effective amount in a given situation can be readily determined by a person skilled in the art through routine experimentation. The methods of treatment or treatment described herein should not be construed as or otherwise limited to "curing" a disease.

[0058] As used herein, the term "treatment" and its cognate words refer to reversing, alleviating or stopping the symptoms, clinical signs and potential lesions of IL-13 related skin diseases or conditions in a manner that improves or stabilizes the condition of the subject. As used herein and as is well understood in the art, "treatment" is a method for obtaining beneficial or desired results including clinical effects. Beneficial or desired results may include, but are not limited to, relieving or improving one or more symptoms or conditions, allergic reactions, stabilizing (i.e., not worsening) the disease state, preventing disease spread, delaying or slowing the progression of the disease, improving or alleviating the disease state, reducing disease recurrence, and alleviating (partial or complete) the disease state. In some embodiments, the term "treating atopic dermatitis" refers to a method for obtaining one or more beneficial or desired results, including but not limited to alleviating or improving dry skin, itching, red to brownish-gray patches, small raised lumps, thickened, cracked scaly skin, and skin damage, allergies, and swelling caused by scratching. In some embodiments, the term "treating atopic dermatitis" refers to a method of reducing the extent of one or more symptoms of atopic dermatitis, wherein the one or more symptoms include but are not limited to dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked scaly skin, and skin damage caused by scratching, allergies, and swelling. In some embodiments, the term "treating atopic dermatitis" refers to a method of stabilizing (i.e., preventing worsening) the state of one or more symptoms of atopic dermatitis, wherein the one or more symptoms include but are not limited to dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked scaly skin, and skin damage caused by scratching, allergies, and swelling. In some embodiments, the term "treating atopic dermatitis" refers to a method of preventing the spread of one or more symptoms of atopic dermatitis, wherein the one or more symptoms include but are not limited to dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked scaly skin, and skin damage caused by scratching, allergies, and swelling. In some embodiments, the term "treating atopic dermatitis" refers to a method of delaying or slowing the progression of one or more symptoms of atopic dermatitis, wherein the one or more symptoms include but are not limited to dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked scaly skin, and skin damage, allergies, and swelling caused by scratching. In some embodiments, the term "treating atopic dermatitis" refers to a method of partially or completely reducing the recurrence or reduction of one or more symptoms of atopic dermatitis, wherein the one or more symptoms include but are not limited to dry skin, itching, red to brownish-gray patches, small raised bumps, thickened, cracked scaly skin, and skin damage, allergies, and swelling caused by scratching.

[0059] As used herein, the term "skin permeability" of a cyclic oligopeptide is measured using artificial skin (Start M, Merck), and refers to the percentage of the cyclic oligopeptide penetrating the artificial skin after a certain period of time. For example, if 60% of the total amount of the cyclic oligopeptide of the present disclosure penetrates the artificial skin after 24 hours, then the skin permeability of the cyclic oligopeptide after 24 hours is 60%.

[0060] As used herein, the term "skin permeability coefficient (Kp)" refers to the rate at which a cyclic oligopeptide penetrates the skin, as measured using artificial skin (Start M, Merck). In some embodiments, the permeability coefficient (Kp) (cm / hr) is calculated using the following formula: Where Q (mg) refers to the total amount of cyclic oligopeptide that passes through the artificial skin within a certain period of time; A (cm 2 ) refers to the internal cross-sectional area of ​​the artificial skin in the diffusion cell; T (hr) refers to the total time for the cyclic oligopeptide to penetrate; and ΔC (mg / mL) refers to the concentration difference of the cyclic oligopeptide between the two sides of the artificial skin. In some embodiments, the diffusion cell is a FranzCell.

[0061] As used herein, the term "fast onset" or "rapid action" refers to an agent that is able to penetrate the skin at a relatively fast rate after application to the skin. In some embodiments, a fast-acting agent or a rapid-acting agent has a skin penetration rate of at least 10% after 1 hour. In some embodiments, a fast-acting agent or a rapid-acting agent has a skin penetration rate of at least 1.0 x 10 -2 In some embodiments, the fast acting agent or rapid acting agent has an average permeability of at least 2.0 x 10 cm / hr after 1 hour. -2 Average permeability in cm / hr.

[0062] As used herein, the term "delayed delivery" refers to the ability of an agent to penetrate the skin for a relatively long period of time after application to the skin. In some embodiments, the long-acting delivery agent has a skin permeation rate of at least 25% after 24 hours. In some embodiments, the long-acting delivery agent has a skin permeation rate of at least 1.0 x 10 -5 In some embodiments, the long-acting delivery agent has an average permeability of at least 2.0 x 10 -5 Average permeability in cm / hr. Cyclic oligopeptides of the present disclosure

[0063] In a first aspect, the present disclosure provides cyclic oligopeptides that bind to IL-13. Without being bound by theory, the cyclic oligopeptides disclosed herein are advantageous for use as active ingredients in disease treatment and other situations because they have both the high specificity of biological molecules and the bioavailability of small molecules. In addition, these cyclic oligopeptides can be applied topically with excellent skin permeability, concentrated on areas of the skin affected by IL-13-related disorders or conditions. Linear oligopeptides have been shown to be effective when used to target extracellular receptors, but their instability due to protease degradation has limited their application. The cyclic oligopeptides disclosed herein are rigid in conformation, which is advantageous compared to their linear counterparts, in part because they have improved target affinity and specificity, and improved stability due to their resistance to proteolysis.

[0064] In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 2 to 22 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 4 to 10 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 6 to 8 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 6 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 7 amino acid residues. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises 8 amino acid residues.

[0065] In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises an L-proline residue or a D-proline residue. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 1. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 3. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 4. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 5. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 6. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 10. In some embodiments, the cyclic oligopeptide that binds to IL-13 comprises the amino acid sequence of SEQ ID NO: 11.

[0066] In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of any one of compounds 1-11 as defined herein (see, e.g., Table 1). In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 1 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 2 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 3 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 4 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 5 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 6 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 7 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 8 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 9 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 10 as defined herein. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 11 as defined herein.

[0067] In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of any one of compounds 1-11 as defined herein (see, e.g., Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 1 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 2 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 3 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 4 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 5 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 6 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 7 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 8 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 9 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 10 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide that binds to IL-13 has the structure of compound 11 as defined herein or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the cyclic oligopeptide that binds to IL-13 is lipidated. In some embodiments, the cyclic oligopeptide that binds to IL-13 is PEGylated.

[0069] In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 25% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 30% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 35% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 40% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 45% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 50% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 55% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of no more than 65% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 25% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 30% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 35% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 40% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 45% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 50% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 55% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin penetration rate of about 60% after 24 hours.

[0070] In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 55% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 50% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 45% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 40% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 35% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 25% to 30% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 30% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 35% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 40% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 45% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 50% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 55% to 60% after 24 hours. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 30% to 50% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 35% to 45% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 30% to 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 35% to 40% after 24 hours. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a skin permeability of 40% to 45% after 24 hours.

[0071] In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 10% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 15% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 20% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of at least 25% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of no more than 30% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 10% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 15% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 20% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of about 25% after 1 hour.

[0072] In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 10% to 25% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 10% to 20% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 10% to 15% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 15% to 25% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 20% to 25% after 1 hour. In some embodiments, the cyclic oligopeptide bound to IL-13 has a skin permeability of 15% to 20% after 1 hour.

[0073] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a cytotoxicity of at least 1.0 x 10 -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 2.0 x 10 cm / hr after 24 hours. -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 5.0 x 10 cm / hr after 24 hours. -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 1.0 x 10 cm / hr after 24 hours. -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 2.0 x 10 cm / hr after 24 hours. -4In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 3.0 x 10 cm / hr after 24 hours. -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 4.0 x 10 cm / hr after 24 hours. -4 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has a mean skin permeability of no more than 5.0 x 10 cm / hr after 24 hours. -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 1.0 x 10 cm / hr after 24 hours. -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 2.0 x 10 cm / hr after 24 hours. -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 5.0 x 10 cm / hr after 24 hours. -5 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 1.0 x 10 cm / hr after 24 hours. -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 2.0 x 10 cm / hr after 24 hours. -4 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 3.0 x 10 -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 4.0 x 10 cm / hr after 24 hours. -4 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 4.5 x 10 -4 Average skin permeability coefficient in cm / hr.

[0074] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a 1.0x10 -5 cm / hr to 5.0 x 10 -4 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 5.0 x 10 -5 cm / hr to 5.0 x 10 -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 cm / hr after 24 hours. -4cm / hr to 5.0 x 10 -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 cm / hr after 24 hours. -5 cm / hr to 1.0x10 -4 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 cm / hr after 24 hours. -5 cm / hr to 5.0 x 10 -5 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 5.0 x 10 -5 cm / hr to 1.0x 10 -4 Average skin permeability coefficient in cm / hr.

[0075] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a molecular weight of at least 1.0 x 10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 2.0 x 10 cm / hr after 1 hour. -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 3.0 x 10 cm / hr after 1 hour. -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 4.0 x 10 cm / hr after 1 hour. -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of at least 5.0 x 10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability coefficient of no more than 6.0 x 10 cm / hr after 1 hour. -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 1.0 x 10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 2.0 x 10 cm / hr after 1 hour. -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 3.0 x 10 cm / hr after 1 hour. - 2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 4.0 x 10 cm / hr after 1 hour. -2In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 5.0 x 10 cm / hr after 1 hour. -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of about 5.5 x 10 cm / hr after 1 hour. -2 Average skin permeability coefficient in cm / hr.

[0076] In some embodiments, the cyclic oligopeptide that binds to IL-13 has a 1.0x10 -2 cm / hr to 5.0x10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 2.0 x 10 cm / hr after 1 hour. -2 cm / hr to 5.0 x 10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 3.0 x 10 -2 cm / hr to 5.0 x 10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 4.0 x 10 -2 cm / hr to 5.0 x 10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 -2 cm / hr to 4.0 x 10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 cm / hr after 1 hour. -2 cm / hr to 3.0x 10 -2 In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 1.0 x 10 cm / hr after 1 hour. -2 cm / hr to 2.0 x 10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 2.0 x 10 cm / hr after 1 hour. -2 cm / hr to 4.0 x 10 -2 cm / hr. In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 3.0 x 10 -2 cm / hr to 4.0 x 10 -2In some embodiments, the cyclic oligopeptide that binds to IL-13 has an average skin permeability of 2.0 x 10 cm / hr after 1 hour. -2 cm / hr to 3.0x 10 -2 Average skin permeability coefficient in cm / hr. Pharmaceutical compositions and administration

[0077] In a second aspect, the present disclosure provides a pharmaceutical formulation comprising the cyclic oligopeptide disclosed herein and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the cyclic oligopeptide described herein.

[0078] The pharmaceutical composition can be in various forms, such as liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersants or suspensions, powders, capsules, pills, tablets and liposomes. The preferred form depends on the intended mode of administration and therapeutic application. In some embodiments, the pharmaceutical composition is in the form of an injectable or infusible solution. Optionally, the mode of administration is topical administration. The pharmaceutical composition can be administered by intravenous infusion or injection. In some embodiments, the pharmaceutical composition is formulated for subcutaneous injection. Optionally, the pharmaceutical composition is formulated for transdermal administration. In some embodiments, the cyclic oligopeptide is formulated into a tape or patch. The preparation for injection can be presented in a unit dose form, for example, in an ampoule, a prefilled syringe, or in a multidose container, with or without the addition of a preservative. The pharmaceutical composition can be in the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain a preparatant, such as a suspending agent, a stabilizer and / or a dispersant. Alternatively, the active ingredient may be prepared in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0079] Under the conditions of preparation and storage, the therapeutic composition must generally be sterile and stable. The composition can be formulated into a solution, microemulsion, dispersion, liposome or other ordered structures suitable for high drug concentration. The preparation method of the sterile injectable solution can be to add the required amount of cyclic oligopeptide and one or a combination of the ingredients listed above to an appropriate solvent as needed, followed by filtration sterilization. When preparing the dispersion, the cyclic oligopeptide can be added to a sterile vehicle, which contains a basic dispersion medium and other required ingredients from the ingredients listed above. For sterile powders for preparing sterile injectable solutions or local solutions, preferred preparation methods include vacuum drying and freeze drying, wherein the powder of the cyclic oligopeptide and any additional required ingredients is obtained from a previously sterile filtered solution thereof. For example, the appropriate fluidity of the solution can be maintained by using a coating such as lecithin, by maintaining the required particle size in the case of a dispersion and / or by using a surfactant. The absorption time extension of the injectable composition can be achieved by including an agent that delays absorption in the composition, such as monostearate and gelatin.

[0080] The pharmaceutical composition can be administered by a variety of methods known in the art. In some embodiments, the route of administration / mode is topical, transdermal, subcutaneous injection, intravenous infusion or oral administration. In some embodiments, the route of administration / mode is topical, transdermal or subcutaneous injection. In some embodiments, the route of administration / mode is topical administration. In some embodiments, the route of administration / mode is transdermal administration. In some embodiments, the route of administration / mode is subcutaneous injection. In some embodiments, the route of administration / mode is intravenous infusion. In some embodiments, the route of administration / mode is oral administration. As will be appreciated by those skilled in the art, the route and / or mode of administration will vary according to the desired result.

[0081] The dosage regimen can be adjusted to provide the best expected response (e.g., treatment or prevention response). For example, a single bolus can be administered, multiple divided doses can be administered over a period of time, or the dosage can be proportionally reduced or increased as indicated by the urgency of the treatment situation. In order to facilitate the uniformity of administration and dosage, it may be advantageous to formulate the pharmaceutical composition into a dosage unit form. The specifications of the dosage unit form may depend on and directly depend on the following aspects, (a) the unique characteristics of the cyclic oligopeptide and the specific treatment or prevention effect to be achieved, and (b) the inherent limitations in the technology of preparing such cyclic oligopeptides for treating individual sensitivity. The dosage value may vary with the type and severity of the condition to be alleviated. For any particular subject, the specific dosage regimen may be adjusted over time according to the professional judgment of the personnel who administer or supervise the administration of the composition, and the dosage ranges listed herein are exemplary only and are not intended to limit the scope or practice of the composition discussed. Methods of treating IL-13 related skin diseases and conditions

[0082] In a third aspect, the present disclosure provides a method for treating or preventing IL-13 related skin disorders or conditions in a subject in need thereof. In some embodiments, the method comprises administering to the subject a therapeutically effective amount of any one or a combination of the cyclic oligopeptides disclosed herein. In some embodiments, the subject is human. The cyclic oligopeptide can be administered in the form of a pharmaceutical composition disclosed herein. The cyclic oligopeptide can be administered according to any administration route disclosed herein.

[0083] In some embodiments, the cyclic oligopeptide for treatment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11. In some embodiments, the cyclic oligopeptide for treatment comprises the amino acid sequence D-ARG D-PHE D-VALTYR GLU PRO (SEQ ID NO: 1). Optionally, the cyclic oligopeptide for treatment comprises the amino acid sequence ARG THR D-VALGLU D-PHE D-PRO (SEQ ID NO: 2). The cyclic oligopeptide for treatment may comprise the amino acid sequence GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3). In some embodiments, the cyclic oligopeptide for treatment comprises the amino acid sequence ARG GLU D-VAL TRP D-PRO D-PRO (SEQ ID NO: 4). Optionally, the cyclic oligopeptide for treatment comprises the amino acid sequence TRP VAL ARG GLU D-PRO D-PRO (SEQ ID NO: 5). The cyclic oligopeptide for treatment may comprise the amino acid sequence TYR ARG GLU D-THR D-VAL D-PRO (SEQ ID NO: 6). In some embodiments, the cyclic oligopeptide for treatment comprises the amino acid sequence THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7). Optionally, the cyclic oligopeptide for treatment comprises the amino acid sequence D-LEU ARG GLU PRO TRP MET PRO (SEQ ID NO: 8). The cyclic oligopeptide for treatment may comprise the amino acid sequence D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQID NO: 9). In some embodiments, the cyclic oligopeptide for treatment comprises the amino acid sequence ARG ASP TYR CYS D-PRO D-TRP D-PRO (SEQ ID NO: 10). Optionally, the cyclic oligopeptide for treatment comprises the amino acid sequence VAL PROD-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11).

[0084] In some embodiments, the cyclic oligopeptide for treatment has the structure of any one of compounds 1-11 as defined herein (see, e.g., Table 1). In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 1 as defined herein. Optionally, the cyclic oligopeptide for treatment has the structure of compound 2 as defined herein. The cyclic oligopeptide for treatment may have the structure of compound 3 as defined herein. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 4 as defined herein. Optionally, the cyclic oligopeptide for treatment has the structure of compound 5 as defined herein. The cyclic oligopeptide for treatment may have the structure of compound 6 as defined herein. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 7 as defined herein. Optionally, the cyclic oligopeptide for treatment has the structure of compound 8 as defined herein. The cyclic oligopeptide for treatment may have the structure of compound 9 as defined herein. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 10 as defined herein. Optionally, the cyclic oligopeptide for treatment has the structure of compound 11 as defined herein.

[0085] In some embodiments, the cyclic oligopeptide for treatment has the structure of any one of compounds 1-11 as defined herein (see, e.g., Table 1) or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 1 as defined herein or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide for treatment has the structure of compound 2 as defined herein or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide for treatment may have the structure of compound 3 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 4 as defined herein or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide for treatment has the structure of compound 5 as defined herein or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide for treatment may have the structure of compound 6 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 7 as defined herein or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide for treatment has the structure of compound 8 as defined herein or a pharmaceutically acceptable salt thereof. The cyclic oligopeptide for treatment may have the structure of compound 9 as defined herein or a pharmaceutically acceptable salt thereof. In some embodiments, the cyclic oligopeptide for treatment has the structure of compound 10 as defined herein or a pharmaceutically acceptable salt thereof. Optionally, the cyclic oligopeptide for treatment has the structure of compound 11 as defined herein or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the skin disorder or condition associated with IL-13 is an inflammatory, allergic or autoimmune disorder or condition. In some embodiments, the skin disorder or condition associated with IL-13 is an inflammatory disorder or condition. In some embodiments, the skin disorder or condition associated with IL-13 is an allergic disorder or condition. In some embodiments, the skin disorder or condition associated with IL-13 is an autoimmune disorder or condition. In some embodiments, the skin disorder or condition associated with IL-13 is selected from the group consisting of: atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata and prurigo, and molluscum contagiosum. In some embodiments, the skin disorder or condition associated with IL-13 is atopic dermatitis. In some embodiments, the skin disorder or condition associated with IL-13 is allergic contact dermatitis. In some embodiments, the skin disorder or condition associated with IL-13 is urticaria. In some embodiments, the skin disorder or condition associated with IL-13 is eczema. In some embodiments, the IL-13 related skin disorder or condition is chronic hand eczema. In some embodiments, the IL-13 related skin disorder or condition is a bullous disease (bullous pemphigoid). In some embodiments, the IL-13 related skin disorder or condition is alopecia areata. In some embodiments, the IL-13 related skin disorder or condition is prurigo. In some embodiments, the IL-13 related skin disorder or condition is molluscum contagiosum.

[0087] In some embodiments, the one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 and / or IL-13 receptor (IL-13R). In some embodiments, the one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13. In some embodiments, the one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 receptor (IL-13R). In some embodiments, the one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 or IL-13 receptor (IL-13R). In some embodiments, the one or more cyclic oligopeptides bind to IL-13 and reduce the biological activity of IL-13 and IL-13 receptor (IL-13R).

[0088] In some embodiments, the present disclosure provides a method for treating or preventing IL-13 related skin disorders or conditions in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any one or a combination of the cyclic oligopeptides of the present disclosure. In some embodiments, the cyclic oligopeptide or a combination thereof is topically administered. In some embodiments, the cyclic oligopeptide or a combination thereof is transdermally administered. In some embodiments, the cyclic oligopeptide or a combination thereof is subcutaneously administered. In some embodiments, the cyclic oligopeptide or a combination thereof is intravenously administered. In some embodiments, the cyclic oligopeptide or a combination thereof is orally administered. Methods for oral administration of biologically active proteins and peptides are known in the art. Many strategies for preventing degradation of orally administered peptides have been proposed. Examples of methods for oral administration of cyclic oligopeptides include, but are not limited to, the use of core-shell particles (US 7,090,868) and nanotubes (US 7,195,780); liposomes and aqueous emulsions and suspensions (US 7,316,818; WO 06 / 062544; US 6,071,535; and US 5,874,105); gas-filled liposomes (US 6,551,576; US 6,808,720; and US 7,083,572); nanodroplets dispersed in an aqueous medium (US 2007 / 0184076); matrix carriers containing peptide effectors that provide permeability across biological barriers for administration of hydrophobic proteins (WO 06 / 097793, WO 05 / 094785, and WO03 / 066859); using non-covalent protein-polysaccharide complexes (EP0491114B1); using the pharmaceutical compositions described in US 8,936,786; using systems (US 8,377,863; WO 2014 / 138241; and WO 2016 / 115082); all of these publications and patents are expressly incorporated herein by reference. Methods for producing cyclic oligopeptides

[0089] In a fourth aspect, the present disclosure provides a method for producing a cyclic oligopeptide that binds to IL-13. In some embodiments, the method comprises the following steps: (1) contacting FMOC (9-fluorenylmethoxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue under conditions suitable for forming a peptide bond between the first amino acid residue and the resin-bound D-Pro or Pro to form a resin-bound oligopeptide; (2) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (3) contacting the resin-bound oligopeptide with another amino acid residue under conditions suitable for forming a peptide bond between the other amino acid residue and the resin-bound oligopeptide; (4) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) cyclizing the oligopeptide.

[0090] In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU). In some embodiments, the conditions suitable for forming a peptide bond in steps (1) and (3) also include the addition of N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA). In some embodiments, steps (3) and (4) are repeated 1 to 20 times, after which the resin is removed from the oligopeptide.

[0091] In some embodiments, the cyclization step includes forming a covalent bond between the carboxyl group of the D-Pro or Pro residue and one or more amino groups of the linear oligopeptide. In some embodiments, the cyclization step includes adding DMF, PyBOP (benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole) and DIEA to the linear oligopeptide and incubating the mixture at room temperature.

[0092] In some embodiments, the cyclic oligopeptide that binds to IL-13 is a cyclic oligopeptide disclosed herein. In some embodiments, the methods disclosed herein are used to produce the cyclic oligopeptides of the present disclosure. Example

[0093] Exemplary methods and materials are described herein, but methods and materials similar or equivalent to those described herein can also be used to practice or test various aspects and embodiments of the present disclosure. The materials, methods, and examples are illustrative only and not intended to be limiting. Example 1. Production of Cyclic Oligopeptides Binding to IL-13

[0094] The cyclic oligopeptides of the present disclosure were produced using the following steps: 1) Weigh FMOC (9-fluorenylmethoxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin (selected according to the sequence and structure of the oligopeptide to be produced) and place it in a glass reaction column, then add dichloromethane (methylene chloride or DCM) and incubate for 30 minutes to swell the resin. 2) Remove DCM by vacuum. 3) Wash the resin three times with N,N-dimethylformamide (DMF). 4) Add 20% piperidine / DMF solution and incubate for 20 minutes to remove the FMOC protecting group. 5) The liquid solution was removed by vacuum and the resin was washed 6 times with DMF. 6) The second amino acid to be added to the N-terminus of D-Pro or Pro and TBTU (O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate) were weighed and added to the resin. 7) Dissolve DIEA (N,N-diisopropylethylamine) in DMF, add to the resin and react for 30 minutes. Use color detection reaction to track the progress of the reaction. The reaction is considered complete when the solution is bright yellow and the resin is yellow. 8) Remove the solvent by vacuum. 9) Steps 6) to 8) were repeated to add each additional amino acid residue to the N-terminus of the continuously extending oligopeptide until the last amino acid residue was added to the oligopeptide. The last amino acid residue was the residue that was subsequently cyclized to the C-terminus of the initial D-Pro or Pro residue, as shown in the structure of Table 1 below. 10) The resin was washed 3 times with DMF, DCM and methanol and dried under vacuum. 11) Add full protection cleavage solution and remove the resin by filtering the solution using a sand core. 12) Add 0.5 ml of DIEA (N,N-diisopropylethylamine) to the permeate. 13) Remove DCM from the permeate by rotary drying using a vacuum rotary evaporator until the solution becomes viscous. Add analytical grade DMF, PyBOP (benzotriazol-1-yl-oxotripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole) and DIEA and incubate at room temperature for 4 hours. 14) After the reaction is complete, add an acidic solution to separate the solid, which is dried under vacuum. 15) Add cleavage solution to remove the protecting groups on the amino acid side chains. 16) Diethyl ether was added to the solution to separate the solid product, which was centrifuged and washed three times and then dried under vacuum.

[0095] By MS (mass spectrometry) (see Figure 2A , 3A , 4A, 5A, 6A, 7A, 8A, 9A, 10A, 11A and 12A) and HPLC (see Figure 2B , 3B , 4B, 5B, 6B, 7B, 8B, 9B, 10B, 11B and 12B) to analyze the purity and structural characteristics of the synthesized cyclic oligopeptides. The exemplary structures and amino acid sequences of the cyclic oligopeptides that bind to IL-13 are shown in Table 1. Table 1. Structure and amino acid sequence of cyclic oligopeptides Example 2. Evaluation of cyclic oligopeptides by surface plasmon resonance (SPR)

[0096] SPR assays were performed using a BIAcore 8K plus instrument (GE Healthcare) to determine the binding affinity of the cyclic oligopeptide generated in Example 1 to IL-13. Human IL-13 with an Fc tag was immobilized on the surface of an S series sensor CM5 (GE Healthcare) chip with a range of 5000 resonance units (RU). Binding kinetics were performed at 25°C with a flow rate of 30 μL / min. Using the solvent correction mode, the cyclic oligopeptide was analyzed in a running buffer containing 20 mM PBS, 2.7 mM KCl, 37 mM NaCl, 0.05% surfactant P20, pH 7.4, 1% DMSO, with a starting concentration of 100 μM and a gradient of 10 two-fold dilutions. The affinity between IL-13 and the cyclic oligopeptide was determined using the BIAcore 8K plus evaluation software, such as K D Values ​​shown.

[0097] The efficiency and validity of the SPR assay were confirmed using troloxinumab, a monoclonal antibody against IL-13, as a positive control. Figure 2C , 3C , 4C, 5C, 6C, 7C, 8C, 9C, 10C, 11C and 12C provide SPR response curves of the cyclic oligopeptides generated in Example 1, wherein the x-axis represents the reaction time and the y-axis represents the response height (response unit). As summarized in Table 2 below, the SPR results show that the exemplary cyclic oligopeptides of the present disclosure bind to IL-13 with a K D The values ​​ranged from 16 to 622 μM. Table 2. Binding affinity (K) of exemplary cyclic oligopeptides for IL-13 D ) Cyclic oligopeptides KD Compound 1 16μM Compound 2 17.4μM Compound 3 22.8μM Compound 4 26.2μM Compound 5 47.1μM Compound 6 55.4μM Compound 7 85.1μM Compound 8 99.5μM Compound 9 337μM Compound 10 368μM Compound 11 622μM Traloxinumab 309pM Example 3. Skin permeability of cyclic oligopeptides

[0098] The skin permeability of the cyclic oligopeptide generated in Example 1 was measured using a transdermal diffusion tester (TK-12D, Shanghai Kaikai Industrial Co., Ltd.) and artificial skin (StartM, Merck). Three parallel experimental groups were set up for each sample. The skin permeability of the cyclic oligopeptide was evaluated by the following steps: 1) Weigh 2.0 mg of cyclic oligopeptide and dissolve it in 100 μL DMSO. Set up three parallel experimental groups for each cyclic oligopeptide. Then, slowly add the solution containing the cyclic oligopeptide to 1900 μL 1× PBS solution and mix well to prepare a PBS solution with a final concentration of 1.0 mg / mL cyclic polypeptide. 2) Insert the magnetron into the Franz Cell diffusion cell and clamp the artificial skin in the middle of the diffusion cell with the smooth side of the artificial skin facing upward. Then, fix the diffusion cell with a clamp after assembly. 3) Then add 7.75 ml of 1xPBS solution to the diffusion cell without creating bubbles in the diffusion cell. Then seal the sampling port of the diffusion cell with parafilm to reduce evaporation. 4) Then set the temperature of the transdermal diffusion tester to 32°C and the speed of the magnet to 180 r / min. 5) Then place the assembled diffusion cell into the transdermal diffusion tester and preheat for 5-10 minutes. 6) Then 400 μL of the 1.0 mg / mL cyclic oligopeptide solution prepared in step 1) was added to the upper chamber of the diffusion cell so that it was evenly dispersed on the surface of the artificial skin without bubbles. The top port of the diffusion cell was then covered with a parafilm sealing film to reduce evaporation. 7) Starting from the time of adding the cyclic oligopeptide solution, take samples of about 0.5 mL of the receiving solution at 6 time points, namely 1 h, 2 h, 4 h, 8 h, 12 h and 24 h, by using a plastic dropper to take out the sample from the sampling port of the diffusion cell. Add 0.5 mL of 1×PBS solution to the diffusion cell to restore the initial volume of the receiving solution. When sampling, tilt the diffusion cell appropriately to avoid bubbles. The samples are then numbered and stored at -20°C. 8) Perform BCA assay (micro BCA protein assay kit, Thermo Scientific) to measure the concentration of cyclic oligopeptides in the samples obtained in step 7) (the actual concentration of cyclic oligopeptides at a specific time point). Three parallel groups were used. The weight of cyclic oligopeptides in each sample obtained in step 7) was equal to the actual concentration x 0.5 mL. 9) Calculate the permeability of each cyclic oligopeptide at each time point according to the following formula: 10) The relationship between the permeability and time of each cyclic oligopeptide was calculated based on the average results of three repeated experimental groups (e.g. Figure 2D , Figure 3D , Figure 4D , Figure 5D , Fig.6D , Fig.7D , Fig.8D , Fig.9D , Fig. 10D , Fig.11D and Fig.12D shown).

[0099] All cyclic oligopeptides had an average permeability of more than 25% after 24 hours. As shown in Table 3, Compound 9 and Compound 10 had a permeability of more than 60% after 24 hours. Compound 1 and Compound 5 had a permeability of 40% to 50% after 24 hours. Compound 2, Compound 3, Compound 4, Compound 6, Compound 7, and Compound 8 had a permeability of 30% to 40% after 24 hours. Compound 11 had a permeability of about 26% after 24 hours. Figure 2D , Figure 3D , Figure 4D , Figure 5D , Fig.6D , Fig.7D , Fig.8D , Fig.9D , Fig. 10D , Fig.11D and Fig.12D As shown, the permeability of the oligopeptide increases steadily from 1 hour to 24 hours. These data demonstrate that the cyclic oligopeptide disclosed in the present invention has a relatively high skin permeation efficiency over a relatively long period of time.

[0100] In addition, as shown in Table 3 and Figure 2D , Figure 3D , Figure 4D , Figure 5D , Fig.6D , Fig.7D , Fig.8D , Fig.9D , Fig. 10D , Fig.11D and Fig.12D As shown, all cyclic oligopeptides have an average permeability of more than 10% after 1 hour. Compound 5, Compound 7 and Compound 9 have a permeability greater than 20% after 1 hour. Compound 1, Compound 3, Compound 4, Compound 6 and Compound 10 have a permeability of 15% to 20% after 1 hour. Compound 2, Compound 8 and Compound 11 have a permeability of 10% to 15% after 24 hours. These data demonstrate the rapid onset of action of the oligopeptides of the present disclosure when applied topically, which is indicated by the relatively high percentage of skin permeability within the first hour. Table 3. Permeability of exemplary cyclic oligopeptides binding to IL-13 Cyclic oligopeptides Average penetration after 1 hour (%) Average penetration after 24 hours (%) Compound 1 18.54 42.06 Compound 2 14.62 30.51 Compound 3 19.61 36.59 Compound 4 17.28 35.59 Compound 5 22.46 48.73 Compound 6 15.34 33.86 Compound 7 25.42 38.84 Compound 8 12.44 35.20 Compound 9 23.40 60.63 Compound 10 18.96 60.88 Compound 11 11.77 25.75

[0101] The skin permeability coefficient (Kp) (cm / hr) of the cyclic oligopeptide was also calculated using the following formula: Where Q (mg) refers to the total amount of cyclic oligopeptide that passes through the artificial skin within a certain period of time; A (cm 2 ) refers to the internal cross-sectional area of ​​the artificial skin in the diffusion cell; T (hr) refers to the total amount of time for the cyclic oligopeptide to penetrate; and ΔC (mg / mL) refers to the concentration difference of the cyclic oligopeptide between the two sides of the artificial skin.

[0102] As shown in Table 4 and by Figure 2E , Figure 3E , Figure 4E , Figure 5E , Fig. 6E , Fig. 7E , Fig. 8E , Fig.9E , Fig.10E , Fig.11E and Fig.12E As shown, all cyclic oligopeptides had more than 2x 10 -5 The average Kp value of Compound 1, Compound 4, Compound 8, Compound 9 and Compound 10 was higher than 1x 10 -4 The average Kp value of cm / hr. Compound 2, Compound 3, Compound 5, Compound 6, Compound 7 and Compound 11 had 1x 10 -5 cm / hr to 1x 10 -4 These data also show that the cyclic oligopeptides of the present disclosure are able to penetrate the skin for a relatively long period of time.

[0103] In addition, as shown in Table 4 and by Figure 2E , Figure 3E , Figure 4E , Figure 5E , Fig. 6E , Fig. 7E , Fig. 8E , Fig.9E , Fig.10E , Fig.11E and Fig.12E As shown, all cyclic oligopeptides have more than 2x 10 -2 The average Kp value of 1.347 cm / hr was 2.13, indicating that the cyclic oligopeptides of the present disclosure have a rapid onset of action after topical application to the skin. Table 4. Average permeability coefficients (Kp) of exemplary cyclic oligopeptides binding to IL-13

Claims

1. A cyclic oligopeptide that binds to IL-13.

2. The cyclic oligopeptide of claim 1, wherein the cyclic oligopeptide comprises 2 to 22 amino acid residues.

3. The cyclic oligopeptide according to claim 1 or 2, wherein the cyclic oligopeptide comprises an L-proline residue or a D-proline residue.

4. The cyclic oligopeptide of any one of claims 1 to 3, wherein the cyclic oligopeptide comprises an amino acid sequence selected from the group consisting of: (a) D-ARG D-PHE D-VAL TYR GLU PRO (SEQ ID NO: 1); (b) ARG THR D-VAL GLU D-PHE D-PRO (SEQ ID NO: 2); (c) GLU D-THR D-VAL TRP D-PRO D-PRO (SEQ ID NO: 3); (d) ARG GLU D-VAL TRP D-PRO D-PRO (SEQ ID NO: 4); (e) TRP VAL ARG GLU D-PRO D-PRO (SEQ ID NO: 5); (f) TYR ARG GLU D-THR D-VAL D-PRO (SEQ ID NO: 6); (g) THR ARG D-PHE PRO D-LEU D-PRO (SEQ ID NO: 7); (h) D-LEU ARG GLU PRO TRP MET PRO (SEQ ID NO: 8); (i) D-ARG LEU D-TRP TRP D-THR GLU PRO (SEQ ID NO: 9); (j) ARG ASP TYR CYSD-PRO D-TRP D-PRO (SEQ ID NO: 10); and (k) VAL PRO D-LEU D-TRP D-VAL LEU ARG PRO (SEQ ID NO: 11).

5. The cyclic oligopeptide according to any one of claims 1 to 4, wherein the cyclic oligopeptide has the structure of any one of compounds 1 to 11 or a pharmaceutically acceptable salt thereof, wherein Compound 1 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 2 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 3 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 4 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 5 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 6 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 7 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 8 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 9 has the following structure: or a pharmaceutically acceptable salt thereof; Compound 10 has the following structure: or a pharmaceutically acceptable salt thereof; and Compound 11 has the following structure: or a pharmaceutically acceptable salt thereof.

6. The cyclic oligopeptide according to any one of claims 1 to 5, wherein the cyclic oligopeptide has the structure of any one of compounds 1 to 11, wherein Compound 1 has the following structure: Compound 2 has the following structure: Compound 3 has the following structure: Compound 4 has the following structure: Compound 5 has the following structure: Compound 6 has the following structure: Compound 7 has the following structure: Compound 8 has the following structure: Compound 9 has the following structure: Compound 10 has the following structure: And compound 11 has the following structure:

7. A pharmaceutical preparation or cosmetic preparation comprising the cyclic oligopeptide according to any one of claims 1 to 6 and a pharmaceutically or cosmetically acceptable carrier.

8. A method for treating or preventing an IL-13-related skin disorder or condition in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the cyclic oligopeptide of any one of claims 1 to 6 or the pharmaceutical or cosmetic formulation of claim 7.

9. The method of claim 8, wherein the cyclic oligopeptide: (a) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11; (b) having the structure of any one of Compounds 1-11 or a pharmaceutically acceptable salt thereof; or (c) has the structure of any one of Compounds 1-11.

10. The method of claim 8 or 9, wherein the IL-13 associated skin disorder or condition is an inflammatory, allergic or autoimmune disorder or condition, wherein optionally, the IL-13 associated skin disorder or condition is selected from the group consisting of atopic dermatitis, allergic contact dermatitis, urticaria, eczema, chronic hand eczema, bullous disease (bullous pemphigoid), alopecia areata, prurigo and molluscum contagiosum.

11. The method of any one of claims 8-10, wherein the cyclic oligopeptide or a combination thereof is administered topically, transdermally, subcutaneously or intravenously.

12. A method for producing a cyclic oligopeptide that binds to IL-13, comprising the following steps: (1) contacting FMOC (9-fluorenylmethoxycarbonyl)-D-Pro-2cl-resin or FMOC-Pro-2cl-resin with a first amino acid residue under conditions suitable for forming a peptide bond between the first amino acid residue and the resin-bound D-Pro or Pro to form a resin-bound oligopeptide; (2) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (3) contacting the resin-bound oligopeptide with another amino acid residue under conditions suitable for forming a peptide bond between the other amino acid residue and the resin-bound oligopeptide; (4) washing the resin-bound oligopeptide to remove any unbound amino acid residues; (5) removing the resin from the oligopeptide; and (6) Cyclizing the oligopeptide.

13. The method of claim 12, wherein: a) the conditions suitable for forming peptide bonds in steps (1) and (3) include the addition of O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU); b) the conditions suitable for forming a peptide bond in steps (1) and (3) further include adding N,N-dimethylformamide (DMF) and N,N-diisopropylethylamine (DIEA); c) repeating steps (3) and (4) 1 to 20 times, and then removing the resin from the oligopeptide; d) the cyclization step comprises forming a covalent bond between the carboxyl group of the D-Pro or Pro residue and one or more amino groups of the linear oligopeptide; e) the cyclization step comprises adding DMF, PyBOP (benzotriazol-1-yl-oxotripyrrolidinophosphonium hexafluorophosphate), HOBT (1-hydroxybenzotriazole) and DIEA to the linear oligopeptide and incubating the mixture at room temperature; and / or f) The cyclic oligopeptide that binds to IL-13 is a cyclic oligopeptide according to any one of claims 1 to 6.

14. The cyclic oligopeptide of any one of claims 1-6, wherein the cyclic oligopeptide has a skin permeability of at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% or at least 60% after 24 hours, and / or wherein the cyclic oligopeptide has a skin permeability of at least 10%, at least 15%, at least 20% or at least 25% after 1 hour.

15. The cyclic oligopeptide of any one of claims 1 to 6, wherein the cyclic oligopeptide has a molecular weight of at least 1.0 x 10 -5 cm / hr, at least 2.0x 10 -5 cm / hr, at least 5.0x 10 -5 cm / hr or at least 1.0x 10 -4 cm / hr, and / or wherein the cyclic oligopeptide has a mean skin permeability of at least 1.0 x 10 -2 cm / hr, at least 2.0x 10 - 2 cm / hr, at least 3.0x 10 -2 cm / hr or at least 4.0x 10 -2 Average skin permeability coefficient in cm / hr.

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