Peptides and methods for reducing skin pigmentation - Patents.com

Abstract

The present disclosure relates to novel peptide antagonists that inhibit the binding of melanocyte stimulating hormone to the melanocortin 1 receptor. The peptide antagonists of the present invention are useful in cosmetic compositions that prevent or reduce the appearance of skin discoloration caused by pigmentation. The present disclosure also relates to cosmetic compositions that include the peptide antagonists of the present disclosure and methods of use thereof to prevent or reduce the appearance of skin discoloration in a subject in need thereof.

Description

[Technical field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 271,646, filed October 25, 2021, and U.S. Provisional Application No. 63 / 165,611, filed March 24, 2021, each of which is incorporated by reference in its entirety herein. [Background technology]

[0002] Skin pigmentation occurs through a pathway that involves interactions between keratinocytes in the epidermis and melanocytes in the basal layer of the epidermis. Upon exposure to UV light, keratinocytes release melanocyte-stimulating hormone (MSH). In humans, MSH binds to and activates the melanocortin 1 receptor (MC1R) on the plasma membrane of melanocytes. This initiates an MC1R-mediated signaling cascade that increases melanocyte production of black pigmented melanin, known as eumelanin, and increases the transfer of melanosomes (small secretable vesicles that contain melanin) to keratinocytes. This can result in undesirable skin discoloration, e.g., dark spots. There is a need for safe and effective compositions and methods that prevent and / or reduce skin discoloration by inhibiting the skin pigmentation pathway. Summary of the Invention

[0003] The present invention includes compositions and methods relating to novel peptide antagonists that inhibit the binding of melanocyte stimulating hormone (MSH) to the melanocortin 1 receptor (MC1R). In some embodiments, the present invention includes cosmetic compositions comprising the peptide antagonists of the present invention. In some embodiments, the peptide antagonists of the present invention are useful in topical cosmetic compositions for preventing or reducing the appearance of skin discoloration due to pigmentation, or both. In some embodiments, the present invention relates to methods of using cosmetic compositions comprising the peptide antagonists of the present invention, for example, to prevent or reduce skin discoloration due to pigmentation in an individual in need thereof. In some embodiments, the present invention relates to methods for blocking or inhibiting the interaction of MSH with MC1R using the compositions or methods of the present invention.

[0004] In some aspects, provided herein are Group A melanocortin 1 receptor (MC1R) peptide antagonists comprising the amino acid sequence: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9, where Xaa1 is absent or selected from the group consisting of Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, , D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, D-Glu, and derivatives of Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln or D-Glu; Xaa2 is selected from Pro, Xaa3 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr; Xaa4 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, Xaa5 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr; Xaa6 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr; Xaa7 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys,and a derivative of Arg, His, Lys, D-Arg, D-His or D-Lys; Xaa8 is selected from Pro, D-Pro, and a derivative of Pro or D-Pro; Xaa9 is selected from Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and a derivative of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu or D-Ile; and when Xaa1 is Met, Xaa2 is not Pro, the N-terminus is optionally modified, and the C-terminus is optionally modified. In some embodiments, Xaa2 of the Group A peptide antagonist is selected from D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile. In some embodiments, Xaa2 of the Group A peptide antagonist is selected from Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile. In some embodiments, Xaa1 of the Group A peptide antagonists is absent or is selected from the group consisting of Cys, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Gl u, D-Asn, D-Asp, D-Gln, D-Glu, and Cys, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp,In some embodiments, Xaa1 of the Group A peptide antagonists is absent or is selected from D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp. , D-Gln, D-Glu, and derivatives of D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln or D-Glu. In some embodiments, Xaa1 of the Group A peptide antagonists is absent or selected from Cys, Sec, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Gly, Val, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, D-Phe, D-Trp, D-Tyr, Asn, Asp, D-Asn, D-Asp, D-Gln, D-Glu, and derivatives of Cys, Sec, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Gly, Val, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, D-Phe, D-Trp, D-Tyr, Asn, Asp, D-Asn, D-Asp, D-Gln, or D-Glu. In some embodiments, Xaa2 of the Group A peptide antagonists is selected from D-Pro, Gly, Val, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of D-Pro, Gly, Val, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile. In some embodiments, Xaa1 of the Group A peptide antagonists is absent or selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr, and Xaa2 is selected from Ala, Gly, Val, Leu, Ile,Xaa3 is selected from D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile, and Xaa4 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr. Xaa4 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys; and Xaa5 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr. Xaa6 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr, and Xaa7 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys. Xaa8 is selected from Pro, D-Pro, and derivatives of Pro or D-Pro, and Xaa9 is selected from Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile.

[0005] In some aspects, provided herein is a Group B melanocortin 1 receptor (MC1R) peptide antagonist comprising the amino acid sequence: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26, wherein Xaa1 is absent or Xaa1 and Xaa19 are joined together. Xaa2 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa3 is absent or selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu; Xaa4 is absent or selected from Pro and derivatives of Pro; Xaa5 is absent or Xaa5 and Xaa26 form the bond Xaa5-Xaa26; and Xaa6 is absent or selected from or Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa7 is absent or selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr; Xaa8 is absent or selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or G and / or Xaa8 and Xaa19 form the bond Xaa8-Xaa19, Xaa9 being absent or selected from Phe, Trp, Tyr, Asn, Asp, Gln, Glu, and derivatives of Phe, Trp, Tyr, Asn, Asp, Gln, or Glu, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 being selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 being Phe, Trp, Tyr, and Phe,Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; a18 is absent or selected from Phe, Trp, Tyr, Cys, Met, Sec, Ser, Thr, and derivatives of Phe, Trp, Tyr, Cys, Met, Sec, Ser, or Thr; Xaa19 is absent or selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu; and / or Xaa8 and Xaa19 are absent or selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu. aa19 forms the bond Xaa8-Xaa19, or Xaa1 and Xaa19 form the bond Xaa1-Xaa19, Xaa20 is absent or selected from Arg, His, Lys, and derivatives of Arg, His or Lys, Xaa21 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile, and Xaa22 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile. Xaa23 is absent or selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa24 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa25 is absent or selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu; and Xaa26 is absent or selected fromThe melanocortin 1 receptor (MC1R) peptide antagonists of Group B, wherein Xaa5 and Xaa26 form the bond Xaa5-Xaa26, the N-terminus is optionally modified, and the C-terminus is optionally modified. In some embodiments, Xaa1 of the Group B antagonists is absent, Xaa2 is absent, Xaa3 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu, Xaa4 is selected from Pro and derivatives of Pro, Xaa5 and Xaa26 form the bond Xaa5-Xaa26, Xaa6 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile, and Xaa7 is Cys , Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr; Xaa8 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa9 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa10 and Xaa17 form the bond Xaa10-Xaa17; Xaa11 is Arg, His, Lys, and also Arg, His. or derivatives of Lys; Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa19 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa20 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; and Xaa21 isXaa22 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa23 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa24 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa25 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu. In some embodiments, Xaa1 of the Group B peptide antagonists is absent, Xaa2 is absent, Xaa3 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu, Xaa4 is selected from Pro and derivatives of Pro, Xaa5 and Xaa26 form the bond Xaa5-Xaa26, Xaa6 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile, Xaa7 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr, and Xaa8 is selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Xaa9 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa10 and Xaa17 form the bond Xaa10-Xaa17; and Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys. Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser,Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa19 is selected from Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Arg, His, Lys, Asn, Asp, Gln, or Glu; Xaa20 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa21 is selected from Ala, Gly, V Xaa22 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa23 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa24 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa25 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu. In some embodiments, Xaa1 of the Group B antagonists is absent, Xaa2 is absent, Xaa3 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln or Glu, Xaa4 is selected from Pro and derivatives of Pro, Xaa5 and Xaa26 form the bond Xaa5-Xaa26, and Xaa6 is Ala, Gly, Val, Leu, Ile, and Ala, Gly, Val, Leu, or Ile. Xaa7 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr; Xaa8 and Xaa19 form the bond Xaa8-Xaa19; Xaa9 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa10 and Xaa17 form the bond Xaa10-Xaa17; Xaa11 is selected from Arg, His, Lys, andXaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa14 is selected from Arg, His, Lys, and Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa20 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa21 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of ... Xaa22 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa23 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa24 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa25 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu. In some embodiments, Xaa1 and Xaa19 of the Group B antagonists form the bond Xaa1-Xaa19, Xaa2 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile, Xaa3 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu, Xaa4 is selected from Pro and derivatives of Pro, and Xaa5 and Xaa26 are bond Xaa5-Xaa2 Xaa7 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr; Xaa8 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa9 is selected from Phe, Trp, Tyr, and Phe,Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, and Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr. Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa18 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp or Tyr, Xaa20 is selected from Arg, His, Lys and derivatives of Arg, His or Lys, Xaa21 is selected from Ala, Gly, Val, Leu, Ile and derivatives of Ala, Gly, Val, Leu or Ile, Xaa22 is selected from Ala, Gly, Val, Leu, Ile and derivatives of Ala, Gly, Val, Leu or Ile, Xaa23 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa24 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa25 is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu. In some embodiments, Xaa1 of the Group B antagonists is absent, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His or Lys, Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp or Tyr, Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp or Tyr, and Xaa14 is selected from Arg, His,Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa18 to Xaa26 are absent. In some embodiments, Xaa1-Xaa8 of the Group B antagonists are absent, Xaa1-Xaa8 are absent, Xaa9 is selected from Phe, Trp, Tyr, Asn, Asp, Gln, Glu, and derivatives of Phe, Trp, Tyr, Asn, Asp, Gln, or Glu, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, and Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr. is selected from derivatives of Tyr; Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is selected from Cys, Met, Sec, Ser, Thr, Phe, Trp, Tyr, and derivatives of Cys, Met, Sec, Ser, Thr, Phe, Trp, or Tyr; and Xaa19 to Xaa26 are absent. In some embodiments, Xaa1-Xaa7 of the Group B antagonists are absent, Xaa8 and Xaa19 form the bond Xaa8-Xaa19, where Xaa9 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 is Phe, Trp, Tyr, and Phe,Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr; and Xaa20 to Xaa26 are absent. In some embodiments, Xaa1-Xaa8 of the Group B antagonists are absent, Xaa9 is absent or selected from Phe, Trp, Tyr, Asn, Asp, Gln, Glu, and derivatives of Phe, Trp, Tyr, Asn, Asp, Gln, or Glu, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, and Xaa13 is Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr. Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys; Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is absent or selected from Cys, Met, Sec, Ser, Thr, Phe, Trp, Tyr, and derivatives of Cys, Met, Sec, Ser, Thr, Phe, Trp, or Tyr; and Xaa19 to Xaa26 are absent.

[0006] In some aspects, provided herein are melanocortin 1 receptor peptide antagonists comprising an amino acid sequence set forth as any of SEQ ID NOs: 4-90. In some embodiments, the N- and C-terminal modifications are as shown in Tables 1 and 2 for these peptides. In some embodiments, the N- and C-terminal modifications are selected from any known in the art or described herein.

[0007] In some embodiments, provided herein are MC1R peptide antagonists, wherein the amino acid sequence of the MC1R peptide antagonist consists of the amino acid sequence of a Group A or Group B MC1R peptide antagonist as described herein, including, but not limited to, any one of SEQ ID NOs: 4-90. In some embodiments, provided herein are MC1R peptide antagonists, wherein the amino acid sequence of the MC1R peptide antagonist consists of the amino acid sequence of a separate Group A or Group B MC1R peptide antagonist as described herein, including, but not limited to, any one of SEQ ID NOs: 4-90.

[0008] In some embodiments, each bond of the MC1R peptide antagonist is independently selected from a Cys-Cys bond, a Sec-Sec bond, a cystathionine bond, a lactam bridge, a Gly-Gly bond, a thioether bond, a dicarba bond, and a diproline bond selected from Pro--Pro, D-Pro--D-Pro, D-Pro--Pro, and Pro--D-Pro in the amino-terminal to carboxy-terminal direction. In some embodiments, the bonds have a spatial separation of about 3.5 to about 10 angstroms between the alpha carbons or geometric centers of each amino acid residue, the bonds have a spatial separation of about 3.5 to about 10 angstroms between the respective alpha carbons or geometric centers of the residues, or both. In some embodiments, the N-terminus of the MC1R peptide antagonist is selected from a C1-C6 acyl, a C1-C8 alkyl, a C6-C 12 Aralkyl, C5-C 10 In some embodiments, the C-terminus of the MC1R peptide antagonist is modified to NH2, amino-acyl, amino-C1-C8 alkyl, amino-C6-C 12 -Aralkyl, Amino-C5-C 10 In some embodiments, the lipid is covalently attached to a cysteine, serine, lysine, threonine, or tyrosine residue of the MC1R peptide antagonist. In some embodiments, the lipid is covalently attached to an amino acid residue of the MC1R peptide antagonist. In some embodiments, the lipid is covalently attached to a C6-C8 amino acid residue of the MC1R peptide antagonist. 20 Alkyl groups, C6-C 20 Alkenyl groups, C6-C 20 Alkynyl group, or C6-C 20The lipid comprises an acyl group. In some embodiments, the lipid comprises a geranyl group, a farnesyl group, or a geranylgeranyl group. In some embodiments, the lipid comprises an undecyloyl group, a lauroyl group, a tridecyloyl group, a myristoyl group, a palmitoyl group, or a stearoyl group. In some embodiments, the lipid is a covalent modification of Cys added by palmitoylation or prenylation. In some embodiments, the MC1R receptor peptide antagonist comprises at least one derivative that is a non-standard amino acid selected from the group consisting of aromatic side chain amino acids, non-aromatic side chain amino acids, aliphatic side chain amino acids, side chain amide amino acids, side chain ester amino acids, heteroaromatic side chain amino acids, side chain thiol amino acids, beta amino acids, and backbone modified amino acids. In some embodiments, the aromatic side chain amino acid is a derivative of tyrosine, histidine, tryptophan, or phenylalanine. In some embodiments, the non-aromatic side chain amino acid is a derivative of serine, threonine, cysteine, methionine, arginine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, proline, glycine, alanine, valine, isoleucine, or leucine. In some embodiments, the at least one derivative is a non-standard amino acid selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, β-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid, desmosine, 2,2′-diaminopimelic acid, 2,3-diaminoproprionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, n-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, and ornithine. In some embodiments, one or more amino acids in the peptide have a D-amino acid configuration, and the remaining amino acids in the peptide have an L-amino acid configuration.

[0009] In some aspects, the melanocortin 1 receptor peptide antagonist inhibits the melanocortin 1 receptor. In some embodiments, the inhibition is selective. In some embodiments, the inhibition comprises blocking the binding of MSH to the melanocortin 1 receptor. In some embodiments, the IC 50 is about 1 millimolar to about 1 picomolar, less than about 200 nM, less than about 150 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, or less than about 25 nM. In some embodiments, the melanocortin 1 receptor peptide antagonist inhibits a melanocortin 1 receptor that exhibits enhanced activity compared to the activity of a control. In some embodiments, the melanocortin 1 receptor peptide antagonist is a Group A MC1R peptide antagonist, and the control is a peptide having the amino acid sequence of SEQ ID NO: 1. In some embodiments, the melanocortin 1 receptor peptide antagonist is a Group B MC1R peptide antagonist, and the control is a peptide having the amino acid sequence of SEQ ID NO: 2, 3, 91, 92, 93, and 94. In some embodiments, the melanocortin 1 receptor peptide antagonist has an amino acid sequence of any one of SEQ ID NOs: 44-90, and the control is a peptide having an amino acid sequence set forth as any one of SEQ ID NOs: 2, 3, 91, 92, 93, and 94. In some embodiments, the melanocortin 1 receptor peptide antagonist is a Group A or Group B MC1R peptide antagonist, and the control is a peptide having an amino acid sequence set forth as any one of SEQ ID NOs: 1, 2, 3, 91, 92, 93, and 94. In some embodiments, the melanocortin 1 receptor peptide antagonist is an IC 50 About 0.4 to 0.8 times the IC 50In some embodiments, the activity of the melanocortin 1 receptor peptide antagonist is about 1.25-fold to about 5-fold greater than the activity of the control. In some embodiments, the activity of the melanocortin 1 receptor peptide antagonist and the activity of the control are determined using the same assay method, in the same experiment, or both.

[0010] In some aspects, provided herein is a composition comprising an MC1R peptide antagonist as described herein. In some embodiments, the composition is a cosmetic composition for preventing, reducing, and / or improving the appearance of skin discoloration in an individual in need thereof. In some embodiments, the cosmetic composition is formulated for topical use. The skin discoloration may be caused by pigmentation. The skin discoloration may be caused by hyperpigmentation. In some embodiments, the skin discoloration, for example, pigmentation or hyperpigmentation, includes melanin hyperpigmentation, melasma, melasma, age spots, freckles, or a combination thereof.

[0011] In some aspects, provided herein is a method for preventing or improving skin discoloration in an individual, comprising applying an effective amount of a cosmetic composition comprising an MC1R peptide antagonist to the skin of the individual. In some aspects, the cosmetic composition comprises more than one active ingredient. In some aspects, the cosmetic composition comprises more than one MC1R peptide antagonist of the present disclosure. In some embodiments, the cosmetic composition comprises one or more excipients selected from the group consisting of water, buffer, absorption enhancer, stability enhancer, diaminobutyroylbenzylamide, diacetate, glycerin, gum, hydrocolloid or derivative, cellulose derivative, emulsifier, fatty alcohol, acrylic derivative, mineral, surfactant, fat, oil, preservative, monosaccharide, disaccharide, polysaccharide, glycosaminoglycan, and chelating agent. In some embodiments, the absorption enhancer is selected from the group consisting of liposome delivery systems, transfersome delivery systems, ethosome delivery systems, short chain alcohols, long chain alcohols, polyhydric alcohols, urea, amino acids, amino acid esters, amines, amides, 1-dodecylazacycloheptan-2-one (AZONE®), derivatives of 1-dodecylazacycloheptan-2-one, pyrrolidones, pyrrolidone derivatives, terpenes, terpene derivatives, fatty acids, fatty acid esters, macrocycles, tensides, sulfoxides, lecithin vesicles, water surfactants, polyols, small molecule tripeptides, tetrapeptides, pentapeptides, hexapeptides, septapeptides or octapeptides, isoceteth-20, ethoxydiglycol, dimethylsulfoxide, dimethylisosorbide, and phloretin. In some embodiments, the stability enhancer is a small molecule peptide.In some embodiments, the small peptide is a tripeptide, tetrapeptide, pentapeptide, hexapeptide, septapeptide, octapeptide, cosmetic topical peptide of acetyl hexapeptide-3, Melanotan II, ACVR2B (ACE-031), Argireline® Asetate, Argireline, Matrixyl acetate (palmitoyl pentapeptide), peptide GHK spontaneous complex with copper, palmitoyl tetrapeptide-3, Argireline, acetyl glutamyl heptapeptide, Matrixyl', Snap-8, Syn-Tracks, Syn-Coll, Syn-Hycan, Leuphasyl, Pepha-Tight, T. ego (R) Pep4-17, and Trylagen. In some embodiments, the cosmetic composition comprises one or more other active ingredients. In some embodiments, the one or more other active ingredients are selected from the group consisting of a second different MC1R peptide antagonist, an antioxidant, a retinoid, a growth factor, a collagen stimulating peptide, a carrier peptide, a peptide that inhibits tTAT-superoxide dismutase, a peptide that inhibits proteinases, a peptide that stimulates hyaluronan synthase 2, and a keratin-based peptide. In some embodiments, the cosmetic composition comprises a liposomal delivery system. In some embodiments, the cosmetic composition is a cream, balm, gel, solution, serum, cosmetic, liquid, lotion, ointment, emulsion, milk, spray, mask, etc. In some embodiments, the cosmetic composition comprises about 0.01% to about 5% w / w of the MC1R receptor peptide antagonist.

[0012] In some aspects, provided herein are cosmetic compositions comprising a melanocortin 1 receptor peptide antagonist for use in preventing or ameliorating skin discoloration in an individual.

[0013] In some aspects, provided herein is an invention that includes a method for preventing or temporarily improving the appearance of skin discoloration caused by pigmentation in an individual, comprising applying to the individual an effective amount of a cosmetic composition comprising an MC1R receptor peptide antagonist of the present disclosure. In some embodiments, the MC1R receptor peptide antagonist is applied in one or more doses of the cosmetic composition. In some embodiments, a single dose of the cosmetic composition is applied from about once an hour to about once every two weeks. In some embodiments, a single dose of the cosmetic composition is applied about once a day. In some embodiments, the cosmetic composition may be applied indefinitely without side effects. In some embodiments, the dose of the cosmetic composition is less than an immunological dose.

[0014] In some aspects, provided herein are lipid vesicle compositions comprising: (a) lipid vesicles, each comprising a lipid bilayer comprising vesicle-forming lipids; (b) an oil-in-water emulsion entrapped in the lipid vesicles and stabilized by one or more surfactants; and (c) a peptide antagonist of the melanocortin 1 receptor entrapped in the lipid bilayer and / or the oil-in-water emulsion. In some embodiments, the peptide antagonist of the melanocortin 1 receptor comprises the amino acid sequence: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9, where Xaa1 is absent or is selected from the group consisting of Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile. , Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, D-Glu, and , Cys, Met, Sec, Ser, Thr, D-Cys, D-M et, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn , Asp, Gln, Glu, D-Asn, D-Asp, D-Gln or D-Glu derivatives; Xaa2 is selected from Pro, D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile and derivatives of Pro, D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu or D-Ile; Xaa3 is selected from Phe, Trp, T Xaa4 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys; Xaa5 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe,Xaa6 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr; Xaa7 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys; Xaa8 is Pro, D-Pro and a derivative of Pro or D-Pro, Xaa9 is selected from Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and a derivative of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu or D-Ile, when Xaa1 is Met, Xaa2 is not Pro, the N-terminus is optionally modified, and the C-terminus is optionally modified. In some embodiments, the peptide antagonist of the melanocortin 1 receptor comprises the amino acid sequence: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaall-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26, wherein Xaa1 is absent or Xaa1 and Xaa19 form the bond Xaa1-Xaa19 and Xaa2 is absent or is selected from the group consisting of Ala, Gly, Val, Leu, Ile, and Ala, Gly, Val, Xaa3 is absent or is selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu, Xaa4 is absent or is selected from Pro and derivatives of Pro, Xaa5 is absent or is selected from Xaa5 and Xaa26 form the bond Xaa5-Xaa26, Xaa6 is absent or is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile, Xaa7 is absent or is selected from Cys, Met, Sec, Ser, Thr, and Cys, Met, Sec,Xaa8 is selected from a derivative of Ser or Thr, Xaa8 is absent or is selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and a derivative of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu; and / or Xaa8 and Xaa19 form the bond Xaa8-Xaa19, Xaa9 is absent or is selected from Phe, Trp, Tyr, Asn, Asp, Gln, Glu, and Phe, Trp, Xaa10 and Xaa17 form the bond Xaa10-Xaa17, Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys, Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr, and Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys. Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, Thr; Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa18 is absent or selected from Phe, Trp, Tyr, Cys, Met, Sec, Ser, Thr, and derivatives of Phe, Trp, Tyr, Cys, Met, Sec, Ser, or Thr; Xaa19 is absent or is selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu; and / or Xaa8 and Xaa19 form the bond Xaa8-Xaa19, or Xaa1 and Xaa19 form the bond Xaa1-Xaa19, and Xaa20 is absent or is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys;Xaa21 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa22 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; and Xaa23 is absent or selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr. Xaa24 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile; Xaa25 is absent or selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu; Xaa26 is absent or Xaa5 and Xaa26 form the bond Xaa5-Xaa26; the N-terminus is optionally modified; and the C-terminus is optionally modified. In some embodiments, the peptide antagonist of the melanocortin 1 receptor comprises an amino acid sequence set forth as any one of SEQ ID NOs: 4-90. In some embodiments, the peptide antagonist of the melanocortin 1 receptor consists of any one of the amino acid sequences described herein. In some embodiments, the peptide antagonist is present at a concentration of about 0.1 mg / mL to about 10 mg / mL. In some embodiments, the lipid vesicle composition further comprises one or more penetration enhancers. In some embodiments, the one or more penetration enhancers comprise a non-ionic surfactant or a combination of non-ionic surfactants. In some embodiments, the non-ionic surfactant or the combination of non-ionic surfactants is selected from polyethylene glycol ethers of fatty alcohols, sorbitan esters, polysorbates, sorbitan esters, and polyethylene glycol fatty acid esters, and combinations thereof. In some embodiments, the polyethylene glycol ethers of fatty alcohols are selected from C8-C, 2253. The lipid vesicle composition of claim 50, wherein the sorbitan ester comprises sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, or sorbitan isostearate, or any combination thereof. In some embodiments, the polyethylene glycol fatty acid ester comprises PEG-8 dilaurate, PEG-4 dilaurate, PEG-4 laurate, PEG-8 dioleate, PEG-8 distearate, PEG-8 distearate, PEG-7 glyceryl cocoate, and PEG-20 glyceryl almondate, or any combination thereof. In some embodiments, the polysorbate comprises polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, or any combination thereof. In some embodiments, each of the nonionic surfactants has a hydrophobic-lipophilic balance (HLB) of about 10 or less. In some embodiments, the nonionic surfactant, or combination of nonionic surfactants, is present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, at least one nonionic surfactant is present in the oil-in-water emulsion. In some embodiments, at least one nonionic surfactant is present in the lipid bilayer. In some embodiments, the one or more penetration enhancers include a combination of sorbitan esters, polysorbates, and polyethylene glycol fatty acid esters.In some embodiments, the one or more penetration enhancers include a combination of polyethylene glycol ethers of aliphatic alcohols, sorbitan esters, and polysorbates. In some embodiments, the one or more penetration enhancers include monolauroyl lysine or dipalmitoyl lysine, or a combination thereof. In some embodiments, the vesicle-forming lipid is a phospholipid, glycolipid, lecithin, ceramide, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin,. phosphatidic acid, cerebroside, or any combination thereof. In some embodiments, the vesicle-forming lipid comprises a phospholipid. In some embodiments, the composition comprises a vesicle-forming lipid in an amount of about 0.5% to about 25% (w / w) of the composition. In some embodiments, the composition comprises a cationic surfactant. In some embodiments, the cationic surfactant is a monocationic surfactant. In some embodiments, the cationic surfactant comprises an amino acid and a fatty acid. In some embodiments, the amino acid comprises lysine, arginine, or histidine. In some embodiments, the cationic surfactant is present in an amount of about 1% to about 20% (w / w) of the composition. In some embodiments, the oil-in-water emulsion comprises a triglyceride in the oil component. In some embodiments, the triglyceride comprises a medium chain triglyceride. In some embodiments, the triglyceride is present in an amount of about 1% to about 35% (w / w) of the composition. In some embodiments, the composition comprises a sterol. In some embodiments, the sterol is present in an amount of about 1% to about 5% (w / w) of the composition. In some embodiments, the composition includes propylene glycol. In some embodiments, the propylene glycol is present in an amount of about 1% to about 25% (w / w) of the composition. In some embodiments, the composition includes one or more viscosity enhancing agents. In some embodiments, the one or more viscosity enhancing agents are present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, the composition further includes one or more additional agents. In some embodiments, the additional agents include one or more of a thickening agent, a preservative, a moisturizer, an emollient, a humectant, an antimicrobial agent, or any combination thereof. In some embodiments, the composition is formulated for topical application to the skin of a subject. In some embodiments, the composition is formulated to deliver the peptide antagonist to a specific layer of the skin of a subject. In some embodiments, the composition is formulated as a cream, a lotion, a suspension, or an emulsion.

[0015] In some embodiments, provided herein are methods of preparing a lipid vesicle composition comprising: a) preparing an oil-in-water emulsion comprising a peptide antagonist of the melanocortin 1 receptor by mixing an oil component of the oil-in-water emulsion with an aqueous component of the oil-in-water emulsion, wherein the aqueous component comprises the peptide antagonist of the melanocortin 1 receptor, and the oil component and / or the aqueous component of the oil-in-water emulsion comprise one or more surfactants; b) solubilizing vesicle-forming lipids in an acceptable solvent other than water; c) adding the oil-in-water emulsion to the solubilized vesicle-forming lipids; and d) mixing the oil-in-water emulsion with the solubilized vesicle-forming lipids under mixing conditions effective to form lipid vesicles comprising a lipid bilayer comprising the vesicle-forming lipids and the oil-in-water emulsion entrapped in the lipid vesicles.

[0016] In some aspects, provided herein are methods of preventing or reducing skin discoloration in a subject, the methods comprising administering to said subject a lipid composition, the lipid vesicle composition comprising (a) lipid vesicles each comprising a lipid bilayer comprising vesicle-forming lipids, (b) an oil-in-water emulsion entrapped in the lipid vesicles and stabilized by one or more surfactants, and (c) a peptide antagonist of the melanocortin 1 receptor entrapped in the lipid bilayer and / or the oil-in-water emulsion. In some embodiments, the skin discoloration is melanin hyperpigmentation, melasma, melasma, age spots, freckles, or a combination thereof.

[0017] Citation by reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. [Brief description of the drawings]

[0018] The novel features of the invention are set forth with particularity in the appended claims. To better understand the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments in which the principles of the invention are utilized and the accompanying drawings. [Figure 1] 1 shows an exemplary pictorial workflow for the preparation of lipid vesicles provided herein. [Diagram 2] 1 shows an exemplary workflow for the preparation of lipid vesicles containing peptides as provided herein. [Diagram 3] 1 shows exemplary subject results from a clinical trial. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] definition As used herein, the term "comprise" or variations thereof such as "comprises" or "comprising" are intended to indicate the inclusion of any recited features but not the exclusion of any other features. Thus, as used herein, the term "comprising" is inclusive and does not exclude additional features not recited. In some embodiments for any of the compositions and methods provided herein, "comprising" may be replaced with "consisting essentially of" or "consisting of." The phrase "consisting essentially of" is used herein to require the specified characteristics as well as characteristics that do not materially affect the characteristics or function of the invention. As used herein, the term "consisting" is used to indicate the sole presence of the recited characteristics.

[0020] As used in this specification and the appended claims, unless indicated to the contrary, the following terms have the meanings specified below.

[0021] "Amino" refers to the -NH2 radical.

[0022] "Cyano" refers to the -CN radical.

[0023] "Nitro" refers to the -NO2 radical.

[0024] "Oxa" refers to the radical --O--.

[0025] "Oxo" refers to the =O radical.

[0026] "Thioxo" refers to the =S radical.

[0027] "Imino" refers to the =NH radical.

[0028] "Oximo" refers to the =N-OH radical.

[0029] "Hydrazino" refers to the =N-NH2 radical.

[0030] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 15 carbon atoms (e.g., C1-C 15 In certain embodiments, alkyl includes 1 to 13 carbon atoms (e.g., C-C 13 In certain embodiments, the alkyl comprises 1-8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl comprises 1-5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl comprises 1-4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl comprises 1-3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl comprises 1-2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl comprises 5-15 carbon atoms (e.g., C5-C6 alkyl). 15In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group comprises methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tent-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may be selected from the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )C(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), optionally replaced by one or more of R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0031] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0032] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkenyl contains from 2 to 8 carbon atoms. In other embodiments, an alkenyl contains from 2 to 4 carbon atoms. An alkenyl is attached to the remainder of the molecule by a single bond, and is, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified in the specification, an alkenyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(Ra )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )C(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), optionally replaced by one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0033] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, an alkynyl contains from 2 to 8 carbon atoms. In other embodiments, an alkynyl contains from 2 to 6 carbon atoms. In other embodiments, an alkynyl contains from 2 to 4 carbon atoms. An alkynyl is attached to the remainder of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless otherwise specified in the specification, an alkyl group may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )C(O) t R a (t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), optionally replaced by one or more of R aare each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0034] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain that connects the remainder of the molecule to a radical group, consists solely of carbon and hydrogen, contains no unsaturation, and has 1 to 12 carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through one carbon in the alkylene chain, or through any two carbons within the chain. In certain embodiments, the alkylene contains 1 to 8 carbon atoms (e.g., C1-C8 alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (e.g., C1-C5 alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (e.g., C1-C4 alkylene). In other embodiments, the alkylene contains 1 to 3 carbon atoms (e.g., C1-C3 alkylene). In other embodiments, the alkylene comprises 1 to 2 carbon atoms (e.g., C1-C2 alkylene). In other embodiments, the alkylene comprises 1 carbon atom (e.g., C1 alkylene). In other embodiments, the alkylene comprises 5 to 8 carbon atoms (e.g., C5-C8 alkylene). In other embodiments, the alkylene comprises 2 to 5 carbon atoms (e.g., C2-C5 alkylene). In other embodiments, the alkylene comprises 3 to 5 carbon atoms (e.g., C3-C5 alkylene). Unless otherwise specified in the specification, the alkylene chain may include the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR, -O- ... a , -SR a , -OC(O)-R a , -N(R a )2, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR a , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )C(O) t R a(t is 1 or 2), -S(O) t OR a (t is 1 or 2), -S(O) t R a (t is 1 or 2), and -S(O) t N(R a )2 (where t is 1 or 2), optionally replaced by one or more of R a are each independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0035] "Aryl" refers to a radical derived from a monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon of 5 to 18 carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to Hückel's theory. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless otherwise specifically stated in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is intended to include aryl radicals that are optionally substituted with one or more substituents, where the one or more substituents are independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra)2, -R b -N(R a )C(O)OR a , -R b -N(Ra )C(O)R a , -R b -N(R a )S(O) t Ra (t is 1 or 2), -R b -S(O) t Ra (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0036] "Aralkyl" is a group of the formula -R c -aryl radical, R cis an alkylene chain as defined above, e.g., methylene or ethylene. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0037] "Carbocyclyl" or "cycloalkyl" refers to a non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting exclusively of carbon and hydrogen atoms, including fused or bridged ring systems, having from 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains from 3 to 10 carbon atoms. In other embodiments, a carbocyclyl contains from 5 to 7 carbon atoms. A carbocyclyl is attached to the remainder of the molecule by a single bond. A carbocyclyl is saturated (i.e., contains only single C-C bonds) or unsaturated (i.e., contains one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as "cycloalkenyls". Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise specifically stated in the specification, the term "carbocyclyl" is intended to include carbocyclyl radicals optionally substituted by one or more substituents, the one or more substituents being independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-R a , -R b -OC(O)-ORa , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra)2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t Ra (t is 1 or 2), -R b -S(O) t Ra (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0038] A "carbocyclylalkyl" is a group of the formula -R c - refers to the carbocyclyl radical, R c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical are optionally substituted as defined above.

[0039] "Halo" or "halogen" refers to a bromo, chloro, fluoro, or iodo substituent.

[0040] "Fluoroalkyl" refers to an alkyl radical, as defined above, which is substituted with one or more fluoro radicals, as defined above, such as, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0041] "Heterocyclyl" or "heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specified in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, optionally including fused or bridged ring systems. The heteroatoms in a heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the remainder of the molecule by any atom of the ring. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specifically stated in the specification, the term "heterocyclyl" is intended to include heterocyclyl radicals, as defined above, optionally substituted by one or more substituents, said one or more substituents being alkyl, alkenyl, alkynyl, halo, fluoroalkyl, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R b -OR a , -R b -OC(O)-Ra , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra)2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t Ra (t is 1 or 2), -R b -S(O) t Ra (t is 1 or 2), -R b -S(O) t OR a (t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R aare independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0042] "N-heterocyclyl" or "N-linked heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but are not limited to, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0043] "C-heterocyclyl" or "C-linked heterocyclyl" refers to a heterocyclyl radical as defined above that contains at least one heteroatom, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0044] "Heteroaryl" refers to a radical derived from a 3-18 membered aromatic ring radical containing 2-17 carbon atoms and 1-6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, where at least one of the rings in the ring system is fully unsaturated, i.e., contains a cyclic delocalized (4n+2) π-electron system according to the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatoms in a heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the remainder of the molecule through any atom of the ring. Examples of heteroaryls include azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl yl), oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, Pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6, 7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-d]pyridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated herein, the term "heteroaryl" is intended to include heteroaryl radicals as defined above, optionally substituted by one or more substituents, said one or more substituents being alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a , -R b -OC(O)-R a , -R b -OC(O)-OR a , -R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a , -R b -C(O)OR a , -R b -C(O)N(R a )2, -R b -OR c -C(O)N(Ra)2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t Ra (t is 1 or 2), -R b -S(O) t Ra (t is 1 or 2), -R b -S(O) t OR a(t is 1 or 2), and -R b -S(O) t N(R a ) 2 (t is 1 or 2), and each R a are independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl); R b are each independently a straight bond, or a straight or branched alkylene or alkenylene chain; R c is a straight or branched alkylene or alkenylene chain and each of the above substituents is unsubstituted unless otherwise specified.

[0045] "N-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above, where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] In some embodiments, the compounds disclosed herein contain one or more asymmetric centers, which give rise to enantiomers, diastereomers, and other stereoisomeric forms defined in terms of absolute stereochemistry as (R) or (S). Unless otherwise specified, all stereoisomeric forms of the compounds disclosed herein are intended to be contemplated by the present disclosure. When the compounds described herein contain an alkene double bond, the present disclosure is intended to include both E and Z geometric isomers (e.g., cis or trans), unless otherwise specified. Similarly, all possible isomers, their racemic and optically pure forms, and all tautomers are intended to be included. The term "geometric isomer" refers to the E or Z geometric isomers (e.g., cis or trans) of the alkene double bond. The term "positional isomer" refers to structural isomers around a central ring, such as ortho, meta, and para isomers around a benzene ring.

[0048] "Tautomer" refers to a molecule that can undergo proton transfer from one atom of the molecule to another atom of the same molecule. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on various factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium include the following:

[0049] [ka]

[0050] In some embodiments, the compounds disclosed herein are used in various isotopic enriched forms, e.g., 2 H, 3 H, 11 C. 13 C, and / or 14 In one particular embodiment, the compound is deuterated at at least one position. Such deuterated forms can be made by the procedures described in U.S. Patents 5,846,514 and 6,334,997. As described in U.S. Patents 5,846,514 and 6,334,997, deuteration can improve metabolic stability or efficacy, thereby increasing the duration of action of pharmaceutical agents.

[0051] Unless otherwise stated, structures depicted herein are meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of a hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure, except for the replacement of a carbon with a C-rich carbon, are within the scope of this disclosure.

[0052] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I), or carbon-14 ( 14 C) may be labeled with an isotope. 2 H, 11 C. 13 C. 14 C. 15 C. 12 N, 13 N, 15 N, 16 N, 16 O. 17 O. 14 F, 15 F, 16 F, 17 F, 18 F, 33 S,34 S, 35 S, 36 S, 35 Cl, 37 Cl, 79 Br, 81 Br, 125 All isotopic substitutions at I are contemplated. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.

[0053] In certain embodiments, the compounds disclosed herein are 2 Substituted with H atom 1 Having some or all of the H atoms. Methods for synthesizing compounds containing deuterium are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0054] Deuterium substituted compounds are synthesized using a variety of methods such as those described in Dean, Dennis C., ed., Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000;6(10)] 2000, 110pp, George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21, and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0055] Deuterated starting materials are readily available and amenable to the synthesis methods described herein to effect the synthesis of compounds containing deuterium. Many deuterium-containing reagents and building blocks are commercially available from chemical companies such as Aldrich Chemical Co.

[0056] "Pharmaceutically acceptable salts" include both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. In certain pharmaceutical embodiments of the present disclosure, "pharmaceutically acceptable salts" may be utilized.

[0057] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and are formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, hydroiodic, hydrofluoric, phosphorous, etc. Also included are salts formed with organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, such as, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared in some embodiments by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to those of skill in the art. In certain pharmaceutical embodiments of the present disclosure, a "pharmaceutically acceptable acid addition salt" may be utilized.

[0058] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali, alkaline earth metals, or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and base ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra. Certain pharmaceutical embodiments of the present disclosure may utilize "pharmaceutical acceptable base addition salts."

[0059] As used herein, "treatment of" or "treating", "applying", "palliating" or "ameliorating" are used interchangeably. Such terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, therapeutic benefit and / or prophylactic benefit. "Therapeutic benefit" refers to the eradication or alleviation of the underlying disease or condition being treated. Similarly, therapeutic benefit is achieved by the eradication or alleviation of one or more physiological symptoms associated with the underlying disease or condition, such that an improvement is observed in the patient despite the patient still suffering from the underlying disease or condition. For prophylactic benefit, the composition is administered in some embodiments to a patient at risk of developing a particular disorder or condition, or a patient reporting one or more physiological symptoms of the disorder or condition, even if the disorder or condition has not been diagnosed. In certain pharmaceutical embodiments of the present disclosure, the terms "treatment of" or "treating," "applying," "palliating," or "ameliorating" may be utilized.

[0060] "Prodrug" is intended to refer to a compound that, in some embodiments, is converted under physiological conditions or by solvolysis to a biologically active compound as described herein. Thus, the term "prodrug" refers to a pharma- ceutically acceptable precursor of a biologically active compound. Prodrugs are usually inactive when administered to a subject, but are converted to an active compound in vivo, for example, by hydrolysis. Prodrug compounds often have advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 79, 21 24 (Elsevier, Amsterdam)). In certain pharmaceutical embodiments of the present disclosure, the term "prodrug" may be utilized.

[0061] A discussion of prodrugs is provided in Higuchi, T. et al., "Pro drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0062] The term "prodrug" is also intended to include any covalently bonded carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds as described herein are prepared by modifying functional groups present in the active compound in a manner such that the functional group modification is cleaved in vivo to the parent active compound by routine manipulation. Prodrugs include compounds bonded to any group that cleaves a hydroxy, amino, or mercapto group to form a free hydroxy, free amino, or free mercapto group, respectively, when the prodrug of the active compound is administered to a mammalian subject. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate derivatives of alcohol or amine functional groups in the active compound, and the like.

[0063] As used herein, "conservative substitution" refers to the replacement of one amino acid with another amino acid that has similar properties such as size, charge, and polarity. Substitutions may be made to natural or modified (e.g., non-natural amino acids). Non-limiting examples of what may be replaced with conservative substitutions include large hydrophobic substances (valine, leucine, isoleucine, phenylalanine, tryptophan, tyrosine, methionine), small non-polar substances (alanine, glycine), polar substances (serine, threonine, glutamine, asparagine, cysteine, histidine), positively charged substances (lysine, arginine), and negatively charged substances (glutamate, aspartate).

[0064] When % is used herein to refer to the amount of an ingredient, it is intended to be % w / w unless otherwise specified.

[0065] The terms "penetration enhancer" and "penetration enhancer" are used interchangeably herein. As used herein, the terms refer to one or more components that promote or enhance the penetration of one or more active ingredients (e.g., anionic polymeric substances such as hyaluronic acid, or peptide antagonists) through one or more layers of the skin of a subject. In some embodiments, the penetration enhancer is, for example, a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of about 10 or less, a cationic group, or another agent, such as a terpene, an alkaloid, a salicylate derivative, a nicotinic acid derivative, or any combination thereof.

[0066] As used herein, the term "multisome" refers to lipid vesicles (such as biphasic lipid vesicles) that contain one or more penetration enhancers, and in preferred embodiments, to those that contain multiple penetration enhancers that act synergistically. In some embodiments, multisomes include vesicles in which the central core compartment is occupied by an oil-in-water emulsion composed of a continuous aqueous phase and a dispersed hydrophobic, hydrophilic, or oil phase. In one embodiment, the space between adjacent bilayers of the lipid vesicle may also be occupied by an emulsion.

[0067] As used herein, the term "lipid vesicle composition" refers to a composition that includes one or more lipid vesicles (e.g., multisome lipid vesicles, lipid bilayer vesicles, etc.). When a lipid vesicle is described as "comprising" one or more additional components (e.g., an anionic polymeric substance provided herein, or a peptide antagonist), it is intended that the additional components are included in the composition in any manner (e.g., encapsulated within the lipid vesicle). For example, a lipid vesicle composition that includes an anionic polymeric substance may include an anionic polymeric substance encapsulated within the lipid bilayer of the lipid vesicle composition.

[0068] As used herein, the term "emulsion" refers to a mixture of two immiscible substances.

[0069] As used herein, the term "bilayer" refers to a structure composed of amphipathic lipid molecules arranged in two molecular layers, with hydrophobic tails on the inner surface and polar head groups on the outer surface.

[0070] As used herein, the term "topical administration" or "topical delivery" refers to intradermal, transdermal, and / or transmucosal delivery of a compound by administering a compound or a composition containing multiple compounds to the skin and / or mucosa.

[0071] As used herein, the term "gemini surfactant" refers to a surfactant molecule that includes more than one hydrophobic tail, each of which has a hydrophilic head, and the hydrophobic tails or hydrophilic heads are linked together by a spacer moiety. The hydrophobic tails may be the same or different. Similarly, the hydrophilic heads may be the same or different. The hydrophilic heads may be anionic, cationic, or neutral.

[0072] The term "HLB" or "hydrophilic-lipophilic balance" value refers to the standard HLB as set forth in Griffin, J. Soc. Cosm. Chem., vol. 5, 249 (1954), and indicates the degree of hydrophilicity and lipophilicity of a surfactant.

[0073] Melanocortin 1 receptor (MC1R) The present disclosure relates to peptide antagonists of the melanocortin 1 receptor, also called MC1R, a G protein-coupled receptor at amino acid 317 found in the melanocyte plasma membrane. MC1R has seven alpha-helical transmembrane domains with a DRY (Asp-Arg-Tyr) motif at the binding site of the third transmembrane domain, an intracellular C-terminus with a palmitoylation site, and an extracellular N-terminus with an N-linked glycosylation site. Three intracellular and three extracellular loops are formed by insertion into the membrane. The extracellular transmembrane domain interacts with MC1R ligands. The intracellular transmembrane domain regulates signal transduction, including interaction with adenylyl cyclase. (See, e.g., Wolf Horrell, 2016, Frontiers in Genetics 7(95):1-16, incorporated herein by reference.)

[0074] MC1R binds to pituitary hormones, including adrenocorticotropic hormone (ACTH), and alpha-MSH (α-MSH), a nonselective agonist of the melanocortin receptors (MCR-1, 3, 4, and 5). Upon binding by α-MSH, MC1R becomes activated, causing melanocytes to switch from producing yellow / red pheomelanin (default) to producing brown / black eumelanin.

[0075] In the adaptive pigmentation pathway, α-melanocyte-stimulating hormone (α-MSH) is produced in response to UV radiation damage in epidermal keratinocytes. α-MSH binds to MC1R on the surface of melanocytes to signal enhanced synthesis of melanin pigment. α-MSH agonism of MC1R increases melanocyte production of darkly pigmented eumelanin and increases the transfer of eumelanin-containing melanosomes to keratinocytes. Although dark pigmentation can protect an individual from further damage caused by exposure to UV radiation, in many cases, excessive pigmentation is undesirable.

[0076] The peptide antagonists of the present disclosure bind to the active site of MC1R and block the binding of α-MSH to MC1R, ultimately decreasing the production of eumelanin and decreasing melanin deposits present in the epidermis.

[0077] Melanocortin 1 receptor peptide antagonists The present disclosure provides peptide antagonists of MC1R and compositions thereof. In some embodiments, the peptide antagonists of the present disclosure have desirable or improved properties compared to MC1R antagonists known in the art. Such properties include, for example, pharmacokinetic properties (including, but not limited to, absorption, bioavailability, distribution, metabolism, and excretion), pharmacodynamic properties (including, but not limited to, receptor binding characteristics, such as binding half-life, post-receptor effects, and chemical interactions), enhanced activity (e.g., IC 50 These properties may include the ability to tolerate a given concentration of a peptide antagonist, stability (e.g., as expressed by half-life), solubility (e.g., in a formulation), or permeability (e.g., skin permeability of a formulation containing a peptide antagonist). In some embodiments, a formulation containing a peptide antagonist of the present disclosure has desirable properties or improved properties compared to formulations containing MC1R antagonists known in the art. In some embodiments, the desirable or improved properties of a formulation of the present disclosure are properties associated with the use of the formulation for an indication as described elsewhere herein, e.g., use to reduce or ameliorate the appearance of skin discoloration.

[0078] Class A MC1R peptide antagonists

[0079] In some embodiments, the MC1R peptide antagonists of the present disclosure are Group A MC1R peptide antagonists, also referred to herein as Group A peptide antagonists. In some embodiments, the Group A MC1R peptide antagonists of the present disclosure have 8-9 amino acid residues and comprise or consist of the following amino acid sequence:

[0080] Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9

[0081] During the ceremony,

[0082] Xaa1 is absent or Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D -Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, D-Glu, and a derivative of Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln or D-Glu;

[0083] Xaa2 is selected from Pro, D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of Pro, D-Pro, Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile;

[0084] Xaa3 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr;

[0085] Xaa4 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys;

[0086] Xaa5 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr;

[0087] Xaa6 is selected from Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, and derivatives of Phe, Trp, Tyr, D-Phe, D-Trp, or D-Tyr;

[0088] Xaa7 is selected from Arg, His, Lys, D-Arg, D-His, D-Lys, and derivatives of Arg, His, Lys, D-Arg, D-His, or D-Lys;

[0089] Xaa8 is selected from Pro, D-Pro, and derivatives of Pro or D-Pro;

[0090] Xaa9 is selected from Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, D-Ile, and derivatives of Ala, Gly, Val, Leu, Ile, D-Ala, D-Gly, D-Val, D-Leu, or D-Ile;

[0091] The N-terminus is optionally modified,

[0092] The C-terminus is optionally modified.

[0093] In some embodiments, the peptide antagonist of the present disclosure does not consist of the following amino acid sequence:

[0094] Met-Pro-D-Phe-Arg-D-Trp-Phe-Lys-Pro-Val (SEQ ID NO: 1) (melanostatin-5, or nonapeptide-1).

[0095] In some embodiments, the number of amino acid residues in the Group A peptide antagonists of the present disclosure is no more than 8 or no more than 9. In embodiments, the Group A peptide antagonists of the present disclosure consist of 8 or 9 amino acid residues.

[0096] Non-limiting examples of amino acid sequences of Group A peptide antagonists of the present disclosure are provided in Table 1. In some embodiments, the Group A MC1R peptide antagonists of the present disclosure comprise or consist of the amino acid sequences set forth in Table 1. The MC1R peptide antagonists described herein, including those set forth in Tables 1 and 2, may comprise or consist of amino acid sequences of the present disclosure having amino- and / or carboxy-terminal modifications other than those shown.

[0097] [Table 1]

[0098] In some embodiments, SEQ ID NO: 16 or 32 has a lower IC when compared to a reference (e.g., SEQ ID NO: 1) using a competitive assay. 50 In some embodiments, the IC 50 In some embodiments, the IC 50Values ​​include, for example, from about 70 nM to about 75 nM, from about 70 nM to about 80 nM, from about 70 nM to about 85 nM, from about 70 nM to about 90 nM, from about 70 nM to about 100 nM, from about 70 nM to about 110 nM, from about 70 nM to about 120 nM, from about 70 nM to about 130 nM, from about 70 nM to about 140 nM, from about 70 nM to about 150 nM, from about 70 nM to about 160 nM, from about 75 nM to about 80 nM, from about 75 nM to about 85 nM, from about 75 nM to about 90 nM, from about 75 nM to about 100 nM, from about 75 nM to about 110 nM, from about 75 nM to about 120 nM, 5nM to about 130nM, about 75nM to about 140nM, about 75nM to about 150nM, about 75nM to about 160nM, about 80nM to about 85nM, about 80nM to about 90nM, about 80nM to about 100nM, about 80nM to about 110nM, about 80nM to about 120nM, about 80nM to about 130nM, about 80nM to about 140nM, about 80nM to about 150nM, about 80nM to about 160nM, about 85nM to about 90nM, about 85nM to about 100nM, about 85nM to about 110nM, about 85nM to about 120nM, about 85 nM to about 130 nM, about 85 nM to about 140 nM, about 85 nM to about 150 nM, about 85 nM to about 160 nM, about 90 nM to about 100 nM, about 90 nM to about 110 nM, about 90 nM to about 120 nM, about 90 nM to about 130 nM, about 90 nM to about 140 nM, about 90 nM to about 150 nM, about 90 nM to about 160 nM, about 100 nM to about 110 nM, about 100 nM to about 120 nM, about 100 nM to about 130 nM, about 100 nM to about 140 nM, about 100 nM to about 150 nM, about 100 nM to about 1 60 nM, about 110 nM to about 120 nM, about 110 nM to about 130 nM, about 110 nM to about 140 nM, about 110 nM to about 150 nM, about 110 nM to about 160 nM, about 120 nM to about 130 nM, about 120 nM to about 140 nM, about 120 nM to about 150 nM, about 120 nM to about 160 nM, about 130 nM to about 140 nM, about 130 nM to about 150 nM, about 130 nM to about 160 nM, about 140 nM to about 150 nM, about 140 nM to about 160 nM, or about 150 nM to about 160 nM. 50The value is about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 100 nM, about 110 nM, about 120 nM, about 130 nM, about 140 nM, about 150 nM, or about 160 nM. 50 The value is at least about 70 nM, about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 100 nM, about 110 nM, about 120 nM, about 130 nM, about 140 nM, or about 150 nM. 50 The value is up to about 75 nM, about 80 nM, about 85 nM, about 90 nM, about 100 nM, about 110 nM, about 120 nM, about 130 nM, about 140 nM, about 150 nM, or about 160 nM.

[0099] Group B peptide antagonists

[0100] In some embodiments, the MC1R peptide antagonists of the present disclosure are Group B MC1R peptide antagonists, also referred to herein as Group B peptide antagonists. In some embodiments, the Group B peptide antagonists of the present disclosure have between 8 and 26 amino acid residues and comprise the amino acid sequence:

[0101] Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa1 4-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Xaa22-Xaa23-Xaa24-Xaa25-Xaa26

[0102] During the ceremony,

[0103] Xaa1 is absent or Xaa1 and Xaa19 form the bond Xaa1-Xaa19;

[0104] Xaa2 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0105] Xaa3 is absent or selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu;

[0106] Xaa4 is absent or is selected from Pro and derivatives of Pro;

[0107] Xaa5 is absent or Xaa5 and Xaa26 form the bond Xaa5-Xaa26;

[0108] Xaa6 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0109] Xaa7 is absent or selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, or Thr;

[0110] Xaa8 is absent or selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu, and / or Xaa8 and Xaa19 form the bond Xaa8-Xaa19,

[0111] Xaa9 is absent or selected from Phe, Trp, Tyr, Asn, Asp, Gln, Glu, and derivatives of Phe, Trp, Tyr, Asn, Asp, Gln, or Glu;

[0112] Xaa10 and Xaa17 form the bond Xaa10-Xaa17,

[0113] Xaa11 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys;

[0114] Xaa12 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr;

[0115] Xaa13 is selected from Phe, Trp, Tyr, and derivatives of Phe, Trp, or Tyr;

[0116] Xaa14 is selected from Arg, His, Lys, and derivatives of Arg, His, or Lys;

[0117] Xaa15 is selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr;

[0118] Xaa16 is selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0119] Xaa18 is absent or selected from Phe, Trp, Tyr, Cys, Met, Sec, Ser, Thr, and derivatives of Phe, Trp, Tyr, Cys, Met, Sec, Ser, or Thr;

[0120] Xaa19 is absent or is selected from Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, Glu, and derivatives of Ala, Gly, Val, Leu, Ile, Arg, His, Lys, Asn, Asp, Gln, or Glu, and / or Xaa8 and Xaa19 form the bond Xaa8-Xaa19, or Xaa1 and Xaa19 form the bond Xaa1-Xaa19,

[0121] Xaa20 is absent or selected from Arg, His, Lys, and derivatives of Arg, His, or Lys;

[0122] Xaa21 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0123] Xaa22 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0124] Xaa23 is absent or selected from Cys, Met, Sec, Ser, Thr, and derivatives of Cys, Met, Sec, Ser, and Thr;

[0125] Xaa24 is absent or selected from Ala, Gly, Val, Leu, Ile, and derivatives of Ala, Gly, Val, Leu, or Ile;

[0126] Xaa25 is absent or selected from Asn, Asp, Gln, Glu, and derivatives of Asn, Asp, Gln, or Glu;

[0127] Xaa26 is absent or Xaa5 and Xaa26 form the bond Xaa5-Xaa26;

[0128] The N-terminus is optionally modified,

[0129] The C-terminus is optionally modified.

[0130] In some embodiments, the amino acid sequence of the peptide antagonist of the present disclosure does not consist of Cys-Cys-Asp-Pro-Cys-Ala-Ser-Cys-Gln-Cys-Arg-Phe-Phe-Arg-Ser-Ala-Cys-Ser-Cys-Arg-Val-Leu-Ser-Leu-Asn-Cys (SEQ ID NO:2) (the agouti signal protein, or ASIP-subdomain, residues 107-132 of full-length ASIP (SEQ ID NO:91)). See, e.g., Wolf Horrell, 2016, cited above and incorporated by reference herein. With reference to the amino acid numbering of SEQ ID NO:2, the ASIP subdomain includes bonds between residues 1 to 19, between 5 to 26, and between 10 to 17. In some embodiments, the amino acid sequence of a peptide antagonist of the disclosure does not consist of SEQ ID NO:2, which contains a bond between residues 1 and 19 (also referred to herein in the context of Group B peptides as a "Xaa1-Xaa19" bond), a bond between 5 and 26 (also referred to herein in the context of Group B peptides as a "Xaa5-Xaa26" bond), and / or a bond between 10 and 17 ("Xaa10-Xaa17" bond in Group B peptides).

[0131] In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of the amino acid sequence of agouti signal protein set forth as SEQ ID NO: 91. (See, e.g., UniProtKB-P42127, incorporated herein by reference.) In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of a portion of SEQ ID NO: 91 having an N-terminus at any one of positions 1-106, a C-terminus at any one of positions 125-132, or both. In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of a portion of SEQ ID NO: 91 having an N-terminus at any one of positions 1-106, a C-terminus at any one of positions 125-132, or both, and including bonds between residues 107-125, between 111-132, and / or between residues 116-123. In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of a portion of SEQ ID NO: 91 selected from 23-132 (mature ASIP, SEQ ID NO: 92), 80-132, 93-132, and 106-132, with or without bonds between residues 107-125, between 111-132, and / or between 116-123, respectively.

[0132] In some embodiments the amino acid sequence of the peptide antagonist of the disclosure does not consist of Lys-Lys-Val-Val-Arg-Pro-Arg-Thr-Pro-Leu-Ser-Ala-Pro-Cys-Val-Ala-Thr-Arg-Asn-Ser-Cys-Lys-Pro-Pro-Ala-Pro-Ala-Cys-Cys-Asp-Pro-Cys-Ala-Ser-Cys-Tyr-Cys-Arg-Phe-Phe-Arg-Ser-Ala-Cys-Tyr-Cys-Arg-Val-Leu-Ser-Leu-Asn-Cys (ASIP-YY, SEQ ID NO: 93, which is ASIP80-132, Q115Y, S124Y). ASIP-YY is described, for example, in McNulty et al., 2005, J. Mol. Bio. 346:1059-1070, the entire contents of which are incorporated herein by reference. In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of a portion of SEQ ID NO: 93 having an N-terminus at any one of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27. In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure has an N-terminus selected from any one of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27, and does not consist of a sequence selected from a portion of SEQ ID NO: 3 having a bond between or without residues 28 to 46, 32 to 53, and / or 37 to 44. In some embodiments, the amino acid sequence of a peptide antagonist of the present disclosure does not consist of residues 28-53 of the ASIP-YY subdomain of SEQ ID NO: 94 having a bond between or without residues 15 to 33, 19 to 40, and / or 22 to 31.

[0133] In some embodiments, the amino acid sequence of the peptide antagonist of the present disclosure does not consist of Cys-Cys-Asp-Pro-Cys-Ala-Ser-Cys-Tyr-Cys-Arg-Phe-Phe-Arg-Ser-Ala-Cys-Tyr-Cys-Arg-Val-Leu-Ser-Leu-Asn-Cys (SEQ ID NO: 3) (ASIP-YY subdomain, ASIP-YY residue 2853, corresponding to ASIP residues 107-132). In some embodiments, the amino acid sequence of the peptide antagonist of the present disclosure does not consist of SEQ ID NO: 3 having a bond between residues 1 to 19, between 5 to 26, and / or between 10 to 17, or no bond therebetween. In some embodiments, the peptide antagonist of the present disclosure does not consist of a sequence selected from a portion of SEQ ID NO: 3 having an N-terminus selected from any one of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9. In some embodiments, the peptide antagonists of the disclosure have an N-terminus selected from any one of positions 1, 2, 3, 4, 5, 6, 7, 8, or 9, and do not consist of a sequence selected from a portion of SEQ ID NO:3 having a bond between residues 1 and 19, between 5 and 26, and / or between 10 and 17, or having no bond therebetween.

[0134] In some embodiments, the number of amino acid residues in the Group B peptide antagonists of the present disclosure is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26. In some embodiments, the number of amino acid residues in the Group B peptide antagonists of the present disclosure is no more than 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26. In some embodiments, the number of amino acid residues in the Group B peptide antagonists of the present disclosure is no more than 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26.

[0135] Non-limiting examples of amino acid sequences of Group B peptide antagonists of the present disclosure are provided in Table 2. In some embodiments, the Group B MC1R peptide antagonists of the present disclosure comprise or consist of the amino acid sequences set forth in Table 2.

[0136] [Table 2-1]

[0137] [Table 2-2]

[0138] 1 contains a disulfide (Cys-Cys) bond at (Xaa5-Xaa26), 2 contains a disulfide (Cys-Cys) bond at (Xaa10-Xaa17), 3 contains a disulfide (Cys-Cys) bond at (Xaa1-Xaa19), 4 contains a lactam bridge at (Xaa8-Xaa19) (see bold), 5 contains a diproline bond at (Xaa10-Xaa17), 6 contains a glycine-glycine head-to-tail bond at (Xaa8-Xaa19) and all numbering refers to the numbering of Xaa1-Xaa26 of Group B peptides (absent positions are not shown in the table).

[0139] The peptides of the disclosure, including those listed in Tables 1 and 2, may include L-amino acids, D-amino acids, or combinations thereof. L-amino acids are designated without further designation, e.g., "Pro", or with or without punctuation, e.g., upper or lower case L, e.g., "L-" as in "L-Pro", "(L)" as in "(L)Pro". D-amino acids are designated with or without punctuation, e.g., upper or lower case D, e.g., "D-" as in "D-Pro", "(d)" as in "(d)Pro", "d" as in "dPro".

[0140] Amino acid substitutions

[0141] In any of the embodiments herein, amino acid substitutions are made at one or more positions, as desired.

[0142] Amino acids can be classified based on the chemical and structural properties of their side chains; for example, naturally occurring amino acids can be classified as hydrophobic (norleucine, Met, Ala, Val, Leu, and Ile), neutral hydrophilic (Cys, Ser, Thr, Asn, and Gln), acidic (Asp and Glu), basic (His, Lys, and Arg), chain orienting (Gly and Pro), and aromatic (Trp, Tyr, and Phe).

[0143] In some embodiments, conservative amino acid substitutions are made by replacing an amino acid of one of the above-mentioned classes with a different member of that class, hi some embodiments, conservative substitutions encompass non-naturally occurring amino acid residues, including peptidomimetics and other reversed or inverted forms of amino acid moieties.

[0144] In some embodiments, non-conservative substitutions are made by replacing an amino acid of one of the above-mentioned classes with a different member of that class.

[0145] In some embodiments, substitutions take into account the hydropathic index of amino acids (see, e.g., Kyte et al., 1982, J. Mol. Biol. 157:105-131, incorporated herein by reference). The hydropathic profile of a peptide can be calculated by giving each amino acid a numerical value, i.e., hydropathic index, and iteratively averaging these values ​​along the peptide chain. In such embodiments, each amino acid is assigned a hydropathic index based on its hydrophobicity and charge characteristics. In some embodiments, the hydropathic indexes used are isoleucine (+4.5), valine (+4.2), leucine (+3.8), phenylalanine (+2.8), cysteine / cystine (+2.5), methionine (+1.9), alanine (+1.8), glycine (-0.4), threonine (-0.7), serine (-0.8), tryptophan (-0.9), tyrosine (-1.3), proline (-1.6), histidine (-3.2), glutamate (-3.5), glutamine (-3.5), aspartate (-3.5), asparagine (-3.5), lysine (-3.9), and arginine (-4.5). In some embodiments, an amino acid is replaced with a different amino acid whose hydropathic index is within 0.1 to 0.5 of the original amino acid. In some embodiments, the hydropathic index is within 0.1, 0.2, 0.3, 0.4, or 0.5 of the original amino acid.

[0146] In some embodiments, amino acid substitutions are made based on hydrophilicity. In some embodiments, the hydrophobicity values ​​used are arginine (+3.0), lysine (+3.0), aspartate (+3.0.+-.1), glutamate (+3.0.+-.1), serine (+0.3), asparagine (+0.2), glutamine (+0.2), glycine (0), threonine (-0.4), proline (-0.5.+-.1), alanine (-0.5), histidine (-0.5), cysteine ​​(-1.0), methionine (-1.3), valine (-1.5), leucine (-1.8), isoleucine (-1.8), tyrosine (-2.3), phenylalanine (-2.5), and tryptophan (-3.4).

[0147] In some embodiments, an amino acid is replaced with a different amino acid that has a hydrophobicity value within 0.1 to 0.5 of the original amino acid, hi some embodiments, the hydrophobicity value is within 0.1, 0.2, 0.3, 0.4, or 0.5 of the original amino acid.

[0148] In some embodiments, amino acids are substituted as shown in the table below. In some embodiments, amino acids are substituted with conservative substitutions, or derivatives of conservative substitutions (also referred to herein as analogs), set forth in Table 3(I). In some embodiments, amino acids are substituted with alternative substitutions, or derivatives of alternative substitutions, set forth in Table 3(II), which shows a complete list of each surrogate for each amino acid.

[0149] [Table 3-1]

[0150] [Table 3-2]

[0151] [Table 3-3]

[0152] [Table 3-4]

[0153] [Table 3-5]

[0154] restraint structure

[0155] In some embodiments, the peptide antagonists of the present disclosure comprise a constrained structure, including, but not limited to, a bond between residues at two positions, a cross-link, or any means of ligation. In some embodiments, the peptide is constrained by its termini, at multiple positions within the peptide, or both. In some embodiments, the constrained structure enhances peptide antagonist properties, such as pharmacokinetic properties (including, but not limited to, absorption, bioavailability, distribution, metabolism, and excretion), pharmacodynamic properties (including, but not limited to, receptor binding characteristics, such as binding half-life, post-receptor effects, and chemical interactions), enhanced activity (e.g., IC 50 The constrained structure may affect the stability (e.g., as represented by half-life), solubility (e.g., in a formulation), or permeability (e.g., skin permeability of a formulation containing the peptide antagonist). In certain embodiments, the constrained structure enhances the stability of the peptide antagonist. In certain embodiments, the constrained structure increases the skin permeability of the peptide antagonist. In certain embodiments, the constrained structure increases the solubility of the peptide antagonist in a formulation, e.g., a topical formulation.

[0156] In embodiments, the peptide antagonists constrained as described herein are referred to as macrocyclic peptides or structures. Macrocyclic peptides refer to closed ring structures of linear peptides formed intramolecularly by a bond between two positions in the peptide, and macrocyclic peptides are referred to as linking amino acids, linking amino acid derivatives, linking molecules, linking moieties, linking residues, linking entities, etc., as appropriate. Two linking amino acids, linking amino acid derivatives, linking molecules, linking moieties, linking residues, or linking entities are separated from each other by two or more amino acid residues, are directly bonded to each other, are linked via a linker, etc.

[0157] In embodiments, the bond of the peptide antagonists of the present disclosure is formed by two linked amino acids, linked amino acid derivatives, linked molecules, linked moieties, linked residues, or linked entities that are linked together by, for example, a disulfide bond, a peptide bond, an alkyl bond, an alkenyl bond, an ester bond, a thioester bond, an ether bond, a thioether bond, a phosphonate ether bond, an azo bond, a (C)--S--C bond, a C=N--C bond, a C=N--C bond, an amide bond, a lactam bridge, a carbamoyl bond, a urea bond, a thiourea bond, an amine bond, a thioamide bond, etc. Macrocyclization may be formed by linking the N-terminal amino acid and the C-terminal amino acid of the peptide, by linking a terminal amino acid with a non-terminal amino acid, or by a bond between non-terminal amino acids.

[0158] For convenience, reference to the specific amino acid involved in the bond can use the term for the unlinked amino acid (e.g., the structure that the amino acid may have before the formation of the bond). It is also understood that a particular bond, e.g., a synthetic bond, can be formed by connecting two amino acids or derivatives as commonly referred to in the art. Therefore, reference to linked amino acids herein can use the language that most closely approximates to describe each of the participating chemical entities at a given residue position in the peptide antagonist. Accordingly, linked entities in a peptide sequence, e.g., Xaa5 and Xaa26, Xaa10 and Xaa17, Xaa1 and Xaa19, and Xaa8 and Xaa19 of amino acids in group B, can be referred to as linked amino acids, regardless of whether they are amino acids commonly referred to in the art. In some embodiments, Xaa5, Xaa26, XaalO, Xaal7, Xaal, Xaal9, Xaa8, and Xaal9 may alternatively be referred to as bound (or bond-forming) amino acids, bound (or bond-forming) amino acid derivatives, bound (or bond-forming) molecules, bound (or bond-forming) moieties, bound (or bond-forming) residues, or bound (or bond-forming) entities when the entities are linked to form, for example, the bonds Xaa5-Xaa26, XaalO-Xaal7, Xaal-Xaal9, and / or Xaa8-Xaal9. These terms may be used to refer to amino acids, molecules, moieties, residues, or entities present at any of Xaa5, Xaa26, XaalO, Xaal7, Xaal9, Xaa8, and Xaal9, whether linked or unlinked. For example, when two linking amino acids are unlinked but are intended to be linked in the peptidic antagonists of the disclosure, they may alternatively be referred to as linking (or bond-forming) amino acids, linking (or bond-forming) amino acid derivatives, linking (or bond-forming) molecules, linking (or bond-forming) moieties, linking (or bond-forming) residues, or linking (or bond-forming) entities.When linked, the two linked amino acids may alternatively be referred to as linked (or bond-forming) amino acids, linked (or bond-forming) amino acid derivatives, linked (or bond-forming) molecules, linked (or bond-forming) moieties, linked (or bond-forming) residues, or linked (or bond-forming) entities. When not linked and no linkage is intended, the two linked amino acids may be referred to as unlinked (or non-bond-forming) amino acids, unlinked (or non-bond-forming) amino acid derivatives, unlinked molecules, unlinked moieties, unlinked residues, or unlinked entities. In some embodiments, the residues at unlinked amino acid positions in the peptide antagonists of the present disclosure may each be referred to as an amino acid, amino acid derivative, molecule, moiety, residue, or entity, or an unlinked (or non-bond-forming) amino acid, unlinked (or non-bond-forming) amino acid derivative, unlinked (or non-bond-forming) molecule, unlinked (or non-bond-forming) moiety, unlinked (or non-bond-forming) residue, or unlinked (or non-bond-forming) entity.

[0159] Any constraint structure known to those skilled in the art is contemplated for the bond of residues. Examples of constraint structures and their respective bond residues include, but are not limited to, bonds or bridges selected from disulfide bridges (e.g., Cys-Cys bond, where each bond amino acid is Cys), Sec-Sec bond (selenocysteine ​​bond, where each bond amino acid is selenocysteine), cystathionine bond or bridge (e.g., Ser-homocysteine ​​bond), also referred to herein as Cyt-Cyt (e.g., CH2-CH2-S-CH2), lactam bridges (e.g., Asp-Lys or Glu-Lys bond), thioether bond (e.g., Cys-lanthionine bond, including but not limited to dehydroalanine or methyl variants), diproline bond, diglycine bond, and dicarba bond (e.g., bond of olefin-containing amino acids, e.g., allylglycine or prenylglycine). In some embodiments, the linkage is selected from a disulfide bridge with linkage residues Cys-Cys, a selenocysteine ​​linkage with linkage residues Sec-Sec, a cystathionine linkage with linkage residues Ser-homocysteine, a lactam bridge with residues Asp-Lys or Glu-Lys, a lanthionine linkage with linkage residues Cys-dehydroalanine or methyl variants, a diproline linkage with linkage residues L-proline, D-proline, or any combination thereof, a diglycine linkage with linkage residues glycine, and a dicarba linkage with linkage residues allylglycine or prenylglycine. In embodiments, the linkage amino acid, linkage amino acid derivative, linkage molecule, linkage moiety, linkage residue, or linkage entity is selected from Cys, Sec, Ser, homocysteine, Asp, Lys, Glu, dehydroalanine, D-Pro, L-Pro, Gly, or an olefin-containing amino acid (e.g., allylglycine or prenylglycine). In some embodiments, a salt bridge is formed between Lys and Glu (amino to carboxy terminal) or between Glu and Lys (amino to carboxy terminal).

[0160] In some embodiments, each bond of the peptide antagonists of the disclosure, e.g., Xaa5-Xaa26, Xaa10-Xaa17, Xaa1-Xaa19, or Xaa8-Xaa19 of the Group B MC1R peptide antagonists, is a disulfide bridge formed by two Cys bond residues, a Sec-Sec bond formed by two selenocysteine ​​bond residues, a cystathionine bond formed by a Ser bond residue and a homocysteine ​​bond residue, an Asp bond residue and a Lys bond residue, or a Glu bond residue and a Lys bond residue. The bond is independently selected from any of the bonds described in the preceding paragraph, including any of the bonds selected from the lactam bridge formed by Cys, the lanthionine bond formed by Cys and a residue of dehydroalanine or methyl variant, a diproline bond, a diglycine bond, a salt bridge, an olefin-containing bond residue, such as a dicarba bond formed by a bond residue of allylglycine or prenylglycine, or any of these bonds formed by a bond residue known and described in the art. In some embodiments, the peptide antagonist of the present disclosure comprises bonds that are the same or different from each other. The peptide antagonist of the present disclosure may be a group B peptide antagonist that comprises one or more bonds between two terminal residues, between two non-terminal residues, or between a terminal residue and a non-terminal residue. Group B peptide antagonists may comprise bonds (i) Xaa5-Xaa26 and XaalO-Xaal7, (ii) Xaa5-Xaa26, XaalO-Xaal7, and Xaa8-Xaal9, (iii) Xaa5-Xaa26, XaalO-Xaal7, and Xaal-Xaal9, or (iv) XaalO-Xaal7. In some embodiments, Group B peptide antagonists are 24 amino acids in length and comprise bonds Xaa5-Xaa26 and XaalO-Xaal7. In some embodiments, Group B peptide antagonists are 24 amino acids in length and comprise bonds Xaa5-Xaa26 and XaalO-Xaal7, and Xaa8-Xaal9. In some embodiments, Group B peptide antagonists are 24 amino acids in length and include Xaa5-Xaa26 and XaalO-Xaal7, and form a salt bridge to Xaa8-Xaa19.In some embodiments, a salt bridge is formed between Lys and Glu (amino to carboxy terminal direction) or between Glu and Lys (amino to carboxy terminal direction). In some embodiments, the Group B peptide antagonists are 24 amino acids in length and contain bonds at Xaa5-Xaa26 and Xaa10-Xaa17, and Xaa8-Xaa19, where Xaa8-Xaa19 is a lactam bridge. In some embodiments, the Group B peptide antagonists are 24 amino acids in length and contain disulfide bonds at Xaa5-Xaa26 and Xaa10-Xaa17, forming a salt bridge or lactam bridge at Xaa8-Xaa19. In some embodiments, the Group B peptide antagonists are 26 amino acids in length and contain bonds at Xaa5-Xaa26 and Xaa10-Xaa17, and Xaa1-Xaa19. In some embodiments, the Group B peptide antagonists are 26 amino acids in length and comprise disulfide bonds at Xaa5-Xaa26 and Xaa10-Xaa17, and Xaa1-Xaa19. In some embodiments, the Group B peptide antagonists are 8 amino acids in length and comprise a bond at Xaa10-Xaa17. In some embodiments, the Group B peptide antagonists are 8 amino acids in length and comprise a disulfide bond at Xaa10-Xaa17. In some embodiments, the Group B peptide antagonists are 8 amino acids in length and comprise a disulfide bond at Xaa10-Xaa17. In some embodiments, the Group B peptide antagonists are 10 amino acids in length and comprise a bond at Xaa10-Xaa17. In some embodiments, the Group B peptide antagonists are 10 amino acids in length and comprise a disulfide bond at Xaa10-Xaa17. In some embodiments, Group B peptide antagonists are 12 amino acids in length and contain bonds at Xaa10-Xaa17 and Xaa8-Xaa19, where Xaa8 and Xaa19 are the N-terminal and C-terminal residues, respectively.In some embodiments, Group B peptide antagonists are 12 amino acids in length, contain a disulfide bond at Xaa10-Xaa17, and contain a bond between the N-terminal residue Xaa8 and the C-terminal residue Xaa19. In some embodiments, Group B peptide antagonists are 12 amino acids in length, contain a disulfide bond at Xaa10-Xaa17, and contain a diglycine bond between the N-terminal residue Xaa8 and the C-terminal residue Xaa19.(e.g., Knerr et al., 2011, “Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin”, ACS Chem Biol. 6(7):753–760; DiMarco et al., 2006, “Discovery of novel, highly potent and selective b-hairpin mimetic CXCR4 inhibitors with excellent anti-HIV activity and pharmacokinetic profiles”, Bioorganic & Medicinal Chemistry 14:8396~8404; Dekan et al., 2011, "a-Conotoxin ImI incorporating stable cystathionine bridges maintains full potency and identical three-dimensional structure" J.Am.Chem.Soc.2011, 133:15866~15869, Nguyen and Wong, 2017, "Making circles:Chemical and enzymatic approaches in peptide macrocyclization” Journal of Biochemistry and Chemical Sciences 1(1):1-13; Tam and Wong, 2012, "Chemical Synthesis of Circular Proteins," The Journal of Biological Chemistry 287(32):27020-27025, the entire contents of which are incorporated herein by reference.) In some embodiments, any suitable constrained structure resulting from the use of linking residues known in the art is contemplated for use in the peptide antagonists of the present disclosure.

[0161] In some embodiments, a particular constrained structure is selected based on resistance to degradation, for example degradation caused by reduction of the disulfide bond constrained structure. In some embodiments, the peptide antagonist comprises a constrained structure that resists degradation by reduction. For example, in a reducing environment, disulfide bonds may be susceptible to degradation and the resulting loss of activity or other desired peptide antagonist properties. In some embodiments, cystathione linkages, or bonds of at least two C1-C6 heterocycloalkyl rings, have increased stability compared to disulfide bonds.

[0162] In some embodiments, a bond connects two amino acids in a chain to create a macrocyclic ring structure. In some embodiments, the bond mimics a hairpin turn in a peptide. In some embodiments, the bond comprises a covalent bond between standard or non-standard amino acids, such as a cystathionine bond, a lactam bridge, a diproline bridge, a diglycine bridge, or a thioether bridge (e.g., a lanthionine bond). In some embodiments, the bond comprises a non-covalent bond between standard or non-standard amino acids, such as a salt bridge. In some embodiments, the bond comprises a dipeptide. In some embodiments, the bond comprises a covalent bond between standard or non-standard amino acids, such as a lanthionine bond or a methyllanthionine bond. In some embodiments, the bond comprises at least one aromatic or non-aromatic ring. In some embodiments, the bond comprises at least one cycloalkyl ring. In some embodiments, the bond comprises at least one heterocyclic ring. In some embodiments, the bond comprises at least two heterocyclic rings. In some embodiments, the bond comprises at least one nitrogen-containing heterocycloalkyl ring.

[0163] In some embodiments, the bond has the structure

[0164] [ka] wherein A and B are heterocycles. In some embodiments, the bond is represented by the structure

[0165] [ka] wherein A and B are heterocycles.

[0166] In some embodiments, the bond comprises pyrrolidine, piperidine, dehydropyrrolidine, dehydropiperidine, aziridine, azetidine, oxazolidine, or thiazolidine. In some embodiments, the bond comprises two C1-C6 heterocycloalkyl rings. In some embodiments, the bond comprises at least one 5-membered heterocycloalkyl ring. In some embodiments, the bond comprises at least one 6-membered heterocycloalkyl ring. In some embodiments, the bond comprises two 5-membered heterocycloalkyl rings. In some embodiments, the bond comprises two 5-membered heterocycloalkyl rings, each ring comprising at least one nitrogen atom. In some embodiments, the bond comprises two 5-membered heterocycloalkyl rings, at least one ring comprising at least one nitrogen atom. In some embodiments, the bond comprises two 6-membered heterocycloalkyl rings. In some embodiments, the bond comprises two C1-C6 heterocycloalkyl rings connected by an amide bond. In some embodiments, the bond comprises two C1-C6 heterocycloalkyl rings connected by -C(=O)NH-. In some embodiments, the bond comprises two pyrrolidine rings. In some embodiments, the bond comprises at least one non-standard amino (unnatural) acid residue. In some embodiments, the bond comprises two amino acids (standard or non-standard), where the alpha position of the first amino acid has an (S) configuration and the alpha position of the second amino acid has an (R) configuration. In some embodiments, the bond comprises two amino acids (standard or non-standard) connected by a peptide bond. In some embodiments, the bond comprises two proline residues (diproline bond). In some embodiments, the bond comprises two proline residues connected by a peptide bond. In some embodiments, the bond comprises D-proline and L-proline (D-proline-L-proline or L-proline-D-proline), two D-prolines, or two L-prolines. In some embodiments, the bond (N-terminus to C-terminus) comprises L-proline-D-proline. In some embodiments, the bond (C-terminus to N-terminus) comprises L-proline-D-proline.

[0167] In some embodiments, the linkage comprises D-proline, L-proline, or a derivative thereof. In some embodiments, the linkage comprises L-proline and a proline derivative. In some embodiments, the linkage comprises L-proline and a proline derivative, where the proline derivative has the R configuration. In some embodiments, the linkage comprises L-proline and a proline derivative, where the proline derivative has the S configuration. In some embodiments, the linkage comprises D-proline-D-proline or a derivative thereof. In some embodiments, the linkage comprises L-proline-L-proline or a derivative thereof. In some embodiments, such derivatives include a substituent on the pyrrolidine ring of the proline. In some embodiments, the linkage comprises a non-canonical amino acid residue selected from 3-fluoroproline, 4-fluoroproline, 3-hydroxyproline, 4-hydroxyproline, 3-aminoproline, 4-aminoproline, 3,4-dehydroproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, 4-oxa-proline, 3-thiaproline, or 4-thiaproline. In some embodiments, the linkage comprises two amino acids selected from proline, 3-fluoroproline, 4-fluoroproline, 3-hydroxyproline, 4-hydroxyproline, 3-aminoproline, 4-aminoproline, 3,4-dehydroproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, 4-oxa-proline, 3-thiaproline, or 4-thiaproline.

[0168] In some embodiments, the bond comprises a bond between the C-terminal residue and the N-terminal residue of the peptide, forming a macrocyclic structure. In some embodiments, the bond between the C-terminal residue and the N-terminal residue of the peptide is a bond between the N-terminal amine of the N-terminal residue and the C-terminal carboxyl group of the C-terminal residue, a bond between the side chain of the N-terminal residue and the C-terminal carboxyl group of the C-terminal residue, a bond between the N-terminal amine of the N-terminal residue and the side chain of the C-terminal residue, or a bond between the side chain of the N-terminal residue and the side chain of the C-terminal residue. In some embodiments, the bond between the C-terminal residue and the N-terminal residue of the peptide is a bond between the N-terminal amine of the N-terminal residue and the C-terminal carboxyl group of the C-terminal residue. In some embodiments, the bond between the C-terminal residue and the N-terminal residue is a peptide bond. In some embodiments, both the N-terminal residue and the C-terminal residue are glycine.

[0169] In some embodiments, the connection between the C-terminal and N-terminal residues of the peptide comprises a linker between the C-terminal and N-terminal residues, such as an alkylene linker or a heteroalkylene linker. In some embodiments, the linker is attached to the N-terminal amine of the N-terminal residue, the C-terminal carboxyl group of the C-terminal residue, or to the side chains of either or both of the N- or C-terminal residues. In some embodiments, the linker is a polymer linker, such as a polyethylene glycol (PEG) linker. In some embodiments, the C-terminal and N-terminal residues of the peptide are separated by about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive amino acid residues.

[0170] In some embodiments, the linkage comprises a covalent bond between standard or non-standard amino acids, such as a lactam bridge. In some embodiments, the linkage comprises the following structure:

[0171] [ka]

[0172] In some embodiments, the linkage comprises a covalent bond between standard or non-standard amino acids, such as a thioether bridge. In some embodiments, the linkage comprises the following structure:

[0173] [ka]

[0174] These and similar constraints may be used to link residues at terminal and / or non-terminal positions in a peptide. In some embodiments, Xaa3 and Xaa8 of the peptide antagonists of the present disclosure are linked. In some embodiments, Xaa4 and Xaa14 of the peptide antagonists of the present disclosure are linked. In some embodiments, Xaa3 and Xaa8, and Xaa4 and Xaa14 of the peptide antagonists of the present disclosure are linked.

[0175] Bond Spacing

[0176] In some embodiments, the constrained structures as described herein are selected based on the resulting spatial separation between the constrained residues. In some embodiments, the spatial separation affects the peptide antagonist properties as described above. The peptide antagonists of the present disclosure may include a constrained structure that results in a spatial separation between the alpha carbons of two bonded amino acid residues or between the geometric centers of two bonded residues (e.g., amino acid derivatives) of about 3.5 to about 10 angstroms. In some embodiments, the spatial separation between the alpha carbons of two bonded amino acid residues or between the geometric centers of two bonded residues is about 3.5 angstroms to about 10 angstroms. In some embodiments, the spatial separation between the alpha carbons of two bonded amino acid residues or between the geometric centers of two bonded residues is at least about 3.5 angstroms. In some embodiments, the spatial separation between the alpha carbons of two bonded amino acid residues or between the geometric centers of two bonded residues is at most about 10 angstroms. In some embodiments, the spatial separation between the alpha carbons of two linked amino acid residues, or the spatial separation between the geometric centers of two linked residues, is from about 3.5 angstroms to about 4.5 angstroms, from about 3.5 angstroms to about 5 angstroms, from about 3.5 angstroms to about 5.5 angstroms, from about 3.5 angstroms to about 6 angstroms, from about 3.5 angstroms to about 6.5 angstroms, from about 3.5 angstroms to about 7 angstroms, from about 3.5 angstroms to about 7.5 angstroms, from about 3.5 angstroms to about 8 angstroms, from about 3.5 angstroms to about 9 angstroms, from about 3.5 angstroms to about 10 angstroms, from about 3.5 angstroms to about 11 angstroms, from about 3.5 angstroms to about 12 angstroms, from about 3.5 angstroms to about 13 angstroms, from about 3.5 angstroms to about 14 angstroms, from about 3.5 angstroms to about 15 angstroms, from about 3.5 angstroms to about 16 angstroms, from about 3.5 angstroms to about 17 angstroms, from about 3.5 angstroms to about 18 angstroms, from about 3.5 angstroms to about 19 angstroms, from about 3.5 angstroms to about 20 angstroms, from about 3.5 angstroms to about 21 angstroms, from about 3.5 angstroms to about 22 angstroms, from about 3.5 angstroms to about 23 angstroms, from about 3.5 angstroms to about 24 Angstroms to about 8 Angstroms, about 3.5 Angstroms to about 8.5 Angstroms, about 3.5 Angstroms to about 9 Angstroms, about 3.5 Angstroms to about 10 Angstroms, about 4.5 Angstroms to about 5 Angstroms, about 4.5 Angstroms to about 5.5 Angstroms, about 4.5 Angstroms to about 6 Angstroms, about 4.5 Angstroms to about 6.5 Angstroms, about 4.5 Angstroms to about 7 Angstroms, about 4.5 Angstroms to about 7.5 Angstroms, about 4.5 angstroms to about 8 angstroms, about 4.5 angstroms to about 8.5 angstroms, about 4.5 angstroms to about 9 angstroms, about 4.5 angstroms to about 10 angstroms, about 5 angstroms to about 5.5 angstroms, about 5 angstroms to about 6 angstroms, about 5 angstroms to about 6.5 angstroms, about 5 angstroms to about 7 angstroms, about 5 angstroms to about 7.5 angstroms, about 5 angstroms to about 8 angstroms, about 5 angstroms to about 9 angstroms, about 5 angstroms to about 10 angstroms, about 5 angstroms to about 5.5 angstroms, about 5 angstroms to about 6 angstroms, about 5 angstroms to about 6.5 angstroms, about 5 angstroms to about 7 angstroms, about 5 angstroms to about 7.5 angstroms, about 5 angstroms to about 8 angstroms, about from about 5.5 angstroms to about 8.5 angstroms, from about 5 angstroms to about 9 angstroms, from about 5 angstroms to about 10 angstroms, from about 5.5 angstroms to about 6 angstroms, from about 5.5 angstroms to about 6.5 angstroms, from about 5.5 angstroms to about 7 angstroms, from about 5.5 angstroms to about 7.5 angstroms, from about 5.5 angstroms to about 8 angstroms, from about 5.5 angstroms to about 8.5 angstroms, from about 5.5 angstroms to about 9 angstroms, about 5.5 angstroms to about 10 angstroms, about 6 angstroms to about 6.5 angstroms, about 6 angstroms to about 7 angstroms, about 6 angstroms to about 7.5 angstroms, about 6 angstroms to about 8 angstroms, about 6 angstroms to about 8.5 angstroms, about 6 angstroms to about 9 angstroms, about 6 angstroms to about 10 angstroms, about 6.5 angstroms to about 7 angstroms, about 6.5 angstroms to about 7.5 angstroms, about 6 .5 Angstroms to about 8 Angstroms, about 6.5 Angstroms to about 8.5 Angstroms, about 6.5 Angstroms to about 9 Angstroms, about 6.5 Angstroms to about 10 Angstroms, about 7 Angstroms to about 7.5 Angstroms, about 7 Angstroms to about 8 Angstroms, about 7 Angstroms to about 8.5 Angstroms, about 7 Angstroms to about 9 Angstroms, about 7 Angstroms to about 10 Angstroms, about 7.5 ....5 Angstroms to about 8.5 Angstroms, about 7.5 Angstroms to about 9 Angstroms, about 7.5 Angstroms to about 10 Angstroms, about 8 Angstroms to about 8.5 Angstroms, about 8 Angstroms to about 9 Angstroms, about 8 Angstroms to about 10 Angstroms, about 8.5 Angstroms to about 9 Angstroms, about 8.5 Angstroms to about 10 Angstroms, or about 9 Angstroms to about 10 Angstroms. In some embodiments, the spatial separation between the alpha carbons of two linked amino acid residues, or between the geometric centers of two linked residues, is about 3.5 angstroms, about 4.5 angstroms, about 5 angstroms, about 5.5 angstroms, about 6 angstroms, about 6.5 angstroms, about 7 angstroms, about 7.5 angstroms, about 8 angstroms, about 8.5 angstroms, about 9 angstroms, or about 10 angstroms. In embodiments, the specific spatial separation is achieved using linker or spacer molecules as known in the art.

[0177] Amino Acid Derivatives

[0178] The present disclosure contemplates the use of any amino acid derivative or analogue of any amino acid in any of the peptide antagonists of the present disclosure.In some embodiments, amino acid modification can be chemically performed using any known method.Selective protein modification is described in, for example, Spicer and Davis, 2014, "Selective chemical protein modification," Nature Communications 5:4740, which is incorporated herein by reference.

[0179] In some embodiments, the amino acid derivative is a non-standard amino acid. In some embodiments, the alpha position of the non-standard amino acid has the (S) configuration. In some embodiments, the alpha position of the non-standard amino acid has the (R) configuration. In some embodiments, the non-standard amino acid is an alpha amino acid. In some embodiments, the non-standard amino acid is a beta amino acid or a gamma amino acid. In some embodiments, the non-standard amino acid is selected from the group consisting of aromatic side chain amino acids, non-aromatic side chain amino acids, aliphatic side chain amino acids, side chain amide amino acids, side chain ester amino acids, heteroaromatic side chain amino acids, side chain thiol amino acids, beta amino acids, and backbone modified amino acids. In some embodiments, the non-standard amino acid is a derivative of tyrosine, histidine, tryptophan, or phenylalanine. In some embodiments, derivatives of amino acids include esters, amides, disulfides, carbamates, ureas, phosphates, ethers of amino acids. In some embodiments, the non-aromatic side chain amino acid is a derivative of serine, threonine, cysteine, methionine, arginine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, proline, glycine, alanine, valine, isoleucine, or leucine. In some embodiments, the non-standard amino acid is selected from the group consisting of 2-aminoadipic acid, 3-aminoadipic acid, β-alanine, β-aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, piperidinic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, 2,4-diaminobutyric acid, desmosine, 2,2'-diaminopimelic acid, 2,3-diaminoproprionic acid, N-ethylglycine, N-ethylasparagine, hydroxylysine, allo-hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylglycine, sarcosine, n-methylisoleucine, 6-N-methyllysine, N-methylvaline, norvaline, norleucine, and ornithine. In some embodiments, the non-standard amino acid is a proline derivative. In some embodiments, the proline derivative is hydroxyproline.In some embodiments, the proline derivative is 3-fluoroproline, 4-fluoroproline, 3-hydroxyproline, 4-hydroxyproline, 3-aminoproline, 4-aminoproline, 3,4-dehydroproline, aziridine-2-carboxylic acid, azetidine-2-carboxylic acid, pipecolic acid, 4-oxa-proline, 3-thiaproline, or 4-thiaproline. In some embodiments, the non-standard amino acid comprises a lipid.

[0180] In some embodiments, the peptide antagonists of the disclosure include one or more amino acid derivatives or analogs, e.g., those known to one of skill in the art, those described in the literature, or herein, etc. In some embodiments, the peptide antagonists of the disclosure include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1-2, 1-3, 1-, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, or 1-13 amino acid derivatives.

[0181] In some embodiments, each amino acid derivative in the peptidic antagonists of the disclosure is a non-standard amino acid independently selected from the group consisting of aromatic side chain amino acids, non-aromatic side chain amino acids, aliphatic side chain amino acids, side chain amide amino acids, side chain ester amino acids, heteroaromatic side chain amino acids, side chain thiol amino acids, β-amino acids, and backbone-modified amino acids, e.g., selected from the non-standard amino acids described herein or known in the art, and described in the published literature.

[0182] In some embodiments, the peptide antagonist comprises one or more amino acids having a D-amino acid configuration, with the remaining amino acids in the peptide having an L-amino acid configuration.

[0183] In some embodiments, the non-standard amino acid is a proline derivative. In some embodiments, the proline derivative comprises one or more substituents on the pyrrolidine ring. In some embodiments, the proline derivative comprises one or more substitutions on the pyrrolidine ring, the substituents comprising halogen, alkoxy, amino, hydroxyl, alkyl (methyl, ethyl), thiol, or alkylthio. In some embodiments, the proline derivative comprises one or more substitutions on the pyrrolidine ring, the substituents comprising halogen or alkyl (methyl, ethyl). In some embodiments, the proline derivative comprises one or more substitutions on the pyrrolidine ring, the substituents comprising halogen. In some embodiments, the proline derivative comprises one or more substitutions on the pyrrolidine ring, the substituents comprising alkoxy, hydroxyl, amino. In some embodiments, the proline derivative comprises one or more substitutions on the pyrrolidine ring, the substituents comprising halogen, alkoxy, alkyl (methyl, ethyl), thiol, or alkylthio.

[0184] Tracking peptide antagonists

[0185] In some embodiments, the peptide antagonists of the present disclosure include a tracer amino acid derivative that facilitates tracking of the peptide antagonist. Detection of the presence of a non-standard tracer amino acid in a peptide antagonist during assay of a peptide composition or after administration of the composition to a subject or patient can provide useful information regarding the peptide antagonist properties, such as pharmacokinetic properties (including, but not limited to, absorption, bioavailability, distribution, metabolism, and excretion), pharmacodynamic properties (including, but not limited to, receptor binding characteristics, such as binding half-life, post-receptor effects, and chemical interactions), enhanced activity (e.g., IC 50 The properties of the peptide antagonist may be determined by the following: (e.g., as expressed by the half-life), stability (e.g., as expressed by the half-life), solubility (e.g., in a formulation), or permeability (e.g., skin permeability of a formulation containing the peptide antagonist).

[0186] In some embodiments, peptides containing tracer amino acid derivatives are detected using any assay suitable for detecting the particular tracer amino acid derivative present in the peptide antagonist. In some embodiments, a tryptophan derivative is the tracer amino acid. In some embodiments, the assay comprises a spectroscopic or radiometric detection method. In some embodiments, the assay measures a pharmacokinetic or pharmacodynamic peptide antagonist property.

[0187] N-Terminal Modification of Peptide Antagonists

[0188] In some embodiments, the N-terminal amino group of the peptide antagonists of the present disclosure is modified (N-terminal modification). In some embodiments, the N-terminus of the peptide antagonist is not modified with additional amino acids or amino acid derivatives. In some embodiments, the unmodified N-terminus comprises hydrogen. In some embodiments, the N-terminal modification is C1-C6 acyl, C1-C8 alkyl, C1-C 12 Aralkyl, C5-C 10 In some embodiments, the N-terminal modification comprises aryl, C4-C8 heteroaryl, formyl, or lipid. In some embodiments, the N-terminal modification comprises C1-C6 aralkyl. In some embodiments, the N-terminal modification comprises C1-C6 acyl. In some embodiments, the N-terminal modification comprises acetyl (Ac). In some embodiments, the N-terminal modification comprises C1-C6 alkyl. In some embodiments, the N-terminal modification comprises methyl, ethyl, propyl, or tert-butyl. In some embodiments, the N-terminal modification comprises C1-C6 aralkyl. In some embodiments, the N-terminal modification comprises benzyl. In some embodiments, the N-terminal modification comprises formyl. In some embodiments, the peptides described herein, for example, any peptide having an amino acid sequence as listed in Tables 1 and 2 (regardless of the N-terminus shown in the tables), have either these N-terminal modifications or an unmodified N-terminus.

[0189] C-Terminal Modifications of Peptide Antagonists

[0190] In some embodiments, the C-terminal acid group of the peptide antagonists of the present disclosure is modified (C-terminal modification). In some embodiments, the C-terminus is not modified with an additional amino acid or amino acid derivative. In some embodiments, the C-terminus is not modified with a glycine residue. In some embodiments, the unmodified C-terminus comprises -OH. In some embodiments, the C-terminal modification comprises an amino group, which is optionally substituted. In some embodiments, the C-terminal modification comprises an amino group, which is unsubstituted (-NH2). In some embodiments, the C-terminal modification comprises an amino group, which is substituted. In some embodiments, the C-terminal modification comprises -NH2, -amino-acyl, -amino-C1-C8 alkyl, -amino-C1-C6 aralkyl, -amino-C5-C 10 aryl, -amino-C4-C8 heteroaryl, -amino-C4-C8 heteroaryl, or -O-(C1-C8 alkyl). In some embodiments, the C-terminal modification is -amino-C6-C 12 In some embodiments, the C-terminal modification includes -,O-(C1-C8 alkyl). In some embodiments, the C-terminal modification includes -amino-C6-C 12 In some embodiments, the C-terminal modification includes -NH-CH2phenyl. In some embodiments, the C-terminal modification includes -OEt. In some embodiments, the C-terminal modification includes -OMe. In some embodiments, the peptides described herein, for example, any peptide having an amino acid sequence as listed in Tables 1 and 2 (regardless of the C-terminus shown in the tables), have either these C-terminal modifications or an unmodified C-terminus.

[0191] In some embodiments, both the N-terminal amino group and the C-terminal acid group in the peptide antagonist of the present invention are modified. In some embodiments, the peptides described herein, such as any peptide having an amino acid sequence as listed in Table 1 and Table 2 (regardless of the N-terminus and C-terminus shown in the table), have an N-terminus and a C-terminus independently selected from those described herein. In some embodiments, the peptides described herein, such as any peptide having an amino acid sequence as listed in Table 1 and Table 2 (regardless of the N-terminus and C-terminus shown in the table), have an N-terminus and a C-terminus independently selected from Ac, NH2, and H.

[0192] Lipids

[0193] In some embodiments, the peptide antagonists of the present disclosure comprise a lipid moiety. In some embodiments, the lipid moiety is covalently attached to an amino acid in the peptide. In some embodiments, the lipid is attached to the N-terminus. In some embodiments, the lipid is attached to a cysteine, serine, lysine, threonine, or tyrosine residue (also referred to herein as a "cys-lipid," "ser-lipid," "lys-lipid," "thr-lipid," or "tyr-lipid," respectively) of the peptide antagonist. In some embodiments, the lipid is covalently attached to a cysteine ​​or lysine residue of the peptide antagonist. In some embodiments, the lipid is attached to a non-standard amino acid. In some embodiments, the lipid comprises a hydrophobic group. In some embodiments, the lipid comprises a fatty acid group. In some embodiments, the lipid comprises a C6-C 20 In some embodiments, the lipid comprises a fatty acid group. In some embodiments, the lipid comprises a steroid. In some embodiments, the lipid comprises a wax. In some embodiments, the lipid comprises an alkyl group. In some embodiments, the lipid comprises a C6-C 20 Alkyl groups, C6-C 20 Alkenyl groups, C6-C 20 Alkynyl group, or C6-C 20In some embodiments, the lipid comprises one or more isoprenyl moieties. In some embodiments, the lipid comprises geranyl, farnesyl, or geranylgeranyl groups. In some embodiments, the lipid comprises undecyloyl, lauroyl, tridecyloyl, myristoyl, palmitoyl, or stearoyl groups. In some embodiments, the peptides described herein comprise esters, amides, or thioesters of fatty acids.

[0194] In some embodiments, the lipid is a covalent modification of a cysteine ​​added by palmitoylation. In some embodiments, the lipid added by palmitoylation is a C6-C 20 It is an alkyl or palmitoyl group.

[0195] In some embodiments, the lipid is a covalent modification of a cysteine ​​added by prenylation. In some embodiments, the lipid added by prenylation is a C6-C 20 alkenyl, geranyl, farnesyl, or geranylgeranyl group.

[0196] In some embodiments, the cys-lipid has structure I or II.

[0197] Structure I:

[0198] [ka]

[0199] Structure II:

[0200] [ka]

[0201] Evaluation of MC1R peptide antagonists

[0202] In embodiments, the peptide antagonists of the present disclosure are analyzed to evaluate one or more peptide properties, including pharmacokinetic properties (e.g., absorption, bioavailability, distribution, metabolism, excretion, etc.), pharmacodynamic properties (receptor binding characteristics, e.g., binding half-life, post-receptor effects, and chemical interactions, etc.), enhanced activity (e.g., IC 50 These include, but are not limited to, the ability to measure the amount of a peptide antagonist present in a given formulation ...

[0203] In some embodiments, the assay is used to measure inhibition of binding and / or activation of MC1R to MC1R agonists. In some embodiments, the agonist is α-MSH or β-MSH. In some embodiments, in vivo or in vitro assays known in the art suitable for testing the effect of peptide antagonists on G protein-coupled receptors are contemplated for use in evaluating peptide antagonists of the present disclosure. In some embodiments, the assay is a competitive binding assay. In embodiments, binding specificity is determined based on the ability of the peptide antagonist to compete with a-MSH for binding to MC1R. In some embodiments, the assay is a high-throughput assay. Other assays useful for evaluating the properties of peptide antagonists of the present disclosure, for example, as part of a topical formulation, include skin penetration assays and tissue penetration assays. In some embodiments, the assay measures the apparent treatment effect in a subject, for example, evaluation of potential reduction or prevention of skin pigmentation or discoloration may be used to evaluate peptide antagonists. Melanocytes reside in the basal layer of the epidermis, where the relationship between one melanocyte and 30-40 associated keratinocytes results in the formation of the epidermal melanin unit. Thus, in some embodiments, the assays used herein evaluate the ability of a topically administered MC1R peptide antagonist to reach melanocytes in the basal layer of the epidermis. Specific exemplary assays for evaluating peptide antagonists of the present disclosure are described in detail in the Examples herein. Any assay known in the art may be used.

[0204] In some embodiments, skin lightening by MCR1 peptide antagonists is screened in vitro using the MelanoDerm tissue model (MatTek, Inc.), a highly differentiated 3-dimensional tissue culture model of human epidermis containing normal human melanocytes and keratinocytes. See, e.g., Makino et al., 2013, J. Drugs Dermatol. 12(3 suppl 1):s16-s20, incorporated herein by reference in its entirety. Pigmentation may be assessed over a 2-3 week period using a tristimulus colorimeter to measure lightness (L*) in MelanoDerm tissue generated with normal human melanocytes from black, Asian, or white donors. In parallel with the colorimeter measurements, the total melanin content of the tissue is also quantified. Over time, cultures become increasingly pigmented while retaining normal epithelial morphology, with the expected pigmentation levels of donor tissue when cultured in medium containing α-MSH and β-FGF being, i.e., blacks > Asians > whites. When pigmentation is observed over a 2-3 week treatment period, negative control cultures become increasingly pigmented, while tissues treated topically with cosmetic skin lightening agents containing kojic acid and tyrosinase inhibitors such as magnesium ascorbyl phosphate remain visibly lighter compared to control cultures. After 14 days in culture, total melanin amount was found to be inversely correlated with surface reflectance (L*). Two separate endpoints, total melanin amount, and skin color measurements, may be used to assess skin pigmentation by this method.

[0205] In some embodiments, the properties of the peptide antagonist measured are compared to the properties of a suitable control. Results may be expressed as a comparison to a suitable control, for example, a negative control or a positive control. The negative control may be a non-specific binding protein or may be untreated. The positive control may be any known MC1R antagonist, such as melanostatin-5 / nonapeptide 1 (SEQ ID NO: 1), the 132-amino acid natural MC1R antagonist agouti signal protein (ASIP) (SEQ ID NO: 91), mature ASIP (SEQ ID NO: 92), a fragment of ASIP, such as ASIP107-132 (SEQ ID NO: 2), or a variant or fragment of ASIP, such as ASIP-YY (SEQ ID NO: 93), ASIP-YY107-132 subdomain (SEQ ID NO: 3), or ASIP-YY93-132 subdomain (SEQ ID NO: 94). ASIP blocks the binding of α-MSH to MC1R and subsequent activation of MC1R. See, for example, Wolf Horrell (2016).

[0206] The effect of the peptide antagonist as disclosed herein can be measured in human subjects using any method known to those skilled in the art, for example, as described by Zasada et al. (2016) J. Cosmet. Dermatol. 15(4):493-502, which is incorporated herein by reference. In some embodiments, a composition comprising an MCR1 peptide antagonist may be applied to one side of the subject's face and a control may be applied to the other side. The control may comprise a composition comprising a control as described herein, or a commercially available skin whitening product, for example, a hydroquinone or kojic acid-containing product. This application may be repeated once or multiple times a day, for example, in the morning and evening. A sunscreen may be applied to the skin to minimize the effects of light exposure during the day. The subject's skin may be photographed at regular intervals and evaluated by a professional and / or by self-assessment, for example, by questionnaire. Skin tone may be analyzed by taking measurements on the cheek or forehead using a Multi Probe Adapter (Courage-Khazaka Electronic GmbH, Cologne, Germany), a Mexameter® MX18, or a VISTA® Complexion Analysis system (Can-field Company, Parsippany, NJ, USA). In some embodiments, a composition comprising an MCR1 peptide antagonist prevents, reduces, and / or improves the appearance of skin discoloration. In some embodiments, the skin discoloration comprises pigmentation or hyperpigmentation. In some embodiments, the skin discoloration comprises brown spots, red spots, sun damage (photodamage) score, uneven skin texture, blood vessels, and / or any other parameter understood by one of skill in the art. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50%. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50%. In some embodiments, reduction in discoloration after about 1 week to about 12 weeks of treatment is from about 5% to about 10%, from about 5% to about 15%, from about 5% to about 20%, from about 5% to about 25%, from about 5% to about 30%, from about 5% to about 35%, from about 5% to about 40%,about 5% to about 45%, about 5% to about 50%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 10% to about 30%, about 10% to about 35%, about 10% to about 40%, about 10% to about 45%, about 10% to about 50%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 20% to about 40%, about 20% to about 45%, about 20% to about 50%, about 25% to about 30%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 30% to about 35%, about 30% to about 40%, about 30% to about 45%, about 30% to about 50%, about 35% to about 40%, about 35% to about 45%, about 35% to about 50%, about 40% to about 45%, about 40% to about 50%, or about 45% to about 50%. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is at least about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, or about 45%. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is at most about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50%. In some embodiments, the reduction in discoloration is about 5% to about 50% after about 1 week to about 12 weeks of treatment. In some embodiments, reduction in discoloration occurs after about 1 week of treatment to about 2 weeks of treatment, after about 1 week of treatment to about 3 weeks of treatment, after about 1 week of treatment to about 4 weeks of treatment, after about 1 week of treatment to about 5 weeks of treatment, after about 1 week of treatment to about 6 weeks of treatment, after about 1 week of treatment to about 7 weeks of treatment, after about 1 week of treatment to about 8 weeks of treatment, after about 1 week of treatment to about 9 weeks of treatment, after about 1 week of treatment to about 10 weeks of treatment, after about 1 week of treatment to about 11 weeks of treatment, after about 1 week of treatment to about 12 weeks of treatment, after about 2 weeks of treatment to about 3 weeks of treatment, after about 2 weeks of treatment to about 4 weeks of treatment,from about 2 weeks of treatment to about 5 weeks of treatment, from about 2 weeks of treatment to about 6 weeks of treatment, from about 2 weeks of treatment to about 7 weeks of treatment, from about 2 weeks of treatment to about 8 weeks of treatment, from about 2 weeks of treatment to about 9 weeks of treatment, from about 2 weeks of treatment to about 10 weeks of treatment, from about 2 weeks of treatment to about 11 weeks of treatment, from about 2 weeks of treatment to about 12 weeks of treatment, from about 3 weeks of treatment to about 4 weeks of treatment, from about 3 weeks of treatment to about 5 weeks of treatment, from about 3 weeks of treatment to about 6 weeks of treatment, from about 3 weeks of treatment to about 7 weeks of treatment, from about 3 weeks of treatment to about 8 weeks of treatment, from about 3 weeks of treatment to about after 9 weeks of treatment, after about 3 weeks of treatment to about 10 weeks of treatment, after about 3 weeks of treatment to about 11 weeks of treatment, after about 3 weeks of treatment to about 12 weeks of treatment, after about 4 weeks of treatment to about 5 weeks of treatment, after about 4 weeks of treatment to about 6 weeks of treatment, after about 4 weeks of treatment to about 7 weeks of treatment, after about 4 weeks of treatment to about 8 weeks of treatment, after about 4 weeks of treatment to about 9 weeks of treatment, after about 4 weeks of treatment to about 10 weeks of treatment, after about 4 weeks of treatment to about 11 weeks of treatment, after about 4 weeks of treatment to about 12 weeks of treatment, after about 5 weeks of treatment to about 6 weeks of treatment, after about 5 weeks of treatment to about 7 weeks of treatment. , after about 5 weeks of treatment to about 8 weeks of treatment, after about 5 weeks of treatment to about 9 weeks of treatment, after about 5 weeks of treatment to about 10 weeks of treatment, after about 5 weeks of treatment to about 11 weeks of treatment, after about 5 weeks of treatment to about 12 weeks of treatment, after about 6 weeks of treatment to about 7 weeks of treatment, after about 6 weeks of treatment to about 8 weeks of treatment, after about 6 weeks of treatment to about 9 weeks of treatment, after about 6 weeks of treatment to about 10 weeks of treatment, after about 6 weeks of treatment to about 11 weeks of treatment, after about 6 weeks of treatment to about 12 weeks of treatment, after about 7 weeks of treatment to about 8 weeks of treatment, after about 7 weeks of treatment to about 9 weeks of treatment, after about 7 weeks of treatment from about 10 weeks of treatment, from about 7 weeks of treatment to about 11 weeks of treatment, from about 7 weeks of treatment to about 12 weeks of treatment, from about 8 weeks of treatment to about 9 weeks of treatment, from about 8 weeks of treatment to about 10 weeks of treatment, from about 8 weeks of treatment to about 11 weeks of treatment, from about 8 weeks of treatment to about 12 weeks of treatment, from about 9 weeks of treatment to about 10 weeks of treatment, from about 9 weeks of treatment to about 11 weeks of treatment, from about 9 weeks of treatment to about 12 weeks of treatment, from about 10 weeks of treatment to about 11 weeks of treatment, from about 10 weeks of treatment to about 12 weeks of treatment, or from about 11 weeks of treatment to about 12 weeks of treatment,About 5% to about 50%. In some embodiments, the reduction in discoloration is about 5% to 50% after about 1 week of treatment, about 2 weeks of treatment, about 3 weeks of treatment, about 4 weeks of treatment, about 5 weeks of treatment, about 6 weeks of treatment, about 7 weeks of treatment, about 8 weeks of treatment, about 9 weeks of treatment, about 10 weeks of treatment, about 11 weeks of treatment, or about 12 weeks of treatment. In some embodiments, the reduction in discoloration is about 5% to 50% after at least about 1 week of treatment, about 2 weeks of treatment, about 3 weeks of treatment, about 4 weeks of treatment, about 5 weeks of treatment, about 6 weeks of treatment, about 7 weeks of treatment, about 8 weeks of treatment, about 9 weeks of treatment, about 10 weeks of treatment, or about 11 weeks of treatment. In some embodiments, the reduction in discoloration is about 5% to 50% after about 2 weeks of treatment, about 3 weeks of treatment, about 4 weeks of treatment, about 5 weeks of treatment, about 6 weeks of treatment, about 7 weeks of treatment, about 8 weeks of treatment, about 9 weeks of treatment, about 10 weeks of treatment, about 11 weeks of treatment, or about 12 weeks of treatment. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50% in about 50% to about 100% of subjects. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50% in about 50% to about 100% of subjects. In some embodiments, reduction in discoloration after about 1 week to about 12 weeks of treatment is observed in about 50% to about 55% of subjects, in about 50% to about 60% of subjects, in about 50% to about 65% of subjects, in about 50% to about 70% of subjects, in about 50% to about 75% of subjects, in about 50% to about 80% of subjects, in about 50% to about 85% of subjects, in about 50% to about 90% of subjects, in about 95% of subjects, in about 50% of subjects to about 100% of subjects, in about 55% of subjects to about 60% of subjects, in about 55% of subjects to about 65% of subjects, in about 55% of subjects to about 70% of subjects, in about 55% of subjects to about 75% of subjects, in about 55% of subjects to about 80% of subjects, in about 55% of subjects to about 85% of subjects, in about 55% of subjects to about 90% of subjects, in about 55% of subjects to about 95% of subjects,in about 55% to about 100% of subjects, in about 60% to about 65% of subjects, in about 60% to about 70% of subjects, in about 60% to about 75% of subjects, in about 60% to about 80% of subjects, in about 60% to about 85% of subjects, in about 60% to about 90% of subjects, in about 60% to about 95% of subjects, in about 60% to about 100% of subjects, in about 65% to in about 70% of subjects, in about 65% to about 75% of subjects, in about 65% to about 80% of subjects, in about 65% to about 85% of subjects, in about 65% to about 90% of subjects, in about 65% to about 95% of subjects, in about 65% to about 100% of subjects, in about 70% to about 75% of subjects, in about 70% to about 80% of subjects, in about 70% to about 85% of subjects in about 70% to about 90% of subjects, in about 70% to about 95% of subjects, in about 70% to about 100% of subjects, in about 75% to about 80% of subjects, in about 75% to about 85% of subjects, in about 75% to about 90% of subjects, in about 75% to about 95% of subjects, in about 75% to about 100% of subjects, in about 80% to about 85% of subjects, in about 80% of subjects about 5% to about 50% in about 50% of subjects, about 55% of subjects, about 60% of subjects, about 65% of subjects, about 70% of subjects, about 75% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, about 95% of subjects, about 90% of subjects, about 100% of subjects, about 5% to about 50% in about 50% of subjects, about 55% of subjects, about 60% of subjects, about 65% of subjects, about 70% of subjects, about 75% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, about 95% of subjects, or about 100% of subjects. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50% in about 50% of subjects, about 55% of subjects, about 60% of subjects, about 65% of subjects, about 70% of subjects, about 75% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, about 95% of subjects, or about 100% of subjects. In some embodiments, reduction in discoloration after about 1 week to about 12 weeks of treatment is observed in at least about 50% of subjects, at least about 55% of subjects,In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50% in about 60% of subjects, about 65% of subjects, about 70% of subjects, about 75% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, or about 95% of subjects. In some embodiments, the reduction in discoloration after about 1 week to about 12 weeks of treatment is about 5% to about 50% in about 55% of subjects, about 60% of subjects, about 65% of subjects, about 70% of subjects, about 75% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, or about 95% of subjects. From about 5% to about 50% in about 5% of subjects, about 80% of subjects, about 85% of subjects, about 90% of subjects, about 95% of subjects, or about 100% of subjects.

[0207] Inhibition of MC1R activation by a peptide antagonist of the present disclosure may be compared to inhibition of MC1R activation by a known antagonist, for example, melanostatin-5 (SEQ ID NO: 1), ASIP (SEQ ID NO: 2), or ASIP-YY (SEQ ID NO: 3). In some embodiments, the peptide antagonist is compared to a control in the assay. In some embodiments, the control is a negative control, for example, a random peptide. In some embodiments, the control is a positive control, for example, any MC1R antagonist known in the art. In some embodiments, the MC1R peptide antagonist being tested is a peptide antagonist of Group A, for example, a peptide antagonist having an amino acid sequence of any one of SEQ ID NOs: 4-43, and the control is a peptide having an amino acid sequence set forth as SEQ ID NO: 1. In some embodiments, the MC1R peptide antagonist is a group B peptide antagonist, e.g., a peptide antagonist having an amino acid sequence of any one of SEQ ID NOs: 44-90, and the control is a peptide having an amino acid sequence set forth as any one of SEQ ID NOs: 2, 3, and 91-94. In some embodiments, the MC1R peptide antagonist is a group B peptide antagonist, e.g., a peptide antagonist having an amino acid sequence of any one of SEQ ID NOs: 44-90, and the control is a peptide having an amino acid sequence set forth as SEQ ID NO: 2. In some embodiments, the MC1R peptide antagonist is a group B peptide antagonist, e.g., a peptide antagonist having an amino acid sequence of any one of SEQ ID NOs: 44-90, and the control is a peptide having an amino acid sequence set forth as SEQ ID NO: 3.

[0208] In embodiments, inhibition of MC1R activation by peptide antagonists of the present disclosure is compared to inhibition of MC1R activation by known antagonists using the same assay. In embodiments, inhibition of MC1R activation by peptide antagonists of the present disclosure is compared to inhibition of MC1R activation by known antagonists in the same experiment. In embodiments, inhibition of MC1R activation by peptide antagonists of the present disclosure is compared to inhibition of MC1R activation by known antagonists in the same experiment using the same assay.

[0209] In embodiments, the peptide antagonists of the present disclosure have an IC of about 1 millimolar to about 1 picomolar. 50 In some embodiments, the peptide antagonist inhibits MC1R with an IC of about 1 millimolar to about 1 picomolar in a receptor binding assay. 50 In some embodiments, the IC 50 is about 1 millimolar to about 1 micromolar, about 1 millimolar to about 500 micromolar, about 500 micromolar to about 100 micromolar, about 100 micromolar to about 1 micromolar, about 1 micromolar to about 1 nanomolar, about 1 micromolar to about 1 nanomolar, about 1 micromolar to about 500 nanomolar, about 500 nanomolar to about 100 nanomolar, about 100 nanomolar to about 1 nanomolar, about 1 nanomolar to about 1 picomolar, about 1 nanomolar to about 500 picomolar, about 500 picomolar to about 100 picomolar, about 100 micromolar to about 1 The IC is preferably about 1 picomolar, about 1 millimolar or less, about 500 millimolar or less, about 100 millimolar or less, about 1 millimolar or less, about 1 micromolar or less, about 500 micromolar or less, about 100 micromolar or less, about 50 micromolar or less, about 20 micromolar or less, about 10 micromolar or less, about 5 micromolar or less, about 2 micromolar or less, about 1 micromolar or less, about 1 nanomolar or less, about 500 nanomolar or less, about 100 nanomolar or less, about 1 nanomolar or less, about 1 picomolar or less, about 500 picomolar or less, about 100 picomolar or less, or about 1 picomolar or less. In some embodiments, the IC 50 In some embodiments, the IC 50is about 20 nanomolar to about 25 nanomolar, about 20 nanomolar to about 30 nanomolar, about 20 nanomolar to about 40 nanomolar, about 20 nanomolar to about 50 nanomolar, about 20 nanomolar to about 60 nanomolar, about 20 nanomolar to about 70 nanomolar, about 20 nanomolar to about 75 nanomolar, about 20 nanomolar to about 80 nanomolar, about 20 nanomolar to about 90 nanomolar, about 20 nanomolar to about 100 nanomolar, about 20 nanomolar to about 125 nanomolar, about 25 nanomolar to about 30 nanomolar, about 25 nanomolar to about 40 nanomolar, about 25 nanomolar to about 50 nanomolar, about 25 ... from about 60 nanomolar, from about 25 nanomolar to about 70 nanomolar, from about 25 nanomolar to about 75 nanomolar, from about 25 nanomolar to about 80 nanomolar, from about 25 nanomolar to about 90 nanomolar, from about 25 nanomolar to about 100 nanomolar, from about 25 nanomolar to about 125 nanomolar, from about 30 nanomolar to about 40 nanomolar, from about 30 nanomolar to about 50 nanomolar, from about 30 nanomolar to about 60 nanomolar, from about 30 nanomolar to about 70 nanomolar, from about 30 nanomolar to about 75 nanomolar, from about 30 nanomolar to about 80 nanomolar, from about 30 nanomolar to about 90 nanomolar, from about 30 nanomolar to about 100 nanomolar, about 30 nanomolar to about 125 nanomolar, about 40 nanomolar to about 50 nanomolar, about 40 nanomolar to about 60 nanomolar, about 40 nanomolar to about 70 nanomolar, about 40 nanomolar to about 75 nanomolar, about 40 nanomolar to about 80 nanomolar, about 40 nanomolar to about 90 nanomolar, about 40 nanomolar to about 100 nanomolar, about 40 nanomolar to about 125 nanomolar, about 50 nanomolar to about 60 nanomolar, about 50 nanomolar to about 70 nanomolar, about 50 nanomolar to about 75 nanomolar, about 50 nanomolar to about 80 nanomolar, about 50 nanomolar to about 90 nanomolar molar, about 50 nanomolar to about 100 nanomolar, about 50 nanomolar to about 125 nanomolar, about 60 nanomolar to about 70 nanomolar, about 60 nanomolar to about 75 nanomolar, about 60 nanomolar to about 80 nanomolar, about 60 nanomolar to about 90 nanomolar, about 60 nanomolar to about 100 nanomolar, about 60 nanomolar to about 125 nanomolar, about 70 nanomolar to about 75 nanomolar, about 70 nanomolar to about 80 nanomolar, about 70 nanomolar to about 90 nanomolar, about 70 nanomolar to about 100 nanomolar, about 70 nanomolar to about 125 nanomolar, about 75 nanomolar to about 80 nanomolar,From about 75 nanomolar to about 90 nanomolar, from about 75 nanomolar to about 100 nanomolar, from about 75 nanomolar to about 125 nanomolar, from about 80 nanomolar to about 90 nanomolar, from about 80 nanomolar to about 100 nanomolar, from about 80 nanomolar to about 125 nanomolar, from about 90 nanomolar to about 100 nanomolar, from about 90 nanomolar to about 125 nanomolar, or from about 100 nanomolar to about 125 nanomolar. 50 is about 20 nanomolar, about 25 nanomolar, about 30 nanomolar, about 40 nanomolar, about 50 nanomolar, about 60 nanomolar, about 70 nanomolar, about 75 nanomolar, about 80 nanomolar, about 90 nanomolar, about 100 nanomolar, or about 125 nanomolar. 50 is at least about 20 nanomolar, about 25 nanomolar, about 30 nanomolar, about 40 nanomolar, about 50 nanomolar, about 60 nanomolar, about 70 nanomolar, about 75 nanomolar, about 80 nanomolar, about 90 nanomolar, nanomolar, or about 100 nanomolar. 50 is up to about 25 nanomolar, about 30 nanomolar, about 40 nanomolar, about 50 nanomolar, about 60 nanomolar, about 70 nanomolar, about 75 nanomolar, about 80 nanomolar, about 90 nanomolar, about 100 nanomolar, or about 125 nanomolar.

[0210] In some embodiments, the IC of the peptide antagonist 50 The IC of the peptide antagonist is about 25 nanomolar to about 150 nanomolar. 50 is at least about 25 nanomolar. In some embodiments, the IC 50 In some embodiments, the IC of the peptide antagonist is at most about 150 nanomolar. 50is about 25 nanomolar to about 35 nanomolar, about 25 nanomolar to about 40 nanomolar, about 25 nanomolar to about 45 nanomolar, about 25 nanomolar to about 50 nanomolar, about 25 nanomolar to about 60 nanomolar, about 25 nanomolar to about 70 nanomolar, about 25 nanomolar to about 75 nanomolar, about 25 nanomolar to about 100 nanomolar, about 25 nanomolar to about 110 nanomolar, about 25 nanomolar to about 125 nanomolar, about 25 nanomolar to about 150 nanomolar, about 35 nanomolar to about 40 nanomolar, about 35 nanomolar to about 45 nanomolar, about 35 nanomolar to about 50 nanomolar, about 3 ... from about 60 nanomolar, from about 35 nanomolar to about 70 nanomolar, from about 35 nanomolar to about 75 nanomolar, from about 35 nanomolar to about 100 nanomolar, from about 35 nanomolar to about 110 nanomolar, from about 35 nanomolar to about 125 nanomolar, from about 35 nanomolar to about 150 nanomolar, from about 40 nanomolar to about 45 nanomolar, from about 40 nanomolar to about 50 nanomolar, from about 40 nanomolar to about 60 nanomolar, from about 40 nanomolar to about 70 nanomolar, from about 40 nanomolar to about 75 nanomolar, from about 40 nanomolar to about 100 nanomolar, from about 40 nanomolar to about 110 nanomolar, from about 40 nanomolar to about 125 nanomolar, from about 35 nanomolar to about 150 nanomolar, 5 nanomolar, about 40 nanomolar to about 150 nanomolar, about 45 nanomolar to about 50 nanomolar, about 45 nanomolar to about 60 nanomolar, about 45 nanomolar to about 70 nanomolar, about 45 nanomolar to about 75 nanomolar, about 45 nanomolar to about 100 nanomolar, about 45 nanomolar to about 110 nanomolar, about 45 nanomolar to about 125 nanomolar, about 45 nanomolar to about 150 nanomolar, about 50 nanomolar to about 60 nanomolar, about 50 nanomolar to about 70 nanomolar, about 50 nanomolar to about 75 nanomolar, about 50 nanomolar to about 100 nanomolar, about 50 nanomolar to about 110 nanomolar , about 50 nanomolar to about 125 nanomolar, about 50 nanomolar to about 150 nanomolar, about 60 nanomolar to about 70 nanomolar, about 60 nanomolar to about 75 nanomolar, about 60 nanomolar to about 100 nanomolar, about 60 nanomolar to about 110 nanomolar, about 60 nanomolar to about 125 nanomolar, about 60 nanomolar to about 150 nanomolar, about 70 nanomolar to about 75 nanomolar, about 70 nanomolar to about 100 nanomolar, about 70 nanomolar to about 110 nanomolar, about 70 nanomolar to about 125 nanomolar, about 70 nanomolar to about 150 nanomolar, about 75 nanomolar to about 100 nanomolar,About 75 nanomolar to about 110 nanomolar, about 75 nanomolar to about 125 nanomolar, about 75 nanomolar to about 150 nanomolar, about 100 nanomolar to about 110 nanomolar, about 100 nanomolar to about 125 nanomolar, about 100 nanomolar to about 150 nanomolar, about 110 nanomolar to about 125 nanomolar, about 110 nanomolar to about 150 nanomolar, or about 125 nanomolar to about 150 nanomolar. In some embodiments, the IC50 of the peptide antagonist is about 25 nanomolar, about 35 nanomolar, about 40 nanomolar, about 45 nanomolar, about 50 nanomolar, about 60 nanomolar, about 70 nanomolar, about 75 nanomolar, about 100 nanomolar, about 110 nanomolar, about 125 nanomolar, or about 150 nanomolar.

[0211] In an embodiment, an IC 50 is less than about 200 nM, less than about 150 nM, less than about 100 nM, less than about 75 nM, less than about 50 nM, or less than about 25 nM.

[0212] I C 50 may be determined by any suitable activity assay, such as those described herein or known in the art. In embodiments, the IC 50 represents the concentration of peptide antagonist at which 50% of MC1R binding to the MC1R agonist is blocked.

[0213] In some embodiments, the IC observed using the peptide antagonists of the present disclosure 50is lower than that of a control (comparison) MC1R peptide antagonist. The control MC1R peptide antagonist may be any MC1R antagonist known in the art, such as melanostatin-5 / nonapeptide 1 (SEQ ID NO: 1), the 132-amino acid natural MC1R antagonist agouti signal protein (ASIP) (SEQ ID NO: 91), mature ASIP (SEQ ID NO: 92), a fragment of ASIP, such as ASIP107-132 (SEQ ID NO: 2), or a variant or fragment of ASIP, such as ASIP-YY (SEQ ID NO: 93), ASIP-YY107-132 subdomain (SEQ ID NO: 3), or ASIP-YY93-132 subdomain (SEQ ID NO: 94). In some embodiments, the IC observed using the peptide antagonists of the present disclosure is 50 is about 0.4-fold to about 0.8-fold lower than that of the control antagonist. In some embodiments, the IC observed using the peptide antagonists of the present disclosure is 50 were approximately 2-fold to approximately 10-fold lower than those of the control antagonist, i.e., the IC 50 is about 10-fold to about 50-fold lower. In some embodiments, the IC observed using the peptide antagonists of the present disclosure 50 is about 2-fold to about 10-fold lower than that of the control antagonist. In some embodiments, the IC observed using the peptide antagonists of the present disclosure is 50is about 2-fold to about 3-fold, about 2-fold to about 4-fold, about 2-fold to about 5-fold, about 2-fold to about 6-fold, about 2-fold to about 7-fold, about 2-fold to about 8-fold, about 2-fold to about 9-fold, about 2-fold to about 10-fold, about 3-fold to about 4-fold, about 3-fold to about 5-fold, about 3-fold to about 6-fold, about 3-fold to about 7-fold, about 3-fold to about 8-fold, about 3-fold to about 9-fold, about 3-fold to about 10-fold, about 4-fold to about 5-fold, about 4-fold to about 6-fold, about 4-fold to about 8-fold, about 4-fold to about 9-fold, about 3-fold to about 10-fold, about 4-fold to about 5-fold, about 4-fold to about 6-fold, about 4-fold to about 8-fold, about 4-fold to about 9-fold, about 4 ...8-fold In some embodiments, the IC observed using the peptide antagonists of the present disclosure is about 7-fold, about 4-fold to about 8-fold, about 4-fold to about 9-fold, about 4-fold to about 10-fold, about 5-fold to about 6-fold, about 5-fold to about 7-fold, about 5-fold to about 8-fold, about 5-fold to about 9-fold, about 5-fold to about 10-fold, about 6-fold to about 7-fold, about 6-fold to about 8-fold, about 6-fold to about 9-fold, about 6-fold to about 10-fold, about 7-fold to about 8-fold, about 7-fold to about 9-fold, about 7-fold to about 10-fold, about 8-fold to about 9-fold, about 8-fold to about 10-fold, or about 9-fold to about 10-fold lower. 50 is about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold lower than that of a control antagonist. In some embodiments, the IC observed using the peptide antagonists of the present disclosure 50 is at least about 2-fold, about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, or about 9-fold lower than that of a control antagonist. In some embodiments, the IC observed using the peptide antagonists of the present disclosure 50 is up to about 3-fold, about 4-fold, about 5-fold, about 6-fold, about 7-fold, about 8-fold, about 9-fold, or about 10-fold lower than that of the control antagonist. In some embodiments, the activity of a peptide antagonist of the disclosed activity is about 1.25-fold to about 5-fold greater than the activity of the control.

[0214] In some embodiments, the activity of a peptide antagonist of an activity of the present disclosure is about 1.25-fold to about 5-fold greater than the activity of the control. In some embodiments, the activity of a peptide antagonist of an activity of the present disclosure is about 1.25-fold to about 1.5-fold, about 1.25-fold to about 1.75-fold, about 1.25-fold to about 2-fold, about 1.25-fold to about 2.5-fold, about 1.25-fold to about 3-fold, about 1.25-fold to about 3.5-fold, about 1.25-fold to about 4-fold, about 1.25-fold to about 4.5x, about 1.25x to about 5x, about 1.5x to about 1.75x, about 1.5x to about 2x, about 1.5x to about 2.5x, about 1.5x to about 3x, about 1.5x to about 3.5x, about 1.5x to about 4x, about 1.5x to about 4.5x, about 1.5x to about 5x, about 1.75x to about 2x, about 1.75x to about 2.5x, about 1.75 x to 3x, x 1.75 to 3.5x, x 1.75 to 4x, x 1.75 to 4.5x, x 1.75 to 5x, x 2 to 2.5x, x 2 to 3x, x 2 to 3.5x, x 2 to 4x, x 2 to 4.5x, x 2 to 5x, x 2.5 to 3x, x 2.5 to 3.5x, x 2 .5-fold to about 4-fold, about 2.5-fold to about 4.5-fold, about 2.5-fold to about 5-fold, about 3-fold to about 3.5-fold, about 3-fold to about 4-fold, about 3-fold to about 4.5-fold, about 3-fold to about 5-fold, about 3.5-fold to about 4-fold, about 3.5-fold to about 4.5-fold, about 3.5-fold to about 5-fold, about 4-fold to about 4.5-fold, about 4-fold to about 5-fold, or about 4.5-fold to about 5-fold. In some embodiments, the activity of a peptide antagonist of an active of the present disclosure is about 1.25-fold, about 1.5-fold, about 1.75-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, or about 5-fold greater than the activity of the control. In some embodiments, the activity of a peptide antagonist of an activity of the present disclosure is at least about 1.25-fold, about 1.5-fold, about 1.75-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, or about 4.5-fold greater than the activity of the control. In some embodiments, the activity of a peptide antagonist of an activity of the present disclosure is at most about 1.5-fold, about 1.75-fold, about 2-fold, about 2.5-fold, about 3-fold, about 3.5-fold, about 4-fold, about 4.5-fold, or about 5-fold greater than the activity of the control.

[0215] In some embodiments, the IC observed for the Group A peptide antagonists of the present disclosure 50 is the IC observed in a control, e.g., SEQ ID NO:1. 50 In some embodiments, the IC observed for the Group B peptide antagonists of the present disclosure is about 10% to about 50% of the IC observed for the controls, e.g., SEQ ID NOs: 2, 3, or 91-94. 50 In some embodiments, the IC observed for a Group A or Group B peptide antagonist of the present disclosure is about 10% to about 50% of the IC 50 is the IC observed in a control, e.g., SEQ ID NO: 1, 2, 3, or 91-94. 50 It is about 10% to about 50% of the

[0216] Indications

[0217] The MC1R peptide antagonists of the present disclosure are intended for cosmetic use in subjects in need of an indication, including, but not limited to, preventing, reducing, and / or improving the appearance of undesirable skin discoloration. Skin discoloration may be caused by pigmentation. Skin discoloration may be caused by hyperpigmentation. In some embodiments, skin discoloration, e.g., pigmentation or hyperpigmentation, includes melanin hyperpigmentation, post-inflammatory hyperpigmentation, liver spots, melasma, age spots (e.g., melasma, senile lentigines, solar lentigines, sun spots), freckles, or combinations thereof. The MC1R peptide antagonists of the present disclosure may be used to treat skin discoloration resulting from disorders, e.g., adrenal disorders. In embodiments, the MC1R peptide antagonists of the present disclosure are used to treat skin discoloration caused by Addison's disease, in which the MC1R agonists ACTH and MSH are overproduced. In embodiments, the MC1R peptide antagonists of the present disclosure are used to treat skin discoloration due to any known cause, such as hyperpigmentation due to drug use (e.g., calcium antagonists), cyanic melasma, senile melasma, vitiligo, post-sclerotherapy or adverse sequelae following inflammatory or traumatic reactions. In some embodiments, existing skin discoloration is alleviated. In some embodiments, further skin discoloration is prevented. In some embodiments, the appearance of skin discoloration, for example due to changes in skin texture, is ameliorated.

[0218] In some embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In some embodiments, the human subject is a pediatric or adult subject of any age.

[0219] formulation

[0220] In certain embodiments, including pharmaceutical embodiments, the peptide antagonists of the present disclosure may be provided in a cosmetic or pharmaceutical composition. In some embodiments, the cosmetic or pharmaceutical compositions of the present disclosure are formulated using excipients or carriers that are not toxic to keratinous tissue, e.g., skin, and are cosmetically, medicamentally, and / or dermatologically acceptable, and are administered in treatments that include sub-immunological doses of the composition.

[0221] In certain embodiments, including pharmaceutical embodiments, the administration of the formulations of the present disclosure, such as cosmetic or pharmaceutical compositions, to a subject is not expected to cause side effects, even if administered repeatedly and frequently as described herein. In embodiments, side effects are minor, low, or nonexistent. Side effects of topical application can include, for example, mild to severe skin pain, redness, burning sensation, itching, irritation, or any other side effects commonly associated with topical compositions. More severe effects avoided by the formulations of the present disclosure can include side effects associated with injectable neurotoxins, such as those described on product labels as referenced herein.

[0222] Cosmetic and pharmaceutical compositions

[0223] The present disclosure includes a cosmetic composition comprising the peptide antagonist of the present disclosure. In some embodiments, the cosmetic composition is formulated for topical administration. In some embodiments, the cosmetic composition is formulated for topical administration as a cream, balm, gel, solution, serum, cosmetic, liquid, lotion, ointment, emulsion, milk, spray, or mask.

[0224] In certain embodiments, including pharmaceutical embodiments, the topical cosmetic or pharmaceutical composition comprises one excipient or carrier, or a suitable combination of two, three, or more excipients or carriers. In some embodiments, any suitable excipient or carrier, or combination of excipients and / or carriers, is selected from excipients known to those skilled in the art or described in the literature, such as excipients useful in topical formulations. In some embodiments, the excipients or carriers useful in topical formulations are selected from the group consisting of inert excipients or carriers, buffers, absorption enhancers (penetration agents), and stability enhancers. In some embodiments, the inert excipients or carriers are water, isopropyl alcohol, gaseous fluorocarbons, ethyl alcohol, polyvinylpyrrolidone, propylene glycol, fragrances, gel-forming materials, stearyl alcohol, stearic acid, spermaceti, sorbitan monooleate, or methylcellulose. In some embodiments, the excipient is an inorganic compound. In some embodiments, the excipient is a carbohydrate. In some embodiments, the excipient is diaminobutyroylbenzylamide, diacetate, glycerin, a gum, a hydrocolloid or derivative, a cellulose derivative, an emulsifier, a fatty alcohol, an acrylic derivative, a mineral, a surfactant, a fat, an oil, a preservative, a monosaccharide, a disaccharide, a polysaccharide, a glycosaminoglycan, or a chelating agent.

[0225] In some embodiments, the absorption enhancer is selected from the group consisting of liposome delivery systems, transferosome delivery systems, ethosome delivery systems, short chain alcohols, long chain alcohols, polyhydric alcohols, urea, amino acids, amino acid esters, amines, amides, azacyclo compounds (e.g., 1-dodecylazacycloheptan-2-one (AZONE®) or derivatives of 1-dodecylazacycloheptan-2-one), pyrrolidones, pyrrolidone derivatives, terpenes, terpene derivatives, fatty acids, fatty acid esters, macrocycles, surfactants, sulfoxides, lecithin vesicles, water surfactants, polyols, small molecule tripeptides, tetrapeptides, pentapeptides, hexapeptides, septapeptides, or octapeptides, isoceteth-20, ethoxydiglycol, dimethylsulfoxide (DMSO), dimethylisosorbide, and phloretin. In some embodiments, the absorption enhancer is selected to minimize allergic or irritant effects.

[0226] In some embodiments, the stability promoter is a small peptide. In some embodiments, the small peptide is selected from the group consisting of tripeptide, tetrapeptide, pentapeptide, hexapeptide, septapeptide, octapeptide, acetyl hexapeptide-3 cosmetic topical peptide, Melanotan II, ACVR2B (ACE-031), Argireline® Asetate, Argireline, Matrixyl acetate (palmitoyl pentapeptide), peptide GHK spontaneous complex with copper, palmitoyl tetrapeptide-3, Argireline, acetyl glutamyl heptapeptide, Matrixyl®, Snap-8, Syn°-Tracks, Syn®-Coll, Syn®-Hycan, Leuphasyl®, Pepha®-Tight, Tego® Pep4-17, and Trylagen®.

[0227] In some embodiments, the cosmetic composition comprises one or more additional active ingredients. In some embodiments, the one or more additional active ingredients are selected from the group consisting of a second different MC1R peptide antagonist, another skin lightening agent, an anti-wrinkle agent, a retinoid, an antioxidant, a growth factor, a collagen stimulating peptide, a carrier peptide, a peptide that inhibits tTAT-superoxide dismutase, a peptide that inhibits proteinase, a peptide that stimulates hyaluronan synthase 2, and a keratin-based peptide.

[0228] In some embodiments, the cosmetic composition comprises a liposomal delivery system. In some embodiments, the liposomal delivery system includes, for example, an oil-in-water emulsion, a micelle, a mixed micelle, or a liposome. In some embodiments, the colloidal system is a liposome or a microsphere. In some embodiments, the composition is formulated as a poly(D,L)lactide microsphere. In certain embodiments, including pharmaceutical embodiments, the cosmetic composition is formulated to incorporate features as described below for use in a pharmaceutical composition.

[0229] In some embodiments, the excipients and / or liposomal delivery systems are selected to achieve a desired degree of penetration, e.g., using methods known to those of skill in the art to achieve substantially localized delivery, hi some embodiments, the excipients and / or liposomal delivery systems are selected to target melanocytes in the basal layer of the epidermis.

[0230] In some embodiments, transdermal delivery of the MC1R peptide antagonist described herein is achieved using a liposome or lipid vesicle composition. In some embodiments, the lipid vesicle composition comprises lipid vesicles each comprising a lipid bilayer comprising vesicle-forming lipids. In some embodiments, the lipid vesicle composition comprises an oil-in-water emulsion entrapped in the lipid vesicle. In some embodiments, the oil-in-water emulsion is stabilized by one or more surfactants. In some embodiments, the MC1R peptide antagonist is entrapped in the lipid bilayer and / or the oil-in-water emulsion. In some embodiments, the MC1R peptide antagonist is entrapped in the lipid bilayer. In some embodiments, the MC1R peptide antagonist is entrapped in the oil-in-water emulsion. In some embodiments, the lipid vesicle composition comprises (a) lipid vesicles, each comprising a lipid bilayer comprising vesicle-forming lipids; (b) an oil-in-water emulsion entrapped in the lipid vesicles and stabilized by one or more surfactants; and (c) an MC1R peptide antagonist entrapped in the lipid bilayer and / or the oil-in-water emulsion.

[0231] In certain embodiments, including pharmaceutical embodiments, the present disclosure also includes pharmaceutical compositions comprising the peptide antagonists of the present disclosure. In some embodiments, the pharmaceutical compositions are formulated as described above for cosmetic compositions comprising the peptide antagonists of the present disclosure.

[0232] In certain embodiments, including pharmaceutical embodiments, the cosmetic or pharmaceutical compositions of the present disclosure are formulated using any excipients, carriers, or additives, as appropriate.

[0233] Methods for using cosmetic or pharmaceutical compositions

[0234] The present disclosure includes compositions comprising one or more MC1R peptide antagonists as described herein, e.g., Group A or Group B MC1R peptide antagonists having an amino acid sequence as described in Tables 1 and 2, or as described herein. In certain embodiments, including pharmaceutical embodiments, the composition is a cosmetic composition or a pharmaceutical composition.

[0235] The present disclosure also relates to a method for preventing or inhibiting the interaction of MSH with MC1R using an MC1R peptide antagonist composition, comprising contacting an MC1R peptide antagonist with an MC1R peptide antagonist composition. The present disclosure also relates to the use of an MC1R peptide antagonist or a composition thereof for preventing or reducing skin discoloration in a subject.

[0236] In certain embodiments, including pharmaceutical embodiments, the present disclosure also relates to methods for using cosmetic or pharmaceutical compositions comprising the peptide antagonists of the present disclosure. In some embodiments, the present disclosure relates to methods for using cosmetic or pharmaceutical compositions to prevent, reduce, and / or ameliorate the appearance of skin discoloration in a subject, comprising applying an effective amount of the cosmetic or pharmaceutical composition to the skin of the subject. In some embodiments, the skin discoloration comprises melanin hyperpigmentation, post-inflammatory hyperpigmentation, liver spots, melasma, age spots (e.g., liver spots, senile lentigines, solar lentigines, sun spots), freckles, or combinations thereof. In some embodiments, the skin discoloration is due to a disorder, e.g., an adrenal disorder. In some embodiments, the MC1R peptide antagonists of the present disclosure are used to prevent or reduce skin discoloration caused by Addison's disease. In some embodiments, the administration is topical. In some embodiments, the administration is to the skin. In some embodiments, the administration is applied topically to the skin.

[0237] In some embodiments, a subject in the context of this disclosure is a mammalian subject. In some embodiments, the mammal is a human. In some embodiments, the human subject is a pediatric, juvenile, or adult subject of any age. In some embodiments, the subject has a disease or disorder that causes undesirable skin pigmentation. In embodiments, the subject has Addison's disease.

[0238] In certain embodiments, including pharmaceutical embodiments, the cosmetic or pharmaceutical composition is applied topically to a subject. Topical application as referred to herein may refer to application to one or more surfaces, such as keratinous tissue. Topical application may refer to direct application to a desired area. The topical cosmetic or pharmaceutical composition or preparation may be applied, for example, by pouring, dropping, or spraying if provided as a liquid or aerosol composition, by dabbing, rubbing, spreading, etc. if provided as an ointment, lotion, cream, gel, or similar composition, by sprinkling if provided as a powder, or by any other suitable means.

[0239] In certain embodiments, including pharmaceutical embodiments, the subject is treated with an effective amount of a topical cosmetic or pharmaceutical composition during the period between treatments with a skin peeling agent.In some embodiments, the subject is treated with the topical cosmetic or pharmaceutical composition of the present disclosure periodically for 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, or 26 weeks after treatment with a skin peeling agent.

[0240] In certain embodiments, including pharmaceutical embodiments, the subject is treated by topically administering an effective amount of the cosmetic or pharmaceutical composition one or more times during the treatment period, for example, 1-3 times per day, 1-21 times per week, once per day, twice per day, or three times per day. In some embodiments, the subject is treated with an effective amount of the cosmetic or pharmaceutical composition about once per week to about 12 times per week. In some embodiments, the subject is treated with an effective amount of the cosmetic or pharmaceutical composition at least about once per week. In some embodiments, the subject is treated with an effective amount of the cosmetic or pharmaceutical composition at most about 12 times per week. In some embodiments, the subject is administered 1x per week to about 2x per week, 1x per week to about 3x per week, 1x per week to about 4x per week, 1x per week to about 5x per week, 1x per week to about 6x per week, 1x per week to about 7x per week, 1x per week to about 8x per week, 1x per week to about 9x per week, 1x per week to about 10x per week, 1x per week to about 11x per week, 1x per week to about 1 ... about 7 times per week, about 2 times per week to about 8 times per week, about 2 times per week to about 9 times per week, about 2 times per week to about 10 times per week, about 2 times per week to about 11 times per week, about 2 times per week to about 12 times per week, about 3 times per week to about 4 times per week, about 3 times per week to about 5 times per week, about 3 times per week to about 6 times per week, about 3 times per week to about 7 times per week, about 3 times per week to about 8 times per week, about 3 times per week to about 9 times per week, about 3 times per week to about 10 times per week, about 3 times per week to about 11 times per week, about 3 times per week to about 12 times per week, about 4 times per week to about 5 times per week, about 4 times per week to about 6 times per week,about 4 times per week to about 7 times per week, about 4 times per week to about 8 times per week, about 4 times per week to about 9 times per week, about 4 times per week to about 10 times per week, about 4 times per week to about 11 times per week, about 4 times per week to about 12 times per week, about 5 times per week to about 6 times per week, about 5 times per week to about 7 times per week, about 5 times per week to about 8 times per week , about 5 times per week to about 9 times per week, about 5 times per week to about 10 times per week, about 5 times per week to about 11 times per week, about 5 times per week to about 12 times per week, about 6 times per week to about 7 times per week, about 6 times per week to about 8 times per week, about 6 times per week to about 9 times per week, about 6 times per week to about 10 times per week, about 6 times per week to about 1 1 time per week, about 6 times per week to about 12 times per week, about 7 times per week to about 8 times per week, about 7 times per week to about 9 times per week, about 7 times per week to about 10 times per week, about 7 times per week to about 11 times per week, about 7 times per week to about 12 times per week, about 8 times per week to about 9 times per week, about 8 times per week to about 10 times per week, about 8 times per week to about 10 times per week, about 8 times per week to about 10 times per week, about 10 ... In one embodiment, the patient is treated with an effective amount of the cosmetic or pharmaceutical composition about 11 times per week, about 8 times per week to about 12 times per week, about 9 times per week to about 10 times per week, about 9 times per week to about 11 times per week, about 9 times per week to about 12 times per week, about 10 times per week to about 11 times per week, about 10 times per week to about 12 times per week, or about 11 times per week to about 12 times per week. In some embodiments, the subject is treated with an effective amount of the cosmetic or pharmaceutical composition about once per week, about twice per week, about three times per week, about four times per week, about five times per week, about six times per week, about seven times per week, about eight times per week, about nine times per week, about ten times per week, about eleven times per week, about 12 times per week, about 13 times per week, or about 14 times per week.

[0241] In certain embodiments, including pharmaceutical embodiments, the pharmaceutical compositions of the present disclosure are administered to a subject for indications, including but not limited to, prevention or reduction of skin discoloration, which comprises applying an effective amount of the cosmetic or pharmaceutical composition to the skin of the subject. In some embodiments, the skin discoloration comprises melanin hyperpigmentation, post-inflammatory hyperpigmentation, liver spots, melasma, age spots (e.g., melasma, senile lentigines, solar lentigines, sun spots), freckles, or combinations thereof. In some embodiments, the skin discoloration is due to a disorder, such as an adrenal disorder. In some embodiments, the MC1R peptide antagonists of the present disclosure are used to treat skin discoloration caused by Addison's disease.

[0242] In some embodiments, the topical cosmetic compositions of the present disclosure are self-applied or administered by a patient. In certain embodiments, including pharmaceutical embodiments, the cosmetic or pharmaceutical compositions of the present disclosure are applied or administered by a medical professional, for example, in a clinic setting.

[0243] Lipid vesicle compositions of melanocortin 1 receptor antagonist peptides for intradermal delivery In one aspect, provided herein is a lipid vesicle composition comprising a peptide antagonist of the melanocortin 1 receptor, such as those described herein (e.g., SEQ ID NOs: 1-90). In some embodiments, the lipid vesicle composition comprises lipid vesicles each comprising a lipid bilayer comprising vesicle-forming lipids. In some embodiments, the lipid vesicle composition comprises an oil-in-water emulsion entrapped in the lipid vesicle. In some embodiments, the oil-in-water emulsion is stabilized by one or more surfactants. In some embodiments, the peptide antagonist is entrapped in the lipid bilayer and / or the oil-in-water emulsion. In some embodiments, the peptide antagonist is entrapped in the lipid bilayer. In some embodiments, the peptide antagonist is entrapped in the oil-in-water emulsion.

[0244] Concentration of peptide antagonist in the composition

[0245] In some embodiments, the peptide antagonist is present in the vesicle composition in an amount of about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the peptide antagonist is present in the vesicle composition in an amount of about 0.1 mg / mL to about 0.5 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 3 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 50 mg / mL, about 0.5 mg / mL to about 1 mg / mL. mL, about 0.5 mg / mL to about 2 mg / mL, about 0.5 mg / mL to about 3 mg / mL, about 0.5 mg / mL to about 4 mg / mL, about 0.5 mg / mL to about 5 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 20 mg / mL, about 0.5 mg / mL to about 50 mg / mL, about 1 mg / mL to about 2 mg / mL, about 1 mg / mL to about 3 mg / mL, about 1 mg / mL to about 4 mg / mL, about 1 mg / mL to about 5 mg / mL, about 1 mg / mL to about 1 0 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 50 mg / mL, about 2 mg / mL to about 3 mg / mL, about 2 mg / mL to about 4 mg / mL, about 2 mg / mL to about 5 mg / mL, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 20 mg / mL, about 2 mg / mL to about 50 mg / mL, about 3 mg / mL to about 4 mg / mL, about 3 mg / mL to about 5 mg / mL, about 3 mg / mL to about 10 mg / mL, about 3 mg / mL to about 20 mg / mL , from about 3 mg / mL to about 50 mg / mL, from about 4 mg / mL to about 5 mg / mL, from about 4 mg / mL to about 10 mg / mL, from about 4 mg / mL to about 20 mg / mL, from about 4 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 20 mg / mL, from about 10 mg / mL to about 50 mg / mL, or from about 20 mg / mL to about 50 mg / mL.In some embodiments, the peptide antagonist is present in the vesicle composition in an amount of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg / mL. In some embodiments, the peptide antagonist is present in the vesicle composition in an amount of at least about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, or about 20 mg / mL. In some embodiments, the peptide antagonist is present in the vesicle composition in an amount of up to about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg / mL. In some embodiments, the peptide antagonist is present in the composition in an amount of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL.

[0246] vesicle-forming lipids

[0247] In some embodiments, the vesicle composition comprises one or more vesicle-forming lipids. The vesicle-forming lipids act to encapsulate a portion of the oil-in-water emulsion. In some embodiments, this allows the oil-in-water emulsion to remain stable for a period of time.

[0248] Vesicle-forming lipids may be any suitable lipid for such purposes.In some embodiments, vesicle-forming lipids include phospholipids, glycolipids, lecithin, ceramide, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, cardiolipin, phosphatidic acid, cerebroside, or any combination thereof.In some embodiments, vesicle-forming lipids include combinations of lipids.

[0249] In some embodiments, the vesicle-forming lipid comprises a phospholipid. In some embodiments, the phospholipid is naturally occurring, semi-synthetic, or synthetically prepared, or a mixture thereof. In one embodiment, the phospholipid is one or more esters of glycerol with one or two (equal or different) fatty acid residues and phosphoric acid, where the phosphoric acid residue is in turn linked to a hydrophilic group, such as choline (phosphatidylcholine--PC), serine (phosphatidylserine--PS), glycerol (phosphatidylglycerol--PG), ethanolamine (phosphatidylethanolamine--PE), or inositol (phosphatidylinositol). The esters of phospholipids with only one fatty acid residue are generally referred to in the art as the "lyso" form of phospholipids or "lysophospholipids". The fatty acid residue present in phospholipids is generally a long chain fatty acid, typically containing 12 to 24 carbon atoms or 14 to 22 carbon atoms, and the fatty chain contains one or more unsaturations or is fully saturated.Examples of suitable fatty acids contained in phospholipids include, for example, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, oleic acid, linoleic acid, and linolenic acid.Saturated fatty acids such as myristic acid, palmitic acid, stearic acid, and arachidic acid may also be used.

[0250] In some embodiments, the phospholipid comprises one or more natural phospholipids. In some embodiments, the phospholipid comprises one or more semi-synthetic phospholipids. In some embodiments, the semi-synthetic phospholipid is a partially or fully hydrogenated derivative of naturally occurring lecithin. In some embodiments, the phospholipid comprises a fatty acid diester of phosphatidylcholine, ethylphosphatidylcholine, phosphatidylglycerol, phosphatidic acid, phosphatidylethanolamine, phosphatidylserine, or sphingomyelin. In some embodiments, the phospholipid comprises a hydrogenated phosphatidylcholine (e.g., Sunlipon 90H). In some embodiments, the phospholipid comprises, for example, dilauroyl-phosphatidylcholine (DLPC), dimyristoyl-phosphatidylcholine (DMPC), dipalmitoyl-phosphatidylcholine (DPPC), diarachidoyl- Phosphatidylcholine (DAPC), distearoyl-phosphatidylcholine (DSPC), dioleoyl-phosphatidylcholine (DOPC), 1,2 distearoyl-sn-glycero-3-ethylphosphocholine (ethyl-DSPC), dipentadecanoyl-phosphatidylcholine (DPDPC), 1-myristoyl-2-palmitoyl-phosphatidylcholine (MPPC), 1-palmitoyl-2-myristoyl-phosphatidylcholine (PMPC), 1-palmitoyl-2-stearoyl-phosphatidylcholine (PSPC), 1-stearoyl-2-palmitoyl-phosphatidylcholine (SPPC), 1-palmitoyl-2-stearo ... Oleyl phosphatidylcholine (POPC), 1-oleyl-2-palmitoyl-phosphatidylcholine (OPPC), dilauroyl phosphatidylglycerol (DLPG) and its alkali metal salts, diarachidoyl phosphatidylglycerol (DAPG) and its alkali metal salts, dimyristoyl phosphatidylglycerol (DMPG) and its alkali metal salts, dipalmitoyl phosphatidylglycerol (DPPG) and its alkali metal salts, distearoyl phosphatidylglycerol (DSPG) and its alkali metal salts, dioleoyl-phosphatidylglycerol (DOPG) and its alkali metal salts,Dimyristoyl phosphatidic acid (DMPA) and its alkali metal salts, dipalmitoyl phosphatidic acid (DPPA) and its alkali metal salts, distearoyl phosphatidic acid (DSPA), diarachidoyl phosphatidic acid (DAPA) and its alkali metal salts, dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidyl-ethanolamine (DSPE), dioleyl phosphatidylethanolamine (DOPE), diarachidoyl phosphatidylethanolamine (DAPE), dilinoleyl phosphatidylethanolamine (DLPE), dimyristoyl phosphatidylserine ( DMPS), diarachidoyl phosphatidylserine (DAPS), dipalmitoyl phosphatidylserine (DPPS), distearoyl phosphatidylserine (DSPS), dioleoyl phosphatidylserine (DOPS), dipalmitoyl sphingomyelin (DPSP), and distearoyl sphingomyelin (DSSP), dilauroyl-phosphatidylinositol (DLPI), diarachidoyl phosphatidylinositol (DAPI), dimyristoyl phosphatidylinositol (DMPI), dipalmitoyl phosphatidylinositol (DPPI), distearoyl phosphatidylinositol (DSPI), and dioleoyl-phosphatidylinositol (DOPI).

[0251] In some embodiments, the vesicle-forming lipid is present in an amount of about 0.5% to about 25% (w / w) of the composition. In some embodiments, the vesicle-forming lipid is present in an amount of about 0.5% to about 2%, about 0.5% to about 5%, about 0.5% to about 8%, about 0.5% to about 10%, about 0.5% to about 12%, about 0.5% to about 15%, about 0.5% to about 20%, about 0.5% to about 25%, about 2% to about 5%, about 2% to about 8%, about 2% to about 10%, about 2% to about 12%, about 2% to about 15%, about 2% to about 20%, about 2% to about 25%, about 5% to about 8%, about 5% to about 10%, about 5% to about 10%, about 5% to about 20%, about 2% to about 25%, about 5% to about 8 ... In some embodiments, the vesicle-forming lipid is present in an amount of about 0.5%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 20%, about 25%, about 8% to about 10%, about 8% to about 12%, about 8% to about 15%, about 8% to about 20%, about 8% to about 25%, about 10% to about 12%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 12% to about 15%, about 12% to about 20%, about 12% to about 25%, about 15% to about 20%, about 15% to about 25%, or about 20% to about 25% (w / w). In some embodiments, the vesicle-forming lipid is present in an amount of about 0.5%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 20%, or about 25%. In some embodiments, the vesicle-forming lipids are present in an amount of at least about 0.5%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, or about 20% (w / w) of the composition. In some embodiments, the vesicle-forming lipids are present in an amount of up to about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 20%, or about 25% (w / w) of the composition.

[0252] In some embodiments, the vesicle-forming lipid is present in an amount of about 5% to about 15% (w / w) of the composition. In some embodiments, the vesicle-forming lipid is present in an amount of about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 11%, about 5% to about 12%, about 5% to about 13%, about 5% to about 14%, about 5% to about 15%, about 8% to about 9%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 13%, about 8% to about 14%, about 8% to about 15%, about 9% to about 10%, about 9% to about 11%, about 9% to about 12%, about 9% to about 13%, about 9% to about 14%, about 9% to about 15%, about 9% to about 15%, about 9% to about 16%, about 9% to about 17%, about 9% to about 18%, about 9% to about 19%, about 9% to about 20%, about 9% to about 21%, about 9% to about 22%, about 9% to about 23%, about 9% to about 24%, about 9% to about 25%, about 9% to about 26%, about 9% to about 27%, about 9% to about 28%, about 9% to about 29%, about 9% to about 30%, about 9% to about 31%, about 9% to about 32%, about 9% to about 33%, about 9% to about 34%, about 9% to about 35%, about 9% to about 36%, about 9% to about 37%, about 9% to about 38%, about 9% to about 39 In some embodiments, the vesicle-forming lipid is present in an amount of about 5%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% (w / w) of the composition. In some embodiments, the vesicle-forming lipids are present in an amount of at least about 5%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, or about 14% (w / w) of the composition. In some embodiments, the vesicle-forming lipids are present in an amount of up to about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% (w / w) of the composition.

[0253] In some embodiments, the composition comprises a short-chain polyol. In some embodiments, the short-chain polyol acts to increase the stability of the resulting lipid vesicle. In some embodiments, the short-chain polyol is a C2-C4 polyol that contains two or three alcohol groups. In some embodiments, the short-chain polyol is propylene glycol. In some embodiments, the composition comprises propylene glycol.

[0254] In some embodiments, propylene glycol is present in an amount of about 0.5% to about 25% (w / w) of the composition. In some embodiments, propylene glycol is present in an amount of about 0.5% to about 2%, about 0.5% to about 5%, about 0.5% to about 8%, about 0.5% to about 10%, about 0.5% to about 12%, about 0.5% to about 15%, about 0.5% to about 20%, about 0.5% to about 25%, about 2% to about 5%, about 2% to about 8%, about 2% to about 10%, about 2% to about 12%, about 2% to about 15%, about 2% to about 20%, about 2% to about 25%, about 5% to about 8%, about 5% to about 10%, about 5 ... About 12%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 8% to about 10%, about 8% to about 12%, about 8% to about 15%, about 8% to about 20%, about 8% to about 25%, about 10% to about 12%, about 10% to about 15%, about 10% to about 20%, about 10% to about 25%, about 12% to about 15%, about 12% to about 20%, about 12% to about 25%, about 15% to about 20%, about 15% to about 25%, or about 20% to about 25% (w / w). In some embodiments, propylene glycol is present in an amount of about 0.5%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 20%, or about 25%. In some embodiments, propylene glycol is present in an amount of at least about 0.5%, about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, or about 20%. In some embodiments, propylene glycol is present in an amount of up to about 2%, about 5%, about 8%, about 10%, about 12%, about 15%, about 20%, or about 25%. In some embodiments, propylene glycol is present in an amount of about 1% to about 10%. In some embodiments, propylene glycol is present in an amount of about 1% to about 2%, about 1% to about 4%, about 1% to about 6%, about 1% to about 8%, about 1% to about 10%, about 2% to about 4%, about 2% to about 6%, about 2% to about 8%, about 2% to about 10%, about 4% to about 6%, about 4% to about 8%, about 4% to about 10%, about 6% to about 8%, about 6% to about 10%, or about 8% to about 10%. In some embodiments, propylene glycol is present in an amount of about 1%, about 2%, about 4%, about 6%, about 8%, or about 10%.In some embodiments, propylene glycol is present in an amount of at least about 1%, about 2%, about 4%, about 6%, or about 8%. In some embodiments, propylene glycol is present in an amount of up to about 2%, about 4%, about 6%, about 8%, or about 10%. In some embodiments, propylene glycol is present in about the same amount as the vesicle-forming lipid. In some embodiments, the ratio of propylene glycol to vesicle-forming lipid in the composition is about 2:1 to about 1:2 (w / w).

[0255] Oil Phase

[0256] The lipid vesicle compositions provided herein include oil-in-water emulsions. The oil component is selected so that the material is liquid at the operating temperature (e.g., room temperature) and immiscible with water.

[0257] Any suitable oil may be used as the oil phase. In some embodiments, the oil comprises naturally occurring oil. In some embodiments, the naturally occurring oil is derived from one or more plants or plant parts (e.g., seeds or nuts). In some embodiments, the oil is naturally occurring oil, such as, for example, olive oil, vegetable oil, sunflower oil, or other similar plant-derived oil.

[0258] In some embodiments, the oil phase is selected from the group consisting of vegetable oils, mono-, di-, and triglycerides, silicone fluids, mineral oils, and combinations thereof.

[0259] In some embodiments, the oil comprises a silicon oil or derivative, such as dimethicone. In some embodiments, the silicon oil comprises a siloxane polymer. In some embodiments, the siloxane polymer comprises C1-C3 substituents. In some embodiments, the siloxane is polydimethylsiloxane (PDMS). In some embodiments, the oil is a mixture that includes a silicon oil (e.g., dimethicone) as a smaller component. In some embodiments, the silicon oil is incorporated to enhance the feel of the resulting composition or as a moisturizer. In some embodiments, the oil comprises an amount of silicon oil up to about 5%, up to about 4%, up to about 3%, up to about 2%, or up to about 1%. In some embodiments, the silicon oil is present in an amount of about 0.1% to about 2% (w / w) of the composition. In some embodiments, the silicon oil is present in an amount of about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, or about 1%.

[0260] In some embodiments, the oil is present in an amount of about 1% to about 35% (w / w) of the composition. In some embodiments, the oil is present in an amount of about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 10% to about 15%, about 10% The oil is present in an amount of about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35%, about 20% to about 25%, about 20% to about 30%, about 20% to about 35%, about 25% to about 30%, about 25% to about 35%, or about 30% to about 35%. In some embodiments, the oil is present in an amount of about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35%. In some embodiments, the oil is present in an amount of at least about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%. In some embodiments, the oil is present in an amount of up to about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35%. In some embodiments, the oil is present in an amount of about 5% to about 15%. In some embodiments, the oil is present in an amount of about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 5% to about 11%, about 5% to about 12%, about 5% to about 13%, about 5% to about 14%, about 5% to about 15%, about 8% to about 9%, about 8% to about 10%, about 8% to about 11%, about 8% to about 12%, about 8% to about 13%, about 8% to about 14%, about 8% to about 15%, about 9% to about 10%, about 9% to about 11%, about 9% to about 12%, about 9% to about 13%, about 9% to about 14%, about 9% to about 15%, about 10% to about 11%, about 10% to about 12%, about 10% to about 13%, about 10% to about 14%, about 10% to about 15%, about 11% to about 12%, about 11% to about 13%, about 11% to about 14%, about 11% to about 15%, about 12% to about 13%, about 12% to about 14%, about 12% to about 15%, about 13% to about 14%, about 13% to about 15%, or about 14% to about 15%.In some embodiments, the oil is present in an amount of about 5%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%. In some embodiments, the oil is present in an amount of at least about 5%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, or about 14%. In some embodiments, the oil is present in an amount of up to about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15%.

[0261] In some embodiments, the oil comprises one or more triglycerides. In some embodiments, the triglycerides are medium chain triglycerides. In some embodiments, the medium chain triglycerides are C6-C 12 The fatty acid esters include those having a chain length of

[0262] In some embodiments, the triglyceride is present in an amount of about 1% to about 35% (w / w) of the composition. In some embodiments, the triglyceride is present in an amount of about 1% to about 5%, about 1% to about 10%, about 1% to about 15%, about 1% to about 20%, about 1% to about 25%, about 1% to about 30%, about 1% to about 35%, about 5% to about 10%, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5% to about 35%, about 10% to about 15%, about In some embodiments, the triglyceride is present in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35%. In some embodiments, triglycerides are present in an amount of at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 10%, about 15%, about 20%, about 25%, or about 30%. In some embodiments, triglycerides are present in an amount of up to about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, or about 35%.

[0263] In some embodiments, the lipid vesicles and / or the oil phase of the lipid vesicle portion of the composition comprises a sterol. In some embodiments, the sterol is cholesterol. In some embodiments, the cholesterol may be plant-derived cholesterol. In some embodiments, the plant-derived cholesterol may be PhytoChol®, SyntheChol®, or any other plant-derived cholesterol (e.g., Avanti#700100), or any combination thereof. In some embodiments, the sterol may be a phytosterol or a derivative thereof. In some embodiments, the phytosterol or a derivative thereof may be phytosterol MM, Advasterol™ 90 IP or 95 IP F, NET Sterol-ISO, rapeseed sterol, sitosterol 700095, lanosterol-95, brassicasterol, or any combination thereof.

[0264] In some embodiments, the sterol is present in an amount of about 1% to about 5% (w / w) of the composition. In some embodiments, the sterol is present in an amount of about 1% to about 1.5%, about 1% to about 2%, about 1% to about 2.5%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1.5% to about 2%, about 1.5% to about 2.5%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 2% to about 2.5%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2.5% to about 3%, about 2.5% to about 4%, about 2.5% to about 5%, about 3% to about 4%, about 3% to about 5%, or about 4% to about 5% (w / w) of the composition. In some embodiments, the sterol is present in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% (w / w) of the composition. In some embodiments, the sterol is present in an amount of at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, or about 4% (w / w) of the composition. In some embodiments, the sterol is present in an amount of up to about 1.5%, about 2%, about 2.5%, about 3%, about 4%, or about 5% (w / w) of the composition.

[0265] Penetration enhancers

[0266] In some embodiments, the lipid vesicle composition comprises one or more penetration enhancers that, when applied to the skin of an individual, act to increase the amount of penetration of an anionic polymeric substance, peptide, or combination thereof through one or more layers of the skin.

[0267] In some embodiments, the penetration enhancer is included in an oil-in-water emulsion of the composition. In some embodiments, the penetration enhancer is included in the lipid bilayer of the composition.

[0268] There are many types of penetration enhancers that can be used, hi some embodiments, the penetration enhancer comprises an ionic surfactant, a non-ionic surfactant, or a combination thereof.

[0269] In some embodiments, the penetration enhancer comprises one non-ionic surfactant or a combination of multiple non-ionic surfactants. In some embodiments, the penetration enhancer is a single non-ionic surfactant. In some embodiments, the penetration enhancer is a combination of at least two, three, four, or more non-ionic surfactants. In some embodiments, the penetration enhancer is a combination of two non-ionic surfactants. In some embodiments, the penetration enhancer is a combination of three non-ionic surfactants.

[0270] In some embodiments, the nonionic surfactant or combination of nonionic surfactants is selected from polyethylene glycol ethers of fatty alcohols, sorbitan esters, polysorbates, and polyethylene glycol fatty acid esters, and combinations thereof.

[0271] In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers and sorbitan esters of aliphatic alcohols. In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers and sorbitan esters of aliphatic alcohols. In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers and sorbitan esters of aliphatic alcohols. In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers and polyethylene glycol fatty acid esters of aliphatic alcohols. In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers, sorbitan esters, and polysorbates of aliphatic alcohols. In some embodiments, the combination of nonionic surfactants is a combination of polyethylene glycol ethers, sorbitan esters, and polyethylene glycol fatty acid esters ... polysorbates, and polyethylene glycol fatty acid esters of aliphatic alcohols.

[0272] In some embodiments, the combination of non-ionic surfactants comprises a polyethylene glycol fatty acid ester and a sorbitan ester. In some embodiments, the combination of non-ionic surfactants comprises a polyethylene glycol fatty acid ester and a polysorbate. In some embodiments, the combination of non-ionic surfactants is a combination of a polyethylene glycol fatty acid ester, a polysorbate, and a sorbitan ester.

[0273] In some embodiments, the nonionic surfactant comprises a polyethylene glycol (PEG) ether of an aliphatic alcohol. In some embodiments, the PEG ether of an aliphatic alcohol comprises from about 2 to about 8 PEG groups and C 12 -C 22In some embodiments, the polyethylene glycol ether of an aliphatic alcohol comprises diethylene glycol hexadecyl ether, 2-(2-octadecoxyethoxy)ethanol, diethylene glycol monooleyl ether, polyoxyethylene(2) oleyl ether, polyoxyethylene(3) oleyl ether, or polyoxyethylene(5) oleyl ether, or any combination thereof. In some embodiments, the polyethylene glycol ether of an aliphatic alcohol comprises 2-(2-octadecoxyethoxy)ethanol. In some embodiments, the PEG ether of an aliphatic alcohol is highly purified Brij® O2 or a derivative thereof.

[0274] In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of about 0.5% to about 2.5%. In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of about 0.5% to about 0.8%, about 0.5% to about 1%, about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 2.5%, about 0.8% to about 1%, about 0.8% to about 1.2%, about 0.8% to about 1.5%, about 0.8% to about 2%, about 0.8% to about 2.5%, about 1% to about 1.2%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 2.5%, about 1.2% to about 1.5%, about 1.2% to about 2%, about 1.2% to about 2.5%, about 1.5% to about 2%, about 1.5% to about 2.5%, or about 2% to about 2.5%. In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%. In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of at least about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, or about 2%. In some embodiments, the PEG ether of an aliphatic alcohol is present in an amount of up to about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%.

[0275] In some embodiments, the nonionic surfactant comprises a fatty acid ester. In some embodiments, the nonionic surfactant comprises PPG benzyl ether myristate, ethylhexyl stearate, isostearyl isostearate (e.g., Crodamol ISIS), myristyl myristate (e.g., Crodamol MM), glyceryl stearate (e.g., Crodamol GMS, Cithrol GMS). In some embodiments, the nonionic surfactant comprises a sorbitan ester. In some embodiments, the sorbitan ester is a fatty acid ester. In some embodiments, the sorbitan ester is a C 12 -C 22 A fatty acid ester. In some embodiments, the sorbitan ester comprises sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, or sorbitan isostearate, or any combination thereof. In some embodiments, the sorbitan ester comprises sorbitan monolaurate. In some embodiments, the sorbitan ester comprises sorbitan monopalmitate. In some embodiments, the sorbitan ester comprises sorbitan monostearate. In some embodiments, the sorbitan ester comprises sorbitan monooleate. In some embodiments, the sorbitan ester comprises sorbitan trioleate. In some embodiments, the sorbitan ester comprises sorbitan sesquioleate. In some embodiments, the sorbitan ester comprises sorbitan isostearate.

[0276] In some embodiments, the sorbitan ester is present in an amount of about 0.1% to about 2.5% (w / w) of the composition. In some embodiments, the sorbitan ester is present in an amount of about 0.1% to about 0.3%, about 0.1% to about 0.5%, about 0.1% to about 0.8%, about 0.1% to about 1%, about 0.1% to about 1.2%, about 0.1% to about 1.5%, about 0.1% to about 2%, about 0.1% to about 2.5%, about 0.3% to about 0.5%, about 0.3% to about 0.8%, about 0.3% to about 1%, about 0.3% to about 1.2%, about 0.3% to about 1.5%, about 0.3% to about 2%, about 0.3% to about 2.5%, about 0.5% to about 0.8%, about 0.5% to about 1%, The compound is present in an amount of about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 2.5%, about 0.8% to about 1%, about 0.8% to about 1.2%, about 0.8% to about 1.5%, about 0.8% to about 2%, about 0.8% to about 2.5%, about 1% to about 1.2%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 2.5%, about 1.2% to about 1.5%, about 1.2% to about 2%, about 1.2% to about 2.5%, about 1.5% to about 2%, about 1.5% to about 2.5%, or about 2% to about 2.5%. In some embodiments, the sorbitan esters are present in an amount of about 0.1%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%. In some embodiments, the sorbitan esters are present in an amount of at least about 0.1%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, or about 2%. In some embodiments, the sorbitan esters are present in an amount of up to about 0.1%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%.

[0277] In some embodiments, the non-ionic surfactant comprises a polysorbate. In some embodiments, the polysorbate comprises polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, or any combination thereof. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the polysorbate is polysorbate 20.

[0278] In some embodiments, the polysorbate is present in an amount of about 0.1% to about 2.5% (w / w) of the composition. In some embodiments, the polysorbate is present in an amount of about 0.1% to about 0.2%, about 0.1% to about 0.3%, about 0.1% to about 0.5%, about 0.1% to about 0.8%, about 0.1% to about 1%, about 0.1% to about 1.2%, about 0.1% to about 1.5%, about 0.1% to about 2%, about 0.1% to about 2.5%, about 0.2% to about 0.3%. %, about 0.2% to about 0.5%, about 0.2% to about 0.8%, about 0.2% to about 1%, about 0.2% to about 1.2%, about 0.2% to about 1.5%, about 0.2% to about 2%, about 0.2% to about 2.5%, about 0.3% to about 0.5%, about 0.3% to about 0.8%, about 0.3% to about 1%, about 0.3% to about 1.2%, about 0.3% or to about 1.5%, about 0.3% to about 2%, about 0.3% to about 2.5%, about 0.5% to about 0.8%, about 0.5% to about 1%, about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 2.5%, about 0.8% to about 1%, about 0.8% to about 1.2%, about 0.8% to about 1.5%, about 0. In some embodiments, the polysorbate is present in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%. In some embodiments, the polysorbate is present in an amount of at least about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, or about 2%. In some embodiments, the polysorbate is present in an amount of up to about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%.

[0279] In some embodiments, the non-ionic surfactant comprises a polyethylene glycol (PEG) fatty acid ester. In some embodiments, the PEG fatty acid ester comprises a C8-C hydroxyl group bonded to each terminal hydroxyl group to form a fatty acid ester. 22 The PEG chain is about 2 to 8 subunits containing fatty acids. In some embodiments, the PEG fatty acid ester comprises PEG-8 dilaurate, PEG-4 dilaurate, PEG-4 laurate, PEG-8 dioleate, PEG-8 distearate, PEG-8 distearate, PEG-7 glyceryl cocoate, and PEG-20 glyceryl almondate, or any combination thereof. In some embodiments, the PEG fatty acid ester is PEG-4 dilaurate.

[0280] In some embodiments, the PEG fatty acid ester is present in an amount of about 0.5% to about 2.5% (w / w) of the composition. In some embodiments, the PEG fatty acid ester is present in an amount of about 0.5% to about 0.8%, about 0.5% to about 1%, about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 2.5%, about 0.8% to about 1%, about 0.8% to about 1.2%, about 0.8% to about 1.5%, about 0.8% to about 2%, about 0.8% to about 2.5%, about 1% to about 1.2%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 2.5%, about 1.2% to about 1.5%, about 1.2% to about 2%, about 1.2% to about 2.5%, about 1.5% to about 2%, about 1.5% to about 2.5%, or about 2% to about 2.5%. In some embodiments, the PEG fatty acid ester is present in an amount of about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%. In some embodiments, the PEG fatty acid ester is present in an amount of at least about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, or about 2%. In some embodiments, the PEG fatty acid ester is present in an amount of up to about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%.

[0281] In some embodiments, the non-ionic surfactant has a hydrophobic-lipophilic balance (HLB) of about 10 or less. In some embodiments, the non-ionic surfactant may be Cithrol GMS 40. In some embodiments, the composition comprises a plurality of non-ionic surfactants each having an HLB of about 10 or less. In some embodiments, the non-ionic surfactants having an HLB of 10 or less are selected from Table 1, or any combination thereof.

[0282] In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5% to about 1%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% to about 4%, about 0.5% to about 5%, about 0.5% to about 6%, about 0.5% to about 7%, about 0.5% to about 8%, about 0.5% to about 10%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 10%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 1.5% to about 6%, about 1.5% to about 7%, about 1.5% to about 8%, about 1.5% to about 10%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 10%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 10% , about 4% to about 5%, about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 10%, about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 10%, about 6% to about 7%, about 6% to about 8%, about 6% to about 10%, about 7% to about 8%, about 7% to about 10%, or about 8% to about 10%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 10%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of at least about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, or about 8%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of up to about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 10%.

[0283] In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion, the lipid bilayer, or both. In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion. In some embodiments, the composition comprises a non-ionic surfactant in the lipid bilayer. In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion and in the lipid bilayer, where the composition comprises two or more different non-ionic surfactants.

[0284] In some embodiments, the penetration enhancer comprises a salicylate or a nicotinate. In some embodiments, the ester is a C1-C6 alkyl ester or a benzyl ester. In some embodiments, the penetration enhancer comprises methyl salicylate or benzyl nicotinate. In some embodiments, the penetration enhancer is a nicotinate present in an amount of up to about 0.1%, 0.5%, 1%, 2%, or 3% (w / w) of the composition. In some embodiments, the nicotinate is present in an amount of about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1%.

[0285] In some embodiments, the penetration enhancer comprises a fatty acid acylated amino acid. In some embodiments, the fatty acid acylated amino acid is lysine. In some embodiments, the lysine is monoacylated with a fatty acid. In some embodiments, the penetration enhancer is monolauryl lysine. In some embodiments, the lysine is diacylated. In some embodiments, the penetration enhancer is dipalmitoyl lysine. In some embodiments, the fatty acid acylated amino acid is present in an amount of about 1%, about 2%, about 3%, about 4%, or about 5% (w / w) of the composition. In some embodiments, the fatty acid acylated amino acid is present in an amount of at least about 1%, about 2%, about 3%, about 4%, or about 5% (w / w) of the composition. In some embodiments, the fatty acid acylated amino acid is present in an amount of at most about 1%, at most about 2%, at most about 3%, at most about 4%, or at most about 5% (w / w) of the composition. In some embodiments, the fatty acylated amino acid is present in an amount of about 0.1% to about 5%, about 0.1% to about 4%, about 0.1% to about 3%, about 0.1% to about 2%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, about 0.5% to about 2%, about 1% to about 5%, about 1% to about 4%, about 1% to about 3%, about 1% to about 2%, or about 1.5% to about 2.5%.

[0286] In some embodiments, the nonionic surfactant has a hydrophobic-lipophilic balance (HLB) of about 10 or less. In some embodiments, the composition comprises a plurality of nonionic surfactants, each having an HLB of about 10 or less. In some embodiments, the nonionic surfactants having an HLB of 10 or less are selected from Table A below, or any combination thereof.

[0287] [Table 4]

[0288] In some embodiments, the nonionic surfactant has a hydrophobic-lipophilic balance (HLB) of about 10 or greater. In some embodiments, the composition comprises multiple nonionic surfactants, each having an HLB of about 10 or greater.

[0289] In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5% to about 1%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 3%, about 0.5% to about 4%, about 0.5% to about 5%, about 0.5% to about 6%, about 0.5% to about 7%, about 0.5% to about 8%, about 0.5% to about 10%, about 1% to about 1.5%, about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 10%, about 1.5% to about 2%, about 1.5% to about 3%, about 1.5% to about 4%, about 1.5% to about 5%, about 1.5% to about 6%, about 1.5% to about 7%, about 1.5% to about 8%, about 1.5% to about 10%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 10%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 10% , about 4% to about 5%, about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 10%, about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 10%, about 6% to about 7%, about 6% to about 8%, about 6% to about 10%, about 7% to about 8%, about 7% to about 10%, or about 8% to about 10%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 10%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of at least about 0.5%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, or about 8%. In some embodiments, the nonionic surfactant or combination of nonionic surfactants is present in an amount of up to about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, or about 10%.

[0290] In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion, the lipid bilayer, or both. In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion. In some embodiments, the composition comprises a non-ionic surfactant in the lipid bilayer. In some embodiments, the composition comprises a non-ionic surfactant in the oil-in-water emulsion and in the lipid bilayer, where the composition comprises two or more different non-ionic surfactants.

[0291] In some embodiments, the penetration enhancer comprises a salicylate or a nicotinate. In some embodiments, the ester is a C1-C6 alkyl ester or a benzyl ester. In some embodiments, the penetration enhancer comprises methyl salicylate or benzyl nicotinate. In some embodiments, the penetration enhancer is a nicotinate present in an amount of up to about 0.1%, 0.5%, 1%, 2%, or 3% (w / w) of the composition. In some embodiments, the nicotinate is present in an amount of about 0.1% to about 3%, about 0.1% to about 2%, or about 0.1% to about 1%.

[0292] Cationic Surfactants

[0293] In some embodiments, the composition comprises an ionic surfactant. In some embodiments, the ionic surfactant is a cationic surfactant. In some embodiments, the cationic surfactant is a monocationic surfactant, a dicationic surfactant, or a polycationic surfactant.

[0294] In some embodiments, a monocationic surfactant is used in the composition to form a submicron emulsion prior to forming the final lipid vesicle composition provided herein (e.g., prior to adding lipid-forming vesicles). In some embodiments, the monocationic surfactant is net monocationic (e.g., a phosphate salt containing two side chains, each with a single cationic functional group, partially neutralized by the phosphate anion).

[0295] In some embodiments, the monocationic surfactant is a propylene glycol-diammonium phosphate ester derived from a fatty amide. The propylene glycol-diammonium phosphate ester derived from a fatty amide is a phospholipid that contains at least one propylene glycol phosphoester bound to a quaternary ammonium group, which is then bound to a fatty acid amide. A non-limiting example of a propylene glycol-diammonium phosphate ester derived from a fatty amide is linoleamidopropyl PG-dimonium chloride phosphate. Similar compounds with different fatty acid amide groups bound are also known. In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide has the following structure:

[0296] [ka] where n is an integer from 1 to 3, m is an integer from 0 to 2, the sum of m and n is 3, X is a cation selected from a proton, sodium, potassium, magnesium, and calcium, and R is a C8-C 30 It is the acyl group of a fatty acid.

[0297] In some embodiments, the fatty acid is 12 -C 24In some embodiments, the monocationic penetration enhancer is a fatty acid. In some embodiments, the fatty acid is an unsaturated fatty acid. In some embodiments, the fatty acid is linoleic acid. In some embodiments, the monocationic penetration enhancer is linoleamidopropyl PG-dimonium chloride phosphate (e.g., Arlasilk™ PTM, Arlasilk™ EFA).

[0298] In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide is present in an amount of about 1% to about 10% (w / w) of the composition. In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide is present in an amount of about 1% to about 2%, about 1% to about 3%, about 1% to about 4%, about 1% to about 5%, about 1% to about 6%, about 1% to about 7%, about 1% to about 8%, about 1% to about 9%, about 1% to about 10%, about 2% to about 3%, about 2% to about 4%, about 2% to about 5%, about 2% to about 6%, about 2% to about 7%, about 2% to about 8%, about 2% to about 9%, about 2% to about 10%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 2% to about 9%, about 2% to about 10%, about 3% to about 4%, about 3% to about 5%, about 3% to about 6%, about 3% to about 7%, about 3% to about 8%, about 3% to about 9%, about 3 ... The compound is present in an amount of about 7%, about 3% to about 8%, about 3% to about 9%, about 3% to about 10%, about 4% to about 5%, about 4% to about 6%, about 4% to about 7%, about 4% to about 8%, about 4% to about 9%, about 4% to about 10%, about 5% to about 6%, about 5% to about 7%, about 5% to about 8%, about 5% to about 9%, about 5% to about 10%, about 6% to about 7%, about 6% to about 8%, about 6% to about 9%, about 6% to about 10%, about 7% to about 8%, about 7% to about 9%, about 7% to about 10%, about 8% to about 9%, about 8% to about 10%, or about 9% to about 10%. In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide is present in an amount of about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10% (w / w) of the composition. In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide is present in an amount of at least about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, or about 9.5%.In some embodiments, the propylene glycol-diammonium phosphate ester derived from a fatty amide is present in an amount up to about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8%, about 8.5%, about 9%, about 9.5%, or about 10%.

[0299] In some embodiments, the cationic surfactant is a dicationic penetration enhancer. In some embodiments, the dicationic surfactant is a gemini surfactant. In some embodiments, the gemini surfactant is a surfactant comprising two quaternary amines represented by the formula: 24 each R is independently an optionally substituted C1-C6 alkyl group; B is an optionally substituted C2-C6 alkyl group; 10 In some embodiments, each of A and C is a C-C alkylene chain. 24 In some embodiments, each of A and C is a C6-C 24 In some embodiments, B is a saturated C-C hydrocarbon. In some embodiments, each R is methyl. In some embodiments, B is a saturated C-C 10 is an alkylene chain. In some cases, gemini surfactants are designated XYZ, where X, Y, and Z are each an integer representing the number of carbon atoms in each substituent, and Y is a spacer between two quaternary amines. Thus, for example, a 12-3-12 gemini surfactant has the formula CH3(CH2)11-[N + (CH3)2]-(CH2)3-[N + (CH3)2]-(CH2) 11In some embodiments, the gemini surfactant is a 10-2-10, 12-2-12, 14-2-14, 10-3-10, 12-3-12, 14-3-14, 10-4-10, 12-4-12, or 14-4-14 gemini surfactant. In some embodiments, the gemini surfactant is a 12-3-12 gemini surfactant.

[0300] In some embodiments, the gemini surfactant is present in an amount of about 0.1% to about 1.5% (w / w) of the composition. In some embodiments, the gemini surfactant is present in an amount of about 0.1% to about 0.2%, about 0.1% to about 0.3%, about 0.1% to about 0.5%, about 0.1% to about 0.7%, about 0.1% to about 0.9%, about 0.1% to about 1%, about 0.1% to about 1.2%, about 0.1% to about 1.5%, about 0.2% to about 0.3%, about 0.2% to about 0.5%, about 0.2% to about 0.7%, about 0.2% to about 0.9%, about 0.2% to about 1%, about 0.2% to about 1.2%, about 0.2% to about 1.5%, about 0.3% to about 0.5%, about 0.3% to about 0.7%, The compound is present in an amount of about 0.3% to about 0.9%, about 0.3% to about 1%, about 0.3% to about 1.2%, about 0.3% to about 1.5%, about 0.5% to about 0.7%, about 0.5% to about 0.9%, about 0.5% to about 1%, about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.7% to about 0.9%, about 0.7% to about 1%, about 0.7% to about 1.2%, about 0.7% to about 1.5%, about 0.9% to about 1%, about 0.9% to about 1.2%, about 0.9% to about 1.5%, about 1% to about 1.2%, about 1% to about 1.5%, or about 1.2% to about 1.5%. In some embodiments, the gemini surfactant is present in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, about 1.2%, or about 1.5%. In some embodiments, the gemini surfactant is present in an amount of at least about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, or about 1.2%. In some embodiments, the gemini surfactant is present in an amount of up to about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, about 1.2%, or about 1.5%.

[0301] In some embodiments, the cationic surfactant comprises a polycationic group. In some embodiments, the polycationic group is a polymer in which each monomer of the polymer comprises a charged group (e.g., an amino group). In some embodiments, the polycationic group is polylysine. In some embodiments, the polycationic group is polyarginine.

[0302] In some cases, the cationic surfactant may comprise amino acid and fatty acid. In some cases, the cationic surfactant may be derived from amino acid and fatty acid. In some cases, the amino acid may comprise cationic amino acid such as lysine, arginine, or histidine. In some cases, the fatty acid may comprise undecyloyl group, lauroyl group, tridecyloyl group, myristoyl group, palmitoyl group, or stearoyl group. In some cases, the cationic surfactant may comprise lauroyl lysine or lauroyl arginine.

[0303] In some embodiments, the polylysine has a molecular weight of about 1 kDa to about 10 kDa, about 1 kDa to about 5 kDa, or about 3 kDa to about 5 kDa, hi some embodiments, the polylysine is present in an amount of about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.2%, about 0.05% to about 1%, about 0.05% to about 0.5%, or about 0.05% to about 0.2% (w / w) of the composition.

[0304] Further ingredients

[0305] In some embodiments, the vesicle composition comprises additional components. In some embodiments, these additional components improve one or more properties of the vesicle without dramatically altering the delivery of the active ingredient. In some cases, the active ingredient comprises a peptide antagonist of the melanocortin 1 receptor. In some embodiments, the peptide antagonist is present in the composition in an amount of about 0.1% to about 1.5% (w / w). In some embodiments, the peptide antagonist is from about 0.1% to about 0.2%, from about 0.1% to about 0.3%, from about 0.1% to about 0.5%, from about 0.1% to about 0.7%, from about 0.1% to about 0.9%, from about 0.1% to about 1%, from about 0.1% to about 1.2%, from about 0.1% to about 1.5%, from about 0.2% to about 0.3%, from about 0.2% to about 0.5%, from about 0.2% to about 0.7%, from about 0.2% to about 0.9%, from about 0.2% to about 1%, from about 0.2% to about 1.2%, from about 0.2% to about 1.5%, from about 0.3% to about 0.5%, from about 0.3% to about 0.7%, from about The compound is present in an amount of from 0.3% to about 0.9%, from about 0.3% to about 1%, from about 0.3% to about 1.2%, from about 0.3% to about 1.5%, from about 0.5% to about 0.7%, from about 0.5% to about 0.9%, from about 0.5% to about 1%, from about 0.5% to about 1.2%, from about 0.5% to about 1.5%, from about 0.7% to about 0.9%, from about 0.7% to about 1%, from about 0.7% to about 1.2%, from about 0.7% to about 1.5%, from about 0.9% to about 1%, from about 0.9% to about 1.2%, from about 0.9% to about 1.5%, from about 1% to about 1.2%, from about 1% to about 1.5%, or from about 1.2% to about 1.5%. In some embodiments, the peptide antagonist is present in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, about 1.2%, or about 1.5%. In some embodiments, the peptide antagonist is present in an amount of at least about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, or about 1.2%. In some embodiments, the peptide antagonist is present in an amount of up to about 0.2%, about 0.3%, about 0.5%, about 0.7%, about 0.9%, about 1%, about 1.2%, or about 1.5%.

[0306] In some embodiments, the vesicle composition further comprises one or more viscosity enhancing agents. In some embodiments, the viscosity enhancing agent thickens the composition to enhance the stability and / or feel of the vesicle composition to the user. In some embodiments, the viscosity enhancing agent also acts as a surfactant. In some embodiments, the viscosity enhancing agent comprises one or more of a fatty alcohol, a wax, a fatty acid ester of glycerol, or any combination thereof. In some embodiments, the fatty alcohol is a C8-C 20 In some embodiments, the wax is a fatty alcohol. In some embodiments, the fatty alcohol is cetyl alcohol. In some embodiments, the cetyl alcohol is Crodacol C95. In some embodiments, the wax is a natural or synthetic wax. In some embodiments, the wax is beeswax. In some embodiments, the wax is synthetic beeswax. In some embodiments, the synthetic beeswax is syncrowax™ BB4. In some embodiments, the synthetic beeswax is a non-animal derived beeswax. In some embodiments, the non-animal derived beeswax is syncrowax™ SB1. In some embodiments, the wax comprises jojoba wax, candelilla wax, carnauba wax, or vegetable oil. In some embodiments, the fatty acid ester of glycerol is a monoester. In some embodiments, the monoester is a C8-C 24 An ester of a fatty acid. In some embodiments, the fatty acid ester of glycerol is glycerol monostearate.

[0307] In some embodiments, the viscosity enhancing agent is present in an amount of about 0.5% to about 10% (w / w) of the composition. In some embodiments, the viscosity enhancing agent is present in an amount of about 0.5% to about 5%, about 0.5% to about 5%, about 0.5% to about 4%, about 0.5% to about 3%, or about 0.5% to about 2%. In some embodiments, the viscosity enhancing agent comprises a fatty alcohol in an amount of up to about 2%, a wax in an amount of up to about 2%, and a fatty acid ester of glycerol in an amount of up to about 5%. In some embodiments, the fatty alcohol is present in an amount of about 0.1 to about 1.5%. In some embodiments, the fatty alcohol is present in an amount of about 0.4. In some embodiments, the wax is present in an amount of about 0.1% to about 1%. In some embodiments, the wax is present in an amount of about 0.2. In some embodiments, each of the two or more waxes is present in an amount of about 0.2. In some embodiments, the fatty acid ester of glycerol is present in an amount of about 0.5 to about 2%.

[0308] In some embodiments, the vesicle composition further comprises one or more of a thickening agent, a preservative, a moisturizer, an emollient, a humectant, or any combination thereof. In some embodiments, the vesicle composition further comprises a thickening agent. In some embodiments, the vesicle composition further comprises a preservative. In some embodiments, the vesicle composition further comprises a humectant. In some embodiments, the vesicle composition further comprises an emollient. In some cases, the emollient may be derived from an amino acid and a fatty acid. In some cases, the amino acid may include lysine, arginine, histidine, glutamate, aspartate, or sarcosinate. In some examples, the emollient may include lauroyl lysine, lauroyl arginine, isopropyl lauroyl sarcosinate, phytosteryl lauroyl glutamate, behenyl lauroyl glutamate, octyldodecyl lauroyl glutamate, or cholesteryl lauroyl glutamate. In some embodiments, the vesicle composition further comprises a humectant.

[0309] In some embodiments, the vesicle composition further comprises an antimicrobial agent. In some embodiments, the antimicrobial agent is a paraben ester. In some embodiments, the antimicrobial agent is methylparaben or propylparaben, or a combination thereof. In some embodiments, the antimicrobial agent is present in an amount of up to about 1%, up to about 0.9%, up to about 0.8%, up to about 0.7%, up to about 0.6%, up to about 0.5%, up to about 0.4%, up to about 0.3%, up to about 0.2% (w / w) of the composition.

[0310] In some embodiments, the vesicle composition further comprises a thickening agent. In some embodiments, the thickening agent is an inert polymeric material. In some embodiments, the thickening agent is a siloxane polymer. In some embodiments, the thickening agent is polydimethylsiloxane (PDMS). In some embodiments, the PDMS is present in an amount of up to about 5%, up to about 4%, up to about 3%, up to about 2%, or up to about 1%. In some embodiments, the PDMS is present in an amount of about 0.1% to about 2% (w / w) of the composition.

[0311] In some embodiments, the vesicle composition further comprises a humectant. In some embodiments, the composition comprises glycerol. In some embodiments, the glycerol is present in an amount of about 0.5% to about 25%, about 0.5% to about 20%, about 0.5% to about 15%, or about 0.5% to about 10% (w / w) of the composition. In some embodiments, the glycerol is present in an amount of about 1% to about 10%. In some embodiments, the glycerol is present in an amount of about 1% to about 2%, about 1% to about 4%, about 1% to about 6%, about 1% to about 8%, about 1% to about 10%, about 2% to about 4%, about 2% to about 6%, about 2% to about 8%, about 2% to about 10%, about 4% to about 6%, about 4% to about 8%, about 4% to about 10%, about 6% to about 8%, about 6% to about 10%, or about 8% to about 10%. In some embodiments, glycerol is present in an amount of about 1%, about 2%, about 4%, about 6%, about 8%, or about 10%. In some embodiments, glycerol is present in an amount of at least about 1%, about 2%, about 4%, about 6%, or about 8%. In some embodiments, glycerol is present in an amount of up to about 2%, about 4%, about 6%, about 8%, or about 10%.

[0312] In some embodiments, the vesicle composition further comprises a preservative. In some embodiments, the preservative is a paraben ester. In some embodiments, the preservative is methylparaben or propylparaben, or a combination thereof. In some embodiments, the preservative is present in an amount of up to about 1%, up to about 0.9%, up to about 0.8%, up to about 0.7%, up to about 0.6%, up to about 0.5%, up to about 0.4%, up to about 0.3%, up to about 0.2% (w / w) of the composition. In some embodiments, the preservative is a cosmetic preservative such as Euxyl® PE 9010, or Spectrastat®. In some embodiments, the preservative comprises a mixture of phenoxyethanol / ethylhexylglycerin. In some embodiments, the preservative comprises a combination of caprylhydroxamic acid, caprylyl glycol, and glycerin. In some embodiments, the preservative is present in an amount of up to about 2%, up to about 1.5%, or up to about 1% (w / w) of the composition. In some embodiments, the preservative is present in an amount of about 0.1% to about 2%, about 0.1% to about 1.5%, or about 0.1% to about 1%. In some embodiments, the preservative is present in an amount of about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, or 1.5%.

[0313] In some embodiments, the additional component in the lipid vesicle composition may include a molecule that can directly or indirectly reduce melanin production. In some embodiments, the molecule may directly or indirectly inhibit tyrosinase. In some cases, the additional component is an antioxidant. In some cases, the antioxidant may include vitamin C or a derivative thereof. In some examples, the antioxidant may include ascorbic acid, ascorbyl palmitate, sodium ascorbyl phosphate, magnesium ascorbyl phosphate, retinyl ascorbate, ascorbyl aminopropyl phosphate (K3 Vita-C), tetrahexyldecyl ascorbate, ascorbyl methylsilanol pectinate (ascorbosilane SP), or a combination thereof. In some embodiments, an antioxidant such as vitamin C or a derivative thereof may also aid in collagen synthesis. In some embodiments, the additional component may include resorcinol (e.g., 4-butylresorcinol). In some cases, 4-butylresorcinol may be used to reduce hyperpigmentation in layers of the skin, such as the epidermis. In some embodiments, resorcinol is present in the composition in an amount from about 0.005% to about 0.1%. In some embodiments, resorcinol is present in the composition in an amount of about 0.005% to about 0.01%, about 0.005% to about 0.02%, about 0.005% to about 0.05%, about 0.005% to about 0.07%, about 0.005% to about 0.1%, about 0.01% to about 0.02%, about 0.01% to about 0.05%, about 0.01% to about 0.07%, about 0.01% to about 0.1%, about 0.02% to about 0.05%, about 0.02% to about 0.07%, about 0.02% to about 0.1%, about 0.05% to about 0.07%, about 0.05% to about 0.1%, or about 0.07% to about 0.1%. In some embodiments, resorcinol is present in the composition in an amount of about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.07%, or about 0.1%. In some embodiments, resorcinol is present in the composition in an amount of at least about 0.005%, about 0.01%, about 0.02%, about 0.05%, or about 0.07%.In some embodiments, resorcinol is present in the composition in an amount up to about 0.01%, about 0.02%, about 0.05%, about 0.07%, or about 0.1%.

[0314] In some embodiments, the additional ingredient may include one or more vitamins or derivatives thereof. In some cases, the one or more vitamins or derivatives thereof may provide one or more desired effects (e.g., smoothing, toning, moisturizing, brightening, reducing acne, eczema, wrinkles, etc.) when applied to the skin or epidermis. In some cases, the additional ingredient may include vitamin B, vitamin C (ascorbic acid), vitamin A (retinol), vitamin E, vitamin D, vitamin F, vitamin K, or any derivatives thereof. In some examples, the additional ingredient may include vitamin B3 (niacin). In some cases, the vitamin B3 derivative may include niacinamide. In some examples, the additional ingredient may include provitamin B5 (panthenol). In some embodiments, the one or more vitamins or derivatives thereof are present in the composition at about 0.1% to about 2.5% (w / w).In some embodiments, the one or more vitamins or derivatives thereof are present in an amount of about 0.1% to about 0.2%, about 0.1% to about 0.3%, about 0.1% to about 0.5%, about 0.1% to about 0.8%, about 0.1% to about 1%, about 0.1% to about 1.2%, about 0.1% to about 1.5%, about 0.1% to about 2%, about 0.1% to about 2.5%, about 0. 2% to about 0.3%, about 0.2% to about 0.5%, about 0.2% to about 0.8%, about 0.2% to about 1%, about 0.2% to about 1.2%, about 0.2% to about 1.5%, about 0.2% to about 2%, about 0.2% to about 2.5%, about 0.3% to about 0.5%, about 0.3% to about 0.8%, about 0.3% to about 1%, about 0.3% to about 1.2%, about 0.3% to about 1.5%, about 0.3% to about 2%, about 0.3% to about 2.5%, about 0.5% to about 0.8%, about 0.5% to about 1%, about 0.5% to about 1.2%, about 0.5% to about 1.5%, about 0.5% to about 2%, about 0.5% to about 2.5%, about 0.8% to about 1%, about 0.8% to about 1.2%, about 0.8% to about 1.5%, In some embodiments, the one or more vitamins or derivatives thereof are present in an amount of about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%. In some embodiments, the one or more vitamins or derivatives thereof are present in an amount of at least about 0.1%, about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, or about 2%. In some embodiments, the one or more vitamins or derivatives thereof are present in an amount of up to about 0.2%, about 0.3%, about 0.5%, about 0.8%, about 1%, about 1.2%, about 1.5%, about 2%, or about 2.5%.

[0315] In some aspects, the lipid vesicle compositions provided herein comprise an anionic polymeric material. The anionic polymeric material is preferably adapted for delivery to the subsurface of the skin of a subject. In some embodiments, the anionic polymeric material acts as a volumizing agent or filler after being delivered to the subsurface of the skin. In some embodiments, the anionic polymeric material acts as a supplement to another layer of the skin (e.g., the epidermis) to repair skin depressions or restore facial volume.

[0316] In some embodiments, the anionic polymeric substance comprises an anionic polysaccharide. In some embodiments, the anionic polysaccharide is a non-sulfated glycosaminoglycan. In some embodiments, the anionic polymeric substance is a naturally occurring substance. In some embodiments, the anionic polymeric substance is naturally occurring in humans. In some embodiments, the anionic polymeric substance is naturally occurring in human connective or epithelial tissue. In some embodiments, the anionic polymeric substance is hyaluronic acid or a pharma- ceutically acceptable salt thereof. In some embodiments, the anionic polymeric substance may not be crosslinked in the lipid vesicle compositions as described herein.

[0317] In some embodiments, the hyaluronic acid is a pharma- ceutically acceptable salt of hyaluronic acid. In some embodiments, the salt is a sodium salt, a potassium salt, a magnesium salt, or any combination thereof. In some embodiments, the salt is a sodium salt.

[0318] In some embodiments, the anionic polymeric substance has a molecular weight of about 5 kDa to about 500 kDa. In some embodiments, the molecular weight is a weight average molecular weight. In some embodiments, the anionic polymeric substance has a molecular weight of about 5 kDa to about 500 kDa. In some embodiments, the anionic polymeric substance has a molecular weight of about 5 kDa to about 10 kDa, about 5 kDa to about 20 kDa, about 5 kDa to about 50 kDa, about 5 kDa to about 100 kDa, about 5 kDa to about 200 kDa, about 5 kDa to about 250 kDa, about 5 kDa to about 300 kDa, about 5 kDa to about 400 kDa, about 5 kDa to about 500 kDa, about 10 kDa to about 20 kDa, about 10 kDa to about 5 ... 0 kDa to about 100 kDa, about 10 kDa to about 200 kDa, about 10 kDa to about 250 kDa, about 10 kDa to about 300 kDa, about 10 kDa to about 400 kDa, about 10 kDa to about 500 kDa, about 20 kDa to about 50 kDa, about 20 kDa to about 100 kDa, about 20 kDa to about 200 kDa, about 20 kDa to about 250 kDa, about 20 kDa to about 300 kDa, about 20 kDa to about 400 kDa, From about 20 kDa to about 500 kDa, from about 50 kDa to about 100 kDa, from about 50 kDa to about 200 kDa, from about 50 kDa to about 250 kDa, from about 50 kDa to about 300 kDa, from about 50 kDa to about 400 kDa, from about 50 kDa to about 500 kDa, from about 100 kDa to about 200 kDa, from about 100 kDa to about 250 kDa, from about 100 kDa to about 300 kDa, from about 100 kDa to about 400 kDa, from about 100 kDa to about The polypeptide has a molecular weight of about 500 kDa, about 200 kDa to about 250 kDa, about 200 kDa to about 300 kDa, about 200 kDa to about 400 kDa, about 200 kDa to about 500 kDa, about 250 kDa to about 300 kDa, about 250 kDa to about 400 kDa, about 250 kDa to about 500 kDa, about 300 kDa to about 400 kDa, about 300 kDa to about 500 kDa, or about 400 kDa to about 500 kDa. In some embodiments, the anionic polymeric agent has a molecular weight of about 5 kDa, about 10 kDa, about 20 kDa, about 50 kDa, about 100 kDa, about 200 kDa, about 250 kDa, about 300 kDa, about 400 kDa, or about 500 kDa.In some embodiments, the anionic polymeric substance has a molecular weight of at least about 5 kDa, about 10 kDa, about 20 kDa, about 50 kDa, about 100 kDa, about 200 kDa, about 250 kDa, about 300 kDa, or about 400 kDa. In some embodiments, the anionic polymeric substance has a molecular weight of at most about 10 kDa, about 20 kDa, about 50 kDa, about 100 kDa, about 200 kDa, about 250 kDa, about 300 kDa, about 400 kDa, or about 500 kDa.

[0319] In some embodiments, the lipid vesicle composition comprises a first and a second anionic polymeric agent. In some embodiments, the lipid vesicle composition further comprises a third anionic polymeric agent.

[0320] In some embodiments, the first and second anionic polymeric substances are the same type. In some embodiments, each of the first and second anionic polymeric substances is an anionic polysaccharide. In some embodiments, each of the first and second anionic polymers is hyaluronic acid.

[0321] When the first and second anionic polymeric substances are of the same type, each of the anionic polymeric substances has a different molecular weight. In some embodiments, the first anionic polymeric substance has a molecular weight of up to about 75 kDa, and the second anionic polymeric substance has a molecular weight of more than about 75 kDa. In some embodiments, the first anionic polymeric substance has a molecular weight of up to about 75 kDa, and the second anionic polymeric substance has a molecular weight of more than about 75 kDa.

[0322] When the lipid vesicle comprises a first and a second anionic polymeric substance, each component may be present in different amounts. In some embodiments, the first and the second anionic polymeric substances are present in approximately the same amount. In some embodiments, the ratio of the first anionic substance to the second anionic substance is about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 3:2, 2:1, or about 1:1.

[0323] In some embodiments, when the composition comprises a first, second, and third anionic polymeric substance, each of the anionic polymeric substances may be of the same type (e.g., three different molecular weights of hyaluronic acid). In some embodiments, the composition comprises a first, second, and third anionic polymeric substance, the first anionic polymeric substance has a molecular weight of about 5 kDa to about 20 kDa, the second anionic polymeric substance has a molecular weight of about 20 kDa to about 75 kDa, and the third anionic polymeric substance has a molecular weight of more than about 75 kDa. In some embodiments, each of the three anionic polymeric substances is present in approximately the same amount.

[0324] In some embodiments, the anionic polymeric material is present in an amount of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the anionic polymeric material is present in an amount of about 0.01 mg / mL to about 0.05 mg / mL, about 0.01 mg / mL to about 0.1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 1.25 mg / mL, about 0.01 mg / mL to about 1.5 mg / mL, about 0.01 mg / mL to about 1.75 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 5 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.01 mg / mL to about 20 mg / mL, about 0.01 mg / mL to about 25 mg / mL, about 0.01 mg / mL to about 20 ... mg / mL, about 0.05 mg / mL to about 0.1 mg / mL, about 0.05 mg / mL to about 0.5 mg / mL, about 0.05 mg / mL to about 1 mg / mL, about 0.05 mg / mL to about 1.25 mg / mL, about 0.05 mg / mL to about 1.5 mg / mL, about 0.05 mg / mL to about 1.75 mg / mL, about 0.05 mg / mL to about 2 mg / mL, about 0.05 mg / mL to about 5 mg / mL, about 0.05 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 0.5 mg / mL, about 0.1 mg / mL to about 1 mg / mL g / mL, about 0.1 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.1 mg / mL to about 1.75 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 0.5 mg / mL to about 1.25 mg / mL, about 0.5 mg / mL to about 1.5 mg / mL, about 0.5 mg / mL to about 1.75 mg / mL, about 0.5 mg / mL to about 2 mg / mL, about 0. 5mg / mL to about 5mg / mL, about 0.5mg / mL to about 10mg / mL, about 1mg / mL to about 1.25mg / mL, about 1mg / mL to about 1.5mg / mL, about 1mg / mL to about 1.75mg / mL, about 1mg / mL to about 2mg / mL, about 1mg / mL to about 5mg / mL, about 1mg / mL to about 10mg / mL, about 1.25mg / mL to about 1.5mg / mL, about 1.25mg / mL to about 1.75mg / mL, about 1.25mg / mL to about 2mg / mL, about 1.25mg / mL to about 5mg / mL, about 1.It is present in an amount of 25 mg / mL to about 10 mg / mL, about 1.5 mg / mL to about 1.75 mg / mL, about 1.5 mg / mL to about 2 mg / mL, about 1.5 mg / mL to about 5 mg / mL, about 1.5 mg / mL to about 10 mg / mL, about 1.75 mg / mL to about 2 mg / mL, about 1.75 mg / mL to about 5 mg / mL, about 1.75 mg / mL to about 10 mg / mL, about 2 mg / mL to about 5 mg / mL, about 2 mg / mL to about 10 mg / mL, or about 5 mg / mL to about 10 mg / mL. In some embodiments, the anionic polymeric substance is present in an amount of about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 5 mg / mL, or about 10 mg / mL. In some embodiments, the anionic polymeric substance is present in an amount of at least about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, or about 5 mg / mL. In some embodiments, the anionic polymeric substance is present in an amount of up to about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 5 mg / mL, or about 10 mg / mL.

[0325] In some embodiments, the additional component comprises purified water, hi some embodiments, the purified water is present in an amount of about 50% to 90% (w / w). In some embodiments, purified water is present in an amount of about 50% to about 55%, about 50% to about 60%, about 50% to about 65%, about 50% to about 70%, about 50% to about 75%, about 50% to about 80%, about 55% to about 60%, about 55% to about 65%, about 55% to about 70%, about 55% to about 75%, about 55% to about 80%, about 60% to about 65%, about 60% to about 70%, about 60% to about 75%, about 60% to about 80%, about 65% to about 70%, about 65% to about 75%, about 65% to about 80%, about 70% to about 75%, about 70% to about 80%, or about 75% to about 80%. In some embodiments, purified water is present in an amount of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%. In some embodiments, purified water is present in an amount of at least about 50%, about 55%, about 60%, about 65%, about 70%, or about 75%. In some embodiments, purified water is present in an amount of up to about 55%, about 60%, about 65%, about 70%, about 75%, or about 80%.

[0326] Exemplary Compositions for Delivering Peptide Antagonists

[0327] The following provides exemplary compositions for delivering anionic macromolecular substances. In some embodiments, the delivery of peptide antagonists includes a method of preparing lipid vesicle compositions, comprising: a) preparing an oil-in-water emulsion comprising a peptide antagonist of melanocortin 1 receptor by mixing an oil component of an oil-in-water emulsion with an aqueous component of an oil-in-water emulsion; b) solubilizing vesicle-forming lipids in an acceptable solvent other than water; c) adding the oil-in-water emulsion to the solubilized vesicle-forming lipids; and d) mixing the oil-in-water emulsion with the solubilized vesicle-forming lipids under mixing conditions effective to form lipid vesicles comprising lipid bilayers comprising vesicle-forming lipids and the oil-in-water emulsion entrapped in the lipid vesicles. In some cases, the aqueous component comprises a peptide antagonist of melanocortin 1 receptor. In some cases, the oil component and / or the aqueous component of the oil-in-water emulsion comprises one or more surfactants. The following embodiments may additionally include any of the other ingredients or components provided herein.

[0328] Peptide Composition 1: In one aspect, provided herein is a lipid vesicle composition comprising: (a) lipid vesicles, each comprising a lipid bilayer comprising a vesicle-forming lipid present in an amount of about 5% to about 20%; (b) an oil-in-water emulsion entrapped in lipid vesicles and stabilized by one or more surfactants; (c) a peptide antagonist of the melanocortin 1 receptor in an amount of about 0.1 mg / mL to about 50 mg / mL, entrapped in the lipid bilayer and / or oil-in-water emulsion; Including, propylene glycol-diammonium phosphate ester derived from a fatty amide in an amount of about 1% to about 10%; a nonionic surfactant in an amount of about 0.1% to about 3%; The lipid vesicle composition further comprises:

[0329] In some embodiments, the oil component is present in an amount from about 2.5% to about 20%.

[0330] In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL to about 0.5 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 3 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL.

[0331] In some embodiments, the composition further comprises a fatty acylated amino acid in an amount of about 0.5% to about 3%. In some embodiments, the fatty acylated amino acid is monolauryl lysine.

[0332] In some embodiments, the lipid vesicle composition further comprises a viscosity enhancing agent in an amount of about 0.5% to about 5%. In some embodiments, the viscosity enhancing agent comprises one or more of a fatty alcohol, a wax, a fatty acid ester of glycerol, or any combination thereof.

[0333] In some embodiments, the non-ionic surfactant comprises a PEG ether of an aliphatic alcohol.

[0334] In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 10 mg / mL entrapped in the lipid bilayer, oil-in-water emulsion, or a combination thereof. In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 0.05 mg / mL, about 0.01 mg / mL to about 0.1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 1.25 mg / mL, about 0.01 mg / mL to about 1.5 mg / mL, about 0.01 mg / mL to about 1.75 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 5 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 0.5 about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.1 mg / mL to about 1.75 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 1 mg / mL to about 1.5 mg / mL, about 1 mg / mL to about 1.75 mg / mL, about 1 mg / mL to about 2 mg / mL, about 1 mg / mL to about 5 mg / mL, and about 1 mg / mL to about 10 mg / mL. In some embodiments, the lipid vesicle composition comprises an anionic polymeric substance in an amount of about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 5 mg / mL, or about 10 mg / mL.

[0335] Peptide Composition 2: In one aspect, provided herein is a lipid vesicle composition comprising: (a) lipid vesicles, each comprising a lipid bilayer comprising a vesicle-forming lipid present in an amount of about 2% to about 20%; (b) an oil-in-water emulsion entrapped in lipid vesicles and stabilized by one or more surfactants; (c) a peptide antagonist of the melanocortin 1 receptor in an amount of about 0.1 mg / mL to about 50 mg / mL, entrapped in the lipid bilayer and / or oil-in-water emulsion; Including, PEG fatty acid ester in an amount of about 0.1% to about 2%; Polysorbate in an amount of about 0.5% to about 3%; sorbic acid esters in an amount of about 0.1% to about 2%; The lipid vesicle composition further comprises:

[0336] In some embodiments, the oil component is present in an amount from about 2.5% to about 20%.

[0337] In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL to about 0.5 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 3 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL.

[0338] In some embodiments, the lipid vesicle composition further comprises a viscosity enhancing agent in an amount of about 0.5% to about 5%. In some embodiments, the viscosity enhancing agent comprises one or more of a fatty alcohol, a wax, a fatty acid ester of glycerol, or any combination thereof.

[0339] In some embodiments, the PEG fatty acid ester comprises PEG 4 dilaurate. In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the sorbic acid ester is sorbitan palmitate.

[0340] In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 10 mg / mL entrapped in the lipid bilayer, oil-in-water emulsion, or a combination thereof. In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 0.05 mg / mL, about 0.01 mg / mL to about 0.1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 1.25 mg / mL, about 0.01 mg / mL to about 1.5 mg / mL, about 0.01 mg / mL to about 1.75 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 5 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 0.5 about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.1 mg / mL to about 1.75 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 1 mg / mL to about 1.5 mg / mL, about 1 mg / mL to about 1.75 mg / mL, about 1 mg / mL to about 2 mg / mL, about 1 mg / mL to about 5 mg / mL, and about 1 mg / mL to about 10 mg / mL. In some embodiments, the lipid vesicle composition comprises an anionic polymeric substance in an amount of about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 5 mg / mL, or about 10 mg / mL.

[0341] Peptide Composition 3: In one aspect, provided herein is a lipid vesicle composition comprising: (a) lipid vesicles, each comprising a lipid bilayer comprising a vesicle-forming lipid present in an amount of about 5% to about 20%; (b) an oil-in-water emulsion entrapped in lipid vesicles and stabilized by one or more surfactants; (c) a peptide antagonist of the melanocortin 1 receptor in an amount of about 0.1 mg / mL to about 50 mg / mL, entrapped in the lipid bilayer and / or oil-in-water emulsion; Including, propylene glycol-diammonium phosphate ester derived from a fatty amide in an amount of about 1% to about 10%; a PEG ether of an aliphatic alcohol in an amount of about 0.1% to about 3%; Polysorbate in an amount of about 0.5% to about 3%; sorbic acid esters in an amount of about 0.1% to about 2%; The lipid vesicle composition further comprises:

[0342] In some embodiments, the oil component is present in an amount from about 2.5% to about 20%.

[0343] In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL to about 0.5 mg / mL, about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 3 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 20 mg / mL, about 0.1 mg / mL to about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 10 mg / mL, about 20 mg / mL, or about 50 mg / mL. In some embodiments, the lipid vesicle composition comprises the peptide antagonist in an amount of about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 4 mg / mL, or about 5 mg / mL.

[0344] In some embodiments, the lipid vesicle composition further comprises a viscosity enhancing agent in an amount of about 0.5% to about 5%. In some embodiments, the viscosity enhancing agent comprises one or more of a fatty alcohol, a wax, a fatty acid ester of glycerol, or any combination thereof.

[0345] In some embodiments, the polysorbate is polysorbate 80. In some embodiments, the sorbic acid ester is sorbitan palmitate. In some embodiments, the PEG ether of an aliphatic alcohol is diethylene glycol monooleyl ether.

[0346] In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 10 mg / mL entrapped in the lipid bilayer, oil-in-water emulsion, or a combination thereof. In some embodiments, the lipid vesicle composition further comprises an anionic polymeric substance in an amount of about 0.01 mg / mL to about 0.05 mg / mL, about 0.01 mg / mL to about 0.1 mg / mL, about 0.01 mg / mL to about 0.5 mg / mL, about 0.01 mg / mL to about 1 mg / mL, about 0.01 mg / mL to about 1.25 mg / mL, about 0.01 mg / mL to about 1.5 mg / mL, about 0.01 mg / mL to about 1.75 mg / mL, about 0.01 mg / mL to about 2 mg / mL, about 0.01 mg / mL to about 5 mg / mL, about 0.01 mg / mL to about 10 mg / mL, about 0.1 mg / mL to about 0.5 about 0.1 mg / mL to about 1 mg / mL, about 0.1 mg / mL to about 1.25 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.1 mg / mL to about 1.75 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 0.1 mg / mL to about 5 mg / mL, about 0.1 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 1 mg / mL, about 1 mg / mL to about 1.5 mg / mL, about 1 mg / mL to about 1.75 mg / mL, about 1 mg / mL to about 2 mg / mL, about 1 mg / mL to about 5 mg / mL, and about 1 mg / mL to about 10 mg / mL. In some embodiments, the lipid vesicle composition comprises an anionic polymeric substance in an amount of about 0.01 mg / mL, about 0.05 mg / mL, about 0.1 mg / mL, about 0.5 mg / mL, about 1 mg / mL, about 1.25 mg / mL, about 1.5 mg / mL, about 1.75 mg / mL, about 2 mg / mL, about 5 mg / mL, or about 10 mg / mL.

[0347] Methods of using the lipid vesicle compositions provided herein The lipid vesicle compositions provided herein are intended for cosmetic use in a subject for indications including, but not limited to, preventing, reducing, or both the appearance of skin discoloration due to pigmentation.

[0348] In certain embodiments, including pharmaceutical embodiments, the lipid vesicle compositions provided herein are intended for medical use in subjects for indications including, but not limited to, pigmentation or hyperpigmentation, melanin hyperpigmentation, melasma, melasma, age spots, freckles, or combinations thereof.In some embodiments, the skin discoloration is caused by disorders, such as adrenal disorders.In some embodiments, the MC1R peptide antagonists of the present disclosure are used to treat the skin discoloration caused by Addison's disease.

[0349] In some embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In some embodiments, the human subject is a pediatric or adult subject of any age.

[0350] Methods for using cosmetic or pharmaceutical compositions

[0351] In certain embodiments, including pharmaceutical embodiments, the present disclosure also relates to methods for using cosmetic or pharmaceutical compositions comprising peptide antagonists. In some embodiments, the present disclosure relates to a method for preventing or reducing skin discoloration in a subject, comprising administering to said subject a lipid composition, the lipid vesicle composition comprising (a) lipid vesicles each comprising a lipid bilayer comprising vesicle-forming lipids, (b) an oil-in-water emulsion entrapped in the lipid vesicles and stabilized by one or more surfactants, and (c) a peptide antagonist of the melanocortin 1 receptor entrapped in the lipid bilayer and / or the oil-in-water emulsion. In some embodiments, the skin discoloration comprises melanin hyperpigmentation, melasma, melasma, age spots, freckles, or a combination thereof. In some embodiments, the present disclosure relates to a method for using cosmetic or pharmaceutical compositions to prevent or reduce skin discoloration, comprising applying an effective amount of the cosmetic or pharmaceutical composition to the skin of a subject. In some embodiments, the skin discoloration includes...

Claims

1. Amino acid sequence: Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9 1. A melanocortin 1 receptor (MC1R) peptide antagonist comprising: During the ceremony, Xaal is absent or is selected from the group consisting of Cys, Met, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, and D-Glu; Xaa2 is selected from the group consisting of Val, Ile, D-Val, and D-Ile; Xaa3 is selected from the group consisting of Phe and D-Phe; Xaa4 is selected from the group consisting of Arg and D-Arg; Xaa5 is selected from the group consisting of Trp and D-Trp; Xaa6 is selected from the group consisting of Phe and D-Phe; Xaa7 is selected from the group consisting of Lys and D-Lys; Xaa8 is selected from the group consisting of Pro and D-Pro; Xaa9 is selected from the group consisting of Val and D-Val; Xaa1 or Xaa2, and Xaa9 are the terminal amino acids, melanocortin 1 receptor peptide antagonists.

2. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa2 is selected from the group consisting of Val and D-Val.

3. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa2 is selected from the group consisting of Ile and D-Ile.

4. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa1 is absent or selected from the group consisting of Cys, Sec, Ser, Thr, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, D-Ala, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, and D-Glu.

5. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa1 is absent or selected from the group consisting of D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Ala, Gly, Val, Leu, Ile, D-Ala, D-Val, D-Leu, D-Ile, Phe, Trp, Tyr, D-Phe, D-Trp, D-Tyr, Asn, Asp, Gln, Glu, D-Asn, D-Asp, D-Gln, and D-Glu.

6. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa1 is absent or selected from the group consisting of Cys, Sec, D-Cys, D-Met, D-Sec, D-Ser, D-Thr, Gly, Val, Ile, D-Ala, D-Val, D-Leu, D-Ile, D-Phe, D-Trp, D-Tyr, Asn, Asp, D-Asn, D-Asp, D-Gln, and D-Glu.

7. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa2 is selected from the group consisting of Val and Ile.

8. Xaa1 is absent or selected from the group consisting of Phe, Trp, Tyr, D-Phe, D-Trp, and D-Tyr; Xaa2 is selected from the group consisting of Val, Ile, D-Val, and D-Ile; Xaa3 is selected from the group consisting of Phe and D-Phe; Xaa4 is selected from the group consisting of Arg and D-Arg; Xaa5 is selected from the group consisting of Trp and D-Trp; Xaa6 is selected from the group consisting of Phe and D-Phe; Xaa7 is selected from the group consisting of Lys and D-Lys; Xaa8 is selected from the group consisting of Pro and D-Pro; 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein Xaa9 is selected from the group consisting of Val and D-Val.

9. The N-terminus is C １ -C ６ Acyl, C １ -C ８ Alkyl, C ６ -C １２ Aralkyl, C ５ -C １０ Aryl, C ４ -C ８ 2. The melanocortin 1 receptor peptide antagonist of claim 1, which is modified to include a heteroaryl, formyl, or lipid.

10. The C-terminus is NH ２ , amino-acyl, amino-C １ -C ８ Alkyl, Amino-C ６ -C １２ -Aralkyl, amino-C ５ -C １０ Aryl, Amino-C ４ -C ８ Heteroaryl, or O—(C １ -C ８ 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein the melanocortin 1 receptor peptide antagonist is modified to include a aryl group (alkyl).

11. 2. The melanocortin 1 receptor peptide antagonist of claim 1, wherein the lipid is covalently attached to a cysteine, serine, lysine, threonine, or tyrosine.

12. A melanocortin 1 receptor peptide antagonist comprising the amino acid sequence of any of SEQ ID NOs: 4-90.

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