Injectable formulations for non-naturally occurring melanocortin analogs for modulating weight loss

Abstract

The present technology comprises stable aqueous pharmaceutical compositions and formulation comprising non-naturally occurring melanocortin agonist analogs. In some embodiments, the non-naturally occurring melanocortin analogs may be full agonists of the melanocortin 3 receptor (MC3R) and full or partial agonists of the melanocortin 4 receptor (MC4R) with sub-micromolar and / or low-nanomolar binding activity.

Description

INJECTABLE FORMULATIONS FOR NON-NATURALLY OCCURRING MELANOCORTIN ANALOGS FOR MODULATING WEIGHT LOSSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 704,486, filed October 7, 2024, which is incorporated herein by reference in its entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] This application contains an ST.26 compliant Sequence Listing, which is submitted concurrently in xml format and is hereby incorporated by reference in its entirety. The .xml copy, created on October 3, 2025 is titled “183B-419708-WO_SL.xml” and is 193,740 bytes in size.BACKGROUND

[0003] A major challenge in the development of peptide-based therapeutics formulations is maintaining solubility, stability, and potency of the peptide. It is particularly desirable to avoid aggregates and particulates in injectable formulations that require sterile filtration before administration (e.g., parenteral injection). Further, the formation of aggregates in injectable formulations may cause adverse reactions at the injection site.

[0004] Melanocortin analogs have been synthesized for the potential regulation and treatment of many conditions, including weight regulation (e.g., obesity, anorexia, and cachexia), hormonal secretion, and hyposecretion of many exocrine glands. Despite recent advances, there is still a need for melanocortin analog-containing compositions that are stable, effective, and suitable for parenteral administration, including subcutaneous injection.SUMMARY

[0005] Provided herein are pharmaceutical compositions and formulations of non- naturally occurring melanocortin agonist analogs.-1 -169954513.1

[0006] In some aspects, provided herein is a pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0007] In some aspects, provided herein is a pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and no anionic amino acid residues, an osmolyte, a pH adjusting agent, and a buffer, wherein at least one of the one or more cationic amino acid residues is protonated and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0008] In some aspects, provided herein is a pharmaceutical composition comprising a cyclic non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-0m]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0009] In some aspects, provided herein is a pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and an isoelectric point of about 10 to about 12.5, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.-2-169954513.1

[0010] In some aspects, provided herein is a pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, an osmolyte, a pH adjusting agent, and a buffer wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0011] In some aspects, provided herein is a pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having a cyclic region with an arginine residue positioned therein and an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier comprising a base and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0012] In some aspects, provided herein is a pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A):XI-RI-R2-R3-R4-R5-R6-R7-YI (A), wherein:Ri is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl; at least one of R2-R? is a cationic amino acid residue;Xi is an optionally present N-terminus;Yi is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a side chain linkage between R2and R?;-3-169954513.1provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0013] In some aspects, provided herein is a pharmaceutical formulation comprising a peptide composition and a pharmaceutically acceptable carrier composition, the peptide composition comprising a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in an aqueous solution, the pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0014] In some aspects, provided herein is a pharmaceutical composition comprising an osmolyte, a pH adjusting agent, a histidine buffer, and a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and comprising a cyclic region with an arginine residue positioned therein, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0015] In some aspects, provided herein is a pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of about 10 to about 12.5 and a pharmaceutically acceptable carrier comprising an osmolyte, a pH adjusting agent, and a histidine buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A):X1-R1-R2-R3-R4-R5-R6-R7-Y1 (A), wherein:R1 is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl;-4-169954513.1at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a side chain linkage between R2 and R7; provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0016] In some aspects, provided herein is a pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by combining an aqueous peptide composition comprising the agonist analog, and a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 1 1 .0 comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical formulation such that no local region of the analog has a pH equal to the isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0017] In some aspects, provided herein is a pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by combining an aqueous peptide composition comprising the non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, and a pharmaceutically acceptable carrier composition comprising a base and a buffer and having a pH of about 5.5 to about 7.0, wherein the non- naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro--5-169954513.1(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0018] Further provided herein are methods of preparing pharmaceutical compositions and formulations described herein.

[0019] In some aspects, provided herein is a method of producing a pharmaceutical composition of a non-naturally occurring melanocortin agonist analog, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 with a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 and comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0020] In other aspects, provided herein is a method of producing a pharmaceutical formulation having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical composition such that no local region has a pH that is equal to the isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro- NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1 .0.

[0021] In still other aspects, provided herein is a method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of the-6-169954513.1non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog has an arginine residue and an isoelectric point of at least about 10 and does not comprise a sequence of: Ac-Nle-c[Glu- Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe- Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1 .0.

[0022] In yet other aspects, provided herein is a method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog, the method comprising providing a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a histidine buffer; dissolving a non-naturally melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in water to provide an aqueous peptide composition; and adding the pharmaceutically acceptable carrier composition to the aqueous peptide composition while mixing to maintain dissolution of the non-naturally occurring melanocortin agonist analog, wherein the pharmaceutical formulation has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.DETAILED DESCRIPTION

[0023] The present technology provides stable aqueous pharmaceutical compositions of non-naturally occurring melanocortin agonist analogs, also referred to herein as “non- naturally occurring melanocortin analogs,” “melanocortin analogs,” and “agonist analogs.” Pharmaceutical compositions described herein have a pH of less than 7.0 and include a non-naturally occurring melanocortin analog and one or more pharmaceutically acceptable carriers and / or excipients. In some embodiments, the pharmaceutical compositions have a pH of about 4.0 to about 6.5.-7-169954513.1

[0024] Pharmaceutical compositions comprising non-naturally occurring melanocortin agonist analogs of the present technology may be administered to a subject in need thereof to treat and / or prevent conditions associated with weight regulation, such as, for example, obesity. To achieve desired therapeutic outcomes, the pharmaceutical compositions may be formulated for specific routes of administration, such as parenteral delivery, including, but not limited to, subcutaneous delivery. Accordingly, the one or more pharmaceutically acceptable carriers and / or excipients included in the pharmaceutical compositions described herein may be useful for subcutaneous delivery of the non-naturally occurring melanocortin peptides. In some embodiments, the one or more carriers and / or excipients are selected based on desirable properties, such as reduced or lack of delivery site reactions, solubility, stability (e.g., shelf-life), pH, buffering, pharmacokinetics, bioavailability, or the like, of the pharmaceutical composition. In some embodiments, the one or more pharmaceutically acceptable carriers and / or excipients may include a buffer, an osmolyte, and a pH adjusting agent.

[0025] Methods of preparing the stable aqueous pharmaceutical compositions are also described herein. In some embodiments, the pharmaceutical compositions are prepared by combining an aqueous peptide composition with a pharmaceutically acceptable carrier composition.

[0026] The following description is merely exemplary in nature and is not intended to limit the present technology, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present technology are intended for purposes of illustration only and are not intended to limit the scope of the present technology disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features.

[0027] Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing / FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled-8-169954513.1in the art to practice the present technology, it should be understood that other embodiments may be realized, and that logical and mechanical changes may be made without departing from the spirit and scope of the present technology. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in any description, method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the steps or functions thereof may be outsourced to or performed by one or more third parties.Definitions

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present technology belongs. For the purposes of the present technology, the following terms are defined below.

[0029] The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0030] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth.

[0031] As used herein, a “composition” or a “pharmaceutical composition” refers to a mixture of the active ingredient with other chemical components, such as pharmaceutically acceptable carriers and / or excipients.

[0032] As used herein, a “pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to an organism, does not abrogate the biological activity and properties of the administered active ingredient, and / or does not-9-169954513.1interact in a deleterious manner with the other components of the composition in which it is contained.

[0033] “Melanocortin analogs,” “melanocortin peptides,” or “melanocortins,” are used interchangeably and refer to melanocortin-receptor ligands, which are macromolecules containing at least one melanocortin pharmacophore. Melanocortin analogs are typically peptides that bind melanocortin receptors under physiological conditions. Melanocortin analogs include non-naturally occurring melanocortin peptides and truncated and / or modified versions of melanocortin full-length protein or peptides. For example, the full-length pro-opiomelanocortin protein (POMC), prior to proteolytic cleavage of “sub-peptides,” consists of 241 amino acids. Tissue-specific proteolytic cleavage of POMC yields peptides ranging in size from 13 amino acids to 76 amino acids. See Bicknell and Lawry, Encyclopedia of Stress, vol. 3, 257-265, Academic Press (2000). Synthesized, non- naturally occurring melanocortin analogs having increased melanocortin receptor activity as discussed herein are approximately 7-12 amino acids in size. Melanocortin analogs exhibit binding functionality with melanocortin receptors. The binding to the melanocortin receptor is activating (agonist). In addition to peptides, the melanocortin analogs include small molecule analogs of melanocortin or portions thereof comprised of organic compounds, inorganic compounds, or combinations of peptide and small molecule— i.e., peptide mimetics, or various combinations thereof. “Melanocortin peptides” can be structurally similar and / or functionally similar to biological melanocortin proteins in their ability to bind melanocortin receptors. Further, the melanocortin analogs generally contain the pharmacophore: His-Phe-Arg-Trp (SEQ ID NO: 1 ) or a modified version thereof, or a structural or functional peptide mimetic thereof.

[0034] A “pharmacophore” is the minimum set of amino acid residues necessary to achieve a physiological effect; or a small molecule that is (with respect to a receptor) a structural mimic of the amino acid residues required for binding to and activation of a receptor. His-Phe-Arg-Trp (SEQ ID NO: 1 ) and their analogs are the pharmacophore of melanocortin for the regulated physiological effect. Therefore, non-naturally occurring melanocortin pharmacophore analogs can be small peptides or organic molecules designed-10-169954513.1to mimic the appearance or function (including activation or deactivation of receptor activity) of the melanocortin pharmacophore core sequence peptide.

[0035] A “melanocortin receptor agonist” or “melanocortin agonist” is a naturally occurring substance or manufactured drug substance or composition that can interact with a melanocortin receptor and initiate a pharmacological response characteristic of the melanocortin receptor.

[0036] The terms “bind,” “binding,” “complex,” and “complexing,” refer to all types of physical and chemical binding, reactions, complexing, attraction, chelating and the like.

[0037] The “peptides” described herein can be (a) naturally occurring, (b) produced by chemical synthesis, (c) produced by recombinant DNA technology, (d) produced by biochemical or enzymatic fragmentation of larger molecules, (e) produced by methods resulting from a combination of methods (a) through (d) listed above, or (f) produced by any other means for producing peptides.

[0038] The term “peptide” as used herein includes any structure comprised of two or more amino acids, including chemical modifications and derivatives of amino acids. The amino acids forming all or a part of a peptide may be naturally occurring amino acids, stereoisomers and modifications of such amino acids, non-protein amino acids, post- translationally modified amino acids, enzymatically modified amino acids, constructs or structures designed to mimic amino acids, and the like, so that the term “peptide” includes pseudopeptides and peptidomimetics, including structures which have a non-peptidic backbone. The term “peptide” also includes dimers or multimers of peptides. A “manufactured” peptide includes a peptide produced by chemical synthesis, recombinant DNA technology, biochemical, or enzymatic fragmentation of larger molecules, combinations of the foregoing or, in general, made by any other method. The term “peptide” includes peptides containing a variable number of amino acid residues, optionally with nonamino acid residue groups at the N- and C-termini, such groups including acyl, acetyl, alkenyl, alkyl, N-alkyl, amine, or amide groups, among others.

[0039] By employing chemical synthesis, a useful means of production, it is possible to introduce various amino acids which do not naturally occur along the chain, modify the N--11 -169954513.1or C-terminus, and the like, thereby providing for improved stability and formulation, resistance to protease degradation, and the like.

[0040] “Amino acids” are molecules containing an amine group, a carboxylic acid group, and a side-chain that is specific to each amino acid. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen and have the generic formula H2N — CHR — COOH, wherein R represents a side chain group. The various a-amino acids differ in the side-chain moiety that is attached to the a-carbon. The “amino acids” of the present technology include the known naturally occurring protein amino acids, which are referred to by both their common three letter abbreviation and single letter abbreviation. See generally Synthetic Peptides: A User’s Guide, G. A. Grant, editor, W.H. Freeman & Co., New York (1992), the teachings of which are incorporated herein by reference, including the text and table set forth at pages 11 through 24. As set forth above, the term “amino acid” also includes stereoisomers and modifications of naturally occurring protein amino acids, nonprotein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs or structures designed to mimic amino acids, and the like. Modified and unusual amino acids are described generally in Synthetic Peptides: A User’s Guide, supra; Hruby et al., Biochem. J. 268:249-262 (1990); and Toniolo, Int. J. Peptide Protein Res. 35:287-300 (1990); the teachings of all of which are incorporated herein by reference.

[0041] The phrase “amino acid side chain moiety” used herein, including as used in the specification and claims, includes any side chain of any amino acid, as the term “amino acid” is defined herein. This thus includes the side chain moiety present in naturally occurring amino acids. It further includes side chain moieties in modified naturally occurring amino acids, such as glycosylated amino acids. It further includes side chain moieties in stereoisomers and modifications of naturally occurring protein amino acids, non-protein amino acids, post-translationally modified amino acids, enzymatically synthesized amino acids, derivatized amino acids, constructs, or structures designed to mimic amino acids, and the like. For example, the side chain moiety of any amino acid disclosed herein is included within the definition. A “derivative” of an amino acid side chain moiety is included within the definition of an amino acid side chain moiety.-12-169954513.1

[0042] The “derivative” of an amino acid side chain moiety includes any modification to or variation in any amino acid side chain moieties, including a modification of naturally occurring amino acid side chain moieties. By way of example, derivatives of amino acid side chain moieties include straight chain or branched, cyclic or noncyclic, substituted or unsubstituted, saturated or unsaturated, alkyl, aryl or aralkyl moieties.

[0043] In the peptides described herein, conventional amino acid residues have their conventional meaning as given in Chapter 2400, of the Manual of Patent Examining Procedure, 8th Ed. Thus, “Ala” is alanine; “Arg” is arginine; “Asn” is asparagine; “Asp” is aspartic acid; “Cys” is cysteine; “Gin” is glutamine; “Glu” is glutamic acid; “His” is histidine; “lie” is isoleucine; “Leu” is leucine; “Lys” is lysine; “Met” is methionine; “Phe” is phenylalanine; “Pro” is proline; “Ser” is serine; Thr is threonine; “Trp” is tryptophan; “Tyr” is tryosine; and “Vai” is valine. Unless otherwise indicated, all amino acids abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof can be used. Thus, for example, “L-Phe” or “IPhe” is L-phenylalanine; “D-Phe” or “dPhe” is D- phenylalanine; dVal is D-valine; dPro is D-proline; “D- / L-Phe” or “d / IPhe” is D-phenylalanine, L-phenylalanine, or combinations thereof; “Phe” is also D-phenylalanine, L-phenylalanine, or combinations thereof, and so on.

[0044] An alpha (a)-amino acid has the generic formula H2N— CaHR— COOH, where R is a side chain moiety and the amino group is attached to the carbon atom immediately adjacent to the carboxylate group (i.e., the cc-carbon). Other types of amino acids exist when the amino group is attached to a different carbon atom, such as, for example p-amino acids and y-amino acids.

[0045] When p-amino acids are incorporated into peptides, two main types of p- peptides exist: those with the side chain residue, R, on the carbon next to the amine are called p3peptides and those with the side chain residue on the carbon next to the carbonyl group are called p2amino acids. Further, p-amino acids may adopt L- or D- stereochemistry. Unless otherwise indicated, all p-amino acid abbreviations represent either isomer, i.e., the L-isomer, the D-isomer, or combinations thereof.-13-169954513.1

[0046] Gamma (y)-amino acids are amino acids with the carbon atom to which the amino group attaches is separated from the carboxylate moiety by two carbon atoms.

[0047] For additional modified and unusual amino acids, see §2422 of the MPEP, particularly Table 4 at 2400-24. Additionally, “Ac” indicates N-acetyl and “cyclo” and “c” refers to a cyclic structure. “NH2” indicates an amine group, typically added on the C- terminus of a polypeptide. Accordingly, as used herein, an — NH2 moiety on the C-terminus of a peptide indicates an amidated C-terminus.

[0048] The term “acyl” includes a group RCO — , where R is an organic group. An example is the acetyl group CH3CO — , referred to herein as “Ac.”

[0049] A peptide is “acylated” when an alkyl or substituted alkyl group as defined above is bonded through one or more carbonyl { — (C=O) — } groups. A peptide is most usually acylated at the N-terminus.

[0050] An “amine” includes compounds that contain an amine group ( — NH2).

[0051] An “amide” includes compounds that have a trivalent nitrogen attached to a carbonyl group (i.e., — CO— NH2), such as for example methylamide, ethylamide, propylamide, and the like. A peptide is most usually amidated at the C-terminus by the addition of an amine ( — NH2) moiety to the C-terminal carboxyl group.

[0052] As used herein, sugar alcohols are polyols, typically derived from sugars. The term “sugar” refers to monosaccharides, disaccharides, and / or polysaccharides. Examples of sugars include, but are not limited to, sucrose, lactose, trehalose, maltose, dextrose, and the like.

[0053] The terms “active ingredient” and “active compound” refer to a biologically active substance, whether naturally or non-naturally occurring, that is the main component of the pharmaceutical composition which elicits the intended effect of an administered therapeutic. This can be any component that drives the pharmacological activity or direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, such as obesity.

[0054] A “formulation” or “formula” refers to the combination of substances including an active ingredient and a component, such as a pharmaceutically acceptable carrier, to-14-169954513.1form a pharmaceutical composition. The pharmaceutical composition can be formulated by any means known in the art, including but not limited to formulation as, suspensions, powders, lyophilized preparations, and may be mixed and formulated with buffers, binders, excipients, stabilizers, lubricants, oils, adjuvants, antioxidants and other agents known in the art to yield a formulation suitable for subcutaneous administration.

[0055] The formulations of the present technology are injected parenterally, such as subcutaneously. The terms “administering” or “administer” include delivery of the formulations of the present technology to a subject by parenteral administration, such as subcutaneous administration.

[0056] As used herein, the term “isotonic” refers to fluids such as a solution having the same effective osmotic pressure as another solution, especially one in a cell or a body fluid. In some instances, an isotonic solution has the same concentration of solutes as the blood, such as an isotonic saline solution.

[0057] The terms “treat,” “treatment,” and “treating” refer to a manner of providing a pharmaceutical composition and / or melanocortin analog to alleviate disease outcomes. This includes utilizing administration techniques as described in the context of the present technology. Efficacy of treatment can be determined by measuring biomarkers as described in the context of the present technology.

[0058] The terms “subject” and “patient” refer to anyone being evaluated for disease or being administered a therapeutic or pharmaceutical composition. This includes people without diagnosed or confirmed disease. This also includes people with diagnosed or confirmed disease, such as obesity.Pharmaceutical Compositions and Formulations

[0059] The present technology provides pharmaceutical compositions and formulations comprising a non-naturally occurring melanocortin agonist analog and one or more pharmaceutically acceptable carriers and / or excipients.

[0060] Non-naturally occurring melanocortin analogs described herein may be selective for the melanocortin 3 receptor and / or melanocortin 4 receptor over other melanocortin receptors, i.e., the melanocortin 1 , melanocortin 2, and melanocortin 5-15-169954513.1receptors. Some of the melanocortin analogs bind the melanocortin 3 receptor with greater affinity than the melanocortin 4 receptor. Certain melanocortin analogs bind the melanocortin 3 receptor with the same or generally similar affinity as the melanocortin 4 receptor.

[0061] The non-naturally occurring melanocortin analogs of the present technology may be full agonists for one or more melanocortin receptors. A full agonist may comprise a non-naturally occurring melanocortin analog having a maximum effect (Emax) agonist value of greater than or equal to 80%.

[0062] The non-naturally occurring melanocortin analogs of the present technology may be partial agonists or partial antagonists of one or more melanocortin receptor. A partial agonist or antagonist may comprise a non-naturally occurring melanocortin analog having a maximum effect Emax agonist value of less than 80%.

[0063] If a non-naturally occurring melanocortin analog’s Emax agonist value is greater than it’s Emax antagonist value, then the non-naturally occurring melanocortin analog may be classified as an agonist (e.g., a full agonist or a partial agonist). Similarly, if a non-naturally occurring melanocortin analog’s Emaxantagonist value is greater than it’s Emaxagonist value, then the non-naturally occurring melanocortin analog may be classified as an antagonist (e.g., a full antagonist or a partial antagonist).

[0064] The non-naturally occurring melanocortin analogs of the present technology may be one or more of (i) a full MC3R agonist and a full MC4R agonist; (ii) a full MC3R agonist and a partial MC4R agonist; (iii) a full MC3R agonist having no MC4R agonist or antagonist activity; or (iv) a full MC3R agonist and a partial MC4R antagonist.

[0065] The non-naturally occurring melanocortin analogs in accordance with the present technology may have structural features that impart specific properties on the analogs, such as, for example, degradation resistance, enhanced epithelial, gastrointestinal, and / or blood brain barrier transport, and binding affinity for the MC4R and / or MC3R. For example, in some embodiments, the non-naturally occurring melanocortin analogs comprise one or more of (i) blood brain barrier passage capabilities, (ii) enhanced epithelial and / or gastrointestinal transport; (iii) degradation resistance; or (iv) equipotency on MC3R and-16-169954513.1MC4R activity. In some embodiments, the non-naturally occurring melanocortin analogs comprise two or more of (i)-(iv). In some embodiments, the non-naturally occurring melanocortin analogs comprise each of (i)-(iv). Accordingly, in some embodiments, the melanocortin analogs include a stabilizing N-terminus, and / or a C-terminus that provides enhanced transport of the analog. In some embodiments, melanocortin analogs include a D-valine-D-proline (dVal-dPro) chain as their C-terminus, which may provide enhanced transport and resistance to degradation Additionally, in some embodiments, the melanocortin analogs have one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In general, cyclization and D-amino acids may induce and / or stabilize beta-turns.

[0066] The presence of certain structural features may impart the non-naturally occurring melanocortin analogs of the present technology with specific binding properties. For example, inclusion of p(F)dPhe or dPhe at the R4position may result in enhanced binding and activation of the melanocortin 4 receptor. Accordingly, melanocortin analogs having p(F)dPhe or dPhe at the R4position may be full agonists on MC4R. Further, inclusion of His at the R3position may result in full agonism on MC3R as well. By contrast, inclusion of residues other than His at the R3position, such as, for example, Pro, may decrease activity on the melanocortin 3 receptor, resulting in only partial agonism on MC3R.

[0067] In some embodiments, the non-naturally occurring melanocortin antagonist analog has at least one cationic amino acid residue. As used herein, the term “cationic amino acid residue” refers to an amino acid residue with a side chain that may adopt a positive charge in solution. For example, when lysine exists in a free form, i.e., when the side chain amine is not engaged in a bond or otherwise unable to adopt a positive charge, lysine is a cationic amino acid residue.. On the other hand, when the amine side chain of lysine is engaged in an intramolecular bond or otherwise unable to adopt a positive change,, lysine is not a cationic residue. Likewise, an “anionic amino acid residue” refers to an amino acid residue with a side chain that may adopt a negative charge in solution. For example, when aspartic acid exists in a free form, e.g., when the side chain carboxylic acid is not engage in a bond or otherwise unable to adopt a positive charge, aspartic acid is an anionic amino acid residue. On the other hand, when the carboxylic acid side chain of aspartic acid-17-169954513.1is engaged in a bond or otherwise unable to adopt a negative charge, aspartic acid is not an anionic residue.

[0068] In some embodiments, the non-naturally occurring melanocortin agonist analog has at least one cationic amino acid residue and no anionic amino acid residues.

[0069] The non-naturally occurring melanocortin agonist analog may be linear or cyclized. In some embodiments, the non-naturally occurring melanocortin analog is linear. In some embodiments, the non-naturally occurring melanocortin analog is cyclized. In further embodiments, the non-naturally occurring melanocortin analog is cyclized through a sidechain linkage between an acidic amino acid residue and a basic amino acid residue.

[0070] In some embodiments, the non-naturally occurring melanocortin agonist analog has an isoelectric point (pl) of at least about 10 in an aqueous solution. In some embodiments, the non-naturally occurring melanocortin analog has a pl of about 10 to about 12.5 in an aqueous solution. In further embodiments, the non-naturally occurring melanocortin analog has at least one cationic amino acid residue and a pl of about 10 to about 12.5. In still further embodiments, the non-naturally occurring melanocortin analog has an arginine residue and a pl of about 10 to about 12.5. In still further embodiments, the non- naturally occurring melanocortin analog has a cyclic region with an arginine residue positioned therein and a pl of at least about 10. In yet further embodiments, the non-naturally occurring melanocortin analog has a cyclic region with an arginine residue positioned therein and a pl of about 10 to about 12.5.

[0071] In some embodiments, the non-naturally occurring melanocortin agonist analog comprises the moiety (A),X1-R1-R2-R3-R4-R5-R6-R7-Y1 (A), wherein:R1 is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl; at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and-18-169954513.1the non-naturally occurring melanocortin analog is optionally cyclized via a side chain linkage between R2 and R7; provided that the sequence of Formula (I) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0072] In some embodiments, moiety (A) is cyclized through a lactam bond between R2and R7. In some embodiments, Xi is absent. In some embodiments, Y1 is a C-terminus comprising two amino acids. In further embodiments, Y1 is a C-terminus comprising a dVal- dPro moiety.

[0073] In some embodiments, the non-naturally occurring melanocortin analog comprises moiety (A) and has an isoelectric point of at least about 10 in aqueous solution. In further embodiments, the non-naturally occurring melanocortin analog comprises moiety (A) and has an isoelectric point of about 10 to about 12.5 in aqueous solution.

[0074] In some embodiments, the non-naturally occurring melanocortin agonist analog comprises a sequence according to Formula (I),X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4( I) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);-19-169954513.1Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R4is dPhe, then (i) R1is Asp and R2is Phe-Phe, (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal, and when Y1-Y4are absent, then R3is dAla-His.

[0075] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (I), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);-20-169954513.1Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 10);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);-21 -169954513.1Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 19);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.-22-169954513.1

[0076] In some embodiments of the sequence of Formula (I), Y1and Y2are present. Accordingly, in some embodiments, the sequence of Formula (I) is a sequence of Formula (IA):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4(I A) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R4is dPhe, then (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, and when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal.-23-169954513.1

[0077] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IA):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4(I A) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R4is dPhe, then (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, and when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal.-24-169954513.1

[0078] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IA), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEO ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEO ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);-25-169954513.1Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.

[0079] In some embodiments of the sequence of Formula (I) or (IA), R4is p(F)dPhe. In further embodiments, R3is His. Accordingly, in some embodiments, the sequence of Formula (I) or (IA) is a sequence of Formula (IA(i)):X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(i)) (SEQ ID NO: 42), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);-26-169954513.1R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the C-terminus is amidated, and R1is not dArg when Y1is dVal.

[0080] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IA(i)):X1-R1-R2-R3-R4-R5-R6-R7-Y1-Y2-Y3-Y4(IA(i)) (SEQ ID NO: 42), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;-27-169954513.1Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the C-terminus is amidated, and R1is not dArg when Y1is dVal.

[0081] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IA(i)), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.-28-169954513.1

[0082] In some embodiments of the sequence of Formula (I), R4is dPhe. In further embodiments, X1, Y3, and Y4are absent. In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IB):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Rhe-Rhe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R1is Arg, then R3is dAla-His, when R1is Nle, then R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when Y1-Y4are absent, then R3is dAla-His.

[0083] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IB):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB),-29-169954513.1wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R1is Arg, then R3is dAla-His, when R1is Nle, then R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when Y1-Y4are absent, then R3is dAla-His.

[0084] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of Formula (IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);-30-169954513.1R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);-31 -169954513.1Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.

[0085] In some embodiments, the non-naturally occurring melanocortin agonist of any one of Formulae (l)-(IB) has one or more beta hairpin (p-hairpin) and / or beta turn (p-turn) structures. In some embodiments, the presence of Pro, dPro, or dAla, in the melanocortin agonist provides the p-hairpin and / or p-turn structures of the non-naturally occurring melanocortin agonist.

[0086] As will be appreciated by the skilled artisan, non-naturally occurring melanocortin agonists comprising a sequence of any one of Formulae (l)-(IB), have an N- terminus and a C-terminus. The melanocortin agonists of the present technology are written beginning with the N-terminus at the left-most amino acid residue and ending with the C- terminus at the right most residue. Accordingly, the N-terminus of a non-naturally melanocortin agonist comprising a sequence of any one of Formulae (l)-(IB) may be at X1or R1. Analogously, the C-terminus of a non-naturally occurring melanocortin agonist-32-169954513.1comprising a sequence of any one of Formulae (l)-(ID) may be at any of R7, Y1, Y2, Y3, and Y4.

[0087] In some embodiments, the N-terminus of the non-naturally occurring melanocortin agonist is modified by an acyl group. In some embodiments, the acyl group is acetyl group

[0088] In some embodiments, the N-terminus of the non-naturally occurring melanocortin agonist is not modified.

[0089] In the sequence of any one of Formulae (l)-(ID), Y1Y2Y3Y4represents a C- terminus of the non-naturally occurring melanocortin agonist. In some embodiments, Y1-Y4are absent. In some embodiments, Y1is present and Y2-Y4are absent.

[0090] In some embodiments, Y1and Y2are present and Y3-Y4are absent. In some embodiments, Y3-Y4are absent, and Y1is dVal and Y2is dPro. In some embodiments, Y3- Y4are absent, and Y1is dPro and Y2is dVal. In some embodiments, Y3-Y4are absent, and Y1is dTle and Y2is dPro.

[0091] In some embodiments, Y1-Y3are present and Y4is absent. In some embodiments, Y4is absent and (i) Y1is dPro, (ii) Y2is dVal, and (iii) Y3is dPro. In some embodiments, Y4is absent, and (i) Y1is dTle, Y2is dTle, and Y3is dVal.

[0092] In some embodiments, Y1-Y4are present. In some embodiments, Y1-Y4are present and (i) Y1is dVal, (ii) Y2is dVal, (iii) Y3is dVal, and (iv) Y4is dPro.

[0093] In some embodiments, the C-terminus of the non-naturally occurring melanocortin agonist is modified by an amide groupthe sequence of any one of Formulae (l)-(IB), a non-naturally occurring melanocortin agonist with a C- terminus modified by an amide may be represented by a terminal -NH2.

[0094] In some embodiments, the C-terminus of the non-naturally occurring melanocortin agonist is not modified. In the sequence of any one of Formulae ( l)-(IB), a non--33-169954513.1naturally occurring melanocortin agonist with an unmodified C-terminus may be represented by -OH.

[0095] Non-naturally occurring melanocortin agonists comprising a sequence of any one of Formulae (l)-(IB) are cyclized. For example, the non-naturally occurring melanocortin agonist may be cyclized through a moiety of: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn.

[0096] In some embodiments of the sequence of Formulae (l)-(IB), R3is His. In further embodiments, X1is absent and R1is present. In some embodiments, R1is Nle. In further embodiments, R2is Asp or Glu, R4is dPhe or p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys or Orn. In some embodiments, Y1and Y2are each independently dVal or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 43);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 44);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 45);Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 46); andAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0097] Alternatively, in some embodiments, R1is an amino acid other than Nle. In some embodiments, R1is selected from Arg, dArg, Lys, dLys, His, or dHis. In further embodiments, R2is Asp, R4is p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. In some embodiments, Y1is dVal and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 48);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 49);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 50);-34-169954513.1Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 51 ); andAc-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 52), wherein c represents cyclization through R2and R7via a lactam bond.

[0098] In some embodiments, Y1is dTle and Y2is dPro. In some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 53);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 54);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 55);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 56);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 57); andAc-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 58), wherein c represents cyclization through R2and R7via a lactam bond.

[0099] In some embodiments, R3is His and X1is present. In further embodiments, X1is Nle, In still further embodiments, R1is Nle, R4is p(F)dPhe, R5is Arg, R6is Trp, and R7is Lys. some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 59);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 60); andAc-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 61 ), wherein c represents cyclization through R1and R7via a lactam bond.

[0100] In some embodiments, R3is His and R5is Arg. Alternatively, in some embodiments, R5is an amino acid other than Arg. In further embodiments, R5is His and R4is p(F)dPhe. In some embodiments, the sequence of any one of Formulae (l)-(IB) is: Ac-Nle- c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 62), wherein c represents cyclization through R2and R7via a lactam bond.-35-169954513.1

[0101] In some embodiments, R3is His, Y1is dVal and Y2is dPro. Alternatively, in some embodiments, Y1is an amino acid other than dVal and / or Y2is an amino acid other than dPro. In further embodiments, Y1is dTle, dPro, or dVal, and Y2is dTle, dVal, or dPro. In some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 63);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 64);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 65); andAc-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 66), wherein c represents cyclization through R2and R7via a lactam bond.

[0102] In some embodiments of the sequence of any one of Formula (l)-(IB), R3is a dipeptide. In further embodiments, R3is a dipeptide comprising His. In some embodiments, R3is dAla-His. In further embodiments, R2is Asp, R4is dPhe, R6is Trp, and R7is Lys. In some embodiments, the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 67);Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 68);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 69); andAc-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 70), wherein c represents cyclization through R2and R7via a lactam bond.

[0103] Alternatively, in some embodiments, R3is Pro-His. In further embodiments, R1is Nle, R4is dPhe, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (l)-(IB) is: Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 71 ), wherein c represents cyclization through R2and R7via a lactam bond.

[0104] In some embodiments of the sequence of any one of Formulae (l)-(ID), R3is an amino acid other than His. In some embodiments, R3is dHis or Gin. In further embodiments-36-169954513.1R4is dPhe, R5is Arg, and R6is Trp. In some embodiments, the sequence of any one of Formulae (l)-(ID) is:Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 72); orAc-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a disulfide bond.

[0105] In some embodiments, the non-naturally occurring melanocortin agonist comprises a sequence of any one of SEQ ID NOs: 43-73.

[0106] In some embodiments, the non-naturally occurring melanocortin agonist analog is in the form of a salt. In further embodiments, the non-naturally occurring melanocortin agonist analog is in the form of an acetate salt. In still further embodiments, the non-naturally occurring melanocortin agonist analog is in the form of an acetate salt and comprises a sequence of any one of Formulae (l)-(IB). In yet further embodiments, the non-naturally occurring melanocortin agonist analog is in the form of an acetate salt and comprises a sequence of any one of the sequences provided above.

[0107] The non-naturally occurring melanocortin agonist analog may be present in the pharmaceutical composition or formulation in an amount of about 5 mg / mL to about 200 mg / mL. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 130 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 70 mg / mL or about 5 mg / mL to about 50 mg / mL. In some embodiments, the non- naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 70 mg / mL or about 10 mg / mL to about 50 mg / mL. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 10 mg / mL to about 130 mg / mL. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 10 mg / mL to about 50 mg / mL.

[0108] In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 10 mg / mL, about 12.5-37-169954513.1mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 12.5 mg / mL. In other embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 25 mg / mL. In still other embodiments, the non-naturally occurring melanocortin analog is present in the pharmaceutical composition in an amount of about 50 mg / mL.

[0109] Pharmaceutically acceptable carriers and / or excipients included in the pharmaceutical compositions and formulations of the present technology may be selected based on the carrier or excipient’s ability to confer desirable properties, such as reduced or lack of delivery site reactions, solubility, stability, pH, buffering, pharmacokinetics, bioavailability, and the like, to the pharmaceutical composition or formulation. For example, the one or more pharmaceutically acceptable carriers and / or excipients of the pharmaceutical compositions and formulations described herein may include a buffer, an osmolyte, and a pH adjusting agent.

[0110] The pharmaceutical compositions and formulations of the present technology include a buffer. The buffer may be an organic buffer, i.e., a buffer that does not comprise or chelate a metal cation. In some embodiments, the buffer comprises one or more of histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes, TES, HEPES, DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine. In some embodiments, the buffer comprises histidine.

[0111] Alternatively, the buffer may be an inorganic buffer, i.e., a buffer that comprises or chelates a metal ion. In some embodiments, the buffer comprises an acetate. In further embodiments, the buffer comprises sodium acetate. A sodium acetate buffer may be included in the pharmaceutical compositions and formulations described herein as anhydrous sodium acetate or a sodium acetate hydrate.

[0112] The buffer may be present in the pharmaceutical composition or formulation at a concentration of about 5 mM to about 150 mM. In some embodiments, the buffer is present in the pharmaceutical composition or formulation at a concentration of about 10 mM to about 150 mM, about 5 mM to about 125 mM, about 5 mM to about 100 mM, about 10 mM to about-38-169954513.1120 mM, about 10 mM to about 100 mM, about 5 mM to about 80 mM, about 10 mM to about 80 mM, about 5 mM to about 50 mM, about 10 mM to about 50 mM, about 5 mM to about 25 mM, or about 10 mM to about 25 mM. . In some embodiments, the buffer may be present in the pharmaceutical composition or formulation at a concentration of about 10 mM, about 12.5 mM, about 15 mM, about 17.5 mM, about 20 mM, about 22.5 mM, or about 25 mM.

[0113] In some embodiments, the buffer comprises histidine and the histidine is present in the pharmaceutical composition or formulation at a concentration of about 5 mM to about 150 mM. In some embodiments, the histidine is present in the pharmaceutical composition or formulation at a concentration of about 10 mM to about 150 mM, about 5 mM to about 125 mM, about 5 mM to about 100 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 5 mM to about 80 mM, about 10 mM to about 80 mM, about 5 mM to about 50 mM, about 10 mM to about 50 mM, about 5 mM to about 25 mM, or about 10 mM to about 25 mM. In some embodiments, the histidine is present in the pharmaceutical composition or formulation at a concentration of about 10 mM to about 25 mM. In some embodiments, the histidine is present in the pharmaceutical composition or formulation at a concentration of about 10 mM, about 12.5 mM, about 15 mM, about 17.5 mM, about 20 mM, about 22.5 mM, or about 25 mM.

[0114] In some embodiments, the buffer comprises sodium acetate and the sodium acetate is present in the pharmaceutical composition or formulation at a concentration of about 5 mM to about 150 mM. In some embodiments, the sodium acetate is present in the pharmaceutical composition or formulation at a concentration of about 10 mM to about 150 mM, about 5 mM to about 125 mM, about 5 mM to about 100 mM, about 10 mM to about 120 mM, about 10 mM to about 100 mM, about 5 mM to about 80 mM, about 10 mM to about 80 mM, about 5 mM to about 50 mM, about 10 mM to about 50 mM, about 5 mM to about 25 mM, or about 10 mM to about 25 mM. In some embodiments, the sodium acetate is present in the pharmaceutical composition or formulation at a concentration of about 10 mM, about 12.5 mM, about 15 mM, about 17.5 mM, about 20 mM, about 22.5 mM, or about 25 mM.

[0115] A buffer may be included to maintain a certain pH range of the pharmaceutical composition or formulation. For example, the pharmaceutical compositions and formulations-39-169954513.1of the present technology may include a buffer to maintain a pH range that is acceptable for physiological use and that maintains dissolution of the non-naturally occurring melanocortin analog in the composition or formulation. Such pH range may be from about 4.0 to about 7.0. Accordingly, the pharmaceutical composition or formulation has a pH of about 4.0 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 6.0. In some embodiments, pharmaceutical composition or formulation has a pH of about 4.0 to about 5.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 5.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 6.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.5 to about 5.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.0 to about 7.0. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.0 to about 6.5.

[0116] In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.0 to about 4.5, about 4.2 to about 4.7, about 4.4 to about 4.9, about, about 4.6 to about 5.1 , about 4.8 to about 5.3, or about 5.0 to about 5.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.0 to about 5.5, about 5.2 to about 5.7, about 5.4 to about 5.9, about, about 5.6 to about 6.1 , about 5.8 to about 6.3, or about 6.0 to about 6.5. In some embodiments, the pharmaceutical composition or formulation has a pH of about 4.9. In some embodiments, the pharmaceutical composition or formulation has a pH of about 5.3. In some embodiments, the pharmaceutical composition or formulation has a pH of about 6.3.

[0117] The pharmaceutical compositions and formulations of the present technology include an osmolyte. The osmolyte may be a sugar or derivative thereof, glycerol, glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, or PEG. In some embodiments, the osmolyte is a sugar or derivative thereof such as, for example, a sugar alcohol. Non--40-169954513.1limiting examples of sugar alcohols include sorbitol, mannitol, erythritol, threitol, lactitol, maltitol, glycerol, xylitol, and cellulose. In some embodiments, the osmolyte is mannitol.

[0118] The osmolyte may be present in the pharmaceutical composition or formulation in an amount of about 5 mg / mL to about 100 mg / mL. In some embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, or about 10 mg / mL to about 40 mg / mL. In some embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 15 mg / mL to about 50 mg / mL, about 10 mg / mL to about 45 mg / mL, about 15 mg / mL to about 45 mg / mL, about 15 mg / mL to about 40 mg / mL about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, or about 20 mg / mL to about 40 mg / mL.

[0119] In some embodiments, the osmolyte is present in the pharmaceutical composition or formulations in an amount of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 25 mg / mL. In other embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 27.5 mg / mL. In still other embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 35 mg / mL. In yet other embodiments, the osmolyte is present in the pharmaceutical composition or formulation in an amount of about 37.5 mg / mL.

[0120] In some embodiments, the osmolyte is mannitol and the mannitol is present in the pharmaceutical composition or formulation in an amount of about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, or about 10 mg / mL to about 40 mg / mL. In some embodiments, the mannitol is present in the pharmaceutical composition or formulation in an amount of about 15 mg / mL to about 50 mg / mL, about 10 mg / mL to about 45 mg / mL, about 15 mg / mL to about 45-41 -169954513.1mg / mL, about 15 mg / mL to about 40 mg / mL about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, or about 20 mg / mL to about 40 mg / mL.

[0121] In some embodiments, the osmolyte is mannitol and the mannitol is present in the pharmaceutical composition or formulations in an amount of about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 27.5 mg / mL, about 30 mg / mL, about 32.5 mg / mL, about 35 mg / mL, about 37.5 mg / mL, about 40 mg / mL, about 45 mg / mL, or about 50 mg / mL. In some embodiments, the mannitol is present in the pharmaceutical composition or formulation in an amount of about 25 mg / mL. In other embodiments, the osmolyte is mannitol and the mannitol is present in the pharmaceutical composition or formulation in an amount of about 27.5 mg / mL. In still other embodiments, the mannitol is present in the pharmaceutical composition or formulation in an amount of about 35 mg / mL. In yet other embodiments, the mannitol is present in the pharmaceutical composition or formulation in an amount of about 37.5 mg / mL.

[0122] An osmolyte may be included in the pharmaceutical composition or formulation to achieve a certain osmolality. For example, the pharmaceutical compositions and formulations of the present technology may include an osmolyte to achieve an isotonic or hypertonic solution to minimize injection site pain and cellular damage. An isotonic solution may have an osmolality of about 250 mOsm / kg to about 350 mOsm / kg and a hypertonic solution may have an osmolality of about 350 mOsm / kg to about 600 mOsm / kg. Accordingly, in some embodiments, the osmolyte is included in the pharmaceutical composition or formulation to achieve an osmolality of about 250 mOsm / kg to about 600 mOsm / kg. In some embodiments, the osmolyte is included in the pharmaceutical composition or formulation to achieve an osmolality of about 280 mOsm / kg to about 560 m / Osm, about 280 mOsm / kg to about 520 m / Osm, about 280 mOsm / kg to about 500 mOsm, about 280 mOsm / kg to about 460 m / Osm, about 280 mOsm / kg to about 420 m / Osm, about 280 mOsm / kg to about 400 mOsm, about 280 mOsm / kg to about 360 m / Osm, or about 280 mOsm / kg to about 320 m / Osm.

[0123] In some embodiments, the pharmaceutical composition or formulation is isotonic. In further embodiments, the osmolality of the pharmaceutical composition of formulation is about 250 mOsm / kg to about 350 mOsm / kg. In some embodiments, the-42-169954513.1osmolality of the pharmaceutical composition or formulation is about 260 mOsm / kg to about 330 mOsm / kg, 270 mOsm / kg to about 330 mOsm / kg, about 275 mOsm / kg to about 310 mOsm / kg, about 275 mOsm / kg to about 300 mOsm / kg, or about 280 mOsm / kg to about 290 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition or formulation is about 280 mOsm / kg, 281 mOsm / kg, 282 mOsm / kg, 283 mOsm / kg, 284 mOsm / kg, 286 mOsm / kg, 287 mOsm / kg, 288 mOsm / kg, 289 mOsm / kg, or 290 mOsm / kg.

[0124] In some embodiments, the pharmaceutical composition or formulation is hypertonic. In further embodiments, the osmolality of the pharmaceutical composition of formulation is about 350 mOsm / kg to about 600 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition or formulation is about 360 mOsm / kg to about 550 mOsm / kg, about 365 mOsm / kg to about 530 mOsm / kg, about 370 mOsm / kg to about 510 mOsm / kg, about 375 mOsm / kg to about 500 mOsm / kg, about 380 mOsm / kg to about 490 mOsm / kg, about 385 mOsm / kg to about 470 mOsm / kg, or about 390 mOsm / kg to about 450 mOsm / kg. In some embodiments, the osmolality of the pharmaceutical composition or formulation is about 400 mOsm / kg to about 600 mOsm / kg, about 420 mOsm / kg to about 580 mOsm / kg, about 440 mOsm / kg to about 560 mOsm / kg, about 460 mOsm / kg to about 540 mOsm / kg, or about 480 mOsm / kg to about 520 mOsm / kg.

[0125] The pharmaceutical compositions and formulations of the present technology include a pH adjusting agent. The pH adjusting agent may be an acid or a base. For example, if the pH of the pharmaceutical composition or formulation is too basic before addition of the pH adjusting agent, then the pH adjusting agent may be an acid. On the other hand, if the pH of the pharmaceutical composition or formulation is too acidic before addition of the pH adjusting agent, then the pH adjusting agent may be a base.

[0126] The pH adjusting agent may be present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 0.1 mg / mL to about 9.0 mg / mL, about 0.1 mg / mL to about 8.0 mg / mL, about 0.1 mg / mL to about 7.0 mg / mL, about 0.1 mg / mL to about 6.0 mg / mL, about 0.1 mg / mL to about 5.0 mg / mL, about 0.1 mg / mL to about 4.0 mg / mL, about 0.1 mg / mL to about 3.0 mg / mL, or about 0.1 mg / mL to about 2.0 mg / mL. In some embodiments, the pH adjusting-43-169954513.1agent is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 10 mg / mL, about 1.0 mg / mL to about 5.0 mg / mL, 0.5 mg / mL to about 5.0 mg / mL, or about 02. mg / mL to about 5 mg / mL.

[0127] When the non-naturally occurring melanocortin analog is in the form of an acetate salt, the ratio of acetate to analog may be 1 :1. Alternatively, the ratio of acetate to analog may not be 1 :1 , i.e., the ratio of acetate to analog may be less than or greater than 1 :1 . Accordingly, when a melanocortin analog acetate salt has a high ratio of acetate to analog, the pharmaceutical composition may be more acidic and may require a greater amount of the pH adjusting agent. Alternatively, when a melanocortin analog acetate salt has a low ratio of acetate to analog, the pharmaceutical composition may be less acidic and may require a lower amount of the pH adjusting agent.

[0128] In some embodiments, the pH adjusting agent is present in the pharmaceutical composition in an amount of about 0.01 mg / mL to about 5.0 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 4.0 mg / mL, about 0.01 mg / mL to about 3.0 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, about 0.1 mg / mL to about 5.0 mg / mL, about 0.1 mg / mL to about 4.0 mg / mL, about 0.1 mg / mL to about 3.0 mg / mL, or about 0.1 mg / mL to about 2.0 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition in an amount of about 0.1 mg / mL to about 2.0 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 0.1 mg / mL to about 1 .8 mg / mL, about 0.1 mg / mL to about 1.6 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.2 mg / mL to about 1.8 mg / mL, about 0.2 mg / mL to about 1.6 mg / mL, or about 0.2 mg / mL to about 1.5 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL to about 1 .4 mg / mL, about 0.4 mg / mL to about 1.2 mg / mL, about 0.4 mg / mL to about 1.0 mg / mL, about 0.4 mg / mL to about 0.8 mg / mL, about 0.4 mg / mL to about 0.6 mg / mL, about 0.8 mg / mL to about 1 .4 mg / mL about 0.9 mg / mL to about 1 .3 mg / mL, or about 1 .0 mg / mL to about 1 .2 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of-44-169954513.1about 0.2 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 .0 mg / mL, about 1 .1 mg / mL, about 1 .2 mg / mL, or about 1.4 mg / mL.

[0129] In some embodiments, the pH adjusting agent is present in the pharmaceutical composition in an amount of about 1.0 mg / mL to about 5.0 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 4.5 mg / mL, about 1 .5 mg / mL to about 4.0 mg / mL, about 2.0 mg / mL to about 3.5 mg / mL, or about 2.5 mg / mL to about 3.0 mg / mL. In some embodiments, the pH adjusting agent is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 1 .5 mg / mL, about 1 .0 mg / mL to about 3.0 mg / mL, about 1 .0 mg / mL to about 5.0 mg / mL about 1 .0 mg / mL to about 2.5 mg / mL, or about 2.5 mg / mL to about 5.0 mg / mL.

[0130] In some embodiments, the pH adjusting agent is a base. Non-limiting examples of bases include histidine, arginine, sodium hydroxide, potassium hydroxide, ammonium hydroxide, ammonium carbonate, sodium bicarbonate, sodium carbonate, and sodium borate. In some embodiments, the base is sodium hydroxide.

[0131] In some embodiments, the pH adjusting agent is sodium hydroxide and the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 9.0 mg / mL, about 0.01 mg / mL to about 8.0 mg / mL, about 0.01 mg / mL to about 7.0 mg / mL, about 0.01 mg / mL to about 6.0 mg / mL, about 0.01 mg / mL to about 5.0 mg / mL, about 0.01 mg / mL to about 4.0 mg / mL, about 0.01 mg / mL to about 3.0 mg / mL, or about 0.01 mg / mL to about 2.0 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.1 mg / mL to about 9.0 mg / mL, about 0.1 mg / mL to about 8.0 mg / mL, about 0.1 mg / mL to about 7.0 mg / mL, about 0.1 mg / mL to about 6.0 mg / mL, about 0.1 mg / mL to about 5.0 mg / mL, about 0.1 mg / mL to about 4.0 mg / mL, about 0.1 mg / mL to about 3.0 mg / mL, or about 0.1 mg / mL to about 2.0 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 10 mg / mL, about 0.5-45-169954513.1mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 10 mg / mL, about 1 .0 mg / mL to about 5.0 mg / mL, 0.5 mg / mL to about 5.0 mg / mL, or about 0.2 mg / mL to about 5 mg / mL.

[0132] In some embodiments, the sodium hydroxide is present in an amount of about 0.1 mg / mL to about 2.0 mg / mL, 0.1 mg / mL to about 1 .8 mg / mL, about 0.1 mg / mL to about 1.6 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.2 mg / mL to about 1.8 mg / mL, about 0.2 mg / mL to about 1.6 mg / mL, or about 0.2 mg / mL to about 1.5 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL to about 1 .4 mg / mL, about 0.4 mg / mL to about 1.2 mg / mL, about 0.4 mg / mL to about 1.0 mg / mL, about 0.4 mg / mL to about 0.8 mg / mL, about 0.4 mg / mL to about 0.6 mg / mL, about 0.8 mg / mL to about 1 .4 mg / mL about 0.9 mg / mL to about 1.3 mg / mL, or about 1.0 mg / mL to about 1.2 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 .0 mg / mL, about 1 .1 mg / mL, about 1 .2 mg / mL, or about 1.4 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.4 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 0.5 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 1 .2 mg / mL.

[0133] In some embodiments, the sodium hydroxide is present in the pharmaceutical composition in an amount of about 1.0 mg / mL to about 5.0 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 4.5 mg / mL, about 1 .5 mg / mL to about 4.0 mg / mL, about 2.0 mg / mL to about 3.5 mg / mL, or about 2.5 mg / mL to about 3.0 mg / mL. In some embodiments, the sodium hydroxide is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 1 .5 mg / mL, about 1 .0 mg / mL to about 3.0 mg / mL, about 1 .0 mg / mL to about 5.0 mg / mL about 1 .0 mg / mL to about 2.5 mg / mL, or about 2.5 mg / mL to about 5.0 mg / mL.-46-169954513.1

[0134] In some embodiments, the pH adjusting agent is histidine and the histidine is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 10 mg / mL. In some embodiments, the histidine is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 5.0 mg / mL, about 0.01 mg / mL to about 4.0 mg / mL, about 0.01 mg / mL to about 3.0 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, or about 0.01 mg / mL to about 1.0 mg / mL. In some embodiments, the histidine is present in the pharmaceutical composition or formulation in an amount of about 0.1 mg / mL to about 5.0 mg / mL, about 0.1 mg / mL to about 4.0 mg / mL, about 0.1 mg / mL to about 3.0 mg / mL, about 0.1 mg / mL to about 2.0 mg / mL, about 0.5 mg / mL to about 5.0 mg / mL, about 0.5 mg / mL to about 4.0 mg / mL, about 0.5 mg / mL to about 3.0 mg / mL, or about 0.5 mg / mL to about 2.0 mg / mL. In some embodiments, the histidine is present in the pharmaceutical composition or formulation in an amount of about 1.0 mg / mL to about 5.0 mg / mL, about 1.0 mg / mL to about 4.0 mg / mL, about 1.0 mg / mL to about 3.0 mg / mL, or about 1 .0 mg / mL to about 2.0 mg / mL.

[0135] In some embodiments, the histidine is present in an amount of about 0.1 mg / mL to about 2.0 mg / mL, 0.1 mg / mL to about 1 .8 mg / mL, about 0.1 mg / mL to about 1 .6 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.2 mg / mL to about 1.8 mg / mL, about 0.2 mg / mL to about 1 .6 mg / mL, or about 0.2 mg / mL to about 1 .5 mg / mL. In some embodiments, the histidine is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL to about 1.4 mg / mL, about 0.4 mg / mL to about 1.2 mg / mL, about 0.4 mg / mL to about 1 .0 mg / mL, about 0.4 mg / mL to about 0.8 mg / mL, about 0.4 mg / mL to about 0.6 mg / mL, about 0.8 mg / mL to about 1 .4 mg / mL about 0.9 mg / mL to about 1 .3 mg / mL, or about 1 .0 mg / mL to about 1 .2 mg / mL. In some embodiments, the histidine is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 .0 mg / mL, about 1 .1 mg / mL, about 1 .2 mg / mL, or about 1 .4 mg / mL.

[0136] In some embodiments, the pH adjusting agent is an acid. Non-limiting examples of acids include acetic acid, citric acid, fumaric acid, hydrochloric acid, and nitric acid. In some embodiments, the acid is acetic acid, such as glacial acetic acid.-47-169954513.1

[0137] In some embodiments, the pH adjusting agent is glacial acetic acid and the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 5.0 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.01 mg / mL to about 5.0 mg / mL, about 0.01 mg / mL to about 4.0 mg / mL, about 0.01 mg / mL to about 3.0 mg / mL, about 0.01 mg / mL to about 2.0 mg / mL, or about 0.01 mg / mL to about 1 .0 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.1 mg / mL to about 9.0 mg / mL, about 0.1 mg / mL to about 8.0 mg / mL, about 0.1 mg / mL to about 7.0 mg / mL, about 0.1 mg / mL to about 6.0 mg / mL, about 0.1 mg / mL to about 5.0 mg / mL, about 0.1 mg / mL to about 4.0 mg / mL, about 0.1 mg / mL to about 3.0 mg / mL, or about 0.1 mg / mL to about 2.0 mg / mL.. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 10 mg / mL, about 0.5 mg / mL to about 10 mg / mL, about 0.2 mg / mL to about 10 mg / mL, about 1 .0 mg / mL to about 5.0 mg / mL, 0.5 mg / mL to about 5.0 mg / mL, or about 0.2 mg / mL to about 5 mg / mL.

[0138] In some embodiments, the glacial acetic acid is present in an amount of about 0.1 mg / mL to about 2.0 mg / mL, 0.1 mg / mL to about 1 .8 mg / mL, about 0.1 mg / mL to about 1.6 mg / mL, about 0.1 mg / mL to about 1.5 mg / mL, about 0.2 mg / mL to about 1.8 mg / mL, about 0.2 mg / mL to about 1.6 mg / mL, or about 0.2 mg / mL to about 1.5 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL to about 1 .4 mg / mL, about 0.4 mg / mL to about 1.2 mg / mL, about 0.4 mg / mL to about 1.0 mg / mL, about 0.4 mg / mL to about 0.8 mg / mL, about 0.4 mg / mL to about 0.6 mg / mL, about 0.8 mg / mL to about 1 .4 mg / mL about 0.9 mg / mL to about 1.3 mg / mL, or about 1.0 mg / mL to about 1.2 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.2 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.6 mg / mL, about 0.7 mg / mL, about 0.8 mg / mL, about 0.9 mg / mL, about 1 .0 mg / mL, about 1 .1 mg / mL, about 1 .2 mg / mL, or about 1.4 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 0.4 mg / mL, including about 0.42 mg / mL to about 0.44 mg / mL. In some embodiments, the glacial acetic acid is present-48-169954513.1in the pharmaceutical composition or formulation in an amount of about 1 .1 mg / mL, including about 1.13 mg / mL to about 1 .15 mg / mL.

[0139] In some embodiments, the glacial acetic acid is present in the pharmaceutical composition in an amount of about 1.0 mg / mL to about 5.0 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 4.5 mg / mL, about 1 .5 mg / mL to about 4.0 mg / mL, about 2.0 mg / mL to about 3.5 mg / mL, or about 2.5 mg / mL to about 3.0 mg / mL. In some embodiments, the glacial acetic acid is present in the pharmaceutical composition or formulation in an amount of about 1 .0 mg / mL to about 1 .5 mg / mL, about 1 .0 mg / mL to about 3.0 mg / mL, about 1 .0 mg / mL to about 5.0 mg / mL about 1 .0 mg / mL to about 2.5 mg / mL, or about 2.5 mg / mL to about 5.0 mg / mL.

[0140] The pharmaceutical compositions and formulations of the present technology further comprise water. The water may be sterile water for injection (SWFI), sterile water, bacteriostatic water for injection (BWFI), distilled water, bidistilled water, deionized water, deionized distilled water, and reverse osmosis water. In some embodiments, the water present in the pharmaceutical composition or formulation is sterile water for injection.

[0141] The pharmaceutical compositions and formulations of the present technology may further comprise a surfactant. Non-limiting examples of surfactant that may be included in the pharmaceutical compositions or formulations include anionic surfactants such as alkyl carboxylate-fatty acid salts, sulfates (e.g., sodium lauryl sulfate and alkyl ether sulfates), sulfonates (e.g., dioctyl sodium sulfosuccinate and alkyl benzenesulfonates), and phosphate esters (e.g., alkyl aryl ether phosphates and alkyl ether phosphates); cationic surfactants such as quaternary ammoniums (e.g., cetrimonium bromide, cetylpyridinium chloride, and dimethyldioctadecylammonium chloride), amine-based surfactants (e.g., triethylamine hydrochloride and octenidine dihydrochloride) and pyridinium surfactants (e.g., benzethonium chloride); non-ionic surfactants such as polyol esters (e.g., fatty acid esters of sorbitan), polyoxyethylene esters (e.g., polysorbates), and poloxamers (e.g., poloxamer 188); and amphoteric surfactants such as phospholipids (e.g., phosphatidylcholine and lecithin), carboxylic acid / quaternary ammoniums (e.g., cocamidopropyl betaine and amidosulfobetaine-16), phosphoric acid / quaternary ammoniums (e.g., hexadecyl-49-169954513.1phosphocholine), and betaines (e.g., alkylamidopropyl betaine). In some embodiments, the surfactant is a non-ionic surfactant. In further embodiments, the surfactant is a polysorbate.

[0142] Additionally, or alternatively, the pharmaceutical compositions and formulations of the present technology may further comprise a preservative. Non-limiting examples of preservatives that may be included in the pharmaceutical compositions or formulations include m-cresol, phenol, benzyl alcohol, chlorobutanol, methylparaben, phenoxyethanol, propylparaben, and thimerosal. In some embodiments, the preservative is selected from tricresol, phenol, and benzyl alcohol. In some embodiments, the preservative is m-cresol. In some embodiments, the preservative is phenol. In some embodiments, the preservative is benzyl alcohol.

[0143] A preservative may be included in the pharmaceutical compositions and formulations described herein in an amount sufficient to maintain stability of the composition or formulation over time. For example, the preservative may be present in the pharmaceutical compositions and formulations in an amount of about 0.1 wt% to about 1.0 wt%, relative to a total weight of the composition or formulation. In some embodiments, the preservative is present in the pharmaceutical compositions and formulations in an amount of about 0.1 wt% to about 0.8 wt%, about 0.2 wt% to about 0.6 wt%, or about 0.3 wt% to about 0.5 wt%, relative to a total weight of the composition or formulation. In some embodiments, the preservative is present in the pharmaceutical compositions and formulations in an amount of about 0.3 wt%, relative to a total weight of the composition or formulation. In some embodiments, the preservative is present in the pharmaceutical compositions and formulations in an amount of about 0.5 wt%, relative to a total weight of the composition or formulation.

[0144] In some embodiments, the pharmaceutical composition or formulation comprises substantially no chloride ions. In some embodiments, the pharmaceutical composition or formulation is free from chloride ions.

[0145] In some embodiments, the pharmaceutical composition or formulation comprises substantially no metal ions. In some embodiments, the pharmaceutical composition or formulation is free from metal ions.-50-169954513.1

[0146] In some embodiments, the pharmaceutical composition has a pH of about 5.3, and comprises a non-naturally occurring melanocortin agonist analog in an amount of 12.5 mg / mL, mannitol in an amount of about 30 mg / mL to about 40 mg / mL, an acid in an amount of about 1.3 mg / mL to about 1 .5 mg / mL, and histidine at a concentration of about 25 mM. In further embodiments, the mannitol is present in the composition in an amount of about 37.5 mg / mL. In still further embodiments, the acid is glacial acetic acid.

[0147] In some embodiments, the pharmaceutical composition has a pH of about 5.3, and comprises a non-naturally occurring melanocortin agonist analog in an amount of 25 mg / mL, , mannitol in an amount of about 30 mg / mL to about 40 mg / mL, an acid in an amount of about 0.42 mg / mL to about 0.44 mg / mL, and histidine at a concentration of about 25 mM. In further embodiments, the mannitol is present in the composition in an amount of about 35 mg / mL. In still further embodiments, the acid is glacial acetic acid.

[0148] In some embodiments, the pharmaceutical composition has a pH of about 4.0 to about 6.5 and comprises a non-naturally occurring melanocortin agonist analog in an amount of 50 mg / mL, mannitol in an amount of about 25 mg / mL to about 35 mg / mL, a base in an amount of about 0.4 mg / mL to about 1 .2 mg / mL, and a buffer at a concentration of about 25 mM. In some embodiments, the mannitol is present in the composition in an amount of about 25 mg / mL. In other embodiments, the mannitol is present in the composition in an amount of about 27.5 mg / mL. In further embodiments, the base is sodium hydroxide. In some embodiments, the buffer is histidine. In other embodiments, the buffer is sodium acetate. In some embodiments, the sodium hydroxide is present in an amount of 0.4 mg / mL, the buffer is histidine, and the pH of the pharmaceutical composition is about 5.3. In other embodiments, the sodium hydroxide is present in an amount of 1 .2 mg / mL, the buffer is histidine, and the pH of the pharmaceutical composition is about 6.3. In still other embodiments, the sodium hydroxide is present in an amount of 0.5 mg / mL, the buffer is sodium acetate, and the pH of the pharmaceutical composition is about 5.0.Methods of Preparing Pharmaceutical Compositions and Formulations

[0149] The present technology further provides methods of preparing pharmaceutical compositions and formulations described herein, e.g., pharmaceutical compositions comprising a non-naturally occurring melanocortin agonist analog and one or more-51 -169954513.1pharmaceutically acceptable carriers and / or excipients. In some embodiments, the method produces a pharmaceutical composition or formulation of a non-naturally occurring melanocortin agonist analog that has a pH of about 4.0 to about 6.5.

[0150] Methods of preparing the pharmaceutical compositions and formulations comprise providing an aqueous peptide composition of the non-naturally occurring melanocortin agonist analog. In some embodiments, the aqueous peptide composition is provided by dissolving the non-naturally occurring melanocortin agonist analog in water. In some embodiments, when a surfactant is included in the pharmaceutical composition or formulation, the surfactant is also dissolved in the water to provide the aqueous peptide composition. A surfactant may be included in the aqueous peptide composition to prevent the peptide from adhering to the walls of the reaction vessel or tubing.

[0151] In some embodiments, the non-naturally occurring melanocortin agonist analog has at least one cationic residue and an isoelectric point of at least about 10. In further embodiments, the non-naturally occurring melanocortin analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5. In still further embodiments, the non-naturally occurring melanocortin analog has an arginine residue and an isoelectric point of at least about 10. In yet further embodiments, the non-naturally occurring melanocortin analog has an arginine residue and an isoelectric point of about 10 to about 12.5.

[0152] In some embodiments, the aqueous peptide composition is provided by dissolving the non-naturally occurring melanocortin agonist analog comprising a sequence of any one of Formulae (l)-(IB) in water. In some embodiments, the aqueous peptide composition is provided by dissolving the non-naturally occurring melanocortin analog comprising a sequence of any one of SEQ ID NOs: 43-73. In some embodiments, the aqueous peptide composition is provided by dissolving the non-naturally occurring melanocortin analog comprising a sequence of any one of the sequences provided above in water. The non-naturally occurring melanocortin analog dissolved in the water may be in the form of a salt, such as, for example, an acetate salt. To achieve complete dissolution of the non-naturally occurring melanocortin analog in the water, the aqueous peptide solution may be stirred for a period of time sufficient to achieve a homogenous solution. The period of time sufficient to achieve homogeneity may depend on the batch size of the-52-169954513.1pharmaceutical composition or formulation. In some embodiments, the aqueous peptide composition is stirred for about 10 minutes to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 10 minutes to about 60 minutes, about 15 minutes to about 50 minutes, about 20 minutes to about 40 minutes. In some embodiments, the aqueous peptide composition is stirred for about 30 minutes to achieve homogeneity of the composition. Alternatively, in some embodiments, the aqueous peptide composition is stirred for about 1 hour to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours to achieve homogeneity of the composition. The aqueous peptide composition may be mixed and maintained at ambient temperature.

[0153] When the non-naturally occurring melanocortin agonist analog is in the form of a salt, such as, for example, an acetate salt, the aqueous peptide composition may be acidic. In some embodiments, the aqueous peptide composition has a pH of about 2.5 to about 5.0. In some embodiments, the aqueous peptide composition has a pH of about 2.5, about 2.8, about 3.0, about 3.2, about 3.5, about 3.8, about 4.0, about 4.2, about 4.5, about 4.8, or about 5.0.

[0154] Methods of preparing the pharmaceutical compositions and formulations comprise providing a pharmaceutically acceptable carrier composition. In some embodiments, the pharmaceutically acceptable carrier composition is provided by dissolving one or more pharmaceutically acceptable carriers and / or excipients in water. In further embodiments, the pharmaceutically acceptable carrier composition is provided by dissolving an osmolyte, a pH adjusting agent, and a buffer in water. In some embodiments, when a surfactant is included in the pharmaceutical composition or formulation, the surfactant is also dissolved in the water to provide the pharmaceutically acceptable carrier composition. The pharmaceutically acceptable carrier composition may be mixed for an amount of time sufficient to achieve a homogenous composition. The period of time sufficient to achieve homogeneity may depend on the batch size of the pharmaceutical composition or formulation. In some embodiments, the aqueous peptide composition is stirred for about 5-53-169954513.1minutes to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 5 minutes to about 40 minutes, about 10 minutes to about 30 minutes, about 15 minutes to about 20 minutes. In some embodiments, the aqueous peptide composition is stirred for about 15 minutes to achieve homogeneity of the composition. Alternatively, in some embodiments, the aqueous peptide composition is stirred for about 1 hour to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours to achieve homogeneity of the composition. The pharmaceutically acceptable carrier composition may be mixed and maintained at ambient temperature.

[0155] The pharmaceutically acceptable carrier composition may have a pH that is sufficiently basic to neutralize the aqueous peptide composition, e.g., a pH that is sufficiently basic to produce a pharmaceutical composition or formulation having a pH of about 4.0 to about 7.0. For example, the pharmaceutically acceptable carrier composition may have a pH of about 5.0 to about 11 .0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 7.0 to about 1 1 .0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 8.0 to about 11 .0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 9.0 to about 11.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 10.0 to about 11.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 10.5 to about 11.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 8.0 to about 10.5. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 8.5 to about 10.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 9.0 to about 9.5.

[0156] In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 4.0 to about 7.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 4.0 to about 6.5. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 4.5 to about 6.5. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 5.5 to-54-169954513.1about 6.5. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 4.5 to about 6.0. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 4.5 to about 5.5. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 5.9. In some embodiments, the pharmaceutically acceptable carrier composition has a pH of about 6.2 to about 6.6.

[0157] Methods of preparing the pharmaceutical compositions and formulations comprise combining an aqueous peptide composition with a pharmaceutically acceptable carrier composition. In some embodiments, the aqueous peptide composition is added to the pharmaceutically acceptable carrier composition. In other embodiments, the pharmaceutically acceptable carrier composition is added to the aqueous peptide composition. Once the aqueous peptide composition and the pharmaceutically acceptable carrier composition are combined, the combined solution may be stirred for an amount of time sufficient to achieve a stable homogeneous composition. In some embodiments, the combined solution is stirred for about 10 minutes to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 10 minutes to about 60 minutes, about 15 minutes to about 50 minutes, about 20 minutes to about 40 minutes. In some embodiments, the combined solution is stirred for about 30 minutes to achieve homogeneity. Alternatively, in some embodiments, the aqueous peptide composition is stirred for about 1 hour to about 24 hours. In some embodiments, the aqueous peptide composition is stirred for about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours to achieve homogeneity of the composition. The combined solution may be stirred at ambient temperature.

[0158] While the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, a local pH of the pharmaceutical composition may be maintained such that no local region has a pH that is equal to the isoelectric point of the melanocortin analog so as to prevent aggregation of the melanocortin analog. As used herein, a “local pH” refers to the pH of the composition surrounding the site where the composition is being formed, i.e., where the aqueous peptide composition and the-55-169954513.1pharmaceutically acceptable carrier composition are combined. The area of the site where the local pH is maintained may be relative to the process used to combine the aqueous peptide composition and the pharmaceutically acceptable carrier composition. For example, if the pharmaceutically acceptable carrier composition is poured into the aqueous peptide composition, or vice versa, the area of the site where the local pH is maintained may be larger than the area of the site where the local pH is maintained if the pharmaceutically acceptable carrier composition is cannulated, syringed, or pipetted into the aqueous peptide composition, or vice versa. Methods described herein may prevent aggregation of the non- naturally occurring melanocortin analog by combining the aqueous peptide composition with the pharmaceutically acceptable carrier composition via slow addition, such as for example, drop-wise addition, timed addition, portioned addition, and the like.

[0159] In some embodiments, once the aqueous peptide composition and the pharmaceutically acceptable carrier composition are combined and a homogenous solution is provided, the pH of the solution is adjusted to achieve the desired pH of the pharmaceutical composition or formulation. In further embodiments, the desired pH of the pharmaceutical composition or formulation is about 4.0 to about 6.5. In other embodiments, the pH of the homogenous solution is the desired pH of the pharmaceutical composition or formulation. Accordingly, in some embodiments, the pH is not adjusted.

[0160] In some embodiments, the pharmaceutical composition or formulations produced by the methods described herein comprise substantially no precipitated non- naturally occurring melanocortin analog. In some embodiments, the pharmaceutical composition or formulations produced by the methods described herein are free from precipitated non-naturally occurring melanocortin analog.

[0161] In some embodiments, the method is a method of producing a pharmaceutical composition of a non-naturally occurring melanocortin agonist analog, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 with a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 and comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5.-56-169954513.1

[0162] In some embodiments, the method is a method of producing a pharmaceutical formulation having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical composition such that no local region has a pH that is equal to the isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1.0.

[0163] In some embodiments, the method is a method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of the non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog has an arginine residue and an isoelectric point of at least about 10 and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1 .0.EXAMPLES

[0164] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.-57-169954513.1Example 1: Peptide Synthesis-Generic

[0165] The non-naturally occurring melanocortin analogs described herein were synthesized by conventional procedures (e.g., solution-phase procedure, solid-phase synthesis) for the formation of a peptide linkage between amino acids. The solution-phase procedure involved a condensation between the free alpha amino group of an amino acid or derivative thereof having the carboxyl group or other reactive groups protected and the free primary carboxyl group of another amino acid or derivative thereof having the amino group or other reactive groups protected. The solid-phase synthesis utilized a variety of resins and reagents and may involve additional purification steps.

[0166] The process for synthesizing the non-naturally occurring melanocortin analogs was generally performed by a procedure as follows. Each amino acid in the desired sequence of the non-naturally occurring melanocortin analogs was added one at a time in succession to another amino acid or derivative thereof or by a procedure whereby peptide fragments with the desired amino acid sequence were first synthesized conventionally and then condensed to provide the desired peptide. In most cases, the resulting peptide was then cyclized to yield a cyclic peptide.

[0167] Solid-phase peptide synthesis was carried out by sequentially incorporating the desired amino acid residues one at a time into the growing peptide chain coupled to a solidphase support according to the general principles of solid phase methods (see Merrifield, Angew Chem. 24:799-810 (1985) and Barany et al. , The Peptides, Analysis, Synthesis and Biology, Vol. 2, Gross E. and Meienhofer J., Eds. Academic Press 1 -284 (1980)). An exemplary solid-phase synthesis of non-naturally occurring melanocortin analogs is provided below.

[0168] Initially, the C-terminal amino acid residue of the non-naturally occurring melanocortin analog was coupled to a support, e.g., a solid-phase or tag support. Coupling of the C-terminal amino acid residue and the solid-phase support may be carried out according to any method know in the art. Depending on the coupling method, the alphaamine of the C-terminal amino acid residue may or may not be protected with an amine protecting group, as described below. Likewise, the carboxyl group of the amino acid residue may or may not be activated prior to coupling to the solid-phase support in order to increase-58-169954513.1its electrophilicity. Some methods of coupling rely on the formation of an ester bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin. For example, an amino acid residue may be coupled to a p-benzyloxybenzyl alcohol resin (Wang) or a 2-chlorotrityl chloride resin via an ester linkage. Some methods of coupling rely on the formation of an amide bond between the carboxyl group of the amino acid and a reactive handle on the solid-phase resin For example, an amino acid residue may be coupled to a benzhydrylamine (BHA) resin through an Fmoc-linker such as, for example, p- [(R,S)-a-[1 -(9H-fluor-en-9-yl)-methoxyformamido]-2,4-dimethyloxybenzyl]-phenoxyacetic acid (Rink linker) via an amide linkage.

[0169] The non-naturally occurring melanocortin analog was then synthesized by sequential amino acid addition or combination of peptide fragments. Subsequently, the peptide was cleaved from the solid-phase support and purified by methods known in the art, such as, for example, reverse phase high performance liquid chromatography (RP-HPLC) using a suitable column, such as a C18 column, or crystallization. Additionally, or alternatively, other methods of separation or purification were employed, including, but not limited to, methods based on the size or charge of the peptide, and affinity tag-based purification. Once purified, the peptide was characterized by methods such as high- performance liquid chromatograph (HPLC), amino acid analysis, mass spectrometry, and the like.Example 2: Peptide Synthesis-Protecting Groups

[0170] During synthesis of the non-naturally occurring melanocortin analogs, reactive side chain groups of the various amino acid residues were protected with suitable protecting groups, which prevented undesirable chemical reaction from occurring at that site until the protecting group was removed.

[0171] Additionally, protection of the alpha amino group of an amino acid residue or fragment was performed while that entity reacting with the carboxyl group, followed by the selective removal of the alpha amino protecting group to allow a subsequent reaction to take place at that site. Specific protecting groups for solid phase synthesis methods and solution phase synthesis methods are known to those having ordinary skill in the art. Alpha amino groups were protected by a suitable protecting group, including a urethane-type protecting-59-169954513.1group, such as benzyloxycarbonyl (Z) and substituted benzyloxycarbonyl, such as p- chlorobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p- biphenyl-isopropoxycarbonyl, 9-fluorenylmethoxycarbonyl (Fmoc) and p- methoxybenzyloxycarbonyl (Moz); aliphatic urethane-type protecting groups, such as t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropoxycarbonyl, and allyloxycarbonyl. Fmoc was also used for alpha amino protection. Guanidino groups, if present, were protected by a suitable protecting group, such as nitro, p-toluenesulfonyl (Tos), Z, pentamethylchromanesulfonyl (Pmc), adamantyloxycarbonyl, pentamethyldihydrobenzofuran-5-sulfonyl (Pbf) and Boc. Pmc was used as a protecting group for Arg.

[0172] Alpha aminoprotecting groups may be removed under basic conditions, such as, for example, using a solution of piperidine, piperazine, diethylamine, or morpholine (20- 40% v / v) in N,N-dimethylformamide (DMF). In synthesis methods in which alpha amino protecting groups were used, protecting groups were removed after synthesis of the peptide and before or after cleavage of the solid-phase support.Example 3: Peptide Synthesis-Additional Modifications

[0173] If necessary, the peptides were further modified to obtain N-terminus modifications, such as acetylation, while on resin, or were removed from the resin by use of a cleaving reagent and then modified. Likewise, C-terminus modification (e.g., amidation), was performed if needed.

[0174] Additionally, the cyclized peptide structures were obtained prior to cleavage from the peptide resin. For cyclization through reactive side chain moieties, the desired side chains were deprotected, and the peptide suspended in a suitable solvent and a cyclic coupling agent added. Suitable solvents, for example DMF, dichloromethane (DCM) or 1 - methyl-2-pyrrolidone (NMP), were used for the cyclization. Suitable cyclic coupling reagents (e.g., 2-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TBTLI), 2-(1 H- benzotriazol-1 -yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate (HBTLI), benzotriazole- 1 -yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (BOP), benzotriazole-1 -yl- oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate (PyBOP), 2-(7-aza-1 H-benzotriazol- 1 -yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate (TATU), 2-(2-oxo-1 (2H)-pyridyl)-1 ,1 ,3,3--60-169954513.1tetramethyluronium tetrafluoroborate (TPTU), N,N'-dicyclohexylcarbodiimide / 1 - hydroxybenzotriazole (DCCI / HOBt) hexafluorophosphate azabenzotriazole tetramethyl uranium (HATLI), or ethyl (hydroxyiminojcyanoacetate / diisopropylcarbodiimide (Oxyma / DIC)) were also used for the cyclization. Coupling was initiated by a suitable base, such as N,N-diispropylethylamine (DIPEA), sym-collidine or N-methylmorpholine (NMM).Example 4: Biological Data

[0175] The agonist and antagonist activity of exemplary non-naturally occurring melanocortin analogs at the melanocortin receptors (e.g., MC1 R, MC3R, MC4R, and MC5R) were measured via cAMP accumulation assay, according to the following procedure. Experimental design and execution were conducted by Epics Therapeutics S.A. EuroscreenFast (Bruxelles, Belgium).Compound Handing

[0176] Compounds were delivered as powder (1 mg) or 10 mM solutions (100 pl) in 100% DMSO. Powders were solubilized in 100% DMSO at a concentration of 10 mM (master solution) in a defined solvent volume. Serial dilutions were performed from master solution in 100% DMSO to obtain intermediate concentrations 200-, 300- or 400-fold higher than the concentrations to be tested, depending on the assay. Each sample was diluted 100- fold in the assay buffer and dispensed in a test plate. Amounts, solvents, and dilutions were estimated based on standard small-molecule drugs. Cell lines used for functional assays are shown in Table 1 .Table 1. Cell linesCompound Testing

[0177] Compounds were tested for (i) agonist and / or antagonist activity at the human MC3 (FAST-0232C) and MC4 (FAST-0233C) receptors, (ii) agonist activity at the human-61 -169954513.1MC1 (FAST-0230C) receptor, and / or (iii) agonist activity at the human MC5 (FAST-0233C) receptor at the following nanomolar concentrations, in duplicate: 0.0001 , 0.001 , 0.01 , 0.03, 0.1 , 0.3, 1 , 10, 100, and 1 ,000.Testing Protocol

[0178] Cyclic AMP (cAMP) Homogenous Time-Resolved Fluorescence (HTRF) assay for Gs coupled receptor:

[0179] CHO-K1 cells expressing recombinant human receptor grown prior to the test in media without antibiotic were detached by gentle flushing with PBS-EDTA (5 mM EDTA), recovered by centrifugation and resuspended in assay buffer (KRH: 5 mM KCI, 1.25 mM MgSO4, 124 mM NaCI, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCI2, 0.5 g / l BSA, supplemented with 1 mM IBMX or 25pM Rolipram).

[0180] Dose response curves were performed in parallel with the reference compounds.

[0181] For agonist test (384well): 5 pl of cells were mixed with 5 pl of the test compound at increasing concentrations and then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.

[0182] For antagonist test (384well): 5 pl of cells were mixed in the wells of an assay plate with 5 pl of a mix of test compound at increasing concentrations and reference agonist for a final concentration corresponding to the historical EC80. The plates were then incubated 30 min at room temperature. After addition of the lysis buffer containing cAMP-d2 and anti-cAMP cryptate detection reagents, plates were incubated 1 -hour at room temperature, and fluorescence ratios were measured according to the manufacturer specification, with the HTRF kit.-62-169954513.1Quality Control for Compound Testing

[0183] On each day of experimentation and prior to the testing of compounds, reference compounds were tested at several concentrations in duplicate (n=2) to obtain a dose-response curve and an estimated EC50 and / or IC50 values.

[0184] Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session.

[0185] A session was considered as valid only if the reference value was found to be within a 0.5 logs interval from the historical value.

[0186] For replicate determinations, the maximum variability tolerated in the test was of + / -20% around the average of the replicates.Non-naturally occurring melanocortin analog grouping

[0187] Group A included non-naturally occurring melanocortin analogs A1 to A11 , all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 74). Group A melanocortin analogs also comprise an N-terminus other than Nle and dVal-dPro or dTle-dPro at the C-terminus. Group A non-naturally occurring melanocortin analogs are provided in Table 2.Table 2. Group A non-naturally occurring melanocortin analogs-63-169954513.1

[0188] Group B included non-naturally occurring melanocortin analogs B1 to B10, all of which are cyclic peptides comprising the motif His-p(F)dPhe-Arg-Trp (SEQ ID NO: 74). Group B melanocortin analogs also comprise Nle at the N-terminus. Certain Group B melanocortin analogs have a dVal-dPro C-terminus. Other Group B melanocortin analogs have a moiety other than dVal-dPro at the C-terminus. Some Group B melanocortin analogs have an extended N-terminus. Group B non-naturally occurring melanocortin analogs are provided in Table 3.Table 3. Group B non-naturally occurring melanocortin analogs

[0189] Group C included non-naturally occurring melanocortin analogs C1 to C10, all of which are cyclic peptides comprising the motif His-dPhe-Arg-Trp (SEQ ID NO: 75). Group C melanocortin analogs are cyclized via a lactam bond and include a dVal-dPro C-terminus and / or Nle, Arg, or dArg at the N-terminus. Group C non-naturally occurring melanocortin analogs are provided in Table 4.-64-169954513.1Table 4. Group C non-naturally occurring melanocortin analogsAgonist activity of melanocortin analogs on melanocortin 1 receptor and melanocortin 5 receptor

[0190] Administration of some non-naturally occurring melanocortin analogs activated melanocortin 1 receptor (MC1 R) and melanocortin 5 receptor (MC5R) activity, as measured by cAMP levels (Table 5).Table 5. Dose-response results of melanocortin analogs and control against the melanocortin 1 receptor (MC1 R) and the melanocortin 5 receptor-65-169954513.1= < 1 nM** = 1 nM to 100 nM* = > 100 nMA = > 80% EmaxB = 50 - 80% EmaxC = < 50% EmaxAaonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor

[0191] Administration of all the non-naturally occurring melanocortin analogs activated melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 6).Table 6. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in agonist mode-66-169954513.1** = 1 nM to 100 nM* = > 100 nMA = > 80% EmaxB = 50 ■ 80% EmaxC = < 50% EmaxAntagonist activity of melanocortin analogs on melanocortin 3 receptor and melanocortin 4 receptor-67-169954513.1

[0192] Administration of none of the non-naturally occurring melanocortin analogs substantially inhibited melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) activity, as measured by cAMP levels (Table 7).Table 7. Dose-response results of melanocortin analogs and control against the melanocortin 3 receptor (MC3R) and melanocortin 4 receptor (MC4R) in antagonist mode= < 1 nM** = 1 nM to 100 nM-68-169954513.1* = > 100 nMA = > 80% EmaxB = 50 - 80% EmaxC = < 50% EmaxAdditional Embodiments

[0193] Various embodiments of the present technology are set forth below in paragraphs

[0194] to

[0319] :

[0194] 1. A pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro- (F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0195] 2. A pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and no anionic amino acid residues, an osmolyte, a pH adjusting agent, and a buffer, wherein at least one of the one or more cationic amino acid residues is protonated and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0196] 3. A pharmaceutical composition comprising a cyclic non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.-69-169954513.1

[0197] 4. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and an isoelectric point of about 10 to about 12.5, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0198] 5. A pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, an osmolyte, a pH adjusting agent, and a buffer wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0199] 6. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having a cyclic region with an arginine residue positioned therein and an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier comprising a base and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0200] 7. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A): XI-RI-C(R2-R3-R4-R5-R6-R7)-YI (A), wherein:Ri is absent or is an amino acid or amino acid derivative;-70-169954513.1F is dPhe optionally substituted with F and / or Cl; at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a backbone or side chain linkage between R2 and R7, provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Om]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0201] 8. A pharmaceutical formulation comprising a peptide composition and a pharmaceutically acceptable carrier composition, the peptide composition comprising a non- naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in an aqueous solution, the pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac- Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu- His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0202] 9. A pharmaceutical composition comprising an osmolyte, a pH adjusting agent, a histidine buffer, and a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and comprising a cyclic region with an arginine residue positioned therein, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0203] 10. A pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of about 10 to about 12.5 and a pharmaceutically acceptable carrier comprising an osmolyte, a pH adjusting agent, and a-71 -169954513.1histidine buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A):XI-RI-C(R2-R3-R4-R5-R6-R7)-YI (A), wherein:Ri is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl; at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a backbone or side chain linkage between R2 and R7, provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); orAc-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0204] 11 . The pharmaceutical composition or pharmaceutical formulation of any one of embodiments 8-10, wherein the pharmaceutical composition or the pharmaceutical formulation has a pH of about 4.0 to about 6.5

[0205] 12. A pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by: combining an aqueous peptide composition comprising the agonist analog, and a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical formulation such that no local region of the analog has a pH equal to the isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined,-72-169954513.1wherein the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe- Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0206] 13. A pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by combining: an aqueous peptide composition comprising the non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, and a pharmaceutically acceptable carrier composition comprising a base and a buffer and having a pH of about 5.5 to about 7.0, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu- His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0207] 14. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 5, 8, and 13, wherein the non-naturally occurring melanocortin agonist analog has a cyclic region and the arginine residue is positioned in the cyclic region.

[0208] 15. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -8 and 1 1 -14, wherein the buffer comprises one or more of sodium acetate, histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes, TES, HEPES, DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine.

[0209] 16. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -8 and 11 -15, wherein the buffer is present at a concentration of about 10 mM to about 200 mM.

[0210] 17. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -8 and 11 -15, wherein the buffer comprises histidine.-73-169954513.1

[0211] 18. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 9, 10, and 17, wherein the histidine buffer comprises about 5 mM to about 150 mM histidine.

[0212] 19. The pharmaceutical composition or the pharmaceutical formulation of embodiment 14 or 17, wherein the histidine buffer comprises about 10 mM to about 25 mM histidine.

[0213] 20. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -8 and 11 -15, wherein the buffer comprises sodium acetate.

[0214] 21. The pharmaceutical composition or the pharmaceutical formulation of embodiment 20, wherein the sodium acetate buffer comprises about 5 mM to about 150 mM sodium acetate.

[0215] 22. The pharmaceutical composition or the pharmaceutical formulation of embodiment 20 or 21 , wherein the sodium acetate buffer comprises about 10 mM to about 25 mM sodium acetate.

[0216] 23. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -22, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 130 mg / mL.

[0217] 24. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -23, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 50 mg / mL.

[0218] 25. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 12.5 mg / mL.

[0219] 26. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 25 mg / mL.-74-169954513.1

[0220] 27. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 50 mg / mL.

[0221] 28. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -23, wherein the osmolyte is selected from the group consisting of a sugar or derivative thereof, a glycerol, a glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, and PEG.

[0222] 29. The pharmaceutical composition or pharmaceutical formulation of embodiment 28, wherein the sugar or the derivative thereof is a sugar alcohol.

[0223] 30. The pharmaceutical composition or pharmaceutical formulation of embodiment 29, where the sugar alcohol is mannitol.

[0224] 31. The pharmaceutical composition or pharmaceutical formulation of embodiment 30, wherein the mannitol is present in an amount of about 20 mg / mL to about 40 mg / mL.

[0225] 32. The pharmaceutical composition or pharmaceutical formulation of embodiment 30, wherein the mannitol is present in an amount of about 25 mg / mL.

[0226] 33. The pharmaceutical composition or pharmaceutical formulation of embodiment 30, wherein the mannitol is present in an amount of about 27.5 mg / mL.

[0227] 34. The pharmaceutical composition or pharmaceutical formulation of embodiment 30, wherein the mannitol is present in an amount of about 35 mg / mL.

[0228] 35. The pharmaceutical composition or pharmaceutical formulation of embodiment 30, wherein the mannitol is present in an amount of about 37.5 mg / mL.

[0229] 36. The pharmaceutical composition of formulation of any one of embodiments 1 -35, wherein the pH adjusting agent is present in an amount of about 0.01 mg / mL to about 10 mg / mL.

[0230] 37. The pharmaceutical composition or formulation of any one of embodiments 1 -36, wherein the pH adjusting agent is a base.-75-169954513.1

[0231] 38. The pharmaceutical composition or formulation of embodiment 37, wherein the base is sodium hydroxide.

[0232] 39. The pharmaceutical composition or formulation of embodiment 38, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

[0233] 40. The pharmaceutical composition or formulation of embodiment 38 or39, wherein the sodium hydroxide is present in an amount of about 0.4 mg / mL.

[0234] 41 . The pharmaceutical composition or formulation of embodiment 38 or39, wherein the sodium hydroxide is present in an amount of about 1 .2 mg / mL.

[0235] 42. The pharmaceutical composition or formulation of embodiment 38 or39, wherein the sodium hydroxide is present in an amount of about 1 .6 mg / mL.

[0236] 43. The pharmaceutical composition or formulation of embodiment 37, wherein the base is histidine.

[0237] 44. The pharmaceutical composition or formulation of embodiment 43, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

[0238] 45. The pharmaceutical composition or formulation of any one of embodiments 1 -35, wherein the pH adjusting agent is an acid.

[0239] 46. The pharmaceutical composition or formulation of embodiment 45, wherein the acid is glacial acetic acid.

[0240] 47. The pharmaceutical composition or formulation of embodiment 46, wherein the glacial acetic acid is present in an amount of about 0.01 mg / mL to about 5.0 mg / mL.

[0241] 48. The pharmaceutical composition or formulation of any one of embodiments 1 -47, further comprising a surfactant.

[0242] 49. The pharmaceutical composition or formulation of embodiment 48, wherein the surfactant is selected from an alkyl-carboxylate-fatty acid salt, a sulfate, a-76-169954513.1sulfonate, a phosphate ester, a quaternary ammonium surfactant, a pyridinium surfactant, a polyol ester, a polyoxyethylene ester, a poloxamer, a phospholipid, and a betaine.

[0243] 50. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -49, further comprising substantially no calcium ions.

[0244] 51 . The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 1 -50, further comprising substantially no metal ions.

[0245] 52. The pharmaceutical composition or formulation of any one of embodiments 1 -50, further comprising a preservative.

[0246] 53. The pharmaceutical composition or formulation of embodiment 52, wherein the preservative is selected from the group consisting of m-cresol, phenol, and benzyl alcohol.

[0247] 54. The pharmaceutical composition or formulation of embodiment 52 or53, wherein the preservative is present in an amount of about 0.1 wt% to about 1.0 wt%, relative to a total weight of the composition or formulation.

[0248] 55. A method of producing a pharmaceutical composition of a non-naturally occurring melanocortin agonist analog, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 with a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 and comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0249] 56. A method of producing a pharmaceutical formulation having a pH of about 4.0 to about 6.5, the method comprising: combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer; and-77-169954513.1preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical composition such that no local region has a pH that is equal to the isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein: the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1.0.

[0250] 57. A method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of the non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog has an arginine residue and an isoelectric point of at least about 10 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 11 .0

[0251] 58. A method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog, the method comprising: providing a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a histidine buffer; dissolving a non-naturally melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in water to provide an aqueous peptide composition; and-78-169954513.1adding the pharmaceutically acceptable carrier composition to the aqueous peptide composition while mixing to maintain dissolution of the non-naturally occurring melanocortin agonist analog, wherein the pharmaceutical formulation has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro- (F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

[0252] 59. The method of any one of embodiment 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition through a semi-permeable, size-selective membrane.

[0253] 60. The method of embodiment 59, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises tangential flow filtration.

[0254] 61 . The method of any one of embodiment 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises adding the pharmaceutically acceptable carrier composition to the aqueous peptide composition.

[0255] 62. The method of any one of embodiment 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises adding the aqueous peptide composition to the pharmaceutically acceptable carrier composition.

[0256] 63. The method of any one of embodiments 55-62, wherein the pharmaceutical composition contains substantially no precipitated non-naturally occurring melanocortin agonist analog.

[0257] 64. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 55-57 and 56-62, wherein the buffer comprises one or more of sodium acetate, histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes,-79-169954513.1TES, HEPES, DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine.

[0258] 65. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 55-57 and 56-63, wherein the buffer is present at a concentration of about 10 mM to about 200 mM.

[0259] 66. The method of any one of embodiments 55-57 and 56-64, wherein the buffer comprises histidine.

[0260] 67. The method of embodiment 66, wherein the histidine buffer comprises about 5 mM to about 150 mM histidine.

[0261] 68. The method of embodiment 66 or 67, wherein the histidine buffer comprises about 10 mM to about 25 mM histidine.

[0262] 69. The method of any one of embodiments 55-57 and 56-64, wherein the buffer comprises sodium acetate.

[0263] 70. The method of embodiment 69, wherein the sodium acetate buffer comprises about 5 mM to about 150 mM sodium acetate.

[0264] 71 . The method of embodiment 69 or 70, wherein the sodium acetate buffer comprises about 10 mM to about 25 mM sodium acetate.

[0265] 72. The method of any one of embodiments 55-71 , wherein the aqueous peptide composition comprises the non-naturally occurring melanocortin agonist analog at a concentration of about 10 mg / mL to about 130 mg / mL.

[0266] 73. The pharmaceutical composition or the pharmaceutical formulation of any one of embodiments 55-72, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 50 mg / mL.

[0267] 74. The method of any one of embodiments 55-73, wherein the non- naturally occurring melanocortin agonist analog is present at a concentration of about 12.5 mg / mL.-80-169954513.1

[0268] 75. The method of any one of embodiments 55-73, wherein the non- naturally occurring melanocortin agonist analog is present at a concentration of about 25 mg / mL.

[0269] 76. The method of any one of embodiments 55-73, wherein the non- naturally occurring melanocortin agonist analog is present at a concentration of about 50 mg / mL.

[0270] 77. The method of any one of embodiments 55-76, wherein the osmolyte is selected from the group consisting of a sugar or derivative thereof, a glycerol, a glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, and PEG.

[0271] 78. The method of embodiment 77, wherein the sugar or the derivative thereof is a sugar alcohol.

[0272] 79. The method of embodiment 78, wherein the sugar alcohol is mannitol.

[0273] 80. The method of embodiment 79, wherein the mannitol is present in an amount of about 20 mg / mL to about 40 mg / mL.

[0274] 81 . The method of embodiment 80, wherein the mannitol is present in an amount of about 25 mg / mL.

[0275] 82. The method of embodiment 80, wherein the mannitol is present in an amount of about 27.5 mg / mL.

[0276] 83. The method of embodiment 80, wherein the mannitol is present in an amount of about 35 mg / mL.

[0277] 84. The method of embodiment 80, wherein the mannitol is present in an amount of about 37.5 mg / mL.

[0278] 85. The pharmaceutical composition of formulation of any one of embodiments 1 -84, wherein the pH adjusting agent is present in an amount of about 0.01 mg / mL to about 10 mg / mL.

[0279] 86. The method of any one of embodiments 55-85, wherein the pH adjusting agent is a base.-81 -169954513.1

[0280] 87. The method of embodiment 86, wherein the base is sodium hydroxide.

[0281] 88. The method of embodiment 87, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

[0282] 89. The method of embodiment 87 or 88, wherein the sodium hydroxide is present in an amount of about 0.4 mg / mL.

[0283] 90. The method of embodiment 87 or 88, wherein the sodium hydroxide is present in an amount of about 1 .2 mg / mL.

[0284] 91 . The method of embodiment 87 or 88, wherein the sodium hydroxide is present in an amount of about 1 .6 mg / mL.

[0285] 92. The method of embodiment 86, wherein the base is histidine.

[0286] 93. The method of embodiment 92, wherein the histidine is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

[0287] 94. The method of any one of embodiments 1 -84, wherein the pH adjusting agent is an acid.

[0288] 95. The method of embodiment 94, wherein the acid is glacial acetic acid.

[0289] 96. The method of embodiment 95, wherein the glacial acetic acid is present in an amount of about 0.01 mg / mL to about 5.0 mg / mL.

[0290] 97. The method of any one of embodiments 55-96, wherein the pharmaceutical composition or formulation further comprises a surfactant.

[0291] 98. The method of embodiment 97, wherein the surfactant is selected from an alkyl-carboxylate-fatty acid salt, a sulfate, a sulfonate, a phosphate ester, a quaternary ammonium surfactant, a pyridinium surfactant, a polyol ester, a polyoxyethylene ester, a poloxamer, a phospholipid, and a betaine.

[0292] 99. The method of any one of embodiments 55-98, wherein the pharmaceutically acceptable carrier composition comprises substantially no calcium ions.

[0293] 100. The method any one of embodiments 55-99, wherein the pharmaceutically acceptable carrier composition comprises substantially no metal ions.-82-169954513.1

[0294] 101. The method of any one of embodiments 55-100, wherein the pharmaceutical composition or formulation further comprises a preservative.

[0295] 102. The method of embodiment 101 , wherein the preservative is selected from the group consisting of m-cresol, phenol, and benzyl alcohol.

[0296] 103. The method of embodiment 101 or 102, wherein the preservative is present in the pharmaceutical composition or formulation in an amount of about 0.1 wt% to about 1 .0 wt%, relative to a total weight of the composition or formulation.

[0297] 104. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -103, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3- Y4( I) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Rhe-Rhe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via:-83-169954513.1a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R4is dPhe, then (i) R1is Asp and R2is Phe-Phe, (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal, and when Y1-Y4are absent, then R3is dAla-His.

[0298] 105. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -104, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via:-84-169954513.1a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 10);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);-85-169954513.1Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.

[0299] 106. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -105, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4(I A) , wherein:X1is absent or norleucine (Nle);-86-169954513.1R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R4is dPhe, then (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, and when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal.

[0300] 107. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -106, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);-87-169954513.1R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);-88-169954513.1Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.

[0301] 108. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -107, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3- Y4( I A(i)) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);-89-169954513.1Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the C-terminus is amidated, and R1is not dArg when Y1is dVal.

[0302] 109. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -108, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);-90-169954513.1Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.

[0303] 110. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -105, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R1is Arg, then R3is dAla-His, when R1is Nle, then R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when Y1-Y4are absent, then R3is dAla-His.-91 -169954513.1

[0304] 11 1. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -105 and 1 10, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );-92-169954513.1Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 16);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 18);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 20);Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.

[0305] 112. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -11 1 , wherein R3is His.-93-169954513.1

[0306] 113. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -112, wherein R2is Asp or Glu, R5is Arg, R6is Trp, and R7is Lys or Orn.

[0307] 114. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 13, wherein Y1is dVal, dPro, or dTle, and Y2is dVal or dPro.

[0308] 115. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -114, wherein R1is Nle.

[0309] 116. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 15, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 43);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 44);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 45);Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 46); andAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.

[0310] 117. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -114, wherein R1is selected from Arg, dArg, Lys, dLys, His, or dHis

[0311] 118. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 14 and 117, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 48);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 49);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 50);-94-169954513.1Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 51 ); andAc-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 52), wherein c represents cyclization through R2and R7via a lactam bond.

[0312] 119. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 14 and 117, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 53);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 54);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 55);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 56);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 57); andAc-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 58), wherein c represents cyclization through R2and R7via a lactam bond.

[0313] 120. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -113, wherein the N-terminus is extended and / or the C-terminus comprises a moiety other than dVal-dPro.

[0314] 121. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 13 and 120, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 59);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 60);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 61 );Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 63);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 64);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 65); and-95-169954513.1Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 66), wherein c represents cyclization through R2and R7via a lactam bond.

[0315] 122. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 11 , wherein R3is an amino acid other than His or R5is an amino acid other than Arg.

[0316] 123. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 1 1 and 122, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 62);Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 72); orAc-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a lactam bond.

[0317] 124. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -11 1 , wherein R3is a dipeptide comprising His.

[0318] 125. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -11 1 and 124, wherein R3is a Ala-His or Pro-His.

[0319] 126. The pharmaceutical composition, pharmaceutical formulation, or method of any one of embodiments 1 -1 1 1 , 124, and 125, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 71 );Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 67);Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 68);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 69); andAc-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 70), wherein c represents cyclization through R2and R7via a lactam bond.

[0320] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various-96-169954513.1modifications may be made without deviating from the scope of the invention. Accordingly, the invention is not limited except as by the appended claims.-97-169954513.1

Claims

1. CLAIMS l / We claim:

1. A pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro- (F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

2. A pharmaceutical composition having a pH of about 4.0 to about 6.5, comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and no anionic amino acid residues, an osmolyte, a pH adjusting agent, and a buffer, wherein at least one of the one or more cationic amino acid residues is protonated and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

3. A pharmaceutical composition comprising a cyclic non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue, an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

4. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having at least one cationic amino acid residue and an isoelectric point of about 10-98-169954513.1to about 12.5, an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

5. A pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, an osmolyte, a pH adjusting agent, and a buffer wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

6. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having a cyclic region with an arginine residue positioned therein and an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier comprising a base and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle- c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

7. A pharmaceutical composition having a pH of about 4.0 to about 6.5, the pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A):XI-RI-C(R2-R3-R4-R5-R6-R7)-YI (A), wherein:Ri is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl;-99-169954513.1at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a backbone or side chain linkage between R2 and R7, provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

8. A pharmaceutical formulation comprising a peptide composition and a pharmaceutically acceptable carrier composition, the peptide composition comprising a non- naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in an aqueous solution, the pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac- Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu- His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

9. A pharmaceutical composition comprising an osmolyte, a pH adjusting agent, a histidine buffer, and a non-naturally occurring melanocortin agonist analog having an isoelectric point of at least about 10 and comprising a cyclic region with an arginine residue positioned therein, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

10. A pharmaceutical composition comprising a non-naturally occurring melanocortin agonist analog having an isoelectric point of about 10 to about 12.5 and a-100-169954513.1pharmaceutically acceptable carrier comprising an osmolyte, a pH adjusting agent, and a histidine buffer, wherein the non-naturally occurring melanocortin agonist analog comprises moiety (A):XI-RI-C(R2-R3-R4-R5-R6-R7)-YI (A), wherein:Ri is absent or is an amino acid or amino acid derivative;R4 is dPhe optionally substituted with F and / or Cl; at least one of R2-R7 is a cationic amino acid residue;Xi is an optionally present N-terminus;Y1 is a C-terminus comprising one to four amino acids or amino acid derivatives; and the non-naturally occurring melanocortin analog is optionally cyclized via a backbone or side chain linkage between R2 and R7, provided that moiety (A) is not:Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.1 1 . The pharmaceutical composition or pharmaceutical formulation of any one of claims 8-10, wherein the pharmaceutical composition or the pharmaceutical formulation has a pH of about 4.0 to about 6.5.

12. A pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by: combining an aqueous peptide composition comprising the agonist analog, and a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical formulation such that no local region of the analog has a pH equal to the-101 -169954513.1isoelectric point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe- Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]- dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

13. A pharmaceutical formulation having a pH of about 4.0 to about 6.5 and comprising a non-naturally occurring melanocortin agonist analog, the formulation produced by combining: an aqueous peptide composition comprising the non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of at least about 10, and a pharmaceutically acceptable carrier composition comprising a base and a buffer and having a pH of about 5.5 to about 7.0, wherein the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu- His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

14. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 5, 8, and 13, wherein the non-naturally occurring melanocortin agonist analog has a cyclic region and the arginine residue is positioned in the cyclic region.

15. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -8 and 11 -14, wherein the buffer comprises one or more of sodium acetate, histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes, TES, HEPES, DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine.-102-169954513.

116. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -8 and 1 1 -15, wherein the buffer is present at a concentration of about 10 mM to about 200 mM.

17. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -8 and 1 1 -15, wherein the buffer comprises histidine.

18. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 9, 10, and 17, wherein the histidine buffer comprises about 5 mM to about 150 mM histidine.

19. The pharmaceutical composition or the pharmaceutical formulation of claim 14 or 17, wherein the histidine buffer comprises about 10 mM to about 25 mM histidine.

20. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -8 and 1 1 -15, wherein the buffer comprises sodium acetate.21 . The pharmaceutical composition or the pharmaceutical formulation of claim 20, wherein the sodium acetate buffer comprises about 5 mM to about 150 mM sodium acetate.

22. The pharmaceutical composition or the pharmaceutical formulation of claim 20 or 21 , wherein the sodium acetate buffer comprises about 10 mM to about 25 mM sodium acetate.

23. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -22, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 130 mg / mL.-103-169954513.

124. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -23, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 50 mg / mL.

25. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 12.5 mg / mL.

26. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 25 mg / mL.

27. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -24, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 50 mg / mL.

28. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -23, wherein the osmolyte is selected from the group consisting of a sugar or derivative thereof, a glycerol, a glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, and PEG.

29. The pharmaceutical composition or pharmaceutical formulation of claim 28, wherein the sugar or the derivative thereof is a sugar alcohol.

30. The pharmaceutical composition or pharmaceutical formulation of claim 29, where the sugar alcohol is mannitol.

31. The pharmaceutical composition or pharmaceutical formulation of claim 30, wherein the mannitol is present in an amount of about 20 mg / mL to about 40 mg / mL.-104-169954513.

132. The pharmaceutical composition or pharmaceutical formulation of claim 30, wherein the mannitol is present in an amount of about 25 mg / mL.

33. The pharmaceutical composition or pharmaceutical formulation of claim 30, wherein the mannitol is present in an amount of about 27.5 mg / mL.

34. The pharmaceutical composition or pharmaceutical formulation of claim 30, wherein the mannitol is present in an amount of about 35 mg / mL.

35. The pharmaceutical composition or pharmaceutical formulation of claim 30, wherein the mannitol is present in an amount of about 37.5 mg / mL.

36. The pharmaceutical composition of formulation of any one of claims 1 -35, wherein the pH adjusting agent is present in an amount of about 0.01 mg / mL to about 10 mg / mL.

37. The pharmaceutical composition or formulation of any one of claims 1 -36, wherein the pH adjusting agent is a base.

38. The pharmaceutical composition or formulation of claim 37, wherein the base is sodium hydroxide.

39. The pharmaceutical composition or formulation of claim 38, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

40. The pharmaceutical composition or formulation of claim 38 or 39, wherein the sodium hydroxide is present in an amount of about 0.4 mg / mL.41 . The pharmaceutical composition or formulation of claim 38 or 39, wherein the sodium hydroxide is present in an amount of about 1 .2 mg / mL.-105-169954513.

142. The pharmaceutical composition or formulation of claim 38 or 39, wherein the sodium hydroxide is present in an amount of about 1 .6 mg / mL.

43. The pharmaceutical composition or formulation of claim 37, wherein the base is histidine.

44. The pharmaceutical composition or formulation of claim 43, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

45. The pharmaceutical composition or formulation of any one of claims 1 -35, wherein the pH adjusting agent is an acid.

46. The pharmaceutical composition or formulation of claim 45, wherein the acid is glacial acetic acid.

47. The pharmaceutical composition or formulation of claim 46, wherein the glacial acetic acid is present in an amount of about 0.01 mg / mL to about 5.0 mg / mL.

48. The pharmaceutical composition or formulation of any one of claims 1 -47, further comprising a surfactant.

49. The pharmaceutical composition or formulation of claim 48, wherein the surfactant is selected from an alkyl-carboxylate-fatty acid salt, a sulfate, a sulfonate, a phosphate ester, a quaternary ammonium surfactant, a pyridinium surfactant, a polyol ester, a polyoxyethylene ester, a poloxamer, a phospholipid, and a betaine.

50. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -49, further comprising substantially no calcium ions.-106-169954513.151 . The pharmaceutical composition or the pharmaceutical formulation of any one of claims 1 -50, further comprising substantially no metal ions.

52. The pharmaceutical composition or formulation of any one of claims 1 -50, further comprising a preservative.

53. The pharmaceutical composition or formulation of claim 52, wherein the preservative is selected from the group consisting of m-cresol, phenol, and benzyl alcohol.

54. The pharmaceutical composition or formulation of claim 52 or 53, wherein the preservative is present in an amount of about 0.1 wt% to about 1 .0 wt%, relative to a total weight of the composition or formulation.

55. A method of producing a pharmaceutical composition of a non-naturally occurring melanocortin agonist analog, the method comprising combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 with a pharmaceutically acceptable carrier composition having a pH of about 5.5 to about 11 .0 and comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the pharmaceutical composition has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

56. A method of producing a pharmaceutical formulation having a pH of about 4.0 to about 6.5, the method comprising: combining an aqueous peptide composition of a non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer; and preventing aggregation of the agonist analog by maintaining a local pH of the pharmaceutical composition such that no local region has a pH that is equal to the isoelectric-107-169954513.1point of the agonist analog while the aqueous peptide composition and the pharmaceutically acceptable carrier composition are being combined, wherein: the agonist analog has at least one cationic residue and an isoelectric point of about 10 to about 12.5 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 1 1.0.

57. A method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog having a pH of about 4.0 to about 6.5, the method comprising combining an aqueous peptide composition of the non-naturally occurring melanocortin agonist analog with a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a buffer, wherein the non-naturally occurring melanocortin agonist analog has an arginine residue and an isoelectric point of at least about 10 and does not comprise a sequence of: Ac-Nle-c[Glu-Pro-(F)dPhe-Arg-Trp- Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg-Trp-Orn]-dVal- dPro-NH2(SEQ ID NO: 2), wherein c represents cyclization via a lactam bond, and the pharmaceutically acceptable carrier composition has a pH of about 5.5 to about 11 .0.

58. A method of producing a pharmaceutical formulation of a non-naturally occurring melanocortin agonist analog, the method comprising: providing a pharmaceutically acceptable carrier composition comprising an osmolyte, a pH adjusting agent, and a histidine buffer; dissolving a non-naturally melanocortin agonist analog having an arginine residue and an isoelectric point of about 10 to about 12.5 in water to provide an aqueous peptide composition; and adding the pharmaceutically acceptable carrier composition to the aqueous peptide composition while mixing to maintain dissolution of the non-naturally occurring melanocortin agonist analog,-108-169954513.1wherein the pharmaceutical formulation has a pH of about 4.0 to about 6.5 and the non-naturally occurring agonist analog does not comprise a sequence of: Ac-Nle-c[Glu-Pro- (F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 5); or Ac-Nle-c[Glu-His-p(F)dPhe-Arg- Trp-Orn]-dVal-dPro-NH2 (SEQ ID NO: 2), wherein c represents cyclization via a lactam bond.

59. The method of any one of claim 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition through a semi-permeable, size-selective membrane.

60. The method of claim 59, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises tangential flow filtration.61 . The method of any one of claim 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises adding the pharmaceutically acceptable carrier composition to the aqueous peptide composition.

62. The method of any one of claim 55-57, wherein combining the aqueous peptide composition and the pharmaceutically acceptable carrier composition comprises adding the aqueous peptide composition to the pharmaceutically acceptable carrier composition.

63. The method of any one of claims 55-62, wherein the pharmaceutical composition contains substantially no precipitated non-naturally occurring melanocortin agonist analog.

64. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 55-57 and 56-62, wherein the buffer comprises one or more of sodium acetate, histidine, Tris, arginine, MES, ADA, PIPES, ACES, MOPSO, MOPS, Bes, TES, HEPES,-109-169954513.1DIPSO, TAPSO, POPSO, HEPPSO, HEPPS, TPAS, acetoamidoglycine, glycinamide, glycylglycine, tricine, and bicine.

65. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 55-57 and 56-63, wherein the buffer is present at a concentration of about 10 mM to about 200 mM.

66. The method of any one of claims 55-57 and 56-64, wherein the buffer comprises histidine.

67. The method of claim 66, wherein the histidine buffer comprises about 5 mM to about 150 mM histidine.

68. The method of claim 66 or 67, wherein the histidine buffer comprises about 10 mM to about 25 mM histidine.

69. The method of any one of claims 55-57 and 56-64, wherein the buffer comprises sodium acetate.

70. The method of claim 69, wherein the sodium acetate buffer comprises about 5 mM to about 150 mM sodium acetate.71 . The method of claim 69 or 70, wherein the sodium acetate buffer comprises about 10 mM to about 25 mM sodium acetate.

72. The method of any one of claims 55-71 , wherein the aqueous peptide composition comprises the non-naturally occurring melanocortin agonist analog at a concentration of about 10 mg / mL to about 130 mg / mL.-110-169954513.

173. The pharmaceutical composition or the pharmaceutical formulation of any one of claims 55-72, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 10 mg / mL to about 50 mg / mL.

74. The method of any one of claims 55-73, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 12.5 mg / mL.

75. The method of any one of claims 55-73, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 25 mg / mL.

76. The method of any one of claims 55-73, wherein the non-naturally occurring melanocortin agonist analog is present at a concentration of about 50 mg / mL.

77. The method of any one of claims 55-76, wherein the osmolyte is selected from the group consisting of a sugar or derivative thereof, a glycerol, a glycerin, a gelatin, a propylene glycol, a propylparaben, PVP, PLGA, and PEG.

78. The method of claim 77, wherein the sugar or the derivative thereof is a sugar alcohol.

79. The method of claim 78, wherein the sugar alcohol is mannitol.

80. The method of claim 79, wherein the mannitol is present in an amount of about 20 mg / mL to about 40 mg / mL.81 . The method of claim 80, wherein the mannitol is present in an amount of about 25 mg / mL.

82. The method of claim 80, wherein the mannitol is present in an amount of about 27.5 mg / mL.-111 -169954513.

183. The method of claim 80, wherein the mannitol is present in an amount of about 35 mg / mL.

84. The method of claim 80, wherein the mannitol is present in an amount of about 37.5 mg / mL.

85. The pharmaceutical composition of formulation of any one of claims 1 -84, wherein the pH adjusting agent is present in an amount of about 0.01 mg / mL to about 10 mg / mL.

86. The method of any one of claims 55-85, wherein the pH adjusting agent is a base.

87. The method of claim 86, wherein the base is sodium hydroxide.

88. The method of claim 87, wherein the sodium hydroxide is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

89. The method of claim 87 or 88, wherein the sodium hydroxide is present in an amount of about 0.4 mg / mL.

90. The method of claim 87 or 88, wherein the sodium hydroxide is present in an amount of about 1 .2 mg / mL.91 . The method of claim 87 or 88, wherein the sodium hydroxide is present in an amount of about 1 .6 mg / mL.

92. The method of claim 86, wherein the base is histidine.-112-169954513.

193. The method of claim 92, wherein the histidine is present in an amount of about 0.01 mg / mL to about 5.0 mg / L.

94. The method of any one of claims 1 -84, wherein the pH adjusting agent is an acid.

95. The method of claim 94, wherein the acid is glacial acetic acid.

96. The method of claim 95, wherein the glacial acetic acid is present in an amount of about 0.01 mg / mL to about 5.0 mg / mL.

97. The method of any one of claims 55-96, wherein the pharmaceutical composition or formulation further comprises a surfactant.

98. The method of claim 97, wherein the surfactant is selected from an alkyl- carboxylate-fatty acid salt, a sulfate, a sulfonate, a phosphate ester, a quaternary ammonium surfactant, a pyridinium surfactant, a polyol ester, a polyoxyethylene ester, a poloxamer, a phospholipid, and a betaine.

99. The method of any one of claims 55-98, wherein the pharmaceutically acceptable carrier composition comprises substantially no calcium ions.

100. The method any one of claims 55-99, wherein the pharmaceutically acceptable carrier composition comprises substantially no metal ions.

101. The method of any one of claims 55-100, wherein the pharmaceutical composition or formulation further comprises a preservative.

102. The method of claim 101 , wherein the preservative is selected from the group consisting of m-cresol, phenol, and benzyl alcohol.-113-169954513.1103. The method of claim 101 or 102, wherein the preservative is present in the pharmaceutical composition or formulation in an amount of about 0.1 wt% to about 1 .0 wt%, relative to a total weight of the composition or formulation.

104. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -103, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4( I) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that:-114-169954513.1when R3is Pro-His, then R2is Phe-Phe, when R4is dPhe, then (i) R1is Asp and R2is Phe-Phe, (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal, and when Y1-Y4are absent, then R3is dAla-His.

105. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -104, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (I), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), D-histidine (dHis), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or selected from the group consisting of D-valine (dVal), D-proline (dPro), and D-tertleucine (dTle);Y2is absent or selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn,-115-169954513.1provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-Hyp-NH2(SEQ ID NO: 10);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);-116-169954513.1Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.

106. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -105, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA):X1- R1- R2- R3- R4- R5- R6- R7- Y1-Y2- Y3-Y4(I A) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);-117-169954513.1R2is aspartic acid (Asp) or glutamic acid (Glu);R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R4is dPhe, then (ii) R1is Arg or dArg and R3is dAla-His, or (iii) R1is Nle, R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, and when R4is p(F)dPhe, then R3is His, the C-terminus is amidated, and R1is not dArg when Y1is dVal.

107. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -106, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp) or glutamic acid (Glu);-118-169954513.1R3is selected from the group consisting of histidine (His), D-histidine (dHis), -alanylhistidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe) or para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Lys-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 15);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-His-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 17);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Lys-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 19);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-His-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 21 );Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);-119-169954513.1Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 26);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-dHis-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 31 );Ac-Nle-c[Asp-Gln-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 32);Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.

108. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -107, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)):X1- R1- R2- R3-R4- R5- R6- R7-Y1-Y2-Y3-Y4(I A(i) ) , wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);-120-169954513.1Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the C-terminus is amidated, and R1is not dArg when Y1is dVal.

109. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -108, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IA(i)), wherein:X1is absent or norleucine (Nle);R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), lysine (Lys), D-lysine (dLys), histidine (His), and D-histidine (dHis);R2is aspartic acid (Asp);R3is histidine (His);R4is para-fluoro-D-phenylalanine (p(F)dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is selected from the group consisting of D-valine (dVal), D-proline (dPro), and D- tertleucine (dTle);Y2is selected from the group consisting of dVal, dPro, and dTle;Y3is absent, dVal, or dPro;Y4is absent or dPro; and the non-naturally occurring melanocortin analog is cyclized via a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:-121 -169954513.1Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 33);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 34); andAc-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 35), wherein c represents cyclization via a lactam bond.1 10. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -105, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB):R1-R2-R3-R4-R5-R6-R7-Y1-Y2(IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that: when R3is Pro-His, then R2is Phe-Phe, when R1is Arg, then R3is dAla-His,-122-169954513.1when R1is Nle, then R3is Gin, dHis, or His, Y3-Y4are absent, and either (a) R2is Glu or (ii) R2is Asp, R5is Arg, R7is Lys, and the C-terminus is amidated, when Y1-Y4are absent, then R3is dAla-His.1 1 1. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -105 and 110, wherein the non-naturally occurring melanocortin analog comprises a sequence of Formula (IB), wherein:R1is selected from the group consisting of Nle, arginine (Arg), D-arginine (dArg), and aspartic acid (Asp);R2is selected from the group consisting of Asp, glutamic acid (Glu), and phenylalanylphenylalanine (Phe-Phe);R3is selected from the group consisting of histidine (His), D-histidine (dHis), prolylhistidine (Pro-His), D-alanyl-histidine (dAla-His), and glutamine (Gin);R4is D-phenylalanine (dPhe);R5is Arg or His;R6is Trp;R7is Lys or ornithine (Orn);Y1is absent or D-valine (dVal);Y2is absent or D-proline (dPro); and the non-naturally occurring melanocortin analog is cyclized via: a lactam bond between R1or R2and R7, when R1or R2is Asp and R7is Lys or Orn; or a lactam bond between R2and R7, when R2is Glu, R5is His, and R7is Orn, provided that the non-naturally occurring melanocortin agonist does not comprise a sequence selected from the group consisting of:Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Nle-c[Asp-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 8);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 6);-123-169954513.1Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 9);Ac-Nle-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 7);Ac-Arg-c[Glu-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 1 1 );Ac-Arg-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 12);Ac-Nle-c[Asp-Pro-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 13);Ac-Arg-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 14);Ac-Asp-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 16);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 18);Ac-Asp-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 20);Ac-Arg-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 22);Ac-Arg-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 23);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 24);Ac-Arg-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 25);Ac-Nle-c[Asp-His-dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 27);Ac-Nle-c[Asp-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 28);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-OH (SEQ ID NO: 29);Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 30);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 36);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 37);Ac-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-NH2(SEQ ID NO: 38);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 39);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 40); andAc-Arg-c[Asp-His-dPhe-Arg-Trp-Lys]-OH (SEQ ID NO: 41 ), wherein c represents cyclization via a lactam bond.-124-169954513.11 12. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 , wherein R3is His.1 13. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -1 12, wherein R2is Asp or Glu, R5is Arg, R6is Trp, and R7is Lys or Orn.1 14. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -113, wherein Y1is dVal, dPro, or dTle, and Y2is dVal or dPro.1 15. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -114, wherein R1is Nle.1 16. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -115, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dPro-dVal-NH2(SEQ ID NO: 43);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 44);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 45);Ac-Nle-c[Glu-His-dPhe-His-Trp-Orn]-dVal-dPro-NH2(SEQ ID NO: 46); andAc-Nle-c[Asp-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 47), wherein c represents cyclization through R2and R7via a lactam bond.1 17. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -114, wherein R1is selected from Arg, dArg, Lys, dLys, His, or dHis.1 18. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -114 and 1 17, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:-125-169954513.1Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 48);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 49);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 50);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 51 ); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 52), wherein c represents cyclization through R2and R7via a lactam bond.1 19. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -114 and 1 17, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-dArg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 53);Ac-Arg-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 54);Ac-Lys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 55);Ac-dLys-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 56);Ac-His-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 57); and Ac-dHis-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 58), wherein c represents cyclization through R2and R7via a lactam bond.

120. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -1 13, wherein the N-terminus is extended and / or the C-terminus comprises a moiety other than dVal-dPro.

121. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -113 and 120, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 59);Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 60);-126-169954513.1Ac-Nle-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 61 );Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dTle-dVal-NH2(SEQ ID NO: 63);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dVal-dVal-dVal-dPro-NH2(SEQ ID NO: 64);Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dPro-dVal-dPro-NH2(SEQ ID NO: 65); and Ac-Nle-c[Asp-His-p(F)dPhe-Arg-Trp-Lys]-dTle-dPro-NH2(SEQ ID NO: 66), wherein c represents cyclization through R2and R7via a lactam bond.

122. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 , wherein R3is an amino acid other than His or R5is an amino acid other than Arg.

123. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 and 122, wherein the sequence of any one of Formulae (l)-(IB) is selected from the group consisting of:Ac-Nle-c[Asp-His-p(F)dPhe-His-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 62);Ac-Nle-c[Asp-dHis-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 72); or Ac-Nle-c[Asp-Gln-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 73), wherein c represents cyclization through R2and R7via a lactam bond.

124. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 , wherein R3is a dipeptide comprising His.

125. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 and 124, wherein R3is a Ala-His or Pro-His.

126. The pharmaceutical composition, pharmaceutical formulation, or method of any one of claims 1 -11 1 , 124, and 125, wherein the sequence of any one of Formulae (I)- (IB) is selected from the group consisting of:-127-169954513.1Ac-Nle-c[Asp-Phe-Phe-Pro-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 71 );Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-NH2 (SEQ ID NO: 67);Ac-Nle-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 68);Ac-Arg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2 (SEQ ID NO: 69); andAc-dArg-c[Asp-dAla-His-dPhe-Arg-Trp-Lys]-dVal-dPro-NH2(SEQ ID NO: 70), wherein c represents cyclization through R2and R7via a lactam bond.-128-169954513.1

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