Dermatological compositions and uses thereof

Abstract

Dermatological compositions comprising an amphiphilic peptide, a derivative or a salt thereof are provided, which are particularly useful as dermal fillers and for inducing soft tissue repair and regeneration.

Description

[Technical field]

[0001] The present invention relates to a dermatological composition comprising at least one amphiphilic peptide, derivative or salt thereof. The present invention further relates to a method of using the dermatological composition as a dermal filler and for soft tissue repair and regeneration. [Background technology]

[0002] Amphiphilic peptides, consisting of pairs of alternating hydrophobic-hydrophilic amino acid residues, self-assemble to form β-sheet structures (Rapaport et al. JACS, 2000, 122:12523-12529; Rapaport et al. JACS, 2002, 124:9342-9343). These structures are characterized by the presence of pleated β-strands connected by hydrogen bonds and other molecular interactions between amino acid side chains. Amphiphilic peptides that tend to form β-sheet structures have been shown to assemble into hydrogels suitable for drug delivery as well as for forming biocompatible matrices for tissue engineering (Rapaport et al. Adv. Func. Mater. 2008, 18(19):2889-2896; Segman-Magidovich et al. Adv. Mater. 2008, 20:2156-2161; Amosi et al. Acta Biomater. 2012, 8:2466-2475; Zarzhitsky et al. J. Coll. Int. Sci. 2011, 360:525-531).

[0003] Zarzhitsky et al. (Biopolymers, 2013, 100(6):760-72) describe the effect of peptide concentration, pH, and calcium ion concentration on the self-assembly of amphiphilic and anionic β-sheet peptide hydrogels. It was shown that mechanical stability and resistance to dissolution are highly correlated with these factors.

[0004] WO2007 / 148334 describes amphiphilic peptides containing mainly acidic amino acids, which, alone or in combination with ions and minerals, can form hydrogels at physiological pH and function as a scaffold for mineralization.

[0005] WO2009 / 072119 describes the therapeutic use of amphipathic peptides and pharmaceutical compositions containing them for the treatment and prevention of the progression of osteoporosis and pre-osteoporotic conditions by direct administration into defective, deteriorated or damaged bone, particularly at sites of low bone mineral density. The amphipathic peptides mainly contain acidic amino acids, which alone or in combination with ions and minerals can form β-sheet assemblies and hydrogels at physiological pH and act as a scaffold for mineralization directly at the bone site.

[0006] Jeong et al. (J. Biomed. Mater. Res. A, 2017, 105(12):3315-3325) describe hyaluronic acid (HAc)-hydroxyapatite (HAp) nanocomposite (HAc-nanoHAp) hydrogels compared to pure HAc hydrogels for soft tissue augmentation applications. HAc-nanoHAp was shown to provide significant improvement in wrinkles due to its higher stiffness and gel cohesion compared to pure HAc. HAc-nanoHAp also exhibited significant enhancement in strengthening of the dermal matrix by stimulating collagen and elastin synthesis.

[0007] EP 2552938 describes amphiphilic linear peptides and / or peptoids capable of forming hydrogels. The peptides / peptoids contain short amphiphilic sequences with a hydrophobic portion of aliphatic amino acids and at least one acidic, neutral, or basic polar amino acid. A number of such peptides / peptoids assemble into supramolecular helical fibers, which after assembly form a peptide hydrogel.

[0008] There remains an unmet need for compositions suitable for dermatological use. Summary of the Invention

[0009] The present invention provides a dermatological composition comprising at least one amphipathic peptide, or a derivative or salt thereof, containing alternating hydrophobic / hydrophilic amino acid residues, the hydrophilic amino acid residues being predominantly acidic. The composition is useful as a dermatological filler in achieving improved skin appearance and texture, and in treating various skin disorders and soft tissue defects.

[0010] The present invention is based, in part, on the unexpected discovery that amphipathic peptides containing alternating hydrophobic / hydrophilic amino acid residues (wherein the hydrophilic amino acid residues are predominantly acidic) can form stable hydrogels suitable as dermal or soft tissue fillers. Furthermore, the amphipathic peptides of the present invention have been shown to confer osteoblast and endothelial cell adhesion with structural similarity to fibrin(ogen) scaffolds. Thus, it is disclosed here for the first time that peptides and compositions containing same are useful in the treatment of various skin conditions, such as wounds, burns, surgical wounds, and the like. The compositions of the present invention have also been compared to commercially available dermal fillers composed of cross-linked hyaluronic acid and shown to have superior properties compared to hyaluronic acid-based products in terms of adhesion, swelling, viscoelasticity, rheology, injectability, biocompatibility, and resistance to degradation. As such, the compositions are useful for soft tissue augmentation, for example, in the treatment of soft tissue defects, including facial and body contouring.

[0011] According to one aspect of the present invention, there is provided a dermatological composition comprising at least one amphipathic peptide, or a derivative or salt thereof, comprising alternating hydrophobic / hydrophilic amino acid residues, and a dermatologically acceptable carrier, wherein the peptide comprises 1-20 pairs of alternating hydrophobic-hydrophilic amino acid residues, the hydrophilic amino acid residues being selected from the group consisting of negatively charged amino acids, hydroxyl-containing amino acids, and phosphorylated-hydroxyl-containing amino acids, and said peptide having 10% or less positively charged amino acid residues.

[0012] According to one embodiment, the dermatological composition is a soft tissue filler composition. According to another embodiment, the dermatological composition is a topical composition for use in treating skin conditions. According to yet another embodiment, the dermatological composition is a cosmetic composition.

[0013] According to some embodiments, at least one amphipathic peptide is 2-40 amino acids in length. According to certain embodiments, at least one amphipathic peptide is 7-28 amino acids in length. According to additional embodiments, the peptide further comprises at least one terminal proline (Pro) residue. According to various embodiments, the peptide further comprises two terminal Pro residues. According to some embodiments, the hydrophobic amino acid is selected from the group consisting of phenylalanine (Phe), leucine (Leu), isoleucine (Ile), valine (Val), tryptophan (Trp), and alanine (Ala). Each possibility represents a separate embodiment. According to certain embodiments, the hydrophobic amino acid is Phe or Leu. Each possibility represents a separate embodiment. According to some embodiments, the hydrophilic amino acid is selected from the group consisting of glutamic acid (Glu), aspartic acid (Asp), tyrosine (Tyr), serine (Ser), threonine (Thr), phosphoserine (Ser(PO4)), phosphothreonine (Thr(PO4)), and phosphotyrosine (Tyr(PO4)). Each possibility represents a separate embodiment.

[0014] According to another embodiment, the peptide comprises an amino acid sequence according to Formula I, or a salt thereof: X-(hydrophobic-hydrophilic) n -B (Formula I), where n designates an integer from 1 to 20, hydrophobic designates a hydrophobic amino acid residue, hydrophilic designates a hydrophilic amino acid residue, X designates Pro, Pro-hydrophilic or the peptide amino terminus, and B designates Pro or the peptide carboxy terminus. Each possibility represents a separate embodiment.

[0015] According to various embodiments, the amino terminus is modified. In one embodiment, the amino terminus is acetylated. According to other embodiments, the carboxy terminus is modified. In one embodiment, the carboxy terminus is amidated.

[0016] According to certain embodiments, the peptide has an amino acid sequence of any of the following formulas: X-(Phe-Glu) n -B, X-(Phe-Asp) n -B, X-(Leu-Glu) n -B, and X-(Leu-Asp) n -B or a salt thereof, where n designates an integer from 1 to 20, X designates Pro, a Pro-hydrophilic amino acid residue, or the peptide amino terminus, and B designates Pro or the peptide carboxy terminus. Each possibility represents a separate embodiment.

[0017] According to certain embodiments, the peptide comprises a sequence selected from the group consisting of: Pro-(Asp-Phe)5-Asp-Pro (SEQ ID NO:1), Pro-Glu-(Phe-Glu)5(SEQ ID NO:2), Glu-(Phe-Glu)5-Pro ​​(SEQ ID NO:3), Pro-(Ser-Phe)5-Ser-Pro (SEQ ID NO:4), Pro-(SerPO4-Phe)5-SerPO4-Pro (SEQ ID NO:5), Pro-(TyrPO4-Phe)5-TyrPO4-Pro (SEQ ID NO:6), Pro-(Glu-Leu)5-Glu-Pro (SEQ ID NO:7), Pro-(Asp-Leu)5-Asp-Pro (SEQ ID NO:8), Pro-(Ser-Leu)5-Ser-Pro (SEQ ID NO:9), Pro-(SerPO4-Leu)5-SerPO4-Pro (SEQ ID NO:10), Pro-(TyrPO4-Leu)5-TyrPO4-Pro (SEQ ID NO:11)、 Pro-(Glu-Phe-Ser-Phe)4-Glu-Pro (SEQ ID NO:12)、 Pro-(SerPO4-Phe-Ser-Phe)4-Ser-Pro (SEQ ID NO:13)、 Pro-(SerPO4-Phe-Glu-Phe)4-Glu-Pro (SEQ ID NO:14)、 Pro-(SerPO4-Phe-Asp-Phe)4-Asp-Pro (SEQ ID NO:15)、 Ala-Leu-Glu-(Phe-Glu)3-Pro-Ala-(Glu-Phe)3-Glu-Leu-Pro-Ala-Leu-Glu-(Phe-Glu)3-Pro (SEQ ID NO:16)、 Pro-Glu-(Phe-Glu)2-Lys-(Glu-Phe)2-Glu-Pro (SEQ ID NO:17)、 Pro-Glu-(Phe-Glu)5-(Gly)3-Arg-Gly-Asp-Ser (SEQ ID NO:18)、 (Phe-Glu)3-Pro-(Gly)3-Arg-Gly-Asp-Ser (SEQ ID NO:19)、 Ac-Pro-Asp-(Phe-Asp)5-Pro-NH2(SEQ ID NO:20)、 Pro-Asp-(Phe-Asp)6(SEQ ID NO:21)、 (Phe-Asp)6(SEQ ID NO:22)、 Pro-Glu-(Phe-Glu)5-Pro (SEQ ID NO:23)、 Pro-Asp-(Phe-Asp)5-Pro-NH2(SEQ ID NO:24)、 (Phe-Glu)5(SEQ ID NO:25)、 (Phe-Glu)6(SEQ ID NO:26)、 (Phe-Glu)7(SEQ ID NO:27)、 Pro-Asp-(Phe-Asp)4(SEQ ID NO:28), Pro-Asp-(Phe-Asp)6(SEQ ID NO:29), Pro-Asp-(Phe-Asp)8(SEQ ID NO:30), (Phe-Asp)5 (SEQ ID NO:31), (Phe-Asp)6 (SEQ ID NO:32), (Phe-Asp)7 (SEQ ID NO:33), Pro-Asp-(Phe-Asp)5-Pro-Arg-Gly-Asp-Ser (SEQ ID NO:34), Pro-(Phe-Asp)3-Pro (SEQ ID NO:35), and Pro-(Phe-Asp)3-Pro-(Gly)3-Arg-Gly-Asp-Ser (SEQ ID NO:36).

[0018] Each possibility represents a separate embodiment.

[0019] According to one embodiment, the peptide comprises Pro-(Asp-Phe)5-Asp-Pro (SEQ ID NO:1; designated herein as "PFD5"). In another embodiment, the peptide comprises the sodium salt of the peptide having the sequence set forth in SEQ ID NO:1 (designated herein as "PFD5 sodium").

[0020] According to certain embodiments, the composition comprises about 0.2% to about 20% w / v of the peptide or salt thereof (including individual values ​​within the ranges specified). According to particular embodiments, the composition comprises about 0.5% to about 10% w / v of the peptide or salt thereof (including individual values ​​within the ranges specified). According to particular embodiments, the composition comprises about 0.5% to about 5% w / v of the peptide or salt thereof (including individual values ​​within the ranges specified).

[0021] According to some embodiments, the composition is formulated for topical administration. According to other embodiments, the composition is formulated for intradermal administration. According to yet other embodiments, the composition is formulated for subcutaneous administration.

[0022] According to various embodiments, the composition is in a form selected from the group consisting of a gel, a hydrogel, a lotion, a cream, a milk, an aerosol, a spray, a foam, a mousse, a drop, a wash, an emulsion, and a suspension. Each possibility represents a separate embodiment. According to an exemplary embodiment, the composition is in the form of a hydrogel.

[0023] According to certain embodiments, the dermatologically acceptable carrier comprises at least one thickener, diluent, humectant, emulsifier, humectant, surfactant, buffer or pH adjuster, film former, foaming agent, antifoaming agent, preservative, antioxidant, fragrance, solvent, propellant, colorant, and combinations or mixtures thereof, with each possibility representing a separate embodiment.

[0024] According to certain embodiments, the composition is useful as a skin or soft tissue filler. According to certain embodiments, the present invention provides a method for skin filling, the method comprising topically administering to a subject in need thereof an effective amount of the skin composition disclosed herein. According to one embodiment, the composition is administered into or under the skin at the site where skin filling is desired.

[0025] According to other embodiments, the composition is useful in treating soft tissue defects. According to certain embodiments, the present invention provides a method for treating soft tissue defects, the method comprising injecting or implanting an effective amount of the dermatological composition disclosed herein into a subject in need thereof. According to various embodiments, the treatment of the soft tissue defect comprises facial or body contouring. According to further embodiments, the treatment of the soft tissue defect comprises breast augmentation following mastectomy.

[0026] According to additional embodiments, the skin composition may further comprise a plurality of cells obtained from adipose tissue. According to certain embodiments, the plurality of cells obtained from adipose tissue comprises adipocytes and / or adipose-derived stem cells. According to some embodiments, the plurality of cells obtained from adipose tissue is autologous. According to certain embodiments, the autologous cells obtained from adipose tissue are obtained by liposuction. According to other embodiments, the plurality of cells obtained from adipose tissue is allogeneic. According to further embodiments, the skin composition further comprising a plurality of cells obtained from adipose tissue is useful for treating soft tissue defects.

[0027] According to further embodiments, the dermatological composition may further comprise at least one of hyaluronic acid, collagen, gelatin, elastin, laminin, and fibronectin. Each possibility represents a separate embodiment.

[0028] According to some embodiments, the dermatological compositions are useful for 3D bioprinting of artificial tissue. In accordance with these embodiments, the present invention provides a method for 3D bioprinting of artificial tissue, the method comprising refilling a 3D bioprinter with the dermatological composition disclosed herein.

[0029] According to various embodiments, the present invention provides a pre-filled syringe comprising the dermatological composition disclosed herein. According to some embodiments, the dermatological composition is sterile.

[0030] According to other embodiments, the composition is useful as a topical composition for treating a skin condition. According to various embodiments, the skin condition is selected from the group consisting of cuts, wounds, burns, insect bites, jellyfish stings, rashes, skin allergy responses, and skin lesions. Each possibility represents a separate embodiment. According to certain embodiments, the present invention provides a method for treating a skin condition selected from the group consisting of cuts, wounds, burns, insect bites, jellyfish stings, rashes, skin allergy responses, and skin lesions, the method comprising topically administering to a subject in need thereof an effective amount of a dermatological composition disclosed herein. Each possibility represents a separate embodiment.

[0031] According to additional embodiments, the composition is useful as a cosmetic composition. According to these embodiments, the composition is useful in treating an age-related epithelial condition selected from the group consisting of elastosis, skin atrophy, fine lines, wrinkles, dilated pores, hyperpigmentation, depigmentation, sagging skin, rough skin, and dry skin. Each possibility represents a separate embodiment. According to further embodiments, the present invention provides a method for treating an age-related epithelial condition selected from the group consisting of elastosis, skin atrophy, fine lines, wrinkles, dilated pores, hyperpigmentation, depigmentation, sagging skin, rough skin, and dry skin, the method comprising topically administering to a subject in need thereof an effective amount of a dermatological composition disclosed herein. Each possibility represents a separate embodiment.

[0032] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting. [Brief description of the drawings]

[0033] [Figure 1A-1B]1A shows the (1A) elastic and loss modulus and (1B) viscosity of a PFD5 2.5% w / v hydrogel according to certain embodiments of the present invention versus a commercially available hyaluronic acid, cross-linked, dermal filler (HA syringe), indicating a higher G' for the PFD5 hydrogel. [Figure 2A-2B] 2A and 2B are images of commercially available cross-linked hyaluronic acid and PFD5 2.5% w / v hydrogel, respectively, injected using a 27 gauge needle, showing the smoother texture of the PFD5 hydrogel. [Figures 3A-3H] Images of commercial cross-linked hyaluronic acid and PFD5 2.5% w / v hydrogels incubated in fetal bovine serum for different periods of time, showing little swelling and dissolution of the PFD5 hydrogel and significant swelling and complete dissolution of the hyaluronic acid hydrogel. (3A) PFD5 hydrogel in fetal bovine serum at T=0; (3B) cross-linked hyaluronic acid in fetal bovine serum at T=0; (3C) PFD5 hydrogel at T=0; (3D) cross-linked hyaluronic acid at T=0; (3E) PFD5 hydrogel in fetal bovine serum at T=17 hours; (3F) cross-linked hyaluronic acid in fetal bovine serum at T=17 hours; (3G) PFD5 hydrogel removed from fetal bovine serum after 17 hours; (3H) PFD5 hydrogel removed from fetal bovine serum after 64 hours. [Figure 4] The figure shows a histological section (H&E stained) of tissues implanted with a PFD5-containing formulation. The arrows indicate new blood vessels in the regenerated tissue. [Figure 5A-5B] (5A) Images of hydrogels composed of 1.5, 2, 2.5, 3, 3.5, and 5% w / v PFD5 (two vials per peptide concentration) in inverted vials placed in front of line-printed paper, showing increasing turbidity with increasing PFD5 concentration; (5B) shows the turbidity of the hydrogels measured by light absorbance at 600 nm. [Figure 6A-6B] 6A-6C are TEM micrographs of PFD5 hydrogels according to certain embodiments of the present invention, with dimensions corresponding to PFD5, which are shown to be in a β-sheet conformation and packed as bilayers (6A), and hyaluronic acid-based hydrogels showing strong aggregates (6B). [Figure 7A-7C] 7A-7C are images of hydrogel-containing vials stained with methylene blue for adhesion evaluation at T=0, 5, 30, 60 and 90 seconds after injection into buffer solution, showing stronger adhesion of PFD5 hydrogel. (7A) PFD5 hydrogel according to certain embodiments of the invention; (7B) hyaluronic acid-based hydrogel (Teosyal Ultimate); (7C) hyaluronic acid-based hydrogel (Juvederm ultra3). [Figure 8A-8C] 8A-8C are images of inverted tubes containing hydrogels in a swelling assessment using fetal bovine serum (FBS), showing reduced swelling of PFD5 hydrogels compared to hyaluronic acid-based hydrogels. (8A) PFD5 hydrogels according to certain embodiments of the invention at T=0 and 1, 4, 7, and 11 days after incubation in 200% (v / v) serum, showing swelling; HA1 (8B) and HA2 (8C) hyaluronic acid-based hydrogels at T=0 and 1 day after incubation, showing complete swelling in 200%, 300%, and 400% (v / v) serum. [Figure 9A-9D] Images of oxidized hydrogels placed on glass slides, showing the resistance of PFD5 hydrogels to oxidation in contrast to the loss of hydrogel stiffness of hyaluronic acid-based hydrogels under similar oxidative conditions. (9A-9B) HA1 and HA2; (9C) PFD5 hydrogel; (9D) PFD5 hydrogel on an inverted glass slide. [Figure 10] Passed through a 27G needle: deionized water (DIW), HA1, oxidized HA1, HA2, and oxidized HA2; and passed through a 30G needle: DIW, PFD5, and oxidized PFD5. Average of the extrusion forces measured, showing that the PFD5 hydrogel maintained its mechanical properties after exposure to oxidative conditions, while the hyaluronic acid based hydrogels lost their stiffness. [Figure 11A-11B]Rheological properties of PFD5 hydrogels according to certain embodiments of the invention before and after sterilization compared to a hyaluronic acid-based hydrogel (HA1), showing that sterilization has a small effect on G' of PFD5 hydrogels. (11A) G' and G''; (11B) Viscosity. [Figures 12A-12C] Viscoelastic properties of PFD5 hydrogels according to certain embodiments of the present invention, showing increasing rheological coefficient and viscosity values ​​with increasing PFD5 concentration. (12A) G' at 1 Hz; (12B) G'' at 1 Hz; (12C) Viscosity at 1 Hz. [Figure 13A-13B] Average extrusion force of PFD5 hydrogels according to certain embodiments of the present invention injected through a syringe with a 30G needle, showing increased extrusion force with increasing PFD5 concentration (13A) and complete extrusion force profile for PFD5 hydrogel compared to a hyaluronic acid based hydrogel (HA1) measured through a syringe with a 30G needle, showing the uniformity of PFD5 hydrogel injection and the non-uniformity of HA1 hydrogel injection (13B). [Figure 14] FIG. 14 is a compression measurement of PFD5 hydrogels according to certain embodiments of the present invention, showing the less area occupied by compressed PFD5 hydrogels as a function of concentration. [Figures 15A-15C] Rheological properties and extrusion force of PFD5 hydrogels according to certain embodiments of the present invention with and without lidocaine, showing no effect of lidocaine on the rheological properties of PFD5. (15A) G' and G''; (15B) Viscosity; (15C) Extrusion force through a 30G needle. [Figures 16A-16C] Rheological properties and extrusion force of hydrogels containing a combination of PFD5 and hyaluronic acid, showing that the combination provides higher rheological modulus and viscosity, yet lower extrusion force, compared to hyaluronic acid hydrogel alone. (16A) G' and G''; (16B) Viscosity; (16C) Extrusion force through a syringe with a 27G needle. [Figure 17]FIG. 13 shows the total implant area of ​​PFD5 hydrogels according to certain embodiments of the present invention compared to hyaluronic acid-based hydrogels in a subcutaneous rat model. [Figure 18] 1 is a histological section of an implant obtained after subcutaneous injection of a PFD5 hydrogel according to certain embodiments of the present invention, with the arrow indicating an adipocyte adjacent to the implant. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] The present invention relates to dermatological compositions comprising amphiphilic peptides and their salts or derivatives, useful as dermal or soft tissue fillers and in treating, preventing, minimizing, reducing or reversing various skin-related conditions.

[0035] The principles and operation of the present invention may be better understood with reference to the accompanying description. Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or illustrated by way of example. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting.

[0036] It is disclosed here for the first time that peptides containing alternating hydrophobic / hydrophilic amino acid residues (wherein the hydrophilic amino acid residues are predominantly acidic) can be used as dermal fillers for facial and body contouring, skin atrophy correction, improving skin firmness or elasticity, and smoothing fine lines or wrinkles. The peptides can further be used to treat various skin-related conditions, including age-related pathologies and traumatic skin disorders. The use of peptides and compositions containing said peptides for filling, augmenting, and regenerating soft tissue in target areas of subjects in need thereof, and as components of bioinks for 3D artificial tissue bioprinting, are also encompassed by the present invention.

[0037] According to certain aspects and embodiments, there is provided a skin composition comprising a peptide comprising 1-20 pairs of alternating hydrophobic-hydrophilic amino acid residues or a derivative or salt thereof, and a dermatologically acceptable carrier, wherein the hydrophilic amino acid residues are selected from the group consisting of negatively charged amino acids, hydroxyl-containing amino acids, and phosphorylated-hydroxyl-containing amino acids, and the peptide has 10% or less positively charged amino acid residues.

[0038] As used herein, the term "dermatological composition" refers to a formulation for use in cosmetics, plastic surgery, restorative surgery, tissue bulking, or in the field of cosmetics. Each possibility represents a separate embodiment. The term "dermatological composition" also refers to a formulation that promotes wound healing and tissue regeneration and / or acts as a scaffold for the growth of cultured cells to generate artificial tissue. In certain embodiments, the composition provides tissue augmentation, for example, for facial and body contouring, or as a biocompatible filler material for augmenting body cavities or voids.

[0039] Exemplary peptide lengths within the scope of the present invention include, but are not limited to, 2 to 40 amino acids (including each integer within the specified range). In other embodiments, the peptide length is about 7 to about 28 amino acids, about 9 to about 20 amino acids, or about 11 to about 18 amino acids (including each integer within the specified range). For example, the dermatological compositions of the present invention encompass peptides having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids, with each possibility representing a separate embodiment.

[0040] Salts and derivatives of the peptides used in the disclosed compositions and methods are also included within the scope of the invention.

[0041] As used herein, the term "salt" refers to salts of carboxyl groups, also referred to as base addition salts, and acid addition salts of amino or guanidino groups of peptide molecules. Suitable base addition salts include, but are not limited to, metal salts of calcium, lithium, magnesium, potassium, sodium, aluminum, iron and zinc; ammonium salts derived from ammonia, primary, secondary, tertiary and quaternary amines, non-limiting examples of which are trimethylamine, cyclohexylamine, benzylamine, dibenzylamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)amine, phenylethylbenzylamine, dibenzylethylenediamine, procaine, chloroprocaine, piperidine, monoethanolamine, triethanolamine, quinine, choline, N-methylglucosamine. Each possibility represents a separate embodiment. Salts with amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine are contemplated. Each possibility represents a separate embodiment. Additionally, any zwitterionic salts formed with carboxylic acids and amino or guanidino groups of the peptide molecule are also contemplated.

[0042] Suitable acid addition salts include those derived from inorganic acids such as, but not limited to, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, etc., as well as organic acids such as aliphatic mono- and dicarboxylic acids, such as acetic acid or oxalic acid, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Each possibility represents a separate embodiment. Thus, salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Each possibility represents a separate embodiment. Salts of amino acids, such as alginate, and gluconate or galacturonate are also contemplated. Each possibility represents a separate embodiment.

[0043] Acid addition salts can be prepared by methods known in the art in which the free base form is contacted with a sufficient amount of the desired acid to produce the salt, and base addition salts are prepared by methods known in the art in which the free acid form is contacted with a sufficient amount of the desired base to produce the salt.

[0044] As used herein, "derivatives" of the peptides of the invention encompass derivatives that may be prepared by means known in the art from functional groups occurring as side chains on the residues or as N- or C-terminal groups, and are included in the invention, provided that they do not adversely affect the benefits of the compositions containing them and do not impart toxicity to said compositions.

[0045] These derivatives may include, for example, aliphatic esters of carboxyl groups, amides of carboxyl groups produced by reaction with ammonia or primary or secondary amines, N-acyl derivatives of free amino groups of amino acid residues formed by reaction with acyl moieties (e.g., alkanoyl or aroyl groups), or O-acyl derivatives of free hydroxyl groups formed by reaction with acyl moieties (e.g., that of seryl or threonyl residues). Additional derivatives within the scope of the present invention include peptides formed by phosphorylation of hydroxyl-containing amino acids. It is contemplated that the amino acid residues of the present invention include both D- and L-amino acids, preferably L-amino acids.

[0046] As used herein, the term "hydrophobic amino acid residue" refers to the following amino acids: alanine (Ala; A), isoleucine (Ile; I), leucine (Leu; L), phenylalanine (Phe; F), valine (Val; V), and tryptophan (Trp; W). Each possibility represents a separate embodiment. Phenylalanine (Phe; F) and leucine (Leu; L) are currently preferred. Each possibility represents a separate embodiment.

[0047] As used herein, the term "hydrophilic amino acid residue" refers to the following amino acids: glutamic acid (Glu; E), aspartic acid (Asp; D), tyrosine (Tyr; Y), serine (Ser; S), threonine (Thr; T), phosphoserine (Ser(PO4); S(PO4)), phosphothreonine (Thr(PO4); T(PO4)), and phosphotyrosine (Tyr(PO4); Y(PO4)). Each possibility represents a separate embodiment.

[0048] According to additional embodiments, the peptide further comprises at least one terminal proline (Pro) residue. According to various embodiments, the peptide further comprises two terminal Pro residues.

[0049] According to certain aspects and embodiments, the peptide comprises an amino acid sequence represented by Formula I, or a salt thereof: X-(hydrophobic-hydrophilic)n -B (Formula I), The following is specified: -n is an integer from 1 to 20, inclusive; - hydrophobic is a hydrophobic amino acid residue as defined above; -hydrophilic is a hydrophilic amino acid residue as defined above; -X is Pro, Pro-hydrophilic or a peptide amino terminus; and -B is Pro or the peptide carboxy terminus.

[0050] In various aspects and embodiments, the peptide comprises a sequence comprising any of the following formulas, or a salt thereof: X-(Phe-Glu) n -B, X-(Phe-Asp) n -B, X-(Leu-Glu) n -B, and X-(Leu-Asp) n -B, where n, X, and B are as defined above. Each possibility represents a separate embodiment.

[0051] Non-limiting examples of peptides within the scope of the present invention are listed in Table 1 below: [Table 1]

[0052] The peptides, derivatives and salts used in the compositions and methods of the present invention can be synthesized using any method known in the art, including, but not limited to, solid-phase and solution-phase peptide synthesis. In some embodiments, the peptides are synthesized using conventional synthesis techniques, for example, by chemical synthesis techniques. These methods include exclusive solid-phase synthesis, partial solid-phase synthesis, fragment condensation, and classical solution synthesis. Solid-phase peptide synthesis procedures are well known in the art and are described, for example, by Stewart & Young, Solid Phase Peptide Syntheses, Pierce Chemical Company, 1984, 2nd Edition. Those skilled in the art can synthesize any of the peptides of the present invention using an automated peptide synthesizer, using standard chemistry, for example, t-Boc or Fmoc chemistry. The synthetic peptides can be purified by preparative high performance liquid chromatography (HPLC) as known in the art, and their sequences can be confirmed by amino acid sequencing.

[0053] Alternatively, the peptides can be prepared by cloning and expressing a DNA fragment containing the coding sequence of a selected peptide or construct in a host microorganism or cell by known recombinant DNA techniques. Such techniques are described, for example, in Bitter et al. Met. Enzymol. 1987, 153:516-544; Studier et al. Met. Enzymol. 1990, 185:60-89; Brisson et al. Nature, 1984, 310:511-514; Takamatsu et al. 6:307-311; Coruzzi et al. EMBO J. 1984, 3:1671-1680; Brogli et al. Sci. 1984, 224:838-843, Gurley et al. Mol. Cell. Biol. 1986, 6:559-565; and Weissbach & Weissbach, Met. Plant Mol. Biol. 1988, Academic Press, NY, VIII: Coding sequences for the peptides can be prepared synthetically or derived by known techniques from viral RNA or from available cDNA-containing plasmids.

[0054] In some aspects and embodiments, the peptide of the invention is present in the composition in an amount of about 0.2% to about 20% (w / v) of the total weight of the composition, including each value within the range specified. Typically, the amount of peptide in the composition is in the range of about 0.5% to about 10% (w / v) of the total weight of the composition, including each value within the range specified. In certain embodiments, the amount of peptide in the composition is in the range of about 0.5% to about 5% (w / v) of the total weight of the composition, including each value within the range specified. For example, the amount of peptide in the composition is about 0.2%, about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% (w / v) of the total weight of the composition, with each possibility representing a separate embodiment.

[0055] According to the principles of the present invention, the peptide is mixed with one or more chemical components, such as a dermatologically acceptable carrier designed to facilitate administration of the compound to a subject, preferably a human subject. The term "dermatologically acceptable carrier" as used herein refers to an excipient that is biocompatible and does not cause significant irritation to the skin or inhibit the beneficial activity and properties of the peptide of the present invention. Suitable dermatologically acceptable carriers within the scope of the present invention include, but are not limited to, thickeners, diluents, humectants, emulsifiers, humectants, surfactants, buffers or pH adjusters, film formers, foaming agents, antifoaming agents, preservatives, antioxidants, fragrances, solvents, propellants, colorants, and combinations or mixtures thereof. Each possibility represents a separate embodiment.

[0056] Suitable thickening agents include, but are not limited to, fatty acids and alcohols, such as stearic acid and stearyl alcohol; gums, such as xanthan, carrageenan, gelatin, cellulose gum, agarose, karaya, pectin, amylopectin, and locust bean gum; and various polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose, polyvinylpyrrolidone (povidone, PVP), polyvinyl alcohol, medium to high viscosity. Molecular weight polyethylene glycols (PEG-3350, PEG-6000, etc.), glucosides, tetrasodium etidronate, polyacrylic acid, polymethacrylic acid, acrylamide copolymers, sodium acrylate copolymers, sodium alginate, calcium alginate, magnesium alginate, alginic acid, hyaluronic acid, polyglucuronic acid (poly-α- and -β-1,4-glucuronic acid), chondroitin sulfate, phacerane, polycarboxylic acids, carbomer, bentonite, chitin, chitosan, carboxymethyl chitin, and cross-linked polyacrylate materials available under the trademark Carbopol®. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0.5% to about 50% w / w of a thickening agent (including individual values ​​within the specified ranges).

[0057] Suitable diluents include, but are not limited to, minerals such as hydroxyapatite, calcium phosphate, calcium carbonate, calcium gluconate, calcium oxalate, calcium sulfate, calcium chloride, magnesium phosphate, magnesium carbonate, magnesium gluconate, magnesium oxalate, magnesium sulfate, magnesium chloride, zinc phosphate, zinc carbonate, zinc gluconate, zinc oxalate, zinc sulfate, zinc chloride, sodium bicarbonate, mica, talc, kaolin, silicon dioxide (e.g., silica), as well as mixtures or combinations thereof. Each possibility represents a separate embodiment. Additional diluents include, but are not limited to, biodegradable or non-biodegradable polymers such as nylon, polyethylene, polymethacrylate, Teflon, poly(D,L-lactide-co-glycolide) (PLGA), poly(D,L-lactide) (PLA), polyglycolide (PGA), polycaprolactone, polyhydroxybutyric acid, polyorthoesters, polyalkane anhydrides, polyester anhydrides, gelatin, collagen, cellulose, polyphosphazenes, and mixtures or combinations thereof. Each possibility represents a separate embodiment. Additional diluents within the scope of the present invention include, but are not limited to, various sugar and starch types, polysaccharides, dextrins, cyclodextrins (e.g., β-CD, hydroxypropyl-β-CD, sulfobutylether-CD), microcrystalline cellulose, and mixtures or combinations thereof. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0.5% to about 50% w / w of diluent (including each individual value within the specified range).

[0058] Suitable moisturizing agents include, but are not limited to, glycerin, hydrocarbon oils and waxes, such as mineral oil, petrolatum, paraffin, ceresin, ozokerite, microcrystalline wax, polyethylene, and perhydrosqualene; silicone oils; triglyceride fats and oils, such as those derived from vegetable, animal, and marine sources, such as jojoba oil and shea butter; acetoglyceride esters, such as acetylated monoglycerides; ethoxylated glycerides, such as ethoxylated glyceryl monostearate; fatty acids, fatty alcohols, and derivatives thereof. Each possibility represents a separate embodiment. Other suitable emollients include, but are not limited to, tri(caprylic or capric)glyceryl; lanolin and lanolin derivatives; polyhydric alcohols and polyether derivatives; polyhydric alcohol esters; wax esters; vegetable waxes; phospholipids, such as lecithin and derivatives; sterols, such as, but not limited to, cholesterol and cholesterol fatty acid esters; amides, such as fatty acid amides, ethoxylated fatty acid amides, and solid fatty acid alkanolamides. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 10% w / w of a moisturizer (including the individual values ​​within the ranges specified).

[0059] Suitable emulsifiers include, but are not limited to, polyethylene glycol ethers of stearic acid, such as steareth-2, steareth-4, steareth-6, steareth-7, steareth-10, steareth-11, steareth-13, steareth-15, and steareth-20, glyceryl stearate, stearyl alcohol, cetyl alcohol, cetearyl alcohol, behenyl alcohol, diethanolamine, lecithin, and polyethylene glycol. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 10% w / w emulsifier (including individual values ​​within the ranges specified). In another embodiment, the composition comprises about 0% to about 5% w / w emulsifier (including individual values ​​within the ranges specified).

[0060] Suitable humectants include, but are not limited to, glycols such as triethylene glycol, tripropylene glycol, propylene glycol, polypropylene glycol, butylene glycol, polyethylene glycol, sugar alcohols such as sorbitol, hexylene, urea, and collagen. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 5% w / w humectant (including each individual value within the specified range).

[0061] Suitable surfactants are cationic, anionic or zwitterionic and include, but are not limited to, polyoxyethylene glycol octylphenol ether, polyoxyethylene glycol alkylphenol ether, polyoxyethylene glycol sorbitan alkyl esters (Polysorbate 60, Polysorbate 80, etc.), sorbitan alkyl esters, block copolymers of polyethylene glycol and polypropylene glycol (poloxamers), polyethylene glycol-tocopherol succinate, DL alpha tocopherol acetate, and the like. cellulose, polyethoxylated castor oil derivatives (Cremophor EL, Cremophor RH40), dioctyl sodium sulfosuccinate, perfluorooctane sulfonate, alkylbenzene sulfonate, sodium lauryl ether sulfate, ammonium laureth sulfate, ammonium lauryl sulfate, disodium laureth sulfosuccinate, lignosulfonate, sodium stearate, benzalkonium chloride, cetylpyridinium chloride, benzethonium chloride, cetyltrimethylammonium bromide, cetyltrimethylammonium chloride, and betaine. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 30% w / w surfactant (including individual values ​​within the ranges specified). In another embodiment, the composition comprises from about 0% to about 20% w / w surfactant (including individual values ​​within the ranges specified). In yet another embodiment, the composition comprises from about 0% to about 5% w / w surfactant (including individual values ​​within the ranges specified).

[0062] Suitable buffering or pH adjusting agents include, but are not limited to: acidic buffering or pH adjusting agents, such as short chain fatty acids, citric acid, acetic acid, hydrochloric acid, sulfuric acid, and fumaric acid; and basic buffering or pH adjusting agents, such as Tris, HEPES, Hanks Balanced Salt Solution (HBSS), sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 10% w / w of a buffering or pH adjusting agent (including individual values ​​within the ranges specified). In another embodiment, the composition comprises about 0% to about 5% w / w of a buffering or pH adjusting agent (including individual values ​​within the ranges specified). In yet another embodiment, the composition comprises about 0% to about 1% w / w of a buffering or pH adjusting agent (including individual values ​​within the ranges specified). In certain embodiments, the composition has a pH in the range of about 4 to about 8 (including individual values ​​within the ranges specified). In other embodiments, the composition has a pH in the range of about 5 to about 7 (including each individual value within the specified range). Exemplary pH values ​​of the composition include, but are not limited to, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, or about 8.0. Each possibility represents a separate embodiment.

[0063] Suitable film formers include, but are not limited to, polyvinylpyrrolidone, acrylates, acrylamides, methacrylates, shellac, gum arabic, and hydroxyethylcellulose. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 20% w / w film former (including each individual value within the specified range).

[0064] Suitable foaming agents include, but are not limited to, isopropyl myristate, oxyalkylated sulfates, and ethoxylated alcohol sulfates. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 10% w / w foaming agent (including each value within the specified range).

[0065] Suitable anti-foaming agents include, but are not limited to, simethicone, and sorbitan sesquoleate. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 10% w / w of anti-foaming agent (including individual values ​​within the specified ranges).

[0066] Suitable preservatives include, but are not limited to, methylparaben, propylparaben, butylparaben, ethylparaben, potassium sorbate, trisodium EDTA, tetrasodium EDT, disodium edetate, benzophenone, 2-bromo-2-nitropane-1,3-diol, butylhydroxytoluene, chlorhexidine gluconate, citric acid, DMDM ​​hydantoin, formaldehyde, methylchloroisothiazolinone, methylisothiazolinone, methyldibromoglutaronitrile, sodium benzoate, phenoxyethanol, ethyl alcohol, benzyl alcohol, diazolidinyl urea, imidazolidinyl urea, and quaternium-15. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 5% w / w of a preservative (including the individual values ​​within the specified ranges).

[0067] Suitable antioxidants include, but are not limited to, ascorbic acid, ubiquinone, tocophenyl acetate, N-acetylcysteine ​​(NAC) or its derivatives, and sodium bisulfite. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 10% w / w antioxidant (including individual values ​​within the specified ranges).

[0068] Suitable fragrances include, but are not limited to, chamomile oil, lavender oil, and various plant extracts, such as camellia sinesis. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 5% w / w fragrance (including individual values ​​within the specified ranges).

[0069] Suitable solvents include, but are not limited to, water, lower alcohols such as ethanol and isopropanol, propylene glycol, ammonium xylene sulfonate, and low molecular weight polyethylene glycols such as, for example, PEG-300, PEG-1450, and the like. Each possibility represents a separate embodiment. In one embodiment, the composition comprises from about 0% to about 99% w / w of the solvent (including each value within the specified range). In another embodiment, the composition comprises from about 10% to about 90% w / w of the solvent (including each value within the specified range). In yet another embodiment, the composition comprises from about 20% to about 80% w / w of the solvent (including each value within the specified range).

[0070] Suitable propellants include, but are not limited to, hydrocarbons having 4-7 carbon atoms, such as isopentane. Additional propellants include, but are not limited to, chlorinated, fluorinated and chlorofluorinated low molecular weight hydrocarbons as well as nitrous oxide, carbon dioxide, butane, and propane. Each possibility represents a separate embodiment. Propellants may be used in amounts and under pressures suitable to provide proper release of the peptide from the container in the proper amount.

[0071] Suitable coloring agents include, but are not limited to, alumina (dried aluminum hydroxide), annatto extract, calcium carbonate, canthaxanthin, caramel, beta-carotene, cochineal extract, carmine, potassium sodium copper chlorophyllin (chlorophyllin-copper complex), dihydroxyacetone, bismuth oxychloride, synthetic iron oxide, ferric ammonium ferrocyanide, ferric ferrocyanide, chromium hydroxide green, chromium oxide green, guanine, mica-based pearlescent pigments, pyrophyllite, disodium dityrylbiphenyl, mica, dentifrice, talc, titanium dioxide, aluminum powder, bronze powder, copper powder, and zinc oxide, or mixtures or combinations thereof. Each possibility represents a separate embodiment. In one embodiment, the composition comprises about 0% to about 5% w / w coloring agent (including individual values ​​within the specified ranges).

[0072] Additional ingredients that can be included in the compositions of the present invention are sunscreens and tanning agents. Sunscreens include those materials commonly used to block UV light. Exemplary compounds are derivatives of PABA, cinnamates and salicylates. For example, octyl methoxycinnamate and 2-hydroxy-4-methoxybenzophenone (also known as oxybenzone) can be used. Octyl methoxycinnamate and 2-hydroxy-4-methoxybenzophenone are also known as Parsol MCX and Benzophenone-3, respectively. When present in the composition, the amount of sunscreen used can vary depending on the degree of protection desired from UV radiation. The sunscreen must be compatible with the active compound, but generally the composition can contain from about 0.5% to about 20% w / w sunscreen (including individual values ​​within the ranges specified). The exact amount will vary depending on the sunscreen selected and the desired sun protection factor (SPF).

[0073] Further ingredients that can be included in the compositions of the present invention are vitamins and vitamin derivatives, such as, for example, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin K and their derivatives, such as, for example, alpha tocopherol; and various plant extracts, such as, for example, aloe vera, aloe barbadensis, castor oil, citrus limonium, citrus paradise, citrus sinensis, elaesis guineensis, etc. Each possibility represents a separate embodiment. In addition, depigmenting agents that inhibit the melanocyte metabolic process in the skin and inhibit the enzymatic oxidation of tyrosine to DOPA (3,4-dihydroxyphenylalanine) can also be incorporated into the compositions of the present invention. Further ingredients that can be included in the compositions of the present invention are botulinum toxins of types A, B, C, D, E, F, G, and mixtures thereof, each possibility represents a separate embodiment.

[0074] Further included within the scope of the present invention is the incorporation in the compositions disclosed herein of ingredients including hyaluronic acid, collagen, gelatin, elastin, laminin, fibronectin, or mixtures or combinations thereof. When incorporated as part of a composition, the weight ratio between the peptides of the invention and the ingredients typically ranges from about 100:1 to about 1:100, including all iterations of ratios within the specified range. In one aspect and embodiment, hyaluronic acid and its derivatives are incorporated into the composition. Hyaluronic acid and derivatives of different chain lengths can be mixed with peptides and dermatologically acceptable carriers and / or they can be conjugated to the peptides disclosed herein. Each possibility represents a separate embodiment. In some embodiments, the benefits obtained by using compositions containing mixtures or combinations of hyaluronic acid and peptides disclosed herein are synergistic. When incorporated into the composition, the hyaluronic acid can be a high molecular weight hyaluronic acid having a molecular weight ranging from about 1.0 million Daltons (MDa) to about 4.0 MDa, or a low molecular weight hyaluronic acid having a molecular weight ranging from about 1,000 Da to about 1.0 MDa (including individual values ​​within the specified ranges). The hyaluronic acid can be non-crosslinked or crosslinked to various degrees using crosslinkers such as, but not limited to, 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane, and 1,4-butanediol diglycidyl ether. Each possibility represents a separate embodiment.

[0075] In accordance with the principles of the present invention, the compositions disclosed herein may further comprise a local anesthetic (LA), such as lidocaine, to ameliorate any pain sensation during and / or after administration. The compositions of the present invention may be administered by injection through a needle of 30 gauge or less, but it may be advantageous to add a local anesthetic to the formulation to improve compliance. When administered, the concentration of the local anesthetic is typically less than 10% w / v, such as about 0.01% w / v to 10% w / v (including individual values ​​within the ranges specified). Exemplary concentrations include about 0.05% w / v to about 5% w / v, about 0.1% w / v to about 1% w / v, and the like.

[0076] The incorporation of cells obtained from adipose tissue in the composition is further included within the scope of the present invention.According to one embodiment, the cells are adipocytes.According to another embodiment, the cells are adipose-derived stem cells.The composition supplemented with adipose-derived cells can be used in adipose tissue reconstruction procedures to treat soft tissue defects, for example, but not limited to, in subjects with congenital defects, trauma, or surgical resection.Each possibility represents a separate embodiment.

[0077] Traditional methods of adipose tissue reconstruction are performed by applying harvested autologous tissue with its blood supply or by transplantation of autologous harvested fat. These methods rarely result in sufficient tissue augmentation due to delayed neovascularization associated with subsequent cell necrosis, fibrosis and graft volume shrinkage. Moreover, the survival of implanted fat is highly unpredictable, and resorption generally occurs within 4-6 months after fat injection.

[0078] The peptides of the present invention have been shown to support adipocyte viability and therefore can be used in soft tissue augmentation procedures. Without being bound by any theory or mechanism of action, the peptides can form a semi-solid substrate for adipocyte attachment, enhance collagen formation, which can further support adipocyte viability, and enhance vascularization.

[0079] The adipocytes or adipose-derived stem cells to be incorporated into the composition can be obtained from any source. According to some embodiments, the cells are derived from human subcutaneous fat. According to certain embodiments, the cells are derived from human subcutaneous fat obtained by liposuction. The cells can be obtained by liposuction procedures in various areas of the body, such as the stomach, buttocks, thighs, arms, neck and buttocks. Each possibility represents a separate embodiment. Any liposuction procedure can be used to obtain adipocytes or adipose-derived stem cells according to the present invention, including, but not limited to, fat removal by laser, ultrasound and abdominoplasty, as known in the art.

[0080] The adipose tissue is processed to isolate adipocytes or adipose derived stem cells, which are then harvested by methods known in the art. According to some embodiments, the adipocytes or adipose derived stem cells are autologous. According to other embodiments, the adipocytes or adipose derived stem cells are allogeneic. The peptide to cell ratio can vary, but typically, the adipocytes or adipose derived stem cells are mixed with the hydrogel composition according to certain embodiments of the invention in a volume ratio of 5:95, 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40, 65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5, each possibility representing a separate embodiment. It should be understood that although cells obtained from adipose tissue can be combined with the peptides disclosed herein in a single composition, separate compositions are also contemplated by the present invention.Thus, according to certain embodiments, the present invention provides for the simultaneous administration of a dermatological composition comprising an amphipathic peptide comprising alternating hydrophobic / hydrophilic amino acid residues and a composition comprising a plurality of cells obtained from adipose tissue.

[0081] The compositions of the present invention may be manufactured by processes well known in the art, for example, by conventional mixing, dissolving, suspending, solubilizing, granulating, wet-milling, emulsifying, encapsulating, entrapment, spray-drying, or lyophilizing processes. They may be conventionally formulated using one or more dermatologically acceptable carriers, as described above, which facilitate processing of the peptides and peptide derivatives and salts into dermatologically usable preparations. After their manufacture, the compositions can be packaged and sterilized, for example, using filtration, steam autoclaving, ethylene oxide, gamma-radiation, electron beam irradiation, or biocompatible methods. Autoclaving can be carried out using any suitable temperature, pressure, and time. For example, a temperature of 80-120° C. for 20 minutes is suitable for many preparations. Irradiation can be carried out at an intensity ranging from about 10 to 50 kGy, or from about 1 to 10 megaRad (MRad), including individual values ​​within the ranges specified.

[0082] The appropriate formulation depends on the selected route of administration. In particular, when the composition is designed for soft tissue filling, intradermal and / or subcutaneous administration is contemplated. Each possibility represents a separate embodiment. In one embodiment, administration is epiperiosteal. In other aspects and embodiments, when the composition is designed for wound healing and for treating various skin conditions or for cosmetic applications, the composition of the present invention is formulated for topical administration.

[0083] For topical, intradermal or subcutaneous administration, the compositions of the invention may be formulated as gels, hydrogels, lotions, creams, milks, aerosols, sprays, foams, mousses, drops, washes, emulsions or suspensions. Each possibility represents a separate embodiment. Currently, compositions formulated as hydrogels are preferred for intradermal or subcutaneous administration. The term "hydrogel", according to the present invention, refers to a three-dimensional hydrated assembly of bioactive nanofibers. This definition includes dry "hydrogel-forming peptides", which swell in an aqueous environment, as well as materials that swell with water. Typically, in a hydrated hydrogel, according to the principles of the present invention, the amount of water in a composition comprising a hydrogel ranges from about 1% to about 99% (w / v) of the total weight of the composition (including individual values ​​within the ranges specified). Exemplary ranges of water content include, but are not limited to, about 5% to about 20%, about 10% to about 40%, about 50% to about 70%, about 75% to about 95%, about 80% to about 99% (w / v) of the total weight of the composition, including individual values ​​within the ranges specified. Hydrogels according to the present invention can be tailored to have a range of properties depending on the peptides that make up the hydrogel and additional materials that may be added thereto. Alternative forms of the compositions of the present invention can also be used, including forms designed to be reconstituted with a suitable vehicle prior to use. Intradermal delivery of peptides, peptide derivatives or salts thereof via nano- or micro-needles, for example, using a patch as described in Larraneta et al. (Mater. Sci. Eng. R 104: 1-32, 2016), is also contemplated within the scope of the present invention.

[0084] In some aspects and embodiments, the skin compositions disclosed herein exhibit a modulus and loss modulus in the range of about 20 to about 5,000 Pa, e.g., about 100 to about 1,000 Pa, about 100 to about 1,500 Pa, about 100 to about 2,000 Pa, or about 100 to about 3,000 Pa (including individual values ​​within the specified ranges). Exemplary elastic and loss moduli include, but are not limited to, about 20, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1,000, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, or about 5,000 Pa, with each possibility representing a separate embodiment.

[0085] In some aspects and embodiments, the dermatological compositions disclosed herein have a viscosity of about 1 to about 5,000 Pa * s, for example, about 10 to about 4,000 Pa * s, about 10 to about 2,500Pa * s, or about 10 to about 1,000 Pa * The range of viscosities shown is inclusive of any individual value within the range specified. Exemplary viscosities include, but are not limited to, about 1, about 10, about 20, about 50, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, about 500, about 550, about 600, about 650, about 700, about 750, about 800, about 850, about 900, about 950, about 1,000, about 1,100, about 1,200, about 1,300, about 1,400, about 1,500, about 1,600, about 1,700, about 1,800, about 1,900, about 2,000, about 2,500, about 3,000, about 3,500, about 4,000, about 4,500, or about 5,000 Pa. * s, each possibility represents a separate embodiment.

[0086] In some aspects and embodiments, the dermatological compositions disclosed herein swell by less than 100% of their initial volume upon absorption of an aqueous medium, for example, less than 80%, less than 70%, less than 60%, or less than 50% of their initial volume, each possibility representing a separate embodiment. The dermatological compositions of the present invention are contemplated to have sufficient cohesiveness to remain localized at the site of administration.

[0087] The compositions of the present invention are useful as dermal fillers. Thus, a method for dermal filling is provided, comprising topically administering to a subject in need thereof an effective amount of a dermal composition disclosed herein. The dermal filler can be used to treat moderate to severe facial wrinkles and folds, such as nasolabial folds (i.e., those extending from the nose to the corners of the mouth). In one embodiment, the dermal filler can be a gel implant composition, preferably a hydrogel implant composition, which can be injected into selected areas (e.g., the face) using a syringe into the mid-deep dermis. The dermis is the sub-surface skin layer, which contains connective tissue, nerve endings, and blood vessels. When administered as a dermal filler, the composition can improve the appearance of the skin by lifting wrinkles and folds in the treatment area, adding volume, and thus inducing soft tissue augmentation. Furthermore, in certain embodiments, improvement can be seen due to increased collagen production resulting from administration of the composition.

[0088] The composition of the present invention is useful as a soft tissue filler for treating soft tissue defects on the face or body of a subject in need thereof.Therefore, there is provided a use of the peptide disclosed herein for preparing a dermatological composition for treating soft tissue defects.The dermatological composition is implanted or injected into a selected site.Exemplary soft tissue defects treated by the dermatological composition of the present invention include, but are not limited to, breast defects during breast reconstruction procedures, such as after mastectomy.In some aspects and embodiments, the composition is used for face and body contouring.

[0089] Pre-filled syringes containing the dermatological compositions disclosed herein are within the scope of the present invention. Syringes suitable for use according to the present invention include, but are not limited to, those fitted with needles or cannulas having gauges between about 18G and about 40G (including individual values ​​within the ranges specified) and having an internal volume of about 0.1 to about 5 ml. In some embodiments, a 25G to 31G needle is desirable for minimal injection site damage. The composition is sterilized before being inserted into the syringe, or the syringe already incorporating the composition is sterilized.

[0090] In some aspects and embodiments, the dermatological compositions disclosed herein can be injected with an extrusion force of less than 50 N, for example, in the range of about 1 to about 50 N, about 1 to about 30 N, or about 1 to about 15 N, including individual values ​​within the specified ranges. Exemplary extrusion forces include, but are not limited to, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 N injected through a 27-30 gauge needle. Each possibility represents a separate embodiment.

[0091] The use of the dermatological compositions disclosed herein as components of bioinks for 3D bioprinting of artificial tissues is within the scope of the present invention.Bioprinting is a process in which artificial tissues are produced using bioinks that consist of cultured cells and materials that form a support structure for the cells.The bioinks are added to a bioprinter to produce 3D artificial tissues that can be used for regenerative medicine.

[0092] The compositions of the present invention are further useful in treating various skin conditions by topical administration. Treatment of cuts, wounds, burns, insect bites, jellyfish stings, rashes, skin allergy responses, and / or skin lesions is within the scope of the present invention. Each possibility represents a separate embodiment. Thus, there is provided a use of the peptides disclosed herein for the preparation of a skin composition for treating a skin condition selected from a cut, wound, burns, insect bites, jellyfish stings, rashes, skin allergy responses, and skin lesions. In some embodiments, there is provided a method for treating a skin condition selected from the group consisting of a cut, wound, burns, insect bites, jellyfish stings, rashes, skin allergy responses, and skin lesions, comprising administering to a subject in need thereof an effective amount of a skin composition disclosed herein.

[0093] The term "treating" as used herein refers to administering a therapeutic agent (i.e., a peptide, derivative or salt of the invention or a composition comprising same) effective to ameliorate, minimize, reduce or reverse the condition or symptoms associated therewith. The term "treating" as used herein also includes prevention of symptoms of the skin condition.

[0094] An "effective amount" as used herein is an amount of active ingredient capable of producing the desired effect, i.e., skin filling or treatment of a skin condition. This amount depends on many parameters, such as the exact composition used, the area of ​​administration, the skin condition, etc. Suitable compositions for use in connection with the present invention include compositions in which the peptide, derivative or salt of the invention is included in an amount effective to achieve the intended purpose. Determination of an effective amount is well within the capabilities of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. For any preparation used in the method of the invention, the effective amount can be initially estimated from in vitro and cell culture assays, for example, as described in Nakamura et al. (Exper. Derma. 27:495-500,2018). For example, certain dosages can be formulated in animal models to achieve a desired concentration or potency. Such information can be used to more accurately determine useful doses in humans. Dosages can vary depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration and dosage can be selected taking into account the condition of the subject. The compositions of the present invention can be administered in a single dose, although multiple doses at regular intervals are contemplated within the scope of the present invention. These can be adjusted according to individual characteristics and route of administration, depending on the severity and responsiveness of the epithelial condition. The duration of treatment can last from a few days to a few weeks, months or years, as desired. Exemplary dosages of peptides, derivatives or salts encompassed by the present invention include, but are not limited to, about 0.01 to about 1,000 mg / kg body weight, about 0.1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 100 mg / kg, about 10 mg / kg to about 75 mg / kg, about 0.1 mg / kg to about 1 mg / kg, etc., including individual values ​​within the ranges specified.Exemplary non-limiting amounts include about 0.1 mg / kg, about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 20 mg / kg, about 50 mg / kg, about 60 mg / kg, about 75 mg / kg, about 100 mg / kg, about 200 mg / kg, about 300 mg / kg, about 400 mg / kg, about 500 mg / kg, about 600 mg / kg, about 700 mg / kg, about 800 mg / kg, about 900 mg / kg, or about 1,000 mg / kg. Each possibility represents a separate embodiment. Alternatively, the amount administered can be measured and expressed as the molar concentration of the peptide, derivative, or salt administered. By way of example, and not limitation, the peptide, derivative or salt can be administered in the range of about 0.1 to about 100 mM (including individual values ​​within the ranges specified), e.g., about 0.1, about 0.25, about 0.5, about 1 about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 80, about 90 or about 100 mM. Each possibility represents a separate embodiment. Alternatively, the amount administered can be measured and expressed as mg / ml, μg / ml, or ng / ml.

[0095] As used herein, the term "administering" refers to contacting with the peptide, derivative or salt of the present invention or a composition comprising the same. Typically, administration can be achieved by topical application of an effective amount of the composition to an area of ​​the skin exhibiting the epithelial condition to be treated. As used herein, "topical administration" also refers to administration achieved by intradermal or subcutaneous injection of an effective amount of the composition to an area of ​​the skin exhibiting the epithelial condition to be treated. Administration can be achieved to a living organism, for example a human.

[0096] For soft tissue repair and regeneration, the composition of the present invention may further comprise at least one additional bioactive agent, such as cytokines, growth factors and their activators, platelets, etc. Each possibility represents a separate embodiment. Without wishing to be bound by theory, the incorporation of such agent(s) into the composition of the present invention is contemplated to improve the effectiveness of the composition disclosed herein. For example, fibroblast growth factors and their variants, such as FGF2, FGF4, FGF9 and FGF18, nerve growth factor gene (NGF) and certain FGFs for nerve healing, as well as general growth factors, such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1), keratinocyte growth factor (KGF), endothelial-derived growth supplement (EDGF), epidermal growth factor (EGF) and other proteins, can enhance the action of the skin composition by releasing active material components into the surrounding environment that promote the sequence of wound repair, enhance angiogenesis, and change the proliferation rate of cells. Other bioactive agents that can be incorporated into the compositions include analgesics, anti-inflammatory agents, antimicrobial agents, and enzymes. Each possibility represents a separate embodiment.

[0097] The compositions of the present invention are further useful in cosmetic applications, for example, in treating age-related epithelial conditions. Thus, there is provided a use of the peptides disclosed herein for the preparation of a skin composition for treating age-related epithelial conditions. As used herein, the term "age-related epithelial conditions" refers to age-related elastosis, skin atrophy, fine lines or wrinkles, skin imperfections, enlarged pores, spots including lentigines or solar lentigines, uneven skin tone or texture, UV radiation-induced damaged skin or actinic skin damage, hyperpigmented skin or melasma, hypopigmented skin, dry skin, sagging skin, rough skin, and any combination thereof. Each possibility represents a separate embodiment. The compositions described herein can also be used to treat, prevent, minimize, reduce, or reverse visible signs of scarring, such as, but not limited to, acne scarring and chickenpox scarring. Treatment of aged skin, skin imperfections, and scarring is within the scope of the present invention. The term "treating" in the context of an age-related epithelial condition includes at least one of the following: improving skin firmness or elasticity, smoothing fine lines or wrinkles, reducing skin pores, reducing hyperpigmentation or depigmentation, increasing skin thickness, radiance and / or softness, and reducing dry skin. Each possibility represents a separate embodiment. Treating a condition can be assessed as known in the art and includes beneficial outcomes or improvements, which are manifested by an enhancement in the appearance of the skin, for example, by a reduction in the appearance of wrinkles. This includes, for example, a reduction in oxidative damage in the skin.

[0098] As used herein, the term "about" refers to ±10%.

[0099] The terms "comprises," "has," "includes," "including," "having" and their conjugations mean "including but not limited to."

[0100] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. For example, the term "a peptide" or "a carrier" can include a plurality of peptides and carriers, including mixtures thereof.

[0101] Throughout this application, various embodiments of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Thus, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values ​​within that range. This is true regardless of the breadth of the range. Whenever a numerical range is given herein, it is meant to include any of the preceding numbers (fractional or integer) within the given range. The phrases "range / range between" a first indicated number and a second indicated number, and "range / range from" "to" a first indicated number to a second indicated number are used interchangeably herein and are meant to include the first and second indicated numbers and all fractional and integer numbers therebetween.

[0102] As used herein, the term "method" refers to manners, means, techniques and procedures for accomplishing a given task, including, but not limited to, those manners, means, techniques and procedures that are known or that can be readily developed from known manners, means, techniques and procedures by practitioners in the arts of chemistry, pharmacology, biology, biochemistry and medicine.

[0103] It will be appreciated that certain features of the invention that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for simplicity, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0104] Various embodiments and aspects of the present invention as delineated above and claimed in the claims section below find experimental support in the following examples.

[0105] Working Example Reference is now made to the following examples, which together with the above descriptions illustrate the invention in a non-limiting fashion.

[0106] Example 1 Different molar ratios of PFD5 sodium to HCl were generated by dissolving the peptide in the HCl solution using a magnetic stirrer. After a few minutes of mixing, hydrogel formation was examined (Table 2). In the composition containing 1% (w / v) PFD5 at a concentration of 6 mM (36 mM COO - Equivalent to 1:3, the addition of 18 mM HCl gave stable hydrogels. Therefore, the peptide to acid molar ratio was determined to be at least 1:3 to obtain transparent, homogeneous hydrogels.

[0107] In a composition containing 2.5% (w / v) PFD5 at a concentration of 15 mM (90 mM COO - (equivalent to 1:2) and the addition of 30 mM HCl gave a stable hydrogel. Therefore, the peptide to acid molar ratio was determined to be 1:2 to obtain a transparent, homogeneous hydrogel at this peptide concentration.

[0108] In the composition containing 4.8% (w / v) PFD5 at a concentration of 28.8 mM (173 mM COO -At this peptide concentration, the molar ratio of peptide to acid was determined to be 1:1.67, resulting in a stable, transparent hydrogel. [Table 2]

[0109] Example 2 The rheological data of a composition containing PFD5 (SEQ ID NO:1) at 2.5% w / v in 45 mM HCl was compared to a commercially available hyaluronic acid (HA), cross-linked, dermal filler.

[0110] The viscoelastic properties of the hydrogels were measured by dynamic frequency sweep testing on a Rheometer AR 2000 TA instrument operating in the cone mode with a cone angle of 4° and a diameter of 20 mm. The linear region was first determined by stress sweep measurements at a constant angular frequency of 6.3 rad / s. The elastic and loss moduli, G' and G'', were extracted from dynamic frequency sweeps in the range of 0.5-100 rad / s, performed in the linear stress region. The results are presented in Figures 1A-1B.

[0111] The two formulations were injected using a 27 gauge needle. Figure 2A shows an image of the commercial crosslinked HA hydrogel, and Figure 2B shows an image of the PFD5 2.5% w / v hydrogel. The images show similarities in the lifting ability of the hydrogels.

[0112] Images of commercial cross-linked-HA and PFD5 2.5% w / v hydrogels incubated in fetal bovine serum for different periods of time are shown in Figures 3A-3H. For ease of handling, the hydrogels were placed on metal disks that could be removed from the serum and imaged when placed on the glass slides. Images show the adhesion and slow dissolution or degradation of the PFD5 hydrogels, visible to the naked eye, at 17 and 64 hours. The HA hydrogels appeared to have lost adhesion at 17 hours. Therefore, no images were taken of the HA hydrogels after removal from fetal bovine serum at 17 and 64 hours. The net weight of the gel on the metal disk was measured over time. The results are presented below in Table 3: [Table 3]

[0113] Example 3 Intradermal reactivity studies were performed to test the possible irritant effect of formulations according to certain embodiments of the present invention. Two extracts of 3% w / v PFD5 hydrogel samples, one in a non-polar vehicle, cottonseed oil, and one in a polar vehicle, sodium chloride injection (0.9%), were prepared by immersing the samples in the relevant solvent to reach a weight / volume ratio of 0.2 g / ml and incubating at 37±1° C. for 72±2 hours under dynamic conditions (orbital stirrer). 0.2 ml of the two extracts and 0.2 ml of each solvent were injected intradermally at five sites in three albino rabbits and macroscopic skin reactions, such as erythema, edema and eschar, were evaluated. No abnormalities were observed immediately after intradermal injection of the sodium chloride injection extract and sodium chloride injection (vehicle control). No signs of erythema or edema were detected at 24, 48 and 72 hours after treatment in all sites treated with sodium chloride injection extract and in all control sites treated with sodium chloride injection in all animals. The primary irritation index (treated minus control) for sodium chloride injection was 0.00. No abnormalities were observed immediately after intradermal injection of cottonseed oil extract and cottonseed oil (vehicle control). Slight erythema and slight edema were detected at 24, 48 and 72 hours after treatment in all sites treated with cottonseed oil extract and in all control sites treated with cottonseed oil in all animals. The primary irritation index (treated minus control) for cottonseed oil was 0.00.

[0114] Example 4 To test the local implant efficacy of a 3% w / v PFD5 formulation according to certain embodiments of the present invention, an implantation study was performed.

[0115] Ten albino rabbits were used for the study: each animal was implanted with the test sample in the right thigh and a negative control (USP Reference Standard Control Plastic, HDPE) in the left thigh for a total of 2 sites / animal.

[0116] One explant time was scheduled after 4 weeks. Every day, the animals were subjected to general objective examinations with the aim of detecting possible local effects due to the samples. The behavior of the animals was observed and any abnormalities were recorded. During explantation, all sites implanted with the test samples and the negative control were collected and examined macroscopically to determine any damage. The implantation site and the local lymph nodes of each animal were preserved in 10% buffered formalin and used for histological evaluation. During daily observations (general objective examinations), all animals showed no local effects. No abnormalities were detected macroscopically in both the treated and control sites of all animals. Four weeks after implantation, minimal local effects were determined compared to the negative control. Such minimal local effects were mainly related to minimal neovascularization at the treated sites, which was also seen in the control sites. Furthermore, no inflammatory reaction or necrosis was observed at the implantation sites. Figure 4 shows tissue regeneration after implantation of the test items, shown by H&E staining of tissue sections. Complete resorption accompanied by neovascularization is noted.

[0117] Example 5 To test the effectiveness of hydrogels according to certain embodiments of the present invention as dermal fillers, an in vivo time-course evaluation of the hydrogels by histology is performed. 100 μl bolus injections of the inventive hydrogels are implanted subcutaneously at the dorsal surface of Sprague-Dawley rats. A commercially available cross-linked HA gel is used as a control. Implants are removed at 1, 4, and 18 weeks and analyzed by histology using hematoxylin and eosin (H&E) staining. Sections are taken at the injection site. Two sections are cut from each tissue sample, and the H&E stained sections are stitched using a stitching scope. Samples are then grouped and scored according to the amount of material remaining as follows: none (0%), low (25%), medium (50%), and high (100%).

[0118] Example 6 To test the effectiveness of hydrogels according to certain embodiments of the present invention as dermal fillers, an in vivo periodic evaluation of the hydrogels by magnetic resonance imaging (MRI) is performed. The MRI evaluates the volume and surface area changes over time of hydrogels according to certain embodiments of the present invention and a commercially available crosslinked HA hydrogel after intradermal injection in female Sprague-Dawley rats over a 40 week period.

[0119] Gel is injected at a target volume of 150 μl / implant. Implants are placed at two contralateral sites slightly caudal to the shoulder, two contralateral sites slightly rostral to the knee, and two contralateral sites at the midpoint of the head and tail. MRI scans are performed on a 300 MHz Bruker Biospec MRI scanner. Images are collected on the day of implantation (week 0), 12, 24, and 40 weeks after implantation. The absolute volume of gel at the implantation sites is determined.

[0120] Example 7 Hydrogels were prepared by mixing PFD5 solution with HCl solution at different concentrations, resulting in hydrogels with peptide concentrations of 1.5-5% w / v and a final pH of 5.9 ± 0.05. Hydrogel formation was first assessed by inverting the vials in which the hydrogels were prepared. Figure 5A shows images of inverted vials containing free-standing hydrogels. These images show that the contents of the vial resist flow, thus indicating the solid-like behavior of the formed hydrogels. The transparency of the gels was demonstrated by placing the vials in front of the printed lines and visualizing the quality of the lines projected through the hydrogel in the vial. The quality of the lines projected through the vial indicates the transparency / transparency of the hydrogel. More concentrated hydrogels appeared to be more opaque (Figure 5A). The turbidity of the hydrogels was measured by spectrophotometer at 600 nm (Figure 5B) and was shown to increase with increasing PFD5 concentration.

[0121] Example 8 PFD5 3.5% w / v hydrogel and HA (Juvederm Ultra3) were each dissolved in DIW (1:100 v / v). Ten microliters of each diluted sample was placed on a carbon-coated copper grid, 300 mesh, and equilibrated at room temperature for 20 minutes. The grids were negatively stained with Uranyl-Less and imaged with a Thermo Fisher Scientific (FEI) Talos F200C transmission electron microscope operating at 200 kV. Images were taken with a Ceta 16M CMOS camera. The PFD5 hydrogel was shown to exhibit fibrils with a width according to the length of PFD5 in the β-sheet conformation (0.345×13=4.5 nm) and a thickness of about 2 nm corresponding to the bilayer of the peptide in the β-sheet conformation (FIG. 6A). The tangled-looking fibrils are contemplated to contribute to the elastic strength of the PFD5 hydrogel. In comparison, the hyaluronic acid-based hydrogel (Juvederm Ultra3) appeared to form a continuous dense layer with small (approximately 15 nm) circular shaped domains on the grid (Figure 6B).

[0122] Example 9 PFD5 hydrogel, 3.5% w / v, was mixed with methylene blue (1:25 v / v). The stained hydrogel (0.8 ml) was poured into a stirred beaker containing HEPES (20 mM) supplemented with 2.5 mM CaCl2. Images were acquired at 0, 5, 30, 60, and 90 seconds (Figure 7A). The adhesion of the PFD5 hydrogel was rated as 4.5 based on the Gavard-Sundaram adhesion 1-5 scale (Sundaram et al. Plastic and Reconstructive Surgery, 2015, 136(4): 678-686). In comparison, hyaluronic acid-based hydrogels (HA1, Teosyal Ultimate, Figure 7B; and HA2, Juvederm ultra3, Figure 7C), which underwent a similar procedure, were rated as having adhesion of 2 and 3 on the Gavard-Sundaram adhesion scale.

[0123] Example 10 Fetal bovine serum (FBS) was added to tubes containing PFD5 2.5% w / v hydrogels in a 1:2 v / v ratio. The tubes were incubated at 37 °C for different periods, i.e., 1, 4, 7 and 11 days. At each time point, serum was removed and the hydrogel mass remaining in the tubes was measured. Swelling values ​​were calculated based on the ratio (final hydrogel weight) / (initial hydrogel weight). PFD5 hydrogels incubated with 1:2 v / v FBS showed a constant swelling ratio, ×1.3-1.5 w / w, regardless of incubation time. Figure 8A shows an inverted tube, demonstrating the absence of flow of serum-incubated hydrogels. The same procedure was applied to PFD5 1.5-5% w / v hydrogels, which showed similar swelling ratios of 1:1.2 to 1:1.5 v / v (i.e., ×1.2-1.5). In comparison, hyaluronic acid-based hydrogels HA1 (Teosyal Ultimate) and HA2 (Juvederm ultra3) supplemented with 1:2, 1:3, and 1:4 (HA:FBS) v / v and incubated at 37°C for 1 day swelled to 2-4 times their initial volume, respectively (Figures 8B-8C).

[0124] Example 11 The resistance to oxidation of hydrogels containing PFD5 (3.5% w / v) and HCl according to certain embodiments of the present invention was evaluated based on the procedures detailed in https: / / doi.org / 10.2147 / CCID.S220227 and https: / / doi.org / 10.1371 / journal.pone.0218287 and compared with hyaluronic acid-based hydrogels, designated HA1 and HA2, containing 2.2% and 2.4% w / v hyaluronic acid, respectively. In particular, 0.17 ml of oxidizing solution, 1,248 mM H2O2 (30%, Carlo Erra, Cat #412072) and 12.48 mM CuSO4 in DIW, was added to a syringe containing 0.4 ml of hydrogel (final solution to gel volume ratio of 1:3.33 v / v). The mixture was stirred with a spatula for 1 min and incubated at room temperature for 30 min.

[0125] Each syringe (1 ml, BD, ref 309648) was connected to either a 27 or 30 G needle and subjected to extrusion force measurements (Force Gauge, FG-5000A, Lutron). The piston speed was manually controlled and moved at a rate of 0.8 mm / sec. The average extrusion force was calculated from the recorded values. Independent measurements (n=2) were performed on the PFD5 hydrogels. A single measurement (n=1) was performed on the hyaluronic acid-based hydrogels.

[0126] Figures 9A-9D show images of hydrogels exposed to oxidizing solutions. The hyaluronic acid-based gels underwent oxidation and no longer resisted flow under gravity (9A-9B), whereas the PFD5-containing hydrogels maintained their drop shape (Figure 9C) and even when the glass was turned upside down (Figure 9D).

[0127] FIG. 10 shows that after mixing of the hydrogels with the oxidizing solution, hydrogels according to certain embodiments of the invention maintained their stiffness as shown by extrusion force measurements, while the hyaluronic acid based gels lost their stiffness and exhibited less than 20% of their initial pre-oxidation extrusion force values.

[0128] Example 12 PFD5 3% w / v hydrogel was sterilized in an autoclave at 121° C. for 15 min. The viscoelastic properties of the hydrogel before and after sterilization were measured by dynamic frequency sweep testing using an AR 2000 TA Instruments, controlled stress rheometer operating in cone and plate mode (cone angle 4° and 20 mm diameter).

[0129] A small decrease in the rheological properties (G', G'', viscosity) of PFD5 hydrogels was observed after sterilization, suggesting that autoclave sterilization had a slight effect on the rheological properties of the hydrogels (Figures 11A-11B). PFD5-based hydrogels showed higher G' and G'' values ​​compared to hyaluronic acid-based hydrogels (HA1) before and after sterilization.

[0130] Example 13 Hydrogels were prepared by mixing PFD5 solution with HCl solution at different concentrations to obtain hydrogels with peptide concentrations ranging from 1-5% w / v. The viscoelastic properties of the hydrogels were measured by dynamic frequency sweep testing using an AR2000 controlled stress rheometer operating in cone and plate modes (cone angle 4° and 20 mm diameter). Increasing the PFD5 concentration resulted in higher G', G'' and viscosity values ​​(Figures 12A-12C, respectively).

[0131] Example 14 Hydrogels were prepared by mixing PFD5 solution with HCl solution at different concentrations to obtain hydrogels with peptide concentrations of 1-5% w / v. The extrusion force of water, i.e. 0% w / v PFD5, and hydrogels was measured using a force gauge (FG-5000A, Lutron) by lowering the piston and injecting 0.5 ml gel through a 30 G needle at a constant rate (1 ml / min). Higher extrusion forces were measured for more concentrated PFD5 hydrogels (Figure 13A). The extrusion force was found to be linearly correlated with the PFD5 % w / v concentration. The extrusion force was measured in different syringes connected to a 27 G needle to compare hyaluronic acid based hydrogels (HA1) with PFD5 (2.5 and 3% w / v) (Figure 13B). HA1 showed a significantly higher average extrusion force of 21.6 N compared to about 8-9 N for PFD5. Furthermore, the extrusion force of HA1 showed a non-uniform pattern during injection (Figure 13B), whereas the PFD5 hydrogel was injected more uniformly through the needle.

[0132] Example 15 50 mg of hydrogel was weighed onto a small glass. Another glass was placed on top of the hydrogel, and on top of that, a fixed weight (15 g) was placed above the top glass for 30 seconds. The compression of the hydrogel by the applied weight was recorded, and the area before and after compression was measured by ImageJ software. Figure 14 shows that at higher PFD 5% w / v concentration, the hydrogel was less spreadable, i.e., more cohesive.

[0133] Example 16 Lidocaine was dissolved in 76 mM HCl solution. The solution was mixed with PFD5 solution (1:1 v / v) to form PFD5 3.5% hydrogel with 0.3% lidocaine. PFD5 3.5% hydrogel with lidocaine showed similar rheological properties and extrusion force compared to PFD5 3.5% hydrogel without lidocaine (Figures 15A-15C).

[0134] Example 17 PFD5 5% hydrogel was mixed with HA1 (1:1 v / v) using two syringes to form hydrogels consisting of 2.5% PFD5 and HA1, respectively. The combined hydrogels exhibited higher G' and viscosity values ​​than each of the components alone (Figures 16A-16B) and lower extrusion force than HA1 alone (Figure 16C).

[0135] Example 18 The effect of PFD5 3.5% w / v hydrogel on tissue augmentation was tested in a subcutaneous rat model and compared to the effect obtained in rats treated with a commercial hyaluronic acid dermal filler. Individual rats were treated with 0.2 ml of PFD5 hydrogel or HA injections administered subcutaneously above the parietal bone. Animals were kept for 3 days, 1 month and 4 months, after which the implants were excised and histological examination and analysis was performed on the area occupied by the implants. Based on the analysis of the tissue sections, the PFD5 hydrogels showed a mean area equivalent to that occupied by the HA hydrogels (Figure 17). Due to the lower swelling of the PFD5 hydrogels compared to the HA hydrogels, the area remained more unchanged.

[0136] The PFD5 hydrogel showed complete resorption and sequential biodegradation by macrophages, without multinucleated giant cells or other deleterious effects on nearby tissues. Furthermore, based on histological analysis, the implant supported nearby adipocyte viability (Figure 18).

[0137] Example 19 PFD5 hydrogel was blended with human lipoaspirate tissue in a volume ratio of 5:95, 10:90, 25:75, 50:50, or 75:25, thus forming lipo+gel grafts. The homogeneity and stability of the grafts during incubation in a standard cell culture incubator are evaluated. Adipocyte viability is also evaluated. The grafts are then tested in vivo using a subcutaneous implant model in athymic rats. As a control, the same tissue volume of human lipoaspirate tissue is used. The grafts and controls are implanted subcutaneously for evaluation of retention, tissue morphology, and histological cross-sections over the course of 6-12 months.

[0138] While the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

[0139] All publications, patents, and patent applications mentioned in this specification are incorporated herein in their entirety by reference to the specification to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference.In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention.To the extent that section headings are used, they should not be construed as necessarily limiting.

Claims

1. A dermatological composition comprising at least one amphipathic peptide, or a derivative or salt thereof, comprising alternating hydrophobic / hydrophilic amino acid residues, and a dermatologically acceptable carrier, wherein the peptide comprises 1-20 pairs of alternating hydrophobic-hydrophilic amino acid residues, the hydrophilic amino acid residues being selected from the group consisting of negatively charged amino acids, hydroxyl-containing amino acids, and phosphorylated-hydroxyl-containing amino acids, the peptide having 10% or less positively charged amino acid residues, and the dermatological composition is a soft tissue filler composition.

2. said at least one amphipathic peptide has between 2 and 40 amino acids; or said at least one amphipathic peptide comprises at least one terminal Pro residue, or the hydrophobic amino acid residue is selected from the group consisting of Phe, Leu, lie, Val, Trp, and Ala; or The hydrophilic amino acid residues are Glu, Asp, Tyr, Ser, Thr, Ser (PO ４ ), Thr(PO ４ ), and Tyr(PO ４ 2. The dermatological composition according to claim 1, wherein the composition is selected from the group consisting of:

3. The at least one amphipathic peptide comprises an amino acid sequence according to formula I or a salt thereof: X-(hydrophobic-hydrophilic) ｎ -B (formula I), where n designates an integer from 1 to 20, hydrophobic designates a hydrophobic amino acid residue, hydrophilic designates a hydrophilic amino acid residue, X designates Pro, Pro-hydrophilic or the peptide amino terminus, and B designates Pro or the peptide carboxy terminus; Preferably, the at least one amphipathic peptide has an amino acid sequence of any of the following formulas: X-(Phe-Glu) ｎ -B,X-(Phe-Asp) ｎ -B,X-(Leu-Glu) ｎ -B, and X-(Leu-Asp) ｎ -B, or a salt thereof, or the at least one amphipathic peptide comprises at least one modification selected from a modification of the amino-terminus X and a modification of the carboxy-terminus B; More preferably, the modification comprises acetylation of the amino terminus, amidation of the carboxy terminus, or a combination thereof.

4. The at least one amphipathic peptide has a sequence selected from the group consisting of: Pro-(Asp-Phe) ５ -Asp-Pro (SEQ ID NO: 1), Pro-Glu-(Phe-Glu) ５ (SEQ ID NO:2), Glu-(Phe-Glu) ５ -Pro (SEQ ID NO: 3), Pro-(Ser-Phe) ５ -Ser-Pro (SEQ ID NO: 4), Pro-(SerPO ４ -Phe) ５ -SerPO ４ -Pro (SEQ ID NO:5), Pro-(TyrPO ４ -Phe) ５ -TyrPO ４ -Pro (SEQ ID NO:6), Pro-(Glu-Leu) ５ -Glu-Pro (SEQ ID NO:7), Pro-(Asp-Leu) ５ -Asp-Pro (SEQ ID NO: 8), Pro-(Ser-Leu) ５ -Ser-Pro (SEQ ID NO: 9), Pro-(SerPO ４ -Leu) ５ -SerPO ４ -Pro (SEQ ID NO: 10), Pro-(TyrPO ４ -Leu) ５ -TyrPO ４ -Pro (SEQ ID NO: 11), Pro-(Glu-Phe-Ser-Phe) ４ -Glu-Pro (SEQ ID NO: 12), Pro-(SerPO ４ -Phe-Ser-Phe) ４ -Ser-Pro (SEQ ID NO: 13), Pro-(SerPO ４ -Phe-Glu-Phe) ４ -Glu-Pro (SEQ ID NO: 14), Pro-(SerPO ４ -Phe-Asp-Phe) ４ -Asp-Pro (SEQ ID NO: 15), Ala-Leu-Glu-(Phe-Glu) ３ -Pro-Ala-(Glu-Phe) ３ -Glu-Leu-Pro-Ala-Leu-Glu-(Phe-Glu) ３ -Pro (SEQ ID NO: 16), Pro-Glu-(Phe-Glu) ２ -Lys- (Glu-Phe) ２ -Glu-Pro (SEQ ID NO: 17), Pro-Glu-(Phe-Glu) ５ - (Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 18), (Phe-Glu) ３ -Pro-(Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 19), Ac-Pro-Asp-(Phe-Asp) ５ -Pro-NH ２ (SEQ ID NO: 20), Pro-Asp-(Phe-Asp) ６ (SEQ ID NO:21), (Phe-Asp) ６ (SEQ ID NO: 22), Pro-Glu-(Phe-Glu) ５ -Pro (SEQ ID NO: 23), Pro-Asp-(Phe-Asp) ５ -Pro-NH ２ (SEQ ID NO:24), (Phe-Glu) ５ (SEQ ID NO:25), (Phe-Glu) ６ (SEQ ID NO:26), (Phe-Glu) ７ (SEQ ID NO:27), Pro-Asp-(Phe-Asp) ４ (SEQ ID NO:28), Pro-Asp-(Phe-Asp) ６ (SEQ ID NO:29), Pro-Asp-(Phe-Asp) ８ (SEQ ID NO: 30), (Phe-Asp) ５ (SEQ ID NO:31), (Phe-Asp) ６ (SEQ ID NO: 32), (Phe-Asp) ７ (SEQ ID NO: 33), Pro-Asp-(Phe-Asp) ５ -Pro-Arg-Gly-Asp-Ser (SEQ ID NO: 34), Pro-(Phe-Asp) ３ -Pro (SEQ ID NO: 35), and Pro-(Phe-Asp) ３ -Pro-(Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 36), or a salt thereof; The dermatological composition according to claim 1 , wherein the at least one amphipathic peptide comprises the sequence set forth in SEQ ID NO: 1, or a salt thereof.

5. Formulated for intradermal or subcutaneous administration, The dermatological composition according to any one of claims 1 to 4, preferably in the form of a hydrogel.

6. The skin composition according to any one of claims 1 to 5, further comprising at least one of hyaluronic acid, collagen, gelatin, elastin, laminin, and fibronectin.

7. further comprising a plurality of cells obtained from adipose tissue, Preferably, said plurality of cells obtained from adipose tissue comprises adipocytes and / or adipose-derived stem cells, or the plurality of cells obtained from adipose tissue is autologous; or The plurality of cells obtained from adipose tissue is obtained by liposuction; or The skin composition according to any one of claims 1 to 6, wherein the plurality of cells obtained from adipose tissue is allogeneic.

8. 1. A dermatological composition for use in the treatment of a soft tissue defect, comprising: Preferably, the treatment of the soft tissue defect comprises facial or body contouring, or A dermatological composition for use according to any one of claims 1 to 7, wherein the treatment of soft tissue defects comprises post-mastectomy breast augmentation.

9. A dermatological composition according to any one of claims 1 to 7 for use in 3D bioprinting of artificial tissue.

10. A pre-filled syringe comprising the dermatological composition according to any one of claims 1 to 7.

11. A skin composition comprising at least one amphipathic peptide, or a derivative or salt thereof, comprising alternating hydrophobic / hydrophilic amino acid residues, and a dermatologically acceptable carrier, said peptide comprising 1-20 pairs of alternating hydrophobic-hydrophilic amino acid residues, said hydrophilic amino acid residues being selected from the group consisting of negatively charged amino acids, hydroxyl-containing amino acids, and phosphorylated-hydroxyl-containing amino acids, said peptide having 10% or less positively charged amino acid residues, and said skin composition being a cosmetic composition.

12. said at least one amphipathic peptide has between 2 and 40 amino acids; or said at least one amphipathic peptide comprises at least one terminal Pro residue, or the hydrophobic amino acid residue is selected from the group consisting of Phe, Leu, lie, Val, Trp, and Ala; or The hydrophilic amino acid residues are Glu, Asp, Tyr, Ser, Thr, Ser (PO ４ ), Thr(PO ４ ), and Tyr(PO ４ or The at least one amphipathic peptide comprises an amino acid sequence according to formula I or a salt thereof: X-(hydrophobic-hydrophilic) ｎ -B (formula I), where n designates an integer from 1 to 20, hydrophobic designates a hydrophobic amino acid residue, hydrophilic designates a hydrophilic amino acid residue, X designates Pro, Pro-hydrophilic or the peptide amino terminus, and B designates Pro or the peptide carboxy terminus; Preferably, the at least one amphipathic peptide has an amino acid sequence of any of the following formulas: X-(Phe-Glu) ｎ -B,X-(Phe-Asp) ｎ -B,X-(Leu-Glu) ｎ -B, and X-(Leu-Asp) ｎ -B, or a salt thereof, or the at least one amphipathic peptide comprises at least one modification selected from a modification of the amino-terminus X and a modification of the carboxy-terminus B; The dermatological composition of claim 11, wherein the modification preferably comprises acetylation of the amino terminus, amidation of the carboxy terminus, or a combination thereof.

13. The at least one amphipathic peptide has a sequence selected from the group consisting of: Pro-(Asp-Phe) ５ -Asp-Pro (SEQ ID NO: 1), Pro-Glu-(Phe-Glu) ５ (SEQ ID NO:2), Glu-(Phe-Glu) ５ -Pro (SEQ ID NO: 3), Pro-(Ser-Phe) ５ -Ser-Pro (SEQ ID NO: 4), Pro-(SerPO ４ -Phe) ５ -SerPO ４ -Pro (SEQ ID NO:5), Pro-(TyrPO ４ -Phe) ５ -TyrPO ４ -Pro (SEQ ID NO:6), Pro-(Glu-Leu) ５ -Glu-Pro (SEQ ID NO:7), Pro-(Asp-Leu) ５ -Asp-Pro (SEQ ID NO: 8), Pro-(Ser-Leu) ５ -Ser-Pro (SEQ ID NO: 9), Pro-(SerPO ４ -Leu) ５ -SerPO ４ -Pro (SEQ ID NO: 10), Pro-(TyrPO ４ -Leu) ５ -TyrPO ４ -Pro (SEQ ID NO: 11), Pro-(Glu-Phe-Ser-Phe) ４ -Glu-Pro (SEQ ID NO: 12), Pro-(SerPO ４ -Phe-Ser-Phe) ４ -Ser-Pro (SEQ ID NO: 13), Pro-(SerPO ４ -Phe-Glu-Phe) ４ -Glu-Pro (SEQ ID NO: 14), Pro-(SerPO ４ -Phe-Asp-Phe) ４ -Asp-Pro (SEQ ID NO: 15), Ala-Leu-Glu-(Phe-Glu) ３ -Pro-Ala-(Glu-Phe) ３ -Glu-Leu-Pro-Ala-Leu-Glu-(Phe-Glu) ３ -Pro (SEQ ID NO: 16), Pro-Glu-(Phe-Glu) ２ -Lys- (Glu-Phe) ２ -Glu-Pro (SEQ ID NO: 17), Pro-Glu-(Phe-Glu) ５ - (Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 18), (Phe-Glu) ３ -Pro-(Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 19), Ac-Pro-Asp-(Phe-Asp) ５ -Pro-NH ２ (SEQ ID NO: 20), Pro-Asp-(Phe-Asp) ６ (SEQ ID NO:21), (Phe-Asp) ６ (SEQ ID NO: 22), Pro-Glu-(Phe-Glu) ５ -Pro (SEQ ID NO: 23), Pro-Asp-(Phe-Asp) ５ -Pro-NH ２ (SEQ ID NO:24), (Phe-Glu) ５ (SEQ ID NO:25), (Phe-Glu) ６ (SEQ ID NO:26), (Phe-Glu) ７ (SEQ ID NO:27), Pro-Asp-(Phe-Asp) ４ (SEQ ID NO:28), Pro-Asp-(Phe-Asp) ６ (SEQ ID NO:29), Pro-Asp-(Phe-Asp) ８ (SEQ ID NO: 30), (Phe-Asp) ５ (SEQ ID NO:31), (Phe-Asp) ６ (SEQ ID NO: 32), (Phe-Asp) ７ (SEQ ID NO: 33), Pro-Asp-(Phe-Asp) ５ -Pro-Arg-Gly-Asp-Ser (SEQ ID NO: 34), Pro-(Phe-Asp) ３ -Pro (SEQ ID NO: 35), and Pro-(Phe-Asp) ３ -Pro-(Gly) ３ -Arg-Gly-Asp-Ser (SEQ ID NO: 36), or a salt thereof; The dermatological composition according to claim 11, wherein the at least one amphipathic peptide comprises the sequence set forth in SEQ ID NO: 1, or a salt thereof.

14. A dermatological composition according to any one of claims 11 to 13, formulated for topical administration, preferably in the form of a hydrogel.

15. 1. A topical composition for use in the treatment of an age-related epithelial condition or for use in the treatment of a skin condition selected from the group consisting of elastosis, skin atrophy, fine lines, wrinkles, dilated pores, hyperpigmentation, depigmentation, sagging skin, rough skin, and dry skin, comprising: The dermatological composition according to any one of claims 11 to 14, wherein the skin condition is selected from the group consisting of cuts, wounds, burns, insect bites, jellyfish stings, rashes, skin allergic responses, and skin lesions.

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