Compositions and methods for stimulating hair growth

Abstract

This specification discloses compositions comprising peptides containing a CD44 binding site and / or a calcium binding site, and a method for stimulating hair growth using said compositions.

Description

Cross-reference of related applications

[0001] This application claims the benefits of U.S. Provisional Patent No. 63 / 522,012, filed on June 20, 2023, which is incorporated by reference. [Technical Field]

[0002] The present invention relates to a composition comprising a peptide containing a CD44 binding site and / or a calcium binding site, and a method for stimulating hair growth using the composition. [Background technology]

[0003] Alopecia often has negative social and psychological impacts on individuals suffering from it. Many factors are thought to influence alopecia, including genetics, hormones, environmental exposure, medication, psychological stress, and nutrition. One known treatment is hair transplantation, which requires anesthesia, is costly, time-consuming, and can be painful. Other approaches include massage and acupuncture, but these have not been shown to be effective. Hormones and other medications have been used to treat alopecia. However, these treatments frequently cause undesirable side effects, such as hair growth in unwanted areas. Therefore, there is a need for effective treatments to stimulate hair growth. [Overview of the project]

[0004] In a first embodiment, this disclosure provides a peptide for stimulating hair growth, comprising a sequence selected from the group consisting of SEQ ID NOs: 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity. In some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 96. In some embodiments, the peptide comprises a CD44 binding site, for example, the amino acid sequence of KSKEEDKHLKFRISHEL (SEQ ID NO: 97) or a variant thereof. In some embodiments, the peptide comprises a calcium binding site, for example, the amino acid sequence of DWDSRGKDSYETS (SEQ ID NO: 98) or a variant thereof. In some embodiments, the peptide comprises a CD44 binding site and a calcium binding site. In some embodiments, the peptide has a length of 295 amino acids or less, for example, 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0005] In another embodiment, the disclosure provides a composition for stimulating hair growth, comprising a peptide comprising a sequence selected from the group consisting of SEQ ID NOs: 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity. In some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 96. In some embodiments, the peptide comprises a CD44 binding site, for example, the amino acid sequence of KSKEEDKHLKFRISHEL (SEQ ID NO: 97) or a variant thereof. In some embodiments, the peptide comprises a calcium binding site, for example, the amino acid sequence of DWDSRGKDSYETS (SEQ ID NO: 98) or a variant thereof. In some embodiments, the peptide comprises a CD44 binding site and a calcium binding site. In some embodiments, the peptide has a length of 295 amino acids or less, for example, 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0006] In some embodiments, the composition contains about 0.01% by weight or more of the peptide. In some embodiments, the composition contains about 0.025% by weight or more of the peptide, for example, about 0.05% by weight or more, about 0.075% by weight or more, about 0.1% by weight or more, about 0.25% by weight or more, about 0.5% by weight or more, about 0.75% by weight or more, about 1% by weight or more, about 2.5% by weight or more, about 5% by weight or more, about 7.5% by weight or more, or about 10% by weight or more of the peptide.

[0007] In some embodiments, the composition further comprises one or more additional ligands that bind to CD44. In some embodiments, the one or more additional ligands that bind to CD44 are selected from the group consisting of cerglycine, chondroitin or a salt thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor-binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6), green fluorescent protein (GFP), and any combination thereof.

[0008] In some embodiments, the composition further comprises hyaluronic acid. The hyaluronic acid may have an average molecular weight in the range of about 20 kDa to 1350 kDa, about 4 kDa to about 10 kDa, about 10 kDa to about 100 kDa, about 15 kDa to about 50 kDa, or about 75 kDa to about 350 kDa. The hyaluronic acid may be crosslinked. In some embodiments, the hyaluronic acid has a crosslinking density of about 20% or more. In some embodiments, the hyaluronic acid is present at concentrations of 25 mcg / mL or more, about 25 mcg / mL to about 250 mcg / mL, about 25 mcg / mL to about 100 mcg / mL, about 100 mcg / mL to about 250 mcg / mL, about 1 mcg / mL to about 250 mcg / mL, or about 100 μg / mL or less. In some embodiments, hyaluronic acid is present at concentrations of approximately 100 mcg / mL to approximately 950 mcg / mL, approximately 200 mcg / mL to approximately 400 mcg / mL, approximately 400 mcg / mL to approximately 600 mcg / mL, approximately 600 mcg / mL to approximately 800 mcg / mL, or approximately 800 mcg / mL to approximately 950 mcg / mL.

[0009] In some embodiments, the composition further comprises a hyaluronidase inhibitor. In some embodiments, the hyaluronidase inhibitor is selected from high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurthiomalate, fenoprofen, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin, and O-sulfated hyaluronic acid (sHA), or any combination thereof.

[0010] In another embodiment, the Disclosure further provides a method for stimulating hair growth in the skin of a patient in need of hair growth, comprising administering an effective amount of the composition disclosed herein to the patient's skin. In some embodiments, administration involves applying the composition to the surface of the skin, while in other embodiments, administration involves injecting the composition into the dermis layer of the skin. The composition may be injected into the skin to a depth of about 400 micrometers to about 2 mm. In some embodiments, the composition is injected about 400 times per 1 cm of skin. 2 ~Approximately 650 injections / 1cm of skin 2 It is administered in multiple injections in a given quantity. In some embodiments, the needle is a microneedle. In some embodiments, the composition can be encapsulated in liposomes, for example, liposomes containing hydrogenated phospholipids.

[0011] In some embodiments, the method for stimulating hair growth further includes applying iontophoresis to the skin. In some embodiments, the method for stimulating hair growth further includes applying electroporation to the skin. In some embodiments, the method for stimulating hair growth further includes applying laser ablation to the skin. In some embodiments, the method for stimulating hair growth further includes applying radiofrequency thermal ablation to the skin. In some embodiments, the method for stimulating hair growth further includes applying a microneedle device to the skin.

[0012] Further areas to which this disclosure may apply will become apparent from the detailed description provided herein. The detailed description and specific examples, while illustrating preferred embodiments of this disclosure, are intended for illustrative purposes only and should be understood not to limit the scope of this disclosure. [Modes for carrying out the invention]

[0013] The following description of preferred embodiments(s) is purely illustrative and is intended not to limit in any way the Disclosure, the Application, or any use thereof.

[0014] As used throughout, ranges are used as abbreviations to indicate each value and all values ​​within that range. Any value within a range can be selected as the end of that range. Furthermore, all references cited herein are incorporated herein in their entirety for reference purposes. In the event of any conflict between definitions in this disclosure and definitions in the cited references, this disclosure shall prevail.

[0015] Unless otherwise specified, all percentages and quantities expressed herein and elsewhere shall be understood to refer to weight percentages. The quantities given are based on the active weight of the material.

[0016] In one aspect, the present invention provides a peptide (peptide 1.0) for stimulating hair growth, comprising a sequence selected from the group consisting of SEQ ID NOs: 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity. The term polypeptide may be used to describe the sequences detailed by SEQ ID NOs: 1 to 98, and it is understood, and is customary, that such terms may be used interchangeably.

[0017] For example, the present invention includes: 1.1. Peptide 1.0, wherein the peptide contains a sequence selected from the group consisting of SEQ ID NOs: 1 to 96.

[0018] 1.2. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 20, and optionally the peptide contains a sequence selected from the group consisting of SEQ ID NOs: 1 to 20.

[0019] 1.3. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 21 to 39, and optionally, the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 21 to 39.

[0020] 1.4. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 40 to 60, and optionally, the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 40 to 60.

[0021] 1.5. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 61-63, and optionally the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 61-63.

[0022] 1.6. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 64 to 71, and optionally the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 64 to 71.

[0023] 1.7. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 72-79, and optionally, the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 72-79.

[0024] 1.8. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 80 to 87, and optionally, the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 80 to 87.

[0025] 1.9. Peptide 1.0, wherein the peptide contains a sequence that has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 88 to 95, and optionally, the peptide contains a sequence selected from the group consisting of SEQ ID NOs. 88 to 95.

[0026] 1.10. Peptide 1.0, wherein the peptide contains a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 96, and optionally the peptide contains SEQ ID NO: 96.

[0027] 1.11. A peptide described in any one of the preceding items, wherein the peptide contains a CD44 binding site.

[0028] 1.12. Peptide 1.11, wherein the peptide contains SEQ ID NO: 97 or a variant thereof.

[0029] 1.13. Peptide 1.12, wherein a variant of sequence number 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 97.

[0030] 1.14. A peptide described in any one of the preceding paragraphs, wherein the peptide contains a calcium-binding site.

[0031] 1.15. Peptide 1.14, comprising SEQ ID NO: 98 or a variant thereof.

[0032] 1.16. Peptide 1.15, wherein a variant of sequence number 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 98.

[0033] 1.17. A peptide according to any one of the preceding paragraphs, wherein the peptide includes a CD4 binding site or a calcium binding site.

[0034] 1.18. Peptide 1.17, comprising SEQ ID NO: 97 or its variants, and SEQ ID NO: 98 or its variants.

[0035] 1.19. Peptide 1.18, wherein a variant of SEQ ID NO: 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 97, and a variant of SEQ ID NO: 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 98.

[0036] 1.20. A peptide according to any one of the preceding items, wherein the peptide has a length of 295 amino acids or less.

[0037] 1.21. A peptide according to any one of the preceding paragraphs, wherein the peptide has a length of 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0038] In another aspect, the present invention provides a composition (Composition 2.0) for stimulating hair growth, comprising a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity. For example, the present invention includes: 2.1. Composition 2.0, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 96.

[0039] 2.2. Composition 2.0 wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 20, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 20.

[0040] 2.3. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 21 to 39, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 21 to 39.

[0041] 2.4. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 40 to 60, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 40 to 60.

[0042] 2.5. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 61 to 63, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 61 to 63.

[0043] 2.6. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 64 to 71, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 64 to 71.

[0044] 2.7. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 72 to 79, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 72 to 79.

[0045] 2.8. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 80 to 87, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 80 to 87.

[0046] 2.9. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 88 to 95, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 88 to 95.

[0047] 2.10. Composition 2.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 96, and optionally the peptide comprises SEQ ID NO: 96.

[0048] 2.11. A composition according to any one of the preceding items, wherein the peptide contains a CD44 binding site.

[0049] 2.12. Composition 2.11, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof.

[0050] 2.13. Composition 2.12, wherein a variant of sequence number 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 97.

[0051] 2.14. A composition according to any one of the preceding items, wherein the peptide contains a calcium binding site.

[0052] 2.15. Composition 2.14, wherein the peptide comprises SEQ ID NO: 98 or a variant thereof.

[0053] 2.16. Composition 2.15, wherein a variant of sequence number 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 98.

[0054] 2.17. A composition according to any one of the preceding paragraphs, wherein the peptide comprises a CD4 binding site or a calcium binding site.

[0055] 2.18. Composition 2.17, comprising peptides SEQ ID NO: 97 or its variants, and SEQ ID NO: 98 or its variants.

[0056] 2.19. Composition 2.18, wherein a variant of sequence number 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 97, and a variant of sequence number 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 98.

[0057] 2.20. A composition according to any one of the preceding items, wherein the peptide has a length of 295 amino acids or less.

[0058] 2.21. Composition 2.20 in which the peptide has a length of 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0059] 2.22. A composition according to any one of the preceding items, wherein the composition comprises about 0.01% by weight or more of peptides, and optionally comprises about 0.025% by weight or more, for example, about 0.05% by weight or more, about 0.075% by weight or more, about 0.1% by weight or more, about 0.25% by weight or more, about 0.5% by weight or more, about 0.75% by weight or more, about 1% by weight or more, about 2.5% by weight or more, about 5% by weight or more, about 7.5% by weight or more, or about 10% by weight or more of peptides.

[0060] 2.23. The composition contains 0.01 to 20% by weight of peptides, and optionally the composition contains 0.025 to 20% by weight, 0.05 to 20% by weight, 0.75 to 20% by weight, 0.1 to 20% by weight, 0.25 to 20% by weight, 0.5 to 20% by weight, 0.75 to 20% by weight, 1 to 20% by weight, 2.5 to 20% by weight, 5 to 20% by weight, 7.5 to 20% by weight, 10 to 20% by weight, 0.01 to 15% by weight, 0.025 to 15% by weight, 0.05 to 15% by weight, 0.75 to 15% by weight, 0.1 to 15% by weight, 0.25 to 15% by weight, 0.5 to 15% by weight, 0.75 to 15% by weight, 1 to 15% by weight, 2.5 to 15% by weight, 5 to 15% by weight, 7.5 A composition according to any one of the preceding items, comprising 15% by weight, or 10-15% by weight, of a peptide.

[0061] 2.24. The composition is approximately 0.01% to approximately 0.025% by weight, approximately 0.025% to approximately 0.05% by weight, approximately 0.025% to approximately 0.075% by weight, approximately 0.025% to approximately 0.1% by weight, approximately 0.01% to approximately 0.1% by weight, approximately 0.05% to approximately 0.075% by weight, approximately 0.05% to approximately 0.1% by weight, approximately 0.075% to approximately 0.1% by weight, approximately 0.1% to approximately 0.2% by weight, approximately 0.1% to approximately 0.5% by weight A composition according to any one of the preceding items, comprising a peptide in an amount of %, approximately 0.2% to approximately 0.4% by weight, approximately 0.5% to approximately 1% by weight, approximately 0.4% to approximately 0.6% by weight, approximately 0.6% to approximately 0.8% by weight, approximately 0.8% to approximately 1% by weight, approximately 1% to approximately 2% by weight, approximately 1% to approximately 5% by weight, approximately 2% to approximately 4% by weight, approximately 5% to approximately 10% by weight, approximately 4% to approximately 6% by weight, approximately 6% to approximately 8% by weight, or approximately 8% to approximately 10% by weight.

[0062] 2.25. A composition according to any one of the preceding items, wherein the composition comprises one or more additional ligands that bind to CD44.

[0063] 2.26. Composition 2.25, wherein one or more additional ligands that bind to CD44 are selected from the group consisting of cerglycine, chondroitin or a salt thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor-binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6), green fluorescent protein (GFP), and any combination thereof.

[0064] 2.27. A composition according to any one of the preceding items, wherein the composition comprises cerglycine, and optionally comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of cerglycine.

[0065] 2.28. A composition according to any one of the preceding items, wherein the composition comprises chondroitin or a salt thereof, and optionally, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of chondroitin or a salt thereof.

[0066] 2.29. Composition 2.28, which contains chondroitin sulfate.

[0067] 2.30. A composition according to any one of the preceding items, wherein the composition comprises fibrin, and optionally comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of fibrin.

[0068] 2.31. A composition according to any one of the preceding items, wherein the composition comprises collagen, and optionally comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of collagen.

[0069] 2.32. A composition according to any one of the preceding items, wherein the composition comprises fibronectin, and optionally, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of fibronectin.

[0070] 2.33. A composition according to any one of the preceding items, wherein the composition comprises insulin-like growth factor-binding protein (IGFBP), and optionally, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of insulin-like growth factor-binding protein.

[0071] 2.34. A composition according to any one of the preceding items, wherein the composition comprises green fluorescent protein (GFP), and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of GFP.

[0072] 2.35. A composition according to any one of the preceding items, wherein the composition comprises hyaluronic acid.

[0073] 2.36. Composition 2.35, wherein hyaluronic acid has a molecular weight in the range of approximately 20 kDa to 1350 kDa, approximately 4 kDa to approximately 10 kDa, approximately 10 kDa to approximately 100 kDa, approximately 15 kDa to approximately 50 kDa, or approximately 75 kDa to approximately 350 kDa.

[0074] 2.37. A composition according to any one of items 2.35 to 2.36, wherein hyaluronic acid is crosslinked, and optionally the hyaluronic acid has a crosslinking density of about 20% or more.

[0075] 2.38. A composition according to any one of sections 2.35 to 2.37, wherein hyaluronic acid is present at a concentration of 25 mcg / mL or more, approximately 25 mcg / mL to approximately 250 mcg / mL, approximately 25 mcg / mL to approximately 100 mcg / mL, approximately 100 mcg / mL to approximately 250 mcg / mL, approximately 1 mcg / mL to approximately 250 mcg / mL, approximately 100 μg / mL or less, approximately 100 mcg / mL to approximately 950 mcg / mL, approximately 200 mcg / mL to approximately 400 mcg / mL, approximately 400 mcg / mL to approximately 600 mcg / mL, approximately 600 mcg / mL to approximately 800 mcg / mL, or approximately 800 mcg / mL to approximately 950 mcg / mL.

[0076] 2.39. A composition according to any one of the preceding items, wherein the composition comprises a hyaluronidase inhibitor.

[0077] 2.40. Composition 2.39 in which the hyaluronidase inhibitor is selected from high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurthiomalate, fenoprofen, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin, and O-sulfated hyaluronic acid (sHA), or any combination thereof.

[0078] 2.41. A composition according to any one of the compositions 2.39 to 2.40, wherein the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of a hyaluronidase inhibitor.

[0079] 2.42. A composition according to any one of the preceding paragraphs, wherein the composition comprises a carrier medium.

[0080] 2.43. Composition 2.42, in which the carrier medium contains saline solution.

[0081] 2.44. A composition according to any one of the preceding paragraphs, wherein the composition contains a preservative or a biocide.

[0082] 2.45. A composition according to any one of the preceding items, wherein the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, a liposome, or a vesicle.

[0083] 2.46. A composition according to any one of the preceding paragraphs, wherein the composition comprises a surfactant.

[0084] 2.47. A composition according to any one of the preceding items, wherein the composition comprises one or more of the following: soybean oil, jojoba oil, aloe vera oil, soy phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropyl alcohol, glycerin, glyceryl monostearate, and propylene glycol.

[0085] The composition of the present invention comprises a peptide containing a CD44-binding and / or calcium-binding fragment of osteopontin or a variant thereof. Osteopontin is an extracellular signaling protein that is a natural ligand for CD44. Although not bound by theory, it is thought that osteopontin may induce CD44 activation by proteolytic cleavage of CD44, thereby leading to the intracellular release of the CD44 intracellular domain (ICD). The CD44-ICD is then released, translocated to the nucleus, and regulates gene expression. Osteopontin is described in International Patent Publication No. 2018175630 and International Patent Publication No. 2023028542, both of which are incorporated by reference. Osteopontin is composed of approximately 300 amino acids (314 amino acids in humans). Osteopontin contains a putative CD44 binding site (KSKEEDKHLKFRISHEL, SEQ ID NO: 97) and a putative calcium binding site (DWDSRGKDSYETS, SEQ ID NO: 98) in its C-terminal region. In some embodiments, the peptide of the present invention includes a CD44 binding site, e.g., SEQ ID NO: 97 or a variant thereof. Variants of SEQ ID NO: 97 may have at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 97. In some embodiments, the peptide includes a calcium binding site, e.g., SEQ ID NO: 98 or a variant thereof. Variants of SEQ ID NO: 98 may have at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 98. In some embodiments, the peptide includes a CD44 binding site, e.g., SEQ ID NO: 97 or a variant thereof, and a calcium binding site, e.g., SEQ ID NO: 98 or a variant thereof.

[0086] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity. In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 96. The sequences of SEQ ID NOs: 1 to 96 are shown in Table 1.

[0087] [Table 1-1]

[0088] [Table 1-2]

[0089] [Table 1-3]

[0090] [Table 1-4]

[0091] [Table 1-5]

[0092] [Table 1-6]

[0093] [Table 1-7]

[0094] [Table 1-8]

[0095] [Table 1-9]

[0096] [Table 1-10]

[0097] [Table 1-11]

[0098] [Table 1-12]

[0099] [Table 1-13]

[0100] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 1 to 20 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0101] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 21 to 39 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0102] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 40 to 60 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0103] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 61 to 63 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0104] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 64 to 71 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0105] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 72-79 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0106] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 80 to 87 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0107] In some embodiments, the composition comprises a peptide containing a sequence selected from the group consisting of SEQ ID NOs: 88 to 95 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

[0108] In some embodiments, the composition comprises a peptide having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 96. In some embodiments, the composition comprises a peptide containing SEQ ID NO: 96.

[0109] In some embodiments, the peptide has a length of 295 amino acids or less, for example, 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0110] In some embodiments, the composition contains about 0.01% by weight or more of the peptide. In some embodiments, the composition contains about 0.025% by weight or more of the peptide, for example, about 0.05% by weight or more, about 0.075% by weight or more, about 0.1% by weight or more, about 0.25% by weight or more, about 0.5% by weight or more, about 0.75% by weight or more, about 1% by weight or more, about 2.5% by weight or more, about 5% by weight or more, about 7.5% by weight or more, or about 10% by weight or more of the peptide.

[0111] In some embodiments, the composition contains 0.01-20% by weight, 0.025-20% by weight, 0.05-20% by weight, 0.75-20% by weight, 0.1-20% by weight, 0.25-20% by weight, 0.5-20% by weight, 0.75-20% by weight, 1-20% by weight, 2.5-20% by weight, 5-20% by weight, 7.5-20% by weight, or 10-20% by weight of peptides. In some embodiments, the composition contains 0.01-15% by weight, 0.025-15% by weight, 0.05-15% by weight, 0.75-15% by weight, 0.1-15% by weight, 0.25-15% by weight, 0.5-15% by weight, 0.75-15% by weight, 1-15% by weight, 2.5-15% by weight, 5-15% by weight, 7.5-15% by weight, or 10-15% by weight of peptides.

[0112] In some embodiments, the composition is approximately 0.01% to approximately 0.025% by weight, approximately 0.025% to approximately 0.05% by weight, approximately 0.025% to approximately 0.075% by weight, approximately 0.025% to approximately 0.1% by weight, approximately 0.01% to approximately 0.1% by weight, approximately 0.05% to approximately 0.075% by weight, approximately 0.05% to approximately 0.1% by weight, approximately 0.075% to approximately 0.1% by weight, approximately 0.1% to approximately 0.2% by weight, approximately Contains peptides in amounts of 0.1% to approximately 0.5% by weight, approximately 0.2% to approximately 0.4% by weight, approximately 0.5% to approximately 1% by weight, approximately 0.4% to approximately 0.6% by weight, approximately 0.6% to approximately 0.8% by weight, approximately 0.8% to approximately 1% by weight, approximately 1% to approximately 2% by weight, approximately 1% to approximately 5% by weight, approximately 2% to approximately 4% by weight, approximately 5% to approximately 10% by weight, approximately 4% to approximately 6% by weight, approximately 6% to approximately 8% by weight, or approximately 8% to approximately 10% by weight.

[0113] In some embodiments, the compositions of the present invention may further comprise one or more additional ligands that bind to CD44. In some embodiments, the one or more additional ligands that bind to CD44 are selected from the group consisting of cerglycine, chondroitin or a salt thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor-binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6), green fluorescent protein, and any combination thereof.

[0114] In some embodiments, the composition comprises about 0.01% by weight or more of cellglycine, about 0.025% by weight or more of cellglycine, about 0.050% by weight or more of cellglycine, about 0.075% by weight or more of cellglycine, about 0.1% by weight or more of cellglycine, about 0.25% by weight or more of cellglycine, about 0.5% by weight or more of cellglycine, about 0.75% by weight or more of cellglycine, about 1% by weight or more of cellglycine, about 2.5% by weight or more of cellglycine, about 5% by weight or more of cellglycine, about 7.5% by weight or more of cellglycine, or about 10% by weight or more of cellglycine. In some embodiments, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of cellglycine. In some embodiments, the composition contains approximately 0.01% to approximately 0.025% by weight of selglycine, approximately 0.025% to approximately 0.05% by weight of selglycine, approximately 0.025% to approximately 0.075% by weight of selglycine, approximately 0.025% to approximately 0.1% by weight of selglycine, approximately 0.01% to approximately 0.1% by weight of selglycine, approximately 0.05% to approximately 0.075% by weight of selglycine, approximately 0.05% to approximately 0.1% by weight of selglycine, approximately 0.075% to approximately 0.1% by weight of selglycine, approximately 0.1% to approximately 0.2% by weight of selglycine, and approximately 0.1% to approximately 0.5% by weight of selglycine. Contains selglycine by weight %, approximately 0.2% to approximately 0.4% by weight, approximately 0.5% to approximately 1% by weight, approximately 0.4% to approximately 0.6% by weight, approximately 0.6% to approximately 0.8% by weight, approximately 0.8% to approximately 1% by weight, approximately 1% to approximately 2% by weight, approximately 1% to approximately 5% by weight, approximately 2% to approximately 4% by weight, approximately 5% to approximately 10% by weight, approximately 4% to approximately 6% by weight, approximately 6% to approximately 8% by weight, or approximately 8% to approximately 10% by weight of selglycine.

[0115] In some embodiments, the composition comprises chondroitin or a salt thereof, for example, chondroitin sulfate. In some embodiments, the composition comprises about 0.01% by weight or more of chondroitin or a salt thereof, about 0.025% by weight or more of chondroitin or a salt thereof, about 0.050% by weight or more of chondroitin or a salt thereof, about 0.075% by weight or more of chondroitin or a salt thereof, about 0.1% by weight or more of chondroitin or a salt thereof, about 0.25% by weight or more of chondroitin or a salt thereof, about 0.5% by weight or more of chondroitin or a salt thereof, about 0.75% by weight or more of chondroitin or a salt thereof, about 1% by weight or more of chondroitin or a salt thereof, about 2.5% by weight or more of chondroitin or a salt thereof, about 5% by weight or more of chondroitin or a salt thereof, about 7.5% by weight or more of chondroitin or a salt thereof, or about 10% by weight or more of chondroitin or a salt thereof. In some embodiments, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of chondroitin or a salt thereof.In some embodiments, the composition contains about 0.01% to about 0.025% by weight of chondroitin or its salt, about 0.025% to about 0.05% by weight of chondroitin or its salt, about 0.025% to about 0.075% by weight of chondroitin or its salt, about 0.025% to about 0.1% by weight of chondroitin or its salt, about 0.01% to about 0.1% by weight of chondroitin or its salt, about 0.05% to about 0.075% by weight of chondroitin or its salt, about 0.05% to about 0.1% by weight of chondroitin or its salt, about 0.075% to about 0.1% by weight of chondroitin or its salt, about 0.1% to about 0.2% by weight of chondroitin or its salt, about 0.1% to about 0.5% by weight of chondroitin or The salt contains approximately 0.2% to 0.4% by weight of chondroitin or its salt, approximately 0.5% to 1% by weight of chondroitin or its salt, approximately 0.4% to 0.6% by weight of chondroitin or its salt, approximately 0.6% to 0.8% by weight of chondroitin or its salt, approximately 0.8% to 1% by weight of chondroitin or its salt, approximately 1% to 2% by weight of chondroitin or its salt, approximately 1% to 5% by weight of chondroitin or its salt, approximately 2% to 4% by weight of chondroitin or its salt, approximately 5% to 10% by weight of chondroitin or its salt, approximately 4% to 6% by weight of chondroitin or its salt, approximately 6% to 8% by weight of chondroitin or its salt, or approximately 8% to 10% by weight of chondroitin or its salt.

[0116] In some embodiments, the composition comprises about 0.01% by weight or more of fibrin, about 0.025% by weight or more of fibrin, about 0.050% by weight or more of fibrin, about 0.075% by weight or more of fibrin, about 0.1% by weight or more of fibrin, about 0.25% by weight or more of fibrin, about 0.5% by weight or more of fibrin, about 0.75% by weight or more of fibrin, about 1% by weight or more of fibrin, about 2.5% by weight or more of fibrin, about 5% by weight or more of fibrin, about 7.5% by weight or more of fibrin, or about 10% by weight or more of fibrin. In some embodiments, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of fibrin. In some embodiments, the composition is approximately 0.01% to approximately 0.025% by weight of fibrin, approximately 0.025% to approximately 0.05% by weight of fibrin, approximately 0.025% to approximately 0.075% by weight of fibrin, approximately 0.025% to approximately 0.1% by weight of fibrin, approximately 0.01% to approximately 0.1% by weight of fibrin, approximately 0.05% to approximately 0.075% by weight of fibrin, approximately 0.05% to approximately 0.1% by weight of fibrin, approximately 0.075% to approximately 0.1% by weight of fibrin, approximately 0.1% to approximately 0.2% by weight of fibrin, approximately 0.1% to approximately 0 Contains 0.5% by weight fibrin, approximately 0.2% to approximately 0.4% by weight fibrin, approximately 0.5% to approximately 1% by weight fibrin, approximately 0.4% to approximately 0.6% by weight fibrin, approximately 0.6% to approximately 0.8% by weight fibrin, approximately 0.8% to approximately 1% by weight fibrin, approximately 1% to approximately 2% by weight fibrin, approximately 1% to approximately 5% by weight fibrin, approximately 2% to approximately 4% by weight fibrin, approximately 5% to approximately 10% by weight fibrin, approximately 4% to approximately 6% by weight fibrin, approximately 6% to approximately 8% by weight fibrin, or approximately 8% to approximately 10% by weight fibrin.

[0117] In some embodiments, the composition contains about 0.01% by weight or more of collagen, about 0.025% by weight or more of collagen, about 0.050% by weight or more of collagen, about 0.075% by weight or more of collagen, about 0.1% by weight or more of collagen, about 0.25% by weight or more of collagen, about 0.5% by weight or more of collagen, about 0.75% by weight or more of collagen, about 1% by weight or more of collagen, about 2.5% by weight or more of collagen, about 5% by weight or more of collagen, about 7.5% by weight or more of collagen, or about 10% by weight or more of collagen. In some embodiments, the composition contains 0.01 to 15% by weight of collagen, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of collagen. In some embodiments, the composition contains approximately 0.01% to approximately 0.025% by weight of collagen, approximately 0.025% to approximately 0.05% by weight of collagen, approximately 0.025% to approximately 0.075% by weight of collagen, approximately 0.025% to approximately 0.1% by weight of collagen, approximately 0.01% to approximately 0.1% by weight of collagen, approximately 0.05% to approximately 0.075% by weight of collagen, approximately 0.05% to approximately 0.1% by weight of collagen, approximately 0.075% to approximately 0.1% by weight of collagen, approximately 0.1% to approximately 0.2% by weight of collagen, and approximately 0.1% to approximately 0 Contains 0.5% by weight collagen, approximately 0.2% to approximately 0.4% by weight collagen, approximately 0.5% to approximately 1% by weight collagen, approximately 0.4% to approximately 0.6% by weight collagen, approximately 0.6% to approximately 0.8% by weight collagen, approximately 0.8% to approximately 1% by weight collagen, approximately 1% to approximately 2% by weight collagen, approximately 1% to approximately 5% by weight collagen, approximately 2% to approximately 4% by weight collagen, approximately 5% to approximately 10% by weight collagen, approximately 4% to approximately 6% by weight collagen, approximately 6% to approximately 8% by weight collagen, or approximately 8% to approximately 10% by weight collagen.

[0118] In some embodiments, the composition comprises about 0.01% by weight or more of fibronectin, about 0.025% by weight or more of fibronectin, about 0.050% by weight or more of fibronectin, about 0.075% by weight or more of fibronectin, about 0.1% by weight or more of fibronectin, about 0.25% by weight or more of fibronectin, about 0.5% by weight or more of fibronectin, about 0.75% by weight or more of fibronectin, about 1% by weight or more of fibronectin, about 2.5% by weight or more of fibronectin, about 5% by weight or more of fibronectin, about 7.5% by weight or more of fibronectin, or about 10% by weight or more of fibronectin. In some embodiments, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of fibronectin. In some embodiments, the composition contains about 0.01% to about 0.025% by weight of fibronectin, about 0.025% to about 0.05% by weight of fibronectin, about 0.025% to about 0.075% by weight of fibronectin, about 0.025% to about 0.1% by weight of fibronectin, about 0.01% to about 0.1% by weight of fibronectin, about 0.05% to about 0.075% by weight of fibronectin, about 0.05% to about 0.1% by weight of fibronectin, about 0.075% to about 0.1% by weight of fibronectin, about 0.1% to about 0.2% by weight of fibronectin, and about 0.1% to about 0.5% by weight of Contains fibronectin, approximately 0.2% to 0.4% by weight of fibronectin, approximately 0.5% to 1% by weight of fibronectin, approximately 0.4% to 0.6% by weight of fibronectin, approximately 0.6% to 0.8% by weight of fibronectin, approximately 0.8% to 1% by weight of fibronectin, approximately 1% to 2% by weight of fibronectin, approximately 1% to 5% by weight of fibronectin, approximately 2% to 4% by weight of fibronectin, approximately 5% to 10% by weight of fibronectin, approximately 4% to 6% by weight of fibronectin, approximately 6% to 8% by weight of fibronectin, or approximately 8% to 10% by weight of fibronectin.

[0119] In some embodiments, the composition contains about 0.01% by weight or more of insulin-like growth factor-binding protein, about 0.025% by weight or more of insulin-like growth factor-binding protein, about 0.050% by weight or more of insulin-like growth factor-binding protein, about 0.075% by weight or more of insulin-like growth factor-binding protein, about 0.1% by weight or more of insulin-like growth factor-binding protein, about 0.25% by weight or more of insulin-like growth factor-binding protein, about 0.5% by weight or more of insulin-like growth factor-binding protein, about 0.75% by weight or more of insulin-like growth factor-binding protein, about 1% by weight or more of insulin-like growth factor-binding protein, about 2.5% by weight or more of insulin-like growth factor-binding protein, about 5% by weight or more of insulin-like growth factor-binding protein, about 7.5% by weight or more of insulin-like growth factor-binding protein, or about 10% by weight or more of insulin-like growth factor-binding protein. In some embodiments, the composition contains 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of insulin-like growth factor-binding protein.In some embodiments, the composition contains approximately 0.01% to approximately 0.025% by weight of insulin-like growth factor-binding protein, approximately 0.025% to approximately 0.05% by weight of insulin-like growth factor-binding protein, approximately 0.025% to approximately 0.075% by weight of insulin-like growth factor-binding protein, approximately 0.025% to approximately 0.1% by weight of insulin-like growth factor-binding protein, approximately 0.01% to approximately 0.1% by weight of insulin-like growth factor-binding protein, approximately 0.05% to approximately 0.075% by weight of insulin-like growth factor-binding protein, approximately 0.05% to approximately 0.1% by weight of insulin-like growth factor-binding protein, approximately 0.075% to approximately 0.1% by weight of insulin-like growth factor-binding protein, approximately 0.1% to approximately 0.2% by weight of insulin-like growth factor-binding protein, and approximately 0.1% to approximately 0.5% by weight of insulin-like growth factor-binding protein. It contains approximately 0.2% to 0.4% by weight of insulin-like growth factor-binding protein, approximately 0.5% to 1% by weight of insulin-like growth factor-binding protein, approximately 0.4% to 0.6% by weight of insulin-like growth factor-binding protein, approximately 0.6% to 0.8% by weight of insulin-like growth factor-binding protein, approximately 0.8% to 1% by weight of insulin-like growth factor-binding protein, approximately 1% to 2% by weight of insulin-like growth factor-binding protein, approximately 1% to 5% by weight of insulin-like growth factor-binding protein, approximately 2% to 4% by weight of insulin-like growth factor-binding protein, approximately 5% to 10% by weight of insulin-like growth factor-binding protein, approximately 4% to 6% by weight of insulin-like growth factor-binding protein, approximately 6% to 8% by weight of insulin-like growth factor-binding protein, or approximately 8% to 10% by weight of insulin-like growth factor-binding protein.

[0120] In some embodiments, the composition contains about 0.01% by weight or more of green fluorescent protein, about 0.025% by weight or more of green fluorescent protein, about 0.050% by weight or more of green fluorescent protein, about 0.075% by weight or more of green fluorescent protein, about 0.1% by weight or more of green fluorescent protein, about 0.25% by weight or more of green fluorescent protein, about 0.5% by weight or more of green fluorescent protein, about 0.75% by weight or more of green fluorescent protein, about 1% by weight or more of green fluorescent protein, about 2.5% by weight or more of green fluorescent protein, about 5% by weight or more of green fluorescent protein, about 7.5% by weight or more of green fluorescent protein, or about 10% by weight or more of green fluorescent protein. In some embodiments, the composition contains 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of green fluorescent protein. In some embodiments, the composition contains approximately 0.01% to approximately 0.025% by weight of green fluorescent protein, approximately 0.025% to approximately 0.05% by weight of green fluorescent protein, approximately 0.025% to approximately 0.075% by weight of green fluorescent protein, approximately 0.025% to approximately 0.1% by weight of green fluorescent protein, approximately 0.01% to approximately 0.1% by weight of green fluorescent protein, approximately 0.05% to approximately 0.075% by weight of green fluorescent protein, approximately 0.05% to approximately 0.1% by weight of green fluorescent protein, approximately 0.075% to approximately 0.1% by weight of green fluorescent protein, approximately 0.1% to approximately 0.2% by weight of green fluorescent protein, and approximately 0.1% to approximately 0.5% by weight of green It contains fluorescent protein, approximately 0.2% to 0.4% by weight of green fluorescent protein, approximately 0.5% to 1% by weight of green fluorescent protein, approximately 0.4% to 0.6% by weight of green fluorescent protein, approximately 0.6% to 0.8% by weight of green fluorescent protein, approximately 0.8% to 1% by weight of green fluorescent protein, approximately 1% to 2% by weight of green fluorescent protein, approximately 1% to 5% by weight of green fluorescent protein, approximately 2% to 4% by weight of green fluorescent protein, approximately 5% to 10% by weight of green fluorescent protein, approximately 4% to 6% by weight of green fluorescent protein, approximately 6% to 8% by weight of green fluorescent protein, or approximately 8% to 10% by weight of green fluorescent protein.

[0121] In some embodiments, the composition of the present invention may further contain hyaluronic acid. Hyaluronic acid is a natural ligand for CD44, is pro-inflammatory, and stimulates hair growth. Hyaluronic acid is a natural linear polymer containing repeating disaccharide units of β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine. In some embodiments, hyaluronic acid has a low average molecular weight, which, as used herein, refers to a range of about 15,000 Da to about 40,000 Da. In some embodiments, hyaluronic acid has a medium average molecular weight, which, as used herein, refers to a range of about 75,000 Da to about 350,000 Da. In some embodiments, hyaluronic acid has a high average molecular weight, which, as used herein, refers to a range of about 950,000 Da or more.

[0122] In some embodiments, hyaluronic acid has an average molecular weight in the range of about 4,000 Da or less to about 10,000 Da. In some embodiments, hyaluronic acid has an average molecular weight in the range of about 10,000 Da to about 100,000 Da. In some embodiments, hyaluronic acid has an average molecular weight in the range of about 100,000 Da to about 1,500,000 Da or more.

[0123] In some embodiments, hyaluronic acid is present in a range of approximately 1 kDa to 10 kDa, 10 kDa to 50 kDa, 50 kDa to 100 kDa, 100 kDa to 150 kDa, 200 kDa to 250 kDa, 300 kDa to 350 kDa, 400 kDa to 450 kDa, and 500 kDa. Approximately 550kDa, approximately 600kDa to approximately 650kDa, approximately 700kDa to approximately 750kDa, approximately 800kDa to approximately 850kDa, approximately 900kDa to approximately 1000kDa, approximately 1000kDa to approximately 1100kDa, approximately 1100kDa to approximately 1200kDa, approximately 1200kDa to approximately 1300kDa, approximately 1300kDa a ~ approx. 1400kDa, approx. 1400kDa ~ approx. 1500kDa, approx. 1kDa ~ approx. 100kDa, approx. 100kDa ~ approx. 250kDa, approx. 250kDa ~ approx. It has an average molecular weight of approximately ~1500kDa, approximately 1kDa to approximately 250kDa, approximately 1kDa to approximately 500kDa, approximately 100kDa to approximately 500kDa, approximately 250kDa to approximately 750kDa, approximately 500kDa to approximately 1000kDa, approximately 750kDa to approximately 1250kDa, or approximately 1000kDa to approximately 1500kDa.

[0124] In some embodiments, hyaluronic acid is crosslinked. In some embodiments, hyaluronic acid has a crosslinking density of approximately 20% or more. Crosslinking can improve the lifespan of hyaluronic acid, and in some embodiments, a certain degree of crosslinking may be desirable. In some embodiments, hyaluronic acid has sufficient crosslinking to last for about one week. However, although not constrained by the mechanism of action, hyaluronic acid is thought to be effective in stimulating hair growth through interaction with CD44 receptors. Therefore, it is desirable that the crosslinking of hyaluronic acid is not so extensive as to interfere with its ability to interact with CD44 receptors.

[0125] The hydroxyl (-OH), carboxylic acid (-COOH), and / or amide (-NHCOCH3) functional groups of hyaluronic acid can be cross-linked via ether bonds (R-O-R), ester bonds (R-COO-R), or carbodiimides, respectively. In some embodiments, hyaluronic acid is cross-linked with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), glutaraldehyde (GTA), poly(ethylene glycol) diglycidyl ether (PEGDE), ethylene glycol diglycidyl ether (EGDE), divinyl sulfonate (DVS), or pentaerythritol tetraacrylate (PT).

[0126] Hyaluronic acid is about 1×10 -7 mol / cm 3 or more, about 2×10 -7 mol / cm 3 or more, about 3×10 -7 mol / cm 3 or more, about 4×10 -7 mol / cm 3 or more, about 5×10 -7 mol / cm 3 or more, about 6×10 -7 mol / cm 3 or more, about 7×10 -7 0]mol / cm 3 or more, about 8×10 -7 mol / cm 3 or more, about 9×10 -7 mol / cm 3 ; or more, about 1×10 -6 mol / cm 3 or more, about 2×10 -6 mol / cm 3 or more, about 3×10 -6 mol / cm 3 or more, about 4×10 -6 mol / cm 3 or more, about 5×10 -6 mol / cm 3 or more, about 6×10 -6 mol / cm 3 or more, about 7×10 -6 mol / cm 3 or more, about 8×10 -6 mol / cm3 The above is approximately 9 x 10 -6 mol / cm 3 The above, or approximately 1 x 10 -6 mol / cm 3 It may have a crosslinking density of the above. In some embodiments, hyaluronic acid has a crosslinking density of about 1 × 10⁻⁶ -7 mol / cm 3 ~Approx. 1×10 -5 mol / cm 3 , about 1×10 -7 mol / cm 3 ~Approx. 1×10 -6 mol / cm 3 , about 1×10 -7 mol / cm 3 ~Approx. 5×10 -7 mol / cm 3 , about 5×10 -7 mol / cm 3 ~Approx. 1×10 -6 mol / cm 3 , about 1×10 -7 mol / cm 3 ~about 2×10 -7 mol / cm 3 , about 2×10 -7 mol / cm 3 ~Approx. 4×10 -7 mol / cm 3 , about 4×10 -7 mol / cm 3 ~about 6×10 -7 mol / cm 3 , about 6×10 -7 mol / cm 3 ~Approx. 8×10 -7 mol / cm 3 , or approximately 8 x 10 -7 mol / cm 3 ~Approx. 1×10 -6 mol / cm 3 , about 1×10 -6 mol / cm 3 ~Approx. 1×10 -5 mol / cm 3 , about 1×10 -6 mol / cm 3 ~Approx. 5×10 -6 mol / cm 3 , about 5×10 -6 mol / cm 3~about 1×10 -5 mol / cm 3 、about 1×10 -6 mol / cm 3 ~about 2×10 -6 mol / cm 3 、about 2×10 -7 mol / cm 3 ~about 4×10 -7 mol / cm 3 、about 4×10 -7 mol / cm 3 ~about 6×10 -7 mol / cm 3 、about 6×10 -7 mol / cm 3 ~about 8×10 -7 mol / cm 3 、about 8×10 -7 mol / cm 3 ~about 1×10 -5 mol / cm 3 、or about 5×10 -7 mol / cm 3 ~about 5×10 -6 mol / cm 3 and may have a crosslinking density of

[0127] In some embodiments, the composition may contain an amount of hyaluronic acid sufficient to provide a therapeutic effect, for example, to stimulate hair growth in patients who require hair growth. However, high concentrations of hyaluronic acid can cause undesirable inflammation. In some embodiments, the composition of the present invention contains an amount of hyaluronic acid sufficient to provide a therapeutic effect, for example, to stimulate hair growth in patients who require hair growth, but insufficient to cause an unacceptable inflammatory response. As used herein, mcg / mL and μg / mL both refer to micrograms / milliliter. In some embodiments, the hyaluronic acid is about 10 mcg / mL or more in the composition, about 15 mcg / mL or more in the composition, about 20 mcg / mL or more in the composition, about 25 mcg / mL or more in the composition, about 30 mcg / mL or more in the composition, about 35 mcg / mL or more in the composition, about 40 mcg / mL or more in the composition, about 45 mcg / mL or more in the composition, about 50 mcg / mL or more in the composition, about 55 mcg / mL or more in the composition, about 60 mcg / Compositions of mL or more, compositions of approximately 65 mcg / mL or more, compositions of approximately 70 mcg / mL or more, compositions of approximately 75 mcg / mL or more, compositions of approximately 80 mcg / mL or more, compositions of approximately 85 mcg / mL or more, compositions of approximately 90 mcg / mL or more, compositions of approximately 95 mcg / mL or more, compositions of approximately 100 mcg / mL or more, compositions of approximately 120 mcg / mL or more, compositions of approximately 140 mcg / mL or more, compositions of approximately 1600 mcg / mL or more Substances, compositions with approximately 180 mcg / mL or more, compositions with approximately 200 mcg / mL or more, compositions with approximately 220 mcg / mL or more, compositions with approximately 240 mcg / mL or more, compositions with approximately 260 mcg / mL or more, compositions with approximately 280 mcg / mL or more, compositions with approximately 300 mcg / mL or more, compositions with approximately 320 mcg / mL or more, compositions with approximately 340 mcg / mL or more, compositions with approximately 360 mcg / mL or more, compositions with approximately 380 mcg / mL or more , compositions of approximately 400 mcg / mL or more, compositions of approximately 420 mcg / mL or more, compositions of approximately 440 mcg / mL or more, compositions of approximately 460 mcg / mL or more, compositions of approximately 480 mcg / mL or more, compositions of approximately 500 mcg / mL or more, compositions of approximately 520 mcg / mL or more, compositions of approximately 540 mcg / mL or more, compositions of approximately 560 mcg / mL or more, compositions of approximately 580 mcg / mL or more, compositions of approximately 600 mcg / mL or more,It exists in amounts of approximately 620 mcg / mL or more, approximately 640 mcg / mL or more, approximately 660 mcg / mL or more, approximately 680 mcg / mL or more, approximately 700 mcg / mL or more, approximately 720 mcg / mL or more, approximately 740 mcg / mL or more, approximately 760 mcg / mL or more, approximately 780 mcg / mL or more, approximately 800 mcg / mL or more, approximately 820 mcg / mL or more, approximately 840 mcg / mL or more, approximately 860 mcg / mL or more, approximately 880 mcg / mL or more, approximately 900 mcg / mL or more, approximately 920 mcg / mL or more, approximately 940 mcg / mL or more, approximately 960 mcg / mL or more, or approximately 980 mcg / mL or more.

[0128] In some embodiments, hyaluronic acid is used in compositions ranging from approximately 1 mcg / mL to approximately 250 mcg / mL, approximately 10 mcg / mL to approximately 250 mcg / mL, approximately 10 mcg / mL to approximately 200 mcg / mL, approximately 10 mcg / mL to approximately 150 mcg / mL, approximately 10 mcg / mL to approximately 100 mcg / mL, approximately 25 mcg / mL to approximately 250 mcg / mL, and approximately 25 mcg / mL. Compositions containing approximately 200 mcg / mL, compositions containing approximately 25 mcg / mL to approximately 150 mcg / mL, compositions containing approximately 25 mcg / mL to approximately 100 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 250 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 200 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 150 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 100 mcg / mL, and combinations containing approximately 75 mcg / mL. Compositions containing approximately 250 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 200 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 150 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 100 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 250 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 200 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 150 mcg / mL, approximately 150 mcg The compositions exist in the following ranges: compositions of approximately 250 mcg / mL to approximately 200 mcg / mL to approximately 250 mcg / mL, compositions of approximately 60 mcg / mL to approximately 80 mcg / mL, compositions of approximately 50 mcg / mL to approximately 75 mcg / mL, compositions of approximately 25 mcg / mL to approximately 75 mcg / mL, compositions of approximately 10 mcg / mL to approximately 50 mcg / mL, or compositions of approximately 10 mcg / mL to approximately 25 mcg / mL.

[0129] In some embodiments, hyaluronic acid is used in compositions ranging from approximately 1 mcg / mL to approximately 500 mcg / mL, approximately 10 mcg / mL to approximately 500 mcg / mL, approximately 10 mcg / mL to approximately 450 mcg / mL, approximately 10 mcg / mL to approximately 400 mcg / mL, approximately 10 mcg / mL to approximately 350 mcg / mL, approximately 25 mcg / mL to approximately 500 mcg / mL, and approximately 25 mcg / mL to approximately 450 mcg / mL. Compositions of approximately 25 mcg / mL to approximately 400 mcg / mL, compositions of approximately 25 mcg / mL to approximately 350 mcg / mL, compositions of approximately 50 mcg / mL to approximately 500 mcg / mL, compositions of approximately 50 mcg / mL to approximately 450 mcg / mL, compositions of approximately 50 mcg / mL to approximately 400 mcg / mL, compositions of approximately 50 mcg / mL to approximately 350 mcg / mL, compositions of approximately 75 mcg / mL to approximately 500 mcg / mL, compositions of approximately 75 mcg / mL to approximately 4 Compositions containing 50 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 400 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 350 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 500 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 450 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 400 mcg / mL, compositions containing approximately 100 mcg / mL to approximately 350 mcg / mL, compositions containing approximately 200 mcg / mL to approximately 500 mcg / mL The substance exists in the following ranges: compositions of approximately 200 mcg / mL to approximately 450 mcg / mL, compositions of approximately 200 mcg / mL to approximately 400 mcg / mL, compositions of approximately 200 mcg / mL to approximately 350 mcg / mL, compositions of approximately 300 mcg / mL to approximately 500 mcg / mL, compositions of approximately 300 mcg / mL to approximately 450 mcg / mL, compositions of approximately 300 mcg / mL to approximately 400 mcg / mL, and compositions of approximately 300 mcg / mL to approximately 350 mcg / mL.

[0130] In some embodiments, hyaluronic acid is used in compositions ranging from approximately 1 mcg / mL to approximately 750 mcg / mL, approximately 10 mcg / mL to approximately 750 mcg / mL, approximately 10 mcg / mL to approximately 700 mcg / mL, approximately 10 mcg / mL to approximately 650 mcg / mL, approximately 10 mcg / mL to approximately 600 mcg / mL, approximately 25 mcg / mL to approximately 750 mcg / mL, and approximately 25 mcg / mL to approximately 700 mcg / mL. Compositions of approximately 25 mcg / mL to approximately 650 mcg / mL, compositions of approximately 25 mcg / mL to approximately 600 mcg / mL, compositions of approximately 50 mcg / mL to approximately 750 mcg / mL, compositions of approximately 50 mcg / mL to approximately 700 mcg / mL, compositions of approximately 50 mcg / mL to approximately 650 mcg / mL, compositions of approximately 50 mcg / mL to approximately 600 mcg / mL, compositions of approximately 75 mcg / mL to approximately 750 mcg / mL, compositions of approximately 75 mcg / mL to approximately 7 Compositions containing 00mcg / mL, compositions containing approximately 75mcg / mL to approximately 650mcg / mL, compositions containing approximately 75mcg / mL to approximately 600mcg / mL, compositions containing approximately 100mcg / mL to approximately 750mcg / mL, compositions containing approximately 100mcg / mL to approximately 700mcg / mL, compositions containing approximately 100mcg / mL to approximately 650mcg / mL, compositions containing approximately 100mcg / mL to approximately 600mcg / mL, compositions containing approximately 200mcg / mL to approximately 750mcg / mL The substance exists in the following ranges: compositions of approximately 200 mcg / mL to approximately 700 mcg / mL, compositions of approximately 200 mcg / mL to approximately 650 mcg / mL, compositions of approximately 200 mcg / mL to approximately 600 mcg / mL, compositions of approximately 300 mcg / mL to approximately 750 mcg / mL, compositions of approximately 300 mcg / mL to approximately 700 mcg / mL, compositions of approximately 300 mcg / mL to approximately 650 mcg / mL, and compositions of approximately 300 mcg / mL to approximately 600 mcg / mL.

[0131] In some embodiments, hyaluronic acid is used in compositions ranging from approximately 1 mcg / mL to approximately 950 mcg / mL, approximately 10 mcg / mL to approximately 950 mcg / mL, approximately 10 mcg / mL to approximately 900 mcg / mL, approximately 10 mcg / mL to approximately 850 mcg / mL, approximately 10 mcg / mL to approximately 800 mcg / mL, approximately 25 mcg / mL to approximately 950 mcg / mL, approximately 25 mcg / mL to approximately 900 mcg / mL, and approximately 25 mcg / mL to approximately 850 mcg / mL. Compositions containing approximately 25 mcg / mL to approximately 800 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 950 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 900 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 850 mcg / mL, compositions containing approximately 50 mcg / mL to approximately 800 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 950 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 900 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 850 mcg / mL, compositions containing approximately 75 mcg / mL to approximately 950 mcg / mL Compositions of approximately 800 mcg / mL, compositions of approximately 100 mcg / mL to approximately 950 mcg / mL, compositions of approximately 100 mcg / mL to approximately 900 mcg / mL, compositions of approximately 100 mcg / mL to approximately 850 mcg / mL, compositions of approximately 100 mcg / mL to approximately 800 mcg / mL, compositions of approximately 200 mcg / mL to approximately 950 mcg / mL, compositions of approximately 200 mcg / mL to approximately 900 mcg / mL, compositions of approximately 200 mcg / mL to approximately 850 mcg / mL, compositions of approximately 200 mcg / mL to approximately 800 mcg Compositions of approximately 300 mcg / mL to approximately 950 mcg / mL, compositions of approximately 300 mcg / mL to approximately 900 mcg / mL, compositions of approximately 300 mcg / mL to approximately 850 mcg / mL, compositions of approximately 300 mcg / mL to approximately 800 mcg / mL, compositions of approximately 400 mcg / mL to approximately 950 mcg / mL, compositions of approximately 400 mcg / mL to approximately 900 mcg / mL, compositions of approximately 400 mcg / mL to approximately 850 mcg / mL, compositions of approximately 400 mcg / mL to approximately 800 mcg / mL,Compositions of approximately 500 mcg / mL to approximately 950 mcg / mL, compositions of approximately 500 mcg / mL to approximately 900 mcg / mL, compositions of approximately 500 mcg / mL to approximately 850 mcg / mL, compositions of approximately 500 mcg / mL to approximately 800 mcg / mL, compositions of approximately 600 mcg / mL to approximately 950 mcg / mL, compositions of approximately 600 mcg / mL to approximately 900 mcg / mL, compositions of approximately 600 mcg / mL to approximately 850 mcg / mL, compositions of approximately 600 mcg / mL to approximately 800 mcg The compositions exist in the range of g / mL, approximately 700mcg / mL to approximately 950mcg / mL, approximately 700mcg / mL to approximately 900mcg / mL, approximately 700mcg / mL to approximately 850mcg / mL, or approximately 700mcg / mL to approximately 800mcg / mL, approximately 800mcg / mL to approximately 950mcg / mL, approximately 800mcg / mL to approximately 900mcg / mL, or approximately 800mcg / mL to approximately 850mcg / mL.

[0132] In some embodiments, the composition contains about 0.001% by weight or more of hyaluronic acid, about 0.0025% by weight or more of hyaluronic acid, about 0.0050% by weight or more of hyaluronic acid, about 0.0075% by weight or more of hyaluronic acid, about 0.01% by weight or more of hyaluronic acid, about 0.025% by weight or more of hyaluronic acid, about 0.05% by weight or more of hyaluronic acid, about 0.075% by weight or more of hyaluronic acid, about 0.1% by weight or more of hyaluronic acid, about 0.25% by weight or more of hyaluronic acid, about 0.5% by weight or more of hyaluronic acid, about 0.75% by weight or more of hyaluronic acid, about 1% by weight or more of hyaluronic acid, or about 5% by weight or more of hyaluronic acid. In some embodiments, the composition contains approximately 0.001% to approximately 0.0025% by weight of hyaluronic acid, approximately 0.0025% to approximately 0.005% by weight of hyaluronic acid, approximately 0.0025% to approximately 0.0075% by weight of hyaluronic acid, approximately 0.0025% to approximately 0.01% by weight of hyaluronic acid, approximately 0.001% to approximately 0.01% by weight of hyaluronic acid, approximately 0.005% by weight of hyaluronic acid Approximately 0.0075% by weight hyaluronic acid, approximately 0.005% to approximately 0.01% by weight hyaluronic acid, approximately 0.0075% to approximately 0.01% by weight hyaluronic acid, approximately 0.01% to approximately 0.02% by weight hyaluronic acid, approximately 0.01% to approximately 0.05% by weight hyaluronic acid, approximately 0.02% to approximately 0.04% by weight hyaluronic acid, approximately 0.05% to approximately 0.1% by weight hyaluronic acid Hyaluronic acid, approximately 0.04% to 0.06% by weight of hyaluronic acid, approximately 0.06% to 0.08% by weight of hyaluronic acid, approximately 0.08% to 0.1% by weight of hyaluronic acid, approximately 0.1% to 0.2% by weight of hyaluronic acid, approximately 0.1% to 0.5% by weight of hyaluronic acid, approximately 0.2% to 0.4% by weight of hyaluronic acid, approximately 0.5% to 1% by weight of hyaluronic acid It contains approximately 0.4% to 0.6% by weight of hyaluronic acid, approximately 0.6% to 0.8% by weight of hyaluronic acid, approximately 0.8% to 1% by weight of hyaluronic acid, approximately 1% to 2% by weight of hyaluronic acid, approximately 2% to 4% by weight of hyaluronic acid, approximately 4% to 6% by weight of hyaluronic acid, approximately 6% to 8% by weight of hyaluronic acid, or approximately 8% to 10% by weight of hyaluronic acid.In some embodiments, the composition comprises about 0.001% to about 10% by weight of hyaluronic acid, about 0.01% to about 10% by weight of hyaluronic acid, about 0.1% to about 10% by weight of hyaluronic acid, about 1% to about 10% by weight of hyaluronic acid, about 2% to about 10% by weight of hyaluronic acid, about 3% to about 10% by weight of hyaluronic acid, about 4% to about 10% by weight of hyaluronic acid, or about 5% to about 10% by weight of hyaluronic acid.

[0133] In some embodiments, the composition according to one embodiment of the present invention includes a commercially available hyaluronic acid composition. For example, a suitable commercially available hyaluronic acid composition is JUVEDER. (商標) RESTYLANE-L (商標) CAPTIQUE (商標) BELOTERO BALANCE (商標) PREVELLE SILK (商標) , ELEVESS (商標) HYLAFORM (商標) EUFLEXXA (商標) GEL-ONE (商標) HYALGAN (商標) ORTHOVISC (商標) MONOVISC (商標) SUP ARTZ (商標) SYNVISC (商標) and SYNVISC-ONE (商標) Examples of hyaluronic acid products sold under certain brand names include, but are not limited to, those listed above.

[0134] In some embodiments, the composition may include a hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include, but are not limited to, high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurthiomalate, fenoprofen, glycyrrhizic acid, heparin, O-sulfated hyaluronic acid (sHA), and dextran sulfate, or any combination thereof.

[0135] In some embodiments, the composition comprises about 0.01% by weight or more of a hyaluronidase inhibitor, about 0.025% by weight or more of a hyaluronidase inhibitor, about 0.050% by weight or more of a hyaluronidase inhibitor, about 0.075% by weight or more of a hyaluronidase inhibitor, about 0.1% by weight or more of a hyaluronidase inhibitor, about 0.25% by weight or more of a hyaluronidase inhibitor, about 0.5% by weight or more of a hyaluronidase inhibitor, about 0.75% by weight or more of a hyaluronidase inhibitor, about 1% by weight or more of a hyaluronidase inhibitor, about 2.5% by weight or more of a hyaluronidase inhibitor, about 5% by weight or more of a hyaluronidase inhibitor, about 7.5% by weight or more of a hyaluronidase inhibitor, or about 10% by weight or more of a hyaluronidase inhibitor. In some embodiments, the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of a hyaluronidase inhibitor.In some embodiments, the composition contains about 0.01% to about 0.025% by weight of a hyaluronidase inhibitor, about 0.025% to about 0.05% by weight of a hyaluronidase inhibitor, about 0.025% to about 0.075% by weight of a hyaluronidase inhibitor, about 0.025% to about 0.1% by weight of a hyaluronidase inhibitor, about 0.01% to about 0.1% by weight of a hyaluronidase inhibitor, about 0.05% to about 0.075% by weight of a hyaluronidase inhibitor, about 0.05% to about 0.1% by weight of a hyaluronidase inhibitor, about 0.075% to about 0.1% by weight of a hyaluronidase inhibitor, about 0.1% to about 0.2% by weight of a hyaluronidase inhibitor, and about 0.1% to about 0.5% by weight of a hyaluronidase inhibitor. The product contains a hyaluronidase inhibitor, approximately 0.2% to 0.4% by weight of a hyaluronidase inhibitor, approximately 0.5% to 1% by weight of a hyaluronidase inhibitor, approximately 0.4% to 0.6% by weight of a hyaluronidase inhibitor, approximately 0.6% to 0.8% by weight of a hyaluronidase inhibitor, approximately 0.8% to 1% by weight of a hyaluronidase inhibitor, approximately 1% to 2% by weight of a hyaluronidase inhibitor, approximately 1% to 5% by weight of a hyaluronidase inhibitor, approximately 2% to 4% by weight of a hyaluronidase inhibitor, approximately 5% to 10% by weight of a hyaluronidase inhibitor, approximately 4% to 6% by weight of a hyaluronidase inhibitor, approximately 6% to 8% by weight of a hyaluronidase inhibitor, or approximately 8% to 10% by weight of a hyaluronidase inhibitor.

[0136] In some embodiments, the composition includes a carrier medium. Such a carrier medium may be a biocompatible fluid suitable for injection into the skin of mammals. In some embodiments, the carrier medium includes saline solution. In some embodiments, hyaluronic acid serves as both the carrier medium and the active ingredient.

[0137] In some embodiments, the composition includes one or more additives. Such additives may include preservatives or biocides.

[0138] In some embodiments, the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, liposomes, or vesicles.

[0139] In some embodiments, the composition may contain fatty acids (e.g., oleic acid), esters of fatty acids with alcohols (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), medium-chain triglycerides, triacetins, or terpenes (e.g., limonene, menthol, cineole). In some embodiments, the composition may contain surfactants. For example, a suitable surfactant is TWEEN (商標) (Polysorbate), CREMOPHOR (商標) (A mixture of macrogol glycerol hydroxystearate, PEG-40 castor oil, and polyoxyl 40 hydrogenated castor oil), TRANSCUTOL (商標) P (Diethylene glycol monoethyl ether), PLUROL OLEIQUE (商標) (Polyglyceryl-3-oleate), PLUROL ISOSTEARIQUE (商標) (Polyglycerol and isostearate ester of higher oligomers), LABRASOL (商標) Examples include, but are not limited to, monoglycerides, diglycerides, and triglycerides of C8 and C10 fatty acids, and mixtures of monoesters and diesters of PEG, as well as lecithin. In some embodiments, the composition may include auxiliary surfactants. For example, suitable auxiliary surfactants include, but are not limited to, short-chain and medium-chain alcohols and polyglyceryl derivatives, including ethanol, isopropanol, isopropyl myristate, and propylene glycol.

[0140] In some embodiments, the composition comprises one or more of the following: soybean oil, jojoba oil, aloe vera oil, soybean phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropyl alcohol, glycerin, glyceryl monostearate, and propylene glycol.

[0141] A process for preparing a therapeutic composition according to one embodiment of the present invention includes mixing an effective amount of an activator when the composition contains two or more active ingredients. For example, if the composition contains a peptide having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 96, and hyaluronic acid, an effective amount of hyaluronic acid is mixed with an effective amount of the peptide. The process may also include a step of preparing a physiologically acceptable carrier medium to which the activator is added. Preferably, the physiologically acceptable carrier is injectable.

[0142] The preparation method may include the step of forming a microemulsion or nanoemulsion. The microemulsion or nanoemulsion comprises oil, water, a surfactant, and an auxiliary surfactant, and can form a colloidal dispersion with droplet diameters in the range of about 10 nm to about 100 nm. In some embodiments, the microemulsion or nanoemulsion may contain fatty acids (e.g., oleic acid), esters of fatty acids with alcohols (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), medium-chain triglycerides, triacetin, or terpenes (e.g., limonene, menthol, cineole). In some embodiments, the microemulsion or nanoemulsion may contain a surfactant. For example, a suitable surfactant is TWEEN (商標) (Polysorbate), CREMOPHOR (商標) (A mixture of macrogol glycerol hydroxystearate, PEG-40 castor oil, and polyoxyl 40 hydrogenated castor oil), TRANSCUTOL (商標) P (Diethylene glycol monoethyl ether), PLUROL OLEIQUE (商標) (Polyglyceryl-3-oleate), PLUROL ISOSTEARIQUE (商標) (Polyglycerol and isostearate ester of higher oligomers), LABRASOL (商標)Examples include, but are not limited to, (compounds of monoglycerides, diglycerides, and triglycerides of C8 and C10 fatty acids and monoesters and diesters of PEG), and lecithin. In some embodiments, the microemulsion or nanoemulsion may contain auxiliary surfactants. For example, suitable auxiliary surfactants include, but are not limited to, short-chain and medium-chain alcohols and polyglyceryl derivatives, including ethanol, isopropanol, isopropyl myristate, and propylene glycol. In some embodiments, the formation of the microemulsion or nanoemulsion involves the use of a high-pressure homogenizer, a microfluidizer, and / or an ultrasonic crusher.

[0143] The preparation method may include the step of mixing solid nanoparticles with a composition according to one embodiment of the present invention. The solid nanoparticles may include inorganic materials such as metal oxides (e.g., zinc oxide, titanium dioxide) or polymers that are solid at room temperature.

[0144] The preparation method may include the step of mixing a composition according to one embodiment of the present invention with solid lipid nanoparticles. The solid lipid nanoparticles may contain lipids that are solid at room temperature, and their surface is covered with a surfactant to stabilize them as droplets having a size of less than approximately 100 nm when dispersed in water.

[0145] The preparation method may include the step of mixing a composition according to one embodiment of the present invention with a nanostructured lipid support. The nanostructured lipid support may include a fluid solid phase embedded in a solid lipid matrix or localized on the surface of a solid plate and a surfactant layer.

[0146] The preparation method may include the step of mixing a composition according to one embodiment of the present invention with liposomes. The liposomes may comprise spherical vesicles composed of amphiphilic phospholipids and cholesterol, which self-associate into multilamellar, large unilamellar, and small unilamellar vesicles.

[0147] The preparation method may include the step of mixing a composition according to one embodiment of the present invention with flexible vesicles. The flexible vesicles may include a substance that associates to form a bilayer structure and components that impart flexibility. In some embodiments, the flexible vesicles include etosomes (i.e., phospholipids with a high proportion of ethanol), niosomes (i.e., nonionic surfactants), invasosomes (i.e., a mixture of phospholipids, ethanol, and terpene permeation enhancers), SECosomes (i.e., surfactants, ethanol, and cholesterol), or PEVs (i.e., permeation enhancer vesicles). In some embodiments, the PEVs may include oleic acid, limonene, or propylene glycol.

[0148] The preparation method may include the step of mixing a composition according to one embodiment of the present invention with a polymeric micelle or polymeric dendrimer. The polymeric micelle may be a colloidal support having a hydrophilic outer shell and a hydrophobic inner core. The polymeric micelle may be nanosized. The polymeric dendrimer may include a branched polymer structure.

[0149] In another aspect, the present invention provides a method (Method 3.0) for stimulating hair growth in the skin of a patient in need of hair growth, comprising administering to the patient's skin a composition comprising a peptide having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 96. For example, the present invention includes: 3.1. Method 3.0, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 96.

[0150] 3.2. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 1 to 20, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 20.

[0151] 3.3. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs: 21 to 39, and optionally the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 21 to 39.

[0152] 3.4. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 40 to 60, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 40 to 60.

[0153] 3.5. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 61-63, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 61-63.

[0154] 3.6. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 64 to 71, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 64 to 71.

[0155] 3.7. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 72-79, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 72-79.

[0156] 3.8. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 80 to 87, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 80 to 87.

[0157] 3.9. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with a sequence selected from the group consisting of SEQ ID NOs. 88 to 95, and optionally, the peptide comprises a sequence selected from the group consisting of SEQ ID NOs. 88 to 95.

[0158] 3.10. Method 3.0, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO: 96, and optionally the peptide comprises SEQ ID NO: 96.

[0159] 3.11. The method according to any one of the preceding paragraphs, wherein the peptide contains a CD44 binding site.

[0160] 3.12. Method 3.11, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof.

[0161] 3.13. Method 3.12, wherein a variant of sequence number 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 97.

[0162] 3.14. The method according to any one of the preceding paragraphs, wherein the peptide contains a calcium-binding site.

[0163] 3.15. Method 3.14, wherein the peptide comprises SEQ ID NO: 98 or a variant thereof.

[0164] 3.16. Method 3.15, wherein a variant of sequence number 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 98.

[0165] 3.17. The method according to any one of the preceding paragraphs, wherein the peptide includes a CD4 binding site or a calcium binding site.

[0166] 3.18. Method 3.17, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof, and SEQ ID NO: 98 or a variant thereof.

[0167] 3.19. Method 3.18, wherein a variant of sequence number 97 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 97, and a variant of sequence number 98 has at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with sequence number 98.

[0168] 3.20. The method according to any one of the preceding paragraphs, wherein the peptide has a length of 295 amino acids or less.

[0169] 3.21. Method 3.20, wherein the peptide has a length of 290 amino acids or less, 280 amino acids or less, 270 amino acids or less, 260 amino acids or less, 250 amino acids or less, 240 amino acids or less, 230 amino acids or less, 220 amino acids or less, 210 amino acids or less, 200 amino acids or less, 190 amino acids or less, 180 amino acids or less, 170 amino acids or less, 160 amino acids or less, 150 amino acids or less, 140 amino acids or less, 130 amino acids or less, 120 amino acids or less, 110 amino acids or less, 100 amino acids or less, 90 amino acids or less, 80 amino acids or less, 70 amino acids or less, or 60 amino acids or less.

[0170] 3.22. The method according to any one of the preceding items, wherein the composition comprises about 0.01% by weight or more of peptides, and optionally the composition comprises about 0.025% by weight or more, for example, about 0.05% by weight or more, about 0.075% by weight or more, about 0.1% by weight or more, about 0.25% by weight or more, about 0.5% by weight or more, about 0.75% by weight or more, about 1% by weight or more, about 2.5% by weight or more, about 5% by weight or more, about 7.5% by weight or more, or about 10% by weight or more of peptides.

[0171] 3.23. The composition contains 0.01 to 20% by weight of peptides, and optionally the composition contains 0.025 to 20% by weight, 0.05 to 20% by weight, 0.75 to 20% by weight, 0.1 to 20% by weight, 0.25 to 20% by weight, 0.5 to 20% by weight, 0.75 to 20% by weight, 1 to 20% by weight, 2.5 to 20% by weight, 5 to 20% by weight, 7.5 to 20% by weight, 10 to 20% by weight, 0.01 to 15% by weight, 0.025 to 15% by weight, 0.05 to 15% by weight, 0.75 to 15% by weight, 0.1 to 15% by weight, 0.25 to 15% by weight, 0.5 to 15% by weight, 0.75 to 15% by weight, 1 to 15% by weight, 2.5 to 15% by weight, 5 to 15% by weight, 7.5 The method according to any one of the preceding items, comprising 15% by weight, or 10-15% by weight, of the peptide.

[0172] 3.24. The composition is approximately 0.01% to approximately 0.025% by weight, approximately 0.025% to approximately 0.05% by weight, approximately 0.025% to approximately 0.075% by weight, approximately 0.025% to approximately 0.1% by weight, approximately 0.01% to approximately 0.1% by weight, approximately 0.05% to approximately 0.075% by weight, approximately 0.05% to approximately 0.1% by weight, approximately 0.075% to approximately 0.1% by weight, approximately 0.1% to approximately 0.2% by weight, approximately 0.1% to approximately 0.5% by weight The method according to any one of the preceding items, comprising a peptide in an amount of %, approximately 0.2% to approximately 0.4% by weight, approximately 0.5% to approximately 1% by weight, approximately 0.4% to approximately 0.6% by weight, approximately 0.6% to approximately 0.8% by weight, approximately 0.8% to approximately 1% by weight, approximately 1% to approximately 2% by weight, approximately 1% to approximately 5% by weight, approximately 2% to approximately 4% by weight, approximately 5% to approximately 10% by weight, approximately 4% to approximately 6% by weight, approximately 6% to approximately 8% by weight, or approximately 8% to approximately 10% by weight.

[0173] 3.25. The method according to any one of the preceding items, wherein the composition comprises one or more additional ligands that bind to CD44.

[0174] 3.26. Method 3.25, in which one or more additional ligands that bind to CD44 are selected from the group consisting of cerglycine, chondroitin or its salts (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor-binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6), green fluorescent protein (GFP), and any combination thereof.

[0175] 3.27. The method according to any one of the preceding items, wherein the composition comprises cerglycine, and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of cerglycine.

[0176] 3.28. The method according to any one of the preceding items, wherein the composition comprises chondroitin or a salt thereof, and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of chondroitin or a salt thereof.

[0177] 3.29. Method 3.28, wherein the composition comprises chondroitin sulfate.

[0178] 3.30. The method according to any one of the preceding items, wherein the composition comprises fibrin, and optionally the composition comprises 0.01 to 15% by weight of fibrin, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight.

[0179] 3.31. The method according to any one of the preceding items, wherein the composition comprises collagen, and optionally the composition comprises 0.01 to 15% by weight of collagen, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight.

[0180] 3.32. The method according to any one of the preceding items, wherein the composition comprises fibronectin, and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of fibronectin.

[0181] 3.33. The method according to any one of the preceding items, wherein the composition comprises insulin-like growth factor-binding protein (IGFBP), and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of insulin-like growth factor-binding protein.

[0182] 3.34. The method according to any one of the preceding items, wherein the composition comprises green fluorescent protein (GFP), and optionally the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of GFP.

[0183] 3.35. The method according to any one of the preceding items, wherein the composition comprises hyaluronic acid.

[0184] 3.36. Method 3.35, wherein the hyaluronic acid has a molecular weight in the range of approximately 20 kDa to 1350 kDa, approximately 4 kDa to approximately 10 kDa, approximately 10 kDa to approximately 100 kDa, approximately 15 kDa to approximately 50 kDa, or approximately 75 kDa to approximately 350 kDa.

[0185] 3.37. The method according to any one of the methods in 3.35 to 3.36, wherein hyaluronic acid is crosslinked, and optionally the hyaluronic acid has a crosslinking density of approximately 20% or more.

[0186] 3.38. A composition according to any one of sections 3.35 to 3.37, wherein hyaluronic acid is present at a concentration of 25 mcg / mL or more, approximately 25 mcg / mL to approximately 250 mcg / mL, approximately 25 mcg / mL to approximately 100 mcg / mL, approximately 100 mcg / mL to approximately 250 mcg / mL, approximately 1 mcg / mL to approximately 250 mcg / mL, approximately 100 μg / mL or less, approximately 100 mcg / mL to approximately 950 mcg / mL, approximately 200 mcg / mL to approximately 400 mcg / mL, approximately 400 mcg / mL to approximately 600 mcg / mL, approximately 600 mcg / mL to approximately 800 mcg / mL, or approximately 800 mcg / mL to approximately 950 mcg / mL.

[0187] 3.39. The method according to any one of the preceding items, wherein the composition comprises a hyaluronidase inhibitor.

[0188] 3.40. Method 3.39, in which the hyaluronidase inhibitor is selected from high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurantiocalate, fenoprofen, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin, and O-sulfated hyaluronic acid (sHA), or any combination thereof.

[0189] 3.41. The method according to any one of the methods described in 3.39 to 3.40, wherein the composition comprises 0.01 to 15% by weight, for example, 0.1 to 10% by weight, 1 to 10% by weight, or 5 to 10% by weight of a hyaluronidase inhibitor.

[0190] 3.42. The method according to any one of the preceding items, wherein the composition comprises a carrier medium.

[0191] 3.43. Method 3.42, where the carrier medium contains saline solution.

[0192] 3.44. The method according to any one of the preceding items, wherein the composition comprises a preservative or biocide.

[0193] 3.45. The method according to any one of the preceding items, wherein the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, a liposome, or a vesicle.

[0194] 3.46. The method according to any one of the preceding items, wherein the composition comprises a surfactant.

[0195] 3.47. The method according to any one of the preceding items, wherein the composition comprises one or more of the following: soybean oil, jojoba oil, aloe vera oil, soy phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropyl alcohol, glycerin, glyceryl monostearate, and propylene glycol.

[0196] 3.48. The method according to any one of the preceding items, wherein administration comprises applying the composition to the surface of the skin, and optionally further comprising a step of improving penetration before topical administration of the composition.

[0197] 3.49. The method according to any one of the methods in items 3.0 to 3.47, wherein administration comprises injecting the composition into the dermis or subcutaneous layer of the skin, and optionally, administration comprises injecting the composition into the dermis of the skin.

[0198] 3.50. Method 3.49, in which the composition is injected into the skin to a depth of approximately 400 micrometers to approximately 2 mm.

[0199] 3.51. The composition is administered by multiple injections, and optionally, the composition is administered approximately 400 times per 1 cm of skin. 2 ~Approximately 650 injections / 1cm of skin 2 The method described in any one of the methods 3.49 to 3.50, administered in multiple infusions in the specified amount.

[0200] 3.52. The method according to any one of items 3.49 to 3.51, wherein the composition is injected by microneedles.

[0201] 3.53. The method according to any one of the preceding items, wherein the composition is encapsulated in liposomes, and optionally the liposomes contain hydrogenated phospholipids.

[0202] 3.54. The method according to any one of the preceding paragraphs, further comprising applying electroporation to the skin.

[0203] 3.55. The method according to any one of the preceding paragraphs, further comprising applying ultrasound to the skin.

[0204] 3.56. The method according to any one of the preceding paragraphs, further comprising applying laser ablation to the skin.

[0205] 3.57. The method according to any one of the preceding paragraphs, further comprising applying magnetic electrophoresis to the skin.

[0206] 3.58. The method according to any one of the preceding paragraphs, further comprising applying radiofrequency thermal ablation to the skin.

[0207] 3.59. The method according to any one of the preceding paragraphs, further comprising applying a microneedle device to the skin.

[0208] 3.60. The method according to any one of the preceding paragraphs, wherein the composition is administered as a bolus or as an intravenous solution.

[0209] 3.61. The composition is applied to the skin once a day for a day, once a day for a week, once a day for a month, once a day for a year, twice a day for a day, twice a day for a week, twice a day for a month, twice a day for a year, once a week for a week, once a week for a month, once a week for a year, twice a week for a week, twice a week for a month, twice a week for a year, once a month for a month, once a month for two months, once a month for six months, once a month for a year, twice a month for two months. The method according to any one of the preceding paragraphs, administered twice a month for a period of time, twice a month for six months, twice a month for one year, once every two months for two months, once every two months for four months, once every two months for six months, once every two months for one year, once every three months for three months, once every three months for six months, once every three months for nine months, once every three months for one year, once every four months for four months, once every four months for eight months, once every four months for one year, once every six months for six months, or once every six months for one year.

[0210] A method for stimulating hair growth in a patient requiring hair growth involves administering a composition according to any embodiment of the present invention to the surface of or into the skin of the patient. In some embodiments, the composition is administered topically by applying the composition to the surface of the patient's skin. In some embodiments, the composition is administered into the dermis or subcutaneous tissue of the patient's skin, for example, by injection as described herein.

[0211] A method for administering a composition according to one embodiment of the present invention includes delivering the composition according to one embodiment of the present invention to hair follicles. In some embodiments, delivery is performed by topical administration, i.e., by applying the composition to the skin surface and allowing the composition to penetrate the skin. In some embodiments, the administration method includes a step to improve penetration before topical administration of the composition. In some embodiments, delivery is performed by injection into the skin.

[0212] In some embodiments, local delivery is performed after or in conjunction with the application of iontophoresis. For example, iontophoresis may involve applying a moderate current (e.g., 0.1–1.0 mA / cm²) to increase the skin penetration of the composition. While not bound by theory, iontophoresis is thought to improve skin penetration by enhancing electrical transfer, electroosmosis, and / or passive diffusion.

[0213] In some embodiments, local delivery is performed after or in conjunction with the application of electroporation. For example, electroporation may involve applying high-intensity, high-voltage (e.g., 50-1500V) electrical pulses for a short period (10 microseconds to 10 milliseconds) to form aqueous pores in the lipid bilayer of the stratum corneum of the skin.

[0214] In some embodiments, local delivery is performed after or in conjunction with the application of ultrasonic delivery. For example, ultrasonic delivery may include the application of elastic waves at high frequencies (e.g., about 500 kHz to 1250 kHz), low frequencies (e.g., about 20 to about 100 kHz), or (starting from one of the high or low frequencies and progressing to the other).

[0215] In some embodiments, local delivery is performed after or in conjunction with the application of laser ablation. Laser ablation may include the generation of photochemical waves by laser ablation of a target material (e.g., a polymer) placed on the surface of the skin.

[0216] In some embodiments, local delivery is performed after or in conjunction with the application of magnetophoresis. Magnetophoresis may include the application of a magnetic field, such as a pulsed electromagnetic field, to the skin.

[0217] In some embodiments, local delivery is performed after the application of radiofrequency thermal ablation. Thermal ablation may involve the application of excessive heat (e.g., about 300°C / microsecond) to the skin surface. Although not bound by theory, it is thought that thermal ablation can cause a portion of the stratum corneum to evaporate, creating micrometer-scale channels. Thermal ablation is performed by VIADOR (商標) (Syneron Medical Ltd, Israel) and PASSPORT (登録商標) This can be achieved by commercially available devices, including those from Nitto-Denko, Japan. In some embodiments, thermal ablation can be achieved by erbium:yttrium-gallium-garnet (ErYAG) emitting at 2,790 nm, or yttrium:scandium-gallium-garnet (YSGG) emitting at 2,940 nm. In some embodiments, partial laser ablation can be applied to a submicrometer region to generate spots that mimic a microneedle array pattern (e.g., 40-300 pm with a density of 50-600 cm).

[0218] In some embodiments, local delivery is performed after the application of the microneedle device.

[0219] In some embodiments, a method of administering a composition according to one embodiment of the present invention includes injecting a therapeutic dose of the composition into the skin of a patient requiring treatment. In some embodiments, a composition according to one embodiment of the present invention is administered as a bolus, where bolus means, as used herein, a dose delivered in less than 10 minutes. In some embodiments, a composition according to one embodiment of the present invention is administered as an infusion, where infusion means, as used herein, a dose delivered in about 10 minutes or more.

[0220] Such infusions may be prepared by a single needle, microneedle, or similar device, or by an array of needles, microneedles, or similar devices. In some embodiments, the composition according to one embodiment of the present invention is delivered by a conventional syringe. In some embodiments, subcutaneous delivery is performed by a hollow microneedle injector. In some embodiments, subcutaneous delivery is carried out by a microneedle patch coated with the composition according to one embodiment of the present invention, for example, by 3D printing. In some embodiments, the composition is delivered by a jet injector. As used herein, the term “needle” refers to any device for penetrating the skin and injecting the composition according to one embodiment of the present invention.

[0221] Preferably, the composition is administered near the patient's hair follicles. Therefore, in some embodiments, the composition is administered by injecting a therapeutic amount of the composition into the patient's dermis. In some embodiments, the composition is administered by injecting a therapeutic amount of the composition into the patient's subcutaneous tissue. In some embodiments, the composition is administered into the patient's skin to a depth of about 0.4 mm to about 2 mm (i.e., about 0.4 mm to about 3 mm from the surface of the skin). In some embodiments, the composition is administered to the patient's skin to a depth of approximately 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, or up to 3 mm. In some embodiments, the composition is placed in the patient's skin at depths of approximately 0.5mm to 1mm, 1mm to 1.5mm, 1.5mm to 2mm, 2mm to 2.5mm, 2.5mm to 3mm, 1mm to 3mm, 1.5mm to 3mm, 0.4mm to 0.6mm, 0.4mm to 0.8mm, 0.4mm to 1mm, 0.4mm to 1.2mm, 0.4mm to 1.4mm, 0.4mm to 1.6mm, 0.4mm to 1.8mm, 0.4mm to 2mm, 0.4mm to 2.2mm, 0.4mm to 2.4mm, 0.4mm to 2.6mm, 0.4mm to 2.8mm, 0.4mm to 3mm, and 0.6mm to 0. 0.8mm, approx. 0.6mm to approx. 1mm, approx. 0.6mm to approx. 1.2mm, approx. 0.6mm to approx. 1.4mm, approx. 0.6mm to approx. 1.6mm, approx. 0.6mm to approx. 1.8mm, approx. 0.6mm to approx. 2mm, approx. 0.6mm to approx. 2.2mm, approx. 0.6mm to approx. 2.4mm, approx. 0.6mm to approx. 2.6mm, approx. 0.6mm to approx. 2.8mm, approx. 0.6mm m~approx. 3mm, approx. 0.8mm~approx. 1mm, approx. 0.8mm~approx. 1.2mm, approx. 0.8mm~approx. 1.4mm, approx. 0.8mm~approx. 1.6mm, approx. 0.8mm~approx. 1.8mm, approx. 0.8mm~approx. 2mm, approx. 0.8mm~approx. 2.2mm, approx. 0.8mm~approx. 2.4mm, approx. 0.8mm~approx. 2.6mm, approx. 0.8mm~approx. 2.8mm, approx. 0.8mm to about 3mm, about 1mm to about 1.2mm, about 1mm to about 1.4mm, about 1mm to about 1.6mm, about 1mm to about 1.8mm, about 1mm to about 2mm, about 1mm to about 2.2mm, about 1mm to about 2.4mm, about 1mm to about 2.6mm, about 1mm to about 2.8mm, about 1mm to about 3mm, about 1.2mm to about 1.4mm, about 1.2mm to about 1.6mm, about 1.2mm to about 1.8mm, about 1.2mm to about 2mm, about 1.2m m ~ about 2.2mm, about 1.2mm - about 2.4mm, about 1.2mm - about 2.6mm, about 1.2mm - about 2.8mm, about 1.2mm - about 3mm, about 1.4mm - about 1.6mm, about 1.4mm - about 1.8mm, about 1.4mm to about 2mm, about 1.4mm to about 2.2mm, about 1.4mm to about 2.4mm, about 1.4mm to about 2.6mm, about 1.4mm to about 2.8mm, about 1.4mm to about 3mm, about 1.6mm to about 1.8mm Approximately 1.6mm to 2mm, approximately 1.6mm to 2.2mm, approximately 1.6mm to 2.4mm, approximately 1.6mm to 2.6mm, approximately 1.6mm to 2.8mm, approximately 1.6mm to 3mm, approximately 1.8mm to 2mm, approximately 1.8mm to 2.2mm, approximately 1.8mm to 2.4mm, approximately 1.8mm to 2.6mm, approximately 1.8mm to 2.8mm, approximately 1.8mm to 3mm, approximately 2.0mm to 2.2mm, approximately 2.0mm to 2. The drug is administered in doses of 4mm, approximately 2.0mm to 2.6mm, approximately 2.0mm to 2.8mm, approximately 2.0mm to 3mm, approximately 2.2mm to 2.4mm, approximately 2.2mm to 2.6mm, approximately 2.2mm to 2.8mm, approximately 2.2mm to 3mm, approximately 2.4mm to 2.6mm, approximately 2.4mm to 2.8mm, approximately 2.4mm to 3mm, approximately 2.6mm to 2.8mm, approximately 2.6mm to 3mm, or approximately 2.8mm to 3mm.

[0222] In some embodiments, a composition according to one embodiment of the present invention may be administered in multiple injections. In some embodiments, a composition according to one embodiment of the present invention may be administered in about one injection / 1 cm of skin 2 ~Approximately 1000 injections per 1cm of skin 2 Approximately 200 injections per 1cm of skin 2 ~Approximately 800 injections per 1cm of skin 2 , or approximately 400 injections / 1 cm of skin 2~Approximately 650 injections per 1cm of skin 2 It is administered by [method]. In some embodiments, the composition is administered by [method] in approximately 200 injections / 1 cm of skin. 2 Approximately 250 injections per 1 cm of skin 2 Approximately 300 injections per 1cm of skin 2 Approximately 350 injections per 1cm of skin 2 Approximately 400 injections per 1cm of skin 2 Approximately 450 injections per 1cm of skin 2 Approximately 500 injections per 1cm of skin 2 Approximately 550 injections per 1cm of skin 2 Approximately 600 injections per 1cm of skin 2 , or approximately 650 injections per 1 cm of skin 2 It is administered by [method / method].

[0223] In some embodiments, the composition is applied to the patient's skin once a day for a day, once a day for a week, once a day for a month, once a day for a year, twice a day for a day, twice a day for a week, twice a day for a month, twice a day for a year, once a week for a week, once a week for a month, once a week for a year, twice a week for a week, twice a week for a month, twice a week for a year, once a month for a month, once a month for two months, once a month for six months, once a month for a year, once a month It may be administered twice a month, twice a month for two months, twice a month for six months, twice a month for one year, once every other month for two months, once every other month for four months, once every other month for six months, once every other month for one year, once every three months for three months, once every three months for six months, once every three months for nine months, once every three months for one year, once every four months for four months, once every four months for eight months, once every four months for one year, once every six months for six months, once every six months for one year, or as needed.

Claims

1. A peptide for stimulating hair growth, comprising a sequence selected from the group consisting of Sequence IDs 1 to 96 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

2. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1 to 20 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

3. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 21 to 39 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

4. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 40 to 60 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

5. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 61 to 63 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

6. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 64 to 71 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

7. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 72 to 79 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

8. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 80 to 87 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

9. The peptide according to claim 1, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 88 to 95 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

10. The peptide according to claim 1, wherein the peptide comprises a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity with SEQ ID NO:

96.

11. The peptide according to any one of claims 1 to 10, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof.

12. The peptide according to any one of claims 1 to 10, wherein the peptide comprises SEQ ID NO: 98 or a variant thereof.

13. The peptide according to any one of claims 1 to 10, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof, and SEQ ID NO: 98 or a variant thereof.

14. The peptide is the peptide according to any one of the prior claims, having a length of 295 amino acids or less, 250 amino acids or less, 200 amino acids or less, 150 amino acids or less, 100 amino acids or less, or 60 amino acids or less.

15. A composition for stimulating hair growth, comprising the peptide described in any one of claims 1 to 14.

16. The composition according to claim 15, comprising about 0.01% by weight or more of the peptide.

17. The composition according to claim 15 or 16, further comprising one or more additional ligands that bind to CD44 selected from the group consisting of cerglycine, chondroitin or a salt thereof, fibrin, collagen, fibronectin, insulin-like growth factor-binding protein (IGFB), green fluorescent protein (GFP), and any combination thereof.

18. The composition according to any one of claims 15 to 17, further comprising hyaluronic acid.

19. The composition according to claim 18, wherein the hyaluronic acid has a molecular weight in the range of about 20 kDa to 1350 kDa, about 4 kDa to about 10 kDa, about 10 kDa to about 100 kDa, about 15 kDa to about 50 kDa, or about 75 kDa to about 350 kDa.

20. The composition according to claim 18 or 19, wherein the hyaluronic acid is crosslinked.

21. The composition according to any one of claims 15 to 20, wherein the composition comprises a hyaluronidase inhibitor.

22. The composition according to any one of claims 15 to 21, wherein the composition comprises a carrier medium, and optionally the carrier medium comprises saline solution.

23. A method for stimulating hair growth in the skin of a patient requiring hair growth, comprising administering to the patient's skin a composition according to any one of claims 15 to 22.

24. The method according to claim 23, wherein the administration includes applying the composition to the surface of the skin.

25. The method according to claim 23, wherein the administration includes injecting the composition into the dermis or subcutaneous layer of the skin.

26. The method according to any one of claims 23 to 25, wherein the composition is encapsulated in liposomes.

27. The method according to any one of claims 23 to 26, further comprising applying electroporation to the skin.

28. The method according to any one of claims 23 to 27, further comprising applying an ultrasonic introduction method to the skin.

29. The method according to any one of claims 23 to 28, further comprising applying laser ablation to the skin.

30. The method according to any one of claims 23 to 29, further comprising applying magnetic electrophoresis to the skin.

31. The method according to any one of claims 23 to 30, further comprising applying high-frequency thermal ablation to the skin.

32. The method according to any one of claims 23 to 31, further comprising applying a microneedle device to the skin.

33. A peptide for stimulating hair growth, comprising a sequence selected from the group consisting of SEQ ID NOs. 97 or 98 and a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity.

34. A nucleotide encoding any of the peptides described in claims 1 to 33.

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