Compositions and methods for stimulating hair growth

Abstract

Disclosed herein are compositions comprising peptides comprising a CD44 binding site and / or a calcium binding site and methods of stimulating hair growth by using the same.

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Serial No. 63 / 522,012, filed June 20, 2023, the contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to compositions comprising peptides containing CD44 binding sites and / or calcium binding sites, and methods for stimulating hair growth by using the compositions. Background Technology

[0003] Hair loss typically has negative social and psychological effects on individuals suffering from it. Many factors are believed to contribute to hair loss, including genetics, hormones, environmental exposure, medications, psychological stress, and nutrition. One known treatment is hair transplantation, which requires anesthesia, is expensive, time-consuming, and sometimes painful. Other methods include massage and acupuncture, but these have not yet been shown to be effective. Hormones and other medications have been used to treat hair loss. However, these treatments often cause undesirable side effects, such as hair regrowth in unwanted areas. Therefore, there is a need for an effective therapy to stimulate hair growth. Summary of the Invention

[0004] In a first aspect, this disclosure provides a peptide for stimulating hair growth, the peptide comprising 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 NO: 1 to SEQ ID NO: 96. In some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96. In some embodiments, the peptide comprises a CD44 binding site, for example, an 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, an amino acid sequence of DWDSRGKDSYETS (SEQ ID NO: 98) or a variant thereof. In some embodiments, the peptide comprises both a CD44 binding site and a calcium binding site. In some embodiments, the peptide has a length of no more than 295 amino acids (e.g., no more than 290 amino acids, no more than 280 amino acids, no more than 270 amino acids, no more than 260 amino acids, no more than 250 amino acids, no more than 240 amino acids, no more than 230 amino acids, no more than 220 amino acids, no more than 210 amino acids, no more than 200 amino acids, no more than 190 amino acids, no more than 180 amino acids, no more than 170 amino acids, no more than 160 amino acids, no more than 150 amino acids, no more than 140 amino acids, no more than 130 amino acids, no more than 120 amino acids, no more than 110 amino acids, no more than 100 amino acids, no more than 90 amino acids, no more than 80 amino acids, no more than 70 amino acids, or no more than 60 amino acids).

[0005] In another aspect, this disclosure provides a composition for stimulating hair growth, the 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 NO: 1 to SEQ ID NO: 96. In some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96. In some embodiments, the peptide comprises a CD44 binding site, for example, an 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, an amino acid sequence of DWDSRGKDSYETS (SEQ ID NO: 98) or a variant thereof. In some embodiments, the peptide comprises both a CD44 binding site and a calcium binding site. In some embodiments, the peptide has a length of no more than 295 amino acids (e.g., no more than 290 amino acids, no more than 280 amino acids, no more than 270 amino acids, no more than 260 amino acids, no more than 250 amino acids, no more than 240 amino acids, no more than 230 amino acids, no more than 220 amino acids, no more than 210 amino acids, no more than 200 amino acids, no more than 190 amino acids, no more than 180 amino acids, no more than 170 amino acids, no more than 160 amino acids, no more than 150 amino acids, no more than 140 amino acids, no more than 130 amino acids, no more than 120 amino acids, no more than 110 amino acids, no more than 100 amino acids, no more than 90 amino acids, no more than 80 amino acids, no more than 70 amino acids, or no more than 60 amino acids).

[0006] In some embodiments, the composition comprises about 0.01% by weight or more of peptides. In some embodiments, the composition comprises about 0.025% by weight or more (e.g., 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.

[0007] In some embodiments, the composition further comprises one or more additional ligands that bind to CD44. In some embodiments, one or more additional ligands that bind to CD44 are selected from the group consisting of: serine, chondroitin or salts thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP4, 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 cross-linked. In some embodiments, the hyaluronic acid has a cross-linking density of about 20% or greater. In some embodiments, the hyaluronic acid is present at a concentration of 25 mcg / mL or higher, 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 lower. In some embodiments, hyaluronic acid is present at concentrations of about 100 mcg / mL to about 950 mcg / mL, about 200 mcg / mL to about 400 mcg / mL, about 400 mcg / mL to about 600 mcg / mL, about 600 mcg / mL to about 800 mcg / mL, or about 800 mcg / mL to about 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(4-styrene sulfonate) (PSS), gossypol, disodium gold thiobutane, fenofurine, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin, and O-sulfated hyaluronic acid (sHA), or any combination thereof.

[0010] On the other hand, this disclosure also provides a method for stimulating hair growth in the skin of a patient with this need, the method comprising applying an effective amount of the composition as disclosed herein to the patient's skin. In some embodiments, application comprises applying the composition to the surface of the skin, while in other embodiments, application comprises injecting the composition into the dermis of the skin. The composition can be injected into the skin to a depth of about 400 micrometers to about 2 mm. In some embodiments, the composition is injected at a rate of about 400 injections / cm. 2Skin approximately 650 injections / cm 2 The amount administered to the skin is given via multiple injections. In some embodiments, the needle is a microneedle. In some embodiments, the composition may be encapsulated in liposomes (e.g., liposomes containing hydrogenated phospholipids).

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

[0012] Other areas of application of this disclosure will become apparent from the detailed description provided below. It should be understood that while the detailed description and specific examples indicate preferred embodiments of this disclosure, they are intended for illustrative purposes only and are not intended to limit the scope of this disclosure. Detailed Implementation

[0013] The following description of the preferred embodiments is merely illustrative in nature and is in no way intended to limit this disclosure, its application, or its use.

[0014] As used throughout, "range" is used as a shorthand to describe the individual values ​​within that range and for each value. Any value within the range may be chosen as the endpoint of the range. Furthermore, all references cited herein are incorporated herein in their entirety. In the event of any conflict between the definitions in this disclosure and those in the cited references, this disclosure shall prevail.

[0015] Unless otherwise stated, all percentages and quantities expressed herein and elsewhere in the specification should be understood as weight percentages. The quantities given are based on the weight of the active ingredient in the material.

[0016] In one aspect, the present invention provides a peptide (peptide 1.0) for stimulating hair growth, the peptide comprising 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 NO: 1 to SEQ ID NO: 96. It should be understood and generally accepted that the term polypeptide can be used to describe the sequences detailed by SEQ ID NO: 1 to SEQ ID NO: 98, and such terms are used interchangeably.

[0017] For example, the present invention includes: 1.1. A peptide 1.0, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96.

[0018] 1.2. A peptide 1.0, 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 NO: 1 to SEQ ID NO: 20, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 20.

[0019] 1.3. A peptide 1.0, 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 NO: 21 to SEQ ID NO: 39, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO: 39.

[0020] 1.4. A peptide 1.0, 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 NO: 40 to SEQ ID NO: 60, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO: 60.

[0021] 1.5. A peptide 1.0, 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 NO: 61 to SEQ ID NO: 63, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO: 63.

[0022] 1.6. A peptide 1.0, 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 NO: 64 to SEQ ID NO: 71, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO: 71.

[0023] 1.7. A peptide 1.0, 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 NO: 72 to SEQ ID NO: 79, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO: 79.

[0024] 1.8. A peptide 1.0, 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 NO: 80 to SEQ ID NO: 87, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO: 87.

[0025] 1.9. A peptide 1.0, 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 NO: 88 to SEQ ID NO: 95, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 95.

[0026] 1.10. A peptide 1.0, 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, optionally wherein the peptide comprises SEQ ID NO: 96.

[0027] 1.11. The peptide according to any of the aforementioned peptides, wherein the peptide contains a CD44 binding site.

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

[0029] 1.13. Peptide 1.12, 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.

[0030] 1.14. Any of the aforementioned peptides, wherein the peptide contains a calcium-binding site.

[0031] 1.15. A peptide 1.14, wherein the peptide comprises SEQ ID NO: 98 or a variant thereof.

[0032] 1.16. Peptide 1.15, wherein 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.

[0033] 1.17. The peptide according to any of the aforementioned peptides, wherein the peptide contains a CD44 binding site and a calcium binding site.

[0034] 1.18. A peptide 1.17, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof, and SEQ ID NO: 98 or a variant thereof.

[0035] 1.19. A 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. The peptide according to any of the aforementioned peptides, wherein the peptide has a length of no more than 295 amino acids.

[0037] 1.21. The peptide according to any of the aforementioned peptides, wherein the peptide has a length of not more than 290 amino acids, not more than 280 amino acids, not more than 270 amino acids, not more than 260 amino acids, not more than 250 amino acids, not more than 240 amino acids, not more than 230 amino acids, not more than 220 amino acids, not more than 210 amino acids, not more than 200 amino acids, not more than 190 amino acids, not more than 180 amino acids, not more than 170 amino acids, not more than 160 amino acids, not more than 150 amino acids, not more than 140 amino acids, not more than 130 amino acids, not more than 120 amino acids, not more than 110 amino acids, not more than 100 amino acids, not more than 90 amino acids, not more than 80 amino acids, not more than 70 amino acids, or not more than 60 amino acids.

[0038] In another aspect, the present invention provides a composition for stimulating hair growth (composition 2.0), the 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 NO: 1 to SEQ ID NO: 96. For example, the present invention includes: 2.1. A composition 2.0, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96.

[0039] 2.2. A 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 NO: 1 to SEQ ID NO: 20, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 20.

[0040] 2.3. A 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 NO: 21 to SEQ ID NO: 39, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO: 39.

[0041] 2.4. A 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 NO: 40 to SEQ ID NO: 60, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO: 60.

[0042] 2.5. A 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 NO: 61 to SEQ ID NO: 63, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO: 63.

[0043] 2.6. A 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 NO: 64 to SEQ ID NO: 71, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO: 71.

[0044] 2.7. A 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 NO: 72 to SEQ ID NO: 79, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO: 79.

[0045] 2.8. A 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 NO: 80 to SEQ ID NO: 87, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO: 87.

[0046] 2.9. A 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 NO: 88 to SEQ ID NO: 95, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 95.

[0047] 2.10. A peptide 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, optionally wherein the peptide comprises SEQ ID NO: 96.

[0048] 2.11. The composition according to any of the foregoing compositions, wherein the peptide contains a CD44 binding site.

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

[0050] 2.13. A composition 2.12, 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.

[0051] 2.14. The composition according to any of the foregoing compositions, wherein the peptide comprises a calcium binding site.

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

[0053] 2.16. A composition 2.15 wherein 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.

[0054] 2.17. The composition according to any of the foregoing compositions, wherein the peptide comprises a CD44 binding site and a calcium binding site.

[0055] 2.18. A composition 2.17, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof, and SEQ ID NO: 98 or a variant thereof.

[0056] 2.19. A composition 2.18, 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.

[0057] 2.20. The composition according to any of the foregoing compositions, wherein the peptide has a length of not more than 295 amino acids.

[0058] 2.21. A composition 2.20, wherein the peptide has a length of not more than 290 amino acids, not more than 280 amino acids, not more than 270 amino acids, not more than 260 amino acids, not more than 250 amino acids, not more than 240 amino acids, not more than 230 amino acids, not more than 220 amino acids, not more than 210 amino acids, not more than 200 amino acids, not more than 190 amino acids, not more than 180 amino acids, not more than 170 amino acids, not more than 160 amino acids, not more than 150 amino acids, not more than 140 amino acids, not more than 130 amino acids, not more than 120 amino acids, not more than 110 amino acids, not more than 100 amino acids, not more than 90 amino acids, not more than 80 amino acids, not more than 70 amino acids, or not more than 60 amino acids.

[0059] 2.22. The composition according to any of the foregoing compositions, wherein the composition comprises about 0.01% by weight or more of peptides, optionally wherein the composition comprises about 0.025% by weight or more, such as 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 according to any of the foregoing compositions, wherein the composition comprises 0.01% to 20% by weight of peptides, optionally wherein the composition comprises 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. Peptides in the range of 20% by weight, 10% by weight to 20% by weight, 0.01% by weight to 15% by weight, 0.025% by weight to 15% by weight, 0.05% by weight to 15% by weight, 0.75% by weight to 15% by weight, 0.1% by weight to 15% by weight, 0.25% by weight to 15% by weight, 0.5% by weight to 15% by weight, 0.75% by weight to 15% by weight, 1% by weight to 15% by weight, 2.5% by weight to 15% by weight, 5% by weight to 15% by weight, 7.5% by weight to 15% by weight, or 10% by weight.

[0061] 2.24. The composition according to any of the foregoing compositions, wherein the composition comprises between about 0.01 wt% and about 0.025 wt%, between about 0.025 wt% and about 0.05 wt%, between about 0.025 wt% and about 0.075 wt%, between about 0.025 wt% and about 0.1 wt%, between about 0.01 wt% and about 0.1 wt%, between about 0.05 wt% and about 0.075 wt%, between about 0.05 wt% and about 0.1 wt%, between about 0.075 wt% and about 0.1 wt%, between about 0.1 wt% and about 0.2 wt%, between about 0. Peptides ranging from 0.1% to about 0.5% by weight, between about 0.2% and about 0.4% by weight, between about 0.5% and about 1% by weight, between about 0.4% and about 0.6% by weight, between about 0.6% and about 0.8% by weight, between about 0.8% and about 1% by weight, between about 1% and about 2% by weight, between about 1% and about 5% by weight, between about 2% and about 4% by weight, between about 5% and about 10% by weight, between about 4% and about 6% by weight, between about 6% and about 8% by weight, or between about 8% and about 10% by weight.

[0062] 2.25. The composition according to any of the foregoing compositions, wherein the composition comprises one or more additional ligands that bind to CD44.

[0063] 2.26. A composition 2.25, wherein the one or more additional ligands binding to CD44 are selected from the group consisting of: serine, chondroitin or salts thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP4, IGFBP-5 and IGFBP-6), green fluorescent protein (GFP) and any combination thereof.

[0064] 2.27. The composition according to any of the foregoing compositions, wherein the composition comprises seriganin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of seriganin.

[0065] 2.28. The composition according to any of the foregoing compositions, wherein the composition comprises chondroitin or a salt thereof, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 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. A composition 2.28, wherein the composition comprises chondroitin sulfate.

[0067] 2.30. The composition according to any of the foregoing compositions, wherein the composition comprises fibrin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of fibrin.

[0068] 2.31. The composition according to any of the foregoing compositions, wherein the composition comprises collagen, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of collagen.

[0069] 2.32. The composition according to any of the foregoing compositions, wherein the composition comprises fibronectin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of fibronectin.

[0070] 2.33. The composition according to any of the foregoing compositions, wherein the composition comprises insulin-like growth factor binding protein (IGFBP), optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 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. The composition according to any of the foregoing compositions, wherein the composition comprises green fluorescent protein (GFP), optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of GFP.

[0072] 2.35. The composition according to any of the foregoing compositions, wherein the composition comprises hyaluronic acid.

[0073] 2.36. A composition 2.35, 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.

[0074] 2.37. The composition according to any one of compositions 2.35 to 2.36, wherein the hyaluronic acid is cross-linked, optionally wherein the hyaluronic acid has a cross-linking density of about 20% or greater.

[0075] 2.38. The composition according to any one of compositions 2.35 to 2.37, wherein the hyaluronic acid is present at a concentration of 25 mcg / mL or higher, 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, about 100 μg / mL or lower, about 100 mcg / mL to about 950 mcg / mL, about 200 mcg / mL to about 400 mcg / mL, about 400 mcg / mL to about 600 mcg / mL, about 600 mcg / mL to about 800 mcg / mL, or about 800 mcg / mL to about 950 mcg / mL.

[0076] 2.39. The composition according to any of the foregoing compositions, wherein the composition comprises a hyaluronidase inhibitor.

[0077] 2.40. A composition 2.39, wherein the hyaluronidase inhibitor is selected from high molecular weight poly(4-styrene sulfonate) (PSS), gossypol, disodium gold thiobutane, fenofurine, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin and O-sulfated hyaluronic acid (sHA) or any combination thereof.

[0078] 2.41. The composition according to any one of compositions 2.39 to 2.40, wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of a hyaluronidase inhibitor.

[0079] 2.42. The composition according to any of the foregoing compositions, wherein the composition comprises a carrier medium.

[0080] 2.43. A composition 2.42, wherein the carrier medium comprises an aqueous salt solution.

[0081] 2.44. The composition according to any of the foregoing compositions, wherein the composition comprises a preservative or a biocide.

[0082] 2.45. The composition according to any of the foregoing compositions, wherein the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, a liposome, or a vesicle.

[0083] 2.46. The composition according to any of the foregoing compositions, wherein the composition comprises a surfactant.

[0084] 2.47. The composition according to any of the foregoing compositions, wherein the composition comprises one or more of soybean oil, jojoba oil, aloe vera oil, soybean phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropanol, glycerin, glyceryl monostearate, and propylene glycol.

[0085] The compositions of the present invention comprise a peptide comprising a CD44-binding fragment and / or a calcium-binding fragment of osteopontin or a variant thereof. Osteopontin is an extracellular signaling protein and a natural ligand of CD44. Without being bound by theory, it is believed that osteopontin can induce CD44 activation by proteolytically cleaving CD44, resulting in the intracellular release of the CD44 intracellular domain (ICD). The CD44-ICD then freely enters the nucleus and regulates gene expression. Osteopontin is discussed in International Patent Publication Nos. WO2018175630 and WO 2023028542, both of which are incorporated herein by reference in their entirety. Osteopontin consists 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 comprises a CD44 binding site, for example, SEQ ID NO: 97 or a variant thereof. A variant 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 comprises a calcium binding site, for example, SEQ ID NO: 98 or a variant thereof. A variant 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 comprises a CD44 binding site, for example, SEQ ID NO: 97 or a variant thereof, and a calcium binding site, for example, SEQ ID NO: 98 or a variant thereof.

[0086] 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 a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96. The sequences of SEQ ID NO: 1 to SEQ ID NO: 96 are shown in Table 1.

[0087] Table 1 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 a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 20. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 20.

[0088] 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 a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO: 39. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO: 39.

[0089] 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 a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO: 60. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO: 60.

[0090] 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 a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO: 63. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO: 63.

[0091] 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 a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO: 71. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO: 71.

[0092] 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 a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO: 79. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO: 79.

[0093] 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 a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO: 87. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO: 87.

[0094] 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 a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 95. In some embodiments, the composition comprises a peptide having a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 95.

[0095] 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 comprising SEQ ID NO 96.

[0096] In some embodiments, the peptide has a length of no more than 295 amino acids (e.g., no more than 290 amino acids, no more than 280 amino acids, no more than 270 amino acids, no more than 260 amino acids, no more than 250 amino acids, no more than 240 amino acids, no more than 230 amino acids, no more than 220 amino acids, no more than 210 amino acids, no more than 200 amino acids, no more than 190 amino acids, no more than 180 amino acids, no more than 170 amino acids, no more than 160 amino acids, no more than 150 amino acids, no more than 140 amino acids, no more than 130 amino acids, no more than 120 amino acids, no more than 110 amino acids, no more than 100 amino acids, no more than 90 amino acids, no more than 80 amino acids, no more than 70 amino acids, or no more than 60 amino acids).

[0097] In some embodiments, the composition comprises about 0.01% by weight or more of peptides. In some embodiments, the composition comprises about 0.025% by weight or more (e.g., 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.

[0098] In some embodiments, the composition comprises 0.01 wt% to 20 wt%, 0.025 wt% to 20 wt%, 0.05 wt% to 20 wt%, 0.75 wt% to 20 wt%, 0.1 wt% to 20 wt%, 0.25 wt% to 20 wt%, 0.5 wt% to 20 wt%, 0.75 wt% to 20 wt%, 1 wt% to 20 wt%, 2.5 wt% to 20 wt%, 5 wt% to 20 wt%, 7.5 wt% to 20 wt%, or 10 wt% to 20 wt% of peptides. In some embodiments, the composition comprises 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% to 15% by weight, or 10% to 15% by weight of peptides.

[0099] In some embodiments, the composition comprises between about 0.01 wt% and about 0.025 wt%, between about 0.025 wt% and about 0.05 wt%, between about 0.025 wt% and about 0.075 wt%, between about 0.025 wt% and about 0.1 wt%, between about 0.01 wt% and about 0.1 wt%, between about 0.05 wt% and about 0.075 wt%, between about 0.05 wt% and about 0.1 wt%, between about 0.075 wt% and about 0.1 wt%, between about 0.1 wt% and about 0.2 wt%, and between about 0.1 wt%. Peptides in the following proportions: between about 0.5% by weight, between about 0.2% by weight and about 0.4% by weight, between about 0.5% by weight and about 1% by weight, between about 0.4% by weight and about 0.6% by weight, between about 0.6% by weight and about 0.8% by weight, between about 0.8% by weight and about 1% by weight, between about 1% by weight and about 2% by weight, between about 1% by weight and about 5% by weight, between about 2% by weight and about 4% by weight, between about 5% by weight and about 10% by weight, between about 4% by weight and about 6% by weight, between about 6% by weight and about 8% by weight, or between about 8% by weight and about 10% by weight.

[0100] In some embodiments, the compositions of the present invention may further comprise one or more additional ligands that bind to CD44. In some embodiments, one or more additional ligands that bind to CD44 are selected from the group consisting of: serine, chondroitin or salts thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP4, IGFBP-5, and IGFBP-6), green fluorescent protein, and any combination thereof.

[0101] In some embodiments, the composition comprises about 0.01% by weight or more of seriganol, about 0.025% by weight or more of seriganol, about 0.050% by weight or more of seriganol, about 0.075% by weight or more of seriganol, about 0.1% by weight or more of seriganol, about 0.25% by weight or more of seriganol, about 0.5% by weight or more of seriganol, about 0.75% by weight or more of seriganol, about 1% by weight or more of seriganol, about 2.5% by weight or more of seriganol, about 5% by weight or more of seriganol, about 7.5% by weight or more of seriganol, or about 10% by weight or more of seriganol. In some embodiments, the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight, or 5% to 10% by weight) of serigan. In some embodiments, the composition comprises serine between about 0.01% and about 0.025% by weight, serine between about 0.025% and about 0.05% by weight, serine between about 0.025% and about 0.075% by weight, serine between about 0.025% and about 0.1% by weight, serine between about 0.01% and about 0.1% by weight, serine between about 0.05% and about 0.075% by weight, serine between about 0.05% and about 0.1% by weight, serine between about 0.075% and about 0.1% by weight, serine between about 0.1% and about 0.2% by weight, and serine between about 0.1% and about 0.5% by weight. Proteoglycans, including serine proteoglycans in the range of about 0.2% to about 0.4% by weight, serine proteoglycans in the range of about 0.5% to about 1% by weight, serine proteoglycans in the range of about 0.4% to about 0.6% by weight, serine proteoglycans in the range of about 0.6% to about 0.8% by weight, serine proteoglycans in the range of about 0.8% to about 1% by weight, serine proteoglycans in the range of about 1% to about 2% by weight, serine proteoglycans in the range of about 1% to about 5% by weight, serine proteoglycans in the range of about 2% to about 4% by weight, serine proteoglycans in the range of about 5% to about 10% by weight, serine proteoglycans in the range of about 4% to about 6% by weight, serine proteoglycans in the range of about 6% to about 8% by weight, or serine proteoglycans in the range of about 8% to about 10% by weight.

[0102] In some embodiments, the composition comprises chondroitin or a salt thereof, such as chondroitin sulfate. In some embodiments, the composition comprises about 0.01% or more of chondroitin or a salt thereof, about 0.025% or more of chondroitin or a salt thereof, about 0.050% or more of chondroitin or a salt thereof, about 0.075% or more of chondroitin or a salt thereof, about 0.1% or more of chondroitin or a salt thereof, about 0.25% or more of chondroitin or a salt thereof, about 0.5% or more of chondroitin or a salt thereof, about 0.75% or more of chondroitin or a salt thereof, about 1% or more of chondroitin or a salt thereof, about 2.5% or more of chondroitin or a salt thereof, about 5% or more of chondroitin or a salt thereof, about 7.5% or more of chondroitin or a salt thereof, or about 10% or more of chondroitin or a salt thereof. In some embodiments, the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight, or 5% to 10% by weight) of chondroitin or its salts. In some embodiments, the composition comprises chondroitin or a salt thereof between about 0.01% by weight and about 0.025% by weight, chondroitin or a salt thereof between about 0.025% by weight and about 0.05% by weight, chondroitin or a salt thereof between about 0.025% by weight and about 0.075% by weight, chondroitin or a salt thereof between about 0.025% by weight and about 0.1% by weight, chondroitin or a salt thereof between about 0.01% by weight and about 0.1% by weight, chondroitin or a salt thereof between about 0.05% by weight and about 0.075% by weight, chondroitin or a salt thereof between about 0.05% by weight and about 0.1% by weight, chondroitin or a salt thereof between about 0.075% by weight and about 0.1% by weight, chondroitin or a salt thereof between about 0.1% by weight and about 0.2% by weight, and cartilage between about 0.1% by weight and about 0.5% by weight. Chondroitin or its salts, in amounts between about 0.2% and about 0.4% by weight, between about 0.5% and about 1% by weight, between about 0.4% and about 0.6% by weight, between about 0.6% and about 0.8% by weight, between about 0.8% and about 1% by weight, between about 1% and about 2% by weight, between about 1% and about 5% by weight, between about 2% and about 4% by weight, between about 5% and about 10% by weight, between about 4% and about 6% by weight, between about 6% and about 8% by weight, or between about 8% and about 10% by weight.

[0103] 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% by weight to 15% by weight (e.g., 0.1% by weight to 10% by weight, 1% by weight to 10% by weight, or 5% by weight to 10% by weight) of fibrin. In some embodiments, the composition comprises fibrin between about 0.01% by weight and about 0.025% by weight, fibrin between about 0.025% by weight and about 0.05% by weight, fibrin between about 0.025% by weight and about 0.075% by weight, fibrin between about 0.025% by weight and about 0.1% by weight, fibrin between about 0.01% by weight and about 0.1% by weight, fibrin between about 0.05% by weight and about 0.075% by weight, fibrin between about 0.05% by weight and about 0.1% by weight, fibrin between about 0.075% by weight and about 0.1% by weight, fibrin between about 0.1% by weight and about 0.2% by weight, and fibrin between about 0.1% by weight and about 0.5% by weight. Fibrin between approximately 0.2% and approximately 0.4% by weight, between approximately 0.5% and approximately 1% by weight, between approximately 0.4% and approximately 0.6% by weight, between approximately 0.6% and approximately 0.8% by weight, between approximately 0.8% and approximately 1% by weight, between approximately 1% and approximately 2% by weight, between approximately 1% and approximately 5% by weight, between approximately 2% and approximately 4% by weight, between approximately 5% and approximately 10% by weight, between approximately 4% and approximately 6% by weight, between approximately 6% and approximately 8% by weight, or between approximately 8% and approximately 10% by weight.

[0104] In some embodiments, the composition comprises 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 comprises from 0.01% by weight to 15% by weight (e.g., 0.1% by weight to 10% by weight, 1% by weight to 10% by weight, or 5% by weight to 10% by weight) of collagen. In some embodiments, the composition comprises collagen between about 0.01% by weight and about 0.025% by weight, collagen between about 0.025% by weight and about 0.05% by weight, collagen between about 0.025% by weight and about 0.075% by weight, collagen between about 0.025% by weight and about 0.1% by weight, collagen between about 0.01% by weight and about 0.1% by weight, collagen between about 0.05% by weight and about 0.075% by weight, collagen between about 0.05% by weight and about 0.1% by weight, collagen between about 0.075% by weight and about 0.1% by weight, collagen between about 0.1% by weight and about 0.2% by weight, and collagen between about 0.1% by weight and about 0.5% by weight. Collagen in the following weight percentages: between about 0.2% and about 0.4%; between about 0.5% and about 1%; between about 0.4% and about 0.6%; between about 0.6% and about 0.8%; between about 0.8% and about 1%; between about 1% and about 2%; between about 1% and about 5%; between about 2% and about 4%; between about 5% and about 10%; between about 4% and about 6%; between about 6% and about 8%; or between about 8% and about 10%.

[0105] 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% by weight to 15% by weight (e.g., 0.1% by weight to 10% by weight, 1% by weight to 10% by weight, or 5% by weight to 10% by weight) of fibronectin. In some embodiments, the composition comprises fibronectin between about 0.01% and about 0.025% by weight, fibronectin between about 0.025% and about 0.05% by weight, fibronectin between about 0.025% and about 0.075% by weight, fibronectin between about 0.025% and about 0.1% by weight, fibronectin between about 0.01% and about 0.1% by weight, fibronectin between about 0.05% and about 0.075% by weight, fibronectin between about 0.05% and about 0.1% by weight, fibronectin between about 0.075% and about 0.1% by weight, fibronectin between about 0.1% and about 0.2% by weight, and fibronectin between about 0.1% and about 0.5% by weight. Fibronectin in the range 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.

[0106] In some embodiments, the composition comprises 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 comprises 0.01% to 15% by weight (e.g., 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 comprises between about 0.01% by weight and about 0.025% by weight of insulin-like growth factor binding protein, between about 0.025% by weight and about 0.05% by weight of insulin-like growth factor binding protein, between about 0.025% by weight and about 0.075% by weight of insulin-like growth factor binding protein, between about 0.025% by weight and about 0.1% by weight of insulin-like growth factor binding protein, and between about 0.01% by weight and about 0.1% by weight of islets of Langerhans. Insulin-like growth factor binding protein (IGF-B), ranging from about 0.05% to about 0.075% by weight, ranging from about 0.05% to about 0.1% by weight, ranging from about 0.075% to about 0.1% by weight, ranging from about 0.1% to about 0.1% by weight, ranging from about 0.1% to about 0.2% by weight, ranging from about 0.1% to about 0.5% by weight, and other components. Insulin-like growth factor binding protein in amounts between about 0.2% and about 0.4% by weight, between about 0.5% and about 1% by weight, between about 0.4% and about 0.6% by weight, between about 0.6% and about 0.8% by weight, between about 0.8% and about 1% by weight, between about 1% and about 2% by weight, between about 1% and about 5% by weight, between about 2% and about 4% by weight, between about 5% and about 10% by weight, between about 4% and about 6% by weight, between about 6% and about 8% by weight, or between about 8% and about 10% by weight.

[0107] In some embodiments, the composition comprises about 0.01% by weight or more of green fluorescent protein (GFP), about 0.025% by weight or more of GFP, about 0.050% by weight or more of GFP, about 0.075% by weight or more of GFP, about 0.1% by weight or more of GFP, about 0.25% by weight or more of GFP, about 0.5% by weight or more of GFP, about 0.75% by weight or more of GFP, about 1% by weight or more of GFP, about 2.5% by weight or more of GFP, about 5% by weight or more of GFP, about 7.5% by weight or more of GFP, or about 10% by weight or more of GFP. In some embodiments, the composition comprises 0.01% by weight to 15% by weight (e.g., 0.1% by weight to 10% by weight, 1% by weight to 10% by weight, or 5% by weight to 10% by weight) of GFP. In some embodiments, the composition comprises green fluorescent protein (GFP) in amounts between about 0.01% and about 0.025% by weight, between about 0.025% and about 0.05% by weight, between about 0.025% and about 0.075% by weight, between about 0.025% and about 0.1% by weight, between about 0.01% and about 0.1% by weight, between about 0.05% and about 0.075% by weight, between about 0.05% and about 0.1% by weight, between about 0.075% and about 0.1% by weight, between about 0.1% and about 0.2% by weight, and between about 0.1% and about 0.5% by weight. Green fluorescent protein, between about 0.2% and about 0.4% by weight, between about 0.5% and about 1% by weight, between about 0.4% and about 0.6% by weight, between about 0.6% and about 0.8% by weight, between about 0.8% and about 1% by weight, between about 1% and about 2% by weight, between about 1% and about 5% by weight, between about 2% and about 4% by weight, between about 5% and about 10% by weight, between about 4% and about 6% by weight, between about 6% and about 8% by weight, or between about 8% and about 10% by weight.

[0108] In some embodiments, the compositions of the present invention may further comprise hyaluronic acid. Hyaluronic acid is a natural ligand of CD44 and is pro-inflammatory and stimulates hair growth. Hyaluronic acid is a natural linear polymer containing disaccharide repeating units of β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine. In some embodiments, the hyaluronic acid has a low average molecular weight, which, as used herein, refers to the range of about 15,000 Da to about 40,000 Da. In some embodiments, the hyaluronic acid has an intermediate average molecular weight, which, as used herein, refers to the range of about 75,000 Da to about 350,000 Da. In some embodiments, the hyaluronic acid has a high average molecular weight, which, as used herein, refers to about 950,000 Da and greater.

[0109] In some embodiments, hyaluronic acid has an average molecular weight ranging from about 4,000 Da or less to about 10,000 Da. In some embodiments, hyaluronic acid has an average molecular weight ranging from about 10,000 Da to about 100,000 Da. In some embodiments, hyaluronic acid has an average molecular weight ranging from about 100,000 Da to about 1,500,000 Da or greater.

[0110] In some embodiments, the hyaluronic acid has a concentration between about 1 kDa and about 10 kDa, between about 10 kDa and about 50 kDa, between about 50 kDa and about 100 kDa, between about 100 kDa and about 150 kDa, between about 200 kDa and about 250 kDa, between about 300 kDa and about 350 kDa, between about 400 kDa and about 450 kDa, and between about 500 kDa and about 550 kDa. Between 0 kDa, between approximately 600 kDa and approximately 650 kDa, between approximately 700 kDa and approximately 750 kDa, between approximately 800 kDa and approximately 850 kDa, between approximately 900 kDa and approximately 1000 kDa, between approximately 1000 kDa and approximately 1100 kDa, between approximately 1100 kDa and approximately 1200 kDa, between approximately 1200 kDa and approximately 1300 kDa, between approximately 1300 kDa Between approximately 1400 kDa, between approximately 1400 kDa and approximately 1500 kDa, between approximately 1 kDa and approximately 100 kDa, between approximately 100 kDa and approximately 250 kDa, between approximately 250 kDa and approximately 500 kDa, between approximately 500 kDa and approximately 750 kDa, between approximately 750 kDa and approximately 1000 kDa, between approximately 1000 kDa and approximately 1250 kDa, between approximately 12 Average molecular weight between 50 kDa and about 1500 kDa, between about 1 kDa and about 250 kDa, between about 1 kDa and about 500 kDa, between about 100 kDa and about 500 kDa, between about 250 kDa and about 750 kDa, between about 500 kDa and about 1000 kDa, between about 750 kDa and about 1250 kDa, or between about 1000 kDa and about 1500 kDa.

[0111] In some embodiments, hyaluronic acid is cross-linked. In some embodiments, hyaluronic acid has a cross-linking density of about 20% or greater. Cross-linking can increase the lifespan of hyaluronic acid, and in some embodiments, a certain degree of cross-linking is desirable. In some embodiments, hyaluronic acid has sufficient cross-linking to last for about a week. However, regardless of the mechanism of action, hyaluronic acid is believed to effectively stimulate hair growth by interacting with CD44 receptors. Therefore, it is desirable that hyaluronic acid is not so extensively cross-linked that cross-linking interferes with the ability of hyaluronic acid to interact with CD44 receptors.

[0112] The hydroxyl (--OH), carboxylic acid (--COOH), and / or amide (--NHCOCH)3) functional groups of hyaluronic acid can be crosslinked via ether bonds (R--O--R), ester bonds (R--COO--R), or carbodiimide, respectively. In some embodiments, hyaluronic acid is crosslinked with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), glutaraldehyde (GTA), polyethylene glycol diglycidyl ether (PEGDE), ethylene glycol diglycidyl ether (EGDE), divinyl sulfonate (DVS), or pentaerythritol tetraacrylate (PT).

[0113] Hyaluronic acid can have approximately 1x10 -7 mol / cm 3 Or larger, approximately 2 x 10 -7 mol / cm 3 Or larger, approximately 3 x 10 - 7 mol / cm 3 Or larger, approximately 4 x 10 -7 mol / cm 3 Or larger, approximately 5 x 10 -7 mol / cm 3 Or larger, approximately 6 x 10 -7 mol / cm 3 Or larger, approximately 7 x 10 -7 mol / cm 3 Or larger, approximately 8 x 10 -7 mol / cm 3 Or larger, approximately 9 x 10 -7 mol / cm 3 Or larger, approximately 1 x 10 - 6 mol / cm 3 Or larger, approximately 2 x 10 -6 mol / cm 3 Or larger, approximately 3 x 10 -6 mol / cm 3 Or larger, approximately 4 x 10 -6 mol / cm 3 Or larger, approximately 5 x 10 -6 mol / cm 3 Or larger, approximately 6 x 10 -6 mol / cm 3 Or larger, approximately 7 x 10 -6 mol / cm 3 Or larger, approximately 8 x 10 - 6 mol / cm 3 Or larger, approximately 9 x 10 -6mol / cm 3 Or larger, or approximately 1 x 10 -6 mol / cm 3 Or a higher crosslinking density. In some embodiments, hyaluronic acid can have a crosslinking density between approximately 1 x 10⁻⁶. -7 mol / cm 3 1 x 10 -5 mol / cm 3 Between, between approximately 1x10 -7 mol / cm 3 1 x 10 -6 mol / cm 3 Between, between approximately 1 x 10 -7 mol / cm 3 5 x 10 -7 mol / cm 3 Between, between approximately 5 x 10 -7 mol / cm 3 1 x 10 -6 mol / cm 3 Between, between approximately 1 x 10 -7 mol / cm 3 Peace Treaty 2 x 10 -7 mol / cm 3 Between, between approximately 2 x 10 -7 mol / cm 3 4 x 10 -7 mol / cm 3 Between, between approximately 4 x 10 -7 mol / cm 3 6 x 10 -7 mol / cm 3 Between, between approximately 6 x 10 -7 mol / cm 3 8 x 10 -7 mol / cm 3 Or approximately 8 x 10 -7 mol / cm 3 1 x 10 -6 mol / cm 3 Between, between approximately 1 x 10 -6 mol / cm 3 1 x 10 -5 mol / cm 3 Between, between approximately 1 x 10 -6 mol / cm 3 5 x 10 -6 mol / cm 3 Between, between approximately 5 x 10-6 mol / cm 3 1 x 10 -5 mol / cm 3 Between, between approximately 1 x 10 -6 mol / cm 3 Peace Treaty 2 x 10 -6 mol / cm 3 Between, between approximately 2 x 10 -7 mol / cm 3 4 x 10 -7 mol / cm 3 Between, between approximately 4 x 10 -7 mol / cm 3 6 x 10 -7 mol / cm 3 Between, between approximately 6 x 10 -7 mol / cm 3 8 x 10 -7 mol / cm 3 Between, between approximately 8 x 10 -7 mol / cm 3 1 x 10 -5 mol / cm 3 Or between approximately 5 x 10 -7 mol / cm 3 5 x 10 -6 mol / cm 3 The cross-linking density between them.

[0114] In some embodiments, the compositions of the present invention may contain an amount of hyaluronic acid sufficient to provide a therapeutic effect (e.g., stimulating hair growth in a patient with this need). However, higher concentrations of hyaluronic acid may lead to undesirable inflammation. In some embodiments, the compositions of the present invention contain an amount of hyaluronic acid sufficient to provide a therapeutic effect (e.g., stimulating hair growth in a patient with this need) and insufficient to provide an unacceptable inflammatory response. As used throughout this specification, both mcg / mL and μg / mL refer to micrograms per milliliter. In some embodiments, hyaluronic acid is present in compositions of about 10 mcg / mL or more, about 15 mcg / mL or more, about 20 mcg / mL or more, about 25 mcg / mL or more, about 30 mcg / mL or more, about 35 mcg / mL or more, about 40 mcg / mL or more, about 45 mcg / mL or more, about 50 mcg / mL or more, about 55 mcg / mL or more, about 60 mcg / mL or more, about 65 mcg / mL or more. More, about 70 mcg / mL or more, about 75 mcg / mL or more, about 80 mcg / mL or more, about 85 mcg / mL or more, about 90 mcg / mL or more, about 95 mcg / mL or more, about 100 mcg / mL or more, about 120 mcg / mL or more, about 140 mcg / mL or more, about 1600 mcg / mL or more, about 180 mcg / mL or more, about 200 mcg / mL or more, about Compositions with a concentration of 220 mcg / mL or more, compositions with a concentration of about 240 mcg / mL or more, compositions with a concentration of about 260 mcg / mL or more, compositions with a concentration of about 280 mcg / mL or more, compositions with a concentration of about 300 mcg / mL or more, compositions with a concentration of about 320 mcg / mL or more, compositions with a concentration of about 340 mcg / mL or more, compositions with a concentration of about 360 mcg / mL or more, compositions with a concentration of about 380 mcg / mL or more, compositions with a concentration of about 400 mcg / mL or more, compositions with a concentration of about 420 mcg / mL or more, compositions with a concentration of about 440 mcg / mL or more. Compositions with a concentration of approximately 460 mcg / mL or more, compositions with a concentration of approximately 480 mcg / mL or more, compositions with a concentration of approximately 500 mcg / mL or more, compositions with a concentration of approximately 520 mcg / mL or more, compositions with a concentration of approximately 540 mcg / mL or more, compositions with a concentration of approximately 560 mcg / mL or more, compositions with a concentration of approximately 580 mcg / mL or more, compositions with a concentration of approximately 600 mcg / mL or more, compositions with a concentration of approximately 620 mcg / mL or more, compositions with a concentration of approximately 640 mcg / mL or more, compositions with a concentration of approximately 660 mcg / mL or more,The composition is present in amounts of 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, and approximately 980 mcg / mL or more.

[0115] In some embodiments, hyaluronic acid is expressed in concentrations of about 1 mcg / mL to about 250 mcg / mL, about 10 mcg / mL to about 250 mcg / mL, about 10 mcg / mL to about 200 mcg / mL, about 10 mcg / mL to about 150 mcg / mL, about 10 mcg / mL to about 100 mcg / mL, about 25 mcg / mL to about 250 mcg / mL, and about 25 mcg / mL to... Compositions of about 200 mcg / mL, compositions of about 25 mcg / mL to about 150 mcg / mL, compositions of about 25 mcg / mL to about 100 mcg / mL, compositions of about 50 mcg / mL to about 250 mcg / mL, compositions of about 50 mcg / mL to about 200 mcg / mL, compositions of about 50 mcg / mL to about 150 mcg / mL, compositions of about 50 mcg / mL to about 100 mcg / mL, and compositions of about 75 mcg / mL Compositions with a concentration of about 250 mcg / mL, compositions with a concentration of about 75 mcg / mL, compositions with a concentration of about 200 mcg / mL, compositions with a concentration of about 75 mcg / mL, compositions with a concentration of about 150 mcg / mL, compositions with a concentration of about 75 mcg / mL, compositions with a concentration of about 100 mcg / mL, compositions with a concentration of about 100 mcg / mL, compositions with a concentration of about 250 mcg / mL, compositions with a concentration of about 100 mcg / mL, compositions with a concentration of about 200 mcg / mL, compositions with a concentration of about 100 mcg / mL, compositions with a concentration of about 150 mcg / mL, compositions with a concentration of about 150 mcg / mL. The composition is present in amounts ranging from about g / mL to about 250 mcg / mL, from about 200 mcg / mL to about 250 mcg / mL, from about 60 mcg / mL to about 80 mcg / mL, from about 50 mcg / mL to about 75 mcg / mL, from about 25 mcg / mL to about 75 mcg / mL, from about 10 mcg / mL to about 50 mcg / mL, or from about 10 mcg / mL to about 25 mcg / mL.

[0116] In some embodiments, hyaluronic acid is present in concentrations of about 1 mcg / mL to about 500 mcg / mL, about 10 mcg / mL to about 500 mcg / mL, about 10 mcg / mL to about 450 mcg / mL, about 10 mcg / mL to about 400 mcg / mL, about 10 mcg / mL to about 350 mcg / mL, about 25 mcg / mL to about 500 mcg / mL, about 25 mcg / mL to about 450 mcg / mL, and about 2 Compositions of 5 mcg / mL to about 400 mcg / mL, compositions of 25 mcg / mL to about 350 mcg / mL, compositions of 50 mcg / mL to about 500 mcg / mL, compositions of 50 mcg / mL to about 450 mcg / mL, compositions of 50 mcg / mL to about 400 mcg / mL, compositions of 50 mcg / mL to about 350 mcg / mL, compositions of 75 mcg / mL to about 500 mcg / mL, compositions of 75 mcg / mL to about 450 mcg / mL Compositions with concentrations of approximately 100 mcg / mL, approximately 75 mcg / mL to approximately 400 mcg / mL, approximately 75 mcg / mL to approximately 350 mcg / mL, approximately 100 mcg / mL to approximately 500 mcg / mL, approximately 100 mcg / mL to approximately 450 mcg / mL, approximately 100 mcg / mL to approximately 400 mcg / mL, approximately 100 mcg / mL to approximately 350 mcg / mL, and approximately 200 mcg / mL to approximately 500 mcg / mL. The composition is present in amounts ranging from about 200 mcg / mL to about 450 mcg / mL, from about 200 mcg / mL to about 400 mcg / mL, from about 200 mcg / mL to about 350 mcg / mL, from about 300 mcg / mL to about 500 mcg / mL, from about 300 mcg / mL to about 450 mcg / mL, from about 300 mcg / mL to about 400 mcg / mL, and from about 300 mcg / mL to about 350 mcg / mL.

[0117] In some embodiments, hyaluronic acid is present in concentrations of about 1 mcg / mL to about 750 mcg / mL, about 10 mcg / mL to about 750 mcg / mL, about 10 mcg / mL to about 700 mcg / mL, about 10 mcg / mL to about 650 mcg / mL, about 10 mcg / mL to about 600 mcg / mL, about 25 mcg / mL to about 750 mcg / mL, about 25 mcg / mL to about 700 mcg / mL, and about 2 Compositions of 5 mcg / mL to about 650 mcg / mL, compositions of 25 mcg / mL to about 600 mcg / mL, compositions of 50 mcg / mL to about 750 mcg / mL, compositions of 50 mcg / mL to about 700 mcg / mL, compositions of 50 mcg / mL to about 650 mcg / mL, compositions of 50 mcg / mL to about 600 mcg / mL, compositions of 75 mcg / mL to about 750 mcg / mL, compositions of 75 mcg / mL to about 700 mcg / mL Compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 100 mcg / mL, compositions with a concentration of approximately 2 ... The composition is present in amounts ranging from about 200 mcg / mL to about 700 mcg / mL, from about 200 mcg / mL to about 650 mcg / mL, from about 200 mcg / mL to about 600 mcg / mL, from about 300 mcg / mL to about 750 mcg / mL, from about 300 mcg / mL to about 700 mcg / mL, from about 300 mcg / mL to about 650 mcg / mL, and from about 300 mcg / mL to about 600 mcg / mL.

[0118] In some embodiments, hyaluronic acid is expressed in concentrations of about 1 mcg / mL to about 950 mcg / mL, about 10 mcg / mL to about 950 mcg / mL, about 10 mcg / mL to about 900 mcg / mL, about 10 mcg / mL to about 850 mcg / mL, about 10 mcg / mL to about 800 mcg / mL, about 25 mcg / mL to about 950 mcg / mL, about 25 mcg / mL to about 900 mcg / mL, about 25 mcg / mL to about 850 mcg / mL, and about 25 mcg / mL to about 800 mcg / mL. 00 mcg / mL composition, about 50 mcg / mL composition to about 950 mcg / mL composition, about 50 mcg / mL composition to about 900 mcg / mL composition, about 50 mcg / mL composition to about 850 mcg / mL composition, about 50 mcg / mL composition to about 800 mcg / mL composition, about 75 mcg / mL composition to about 950 mcg / mL composition, about 75 mcg / mL composition to about 900 mcg / mL composition, about 75 mcg / mL composition to about 850 mcg / mL composition, about 75 mcg / mL composition to about 800 mcg / mL composition, about 100 mcg / mL composition to about 9 50 mcg / mL composition, about 100 mcg / mL composition to about 900 mcg / mL composition, about 100 mcg / mL composition to about 850 mcg / mL composition, about 100 mcg / mL composition to about 800 mcg / mL composition, about 200 mcg / mL composition to about 950 mcg / mL composition, about 200 mcg / mL composition to about 900 mcg / mL composition, about 200 mcg / mL composition to about 850 mcg / mL composition, about 200 mcg / mL composition to about 800 mcg / mL composition, about 300 mcg / mL composition to about 950 mcg / mL composition, about 300 mcg / mL composition The composition is approximately 300 mcg / mL to about 850 mcg / mL. (Repeated 6 times)Compositions of about 500 mcg / mL to about 850 mcg / mL, compositions of about 500 mcg / mL to about 800 mcg / mL, compositions of about 600 mcg / mL to about 950 mcg / mL, compositions of about 600 mcg / mL to about 900 mcg / mL, compositions of about 600 mcg / mL to about 850 mcg / mL, compositions of about 600 mcg / mL to about 800 mcg / mL, compositions of about 700 mcg / mL to about 950 mcg / mL The composition is present in amounts within the ranges of 0 mcg / mL, about 700 mcg / mL to about 900 mcg / mL, about 700 mcg / mL to about 850 mcg / mL, about 700 mcg / mL to about 800 mcg / mL, about 800 mcg / mL to about 950 mcg / mL, or about 800 mcg / mL to about 850 mcg / mL.

[0119] In some embodiments, the composition comprises 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 comprises hyaluronic acid in the ranges of about 0.001% by weight and about 0.0025% by weight, about 0.0025% by weight and about 0.005% by weight, about 0.0025% by weight and about 0.0075% by weight, about 0.0025% by weight and about 0.01% by weight, about 0.001% by weight and about 0.01% by weight, and about 0.005% by weight and about 0.01% by weight. Hyaluronic acid in the following proportions: approximately 0.75% by weight, approximately 0.005% by weight and approximately 0.01% by weight, approximately 0.0075% by weight and approximately 0.01% by weight, approximately 0.01% by weight and approximately 0.02% by weight, approximately 0.01% by weight and approximately 0.05% by weight, approximately 0.02% by weight and approximately 0.04% by weight, and approximately 0.05% by weight and approximately 0.1% by weight. Hyaluronic acid in the range of approximately 0.04% to approximately 0.06% by weight, approximately 0.06% to approximately 0.08% by weight, approximately 0.08% to approximately 0.1% by weight, approximately 0.1% to approximately 0.2% by weight, approximately 0.1% to approximately 0.5% by weight, approximately 0.2% to approximately 0.4% by weight, and approximately 0.5% to approximately 1% by weight. Hyaluronic acid in the range of about 0.4% to about 0.6% by weight, about 0.6% to about 0.8% by weight, about 0.8% to about 1% by weight, about 1% to about 2% by weight, about 2% to about 4% by weight, about 4% to about 6% by weight, about 6% to about 8% by weight, or about 8% to about 10% by weight.In some embodiments, the composition comprises hyaluronic acid between about 0.001% by weight and about 10% by weight, between about 0.01% by weight and about 10% by weight, between about 0.1% by weight and about 10% by weight, between about 1% by weight and about 10% by weight, between about 2% by weight and about 10% by weight, between about 3% by weight and about 10% by weight, between about 4% by weight and about 10% by weight, or between about 5% by weight and about 10% by weight.

[0120] In some embodiments, the composition according to one embodiment of the invention comprises a commercially available hyaluronic acid composition. For example, suitable commercially available hyaluronic acid compositions include, but are not limited to, hyaluronic acid sold under the trademark JUVEDERM. TM RESTYLANE-L TM CAPTIQUE TM BELOTERO BALANCE TM PREVELLESILK TM ELEVESS TM HYLAFORM TM EUFLEXXA TM GEL-ONE TM HYALGAN TM ORTHOVISC TM MONOVISC TM SUPARTZ TM SYNVISC TM and SYNVISC-ONE TM .

[0121] In some embodiments, the composition may contain a hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include, but are not limited to, high molecular weight poly(4-styrene sulfonate) (PSS), gossypol, disodium gold thiobutane, fenofurine, glycyrrhizic acid, heparin, and O-sulfated hyaluronic acid (sHA) and dextran sulfate, or combinations thereof.

[0122] 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 (e.g., 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 comprises between about 0.01% by weight and about 0.025% by weight, between about 0.025% by weight and about 0.05% by weight, between about 0.025% by weight and about 0.075% by weight, between about 0.025% by weight and about 0.1% by weight, between about 0.01% by weight and about 0.1% by weight, between about 0.05% by weight and about 0.075% by weight, between about 0.05% by weight and about 0.1% by weight, between about 0.075% by weight and about 0.1% by weight, between about 0.075% by weight and about 0.1% by weight, between about 0.1% by weight and about 0.2% by weight, and between about 0.1% by weight and about 0.5% by weight. The formulation includes, but is not limited to, a hyaluronidase inhibitor at a concentration of about 0.2% to about 0.4% by weight, a hyaluronidase inhibitor at a concentration of about 0.5% to about 1% by weight, a hyaluronidase inhibitor at a concentration of about 0.4% to about 0.6% by weight, a hyaluronidase inhibitor at a concentration of about 0.6% to about 0.8% by weight, a hyaluronidase inhibitor at a concentration of about 0.8% to about 1% by weight, a hyaluronidase inhibitor at a concentration of about 1% to about 2% by weight, a hyaluronidase inhibitor at a concentration of about 1% to about 5% by weight, a hyaluronidase inhibitor at a concentration of about 2% to about 4% by weight, a hyaluronidase inhibitor at a concentration of about 5% to about 10% by weight, a hyaluronidase inhibitor at a concentration of about 4% to about 6% by weight, a hyaluronidase inhibitor at a concentration of about 6% to about 8% by weight, or a hyaluronidase inhibitor at a concentration of about 8% to about 10% by weight.

[0123] In some embodiments, the composition comprises a carrier medium. Such a carrier medium may be a biocompatible fluid suitable for injection into mammalian skin. In some embodiments, the carrier medium comprises an aqueous saline solution. In some embodiments, hyaluronic acid serves as both the carrier medium and the active ingredient.

[0124] In some embodiments, the composition comprises one or more additives. Such additives may include preservatives or biocides.

[0125] In some embodiments, the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, a liposome, or a vesicle.

[0126] In some embodiments, the composition may comprise fatty acids (e.g., oleic acid), esters of fatty acids and alcohols (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), medium-chain triglycerides, triacetin, or terpenes (e.g., limonene, menthol, eucalyptol). In some embodiments, the composition may comprise a surfactant. For example, suitable surfactants include, but are not limited to, TWEEN. TM (Polysorbate), Cremophor TM (A mixture of polyethylene glycol glycerol hydroxystearate, PEG-40 castor oil, and polyoxyethylene 40 hydrogenated castor oil), TRANSCUTOL TM P (diethylene glycol monoethyl ether), PLUROLOLEIQUE TM (Polyglycerol-3-oleate), PLUROL ISOSTEARIQUE TM (isostearate of polyglycerol and higher oligomers) and LABRASOL TM (A mixture of monoglycerides, diglycerides, and triglycerides of C8 and C10 fatty acids, and monoglycerides and diesters of PEG) and lecithin. In some embodiments, the composition may contain a co-surfactant. Suitable co-surfactants include, for example, short-chain and medium-chain alcohols and polyglycerol derivatives, including ethanol, isopropanol, isopropyl myristate, and propylene glycol.

[0127] In some embodiments, the composition comprises one or more of soybean oil, jojoba oil, aloe vera oil, soybean phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropanol, glycerol, glyceryl monostearate, and propylene glycol.

[0128] A method for producing a therapeutic composition according to one embodiment of the invention includes mixing an effective amount of an active agent if the composition contains more than one active ingredient. For example, if the composition contains a peptide and hyaluronic acid 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 NO: 1 to SEQ ID NO: 96, an effective amount of hyaluronic acid is mixed with an effective amount of the peptide. The method may further include the step of preparing a physiologically acceptable carrier medium in which the active agent is added. Preferably, the physiologically acceptable carrier medium is injectable.

[0129] The production method may include the step of forming a microemulsion or nanoemulsion. The microemulsion or nanoemulsion may contain oil, water, a surfactant, and a co-surfactant to form a colloidal dispersion with droplet sizes 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 and alcohols (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), medium-chain triglycerides, triacetin, or terpenes (e.g., limonene, menthol, eucalyptol). In some embodiments, the microemulsion or nanoemulsion may contain a surfactant. For example, suitable surfactants include, but are not limited to, TWEEN. TM (Polysorbate), Cremophor TM (A mixture of polyethylene glycol glycerol hydroxystearate, PEG-40 castor oil, and polyoxyethylene 40 hydrogenated castor oil), TRANSCUTOL TM P (diethylene glycol monoethyl ether), PLUROL OLEIQUE TM (Polyglycerol-3-oleate), PLUROL ISOSTEARIQUE TM (isostearate of polyglycerol and higher oligomers) and LABRASOL TM (A mixture of monoglycerides, diglycerides, and triglycerides of C8 and C10 fatty acids, and monoglycerides and diesters of PEG) and lecithin. In some embodiments, the microemulsion or nanoemulsion may contain a co-surfactant. Suitable co-surfactants include, for example, short-chain and medium-chain alcohols and polyglycerol derivatives, including ethanol, isopropanol, isopropyl myristate, and propylene glycol. In some embodiments, the formation of the microemulsion or nanoemulsion includes the use of a high-pressure homogenizer, a microfluidizer, and / or an ultrasonic generator.

[0130] The production method may include the step of mixing a composition according to one embodiment of the invention with solid nanoparticles. The solid nanoparticles may comprise inorganic materials, such as metal oxides (e.g., zinc oxide, titanium dioxide) or polymers that are solid at room temperature.

[0131] The production method may include the step of mixing a composition according to one embodiment of the invention with solid lipid nanoparticles. The solid lipid nanoparticles may comprise lipids that are solid at room temperature, and the solid lipid nanoparticles have a surfactant surface coating to stabilize them as droplets having a size of less than about 100 nm when dispersed in water.

[0132] The production method may include the step of mixing a composition according to one embodiment of the invention with a nanostructured lipid carrier. The nanostructured lipid carrier may comprise a fluid lipid phase embedded in a solid lipid matrix or positioned on the surface of a solid sheet and a surfactant layer.

[0133] The production method may include the step of mixing a composition according to one embodiment of the invention with liposomes. The liposomes may comprise spherical vesicles composed of amphiphilic phospholipids and cholesterol (which self-associate to form multilayer, macromonal, and micromonal vesicles).

[0134] The manufacturing method may include the step of mixing a composition according to one embodiment of the invention with flexible vesicles. The flexible vesicles may comprise materials that will associate into a bilayer structure and components that impart flexibility. In some embodiments, the flexible vesicles comprise olsomes (i.e., phospholipids with a high ethanol content), vesicles (i.e., nonionic surfactants), invasomes (i.e., a mixture of phospholipids, ethanol, and terpene penetration enhancers), SECosomes (i.e., surfactants, ethanol, and cholesterol), or PEVs (i.e., penetration enhancer vesicles). In some embodiments, the PEV may comprise oleic acid, limonene, or propylene glycol.

[0135] The production method may include the step of mixing a composition according to one embodiment of the invention with polymeric micelles or polymeric dendritic polymers. The polymeric micelles may be colloidal carriers having a hydrophilic shell and a hydrophobic core. The polymeric micelles may be nanoscale. The polymeric dendritic polymer may contain branched polymer structures.

[0136] On the other hand, the present invention provides a method (method 3.0) for stimulating hair growth in the skin of a patient with this need, the method comprising applying a composition to the patient's skin, the 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 NO: 1 to SEQ ID NO: 96. For example, the present invention includes: 3.1. A method 3.0, wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 96.

[0137] 3.2. A 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 NO: 1 to SEQ ID NO: 20, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO: 20.

[0138] 3.3. A 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 NO: 21 to SEQ ID NO: 39, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO: 39.

[0139] 3.4. A 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 NO: 40 to SEQ ID NO: 60, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO: 60.

[0140] 3.5. A 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 NO: 61 to SEQ ID NO: 63, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO: 63.

[0141] 3.6. A 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 NO: 64 to SEQ ID NO: 71, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO: 71.

[0142] 3.7. A 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 NO: 72 to SEQ ID NO: 79, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO: 79.

[0143] 3.8. A 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 NO: 80 to SEQ ID NO: 87, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO: 87.

[0144] 3.9. A 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 NO: 88 to SEQ ID NO: 95, optionally wherein the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO: 95.

[0145] 3.10. A 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, optionally wherein the peptide comprises SEQ ID NO: 96.

[0146] 3.11. According to any of the foregoing methods, wherein the peptide contains a CD44 binding site.

[0147] 3.12. A method 3.11, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof.

[0148] 3.13. A method 3.12, 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.

[0149] 3.14. According to any of the foregoing methods, wherein the peptide contains a calcium-binding site.

[0150] 3.15. A method 3.14, wherein the peptide comprises SEQ ID NO: 98 or a variant thereof.

[0151] 3.16. A method 3.15, wherein 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.

[0152] 3.17. According to any of the foregoing methods, wherein the peptide contains a CD44 binding site and a calcium binding site.

[0153] 3.18. A method 3.17, wherein the peptide comprises SEQ ID NO: 97 or a variant thereof, and SEQ ID NO: 98 or a variant thereof.

[0154] 3.19. A method 3.18, 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.

[0155] 3.20. According to any of the methods described above, wherein the peptide has a length of no more than 295 amino acids.

[0156] 3.21. A method 3.20, wherein the peptide has a length of not more than 290 amino acids, not more than 280 amino acids, not more than 270 amino acids, not more than 260 amino acids, not more than 250 amino acids, not more than 240 amino acids, not more than 230 amino acids, not more than 220 amino acids, not more than 210 amino acids, not more than 200 amino acids, not more than 190 amino acids, not more than 180 amino acids, not more than 170 amino acids, not more than 160 amino acids, not more than 150 amino acids, not more than 140 amino acids, not more than 130 amino acids, not more than 120 amino acids, not more than 110 amino acids, not more than 100 amino acids, not more than 90 amino acids, not more than 80 amino acids, not more than 70 amino acids, or not more than 60 amino acids.

[0157] 3.22. According to any of the foregoing methods, wherein the composition comprises about 0.01% by weight or more of peptides, optionally wherein the composition comprises about 0.025% by weight or more (e.g., 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.

[0158] 3.23. According to any of the foregoing methods, wherein the composition comprises 0.01 wt% to 20 wt% of peptides, optionally wherein the composition comprises 0.025 wt% to 20 wt%, 0.05 wt% to 20 wt%, 0.75 wt% to 20 wt%, 0.1 wt% to 20 wt%, 0.25 wt% to 20 wt%, 0.5 wt% to 20 wt%, 0.75 wt% to 20 wt%, 1 wt% to 20 wt%, 2.5 wt% to 20 wt%, 5 wt% to 20 wt%, 7.5 wt% to 2 Peptides in the range of 0 wt%, 10 wt% to 20 wt%, 0.01 wt% to 15 wt%, 0.025 wt% to 15 wt%, 0.05 wt% to 15 wt%, 0.75 wt% to 15 wt%, 0.1 wt% to 15 wt%, 0.25 wt% to 15 wt%, 0.5 wt% to 15 wt%, 0.75 wt% to 15 wt%, 1 wt% to 15 wt%, 2.5 wt% to 15 wt%, 5 wt% to 15 wt%, 7.5 wt% to 15 wt%, or 10 wt% to 15 wt%.

[0159] 3.24. According to any of the foregoing methods, wherein the composition comprises between about 0.01 wt% and about 0.025 wt%, between about 0.025 wt% and about 0.05 wt%, between about 0.025 wt% and about 0.075 wt%, between about 0.025 wt% and about 0.1 wt%, between about 0.01 wt% and about 0.1 wt%, between about 0.05 wt% and about 0.075 wt%, between about 0.05 wt% and about 0.1 wt%, between about 0.075 wt% and about 0.1 wt%, between about 0.1 wt% and about 0.2 wt%, between about 0.1 wt%. Peptides ranging from % to about 0.5% by weight, between about 0.2% by weight and about 0.4% by weight, between about 0.5% by weight and about 1% by weight, between about 0.4% by weight and about 0.6% by weight, between about 0.6% by weight and about 0.8% by weight, between about 0.8% by weight and about 1% by weight, between about 1% by weight and about 2% by weight, between about 1% by weight and about 5% by weight, between about 2% by weight and about 4% by weight, between about 5% by weight and about 10% by weight, between about 4% by weight and about 6% by weight, between about 6% by weight and about 8% by weight, or between about 8% by weight and about 10% by weight.

[0160] 3.25. According to any of the foregoing methods, wherein the composition comprises one or more additional ligands that bind to CD44.

[0161] 3.26. A method 3.25, wherein the one or more additional ligands binding to CD44 are selected from the group consisting of: serine, chondroitin or salts thereof (e.g., chondroitin sulfate), fibrin, collagen, fibronectin, insulin-like growth factor binding protein (IGFBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP4, IGFBP-5 and IGFBP-6), green fluorescent protein (GFP) and any combination thereof.

[0162] 3.27. According to any of the foregoing methods, wherein the composition comprises seriganin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of seriganin.

[0163] 3.28. According to any of the foregoing methods, wherein the composition comprises chondroitin or a salt thereof, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of chondroitin or a salt thereof.

[0164] 3.29. A method 3.28, wherein the composition comprises chondroitin sulfate.

[0165] 3.30. According to any of the foregoing methods, wherein the composition comprises fibrin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of fibrin.

[0166] 3.31. According to any of the foregoing methods, wherein the composition comprises collagen, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of collagen.

[0167] 3.32. According to any of the foregoing methods, wherein the composition comprises fibronectin, optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of fibronectin.

[0168] 3.33. According to any of the foregoing methods, wherein the composition comprises insulin-like growth factor binding protein (IGFBP), optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of insulin-like growth factor binding protein.

[0169] 3.34. According to any of the foregoing methods, wherein the composition comprises green fluorescent protein (GFP), optionally wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight or 5% to 10% by weight) of GFP.

[0170] 3.35. According to any of the foregoing methods, wherein the composition comprises hyaluronic acid.

[0171] 3.36. A method 3.35, 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.

[0172] 3.37. According to any one of methods 3.35 to 3.36, wherein the hyaluronic acid is cross-linked, optionally wherein the hyaluronic acid has a cross-linking density of about 20% or greater.

[0173] 3.38. The composition according to any one of compositions 3.35 to 3.37, wherein the hyaluronic acid is present at a concentration of 25 mcg / mL or higher, 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, about 100 ug / mL or lower, about 100 mcg / mL to about 950 mcg / mL, about 200 mcg / mL to about 400 mcg / mL, about 400 mcg / mL to about 600 mcg / mL, about 600 mcg / mL to about 800 mcg / mL, or about 800 mcg / mL to about 950 mcg / mL.

[0174] 3.39. According to any of the foregoing methods, wherein the composition comprises a hyaluronidase inhibitor.

[0175] 3.40. A method 3.39, wherein the hyaluronidase inhibitor is selected from high molecular weight poly(4-styrene sulfonate) (PSS), gossypol, disodium gold thiobutane, fenofurine, glycyrrhizic acid, fatty acids, plant-derived compounds, heparin and O-sulfated hyaluronic acid (sHA) or any combination thereof.

[0176] 3.41. According to any one of methods 3.39 to 3.40, wherein the composition comprises 0.01% to 15% by weight (e.g., 0.1% to 10% by weight, 1% to 10% by weight, or 5% to 10% by weight) of a hyaluronidase inhibitor.

[0177] 3.42. According to any of the foregoing methods, wherein the composition comprises a carrier medium.

[0178] 3.43. A method 3.42, wherein the carrier medium comprises an aqueous salt solution.

[0179] 3.44. According to any of the foregoing methods, wherein the composition comprises a preservative or a biocide.

[0180] 3.45. According to any of the foregoing methods, wherein the composition comprises a microemulsifier, a nanoemulsifier, solid lipid nanoparticles, a nanostructured lipid carrier, a liposome, or a vesicle.

[0181] 3.46. According to any of the foregoing methods, wherein the composition comprises a surfactant.

[0182] 3.47. According to any of the foregoing methods, wherein the composition comprises one or more of soybean oil, jojoba oil, aloe vera oil, soybean phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropanol, glycerin, glyceryl monostearate, and propylene glycol.

[0183] 3.48. According to any of the foregoing methods, wherein the application includes applying the composition to the surface of the skin, optionally wherein the method further includes a step of enhancing penetration prior to the topical application of the composition.

[0184] 3.49. According to any one of methods 3.0 to 3.47, wherein the application comprises injecting the composition into the dermis or subcutaneous layer of the skin, optionally wherein the application comprises injecting the composition into the dermis of the skin.

[0185] 3.50. A method 3.49, wherein the composition is injected into the skin to a depth of about 400 micrometers to about 2 mm.

[0186] 3.51. According to any one of methods 3.49 to 3.50, wherein the composition is administered by multiple injections, optionally wherein the composition is administered at about 400 injections / cm². 2 Skin approximately 650 injections / cm 2 The amount applied to the skin is administered via multiple injections.

[0187] 3.52. According to any one of methods 3.49 to 3.51, wherein the composition is injected via microneedle.

[0188] 3.53. According to any of the foregoing methods, wherein the composition is encapsulated in liposomes, optionally wherein the liposomes comprise hydrogenated phospholipids.

[0189] 3.54. According to any of the foregoing methods, wherein the method further includes applying electroporation to the skin.

[0190] 3.55. According to any of the foregoing methods, wherein the method further includes applying ultrasound to the skin to enhance penetration.

[0191] 3.56. According to any of the foregoing methods, wherein the method further includes applying laser ablation to the skin.

[0192] 3.57. According to any of the foregoing methods, wherein the method further includes applying magnetic permeation to the skin.

[0193] 3.58. According to any of the foregoing methods, wherein the method further includes applying radiofrequency thermal ablation to the skin.

[0194] 3.59. According to any of the foregoing methods, wherein the method further includes applying a microneedle device to the skin.

[0195] 3.60. According to any of the foregoing methods, wherein the composition is administered as a bolus or as an infusion.

[0196] 3.61. According to any of the foregoing methods, wherein the composition is applied to the skin at the following frequencies: once daily for one day, once daily for one week, once daily for one month, once daily for one year, twice daily for one day, twice daily for one week, twice daily for one month, twice daily for one year, once weekly for one week, once weekly for one month, once weekly for one year, twice weekly for one week, twice weekly for one month, twice weekly for one year, once monthly for one month, once monthly for two months, once monthly for six months, once monthly for one year, twice monthly for one month, twice monthly for two months, twice monthly for two months, twice monthly for six months, twice monthly 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.

[0197] Methods for stimulating hair growth in patients with this need include applying a composition according to any embodiment of the invention to the surface of the patient's skin or into the patient's skin. In some embodiments, the composition is applied topically by applying it to the surface of the patient's skin. In some embodiments, the composition is applied to the dermis or subcutaneous tissue of the patient's skin (e.g., by injection as described herein).

[0198] A method of applying a composition according to one embodiment of the invention includes delivering the composition according to one embodiment of the invention to a hair follicle. In some embodiments, delivery is achieved by topical application, i.e., applying the composition to the surface of the skin and allowing the composition to penetrate the skin. In some embodiments, the application method includes a step to enhance penetration prior to topical application of the composition. In some embodiments, delivery is achieved by injection into the skin.

[0199] In some embodiments, local delivery is performed after or in combination with the application of iontophoresis. For example, iontophoresis may include applying a weak current (e.g., 0.1 mA / cm.sup.2 to 1.0 mA / cm.sup.2) to increase the skin penetration of the composition. Without being bound by theory, iontophoresis is believed to improve skin penetration through electromigration, electroosmosis, and / or enhanced passive diffusion.

[0200] In some implementations, local delivery is performed after or in conjunction with the application of electroporation. For example, electroporation may include applying short-duration (10 microseconds to 10 milliseconds) high-intensity, high-voltage (e.g., 50V to 1500V) electrical pulses to form aqueous pores in the lipid bilayer of the stratum corneum of the skin.

[0201] In some implementations, local delivery is performed after or in conjunction with the application of ultrasound-assisted permeation. For example, ultrasound-assisted permeation may include applying sound waves at a high frequency (e.g., about 500 kHz to 1250 kHz) or a low frequency (e.g., about 20 kHz to about 100 kHz), or starting at one of the high or low frequencies and progressing to the other of the high or low frequencies.

[0202] In some implementations, local delivery is performed after or in conjunction with the application of laser ablation. Laser ablation may include generating photomechanical waves by ablating a target material (e.g., a polymer) placed on the surface of the skin.

[0203] In some implementations, local delivery is performed after or in combination with the application of magnetoperfusion. Magnetoperfusion may include applying a magnetic field (e.g., a pulsed electromagnetic field) to the skin.

[0204] In some implementations, local delivery is performed after the application of radiofrequency thermal ablation. Thermal ablation may include applying extreme heat (e.g., approximately 300°C for several microseconds) to the skin surface. Without being theoretically constrained, it is believed that thermal ablation can partially vaporize the stratum corneum to create micron-scale channels. Thermal ablation can use components including VIADOR... TM (Syneron Medical Ltd, Israel) and Passport ® This can be accomplished using commercially available devices, including the Nitto-Denko device (Japan). In some embodiments, thermal ablation can be performed using an erbium:yttrium-gallium-garnet (Er:YAG) laser emitting at 2,790 nm or a yttrium scandium-gallium-garnet (YSGG) laser emitting at 2,940 nm. In some embodiments, lattice laser ablation can be applied to a submillimeter region to produce dots (e.g., 40-300 μm, density between 50-600 cm⁻¹) mimicking a microneedle array pattern.

[0205] In some implementations, local delivery is performed after the application of the microneedle device.

[0206] In some embodiments, a method of administering a composition according to one embodiment of the invention comprises injecting a therapeutic amount of the composition into the skin of a patient requiring treatment. In some embodiments, the composition according to one embodiment of the invention is administered as a bolus, which, as used herein, refers to a dose delivered in less than ten minutes. In some embodiments, the composition according to one embodiment of the invention is administered as an infusion, which, as used herein, refers to a dose delivered in about ten minutes or longer.

[0207] Such injections can be performed via a single needle, microneedle, or similar device, or an array of needles, microneedles, or similar devices. In some embodiments, the composition according to one embodiment of the invention is delivered via a conventional syringe. In some embodiments, subcutaneous delivery is performed via a hollow microneedle injector. In some embodiments, subcutaneous delivery is performed via a microneedle patch coated with the composition according to one embodiment of the invention, for example, coated by 3D printing. In some embodiments, the composition is delivered via a jet injector. As used herein, the term "needle" refers to any such device used to pierce the skin and inject the composition according to one embodiment of the invention.

[0208] Preferably, the composition is applied near the patient's hair follicles. Therefore, in some embodiments, the composition is applied by injecting a therapeutic amount into the patient's dermis. In some embodiments, the composition is applied by injecting a therapeutic amount into the patient's subcutaneous tissue. In some embodiments, the composition is applied to the patient's skin at a depth of about 0.4 mm to about 2 mm (i.e., about 0.4 mm to about 3 mm from the skin surface). In some embodiments, the composition is applied to the patient's skin at a depth of about 0.4 mm, about 0.5 mm, about 0.6 mm, about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm, about 2 mm, about 2.1 mm, about 2.2 mm, about 2.3 mm, about 2.4 mm, about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3 mm. In some embodiments, the composition is applied to the patient's skin in a depth between about 0.5 mm and about 1 mm, between about 1 mm and about 1.5 mm, between about 1.5 mm and about 2 mm, between about 2 mm and about 2.5 mm, between about 2.5 mm and about 3 mm, between about 1 mm and about 3 mm, between about 1.5 mm and about 3 mm, between about 0.4 mm and about 0.6 mm, between about 0.4 mm and about 0.8 mm, between about 0.4 mm and about 1 mm, between about 0.4 mm and about 1.2 mm, between about 0.4 mm and about 1.4 mm, between about 0.4 mm and about 1.6 mm, between about 0.4 mm and about 1.8 mm, between about 0.4 mm and about 2 mm, between about 0.4 mm and about 2.2 mm, between about 0.4 mm and about 2.4 mm, and between about 0.4 mm and about 2.6 mm. Between m, between approximately 0.4mm and approximately 2.8mm, between approximately 0.4mm and approximately 3mm, between approximately 0.6mm and approximately 0.8mm, between approximately 0.6mm and approximately 1mm, between approximately 0.6mm and approximately 1.2mm, between approximately 0.6mm and approximately 1.4mm, between approximately 0.6mm and approximately 1.6mm, between approximately 0.6mm and approximately 1.8mm, between approximately 0.6mm and approximately 2mm, between Between approximately 0.6mm and approximately 2.2mm, between approximately 0.6mm and approximately 2.4mm, between approximately 0.6mm and approximately 2.6mm, between approximately 0.6mm and approximately 2.8mm, between approximately 0.6mm and approximately 3mm, between approximately 0.8mm and approximately 1mm, between approximately 0.8mm and approximately 1.2mm, between approximately 0.8mm and approximately 1.4mm, between approximately 0.8mm and approximately 1.6mm, between approximately 0.Between 8mm and approximately 1.8mm, between approximately 0.8mm and approximately 2mm, between approximately 0.8mm and approximately 2.2mm, between approximately 0.8mm and approximately 2.4mm, between approximately 0.8mm and approximately 2.6mm, between approximately 0.8mm and approximately 2.8mm, between approximately 0.8mm and approximately 3mm, between approximately 1mm and approximately 1.2mm, between approximately 1mm and approximately 1.4mm, between approximately 1mm and approximately 1.6mm, between approximately 1mm and approximately 1.8mm, between approximately 1mm and approximately 2mm, between approximately 1mm and approximately 2.2mm, between approximately 1mm and approximately 2.4mm, between approximately 1mm and approximately 2.6mm, between approximately 1mm Between approximately 2.8mm, between approximately 1mm and approximately 3mm, between approximately 1.2mm and approximately 1.4mm, between approximately 1.2mm and approximately 1.6mm, between approximately 1.2mm and approximately 1.8mm, between approximately 1.2mm and approximately 2mm, between approximately 1.2mm and approximately 2.2mm, between approximately 1.2mm and approximately 2.4mm, between approximately 1.2mm and approximately 2.6mm, between approximately 1.2mm and approximately 2.8mm, between approximately 1.2mm and approximately 3mm, between approximately 1.4mm and approximately 1.6mm, between approximately 1.4mm and approximately 1.8mm, between approximately 1.4mm and approximately 2mm, between approximately 1.4mm and approximately 2.2mm Between, between approximately 1.4mm and approximately 2.4mm, between approximately 1.4mm and approximately 2.6mm, between approximately 1.4mm and approximately 2.8mm, between approximately 1.4mm and approximately 3mm, between approximately 1.6mm and approximately 1.8mm, between approximately 1.6mm and approximately 2mm, between approximately 1.6mm and approximately 2.2mm, between approximately 1.6mm and approximately 2.4mm, between approximately 1.6mm and approximately 2.6mm, between approximately 1.6mm and approximately 2.8mm, between approximately 1.6mm and approximately 3mm, between approximately 1.8mm and approximately 2mm, between approximately 1.8mm and approximately 2.2mm, between approximately 1.8mm and approximately 2.4mm, between Between approximately 1.8mm and approximately 2.6mm, between approximately 1.8mm and approximately 2.8mm, between approximately 1.8mm and approximately 3mm, between approximately 2.0mm and approximately 2.2mm, between approximately 2.0mm and approximately 2.4mm, between approximately 2.0mm and approximately 2.6mm, between approximately 2.0mm and approximately 2.8mm, between approximately 2.0mm and approximately 3mm, between approximately 2.2mm and approximately 2.4mm, between approximately 2.2mm and approximately 2.6mm, between approximately 2.2mm and approximately 2.8mm, between approximately 2.2mm and approximately 3mm, between approximately 2.4mm and approximately 2.6mm, between approximately 2.4mm and approximately 2.8mm, between approximately 2.Between 4mm and approximately 3mm, between approximately 2.6mm and approximately 2.8mm, between approximately 2.6mm and approximately 3mm, or between approximately 2.8mm and approximately 3mm.

[0209] In some embodiments, the composition according to an embodiment of the invention can be administered via multiple injections. In some embodiments, the composition according to an embodiment of the invention is administered via approximately one injection / cm. 2 Skin approximately 1000 injections / cm 2 Skin, approximately 200 injections / cm 2 Skin approximately 800 injections / cm 2 Skin or approximately 400 injections / cm 2 Skin approximately 650 injections / cm 2 Apply to the skin. In some embodiments, the composition is administered via approximately 200 injections / cm². 2 Skin, approximately 250 injections / cm 2 Skin, approximately 300 injections / cm 2 Skin, approximately 350 injections / cm 2 Skin, approximately 400 injections / cm 2 Skin, approximately 450 injections / cm 2 Skin, approximately 500 injections / cm 2 Skin, approximately 550 injections / cm 2 Skin, approximately 600 injections / cm 2 Skin or approximately 650 injections / cm 2 Apply to the skin.

[0210] In some embodiments, the composition may be applied to the patient's skin at the following frequencies or as needed: once daily for one day, once daily for one week, once daily for one month, once daily for one year, twice daily for one day, twice daily for one week, twice daily for one month, twice daily for one year, once weekly for one week, once weekly for one month, once weekly for one year, twice weekly for one week, twice weekly for one month, twice weekly for one year, once monthly for one month, once monthly for two months, once monthly for six months, once monthly for one year, twice monthly for one month, twice monthly for two months, twice monthly for two months, twice monthly for six months, twice monthly 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, once every six months for one year.

Claims

1. A peptide for stimulating hair growth, the peptide comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO:

96.

2. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 1 to SEQ ID NO:

20.

3. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 21 to SEQ ID NO:

39.

4. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 40 to SEQ ID NO:

60.

5. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 61 to SEQ ID NO:

63.

6. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 64 to SEQ ID NO:

71.

7. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 72 to SEQ ID NO:

79.

8. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 80 to SEQ ID NO:

87.

9. The peptide of 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 to a sequence selected from the group consisting of SEQ ID NO: 88 to SEQ ID NO:

95.

10. The peptide of 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 to SEQ ID NO:

96.

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

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

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

14. The peptide of any one of the preceding claims, wherein the peptide has a length of no more than 295 amino acids, no more than 250 amino acids, no more than 200 amino acids, no more than 150 amino acids, no more than 100 amino acids, or no more than 60 amino acids.

15. A composition for stimulating hair growth, the composition comprising a peptide of any one of claims 1-14.

16. The composition of claim 15, wherein the composition comprises about 0.01% or more by weight of the peptide.

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

18. The composition of any one of claims 15-17, wherein the composition further comprises hyaluronic acid.

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

20. The composition of claim 18 or 19, wherein the hyaluronic acid is cross-linked.

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

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

23. A method of stimulating hair growth in the skin of a patient in need thereof, the method comprising administering to the skin of the patient a composition of any one of claims 15-22.

24. The method of claim 23, wherein the administering comprises applying the composition to a surface of the skin.

25. The method of claim 23, wherein the administering comprises injecting the composition into a dermal layer or a subcutaneous layer of the skin.

26. The method of any one of claims 23-25, wherein the composition is encapsulated in a liposome.

27. The method of any one of claims 23-26, wherein the method further comprises applying electroporation to the skin.

28. The method of any one of claims 23-27, wherein the method further comprises applying sonophoresis to the skin.

29. The method of any one of claims 23-28, wherein the method further comprises applying laser ablation to the skin.

30. The method of any one of claims 23-29, wherein the method further comprises applying magnetic sonophoresis to the skin.

31. The method of any one of claims 23-30, wherein the method further comprises applying radiofrequency heat ablation to the skin.

32. The method of any one of claims 23-31, wherein the method further comprises applying a microneedle device to the skin.

33. A peptide for stimulating hair growth, the peptide comprising a sequence having at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 97 or SEQ ID NO:

98.

34. A nucleotide encoding the peptide of any one of claims 1-33.

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