BR112022016950B1 - NON-THERAPEUTIC METHODS TO STIMULATE HAIR GROWTH AND TO TREAT HAIR LOSS - Google Patents

Abstract

COMPOSITIONS AND METHODS FOR STIMULATING HAIR GROWTH. The present invention relates to methods and compositions for stimulating hair growth. Compositions for stimulating hair growth include two or more of hyaluronic acid, osteopontin and another CD44-binding ligand. Methods for stimulating hair growth include administering such a composition to a patient's skin.

Description

CROSS REFERENCE TO RELATED ORDER

[001] The present patent application claims priority to U.S. Provisional Patent Application no. 62/981,480 filed on February 25, 2020, which is incorporated into this document by reference in its entirety.

BACKGROUND OF THE INVENTION

[002] The present invention generally relates to compositions and methods for stimulating hair growth.

[003] Hair loss often has a negative social and psychological impact on the individual suffering from this loss. Many factors are believed to contribute to hair loss, including genetics, hormones, environmental exposure, medications, psychological stress and nutrition. A well-known treatment is hair transplantation, which requires anesthesia, is expensive, time-consuming and sometimes painful. Other approaches include massage and acupuncture, but these have not been shown to be effective. Hormones and other drugs have been used to treat hair loss, however these treatments often cause undesirable side effects, such as hair growth in unwanted areas. Therefore, there is a need for an effective therapy to stimulate hair growth.

BRIEF SUMMARY OF THE INVENTION

[004] In one embodiment, a composition for stimulating hair growth includes osteopontin and hyaluronic acid. Hyaluronic acid can have an average molecular weight in a range of about 20 KDa to 1,350 KDa. Hyaluronic acid can be cross-linked, and in some embodiments can have a cross-link density of about 20% or more. In some embodiments, hyaluronic acid is present at a concentration of 25 mcg/ml or more, or between about 25 mcg/ml and about 100 mcg/ml. In some embodiments the composition may also include one or more of serglycin, chondroitin sulfate, fibrin, IGFBP4 and GFP10, and in particular may include one or more of serglycin, chondroitin sulfate and fibrin. In some embodiments, the composition may include a hyaluronidase inhibitor, for example, selected from high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurothiomalate, fenoprofen, glycerrhizic acid, fatty acids, derivative compounds of plants, heparin, and O-sulfated HA (sHA), or combinations thereof.

[005] In another embodiment, a composition for stimulating hair growth includes hyaluronic acid and one or more of serglycin, chondroitin sulfate, fibrin, IGFBP4 and GFP10. In particular, the composition may include one or more of serglycin, chondroitin sulfate and fibrin. Hyaluronic acid can have an average molecular weight in a range of about 20 KDa to 1,350 KDa. Hyaluronic acid can be cross-linked, and in some embodiments can have a cross-link density of about 20% or more. In some embodiments, hyaluronic acid is present at a concentration of 25 mcg/ml or more, or between about 25 mcg/ml and about 100 mcg/ml. In some embodiments, the composition may also include osteopontin. In some embodiments, the composition may also include a hyaluronidase inhibitor, for example, selected from high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurothiomalate, fenoprofen, glycerrizic acid, fatty acids, compounds plant derivatives, heparin, and O-sulfated HA (sHA), or combinations thereof.

[006] In one embodiment, a method of stimulating hair growth on the skin of a patient in need thereof includes administering a composition comprising hyaluronic acid and a CD44-binding ligand to the patient's skin. In some embodiments, administration includes applying the composition to a surface of the skin, whereas in other embodiments, administration includes injecting the composition into a dermal layer of the skin. The composition can be injected from about 400 microns to about 2 mm deep into the skin. In some embodiments the composition is administered in a plurality of injections in an amount of from about 400 injections/cm2 of skin to about 650 injections/cm2 of skin. In some embodiments the needle is a microneedle. In some embodiments the composition may be enclosed in a liposome, for example, a liposome comprising hydrogenated phospholipids.

[007] In some embodiments, a method of stimulating hair growth also includes applying iontophoresis to the skin.

[008] In some embodiments, a method of stimulating hair growth also includes applying electroporation to the skin.

[009] In some embodiments, a method of stimulating hair growth also includes applying laser ablation to the skin.

[0010] In some embodiments, a method of stimulating hair growth also includes applying radiofrequency thermal ablation to the skin.

[0011] In some embodiments a method of stimulating hair growth also includes applying a microneedle device to the skin.

[0012] In one embodiment, a method of administering a hair growth composition to a patient in need of treatment for hair loss includes injecting the composition into a patient's skin, wherein the composition comprises acid hyaluronic acid and a CD44-binding ligand. The composition may be injected through a needle, for example, where the needle is inserted 400 microns to about 2 mm into the skin prior to injection. In some embodiments, the needle is a microneedle. In some embodiments, the composition may be enclosed in a liposome, for example, a liposome comprising hydrogenated phospholipids.

[0013] In one embodiment, a composition for stimulating hair growth includes two or more of osteopontin, hyaluronic acid, serglycin, chondroitin sulfate, fibrin, IG-FBP4 and GFP10.

[0014] In some embodiments, a composition for stimulating hair growth comprises hyaluronic acid at a concentration of about 1 mcg/ml to about 250 mcg/ml. Hyaluronic acid may have an average molecular weight, for example, in a range of about 4,000 Da to 10,000 Da, in a range of about 10,000 Da to about 100,000 Da, in a range of about 15 kDa to about 50 kDa, in a range of about 75 kDa to about 350 kDa, or in a range of about 20 kDa to 1,350 kDa. In some embodiments, hyaluronic acid has an average molecular weight of more than about 950 kDa.

[0015] In some embodiments of the composition, hyaluronic acid is cross-linked. For example, hyaluronic acid can have a crosslinking density of about 20% or more.

[0016] In some embodiments of the composition, hyaluronic acid is present at a concentration of 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, or about 100 μg/ml or less.

[0017] In some embodiments, a composition for stimulating hair growth comprising hyaluronic acid at a concentration of about 250 mcg/ml or less also comprises one or more of osteopontin, hyaluronic acid, serglycin, sulfate chondroitin, fibrin, IGFBP4 and GFP10.

[0018] In some embodiments of the invention, a method of stimulating hair growth on the skin of a patient in need thereof includes administering a composition comprising hyaluronic acid at a concentration of about 1 mcg/ml to about of 250 mcg/ml to the patient's skin. In such methods, administration may include injecting the composition into a dermal layer of the skin, for example, from about 400 microns to about 2 mm deep in the skin. In other such methods, administration may include injecting a plurality of injections in an amount of from about 400 injections/cm2 of skin to about 650 injections/cm2 of skin. In some embodiments, a method also includes an additional step, such as applying iontophoresis to the skin, applying electroporation to the skin, applying laser ablation to the skin, applying radiofrequency thermal ablation to the skin, and/or the application of a microneedle device to the skin. In some embodiments, the composition also includes a CD44-binding ligand, for example, osteopontin.

[0019] In some embodiments of the invention, a method of administering a hair growth composition to a patient in need of treatment for hair loss includes injecting the composition into a skin of the patient, wherein the composition comprises the hyaluronic acid at a concentration of about 1 mcg/ml to about 250 mcg/ml. In some embodiments the composition is injected through a needle, in which the needle is inserted, for example, 400 microns to about 2 mm into the skin prior to injection. In some embodiments the needle is a microneedle. In some embodiments, the composition also comprises a CD44-binding ligand, for example, osteopontin.

BRIEF DESCRIPTION OF VARIOUS VIEWS OF THE DRAWINGS

[0020] The following detailed description of embodiments of the compositions and methods for stimulating hair growth will be better understood when read in conjunction with the accompanying drawings. It should be understood, however, that the invention is not limited to the precise arrangements shown.

[0021] In the drawings:

[0022] Figure 1 illustrates the sequence and domains of osteopontin. SEQ ID NO: 1 represents the amino acid residues of Exon 4 of osteopontin; SEQ ID NO: 2 represents the amino acid residues of Exon 5 of osteopontin; SEQ ID NO: 3 represents the integrin binding domain #2 (amino acid residues 162 to 168) of osteopontin.

[0023] Figure 2 illustrates the domains and structure of osteopontin; SEQ ID NO: 4 represents an osteopontin integrin binding site; SEQ ID NO: 5 represents an osteopontin integrin binding site.

[0024] Figure 3 illustrates the domains and structure of osteopontin. SEQ ID NO: 6 represents amino acid residues 17 to 314 of osteopontin.

[0025] Figure 4 illustrates the sequence and domains of osteopontin. SEQ ID NO: 3 represents integrin binding domain #2 (amino acid residues 162 to 168) of osteopontin; SEQ ID NO: 7 represents the calcium binding domain (amino acid residues 216 to 228) of osteopontin; SEQ ID NO: 8 represents the osteopontin sequence including the signal peptide (amino acid residues 1 to 16).

[0026] Figure 5 shows a mouse 18 days after injection with a control solution and 25, 50 and 100 mcg/ml of low molecular weight hyaluronic acid solutions.

[0027] Figure 6 shows a mouse 18 days after injection with a control solution and 25, 50 and 100 mcg/ml of low molecular weight hyaluronic acid solutions.

[0028] Figure 7 shows a mouse 18 days after injection with a control solution and 25, 50 and 100 mcg/ml of high molecular weight hyaluronic acid solutions.

[0029] Figure 8 shows a mouse 18 days after injection with a control solution and 25, 50 and 100 mcg/ml of high molecular weight hyaluronic acid solutions.

DETAILED DESCRIPTION OF THE INVENTION

[0030] The present invention presents methods and compositions useful in stimulating hair growth.

I. Compositions

[0031] In some embodiments, a hair growth stimulating composition includes a natural ligand for CD44, or a fragment or derivative thereof.

[0032] In some embodiments, the natural ligand for CD44 is one or more of osteopontin (OPN, SPP1), serglycin (SRGN), chondroitin sulfate, collagen, fibronectin, fibrin, or a binding fragment CD44, an isoform, or a derivative thereof.

[0033] CD44-binding fragments, isoforms, or derivatives of a naturally occurring ligand for CD44 include synthetic peptides that bind CD44 and are generated on the basis of CD44-binding domains of osteopontin, serglycin, chondroyl sulfate - tin, collagen, fibronectin and/or fibrin.

[0034] In some embodiments, a hair growth stimulation composition includes hyaluronic acid.

[0035] In some embodiments, a hair growth stimulation composition includes one or more natural ligands for CD44, or a fragment or derivative thereof, and hyaluronic acid.

[0036] In some embodiments, a hair growth stimulating composition includes a combination of two or more of hyaluronic acid, osteopontin, serglycin, chondroitin sulfate, collagen, fibronectin, fibrin, and proteolytically or synthetically produced CD44 binding fragments, isoforms, or derivatives thereof. In some embodiments, a hair growth composition includes three or more of hyaluronic acid, osteopontin, serglycin, chondroitin sulfate, collagen, fibronectin, fibrin, and CD44-binding fragments, produced protein. - lytically or synthetically, isoforms, or derivatives thereof. Any of the above components may also include a hyaluronidase inhibitor and/or one or more other constituents.

[0037] Various non-limiting embodiments include the compositions described in the following table, where an "X" indicates that the component is included in the embodiment of the invention:

[0038] In some embodiments, a composition for stimulating hair growth may include one or more CD44 ligands. Such ligands may include osteopontin. Other ligands included within the scope of the invention include serglycin, chondroitin sulfate (e.g., chondroitin 4-sulfate), collagen, fibronectin, fibrin, an insulin growth factor binding protein (IG). - FBP) (e.g., IGFBP-1, IGFBP-2, IGFBP-3, IGFBP4, IGFBP-5 and IGFBP-6), a green fluorescent protein, and hyaluronic acid.

[0039] In some embodiments, a composition may include a fragment, isoform or derivative of a CD44 ligand, wherein such fragment, isoform or derivative has at least 95% identity, at least 90% identity, at least 85% identity, at least 80% identity, at least 75% identity, at least 70% identity, at least 65% identity, or at least 60% identity with the corresponding CD44 ligand.

[0040] In some embodiments, a composition comprises about 0.01% by weight or more of a CD44-binding ligand, about 0.025% by weight or more of a CD44-binding ligand, about 0.050% by weight or more of a CD44-binding ligand, about 0.075% by weight or more of a CD44-binding ligand, about 0.1% by weight or more of a CD44-binding ligand, about 0.25 % by weight or more of a CD44-binding ligand, about 0.5% by weight or more of a CD44-binding ligand, about 0.75% by weight or more of a CD44-binding ligand, about of 1% by weight or more of a CD44-binding ligand, about 2.5% by weight or more of a CD44-binding ligand, about 5% by weight or more of a CD44-binding ligand, about of 7.5% by weight or more of a CD44-binding ligand, or about 10% or more of a CD44-binding ligand. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight of a CD44 binding ligand, between about 0.025% by weight and about 0.05% by weight of a CD44 binding ligand. of a CD44-binding ligand, between about 0.025% by weight and about 0.075% by weight of a CD44-binding ligand, between about 0.025% by weight and about 0.1% by weight of a CD44-binding ligand , between about 0.01% by weight and about 0.1% by weight of a CD44-binding ligand, between about 0.05% by weight and about 0.075% by weight of a CD44-binding ligand , between about 0.05% by weight and about 0.1% by weight of a CD44-binding ligand, between about 0.075% by weight and about 0.1% by weight of a CD44-binding ligand , between about 0.1% by weight and about 0.2% by weight of a CD44 binding ligand, between about 0.1% by weight and about 0.5% by weight of a binding ligand to CD44, between about 0.2% by weight and about 0.4% by weight of a CD44-binding ligand, between about 0.5% by weight and about 1% by weight of a binding ligand to CD44, between about 0.4% by weight and about 0.6% by weight of a CD44-binding ligand, between about 0.6 and about 0.8% by weight of a CD44-binding ligand, between about 0.6 and about 0.8% by weight of a CD44-binding ligand. CD44, between about 0.8% by weight and about 1% by weight of a CD44-binding ligand, between about 1% by weight and about 2% by weight of a CD44-binding ligand, between about 1% by weight and about 5% by weight of a CD44-binding ligand, between about 2% by weight and about 4% by weight of a CD44-binding ligand, between about 5% by weight weight and about 10% by weight of a CD44-binding ligand, between about 4% by weight and about 6% by weight of a CD44-binding ligand, between about 6 and about 8% by weight weight of a CD44-binding ligand, or between about 8% by weight and about 10% by weight of a CD44-binding ligand.

1. Osteopontin

[0041] Osteopontin is an extracellular signaling protein that is a natural ligand for CD44. Figures 1 to 4 describe the sequence and domain structure of osteopontin. Without being limited by theory, it is believed that osteopontin may induce CD44 activation through proteolytic cleavage of CD44, which results in the intracellular release of the CD44 intracellular domain (ICD). CD44ICD is then free to go to the nucleus and modulate gene expression. Osteopontin is discussed in International Patent Publication no. WO 2018175630, which is incorporated into this document by reference in its entirety.

[0042] In some embodiments, a composition useful for stimulating hair growth includes osteopontin, or a CD44 binding fragment, an isoform, or a derivative thereof. In some embodiments, a CD44 binding fragment, an isoform, or an osteopontin derivative includes a peptide that is produced through proteolytic cleavage of a naturally occurring (e.g., full-length) osteopontin protein. In some embodiments, a CD44 binding fragment, isoform, or derivative of osteopontin comprises residues 290 to 305 of osteopontin, 291 to 304 of osteopontin, comprises residues 292 to 303 of osteopontin, comprises residues 293 to 302 of osteopontin, comprises residues 294 to 301 of osteopontin, or comprises residues 295 to 300 of osteopontin. In some embodiments, a CD44 binding fragment, an isoform, or an osteopontin derivative comprises SEQ ID NO. 2. In some embodiments, a CD44 binding fragment, an isoform, or an osteopontin derivative comprises SEQ ID NO. 3.

[0043] In some embodiments, a composition comprises about 0.01% by weight or more osteopontin, about 0.025% by weight or more osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 0.050% by weight or more osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 0.075% by weight or more osteopontin or the CD44 binding fragment, isoform, or the derivative thereof, about 0.1% by weight or more of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 0.25% by weight or more of osteopontin or the binding fragment of CD44, the isoform, or derivative thereof, about 0.5% by weight or more of osteopontin or the binding fragment of CD44, the isoform, or derivative thereof, about 0.75% by weight or more than osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 1% by weight or more of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 2 .5% by weight or more osteopontin or the CD44 binding fragment, isoform, or derivative thereof, about 5% by weight or more osteopontin or the CD44 binding fragment, isoform, or derivative thereof thereof, about 7.5% by weight or more osteopontin or the CD44 binding fragment, isoform, or derivative thereof, or about 10% by weight or more osteopontin or the CD44 binding fragment , the isoform, or its derivative. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight westopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.025% by weight and a Osteopontin of about 0.05% by weight osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.025% by weight and about 0.075% by weight osteopontin or the binding fragment of CD44, the isoform, or derivative thereof, between about 0.025% by weight and about 0.1% by weight of osteopontin or the CD44 binding fragment, the isoform, or derivative thereof, between about 0.01% by weight and about 0.1% by weight osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.05% by weight and about 0.075% by weight of osteopontin or the CD44 binding fragment, the isoform, or the derivative thereof, between about 0.05% by weight and about 0.1% by weight of osteopontin or the CD44 binding fragment, the isoform , or derivative thereof, between about 0.075% by weight and about 0.1% by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.1% by weight weight and about 0.2% by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.1% by weight and about 0.5% by weight of osteopontin or the CD44 binding fragment, the isoform, or the derivative thereof, between about 0.2% by weight and about 0.4% by weight osteopontin or the CD44 binding fragment, the isoform, or of the derivative thereof, between about 0.5% by weight and about 1% by weight or CD44 binding fragment, the isoform, or the derivative thereof, between about 0.4% by weight and about 0 .6% by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 0.6 and about 0.8% by weight of osteopontin or the CD44 binding fragment, of the isoform, or derivative thereof, between about 0.8% by weight and about 1% by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 1% by weight and about 2% by weight osteopontin or the CD44 binding fragment, isoform, or derivative thereof, between about 1% by weight and about 5% by weight osteopontin or the CD44 binding fragment, of the isoform, or the derivative thereof, between about 2% by weight and about 4% by weight or of the CD44 binding fragment, the isoform, or the derivative thereof, between about 5% by weight and about 10% by weight osteopontin or the CD44 binding fragment, the isoform, or derivative thereof, between about 4% by weight and about 6% by weight osteopontin or the CD44 binding fragment, the isoform, or derivative thereof, between about 6 and about 8% by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof, or between about 8% by weight and about 10 % by weight of osteopontin or the CD44 binding fragment, isoform, or derivative thereof.

2. Other Ligands for CD44

[0044] In some embodiments, a composition useful for stimulating hair growth includes one or more ligands for CD44 with the exception of or in addition to osteopontin. Such ligands include serglycin, chondroitin sulfate (e.g., chondroitin 4-sulfate), collagen, fibronectin, fibrin, insulin growth factor binding protein (IGFBP) (e.g., IGFBP-1, IG-FBP-2, IGFBP-3, IGFBP4, IGFBP-5 and IGFBP-6), and a green fluorescent protein (e.g., GFP10). Another ligand for CD44 is hyaluronic acid, discussed later. In some embodiments, the composition comprises IGFBP4 and GFP10.

[0045] Without being limited by theory, it is believed that each of these components can serve as a ligand that binds to CD44. In some embodiments, a composition useful for stimulating hair growth includes a ligand that binds to CD44. In some embodiments, a composition useful for stimulating hair growth includes a combination of two or more (e.g., three or four) ligands that bind to CD44.

The. Serglycin

[0046] In some embodiments, a composition comprises about 0.01% by weight or more serglycine, about 0.025% by weight or more serglycine, about 0.050% by weight or more serglycine, about 0.075% by weight weight or more of serglycine, about 0.1% by weight or more of serglycine, about 0.25% by weight or more of serglycine, about 0.5% by weight or more of serglycine, about 0.75 % by weight or more serglycine, about 1% by weight or more serglycine, about 2.5% by weight or more serglycine, about 5% by weight or more serglycine, about 7.5% by weight weight or more of serglycine, or about 10% by weight or more of serglycine. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight serglycine, between about 0.025% by weight and about 0.05% by weight serglycine, between about 0.025% by weight and about 0.075% by weight serglycine, between about 0.025% by weight and about 0.1% by weight serglycine, between about 0.01% by weight and about 0.1% by weight of serglycine, between about 0.05% by weight and about 0.075% by weight serglycine, between about 0.05% by weight and about 0.1% by weight serglycine, between about 0.075% by weight weight and about 0.1% by weight serglycine, between about 0.1% by weight and about 0.2% by weight serglycine, between about 0.1% by weight and about 0.5% by weight by weight of serglycine, between about 0.2% by weight and about 0.4% by weight serglycine, between about 0.5% by weight and about 1% by weight serglycine, between about 0. 4% by weight and about 0.6% by weight serglycine, between about 0.6 and about 0.8% by weight serglycine, between about 0.8% by weight and about 1% by weight of serglycine, between about 1% by weight and about 2% by weight serglycine, between about 1% by weight and about 5% by weight serglycine, between about 2% by weight and about 4% by weight weight of serglycine, between about 5% by weight and about 10% by weight serglycine, between about 4% by weight and about 6% by weight serglycine, between about 6 and about 8% by weight of serglycine, or between about 8% by weight and about 10% by weight serglycine.

B. Chondroitin

[0047] In some embodiments, a composition comprises chondroitin or a salt thereof, for example, chondroitin sulfate. In some embodiments, a composition comprises about 0.01% by weight or more of chondroitin or a salt thereof, about 0.025% by weight or more of chondroitin or a salt thereof, about 0.050% by weight or more of chondroitin or a salt thereof, about 0.075% by weight or more chondroitin or a salt thereof, about 0.1% by weight or more chondroitin or a salt thereof, about 0.25% by weight or more than chondroitin or a salt thereof, about 0.5% by weight or more of chondroitin or a salt thereof, about 0.75% by weight or more of chondroitin or a salt thereof, about 1% by weight weight or more of chondroitin or a salt thereof, about 2.5% by weight or more of chondroitin or a salt thereof, about 5% by weight or more of chondroitin or a salt thereof, about 7.5 % by weight or more of chondroitin or a salt thereof, or about 10% by weight or more of chondroitin or a salt thereof. In some embodiments, a composition comprises between about 0.01% by weight chondroitin 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 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. 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. therein, in between about 0.1% by weight and about 0.2% by weight chondroitin or a salt thereof, between about 0.1% by weight and about 0.5% by weight chondroitin or a salt thereof, between about 0.2% by weight and about 0.4% by weight chondroitin or a salt thereof, between about 0.5% by weight and about 1% by weight chondroitin or a salt thereof, between about 0.4% by weight and about 0.6% by weight of chondroitin or a salt thereof, between about 0.6% by weight and about 0.8% by weight of chondroitin or a salt thereof, between about 0.8% by weight and about 1% by weight chondroitin or a salt thereof, between about 1% by weight and about 2% by weight chondroitin or a salt thereof thereof, between about 1% by weight and about 5% by weight or a salt thereof, between about 2% by weight and about 4% by weight of chondroitin or a salt thereof, between about 5% by weight and about 10% by weight chondroitin or a salt thereof, between about 4% by weight and about 6% by weight chondroitin or a salt thereof, between about 6% by weight and about 8 % by weight chondroitin or a salt thereof, or between about 8% by weight and about 10% by weight chondroitin or a salt thereof.

w. Fibrin

[0048] In some embodiments, a composition comprises about 0.01% by weight or more fibrin, about 0.025% by weight or more fibrin, about 0.050% by weight or more fibrin, about 0.075% by weight 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 fibrin, about 1% by weight or more fibrin, about 2.5% by weight or more fibrin, about 5% by weight or more fibrin, about 7.5% by weight weight or more of fibrin, or about 10% by weight or more of fibrin. In some embodiments, a composition comprises 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 of 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 fibrin, between about 0.1% by weight and about 0.5% by weight of fibrin, between about 0.2% by weight and about 0.4% by weight fibrin, between about 0.5% by weight and about 1% by weight fibrin, between about 0.4% by weight and about 0.6% by weight fibrin, between about 0.6 and about 0.8% by weight fibrin, between about 0.8% by weight and about 1% by weight of fibrin, between about 1% by weight and about 2% by weight fibrin, between about 1% by weight and about 5% by weight fibrin, between about 2% by weight and about 4 % by weight fibrin, between about 5% by weight and about 10% by weight fibrin, between about 4% by weight and about 6% by weight fibrin, between about 6 and about 8% by weight weight of fibrin, or between about 8% by weight and about 10% by weight fibrin.

d. Collagen

[0049] In some embodiments, a composition comprises about 0.01% by weight or more collagen, about 0.025% by weight or more collagen, about 0.050% by weight or more collagen, about 0.075 % by weight or more collagen, about 0.1% by weight or more collagen, about 0.25% by weight or more collagen, about 0.5% by weight or more collagen, about 0 .75% by weight or more collagen, about 1% by weight or more collagen, about 2.5% by weight or more collagen, about 5% by weight or more collagen, about 7.5 % by weight or more collagen, or about 10% by weight or more collagen. In some embodiments, a composition comprises 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 of 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 collagen, between about 0.1% by weight and about 0. 5% by weight collagen, between about 0.2% by weight and about 0.4% by weight collagen, between about 0.5% by weight and about 1% by weight collagen, between about 0.4% by weight and about 0.6% by weight collagen, between about 0.6 and about 0.8% by weight collagen, between about 0.8% by weight and about 1% by weight of collagen, between about 1% by weight and about 2% by weight collagen, between about 1% by weight and about 5% by weight collagen, between about 2% by weight and about 4 % by weight collagen, between about 5% by weight and about 10% by weight collagen, between about 4% by weight and about 6% by weight collagen, between about 6 and about 8% by weight weight, or between about 8% by weight and about 10% by weight collagen.

It is. Fibronectin

[0050] In some embodiments, a composition comprises about 0.01 wt% or more fibronectin, about 0.025 wt% or more fibronectin, about 0.050 wt% or more fibronectin, about 0.075 % by weight or more fibronectin, about 0.1% by weight or more fibronectin, about 0.25% by weight or more fibronectin, about 0.5% by weight or more fibronectin, about 0 75% by weight or more fibronectin, about 1% by weight or more fibronectin, about 2.5% by weight or more fibronectin, about 5% by weight or more fibronectin, about 7 .5% by weight or more fibronectin, or about 10% by weight or more fibronectin. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight fibronectin, between about 0.025% by weight and about 0.05% by weight fibronectin, between about 0.025% by weight and about 0.075% by weight fibronectin, between about 0.025% by weight and about 0.1% by weight fibronectin, between about 0.01% by weight and about 0.1 % by weight fibronectin, between about 0.05% by weight and about 0.075% by weight fibronectin, between about 0.05% by weight and about 0.1% by weight fibronectin, between about 0.075 % by weight and about 0.1% by weight fibronectin, between about 0.1% by weight and about 0.2% by weight fibronectin, between about 0.1% by weight and about 0. 5% by weight fibronectin, between about 0.2% by weight and about 0.4% by weight fibronectin, between about 0.5% by weight fibronectin and about 1% by weight fibronectin, between about 0.4% by weight and about 0.6% by weight fibronectin, between about 0.6 and about 0.8% by weight fibronectin, between about 0.8% by weight and about 1% by weight fibronectin, between about 1% by weight and about 2% by weight fibronectin, between about 1% by weight and about 5% by weight fibronectin, between about 2% by weight and about from about 4% by weight fibronectin, from about 5% by weight to about 10% by weight fibronectin, from about 4% by weight to about 6% by weight fibronectin, from about 6 to about 8 % by weight fibronectin, or between about 8% by weight and about 10% by weight fibronectin.

f. Insulin-like growth factor-binding protein

[0051] In some embodiments, a composition comprises about 0.01% by weight or more insulin-like growth factor protein, about 0.025% by weight or more insulin-like growth factor protein, about of 0.050% by weight or more insulin-like growth factor protein, about 0.075% by weight or more insulin-like growth factor protein, about 0.1% by weight or more insulin-like growth factor protein insulin-like growth, about 0.25% by weight or more insulin-like growth factor protein, about 0.5% by weight or more insulin-like growth factor protein, about 0.75 % by weight or more of insulin-like growth factor protein, about 1% by weight or more of insulin-like growth factor protein, about 2.5% by weight or more of insulin-like growth factor protein insulin-like, about 5% by weight or more insulin-like growth factor protein, about 7.5% by weight or more insulin-like growth factor protein, or about 10% by weight or more of insulin-like growth factor protein. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight of insulin-like growth factor protein, between about 0.025% by weight and about 0.05% by weight of insulin-like growth factor protein, between about 0.025% by weight and about 0.075% by weight of insulin-like growth factor protein, between about 0.025% by weight and about 0.1% by weight of insulin-like growth factor protein, between about 0.01% by weight and about 0.1% by weight insulin-like growth factor protein, between about 0.05% by weight and about 0.075 % by weight of insulin-like growth factor protein, between about 0.05% by weight and about 0.1% by weight of insulin-like growth factor protein, between about 0.075% by weight and about from 0.1% by weight of insulin-like growth factor protein, between about 0.1% by weight and about 0.2% by weight of insulin-like growth factor protein, between about 0. 1% by weight and about 0.5% by weight insulin-like growth factor protein, between about 0.2% by weight and about 0.4% by weight insulin-like growth factor protein , between about 0.5% by weight and about 1% by weight insulin-like growth factor protein, between about 0.4% by weight and about 0.6% by weight insulin-like growth factor protein insulin-like growth factor protein, between about 0.6 and about 0.8% by weight of insulin-like growth factor protein, between about 0.8% by weight and about 1% by weight of insulin-like growth factor protein of insulin-like growth factor, between about 1% by weight and about 2% by weight of insulin-like growth factor protein, between about 1% by weight and about 5% by weight of growth factor protein insulin-type, between about 2% by weight and about 4% by weight of insulin-type growth factor protein, between about 5% by weight and about 10% by weight of insulin-type growth factor protein insulin, between about 4% by weight and about 6% by weight of insulin-like growth factor protein, between about 6 and about 8% by weight of insulin-like growth factor protein, or between about of 8% by weight and about 10% by weight of insulin-like growth factor protein.

g. Green fluorescent protein

[0052] In some embodiments, a composition comprises about 0.01% by weight or more green fluorescent protein, about 0.025% by weight or more green fluorescent protein, about 0.050% by weight or more green fluorescent protein , about 0.075% by weight or more green fluorescent protein, about 0.1% by weight or more green fluorescent protein, about 0.25% by weight or more green fluorescent protein, about 0.5% by weight or more of green fluorescent protein, about 0.75% by weight or more of green fluorescent protein, about 1% by weight or more of green fluorescent protein, about 2.5% by weight or more of fluorescent protein green, about 5% by weight or more green fluorescent protein, about 7.5% by weight or more green fluorescent protein, or about 10% by weight or more green fluorescent protein. In some embodiments a composition comprises between about 0.01% by weight and about 0.025% by weight green fluorescent protein, between about 0.025% by weight and about 0.05% by weight green fluorescent protein, between about from 0.025% by weight to about 0.075% by weight green fluorescent protein, from about 0.025% by weight to about 0.1% by weight green fluorescent protein, from about 0.01% by weight to about 0.1% by weight green fluorescent protein, between about 0.05% by weight and about 0.075% by weight green fluorescent protein, between about 0.05% by weight and about 0.1% by weight of green fluorescent protein, between about 0.075% by weight and about 0.1% by weight green fluorescent protein, between about 0.1% by weight and about 0.2% by weight green fluorescent protein, between about 0.1% by weight and about 0.5% by weight green fluorescent protein, between about 0.2% by weight and about 0.4% by weight green fluorescent protein, between about 0.5 % by weight and about 1% by weight green fluorescent protein, between about 0.4% by weight and about 0.6% by weight green fluorescent protein, between about 0.6 and about 0.8 % by weight green fluorescent protein, between about 0.8% by weight and about 1% by weight green fluorescent protein, between about 1% by weight and about 2% by weight green fluorescent protein, between about from 1% by weight to about 5% by weight green fluorescent protein, from about 2% by weight to about 4% by weight green fluorescent protein, from about 5% by weight to about 10% by weight of green fluorescent protein, between about 4% by weight and about 6% by weight green fluorescent protein, between about 6 and about 8% by weight green fluorescent protein, or between about 8% by weight and about of 10% by weight of green fluorescent protein.

3. Hyaluronic Acid

[0053] In some embodiments, a composition useful for stimulating hair growth includes hyaluronic acid. Hyaluronic acid is a natural ligand for CD44 and has now been shown to be pro-inflammatory and stimulate hair growth. Hyaluronic acid is a natural linear polymer containing repeating units of a disaccharide of β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamine, as shown in formula I:

[0054] Formula I:

[0055] In some embodiments, hyaluronic acid has a low average molecular weight which, as used herein, refers to ranges of about 15,000 Da to about 40,000 Da. In some embodiments, hyaluronic acid has a weight intermediate molecular weight which, as used herein, refers to ranges from about 75,000 Da to about 350,000 Da. In some embodiments, hyaluronic acid has a high average molecular weight which, as used herein, refers to about 950,000 Da and more.

[0056] 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 of 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 more.

[0057] In some embodiments, hyaluronic acid has an average molecular weight 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 from 100 kDa to about 150 kDa, from about 200 kDa to about 250 kDa, from about 300 kDa to about 350 kDa, from about 400 kDa to about 450 kDa, from about 500 kDa to about 550 kDa, between about 600 kDa and about 650 kDa, between about 700 kDa and about 750 kDa, between about 800 kDa and about 850 kDa, between about 900 kDa and about 1,000 kDa, between about 1,000 kDa and about 1,100 kDa, between about 1,000 kDa and about 1,200 kDa, between about 1,200 kDa and about 1,300 kDa, between about 1,300 kDa and about 1,400 kDa, between about 1,400 kDa and about 1,500 , between about 1 kDa and about 100 kDa, between about 100 kDA and about 250 kDa, between about 250 kDA and about 500 kDa, between about 500 kDA and about 750 kDa, between about 750 kDa and about 1,000 kDa, between about 1,000 kDa and about 1,250 kDa, between about 1,250 kDa and about 1,500 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 1,000 kDa, between about 750 kDa and about 1,250 kDa, or between about 1,000 and about 1,500 kDa.

[0058] In some modalities the hyaluronic acid is cross-linked. Cross-linking can improve the useful life of the hyaluronic acid, and in some modalities some degree of cross-linking may be desirable. In some embodiments, the hyaluronic acid is cross-linked enough to last for about a week. However, without being limited by a mechanism of action, hyaluronic acid is believed to be effective in stimulating hair growth through interaction with CD44 receptors. Therefore, it is desirable that the hyaluronic acid is not cross-linked so extensively that the cross-linking interferes with the ability of the hyaluronic acid to interact with a CD44 receptor.

[0059] The hydroxyl (-OH), carboxyl (-COOH), and/or amide (-NHCOCH3) functional groups of hyaluronic acid can cross-link through an ether bond (R-OO-R), an ester bond (R- COO-R), or carbodiimide, respectively. In some embodiments, hyaluronic acid is cross-linked with 1-1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), glutaraldehyde (GTA), poly(ethylene glycol) diglycidyl ether (PEGDE), poly(ethylene glycol) diglycidyl ether (PEGDE), ethylene glycol (EGDE), divinyl sulfonate (DVS), or pentaerythritol tetraacrylate (PT).

[0060] Hyaluronic acid may have a crosslinking density of about 1 x 10-7 mol/cm3 or more, about 2 x 10-7 mol/cm3 or more, about 3 x 10-7 mol/cm3 or more, about 4 x 10-7 mol/cm3 or more, about 5 x 10-7 mol/cm3 or more, about 6 x 10-7 mol/cm3 or more, about 7 x 10-7 mol/ cm3 or more, about 8 x 10-7 mol/cm3 or more, about 9 x 10-7 mol/cm3 or more, about 1 x 10-6 mol/cm3 or more, about 2 x 10-6 mol/cm3 or more, about 3 x 10-6 mol/cm3 or more, about 4 x 10-6 mol/cm3 or more, about 5x 10-6 mol/cm3 or more, about 6 x 10- 6 mol/cm3 or more, about 7 x 10-6 mol/cm3 or more, about 8 x 10-6 mol/cm3 or more, about 9 x 10-6 mol/cm3, or about 1 x 10 -5 mol/cm3 or more. In some embodiments, the hyaluronic acid may have a crosslinking density between about 1 x 10-7 mol/cm3 and about 1 x 10-5 mol/cm3, between about 1 x 10-7 mol/cm3 and about 1 x 10-6 mol/cm3, between about 1 x 10-7 mol/cm3 and about 5 x 10-7 mol/cm3, between about 5 x 10-7 mol/cm3 and about 1 x 10-6 mol/cm3, between about 1 x 10-7 mol/cm3 and about 2 x 10-7 mol/cm3, between about 2 x 10-7 mol/cm3 and about 4 x 10-7 mol/cm3, between about 4 x 10-7 mol/cm3 and about 6 x 10-7 mol/cm3, between about 6 x 10-7 mol/cm3 and about 8 x 10-7 mol/cm3, or between about 8 x10-7 mol/cm3 and about 1 x 10-6 mol/cm3, between about 1 x 10-6 mol/cm3 and about 1 x 10-5 mol/cm3, between about 1 x 10-6 mol/cm3 and about 5 x 10-6 mol/cm3, between about 5 x 10-6 mol/cm3 and about 1 x 10-5 mol/cm3, between about 1 x 10-6 mol/cm3 and about 2 x 10-6 mol/cm3, between about 2 x 10-6 mol/cm3 and about 4 x 10-6 mol/cm3, between about 4 x 10-6 mol/cm3 and about 6 x 10-6 mol/cm3, between about 6 x 10-6 mol/cm3 and about 8 x 10-6 mol/cm3, between about 8 x 10-6 mol/cm3 and about 1 x 10-5 mol /cm3, or between about 5 x 10-7 mol/cm3 and about 5 x 10-6 mol/cm3.

[0061] The compositions of the invention may include an amount of hyaluronic acid sufficient to confer a therapeutic effect, for example, the stimulation of hair growth in a patient in need thereof. However, higher concentrations of hyaluronic acid can result in unwanted inflammation. In some embodiments, the compositions of the invention include an amount of hyaluronic acid sufficient to confer a therapeutic effect, for example, the stimulation of hair growth in a patient in need thereof, and insufficient to confer an unacceptable inflammatory response. As used throughout this description, mcg/ml and μg/ml refer to micrograms per milliliter. In some embodiments, hyaluronic acid is present in an amount of about 10 mcg/ml of the composition or more, about 15 mcg/ml of the composition or more, about 20 mcg/ml of the composition or more, about of 25 mcg/ml of the composition or more, about 30 mcg/ml of the composition or more, about 35 mcg/ml of the composition or more, about 40 mcg/ml of the composition or more, about 45 mcg/ml of the composition composition or more, about 50 mcg/ml of the composition or more, about 55 mcg/ml of the composition or more, about 60 mcg/ml of the composition or more, about 65 mcg/ml of the composition or more, about 70 mcg/ml of the composition or more, about 75 mcg/ml of the composition or more, about 80 mcg/ml of the composition or more, about 85 mcg/ml of the composition or more, about 90 mcg/ml of the composition or more, about 95 mcg/ml of the composition or more, or about 100 mcg/ml of the composition or more.

[0062] In some embodiments, hyaluronic acid is present in an amount ranging from about 1 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 10 mcg/ml of the composition to about from 250 mcg/ml of the composition, from about 10 mcg/ml of the composition to about 200 mcg/ml of the composition, from 10 mcg/ml of the composition to about 150 mcg/ml of the composition, from 10 mcg/ml of the composition composition to about 100 mcg/ml of the composition, from about 25 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 25 mcg/ml of the composition to about 200 mcg/ml of the composition, of from about 25 mcg/ml of the composition to about 150 mcg/ml of the composition, from about 25 mcg/ml of the composition to about 100 mcg/ml of the composition, from about 50 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 50 mcg/ml of the composition to about 200 mcg/ml of the composition, from about 50 mcg/ml of the composition to about 150 mcg/ml of the composition, from about 50 mcg/ml of the composition, from about 50 mcg/ml of the composition to about 150 mcg/ml of the composition, from about 50 mcg/ml of the composition ml of the composition to about 100 mcg/ml of the composition, from about 75 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 75 mcg/ml of the composition to about 200 mcg/ml of the composition, from about 75 mcg/ml of the composition to about 150 mcg/ml of the composition, from about 75 mcg/ml of the composition to about 100 mcg/ml of the composition, from about 100 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 100 mcg/ml of the composition to about 200 mcg/ml of the composition, from about 100 mcg/ml of the composition to about 150 mcg/ml of the composition, from about 150 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 200 mcg/ml of the composition to about 250 mcg/ml of the composition, from about 60 mcg/ml of the composition to about 80 mcg/ml of the composition, from about 50 mcg/ml of the composition to about 75 mcg/ml of the composition, from about 25 mcg/ml of the composition to about 75 mcg/ml of the composition, from about 10 mcg/ml of the composition to about 50 mcg/ml of the composition, or from about 10 mcg/ml of the composition to about 25 mcg/ml of the composition.

[0063] In some embodiments, a composition comprises about 0.001% by weight or more hyaluronic acid, about 0.0025% by weight or more hyaluronic acid, about 0.0050% by weight or more hyaluronic acid, about 0.0075% by weight or more hyaluronic acid, about 0.01% by weight or more hyaluronic acid, about 0.025% by weight or more 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, or about 1% by weight or more of hyaluronic acid. In some embodiments, a composition comprises between about 0.001% by weight and about 0.0025% by weight hyaluronic acid, between about 0.0025% by weight and about 0.005% by weight hyaluronic acid, between about 0.0025% by weight and about 0.0075% by weight hyaluronic acid, between about 0.0025% by weight and about 0.01% by weight hyaluronic acid, between about 0.001% by weight and about of 0.01% by weight hyaluronic acid, between about 0.005% by weight and about 0.0075% by weight hyaluronic acid, between about 0.005% by weight and about 0.01% by weight hyaluronic acid , between about 0.0075% by weight and about 0.01% by weight hyaluronic acid, between about 0.01% by weight and about 0.02% by weight hyaluronic acid, between about 0.01% by weight and about 0.05% by weight hyaluronic acid, between about 0.02% by weight and about 0.04% by weight hyaluronic acid, between about 0.05% by weight and about 0.1% by weight hyaluronic acid, between about 0.04% by weight and about 0.06% by weight hyaluronic acid, between about 0.06 and about 0.08% by weight of hyaluronic acid, between about 0.08% by weight and about 0.1% by weight hyaluronic acid, between about 0.1% by weight and about 0.2% by weight hyaluronic acid, between about of 0.1% by weight and about 0.5% by weight of hyaluronic acid, between about 0.2% by weight and about 0.4% by weight of hyaluronic acid, between about 0.5 % by weight and about 1% by weight hyaluronic acid, between about 0.4% by weight and about 0.6% by weight hyaluronic acid, between about 0.6 and about 0.8% by weight weight of hyaluronic acid, or between about 0.8% by weight and about 1% by weight of hyaluronic acid.

[0064] In some embodiments, a composition according to an 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 acids sold under the trademarks JUVEDERM™, RESTYLANE-L™, CAPTIQUE™, BELOTERO BALANCE™, PREVELLE SILK™, ELEVESS™, HYLA-FORM™, EUFLEXXA™, GEL-ONE™, HYALGAN™, ORTHOVISC™, MONOVISC™, SUPARTZ™, SYNVISC™, and SYNVISC-ONE™.

C. Hyaluronidase Inhibitor

[0065] In some embodiments according to the invention, a composition includes a hyaluronidase inhibitor. Examples of hyaluronidase inhibitors include, but are not limited to, high molecular weight poly(styrene-4-sulfonate) (PSS), gossypol, sodium aurothiomalate, fenoprofen, glycerrhizic acid, heparin, and acid O-sulfated hyaluronic acid (sHA), and dextran sulfate, or combinations thereof.

[0066] In some embodiments, a composition comprises about 0.01% by weight or more hyaluronidase inhibitor, about 0.025% by weight or more hyaluronidase inhibitor, about 0.050% by weight or more hyaluronidase inhibitor , about 0.075% by weight or more hyaluronidase inhibitor, about 0.1% by weight or more hyaluronidase inhibitor, about 0.25% by weight or more hyaluronidase inhibitor, about 0.5% by weight or more of hyaluronidase inhibitor, about 0.75% by weight or more of hyaluronidase inhibitor, about 1% by weight or more of hyaluronidase inhibitor, about 2.5% by weight or more of hyaluronidase inhibitor hyaluronidase, about 5% by weight or more hyaluronidase inhibitor, about 7.5% by weight or more hyaluronidase inhibitor, or about 10% by weight or more hyaluronidase inhibitor. In some embodiments, a composition comprises between about 0.01% by weight and about 0.025% by weight hyaluronidase inhibitor, between about 0.025% by weight and about 0.05% by weight hyaluronidase inhibitor, between between about 0.025% by weight and about 0.075% by weight hyaluronidase inhibitor, between about 0.025% by weight and about 0.1% by weight hyaluronidase inhibitor, between about 0.01% by weight and about of 0.1% by weight hyaluronidase inhibitor, between about 0.05% by weight and about 0.075% by weight hyaluronidase inhibitor, between about 0.05% by weight and about 0.1% by weight weight of hyaluronidase inhibitor, between about 0.075% by weight and about 0.1% by weight hyaluronidase inhibitor, between about 0.1% by weight and about 0.2% by weight hyaluronidase inhibitor, between about 0.1% by weight and about 0.5% by weight hyaluronidase inhibitor, between about 0.2% by weight and about 0.4% by weight hyaluronidase inhibitor, between about 0 5% by weight and about 1% by weight hyaluronidase inhibitor, between about 0.4% by weight and about 0.6% by weight hyaluronidase inhibitor, between about 0.6% by weight and about 0.8% by weight hyaluronidase inhibitor, between about 0.8% by weight and about 1% by weight hyaluronidase inhibitor, between about 1% by weight and about 2% by weight of hyaluronidase inhibitor, between about 1% by weight and about 5% by weight of hyaluronidase inhibitor, between about 2% by weight and about 4% by weight of hyaluronidase inhibitor, between about 5% by weight and about 10% by weight hyaluronidase inhibitor, between about 4% by weight and about 6% by weight hyaluronidase inhibitor, between about 6% by weight and about 8% by weight hyaluronidase inhibitor. hyaluronidase, or between about 8% by weight and about 10% by weight hyaluronidase inhibitor.

D. Vehicle and Other Additives

[0067] In some embodiments, a composition includes a carrier medium. Such carrier medium may be a suitable biocompatible fluid for injection into mammalian skin. In some embodiments, the carrier medium comprises a saline solution. In some embodiments, hyaluronic acid serves as a carrier medium and also as an active ingredient.

[0068] In some embodiments, a composition includes one or more additives. Such additives may include a preservative or a biocide.

[0069] In some embodiments, a composition includes a microemulsifier, a nanoemulsifier, a solid lipid nanoparticle, a nanostructured lipid carrier, a liposome or a vesicle.

[0070] In some embodiments, a composition may comprise a fatty acid (e.g., oleic acid), a fatty acid ester and alcohol (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), medium-chain triglycerides, triacetin, or a terpene (e.g., limonene, metol, cineole). In some embodiments, a composition may comprise surfactants. For example, suitable surfactants include, but are not limited to, TWEENTM (polysorbates), CREMOFORTM (mixture of macrogol glycerol hydroxy stearate, PEG-40 castor oil, polyoxyl 40 hydrogenated castor oil), TRANSCUTOLTM P (diethylene glycol monoethyl ether), PLUROL OLEIQUETM (polyglyceryl-3-oleate), PLUROL ISOSTEA-RIQUETM (isostearic acid ester of polyglycerols and higher oligomers) and LABRASOLTM (mixture of mono-, di- and tri-glycerides of C8 and C10 fatty acids, and PEG mono- and di-esters), and lecithin. In some embodiments a composition may comprise a cosurfactant. For example, suitable cosurfactants include, but are not limited to, short and medium chain alcohols and polyglyceryl derivatives, including ethanol, isopropanol, isopropyl myristate and propylene glycol.

[0071] In some embodiments, a composition comprises one or more of soybean oil, jojoba oil, aloe vera oil, soy phosphatidylcholine, water, polysorbate 80, ethanol, benzyl alcohol, isopropyl alcohol, glycerin, soybean monostearate. glyceryl, propylene glycol.

II. Methods Production Methods

[0072] A process for producing a therapeutic composition according to an embodiment of the invention comprises mixing an effective amount of active agents. In some embodiments, an effective amount of hyaluronic acid is mixed with an effective amount of osteopontin. In some embodiments, the hyaluronic acid has an average molecular weight in a range of about 4,000 Da to 10,000 Da, in a range of about 10,000 Da to about 100,000 Da, in a range of about 15 kDa to about 50 kDa. kDa, in a range of about 75 kDa to about 350 kDa, or in a range of about 20 kDa to about 1,350 kDa. In some embodiments, hyaluronic acid has an average molecular weight of more than about 950 kDa. In some embodiments, an effective amount of hyaluronic acid is mixed with an effective amount of CD44 binding ligand. In some embodiments, an effective amount of osteopontin is mixed with an effective amount of CD44 binding ligand. In some embodiments, effective amounts of hyaluronic acid and osteopontin respectively are mixed with an effective amount of the CD44-binding ligand. In some embodiments of the compositions according to the invention, effective amounts of hyaluronidase inhibitor are mixed with one or more of hyaluronic acid, osteopontin and CD44 binding ligand. Said processes may also include a step of preparing a physiologically acceptable carrier medium, to which the active agents are added. Preferably, the physiologically acceptable carrier medium is injectable.

[0073] In some embodiments, a production method includes a step of forming a microemulsion or a nanoemulsion. A microemulsion or a nanoemulsion may comprise oil, water, surfactant and cosurfactant to form a colloidal dispersion of droplet sizes in a range of about 10 nm to about 100 nm. In some embodiments, a microemulsion or a nanoemulsion may comprise a fatty acid (e.g., oleic acid), a fatty acid ester and alcohol (e.g., isopropyl myristate, isopropyl palmitate, ethyl oleate), triglycerides medium chain, triacetin, or a terpene (e.g., limonene, metol, cineole). In some embodiments, a microemulsion or a nanoemulsion may comprise surfactants. For example, suitable surfactants include, but are not limited to, TWEENTM (polysorbates), CREMOFORTM (mixture of macrogol glycerol hydroxystearate, PEG-40 castor oil, polyoxyl 40 hydrogenated castor oil), TRANSCUTOLTM P (ether monoethyl diethylene glycol), PLUROL OLEIQUETM (polyglyceryl-3-oleate), PLUROL ISOSTEARIQUETM (isostearic acid ester of poly-glycerols and higher oligomers) and LABRASOLTM (mixture of mono-, di- and triglycerides of C8 and C10 fatty acids, and PEG mono- and di-ester), and lecithin. In some embodiments, a microemulsion or a nanoemulsion may comprise a cosurfactant. For example, suitable cosurfactants include, but are not limited to, short and medium chain alcohols and polyglyceryl derivatives, including ethanol, isopropanol, isopropyl myristate and propylene glycol. In some embodiments, the formation of a microemulsion or a nanoemulsion includes the use of a homogenizer, a microfluidizer and/or a high pressure ultrasonicator.

[0074] In some embodiments, a production method includes a step of mixing a composition according to an embodiment of the invention with a solid nanoparticle. A solid nanoparticle may comprise an inorganic material such as a metal oxide (e.g., zinc oxide, titanium dioxide) or polymers that are solid at room temperature.

[0075] In some embodiments, a production method includes a step of mixing a composition according to an embodiment of the invention with a solid lipid nanoparticle. A solid lipid nanoparticle may comprise a lipid that is solid at room temperature with a surfactant surface coating to stabilize them as droplets having a size less than about 100 nm when dispersed in water.

[0076] In some embodiments, a production method includes a step of mixing a composition according to an 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 located on the surface of solid platelets and the surfactant layer.

[0077] In some embodiments, a production method includes a step of mixing a composition according to an embodiment of the invention with a liposome. A liposome may comprise a spherical vesicle composed of amphiphilic phospholipids and cholesterol, self-associated into multilamellar, large unilamellar and small unilamellar vesicles.

[0078] In some embodiments, a production method includes a step of mixing a composition according to an embodiment of the invention with a flexible vesicle. A flexible vesicle may comprise a material that will associate into bilayer structures, as well as components that confer flexibility. In some embodiments, a flexible vesicle comprises an ethosome (i.e., a phospholipid with a high proportion of ethanol), a niosome (i.e., a nonionic surfactant), an invasome (i.e., phospholipids, ethanol, and a terpene penetration enhancer mixture), a SECosome (i.e., surfactant, ethanol and cholesterol), or a PEV (i.e., penetration enhancer vesicle). In some embodiments, a PEV may comprise oleic acid, limonene or propylene glycol.

[0079] In some embodiments, a production method includes a step of mixing a composition according to an embodiment of the invention with a polymeric micelle or a polymeric dendrimer. A polymeric micelle can be a colloidal vehicle with a hydrophilic outer shell and a hydrophobic inner core. A polymeric micelle can be nanosized. A polymeric dendrimer may comprise a branched polymer structure.

[0080] In some embodiments, any of the CD44 binding fragments, isoforms, or derivatives of a naturally occurring ligand for CD44 described above are produced proteolytically, whereas in other embodiments they are produced synthetically. Administration Methods

[0081] A method of administering a composition according to an embodiment of the invention comprises applying a composition according to an embodiment of the invention to a hair follicle. In some embodiments, application is effected through topical administration, that is, applying the composition to the surface of the skin and then the composition is permeated into the skin. In some embodiments, a method of administration includes a permeation enhancement step prior to topical administration of a composition. In some embodiments, application is carried out by injection into the skin.

[0082] In some embodiments, topical application is performed after, or in conjunction with, the application of iontophoresis. For example, iontophoresis may comprise applying a moderate electrical current (e.g., 0.01 to 1.0 mA/cm2) to increase skin permeation of the composition. Without being limited by theory, it is believed that iontophoresis can improve skin permeation through electromigration, electroosmosis and/or enhanced passive diffusion.

[0083] In some embodiments, topical application is performed after, or in conjunction with, electroporation application. For example, electroporation may comprise the application of high-intensity, high-voltage (e.g., 50 to 1,500 V), short-duration (10 microseconds to 10 milliseconds) electrical pulses to form aqueous pores in the lipid bilayers of the stratum corneum of the skin.

[0084] In some embodiments, topical application is performed after, or in conjunction with, the application of sonophoresis. For example, sonophoresis may comprise the application of acoustic waves at high frequency (e.g., from about 500 kHz to 1250 kHz) or at low frequency (e.g., from about 20 to about 100 kHz) or (e.g., from about 20 to about 100 kHz). measuring with a high-low frequency and progressing to another high or low frequency).

[0085] In some embodiments, topical application is performed after, or in conjunction with, the application of laser ablation. Laser ablation may comprise the generation of a photomechanical wave by means of laser ablation of a target material (e.g., polymer) placed on the surface of the skin.

[0086] In some embodiments, topical application is performed after, or in conjunction with, magnetophoresis. Magnetophoresis may comprise applying a magnetic field, for example pulsed electromagnetic fields, to the skin.

[0087] In some embodiments, topical application is performed after application of radiofrequency thermal ablation. Thermal ablation may comprise the application of extreme heat (e.g., about 300°C per microsecond) to the surface of the skin. Without being limited by theory, it is believed that thermal ablation can vaporize portions of the stratum corneum to create microscale channels. Thermal ablation can be performed with commercially available devices including VIADORTM (Syneron Medical Ltd, Israel) and PASSPORTTM (Nitto-Denko, Japan). In some embodiments, thermal ablation can be performed with an erbium-yttrium-gallium garnet (Er:YAG) laser emitting at 2,790 nm or an yttrium scandium gallium garnet (YSGG) laser emitting at 2,940 nm. In some embodiments, fractional laser ablation can be applied to sub-mm regions to generate spots that mimic a microneedle array-type pattern (e.g., 40 to 300 μm) with densities between 50 and 600 cm-2.

[0088] In some embodiments, topical application is performed after application of the microneedle device.

[0089] A method for administering a composition according to an embodiment of the invention comprises injecting a therapeutic amount of the composition into the skin of a patient in need of treatment. In some embodiments, a composition according to an embodiment of the invention is administered as a bolus which, as used herein, refers to the dosage that is applied in a time of less than ten minutes. In some embodiments, a composition according to an embodiment of the invention is administered as an infusion which, as used herein, refers to the dosage that is applied over a time of about ten minutes or more.

[0090] Such injection can be made through a single needle, a microneedle, or a similar device, or an arrangement of needles, microneedles, or similar devices. In some embodiments, a composition according to an embodiment of the invention is applied via a conventional syringe. In some embodiments, subdermal application is performed through a hollow microneedle injector. In some embodiments, subdermal application is performed by means of a microneedle patch that is coated with a composition according to an embodiment of the invention, e.g., that has been coated with a composition according to an embodiment of the invention by means of printing. 3D. In some embodiments, the composition is applied via a jet injector. The term "needle" as used herein refers to a device for piercing the skin and injecting a composition in accordance with an embodiment of the invention.

[0091] The composition is preferably administered close to the patient's hair follicle. Accordingly, in some embodiments the composition is administered by injecting a therapeutic amount of the composition into the patient's dermis. In some embodiments, the composition is administered by injecting a therapeutic amount of the composition into the patient's hypodermis. In some embodiments, the composition is administered from about 0.4 mm to about 2 mm into the patient's skin (i.e., from about 0.4 mm to about 3 mm from the skin surface). In some embodiments the composition is administered at 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 1mm, about 1.1mm, about 1.2mm, about 1.3mm, about 1.4mm, about 1.5mm, about 1.6mm, about 1 .7mm, about 1.8mm, about 1.9mm, about 2mm, about 2.1mm, about 2.2mm, about 2.3mm, about 2.4mm , about 2.5 mm, about 2.6 mm, about 2.7 mm, about 2.8 mm, about 2.9 mm, or about 3 mm on the patient's skin. In some embodiments, the composition is administered 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, between about 0.4 mm and about 2.6 mm, between about 0.4 mm and about 2.8 mm, between about 0.4 mm and about 3 mm, between about 0.6 mm and about 0.8 mm , between about 0.6 mm and about 1 mm, between about 0.6 mm and about 1.2 mm, between about 0.6 mm and about 1.4 mm, between about 0.6 mm and about 1.6 mm, between about 0.6 mm and about 1.8 mm, between about 0.6 mm and about 2 mm, between about 0.6 mm and about 2.2 mm, between about 0.6 mm and about 2.4 mm, between about 0.6 mm and about 2.6 mm, between about 0.6 mm and about 2.8 mm, between about 0.6mm and about 3mm, between about 0.8mm and about 1mm, between about 0.8mm and about 1.2mm, between about 0.8mm and about 1, 4 mm, between about 0.8 mm and about 1.6 mm, between about 0.8 mm and about 1.8 mm, between about 0.8 mm and about 2 mm, between about 0 .8 mm and about 2.2 mm, between about 0.8 mm and about 2.4 mm, between about 0.8 mm and about 2.6 mm, between about 0.8 mm and about 2 .8 mm, between about 0.8 mm and about 3 mm, between about 1 mm and about 1.2 mm, between about 1 mm and about 1.4 mm, between about 1 mm and about 1.6 mm, between about 1 mm and about 1.8 mm, between about 1 mm and about 2 mm, between about 1 mm and about 2.2 mm, between about 1 mm and about from 2.4 mm, from about 1 mm to about 2.6 mm, from about 1 mm to about 2.8 mm, from about 1 mm to about 3 mm, from about 1.2 mm and about 1.4 mm, between about 1.2 mm and about 1.6 mm, between about 1.2 mm and about 1.8 mm, between about 1.2 mm and about 2 mm , between about 1.2 mm and about 2.2 mm, between about 1.2 mm and about 2.4 mm, between about 1.2 mm and about 2.6 mm, between about 1 .2 mm and about 2.8 mm, between about 1.2 mm and about 3 mm, between about 1.4 mm and about 1.6 mm, between about 1.4 mm and about 1 .8 mm, between about 1.4 mm and about 2 mm, between about 1.4 mm and about 2.2 mm, between about 1.4 mm and about 2.4 mm, between about 1.4 mm and about 2.6 mm, between about 1.4 mm and about 2.8 mm, between about 1.4 mm and about 3 mm, between about 1.6 mm and about 1.8 mm, between about 1.6 mm and about 2 mm, between about 1.6 mm and about 2.2 mm, between about 1.6 mm and about 2.4 mm, between about from 1.6 mm to about 2.6 mm, from about 1.6 mm to about 2.8 mm, from about 1.6 mm to about 3 mm, from about 1.8 mm to about 2 mm between about 1.8 mm and about 2.2 mm, between about 1.8 mm and about 2.4 mm, between about 1.8 mm and about 2.6 mm, between about from 1.8 mm to about 2.8 mm, from about 1.8 mm to about 3 mm, from about 2.0 mm to about 2.2 mm, from about 2.0 mm to about 2.4 mm, between about 2.0 mm and about 2.6 mm, between about 2.0 mm and about 2.8 mm, between about 2.0 mm and about 3 mm, between between about 2.2 mm and about 2.4 mm, between about 2.2 mm and about 2.6 mm, between about 2.2 mm and about 2.8 mm, between about 2.2 mm and about 3 mm, between about 2.4 mm and about 2.6 mm, between about 2.4 mm and about 2.8 mm, between about 2.4 mm and about 3 mm, between about 2.6 mm and about 2.8 mm, between about 2.6 mm and about 3 mm, or between about 2.8 mm and about 3 mm on the patient's skin.

[0092] In some embodiments, a composition according to an embodiment of the invention can be administered in a plurality of injections. In some embodiments, a composition according to an embodiment of the invention is administered by about 1 injection/cm2 of skin to about 1,000 injections/cm2 of skin, from about 200 injections/cm2 to about 800 injections/cm2 of skin. skin, or from about 400 injections/cm2 of skin to about 650 injections/cm2 of skin. In some embodiments a composition is administered by about 200 injections/cm2 of skin, about 250 injections/cm2 of skin, about 300 injections/cm2 of skin, about 350 injections/cm2 of skin, about 400 injections/cm2 of skin. cm2 of skin, about 450 injections/cm2 of skin, about 500 injections/cm2 of skin, about 550 injections/cm2 of skin, about 600 injections/cm2 of skin, or about 650 injections/cm2 of skin.

Treatment Methods

[0093] A method of stimulating hair growth in a patient in need thereof includes administering a composition according to an embodiment of the present invention to the surface or skin of the patient. In some embodiments, the composition is administered topically by applying the composition to the surface of the patient's skin. In some embodiments, the composition is administered into the dermis or hypodermis of the patient's skin, for example, by injection as described herein.

[0094] In some embodiments, a composition according to an embodiment of the invention is administered to the skin of a patient once a day for a day, once a day for a week, once a day for a month, once a day for a day for a year, twice a day for a day, twice a day for a week, twice a day for a month, twice a day for a year, once a week for a week, once a week for a month, once a week for a year, twice a week for a week, twice a week for a month, twice a week for a year, once a month for a month, once a month for two months , once a month for six months, once a month for one year, twice a month for one month, twice a month for two months, twice a month for six months, twice a month for one year, once 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 a year, once every three months for three months, one once every three months for six months, once every three months for nine months, once every three months for a year, once every four months for four months, once every four months for eight months, once once every four months for one year, once every six months for six months, once every six months for one year, or as necessary.

Examples Example 1. Injection of hyaluronic acid ("HA") at concentrations of 100, 250 and 1,000 μg/ml

[0095] Each of three different concentrations (100, 250 and 1,000 μg/ml) of "high" molecular weight hyaluronic acid (molecular weight distribution of more than 950 kDa), "intermediate" (molecular weight distribution of molecular weight between 75 and 350 kDa), and "low" (molecular weight distribution between 15 and 40 kDa) were injected into mice. High molecular weight concentrations above 250 μg/ml have been found to induce a strong inflammatory response, with 1,000 μg/ml being the worst. For low molecular weight concentrations, the response was milder at 250 μg/ml compared to high molecular weight HA, but there was also strong inflammation at 1,000 μg/ml. Adverse side effects were observed for all molecular weight hyaluronic acids at concentrations of 250 μg/ml and above.

Example 2. Injection of HA at concentrations of 25, 50 and 100 μg/ml

[0096] Follow-up experiments included lower concentrations of HA (below 250 μg/ml). A small incision was made using a thin needle (insulin syringe) to facilitate the injection. Three (3) microliters of high molecular weight control hyaluronic acid (molecular weight distribution of more than 950 kDa), intermediate (molecular weight distribution between 75 and 350 kDa), or low (molecular weight distribution between 15 and 40 kDa ) were injected into the dorsal skin of P53 mice for three (3) consecutive days. In Figures 5 to 8, when looking at the back of the mouse with the mouse head up, the control injection (1% BSA) is top left, the 25 μg/ml injection is top right, the injection of 100 μg/ml is lower right, and the 50 μg/ml injection is lower left.

[0097] Figures 5 and 6 show representative images of two mice, each of which received injections of low molecular weight HA. Figures 7 and 8 show representative images of two mice, each of which received injections of high molecular weight HA. Figure 5 shows growth in spots of 25 μg/ml low molecular weight HA and 100 μg/ml low molecular weight HA. Figure 6 shows growth in spots of 25 μg/ml low molecular weight HA and 100 μg/ml low molecular weight HA. Figure 7 shows growth in spots of 50 μg/ml high molecular weight HA and 100 μg/ml high molecular weight HA. Figure 8 shows growth in spots of 25 μg/ml high molecular weight HA and 50 μg/ml high molecular weight HA.

[0098] For high molecular weight, the injection site was monitored for 18 days for total anagen. In both high molecular weight HA and low molecular weight HA pigmentation was apparent at P14. Two mice had good induction of low molecular weight HA and high molecular weight HA, but no induction of intermediate weight HA. Without being limited by theory, the depth of injection of the intermediate weight HA may have affected the intensity of induction.

[0099] Figures 7 and 8 show that high molecular weight HA induces 50 μg/ml and 100 μg/ml without the massive inflammation response that was found in Example 1. In the case of low molecular weight HA, only 100 μg/ml induces hair growth. As shown in Figure 6, the low molecular weight HA mouse 2 has an optimal anagen point at 25 μg/ml (the control injection site is visible below it), but only in one mouse.

[00100] It should be appreciated by those skilled in the art that changes can be made to the exemplary embodiments shown and described above without deviating from their broad concepts of the invention. Therefore, it is to be understood that the present invention is not limited to the exemplary embodiments shown and described, but is intended to cover modifications within the character and scope of the present invention as defined by the claims. For example, specific features of the exemplary embodiments may or may not form part of the claimed invention and the various features of the disclosed embodiments may be combined. Unless specifically stated herein, the terms "a", "an" and "the" are not limited to one element, but should preferably be read as meaning "at least one".

[00101] Furthermore, to the extent that the methods of the present invention are not based on the particular order of steps indicated herein, the particular order of steps should not be interpreted as a limitation on the claims. Any claims directed to the methods of the present invention should not be limited to the performance of its steps in written order, and one skilled in the art can readily appreciate that the steps may be varied and still remain within the character and scope of the present invention. .

Claims (31)

1. Non-therapeutic method for stimulating hair growth on the skin of a patient in need, characterized by the fact that it comprises: administering to the patient's skin a composition comprising hyaluronic acid in a concentration of 1 mcg/mL to 250 mcg/mL. 2. Method according to claim 1, characterized in that the hyaluronic acid comprises an average molecular weight in a range of 4,000 Da to 10,000 Da or in a range of 20 KDa to 1350 KDa. 3. Method according to claim 1, characterized by the fact that the hyaluronic acid is cross-linked. 4. Method according to claim 1, characterized by the fact that hyaluronic acid is present in a concentration of 25 mcg/mL to 250 mcg/mL. 5. Method according to claim 1, characterized by the fact that hyaluronic acid is present in a concentration of 50 mcg/mL to 250 mcg/mL. 6. Method according to claim 1, characterized by the fact that hyaluronic acid is present in a concentration of 100 mcg/mL to 250 mcg/Ml. 7. Method according to claim 1, characterized by the fact that the hyaluronic acid has a concentration of 1 mcg/mL to 100 ug/mL. 8. Method according to claim 1, characterized in that the administration comprises injecting the composition into a dermal layer of the skin. 9. Method according to claim 8, characterized by the fact that the composition is injected 400 microns to 2 mm deep into the skin. 10. Method, according to claim 8, characterized by the fact that the composition is administered in a plurality of injections in an amount of 400 injections/cm2 of skin to 650 injections/cm2 of skin. 11. Method, according to claim 1, characterized by the fact that it further comprises the application of iontophoresis to the skin. 12. Method according to claim 1, characterized by the fact that it further comprises applying electroporation to the skin. 13. Method according to claim 1, characterized by the fact that it further comprises applying laser ablation to the skin. 14. Method, according to claim 1, characterized by the fact that it further comprises the application of radiofrequency thermal ablation to the skin. 15. Method according to claim 1, characterized by the fact that it further comprises applying a microneedling device to the skin. 16. Method according to claim 1, characterized by the fact that the composition further comprises a CD44-binding ligand. 17. Method according to claim 16, characterized by the fact that the CD44 binding ligand is osteopontin. 18. Non-therapeutic method of administering a hair growth composition to a patient in need of treatment for hair loss, characterized by the fact that it comprises: injecting the composition into the patient's skin, wherein the composition comprises acid hyaluronic acid in a concentration of 1 mcg/mL to 250 mcg/ml. 19. Method, according to claim 18, characterized by the fact that the hyaluronic acid comprises an average molecular weight in a range of 4,000 Da to 10,000 Da or in a range of 20 KDa to 1350 KDa. 20. Method according to claim 18, characterized in that the hyaluronic acid is cross-linked. 21. Method according to claim 18, characterized by the fact that hyaluronic acid is present in a concentration of 25 mcg/mL to 250 mcg/mL. 22. Method according to claim 18, characterized by the fact that hyaluronic acid is present in a concentration of 50 mcg/mL to 250 mcg/mL. 23. Method according to claim 18, characterized by the fact that hyaluronic acid is present in a concentration of 100 mcg/mL to 250 mcg/mL. 24. Method according to claim 18, characterized by the fact that the hyaluronic acid has a concentration of 1 mcg/mL to 100 ug/mL. 25. Method according to claim 18, characterized in that the administration comprises injecting the composition into a dermal layer of the skin. 26. The method of claim 25, wherein the composition is injected through a needle and wherein the needle is inserted 400 microns to 2 mm into the skin prior to injection. 27. Method according to claim 26, characterized by the fact that the needle is a microneedle. 28. Method according to claim 18, characterized by the fact that the composition further comprises a CD44-binding ligand. 29. Method according to claim 28, characterized by the fact that the CD44 binding ligand is osteopontin. 30. Method according to claim 3, characterized by the fact that the density of the cross-linked hyaluronic acid is 20% to 100%. 31. Method according to claim 20, characterized by the fact that the density of the cross-linked hyaluronic acid is 20% to 100%.