Topical formulations

Abstract

The present invention relates to a composition comprising a peptide, a sugar and a lipid vehicle, which is suitable for topical delivery.

Description

Topical preparations Technical Field

[0001] This invention relates to compositions for local delivery. Background Technology

[0002] background

[0003] Drug molecules larger than 600 Da generally have difficulty penetrating the skin. For peptides and polypeptides, the problem is even more pronounced, even with molecules smaller than 600 Da, because amino acids are often too polar to penetrate the stratum corneum in a suitable manner. This is why most peptide- or protein-based drugs are administered via parenteral administration, which is undesirable for many purposes, including local targeting (e.g., dermal conditions and diseases).

[0004] Therefore, the polarity of many peptides is also problematic when attempting to apply them to hair follicles (e.g., for treating conditions or diseases related to hair follicles).

[0005] For bioactive peptides intended for parenteral administration, they typically need to be dissolved in aqueous solution, which often leads to serious stability problems and undesirable properties such as shortened shelf life and loss of bioactivity.

[0006] Therefore, there is a need for drug formulations that can overcome these delivery and stability problems. Summary of the Invention

[0007] For a variety of reasons, topical delivery of active ingredients via the skin or other body surfaces to produce local and systemic effects is attractive to patients. For topical therapy, lower doses are required to reduce bioburden. Initial toxicology studies are less expensive and time-consuming, and the amount of drug required is typically smaller. Another advantage of topical delivery is that by establishing a drug reservoir, concentration variations in target tissues are smaller. In addition to convenience, topical formulations avoid the gastrointestinal irritation often associated with pills and capsules.

[0008] The inventors of this invention have developed a topical formulation that facilitates the penetration of high molecular weight molecules while maintaining the drug in a solid state to provide chemical stability throughout the product's shelf life. Importantly, the topical formulation is suitable for delivering high molecular weight molecules to hair follicles and related tissues.

[0009] Sebum, a major component of hair follicles, is a mixture of lipids. The inventors of this invention have developed a pharmaceutical formulation with biophysical properties that is able to dissolve in and penetrate sebum in an amount sufficient to elicit a biological response.

[0010] Follicular delivery represents an improvement over invasive methods. When drugs are injected subcutaneously or intradermally, the drug concentration at the application site drops immediately, and the local drug concentration is insufficient to produce a biological effect within hours. Parenteral delivery is undesirable when treating a localized area of ​​disease. Generally, a constant drug concentration during the treatment period is more advantageous. Follicular delivery is a non-invasive way to overcome this problem. Furthermore, follicular delivery allows for a deposit effect because it maximizes the drug load.

[0011] Hydrophilic particles containing active agents (such as peptides) and sugars dispersed in a lipid-based medium allow drugs to penetrate into the hair follicle and its environment. This method of delivering active agents to the disease area can be used to treat a wide range of conditions and diseases, including, for example, hair loss, hirsutism, psoriasis, atopic dermatitis, eczema, precancerous conditions, and skin infections.

[0012] In one aspect, the present invention provides a composition comprising:

[0013] a) Peptide;

[0014] b) Sugar; and

[0015] c) Lipids.

[0016] In one aspect, the present invention relates to a composition comprising:

[0017] a. 0.01-2% by weight of peptides or peptide derivatives;

[0018] b. 0.01-4% by weight of sugar or modified sugar;

[0019] c. 35-50% by weight of mineral oil; and

[0020] d. 40-60% by weight of isopropyl myristate,

[0021] The prerequisite is that the total sum of the components of the overall composition does not exceed 100% by weight.

[0022] In one respect, the composition is used as a medicine.

[0023] In one aspect, the composition is used to treat dermatological conditions.

[0024] In another aspect, the present invention provides the use of the compounds according to the foregoing for stimulating hair growth in mammals, wherein said use is for cosmetic purposes.

[0025] In another aspect, the present invention provides the use of the compounds according to the above aspects for treating or preventing hair loss.

[0026] In one aspect, the present invention provides a method for stimulating hair growth, the method comprising topically applying an effective amount of any of the above-mentioned compositions to a patient in need of such stimulation.

[0027] In another aspect, the present invention provides a method for treating hair loss, the method comprising topically applying to a patient in need an effective amount of any of the above-mentioned compositions.

[0028] In one aspect, the present invention provides a method for topically delivering a composition according to the above aspects to a patient in need, comprising applying an effective amount of the composition according to the above aspects to the patient's top application site.

[0029] In another aspect, the present invention provides a method for preparing a medicament for local delivery of a composition according to any of the above aspects, the method comprising the following steps:

[0030] a) Mix the peptide or peptide derivative with sugar or modified sugar;

[0031] b) Freeze-dry the mixture of a);

[0032] c) Mix b) with lipids and surfactants;

[0033] d) Grind the mixture from c); and

[0034] e) Optionally, the mixture of d) can be mixed with lipids and thickeners. Attached Figure Description

[0035] Figure 1. Stability Study - Comparison of water-based solution and essentially anhydrous formulation of FOL-005

[0036] The lyophilized powder of FOL-005 was dissolved in phosphate / citrate buffer at pH 5, 6, 7, or 7.6. After storage at 25°C for up to 3 months, the purity of each formulation was analyzed using high-performance liquid chromatography (HPLC). Additionally, the purity of substantially anhydrous formulations of FOL-005 was analyzed after storage at 25°C for up to 12 months.

[0037] Figure 2. Stability study comparison between Na-FOL-005 and Na-FOL-005-sucrose

[0038] The lyophilized powder of FOL-005 / sucrose was formulated into suspensions in dried or undried isopropyl myristate, paraffin oil / petrolatum, sorbitol laurate, and glyceryl behenate. After storage at 2–8, 25, and 30°C for up to 12 months, the purity of each formulation was analyzed by high-performance liquid chromatography (HPLC).

[0039] Figure 3. Stability study - Comparison of dried IPM and ordinary IPM

[0040] The lyophilized powder of FOL-005 / sucrose was formulated into suspensions in dried or undried isopropyl myristate, paraffin oil / petrolatum, sorbitol laurate, and glyceryl behenate. After storage at 2–8, 25, and 30°C for up to 12 months, the purity of each formulation was analyzed by high-performance liquid chromatography (HPLC).

[0041] Figure 4: In vitro study

[0042] Distribution of FOL-005 in porcine inner ear skin sections treated with a FOL-005 / sucrose formulation containing isopropyl myristate, petrolatum, sorbitan laurate, and behenicol glyceryl. The formulation was applied to the skin samples at 0 and 24 hours. At 48 hours, the samples were frozen and subsequently sectioned and analyzed using MALDI MSI. FOL-005 concentrations are shown in black-gray-white. White areas contain high concentrations of FOL-005, and black areas contain low concentrations. A) H&E staining (adjacent tissue sections), B) FOL-005 MSI distribution in treated tissue sections, C) Overlay between MSI distribution and H&E staining.

[0043] Figure 5: In vivo efficacy study

[0044] C57Bl6 mice in the final stage of stable growth (6–9 weeks old) were carefully pruned. Three different strengths of topical FOL-005 and a placebo were applied once daily to the pruned areas, 5 days a week, until day 26. For control, a group was given minoxidil twice daily, 5 days a week, until day 26. Hair growth was scored according to an established system from 0 (no hair growth, pink skin) to 3 (dense, normal epidermal hair).

[0045] Figure 6: Compositions containing peptides

[0046] A) Stability of peptides in anhydrous formulations (see Example 8). Anhydrous formulations of peptides of six different sizes and amino acid sequences were prepared. The peptide concentration was 0.2%, and the following excipients and concentrations (w / w%) were used: sucrose 0.4%, Span20 4%, glyceryl behenate 3%, isopropyl myristate 50%, and petrolatum 42.4%. The formulations were stored at 20 ± 5 °C, and peak purity was analyzed by high-performance liquid chromatography at the start of the study and after 1, 2, and 4 weeks of storage. B) Stability of oxytocin in anhydrous formulations and in PBS solution (see Example 8). Anhydrous formulations of oxytocin were prepared. The following excipients and concentrations (w / w%) were used: oxytocin 0.2%, sucrose 0.4%, Span20 4%, glyceryl behenate 3%, isopropyl myristate 50%, and petrolatum 42.4%. Additionally, a 0.2% solution of oxytocin in PBS (pH 7.4) was prepared. The formulation and solution were stored at 20 ± 5 °C, and peak purity was analyzed by high-performance liquid chromatography (HPLC) at the start of the study and after 1, 2, and 4 weeks of storage. C) Stability of FOL-004 in anhydrous formulation and in PBS solution (see Example 8). Anhydrous formulation of FOL-004 was prepared. The following excipients and concentrations (w / w%) were used: FOL-004 0.2%, sucrose 0.4%, Span20 4%, glyceryl behenate 3%, isopropyl myristate 50%, and petrolatum 42.4%. Additionally, a 0.2% solution of FOL-004 in PBS (pH 7.4) was prepared. The formulation and solution were stored at 20 ± 5 °C, and peak purity was analyzed by HPLC at the start of the study and after 1, 2, and 4 weeks of storage. Detailed Implementation

[0047] Detailed description

[0048] In one aspect, the present invention provides a composition comprising:

[0049] a) Peptide;

[0050] b) Sugar; and

[0051] c) Lipids.

[0052] In one aspect, the present invention relates to a composition comprising:

[0053] a. 0.01-2% by weight of peptides or peptide derivatives;

[0054] b. 0.01-4% by weight of sugar or modified sugar;

[0055] c. 35-50% by weight of mineral oil; and

[0056] d. 40-60% by weight of isopropyl myristate,

[0057] The prerequisite is that the total sum of the components of the overall composition does not exceed 100% by weight.

[0058] peptides

[0059] The compositions of the present invention comprise at least one peptide or peptide derivative. In one embodiment, the peptide or peptide derivative is an active agent. Importantly, the compositions of the present invention facilitate the penetration of the peptide or peptide derivative while simultaneously maintaining the peptide or peptide derivative in a solid state to provide chemical stability throughout the product's shelf life.

[0060] As used herein, the term "peptide" refers to a molecule comprising two or more amino acid residues linked together by peptide bonds. The terms "peptide" and "polypeptide" are used interchangeably throughout this document. In one embodiment, the term "peptide" also includes peptide derivatives.

[0061] As used herein, the term "peptide derivative" refers to a modified or derivatized peptide. In one embodiment, a peptide derivative is a peptide as disclosed herein, conjugated to a portion, such as a portion selected from polyethylene glycol (PEG), monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides. In one embodiment, the peptide is glycosylated.

[0062] In one embodiment, the peptide derivative is a peptide as disclosed herein, which is modified by glycosylation or by polyethylene glycolation, amidation, esterification, acylation, acetylation and / or alkylation.

[0063] In one embodiment, the peptide derivative is a peptide as disclosed herein, fused to another polypeptide, such as a polypeptide selected from glutathione S-transferase (GST) and protein A, or fused to a tag.

[0064] The term “amino acid” as used in this article includes the standard 20 genetically encoded amino acids and their corresponding stereoisomers in the “D” form (as opposed to the natural “L” form), ω-amino acids and other naturally occurring amino acids, unconventional amino acids (e.g., α,α-disubstituted amino acids, N-alkyl amino acids, etc.) and chemically derived amino acids (see below).

[0065] When amino acids are specifically listed, such as "alanine," "Ala," or "A," the term refers to L-alanine and D-alanine unless otherwise explicitly stated. Other unconventional amino acids may also be suitable components of the peptides of the present invention, provided that the peptide retains the desired functional properties. For the peptides shown, each encoded amino acid residue is represented by a single-letter name where appropriate, which corresponds to the common name of a conventional amino acid.

[0066] As is customary, the amino acid sequences disclosed herein are provided in the direction from N-terminus to C-terminus.

[0067] In one embodiment, the peptide comprises or consists of 3 to 50 amino acid residues, such as 3 to 40 amino acid residues, such as 5 to 30 amino acid residues, such as 10 to 25 amino acid residues.

[0068] In one embodiment, the peptide comprises less than 500 amino acids (e.g., less than 400, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 200, 150, 100, 50, 40, 30, 20, 15, 10 or fewer amino acids). In another embodiment, the peptide comprises at least 3 amino acids (e.g., at least 5, at least 10, at least 15, at least 20, at least 25, at least 30 or more amino acids).

[0069] In one embodiment, the peptide comprises or is composed of tandem repeats. In one embodiment, the peptide is cyclic.

[0070] In one embodiment, the peptide is amphiphilic. Amphiphiles are chemical compounds that possess both hydrophilic (water-loving, polar) and lipophilic (fatty) properties. Such compounds are referred to as amphiphilic or amphiphilic compounds.

[0071] In one embodiment, the peptide or peptide derivative is an antimicrobial peptide. In one embodiment, the antimicrobial peptide is selected from polymyxin B, LL37 (SEQ ID NO:188), and FOL-199 (SEQ ID NO:185).

[0072] In one embodiment, the peptide or peptide derivative is an anti-inflammatory peptide. In one embodiment, the anti-inflammatory peptide is selected from FOL-005 (SEQ ID NO:1), FOL-004 (SEQ ID NO:69), and FOL-199 (SEQ ID NO:185).

[0073] In one embodiment, the active component of the compositions of the present invention is derived from naturally occurring peptides, such as osteopontin (e.g., said peptides comprising an amino acid sequence corresponding to a modified form (e.g., a mutant form) of naturally occurring osteopontin). A characterizing feature of the osteopontin-derived peptides in the compositions of the present invention is that the RGD domain naturally present in osteopontin is inactivated, rendering it nonfunctional (at least partially). For example, inactivation of the RGD domain can prevent the osteopontin-derived peptides from binding to one or more integrins that bind to naturally occurring osteopontin.

[0074] Therefore, “modified osteopontin peptides” include peptides corresponding to modified forms of naturally occurring osteopontin, wherein the RGD domain is nonfunctional (at least partially), and fragments and variants thereof that retain the hair-stimulating properties of “full-length” modified osteopontin.

[0075] In one embodiment, the peptide may comprise or consist of a fragment of the amino acid sequence of SEQ ID NO:1FOL-005 or a variant thereof.

[0076] The term "fragment" as used herein can include any fragment, preferably a bioactive fragment of the amino acid sequence described herein. In one embodiment, the fragment is at least six consecutive amino acids of the amino acid sequence of SEQ ID NO:1, for example, at least 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 100, 150, 200, 210, 220, 230, 240, 250, 255, 260, 265, 270, 275, 280, 285, 286, 287, 288, 289, 290, 291, or 292 consecutive amino acids of SEQ ID NO:1.

[0077] A “variant” means that the peptide does not have 100% amino acid sequence identity with SEQ ID NO:1, that is, one or more amino acids in SEQ ID NO:1 must be mutated. For example, the peptide may contain or consist of an amino acid sequence that has at least 50% identity with the amino acid sequence of SEQ ID NO:1, more preferably at least 60%, 70%, 80%, 85%, or 90% identity with said sequence, and most preferably at least 95%, 96%, 97%, 98%, or 99% identity with said amino acid sequence.

[0078] The variant peptide may also contain one or more additional amino acids inserted at the N-terminus and / or C-terminus and / or interior of the amino acid sequence of SEQ ID NO:1. For example, the peptide may contain or consist of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 additional amino acids at the N-terminus and / or C-terminus and / or interior.

[0079] Advantageously, variant peptides are not naturally occurring.

[0080] In one embodiment, the solid material of FOL-005 is used to realize the chemically stabilized formulation of FOL-005 and to guide FOL-005 to the skin through hair follicles. For this purpose, FOL-005 is ground into small particles with the diameter of the main fraction being less than 1 μm and 5 μm.

[0081] In one embodiment, the peptide has an amino acid sequence similarity to a subregion of naturally occurring tendonin. In some embodiments, the peptide may be considered as an active fragment of naturally occurring tendonin or a variant of such a fragment.

[0082] In one embodiment, the peptide comprises or is composed of the following:

[0083] i) The amino acid sequence of the following general formula:

[0084] KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140)

[0085] in:

[0086] X2 is C, P, or G;

[0087] X5 is either E or G;

[0088] X6 is C, D, or I;

[0089] X7 is D, I, S, or G;

[0090] X8 is S, D, or G;

[0091] X 10 It is either E or G;

[0092] X 12 Is it S or T;

[0093] The prerequisite is that if X 12 If it is T, then the peptide contains no more than 25 amino acid residues; and

[0094] The prerequisite is that if X2 is P, X5 is E, X6 is I, X7 is D, X8 is S, and X... 10 It is E and X 12 If it is S, then the peptide contains no more than 85 amino acid residues;

[0095] ii) The amino acid sequence of the following general formula:

[0096] X 10 LX 12 YGIK (SEQ ID NO:177)

[0097] in:

[0098] X 10 It is either E or G;

[0099] X 12 Is it S or T;

[0100] The prerequisite is that if X12 If it is T, then the peptide contains no more than 25 amino acids; and

[0101] The prerequisite is that if X 10 It is E and X 12 If it is S, then the peptide contains no more than 85 amino acid residues;

[0102] iii) The amino acid sequence of the following general formula:

[0103] VDVPZ5GDISLAYZ 13 LR (SEQ ID NO:164)

[0104] in:

[0105] Z5 is either E or N;

[0106] Z 13 Is it R or G;

[0107] iv) The amino acid sequence of the following general formula:

[0108] VDTYDGZ7Z8SVVYGLR(SEQ ID NO:165)

[0109] in:

[0110] Z7 is either D or G;

[0111] Z8 is either I or G;

[0112] v) The amino acid sequence of the following general formula:

[0113] GDPNZ5Z6Z7Z8Z9SVVYGLR(SEQ ID NO:166)

[0114] in:

[0115] Z5 is either D or G;

[0116] Z6 is either D or G.

[0117] Z7 is either I or R;

[0118] Z8 is G or does not exist;

[0119] Z9 is either D or does not exist;

[0120] vi) The amino acid sequence of the following general formula:

[0121] KX2LAX5X6X7X8IX 10 LSYGIK (SEQ ID NO:162)

[0122] in:

[0123] X2 is C, P, or G;

[0124] X5 is either E or G;

[0125] X6 is C, I, or does not exist;

[0126] X7 is D, G, or does not exist;

[0127] X8 is S, G, or does not exist;

[0128] X 10 It is either E or G;

[0129] vii) The amino acid sequence of the following general formula:

[0130] KX2LAX5IX 10 LSYGIK (SEQ ID NO:163)

[0131] in:

[0132] X2 is C, P, or G;

[0133] X5 is either E or G;

[0134] X 10 It is either E or G;

[0135] viii) The amino acid sequence of the following general formula:

[0136] Z7Z8SZ 10 Z 11 YGLR (SEQ ID NO:178)

[0137] in:

[0138] Z7 is either D or G;

[0139] Z8 is either I or G;

[0140] Z 10 It is V or L;

[0141] Z 11 It is V or A;

[0142] or

[0143] ix) The amino acid sequence of the following general formula:

[0144] VDZ3Z4Z5GZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO:68)

[0145] in:

[0146] Z3 is either T or V;

[0147] Z4 is either Y or P;

[0148] Z5 is either D or N;

[0149] Z7 is either D or G;

[0150] Z8 is either I or G;

[0151] Z 10 It is V or L;

[0152] Z 11 It is V or A.

[0153] The term “non-existent” as used in this article, such as “X6 is C, I or non-existent”, should be understood as amino acid residues directly adjacent to the non-existent amino acid being directly linked to each other by conventional amide bonds.

[0154] In one embodiment, the peptide comprises or consists of an amino acid sequence selected from or composed of the following: GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), and VDVPEGDISLAYRLR (SEQ ID NO:161).

[0155] In one embodiment, the peptide comprises or consists of an amino acid sequence selected from or composed of the following: GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), and VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), VDVPEGDISLAYRLR (SEQ ID NO:161), V(β-D)TYDGDISVVYGLR (SEQ ID NO:167), VDTY(β-D)GDISVVYGLR (SEQ ID NO:168), and VDTYDG(β-D)ISVVYGLR (SEQ ID NO:169).

[0156] In one embodiment, the peptide comprises or consists of an amino acid sequence of VDTYDGDISVVYGLR (SEQ ID NO:1; FOL-005) or a fragment / variant thereof.

[0157] In one embodiment, the peptide comprises the amino acid sequence of KPLAEIDSIELSYGIK (SEQ ID NO:136, FOL-014) or a fragment / variant thereof or is composed of therein.

[0158] In one embodiment, the peptide comprises or consists of an amino acid sequence of VDVPNGDISLAYGLR (SEQ ID NO:69, FOL-004) or a fragment / variant thereof.

[0159] In one embodiment, the peptide comprises or consists of an amino acid sequence selected from or formed therefrom: KCLAECDSIELSYGIK (SEQ ID NO:141), CLAEIDSC (SEQ ID NO:142), CFKPLAEIDSIECSYGIK (SEQ ID NO:143), KPLAEDISIELSYGIK (SEQ ID NO:145), KPLAEIGDIELSYGIK (SEQ ID NO:146), KPLAEGDIELSYGIK (SEQ ID NO:147), KPLAEIELSYGIK (SEQ ID NO:148), KPLAEIDSIELTYGIK (SEQ ID NO:149), KPLAEIDGIELSYGIK (SEQ ID NO:150), KPLAEIDGIELTYGIK (SEQ ID NO:151), KPLAEIGSIELSYGIK (SEQ ID NO:152), KGLAEIDSIELSYGIK (SEQ ID NO:153), KPLAGIDSIGLSYGIK (SEQ ID NO:154). NO:154), KCLAEIDSCELSYGIK (SEQ ID NO:155) and CFKPLAEIDSIEC (SEQ ID NO:156), or variants or fragments thereof.

[0160] In one embodiment, the peptide comprises or consists of an amino acid sequence selected from or composed of the following: LAEIDSIELSYGIK (SEQ ID NO:170), AEIDSIELSYGIK (SEQ ID NO:171), EIDSIELSYGIK (SEQ ID NO:172), IDSIELSYGIK (SEQ ID NO:173), DSIELSYGIK (SEQ ID NO:174), SIELSYGIK (SEQ ID NO:175), IELSYGIK (SEQ ID NO:176), or variants or fragments thereof.

[0161] In one embodiment, the peptide comprises or consists of an amino acid sequence selected from or composed of the following: KPLAEIDSIELSYGI (SEQ ID NO:179), KPLAEIDSIELSYG (SEQ ID NO:180), KPLAEIDSIELSY (SEQ ID NO:181), KPLAEIDSIELS (SEQ ID NO:182), KPLAEIDSIEL (SEQ ID NO:183), KPLAEIDSIE (SEQ ID NO:184), or variants or fragments thereof.

[0162] In another embodiment, the peptide is selected from SEQ ID NO: 1, 136, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 1 04, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 137, 138, 139, 141, 142, 143, 144, 14 5, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, and 188.

[0163] In one embodiment, the peptide is selected from GHK (SEQ ID NO:188), oxytocin (SEQ ID NO:186), polymyxin B, LL37 (SEQ ID NO:187), FOL-199 (SEQ ID NO:185), and becappellamine.

[0164] sugar

[0165] The composition comprises at least one sugar or modified sugar. The sugar consists of n monosaccharide units linked together by glycosidic bonds, where n is an integer. In one embodiment, the sugar is selected from monosaccharides, disaccharides, and trisaccharides. For monosaccharides, n is 1; for disaccharides, n is 2; and for trisaccharides, n is 3. In one embodiment, the sugar is substantially composed of monosaccharides, disaccharides, or trisaccharides, and the properties of the sugar are substantially determined by the monosaccharide, disaccharide, or trisaccharide portion. In one embodiment, the sugar is a sugar derivative or modified sugar, such as a sugar alcohol.

[0166] The melting point of a substance is the temperature at which it changes from a solid to a liquid state. At the melting point, the solid and liquid phases are in equilibrium. In one embodiment, the sugar has a melting temperature between 60 and 140°C. In another embodiment, the sugar has a melting temperature between 60 and 65°C, such as between 65 and 70°C, such as between 70 and 75°C, such as between 75 and 80°C, such as between 80 and 85°C, such as between 85 and 90°C, such as between 90 and 95°C, such as between 95 and 100°C, such as between 100 and 105°C, such as between 105 and 110°C, such as between 110 and 115°C, such as between 115 and 120°C, such as between 120 and 125°C, such as between 125 and 130°C, such as between 130 and 135°C, such as between 135 and 140°C.

[0167] In one embodiment, the sugar is sucrose. In one embodiment, the sugar is maltose. In one embodiment, the sugar is trehalose. In one embodiment, the sugar is raffinose. In one embodiment, the sugar is maltotriose. In one embodiment, the sugar is stachyose. In one embodiment, the sugar is glucose. In one embodiment, the sugar is dextran. In one embodiment, the sugar is a sugar alcohol, such as mannitol.

[0168] In one embodiment, the weight ratio of sugar to peptide in the composition is from 1:9 to 9:1, such as 1:9 or 9:1. In another embodiment, the weight ratio of sugar to peptide in the composition is from 5:1 to 1:5, such as 2:1 or 1:1.

[0169] Particles

[0170] The peptides can be freeze-dried together with sucrose to increase the solubility of the peptide particles and enhance their chemical stability. In one embodiment, the peptides and sugars form hydrophilic particles. The particles can be in a solid, glassy, ​​or rubbery state. The particles can be manufactured using standard techniques such as freeze-drying, spray drying, or freeze-spraying, and then manipulated to reduce the particle size to the submicron level.

[0171] In one embodiment, at least 50% of the particles have an average particle size between 0.1 and 10 μm, such as between 0.1 and 1 μm, such as between 1 and 5 μm, such as between 5 and 10 μm, such as between 10 and 15 μm, such as between 15 and 20 μm, such as between 20 and 25 μm, such as between 25 and 30 μm, such as between 30 and 35 μm, such as between 35 and 40 μm, such as between 40 and 45 μm, such as between 45 and 50 μm.

[0172] In one embodiment, at least 50% of the particles have an average particle size between 0.1 and 50 μm, such as between 0.1 and 15 μm, such as between 0.1 and 10 μm, such as between 0.1 and 2 μm.

[0173] In one embodiment, the particle size is less than 50 μm, for example less than 40 μm, such as less than 30 μm, such as less than 20 μm, such as less than 10 μm.

[0174] In one embodiment, the composition comprises 0.01-10% by weight of particles, such as 0.1-5% by weight of particles, such as 0.1-2% by weight of particles.

[0175] In one embodiment, the particles dissolve rapidly upon contact with water. Typically, the particles should dissolve within one minute in water at 37°C.

[0176] lipid mediators

[0177] The compositions of the present invention comprise at least one lipid. The lipid functions as a mediator in the composition, i.e., as a medium for delivering the active ingredient. In one embodiment, the lipid mediator comprises one or more different lipids. In one embodiment, the composition comprises one type of lipid. In one embodiment, the composition comprises two types of lipids.

[0178] Non-limiting examples of suitable lipids are monoesters, diesters, and triesters of C6 to C22 fatty acids with alcohols such as propanol, butanol, propylene glycol, and glycerol, as well as mixtures of lipids such as white or yellow soft paraffin. In one embodiment, the lipid is isopropyl myristate or isopropyl palmitate. In one embodiment, the lipid is selected from petrolatum, isopropyl myristate, and glyceryl behenate.

[0179] As used herein, the term "petroleum jelly" refers to a semi-solid mixture of hydrocarbons (CAS No. 8009-03-8). Petroleum jelly is also known as "petroleum gum," "white petroleum jelly," and "soft paraffin," or polyhydrocarbon. Petroleum jelly is also used as petrolatum. Sale.

[0180] In one embodiment, the lipid is petrolatum or paraffin, such as paraffin oil. Paraffin oil or liquid paraffin oil is obtained during petroleum distillation. Therefore, petroleum can be paraffin oil.

[0181] In one embodiment, isopropyl myristate is mixed with petrolatum in a 1:1 ratio. In one embodiment, the composition comprises isopropyl myristate and petrolatum. In one embodiment, the composition comprises isopropyl myristate and petrolatum in a weight ratio of 2:1 to 1:2, such as 3:2 to 2:3, such as about 1:1.

[0182] In one embodiment, the composition comprises petrolatum, isopropyl myristate, and glyceryl behenate.

[0183] In one embodiment, the lipid is dried. In another embodiment, the isopropyl myristate is dried.

[0184] In one embodiment, the lipid is used to promote distribution to the hair follicle, i.e., a lipid mediator compatible with the sebum content in the hair follicle, and to increase the chemical stability of the peptide. Thus, in one embodiment, the lipid dissolves sebum.

[0185] After distribution to the hair follicle, it is important that the lipid mediator acts as a carrier for the particles and comes into contact with the contents of the hair follicle. An example of such a mediator component is a fluid lipid (at room temperature and body temperature) that dissolves sebum. The amount of solid material in the suspension can vary depending on the required dosage and the size of the area to be covered. Those skilled in the art will be able to recommend the appropriate particle concentration on a case-by-case basis.

[0186] In one embodiment, the lipids have dissolving characteristics similar to sebum. In practice, this means having a solubility of 6.5 and 10 (cal / cm³). 3 ) 1 / 2 A mixture of compounds with Hildebrand solubility coefficients is a suitable solvent for sebum.

[0187] Additional excipients

[0188] In one embodiment, additional excipients are added to the composition.

[0189] In one embodiment, the composition further comprises a surfactant. The hydrophilic-lipophilic balance (HLB) of a surfactant is a measure of its degree of hydrophilicity or lipophilicity. In one embodiment, the HLB of the surfactant is between 9 and 16.

[0190] In one embodiment, a surfactant, such as sorbitol laurate, is added to prevent particle sedimentation, i.e., to maintain uniform suspension of the particles.

[0191] In one embodiment, the surfactant is selected from sorbitol laurate, Span 80, and Brij 72. In one embodiment, the surfactant is sorbitol laurate. The terms sorbitol laurate and Span 20 are used interchangeably herein.

[0192] In one embodiment, the concentration of sorbitol laurate is 1%.

[0193] In another embodiment, the surfactant is sugar-based. In one embodiment, the sugar-based surfactant is selected from sucrose cocoate, dehydrated sorbitol laurate, and polysorbate. In one embodiment, the sugar-based surfactant has an HLB value between 9 and 16.

[0194] In one embodiment, the particles are adjusted to have surface properties that enable the formulation to form a uniform suspension. These surface properties can be adjusted or optimized by using a surfactant. In one embodiment, the surfactant is selected from nonionic surfactants with an HLB of 9-16 and a hydrophilic / lipophilic balance.

[0195] In one embodiment, the composition comprises glycerol and / or propylene glycol.

[0196] In one embodiment, the composition further comprises a thickener. In one embodiment, glyceryl behenate is added as a thickener to obtain an attractive texture. Other thickeners known in the art can be used. In one embodiment, the thickener is glyceryl behenate or carnauba wax.

[0197] In one embodiment, the composition further comprises one or more additional active pharmaceutical ingredients. In one embodiment, the composition further comprises minoxidil. In one embodiment, the composition further comprises finasteride. In one embodiment, the composition further comprises minoxidil and finasteride.

[0198] In one embodiment, conventional pharmaceutical compounds, preservatives, and buffers that increase viscosity are incorporated into the composition to improve the physical properties of the composition.

[0199] Composition

[0200] In one embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition is a cosmetic composition. In one embodiment, the composition is a topical formulation. In one embodiment, the composition is a drug for topical delivery.

[0201] As used herein, “particulate composition” refers to solid particles present in a formulation, while “composition” refers to a composition of an intended product comprising particles and a lipid mediator.

[0202] In one embodiment, the composition comprises at least 0.01% by weight of peptides, such as at least 0.1% by weight of peptides, such as at least 0.5% by weight of peptides, such as at least 1% by weight of peptides, such as at least 1.5% by weight of peptides, such as at least 2% by weight of peptides, such as at least 2.5% by weight of peptides, such as at least 3% by weight of peptides, such as at least 3.5% by weight of peptides, such as at least 6% by weight of peptides, such as at least 6.5% by weight of peptides, such as at least 7% by weight of peptides, such as at least 7.5% by weight of peptides, such as at least 8% by weight of peptides, such as at least 8.5% by weight of peptides, such as at least 9% by weight of peptides, such as at least 9.5% by weight of peptides, such as at least 10% by weight of peptides.

[0203] In one embodiment, the composition comprises no more than 2% by weight of peptides, such as no more than 5% by weight of peptides, such as no more than 10% by weight of peptides, such as no more than 15% by weight of peptides, such as no more than 20% by weight of peptides.

[0204] In one embodiment, the composition comprises between 0.01 and 5 wt% of peptides or peptide derivatives, such as between 0.1 and 5 wt% of peptides or peptide derivatives, such as between 0.1 and 2 wt% of peptides or peptide derivatives, such as between 0.1 and 1 wt% of peptides or peptide derivatives, such as between 1 and 5 wt% of peptides or peptide derivatives, such as between 5 and 10 wt% of peptides or peptide derivatives, such as between 10 and 15 wt% of peptides or peptide derivatives, such as between 15 and 20 wt% of peptides or peptide derivatives. In another embodiment, the composition comprises between 0.01 and 5 wt% of peptides, such as between 0.01 and 2 wt% of peptides, such as between 0.1 and 1 wt% of peptides, such as between 1 and 5 wt% of peptides, such as between 5 and 10 wt% of peptides, such as between 10 and 15 wt% of peptides, such as between 15 and 20 wt% of peptides.

[0205] In one embodiment, the composition comprises at least 40% by weight of lipids, 50% by weight of lipids, such as at least 55% by weight of lipids, such as at least 60% by weight of lipids, such as at least 65% by weight of lipids, such as at least 70% by weight of lipids, such as at least 75% by weight of lipids, such as at least 80% by weight of lipids, such as at least 85% by weight of lipids, such as at least 90% by weight of lipids, such as at least 95% by weight of lipids.

[0206] In one embodiment, the composition comprises no more than 55% by weight of lipids, such as no more than 60% by weight of lipids, such as no more than 65% by weight of lipids, such as no more than 70% by weight of lipids, such as no more than 75% by weight of lipids, such as no more than 80% by weight of lipids, such as no more than 85% by weight of lipids, such as no more than 90% by weight of lipids, such as no more than 95% by weight of lipids.

[0207] In one embodiment, the composition comprises lipids between 40 and 99 wt%, such as lipids between 40 and 60 wt%, such as lipids between 50 and 60 wt%, such as lipids between 60 and 70 wt%, such as lipids between 70 and 80 wt%, such as lipids between 80 and 90 wt%, and such as lipids between 90 and 99.95 wt%.

[0208] In one embodiment, the composition comprises at least 0.1% by weight of sugar, such as at least 0.5% by weight of sugar, such as at least 1% by weight of sugar, such as at least 1.5% by weight of sugar, such as at least 2% by weight of sugar, such as at least 2.5% by weight of sugar, such as at least 3% by weight of sugar, such as at least 3.5% by weight of sugar, such as at least 6% by weight of sugar, such as at least 6.5% by weight of sugar, such as at least 7% by weight of sugar, such as at least 7.5% by weight of sugar, such as at least 8% by weight of sugar, such as at least 8.5% by weight of sugar, such as at least 9% by weight of sugar, such as at least 9.5% by weight of sugar, such as at least 10% by weight of sugar.

[0209] In one embodiment, the composition contains no more than 2% by weight of sugar, such as no more than 5% by weight of sugar, such as no more than 10% by weight of sugar, such as no more than 15% by weight of sugar, such as no more than 20% by weight of sugar.

[0210] In one embodiment, the composition comprises between 0.01 and 5% by weight of sugar or modified sugar, such as between 0.01 and 2% by weight of sugar or modified sugar, such as between 0.1 and 2% by weight of sugar or modified sugar, such as between 1 and 5% by weight of sugar, such as between 5 and 10% by weight of sugar or modified sugar, such as between 10 and 15% by weight of sugar or modified sugar, such as between 15 and 20% by weight of sugar or modified sugar. In another embodiment, the composition comprises between 0.01 and 0.1 and 1% by weight of sugar, such as between 1 and 5% by weight of sugar, such as between 5 and 10% by weight of sugar, such as between 10 and 15% by weight of sugar, such as between 15 and 20% by weight of sugar.

[0211] In one embodiment, the sugar is sucrose and the lipid is isopropyl myristate. In one embodiment, the composition further comprises petrolatum. In one embodiment, the composition further comprises glyceryl behenate. In one embodiment, the composition further comprises sorbitol laurate. In one embodiment, the composition comprises or is substantially composed of the following substances: peptides; sucrose; glyceryl behenate; petrolatum; isopropyl myristate; and sorbitol laurate.

[0212] It should be understood that the total sum of the components of the overall composition does not exceed 100% by weight.

[0213] In one embodiment, the composition comprises or is substantially composed of the following substances: about 0.01-1% by weight of peptides or peptide derivatives; 0.01-4% by weight of sugars or modified sugars; 85-95% by weight of lipids; and optionally 2-10% by weight of surfactants.

[0214] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0215] a. 0.01-1% by weight of peptides or peptide derivatives;

[0216] b. 0.01-2% by weight of sugar or modified sugar;

[0217] c. 35-50% by weight of mineral oil; and

[0218] d. 40-60% by weight of isopropyl myristate.

[0219] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0220] a. 0.01-1% by weight of peptides or peptide derivatives;

[0221] b. 0.01-2% by weight of sugar or modified sugar;

[0222] c. 1-6% by weight of behenate glycerides;

[0223] d. 35-45% by weight of mineral oil;

[0224] e. 40-60% by weight of isopropyl myristate; and

[0225] f. 2-10% by weight of surfactants, such as sorbitol laurate.

[0226] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0227] a. 0.01-1% by weight of peptides or peptide derivatives;

[0228] b. 0.01-2% by weight of sucrose, mannitol or glucose;

[0229] c. 1-8% by weight of glyceryl behenate or carnauba wax;

[0230] d. 35-45% by weight of mineral oil;

[0231] e. 40-60% by weight of isopropyl myristate; and

[0232] f. 2-10% by weight of surfactants, such as sorbitol laurate.

[0233] In one embodiment, the composition comprises 40-60% by weight of isopropyl myristate, 2-6% by weight of sorbitol laurate, and 2-6% by weight of glyceryl behenate. In one embodiment, the composition comprises 50% isopropyl myristate, 0.2% sorbitol laurate, and 3% glyceryl behenate or 6% carnauba wax. In one embodiment, the lipid comprises isopropyl myristate, petrolatum, and glyceryl behenate. In one embodiment, the composition comprises 50% by weight of isopropyl myristate, 4% by weight of sorbitol laurate, and 3% by weight of glyceryl behenate. In one embodiment, the composition comprises 50% isopropyl myristate, 0.2% sorbitol laurate, and 6% carnauba wax.

[0234] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0235] a. 0.01-1% by weight of peptides or peptide derivatives;

[0236] b. 0.01-2% by weight of sucrose;

[0237] c. 1-6% by weight of behenate glycerides;

[0238] d. 35-45% by weight of mineral oil;

[0239] e. 40-60% by weight of isopropyl myristate; and

[0240] f. 2-10% by weight of dehydrated sorbitol lauryl ester.

[0241] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0242] a. 0.01-1% by weight of peptides or peptide derivatives;

[0243] b. 0.01-1% by weight of sucrose;

[0244] c. 1-6% by weight of behenate glycerides;

[0245] d. 35-45% by weight of mineral oil;

[0246] e. 40-60% by weight of isopropyl myristate; and

[0247] f. 2-6% by weight of dehydrated sorbitol lauryl ester.

[0248] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0249] a. 0.2% by weight of peptide;

[0250] b. 0.4% by weight of sucrose;

[0251] c. 3% by weight of behenate glyceryl ester;

[0252] d.42.4% by weight of mineral resin;

[0253] e. 50% by weight of isopropyl myristate; and

[0254] f.4% by weight of dehydrated sorbitol lauryl ester.

[0255] In one embodiment, the total percentage amount of the components does not exceed 100%.

[0256] In one embodiment, the composition comprises or is substantially composed of the following substances: approximately

[0257] a) 1% by weight of peptide;

[0258] b) 2% by weight of sucrose;

[0259] c) 95% by weight lipids; and optional

[0260] d) 2% by weight of dehydrated sorbitol lauryl ester.

[0261] In one embodiment, the composition is substantially anhydrous.

[0262] In one embodiment, the composition is in the form of an ointment, powder, spray, lotion, gel, foam, cream, cosmetic, or shampoo. In one embodiment, the composition is in the form of a powder.

[0263] Preparation method

[0264] The particles can be prepared using standard techniques such as freeze-drying, spray drying, or freeze-spraying, followed by operations to reduce the particle size to the submicron level. Such size reduction can be achieved using standard grinding techniques such as ball milling. Other suitable techniques are emulsification and solvent evaporation, and other techniques for producing particles include the precipitation of surfactants / sugars.

[0265] In one aspect, the present invention provides a method for preparing the composition as described herein, comprising the following steps:

[0266] a) Mix the peptide with sugar;

[0267] b) Freeze-dry the mixture of a);

[0268] c) Mix b) with lipids and surfactants;

[0269] d) Grind the mixture from c); and

[0270] e) Optionally, the mixture of d) can be mixed with lipids and thickeners.

[0271] The peptides can be freeze-dried together with sucrose to increase the solubility of peptide particles and enhance the chemical stability of the peptides.

[0272] In one embodiment, a method for preparing the composition as described herein includes the following steps:

[0273] a) Mix the peptide with a sugar such as sucrose;

[0274] b) Low-pressure freeze-drying of the mixture of a);

[0275] c) Mix lipids (such as isopropyl myristate) with surfactants (e.g., sorbitol laurate) to obtain a homogeneous solution;

[0276] d) Add the peptide-glycan mixture from b) to the lipid-surfactant mixture from c) to obtain a suspension;

[0277] e) Grinding the mixture of d), for example by using standardized beads or wet grinding methods;

[0278] f) Mixing lipids (such as petrolatum) with surfactants (such as sorbitol laurate) and thickeners (such as glyceryl behenate); and

[0279] g) Mix the mixture from e) with the mixture from f).

[0280] Delivery area

[0281] This invention relates to compositions suitable for the topical delivery of one or more active agents, such as peptides. In one embodiment, the topical application site is on the surface of a patient's skin. In another embodiment, the topical application site is on the surface of a patient's tissue. In one embodiment, the product of the invention is intended to deliver a medically active substance into or around a hair follicle.

[0282] In one embodiment, the composition described herein is intended to stimulate hair growth in mammals and is not limited to use on the scalp, but may also be applied to other parts of the body (including the face to promote the growth of beard, eyelashes, eyebrows, etc.).

[0283] Use of the composition

[0284] In one aspect, the present invention provides a method for locally delivering a peptide or variant / fragment to a subject in need, the method comprising applying an effective amount of the composition to a local application site on the subject.

[0285] In one implementation, the composition can be applied for several days, such as several weeks, or even several months.

[0286] This invention is not limited to medical uses, but the compositions described herein can also be used as cosmetic agents (meaning that they do not provide any improvement in physical health but only provide aesthetic benefits to mammals).

[0287] Those skilled in the art will further understand that the compositions of the present invention can be used in vivo, in vitro, or outside the body. For example, when the composition is used to stimulate hair growth, it can be used to stimulate hair growth in vitro, such as in a skin explant prior to skin transplantation onto a mammal.

[0288] In one embodiment, the composition is applied to a subject or patient. In one embodiment, the subject or patient is a mammal. In one embodiment, the mammal is selected from humans, dogs, cats, and horses. In one embodiment, the mammal is a human.

[0289] The composition may have wound healing, anti-aging, anti-irritant, anti-itch, antibacterial, antifungal, antiviral, anti-inflammatory, anti-allergic, anti-wrinkle and / or anti-acne effects.

[0290] Medical use

[0291] In one aspect, the present invention relates to compositions as described herein used as pharmaceuticals. In one embodiment, the peptide of the pharmaceutical composition is an active ingredient, such as an active pharmaceutical ingredient. Thus, in one embodiment, the pharmaceutical composition is suitable for treating the indication for which the peptide is effective.

[0292] In one embodiment, the composition described herein is for treating a dermatological condition. In one aspect, the present invention provides a method for treating a dermatological condition. In one embodiment, the composition is for treating a dermatological condition. In one embodiment, the dermatological condition is selected from psoriasis, atopic dermatitis, eczema, precancerous conditions, and skin infections. Precancerous conditions encompass precancerous skin lesions. Skin infections can be bacterial, viral, fungal, or parasitic infections.

[0293] In one aspect, the present invention relates to the use of compositions as described herein in the preparation of medicaments for the treatment or prevention of diseases or conditions related to hair loss.

[0294] In one aspect, the present invention relates to the use of the compositions described herein in the preparation of a medicament for treating dermatological conditions.

[0295] In one embodiment, an effective amount of the composition is administered to a subject. The term "effective" as used herein means sufficient to achieve the desired, anticipated, or anticipated result. For example, "effective amount," "cosmetic effective amount," or "therapeutic effective amount" refers to an amount sufficient to achieve the desired, anticipated, or anticipated result. This is a predetermined amount of active material calculated to produce the desired therapeutic effect. As those skilled in the art will appreciate, the amount of a compound can vary depending on its specific activity. A suitable dosage may contain a predetermined amount of the active composition, calculated to combine with the desired diluent to produce the desired therapeutic effect. In the methods and uses for preparing the compositions of the present invention, a therapeutically effective amount of the active component is provided. As is well known in the art, a therapeutically effective amount can be determined by a medical or veterinary worker with ordinary skills based on patient characteristics such as age, weight, sex, condition, complications, other diseases, etc.

[0296] As used herein, “therapeutic effective amount” or “effective amount” or “therapeuticly effective” refers to the amount of active ingredient that improves symptoms or conditions. For example, in one embodiment, “therapeutic effective amount” refers to the amount that provides stimulation to hair growth.

[0297] hair loss

[0298] In one embodiment, the composition described herein is for the treatment or prevention of diseases or conditions related to hair loss.

[0299] In one aspect, the present invention provides a method for stimulating hair growth, the method comprising topically applying an effective amount of the composition to a patient in need of it.

[0300] In one aspect, the present invention provides a method for treating hair loss, the method comprising topically applying an effective amount of the composition to a patient in need of such treatment.

[0301] In one embodiment, the composition described herein is for treating hair loss. Hair loss is generally associated with the loss of hair in the early stages of growth. However, it should be understood that the compositions of the present invention can also be used to treat conditions associated with the loss of hair in the telogen effluvium stage.

[0302] In one implementation, the hair loss is selected from:

[0303] (a) Androgenetic alopecia (also known as alopecia areata, alopecia areata, male pattern baldness, or female pattern baldness);

[0304] (b) Traction alopecia;

[0305] (c) Regenerative phase alopecia;

[0306] (d) Tertiary alopecia;

[0307] (e) Alopecia areata;

[0308] (f) Complete baldness;

[0309] (g) Alopecia areata;

[0310] (h) Hair removal (alopecia barbae);

[0311] (i) Mucin-related alopecia;

[0312] (j) Tumor-related alopecia;

[0313] (k) scarring alopecia; and

[0314] (l) Scarring alopecia.

[0315] For example, the hair loss could be androgenetic alopecia.

[0316] Alternatively, the hair loss may be anaplastic alopecia. This condition, caused by hair prematurely entering the telogen effluvium stage, can be caused by a variety of factors, including eating disorders, fever, childbirth, chronic diseases, major surgery, anemia, severe mood disorders, dieting, hypothyroidism, and medications.

[0317] Therefore, in one implementation, the hair loss is induced by radiation therapy and / or chemotherapy agents. For example, hair loss is a common and distressing side effect of treatment with chemotherapy drugs such as cisplatin, etoposide, and paclitaxel.

[0318] In one embodiment, the modified osteopontin peptide present in the composition of the present invention is capable of stimulating hair growth in mammals.

[0319] In one embodiment, the peptide is capable of stimulating the growth of human hair.

[0320] In another embodiment, the peptide is capable of stimulating hair growth in the body.

[0321] Those skilled in the art will understand that stimulation of hair growth can be mediated by the action of existing hair follicles and / or by inducing the formation of new hair follicles. Therefore, in one embodiment, the modified osteopontin peptide is capable of stimulating existing hair follicles (e.g., by prolonging the early growth phase and / or by shortening the telogen phase, thus activating dormant hair follicles).

[0322] In another embodiment, the peptide is capable of inducing the formation of new hair follicles or stem cells for generating them.

[0323] Beauty Uses

[0324] In one respect, the compositions described herein are intended for use, wherein the use is for cosmetic purposes.

[0325] In one aspect, the present invention provides the use of the compositions described herein for stimulating hair growth in mammals, wherein said use is for cosmetic purposes. In one embodiment, the cosmetic composition is used to stimulate the growth of existing hair follicles and / or induce the growth of new hair follicles (or stem cells for generating them).

[0326] In one embodiment, the cosmetic composition is used to treat or prevent hair loss that may be associated with a receding hairline and / or thinning hair.

[0327] Combination therapy

[0328] Those skilled in the art will understand that the compositions of the present invention can be used alone or in combination with other therapeutic or cosmetic agents. For example, the compositions of the present invention can be used in combination therapy with existing treatments to prevent the loss of existing hair and / or stimulate the growth of new hair, such as potassium channel openers, such as minoxidil (Regaine RTM., Pharmacia Corp.) and diazoxide; 5-α-reductase inhibitors, such as finasteride (Propecia RTM., Merck & Co.); and immunosuppressants cyclosporine A.

[0329] project

[0330] 1. A composition comprising

[0331] a) Polypeptide;

[0332] b) Sugar; and

[0333] c) Lipids.

[0334] 2. The composition according to Item 1, wherein the polypeptide is a peptide.

[0335] 3. A composition comprising

[0336] a) Peptides or peptide derivatives;

[0337] b) Sugar or modified sugar; and

[0338] c) Lipids.

[0339] 4. A composition according to any one of the above items, wherein the composition comprises particles, said particles comprising said peptide or peptide derivative and said sugar or modified sugar or substantially composed thereof.

[0340] 5. A composition according to any of the above items, wherein the composition comprises 0.01-10% by weight of particles, such as 0.1-5% by weight of particles, such as 0.1-2% by weight of particles.

[0341] 6. A composition according to any one of the above items, wherein at least 50% of the particles have an average particle size between 1 and 5 μm, such as between 5 and 10 μm, such as between 10 and 15 μm, such as between 15 and 20 μm, such as between 20 and 25 μm, such as between 25 and 30 μm, such as between 30 and 35 μm, such as between 35 and 40 μm, such as between 40 and 45 μm, such as between 45 and 50 μm.

[0342] 7. A composition according to any one of the above items, wherein at least 50% of the particles have a diameter of less than 50 μm, such as less than 40 μm, such as less than 30 μm, such as less than 20 μm, such as less than 10 μm, such as less than 1 μm.

[0343] 8. A composition according to any of the above items, wherein at least 50% of the particles have an average particle size between 0.1 and 50 μm, such as between 0.1 and 15 μm, such as between 0.1 and 10 μm, such as between 0.1 and 2 μm.

[0344] 9. A composition according to any of the foregoing items, wherein the peptide comprises 1-50 amino acid residues, such as 3-40 amino acid residues, such as 5-30 amino acid residues, such as 10-25 amino acid residues.

[0345] 10. A composition according to any one of the above items, wherein the peptide is amphiphilic.

[0346] 11. The composition according to any one of the above items, wherein the peptide or peptide derivative is an antimicrobial peptide or peptide derivative.

[0347] 12. The composition according to any one of the above items, wherein the antimicrobial peptide is selected from polymyxin B, LL37 (SEQ ID NO:188) and FOL-199 (SEQ ID NO:185).

[0348] 13. The composition according to any one of the above items, wherein the peptide or peptide derivative is an anti-inflammatory peptide or peptide derivative.

[0349] 14. The composition according to any one of the above items, wherein the anti-inflammatory peptide is selected from FOL-005 (SEQ ID NO:1), FOL-004 (SEQ ID NO:69) and FOL-199 (SEQ ID NO:185).

[0350] 15. A composition according to any one of the above items, wherein the peptide is selected from GHK (SEQ ID NO:188), oxytocin (SEQ ID NO:186), polymyxin B, LL37 (SEQ ID NO:187), and becapremin.

[0351] 16. The composition according to any one of the foregoing items, wherein the peptide comprises:

[0352] i) The amino acid sequence of the following general formula:

[0353] KX2LAX5X6X7X8IX 10 LX 12 YGIK (SEQ ID NO:140)

[0354] in:

[0355] X2 is C, P, or G;

[0356] X5 is either E or G;

[0357] X6 is C, D, or I;

[0358] X7 is D, I, S, or G;

[0359] X8 is S, D, or G;

[0360] X 10 It is either E or G;

[0361] X 12 Is it S or T;

[0362] The prerequisite is that if X 12 If it is T, then the peptide contains no more than 25 amino acid residues; and

[0363] The prerequisite is that if X2 is P, X5 is E, X6 is I, X7 is D, X8 is S, and X... 10 It is E and X 12 If it is S, then the peptide contains no more than 85 amino acid residues;

[0364] ii) The amino acid sequence of the following general formula:

[0365] X 10 LX 12 YGIK (SEQ ID NO:177)

[0366] in:

[0367] X 10 It is either E or G;

[0368] X12 is either S or T;

[0369] The prerequisite is that if X 12 If it is T, then the peptide contains no more than 25 amino acids; and

[0370] The prerequisite is that if X 10 It is E and X 12 If it is S, then the peptide contains no more than 85 amino acid residues;

[0371] iii) The amino acid sequence of the following general formula:

[0372] VDVPZ5GDISLAYZ 13 LR (SEQ ID NO:164)

[0373] in:

[0374] Z5 is either E or N;

[0375] Z 13 Is it R or G;

[0376] iv) The amino acid sequence of the following general formula:

[0377] VDTYDGZ7Z8SVVYGLR(SEQ ID NO:165)

[0378] in:

[0379] Z7 is either D or G;

[0380] Z8 is either I or G;

[0381] v) The amino acid sequence of the following general formula:

[0382] GDPNZ5Z6Z7Z8Z9SVVYGLR(SEQ ID NO:166)

[0383] in:

[0384] Z5 is either D or G;

[0385] Z6 is D or G; Z7 is I or R.

[0386] Z8 is G or does not exist;

[0387] Z9 is either D or does not exist;

[0388] vi) The amino acid sequence of the following general formula:

[0389] KX2LAX5X6X7X8IX 10 LSYGIK (SEQ ID NO:162)

[0390] in:

[0391] X2 is C, P, or G;

[0392] X5 is either E or G;

[0393] X6 is C, I, or does not exist;

[0394] X7 is D, G, or does not exist;

[0395] X8 is S, G, or does not exist;

[0396] X 10 It is either E or G;

[0397] vii) The amino acid sequence of the following general formula:

[0398] KX2LAX5IX 10 LSYGIK (SEQ ID NO:163)

[0399] in:

[0400] X2 is C, P, or G;

[0401] X5 is either E or G;

[0402] X 10 It is either E or G;

[0403] viii) The amino acid sequence of the following general formula:

[0404] Z7Z8SZ 10 Z 11 YGLR (SEQ ID NO:178)

[0405] in:

[0406] Z7 is either D or G;

[0407] Z8 is either I or G;

[0408] Z 10 It is V or L;

[0409] Z 11 It is V or A;

[0410] or

[0411] ix) The amino acid sequence of the following general formula:

[0412] VDZ3Z4Z5GZ7Z8SZ 10 Z 11 YGLR (SEQ ID NO:68)

[0413] in:

[0414] Z3 is either T or V;

[0415] Z4 is either Y or P;

[0416] Z5 is either D or N;

[0417] Z7 is either D or G;

[0418] Z8 is either I or G;

[0419] Z 10 It is V or L;

[0420] Z 11 It is V or A.

[0421] 17. A composition according to any one of the above items, wherein the peptide comprises or consists of an amino acid sequence selected from or composed of the following: GDPNDGRGDSVVYGLR (SEQ ID NO:137), VDTYDGGISVVYGLR (SEQ ID NO:138), and VDTYDGDGSVVYGLR (SEQ ID NO:139), VDVPEGDISLAYGLR (SEQ ID NO:157), LDGLVRAYDNISPVG (SEQ ID NO:158), GDPNGDISVVYGLR (SEQ ID NO:159), VDVPNGDISLAYRLR (SEQ ID NO:160), and VDVPEGDISLAYRLR (SEQ ID NO:161).

[0422] 18. A composition according to any one of the foregoing items, wherein the peptide comprises or is composed of an amino acid sequence selected from or consisting of the following: GDPNDGRGDSVVYGLR (SEQ ID NO: 137), VDTYDGGISVVYGLR (SEQ ID NO: 138), and VDTYDGDGSVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 167), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 168), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 138), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 139), VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160), VDVPEGDISLAYRLR (SEQ ID NO: 161), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 167), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 168), VDTYDG(β-D)ISV ... NO:169).

[0423] 19. A composition according to any one of the foregoing items, wherein said peptide comprises or is composed of an amino acid sequence selected from or consisting of the following: KCLAECDSIELSYGIK (SEQ ID NO: 141), CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEDISIELSYGIK (SEQ ID NO: 145), KPLAEIGDIELSYGIK (SEQ ID NO: 146), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KPLAEIDSIELTYGIK (SEQ ID NO: 149), KPLAEIDGIELSYGIK (SEQ ID NO: 150), KPLAEIDGIELTYGIK (SEQ ID NO: 151), KPLAEIGSIELSYGIK (SEQ ID NO: 152), KGLAEIDSIELSYGIK (SEQ ID NO: 153), KPLAEIDSIELSYGIK (SEQ ID NO: 145), KPLAEIDGIELSYGIK (SEQ ID NO: 146), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KPLAEIDSIELTYGIK (SEQ ID NO: 149), KPLAEIDGIELSYGIK (SEQ ID NO: 150), KPLAEIDGIELTYGIK (SEQ ID NO: 151), KPLAEIGSIELSYGIK (SEQ ID NO: 152), KGLAEIDSIELSYGIK (SEQ ID NO: 153), KPLAEIDSIELSYGIK (SEQ ID NO: 144), KPLAEIDSIELSYGIK (SEQ ID NO: 145), KPLAEIDSIELSYGIK (SEQ ID NO: 146), KPLAEIDSIELSYGIK (SEQ ID NO: 147), KPLAE NO:153), KPLAGIDSIGLSYGIK (SEQ ID NO:154), KCLAEIDSCELSYGIK (SEQ ID NO:155), and CFKPLAEIDSIEC (SEQ ID NO:156), or variants or fragments thereof.

[0424] 20. A composition according to any of the foregoing items, wherein the peptide comprises or consists of an amino acid sequence selected from or composed of the following: LAEIDSIELSYGIK (SEQ ID NO:170), AEIDSIELSYGIK (SEQ ID NO:171), EIDSIELSYGIK (SEQ ID NO:172), IDSIELSYGIK (SEQ ID NO:173), DSIELSYGIK (SEQ ID NO:174), SIELSYGIK (SEQ ID NO:175), IELSYGIK (SEQ ID NO:176), or variants or fragments thereof.

[0425] 21. A composition according to any of the foregoing items, wherein the peptide comprises or consists of an amino acid sequence selected from or composed of the following: KPLAEIDSIELSYGI (SEQ ID NO:179), KPLAEIDSIELSYG (SEQ ID NO:180), KPLAEIDSIELSY (SEQ ID NO:181), KPLAEIDSIELS (SEQ ID NO:182), KPLAEIDSIEL (SEQ ID NO:183), KPLAEIDSIE (SEQ ID NO:184), or a variant thereof.

[0426] 22. A composition according to any of the above items, wherein the peptide is a modified osteopontin peptide, wherein the RGD domain is deactivated.

[0427] 23. A composition according to any of the above items, wherein the RGD domain is mutated at one or more amino acids in the modified osteopontin peptide.

[0428] 24. A composition according to any of the above items, wherein the RGD domain is at least partially deleted in the modified osteopontin peptide.

[0429] 25. A composition according to any of the above items, wherein the RGD domain is substituted at one or more amino acids in the modified osteopontin peptide.

[0430] 26. A composition according to any of the above items, wherein the peptide comprises or is composed of the following: an amino acid sequence of VDTYDGDISVVYGLR (SEQ ID NO:1; FOL-005) or a fragment / variant thereof.

[0431] 27. A composition according to any of the above items, wherein the peptide comprises or is composed of the following: an amino acid sequence of KPLAEIDSIELSYGIK (SEQ ID NO:136,FOL-014) or a fragment / variant thereof.

[0432] 28. A composition according to any of the above items, wherein the peptide comprises or is composed of the amino acid sequence of VDVPNGDISLAYGLR (SEQ ID NO:69,FOL-004) or a fragment / variant thereof.

[0433] 29. A composition according to any of the foregoing items, wherein the peptide comprises less than 500 amino acids (e.g., less than 400, 350, 340, 330, 320, 310, 300, 290, 280, 270, 260, 250, 200, 150, 100, 50, 40, 30, 20, 15, 10 or fewer amino acids in length).

[0434] 30. A composition according to any one of the above items, wherein the variant comprises or consists of an amino acid sequence having at least 50% identity with the amino acid sequence of SEQ ID NO:1, more preferably having at least 60%, 70%, 80%, 85%, or 90% identity with the sequence, and most preferably having at least 95%, 96%, 97%, 98%, or 99% identity with the amino acid sequence.

[0435] 31. A composition according to any of the above items, wherein the variant comprises or consists of the following: an amino acid sequence of SEQ ID NO:1 or a fragment thereof, wherein one or more amino acids are conservatively substituted.

[0436] 32. A composition according to any of the above items, wherein the peptide is not naturally occurring.

[0437] 33. A composition according to any of the above items, wherein the peptide comprises or is composed of tandem repeats.

[0438] 34. A composition according to any of the above items, wherein the peptide is cyclic.

[0439] 35. A composition according to any one of the above items, wherein the peptide is glycosylated.

[0440] 36. A composition according to any of the foregoing items, wherein the peptide derivative is a peptide conjugated to a portion (such as a portion selected from polyethylene glycol (PEG), monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides).

[0441] 37. A composition according to any of the foregoing items, wherein the peptide derivative is modified by glycosylation or by polyethylene glycolation, amidation, esterification, acylation, acetylation and / or alkylation.

[0442] 38. A composition according to any of the above items, wherein the peptide derivative is fused to another polypeptide (such as a polypeptide selected from glutathione S-transferase (GST) and protein A) or fused to a tag peptide.

[0443] 39. A composition according to any one of the foregoing items, wherein the composition comprises at least 0.1% by weight of peptides, such as at least 0.5% by weight of peptides, such as at least 0.01% by weight of peptides, 1% by weight of peptides, such as at least 1.5% by weight of peptides, such as at least 2% by weight of peptides, such as at least 2.5% by weight of peptides, such as at least 3% by weight of peptides, such as at least 3.5% by weight of peptides, such as at least 6% by weight of peptides, such as at least 6.5% by weight of peptides, such as at least 7% by weight of peptides, such as at least 7.5% by weight of peptides, such as at least 8% by weight of peptides, such as at least 8.5% by weight of peptides, such as at least 9% by weight of peptides, such as at least 9.5% by weight of peptides, such as at least 10% by weight of peptides.

[0444] 40. A composition according to any one of the foregoing items, wherein the composition comprises not more than 2% by weight of peptides, such as not more than 5% by weight of peptides, such as not more than 10% by weight of peptides, such as not more than 15% by weight of peptides, such as not more than 20% by weight of peptides.

[0445] 41. A composition according to any of the foregoing items, wherein the composition comprises a peptide between 0.01 and 5 wt%, such as a peptide between 0.01 and 2 wt%, such as a peptide between 0.1 and 1 wt%, such as a peptide between 1 and 5 wt%, such as a peptide between 5 and 10 wt%, such as a peptide between 10 and 15 wt%, such as a peptide between 15 and 20 wt%.

[0446] 42. The composition according to any one of the above items, wherein the sugar is sugar.

[0447] 43. The composition according to any one of the above items, wherein the sugar has a melting temperature between 60 and 140°C.

[0448] 44. A composition according to any of the above items, wherein the sugar has a melting temperature between 60 and 65, such as between 65 and 70, such as between 70 and 75, such as between 75 and 80, such as between 80 and 85, such as between 85 and 90, such as between 90 and 95, such as between 95 and 100, such as between 100 and 105, such as between 105 and 110, such as between 110 and 115, such as between 115 and 120, such as between 120 and 125, such as between 125 and 130, such as between 130 and 135, such as between 135 and 140.

[0449] 45. A composition according to any one of the above items, wherein the sugar is sucrose.

[0450] 46. ​​A composition according to any one of the above items, wherein the sugar is mannitol.

[0451] 47. A composition according to any one of the above items, wherein the sugar is glucose.

[0452] 48. A composition according to any one of the above items, wherein the sugar is selected from maltose, trehalose, raffinose, maltotriose, stachyose, dextran, glucose, mannitol and sucrose.

[0453] 49. A composition according to any one of the foregoing items, wherein the composition comprises at least 0.1% by weight of sugar, such as at least 0.5% by weight of sugar, such as at least 1% by weight of sugar, such as at least 1.5% by weight of sugar, such as at least 2% by weight of sugar, such as at least 2.5% by weight of sugar, such as at least 3% by weight of sugar, such as at least 3.5% by weight of sugar, such as at least 6% by weight of sugar, such as at least 6.5% by weight of sugar, such as at least 7% by weight of sugar, such as at least 7.5% by weight of sugar, such as at least 8% by weight of sugar, such as at least 8.5% by weight of sugar, such as at least 9% by weight of sugar, such as at least 9.5% by weight of sugar, such as at least 10% by weight of sugar.

[0454] 50. A composition according to any one of the foregoing items, wherein the composition comprises not more than 2% by weight of sugar, such as not more than 5% by weight of sugar, such as not more than 10% by weight of sugar, such as not more than 15% by weight of sugar, such as not more than 20% by weight of sugar.

[0455] 51. A composition according to any one of the foregoing items, wherein the composition comprises between 0.01 and 5% by weight of sugar or modified sugar, such as between 0.01 and 2% by weight of sugar or modified sugar, such as between 0.1 and 2% by weight of sugar or modified sugar, such as between 0.1 and 1% by weight of sugar or modified sugar, such as between 1 and 5% by weight of sugar or modified sugar, such as between 5 and 10% by weight of sugar or modified sugar, such as between 10 and 15% by weight of sugar or modified sugar, such as between 15 and 20% by weight of sugar or modified sugar.

[0456] 52. A composition according to any one of the above items, wherein said lipid compound has a concentration of 6.5 and 10 (cal / cm³). 3 ) 1 / 2 The Hildebrand solubility coefficient between them.

[0457] 53. The composition according to any one of the above items, wherein the lipid is isopropyl myristate.

[0458] 54. A composition according to any of the above items, wherein the lipid is petrolatum and / or isopropyl myristate.

[0459] 55. A composition according to any one of the foregoing items, wherein the composition comprises glycerol or propylene glycol.

[0460] 56. The composition according to any one of the above items, wherein the lipid dissolves sebum.

[0461] 57. A composition according to any of the foregoing items, wherein the composition comprises at least 50% by weight of lipids, such as at least 55% by weight of lipids, such as at least 60% by weight of lipids, such as at least 65% by weight of lipids, such as at least 70% by weight of lipids, such as at least 75% by weight of lipids, such as at least 80% by weight of lipids, such as at least 85% by weight of lipids, such as at least 90% by weight of lipids, such as at least 95% by weight of lipids.

[0462] 58. A composition according to any of the foregoing items, wherein the composition comprises not more than 55% by weight of lipids, such as not more than 60% by weight of lipids, such as not more than 65% by weight of lipids, such as not more than 70% by weight of lipids, such as not more than 75% by weight of lipids, such as not more than 80% by weight of lipids, such as not more than 85% by weight of lipids, such as not more than 90% by weight of lipids, such as not more than 95% by weight of lipids.

[0463] 59. A composition according to any of the foregoing items, wherein the composition comprises between 40 and 99% by weight of lipids, such as between 40 and 60% by weight of lipids, such as between 50 and 60% by weight of lipids, such as between 60 and 70% by weight of lipids, such as between 70 and 80% by weight of lipids, such as between 80 and 90% by weight of lipids, such as between 90 and 99.95% by weight of lipids.

[0464] 60. A composition according to any one of the above items, wherein the composition further comprises a thickener.

[0465] 61. The composition according to any one of the above items, wherein the thickener is glyceryl behenate or carnauba wax.

[0466] 62. A composition according to any one of the above items, wherein the composition further comprises a surfactant.

[0467] 63. The composition according to any one of the above items, wherein the surfactant is sorbitol laurate.

[0468] 64. A composition according to any of the above items, wherein the surfactant is selected from sorbitol laurate, Span 80 and Brij 72.

[0469] 65. A composition according to any one of the foregoing items, wherein the surfactant is a sugar-based surfactant.

[0470] 66. The composition according to any one of the above items, wherein the sugar-based surfactant is selected from sucrose cocoate, sorbitol laurate, and polysorbate.

[0471] 67. The composition according to any one of the above items, wherein the sugar-based surfactant has an HLB value between 9 and 16.

[0472] 68. The composition according to any one of the above items, wherein the lipid is paraffin oil.

[0473] 69. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0474] a. 0.01-1% by weight of peptides or peptide derivatives;

[0475] b. 0.01-2% by weight of sugar or modified sugar;

[0476] c. 35-50% by weight of mineral oil; and

[0477] d. 40-60% by weight of isopropyl myristate.

[0478] 70. A composition according to any one of the above items, wherein the composition comprises 50% by weight of isopropyl myristate, 0.2% by weight of sorbitol laurate and 3% by weight of glyceryl behenate or 6% by weight of carnauba wax.

[0479] 71. A composition according to any one of the above items, wherein the composition comprises 40-60% by weight of isopropyl myristate, 2-6% by weight of sorbitol laurate and 2-6% by weight of behenate glyceryl ester.

[0480] 72. A composition according to any one of the above items, wherein the composition comprises 50% by weight of isopropyl myristate, 0.2% by weight of sorbitol laurate and 6% by weight of carnauba wax.

[0481] 73. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0482] a. 0.01-1% by weight of peptides or peptide derivatives;

[0483] b. 0.01-2% by weight of sugar or modified sugar;

[0484] c. 1-6% by weight of behenate glycerides;

[0485] d. 35-45% by weight of mineral oil;

[0486] e. 40-60% by weight of isopropyl myristate; and

[0487] f. 2-10% by weight of surfactants, such as sorbitol laurate.

[0488] 74. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0489] a. 0.01-1% by weight of peptides or peptide derivatives;

[0490] b. 0.01-2% by weight of sucrose, mannitol or glucose;

[0491] c. 1-8% by weight of glyceryl behenate or carnauba wax;

[0492] d. 35-45% by weight of mineral oil;

[0493] e. 40-60% by weight of isopropyl myristate; and

[0494] f. 2-10% by weight of surfactants, such as sorbitol laurate.

[0495] 75. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0496] a) 0.01-1% by weight of peptides or peptide derivatives;

[0497] b) 0.01-4% by weight of sugar or modified sugar;

[0498] c) 85-95% by weight of lipids; and optional

[0499] d) 2-10% by weight of surfactant.

[0500] 76. The composition according to any of the above items, wherein the lipid comprises isopropyl myristate, petrolatum, and glyceryl behenate.

[0501] 77. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: peptides; sucrose; glyceryl behenate; petrolatum; isopropyl myristate; and sorbitol laurate.

[0502] 78. A composition according to any of the above items, wherein the sugar is sucrose and the lipid is isopropyl myristate.

[0503] 79. The composition according to any one of the above items, wherein the composition further comprises petrolatum.

[0504] 80. A composition according to any one of the above items, wherein the composition further comprises glyceryl behenate.

[0505] 81. A composition according to any one of the above items, wherein the composition further comprises sorbitol laurate.

[0506] 82. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0507] a. 0.01-1% by weight of peptides or peptide derivatives;

[0508] b. 0.01-2% by weight of sucrose;

[0509] c. 1-6% by weight of behenate glycerides;

[0510] d. 35-45% by weight of mineral oil;

[0511] e. 40-60% by weight of isopropyl myristate; and

[0512] f. 2-10% by weight of dehydrated sorbitol lauryl ester.

[0513] 83. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0514] a. 0.01-1% by weight of peptides or peptide derivatives;

[0515] b. 0.01-1% by weight of sucrose;

[0516] c. 1-6% by weight of behenate glycerides;

[0517] d. 35-45% by weight of mineral oil;

[0518] e. 40-60% by weight of isopropyl myristate; and

[0519] f. 2-6% by weight of dehydrated sorbitol lauryl ester.

[0520] 84. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0521] a. 0.2% by weight of peptide or peptide derivative;

[0522] b. 0.4% by weight of sucrose;

[0523] c. 3% by weight of behenate glyceryl ester;

[0524] d.42.4% by weight of mineral resin;

[0525] e. 50% by weight of isopropyl myristate; and

[0526] f.4% by weight of dehydrated sorbitol lauryl ester.

[0527] 85. A composition according to any one of the foregoing items, wherein the composition comprises or is substantially composed of the following substances: about

[0528] a) 1% by weight of peptide;

[0529] b) 2% by weight of sucrose;

[0530] c) 95% by weight lipids; and optional

[0531] d) 2% by weight of dehydrated sorbitol lauryl ester.

[0532] 86. A composition according to any one of the above items, wherein the total percentage amount of said components does not exceed 100%.

[0533] 87. A composition according to any one of the above items, wherein the composition is substantially free of water.

[0534] 88. A composition according to any one of the above items, wherein the composition is in the form of an ointment, powder, spray, lotion, gel, foam, cream, cosmetic or shampoo.

[0535] 89. A composition according to any one of the above items, wherein the composition is capable of stimulating human hair.

[0536] 90. A composition according to any one of the above items, wherein the composition is capable of stimulating existing hair follicles.

[0537] 91. A composition according to any one of the foregoing items, wherein the composition is capable of inducing the formation of new hair follicles or stem cells for generating them.

[0538] 92. A composition according to any one of the above items, wherein the composition further comprises an active pharmaceutical ingredient.

[0539] 93. The composition according to any one of the above items, wherein the composition further comprises minoxidil.

[0540] 94. A composition according to any one of the above items, wherein the composition further comprises finasteride.

[0541] 95. A composition according to any one of the above items, wherein the composition further comprises minoxidil and finasteride.

[0542] 96. A composition according to any one of the above items, wherein the composition is a pharmaceutical composition.

[0543] 97. A composition according to any one of the above items, used as a medicine.

[0544] 98. A composition according to any one of the above items, used for treating dermatological conditions.

[0545] 99. The composition used in Item 98, wherein the dermatological condition is selected from psoriasis, atopic dermatitis, eczema, precancerous conditions, and skin infections.

[0546] 100. A composition according to any one of the above items, used for the treatment or prevention of diseases or conditions related to hair loss.

[0547] 101. A composition according to any one of the above items, used to stimulate hair growth in mammals.

[0548] 102. A composition according to any one of the above items, used to stimulate existing hair follicles.

[0549] 103. A composition according to any one of the above items, used to induce the growth of new hair follicles or stem cells for generating them.

[0550] 104. A composition according to any one of the above items, used for the treatment or prevention of hair loss.

[0551] 105. The composition according to any of the above items, wherein the hair loss is related to the loss of hair in the early stages of growth.

[0552] 106. The composition used in any of the above items, wherein the hair loss is related to the loss of telogen effluvium hair.

[0553] 107. The composition used according to any of the above items, wherein the hair loss is selected from:

[0554] a. Androgenetic alopecia (also known as alopecia areata, male pattern baldness, male pattern baldness, or female pattern baldness);

[0555] b. Traction alopecia;

[0556] c. Regenerative phase hair loss;

[0557] d. Tertiary regrowth;

[0558] e. Alopecia areata;

[0559] f. Complete baldness;

[0560] g. Alopecia areata;

[0561] h. Hair removal;

[0562] i. Mucin-related alopecia;

[0563] j. Tumor-induced alopecia;

[0564] k. Scarring alopecia; and

[0565] l. Scarring alopecia.

[0566] 108. The composition used in any of the above items, wherein the hair loss is androgenetic alopecia.

[0567] 109. The composition used in any of the above items, wherein the hair loss is anaplastic alopecia.

[0568] 110. The composition used in any of the above items, wherein the hair loss is induced by radiotherapy and / or chemotherapy agents.

[0569] 111. The composition used in any of the above items, wherein the mammal is selected from humans, dogs, cats and horses.

[0570] 112. The use of a compound according to any of the above items, wherein said use is for cosmetic purposes.

[0571] 113. The use of a compound according to any one of the foregoing items for stimulating hair growth in mammals, wherein said use is for cosmetic purposes.

[0572] 114. The use of any compound according to any of the above items for the treatment or prevention of hair loss.

[0573] 115. The use of the compound according to any of the above items, wherein the hair loss is related to a receding hairline.

[0574] 116. The use of the compound according to any of the above items, wherein the hair loss is related to a thinning hairline.

[0575] 117. Use of a compound according to any of the above items for promoting the growth of beard, eyelashes or eyebrows.

[0576] 118. The use of the compound according to any of the above items, wherein the mammal is a human.

[0577] 119. A method for stimulating hair growth, the method comprising topically applying to a patient in need an effective amount of a composition or pharmaceutical composition of any of the above items.

[0578] 120. A method for treating hair loss, the method comprising topically applying to a patient in need an effective amount of a composition or pharmaceutical composition of any of the above items.

[0579] 121. A method for topically delivering a composition according to any one of the above items to a patient in need, the method comprising applying an effective amount of the composition according to any one of the above items to a topical application site of the individual.

[0580] 122. A method for treating a dermatological condition, the method comprising topically applying to a patient in need an effective amount of a composition or pharmaceutical composition of any of the above items.

[0581] 123. The method according to any one of items 119-122, wherein the patient is a person.

[0582] 124. The method according to any one of items 119-122, wherein the topical application site is on the individual's skin.

[0583] 125. The method according to any one of items 119-122, wherein the topical application site is on the patient's tissue.

[0584] 126. Use of the composition according to any one of the above items in the preparation of a medicament, wherein the medicament is used to treat or prevent diseases or conditions related to hair loss.

[0585] 127. Use of the composition according to any one of the above items in the preparation of a pharmaceutical product, wherein the pharmaceutical product is used to treat dermatological conditions.

[0586] 128. A method for preparing a composition according to any one of the above items, the method comprising the steps of:

[0587] a) Mix the peptide with sugar;

[0588] b) Freeze-dry the mixture of a);

[0589] c) Mix b) with lipids and surfactants;

[0590] d) Grind the mixture from c); and

[0591] e) Optionally, the mixture of d) can be mixed with lipids and thickeners.

[0592] 129. The method according to item 128, wherein the lipid is isopropyl myristate.

[0593] 130. The method according to item 128, wherein the surfactant is dehydrated sorbitol laurate. Example

[0594] Example 1. Solubility and stability test of FOL-005.

[0595] The most promising local delivery route for FOL-005 is the sebum route. The aim of this study was to determine the solubility and compatibility of FOL-005 in potential excipients and artificial sebum.

[0596] Materials and methods

[0597] Table 1. Chemical substances used for solubility and compatibility testing.

[0598]

[0599] Table 2. Chemical substances used in the preparation of artificial sebum.

[0600]

[0601]

[0602] result

[0603] Solubility of FOL-005 in carrier excipients and artificial sebum

[0604] The solubility of FOL-005 in the medium excipient at room temperature and in artificial sebum at 37°C was tested. The test was performed by adding 0.1% (w / w) of FOL-005 and 99.90% of the excipient. If FOL-005 did not dissolve, double the amount of excipient was added. The mixture was stirred with a magnetic stirrer for 2 hours. If particles of FOL-005 remained, the mixture was centrifuged at 14,000 rpm or 10,000 rpm (artificial sebum) for 5 minutes, and the supernatant was collected for analysis.

[0605] The concentration of FOL-005 was determined by HPLC analysis in all batches.

[0606] Table 3a. Composition of excipient batches containing FOL-005 prepared for solubility testing.

[0607]

[0608]

[0609]

[0610] Table 3b. Results of solubility tests of FOL-005 (sodium salt) in media excipients and artificial sebum.

[0611]

[0612] in conclusion

[0613] Solubility of FOL-005 (sodium salt) at room temperature:

[0614] • Solubility in cithrol-containing paraffin oils: 0.01 mg / ml

[0615] • Solubility in glycerol: 0.31 mg / ml

[0616] Solubility in propylene glycol: 0.16 mg / ml

[0617] • Solubility in sugar solutions of glucose, mannitol, and sucrose > 1 mg / ml

[0618] • Solubility in PBS buffer >1 mg / ml

[0619] • Solubility in artificial sebum at 37°C: 0.27 mg / ml

[0620] FOL-005 (sodium salt) in sugar solution exhibits good chemical stability in aqueous solutions containing glucose and sucrose when stored at 2-8°C for 7 weeks. No change in FOL-005 content was observed in aqueous solutions containing 10% glucose or 10% sucrose after 7 weeks of storage at 2-8°C. However, when stored at room temperature, the FOL-005 content in a 10% glucose solution decreased from 0.9 mg / ml to 0.7 mg / ml, and the FOL-005 content in a 10% sucrose solution decreased from 0.9 mg / ml to 0.04 mg / ml.

[0621] Compared to sucrose and glucose, FOL-005 exhibited poorer chemical stability in aqueous solutions containing mannitol when stored at 2–8°C for 7 weeks. The FOL-005 content in a 10% mannitol solution decreased from 0.9 mg / ml to 0.8 mg / ml after 7 weeks of storage at 2–8°C, and further decreased from 0.8 mg / ml to 0.2 mg / ml after 7 weeks of storage at room temperature.

[0622] FOL-005 exhibits good chemical stability in glycerol. No change in FOL-005 content was observed when stored at 2-8°C for 7 weeks, but the FOL-005 content decreased from 0.3 mg / ml to 0.2 mg / ml when stored at room temperature for 7 weeks.

[0623] The chemical stability of FOL-005 was found to be poor in propylene glycol. When stored at 2-8°C for 7 weeks, the FOL-005 content decreased from 0.16 mg / ml to 0.15 mg / ml, and when stored at room temperature for 7 weeks, it decreased from 1.6 mg / ml to 0.07 mg / ml.

[0624] The solubility of FOL-005 in 10% glucose solution was determined to be greater than 4.38% (w / w).

[0625] Example 2. Stability test of FOL-005.

[0626] Materials and methods

[0627] Preparation of FOL-005 suspension studied in stability screening studies

[0628] Preparation method - suspension:

[0629] • Pour Aerosil into a beaker

[0630] Add paraffin oil to a beaker and mix carefully.

[0631] Stir until a uniform, viscous gel is formed.

[0632] Heat to 70°C while stirring.

[0633] Homogenize at 70°C until a homogeneous gel is obtained.

[0634] Cool to room temperature

[0635] • Added isopropyl myristate

[0636] Stir until a homogeneous suspension is formed.

[0637] • Place FOL-005 sucrose granules and dehydrated sorbitol laurate into a new beaker.

[0638] • Add the suspension to a beaker containing FOL-005 sucrose granules and dehydrated sorbitol laurate.

[0639] Homogenize at 70°C until a homogeneous suspension is formed.

[0640] result

[0641] Table 4a. Results of stability tests of FOL-005 (sodium salt) in three suspensions.

[0642]

[0643]

[0644] *FOL-005 sucrose 1:1 contains 45.8% FOL-005

[0645] 1 Different sample preparation steps in the analytical methods were evaluated. The data presented in the table are from the analysis that yielded the highest recovery rate.

[0646] 2 The relevant substances were not detected due to the small sample size (0.25g sample / 25ml solution).

[0647] 3 Sample preparation: tetrahydrofuran and water

[0648] 4 Sample preparation: Span, water, and acetonitrile

[0649] in conclusion

[0650] Suspension:

[0651] • When stored at 25°C, the recovery rate of FOL-005 in S3 is low. However, it increases when the analytical sampling preparation is improved.

[0652] • No β-ASP (a degradation product of FOL-005) was detected in the three suspensions after storage at 25°C for 4 and 10 weeks and after storage at 30°C for 4 weeks.

[0653] Small amounts of degradation products were observed in S2 and S3 with an RRT of 0.98, while higher amounts were observed in S1.

[0654] The conclusion is that the chemical stability of FOL-005 appears promising in S2 and S3.

[0655] Tables 4b-d show the purity of FOL-005. The data is also shown in Figures 1-3.

[0656] Table 4b. Purity of FOL-005 at different pH values.

[0657]

[0658]

[0659] Table 4c. Purity of FOL-005 under different conditions of isopropyl myristate (IPM).

[0660]

[0661] Table 4d. Purity of FOL-005 at different temperatures with or without sucrose.

[0662]

[0663] in conclusion

[0664] It was confirmed that FOL-005 degrades at various pH values, while degradation is very limited under anhydrous conditions. Furthermore, dried IPM resulted in less degradation of FOL-005 at 25 and 30 °C compared to undried IPM, and sucrose particles resulted in less degradation of FOL-005 at 25 and 30 °C compared to Na salt.

[0665] Example 3. Low-pressure freeze-drying of FOL-005 with mannitol

[0666] The possibility of preparing FOL-005 (acetate) particles by freeze-drying was explored, and the compatibility between the peptide and the prototype mediator was tested.

[0667] Materials and methods

[0668] The following chemicals were used in this study:

[0669] Mannitol, sodium hydroxide, HCl (37%), API, FOL-005 Ac-salt, β-Asp FOL-005 (degradation product), deionized water, paraffin oil, glycerol, propylene glycol, Cithrol TM DPHS, Tween 60 BergaBest MCT oil 60 / 40.

[0670] Preparation of solutions for freeze-drying tests

[0671] The mixtures given in Table 5a were prepared for freeze-drying. The mixtures were dispensed into 2 ml glass vials. The number of vials for each mixture is given in the table below. Each vial contained approximately 2 mg of FOL-005.

[0672] Table 5a. Preparation of composition mixtures for freeze-drying

[0673]

[0674]

[0675] *pH tends to decrease over time. The pH was determined to be 7.1 prior to freeze-drying.

[0676] freeze-drying conditions

[0677] First, store the tubular bottles at -35°C for 2 hours, and then quickly transfer them to a freeze dryer. Freeze-dry the tubular bottles under vacuum at -55°C for 24 hours.

[0678] Preparation of formulations for compatibility testing

[0679] The compatibility between FOL-005 powder and the carrier excipient was tested in pure paraffin oil and in a potential formulation. The composition of the formulation is presented in Table 5b.

[0680] Table 5b. Formulations used for compatibility testing of freeze-dried powders.

[0681]

[0682] Determination methods

[0683] The test items were analyzed by HPLC using the HPLC-UV determination method for FOL-005 in the formulation. The concentration of FOL-005 was determined, and β-asp FOL-005 was also determined.

[0684] result

[0685] Tables 6a-c show the HPLC analysis results of the freeze-dried powder of FOL-005.

[0686] Table 6a. HPLC analysis results of freeze-dried powders of FOL-005 (acetate) and mannitol, preliminary analysis and after storage at 2-8°C and room temperature for 4 weeks.

[0687]

[0688] Table 6b. HPLC analysis results of freeze-dried powders of FOL-005 (acetate) and mannitol in paraffin oil (formulation A), preliminary analysis and after storage at 2-8°C and room temperature for 4 weeks.

[0689]

[0690] Table 6c. Compatibility test results of FOL-005 (acetate) and mannitol in freeze-dried powder of formulation B, preliminary analysis and after storage at 2-8°C and room temperature for 4 weeks.

[0691]

[0692] in conclusion

[0693] The acetate of FOL-005 was successfully freeze-dried using mannitol as a stabilizer. Two different pH values ​​(3.5 and 7.1) of the low-pressure freeze-dried mixture and two different ratios (1:1 and 2:1) between FOL-005 and mannitol were tested. No differences in the chemical stability of the freeze-dried powders due to pH or ratio were observed when stored at 2–8°C for 4 weeks.

[0694] When stored at 2-8°C for 4 weeks, the freeze-dried powders of FOL-005 and mannitol are chemically stable. When stored at room temperature for 4 weeks, an increase of 5% to 6% in the total amount of related substances can be observed.

[0695] It was found that the freeze-dried powder of FOL-005 was chemically stable when dispersed in formulation A containing 100% paraffin oil and stored at 2-8°C and room temperature for 4 weeks.

[0696] The formulation B, containing paraffin oil (16%), glycerol (45%), propylene glycol (30%), Cithrol (3%), Tween 60 (3%), and BergaBest MCT oil (4%), exhibited poor chemical stability. When stored at 2–8°C for 4 weeks, no change in FOL-005 content was observed, but an increase in the amount of related substances was observed from 7.5% to 10%, along with differences in the chromatograms of these related substances. When stored at room temperature for 4 weeks, the FOL-005 content decreased from 0.07% to 0.03%, and the total amount of related substances increased from 7.5% to 50.8%.

[0697] Example 4: Thickening of the placebo formulation.

[0698] In this study, we investigated the potential benefits of forming a viscous formulation using petrolatum and a high concentration of isopropyl myristate.

[0699] Materials and methods

[0700] Petrolatum / isopropyl myristate preparation

[0701] The petrolatum / isopropyl myristate mixture was visually inspected to determine whether these two components could be used to prepare formulations with high viscosity. The composition of the prepared formulations is shown in Table 7.

[0702] Table 7. Formulation composition % (w / w)

[0703] Ingredients: ISM17165, ISM17166, ISM17167, ISM17168, Isopropyl Myristate 50, 30, 20, 10, Petrolatum 50, 70, 80, 90, Total 100, 100, 100, 100, 100 surface

[0704] Addition of thickener

[0705] To increase the viscosity of the petrolatum / isopropyl myristate formulation, a thickener was added and the formulation was visually inspected. The formulation composition is shown in Table 8.

[0706] Table 8. Formulation composition % (w / w)

[0707]

[0708] Placebo formulation containing sucrose particles

[0709] Centrifugation was performed on formulations containing sucrose particles to study particle sedimentation. 2% (w / w) sucrose was added to ISM17167-ISM17172 in Tables 7 and 8, and 1% (w / w) sucrose was added to ISM17166. The formulations were mixed, then centrifuged at 1000 rpm for 3 minutes and observed visually.

[0710] Formulations containing FOL-005 particles

[0711] Particle sedimentation in selected formulations was also studied by analyzing the FOL-005 content at different locations in test tubes containing the centrifuged formulation. 0.2% (w / w) FOL-005 was added to the placebo formulation according to Table 9, and the formulation was then mixed for 2 hours by magnetic stirring. Each formulation was dispensed into two Eppendorf tubes, one of which was centrifuged at 1000 rpm for 3 minutes. The tubes were stored in a refrigerator until the FOL-005 content was determined. Analysis was performed by high-performance liquid chromatography (RP-HPLC) and ultraviolet detection (UV). The compounds were monitored at 220 nm. Unidentified related substances were quantified as % relative area. FOL-005 salt (sodium) was used as an external standard.

[0712] Table 9. Formulation Composition % (w / w)

[0713]

[0714]

[0715] result

[0716] Petrolatum / isopropyl myristate preparation

[0717] As shown in Table 10, it is impossible to produce good viscous formulations using only isopropyl myristate and petrolatum. Formulations containing 50% (w / w) or less petrolatum have low viscosity, while formulations containing 70% (w / w) or more petrolatum show a tendency for phase separation.

[0718] Table 10. Formulation characteristics.

[0719] ISM17165, ISM17166, ISM17167, ISM17168, Isopropyl Myristate 50, 30, 20, 10, Petrolatum 50, 70, 80, 90, Viscosity: Low, Medium, Medium-High; Appearance: Good; Separation Trend: Good; Separation Trend: Good; Separation Trend: Good; Separation Trend: Good; Separation Trend: Good surface

[0720] Addition of thickener

[0721] Thickeners are added to the formulation to increase viscosity. Additionally, 0.2% (w / w) of dehydrated sorbitol laurate is added to the formulation because it has a stabilizing effect on FOL-005 particles. As seen in Table 11, the addition of carnauba wax and glyceryl behenate has a positive effect on the formulation. By adding these components, formulations with medium to high viscosity can be created.

[0722] Table 11. Formulation characteristics.

[0723]

[0724] in conclusion

[0725] The mixture of isopropyl myristate and petrolatum was found to have low viscosity or a tendency to phase separation. However, by adding glyceryl behenate or carnauba wax, the formulation showed a good appearance and medium viscosity.

[0726] Particle sedimentation in formulations containing carnauba wax or glyceryl behenate was investigated, and FOL-005 did not appear to precipitate in these formulations. Therefore, petrolatum formulations containing 50% (w / w) isopropyl myristate, 0.2% (w / w) sorbitol laurate, and 3% (w / w) glyceryl behenate or 6% (w / w) carnauba wax appear to be promising alternatives to FOL-005 particle suspensions.

[0727] Example 5. In vitro testing of FOL-005 granule formulation

[0728] Materials and methods

[0729] The compositions for in vitro testing are given in Table 12.

[0730] Table 12a. Compositions tested in vitro in Experiment 1.

[0731]

[0732] Table 12b. Compositions tested in vitro in Experiment 2.

[0733]

[0734]

[0735] skin membrane

[0736] Prepare a full-thickness membrane for pig ears as follows:

[0737] Rinse the pig ears with lukewarm water to remove dirt, blood, and wax. Dry the ears with tissue paper (Kleenex) and remove the bristles with a beard trimmer. Cut the inner ear skin into pieces approximately 600-700 μm thick using a scalpel and flush the membrane from the cut skin pieces. Determine the thickness of the skin membrane using a micrometer. The skin membranes should be prepared one day before the in vitro experiment and should be stored covered with aluminum foil in the refrigerator until use. Place the skin membranes in a diffusion cell apparatus and hydrate for 1 hour at the temperature selected for the experiment. After 1 hour of hydration, administer 100 mg of each formulation to each cell. Massage the formulation using a small metal spoon, the top of which is "wrapped" in a paraffin membrane and a glass rod. At the end of the experiment, clean the skin samples with the top and solvent / fluid to remove excess formulation. Use anhydrous propylene glycol because the solubility of FOL-005 in propylene glycol is limited (0.16 mg / ml at room temperature) and it does not interact with sebum in the same way as nonpolar solvents.

[0738] In vitro experimental design

[0739] In vitro drug permeation experiments were performed as follows: a 9-cell Franz grid apparatus (Crown Glass Company, Inc.) was used, with each grid volume approximately 7 ml. A full-thickness skin membrane was used for the 48-hour experimental period, and samples were taken at the end of the experiment. The temperature in the Franz grid was maintained at 32°C. Two administrations were performed at 0 and 24 hours. At each administration, 100 mg of the formulation was applied and the tissue was gently massaged for 3 minutes using a glass rod. At the end of the experiment, skin samples were preserved for analysis. The composition of the formulation used in the ex vivo drug permeation experiments is given in Tables 13a and 13b.

[0740] Table 13a. Experimental design for ex vivo drug permeation experiment No. 1.

[0741]

[0742] Table 13b. Experimental design for ex vivo drug permeation experiment No. 2.

[0743]

[0744] At the end of the experiment, clean the skin membrane using the top and liquid. Wash each cell five times with propylene glycol. Collect the recovered material in tubular flasks. Remove the membrane from the apparatus and freeze it rapidly.

[0745] Maldi mass spectrometry (MSI)

[0746] Samples from in vitro experiments were analyzed using MALDI mass spectrometry imaging. An analytical method was developed, and the content of FOL-005 and its distribution in the skin were investigated.

[0747] The detection of FOL-005 in treated porcine inner ear skin samples using MALDI FTICR MS imaging was evaluated and optimized. Four different MALDI matrices (2,5-dihydroxybenzoic acid, α-cyano-4-hydroxycinnamic acid, 9-aminoacridine, and 1,5-diaminonaphthalene) were evaluated, and solvent optimization was performed to find the optimal matrix.

[0748] Mass spectrometric imaging analysis of porcine inner ear skin biopsy samples was performed using a developed MALDI-FTICR method to evaluate frozen skin samples (n=1 for each treatment) and placebo samples (n=1 for each placebo). Briefly, frozen skin samples were sectioned in the hair follicle plane, and one section from each sample was analyzed by 7T-MALDI-FTICR imaging to determine the biodistribution of FOL-005. Adjacent sections were stained with hematoxylin and eosin, and the specific location of the compound was confirmed by combining this with the molecular distribution of FOL-005. Based on the generated MALDI images, the compound concentration in each histological region was calculated using quantitative mass spectrometry (QMSI).

[0749] result

[0750] Analysis of the applied formulation

[0751] The applied formulation was analyzed using high-performance liquid chromatography (RP-HPLC) and ultraviolet (UV) detection. Compounds were monitored at 220 nm. Unidentified related substances were quantified as % relative area. FOL-005 salt (sodium) was used as an external standard.

[0752] Experiment No. 1

[0753] The FOL-005 content was found to be 1.33% (w / w) in ISM17209 and 1.13% (w / w) in ISM17216. The total related substances were 3.30% and 3.39% in ISM17209 and ISM17216, respectively. The measured particle sizes of the two formulations were approximately the same, with the average sizes of FOL-005 / sodium and FOL-005 / sucrose particles being 7.2 μm and 8.4 μm, respectively.

[0754] Experiment No. 2

[0755] The FOL-005 content was found to be 1.35% (w / w) in ISM18097 and 0.47% (w / w) in ISM18098. The total related substances were 1.65% and 1.87% in ISM18097 and ISM18098, respectively. The measured particle sizes of the two formulations were approximately the same, with the average sizes of FOL-005 / sodium and FOL-005 / sucrose particles being 7.2 μm and 8.4 μm, respectively.

[0756] In vitro experiments

[0757] The preferred MALDI matrix is ​​DHB 40 mg / mL methanol / water and 0.1% TFA (v / v). Detection of FOL-005 was also confirmed in treated skin sections, with no interfering peaks detected from control tissues.

[0758] Experiment No. 1

[0759] FOL-005 was detected in both the epidermis and dermis of samples treated with FOL-005 / sucrose suspension and FOL-005 / Na suspension. Furthermore, FOL-005 was detected in the hair follicles of the treated skin.

[0760] FOL-005 was detected in all treated skin types, while no signal was observed in placebo-treated samples. FOL-005 was primarily detected in the epidermis, where a decreasing gradient was observed from the epidermis to the dermis. This indicates that FOL-005 was transported via the transepidermal transport pathway in this experiment. However, some signs of transfollicular penetration were also observed in some hair follicles with a greater signal intensity than the surrounding dermis. Strong heterogeneity between molecular distribution and quantification was observed in both FOL-005 / sucrose and FOL-005 / Na-treated samples. The penetration depth of FOL-005 in each tissue was calculated as the maximum distance from the surface where FOL-005 was detected.

[0761] Furthermore, the concentrations of FOL-005 in the tissues were recorded as epidermal concentration, dermal concentration, and total concentration. The penetration depth and tissue concentration of FOL-005 are shown in Table 14. Despite heterogeneity and high variability, slightly greater FOL-005 accumulation was observed in FOL-005 / sucrose-treated skin (71.4 ± 34.4 μg / g) compared to FOL-005 / Na-treated skin (35.7 ± 24.1 μg / g). However, no difference in penetration depth was detected between the FOL-005 / sucrose suspension and the FOL-005 / Na suspension.

[0762] Table 14. Quantification of FOL-005 in treated skin samples.

[0763]

[0764] The quantification of FOL-005 in hair follicles was determined, and the results are presented in Table 15. Skin samples treated with FOL-005 / sucrose suspension had a greater percentage of hair follicles presenting FOL-005 (56%) compared to skin samples treated with FOL-005 / Na suspension (21%). The depth of hair follicles presenting FOL-005 in skin biopsy tissue treated with sucrose suspension (0.48 ± 0.46 mm) appeared to be greater than that in skin biopsy tissue treated with Na salt suspension (0.15 ± 0.16 mm).

[0765] Table 15. Quantification of FOL-005 in hair follicles.

[0766]

[0767] * The "nd" value is considered as "0" in the average concentration calculation.

[0768] The results indicate that the FOL-005 / sucrose granule formulation exhibits superior penetration properties compared to the FOL-005 / sucrose granule formulation. The observed differences may be due to variations in particle composition, with one of the applied formulations containing granules of both FOL-005 and sucrose, while the other formulation contained only FOL-005 granules. The measured particle sizes of the two formulations were approximately the same, with the average sizes of FOL-005 / sodium and FOL-005 / sucrose granules being 7.2 μm and 8.4 μm, respectively. However, other potentially influential differences exist between the formulations. The amount of sorbitol laurate differs between the formulations, with the formulation containing FOL-005 / sucrose granules containing 4% sorbitol laurate and the formulation containing FOL-005 / sodium granules containing 2% sorbitol laurate.

[0769] Experiment No. 2

[0770] FOL-005 was detected weakly and heterogeneously in the epidermis and / or deep dermis of tissues treated with formulation 18098. A stronger detection was observed in pig ear samples treated with formulation 18097, with similar distribution in both the epidermis and deep dermis. Furthermore, passive diffusion from the epidermis to the dermis was observed. Dermal penetration was quantified at approximately 530 μm (calculated as 51.3% with high biological variability).

[0771] The transfollicular pathway was particularly prominent in some tissues. In these tissues, the overall concentration of FOL-005 was quantified as 144.0 μg / g tissue, with low biological variability calculated at 8.1%.

[0772]

[0773]

[0774] BLOQ lower limit of quantification = 53.7 μg / g

[0775] Figure 4 shows the superposition of hematoxylin and eosin between adjacent sections and the distribution of FOL-005 molecules in tissue samples treated with FOL-005 / sucrose formulation.

[0776] in conclusion

[0777] Experiment No. 1

[0778] FOL-005 was successfully transported into the tissue. Differences were detected between tissues treated with FOL-005 / sucrose granules and tissues treated with FOL-005 / sodium granules. FOL-005 accumulated more in tissues treated with FOL-005 / sucrose compared to tissues treated with FOL-005 / sodium granules. The mean dermal concentrations of FOL-005 in the skin were 71.4 ± 34.4 μg / g and 35.7 ± 24.1 μg / g, respectively, for tissues treated with FOL-005 / sucrose and FOL-005 / sodium granules. FOL-005 was found in hair follicles in all treated tissues. A larger proportion of hair follicles (56%) in tissues treated with FOL-005 / sucrose granules were found to contain FOL-005 compared to tissues treated with FOL-005 / sodium granules (21%). Similarly, compared to tissue treated with FOL-005 / sodium particles (0.15±0.16 mm), the average depth of hair follicles exhibiting FOL-005 in tissue treated with FOL-005 / sucrose particles was greater (0.48±0.46 mm). These results indicate that FOL-005 / sucrose particles possess superior penetration properties compared to FOL-005 / sodium particles.

[0779] Experiment No. 2

[0780] FOL-005 was successfully delivered to the tissues. Differences were detected between tissues treated with the FOL-005 / sucrose formulation and tissues treated with the FOL-005 / sucrose suspension. Greater accumulation of FOL-005 was observed in tissues treated with the FOL-005 / sucrose suspension compared to tissues treated with the FOL-005 / sucrose formulation. This is at least partially explained by the lower concentration of FOL-005 in the formulation compared to the suspension.

[0781] Passive diffusion from the epidermis to the dermis was observed. The transfollicular pathway was particularly prominent in some tissues.

[0782] The data is shown in Figure 4.

[0783] Example 6. In vivo testing

[0784] This study aimed to evaluate the hair growth promoting efficacy of FOL-005 in a C57BL / 6 mouse model via topical application. Male C57BL / 6 mice in the telogen effluvium (resting phase) of the hair growth cycle were used. The hair on the backs of the animals was shaved, and the area was treated with a topical formulation of FOL-005, a placebo, or 5% commercially available minoxidil.

[0785] Materials and methods

[0786] Apply 50 μL / cm to the shaved skin on the back of the animals in each group. 2 Three formulations of FOL-005 (high dose - 0.5%, medium dose - 0.05%, and low dose - 0.005%) were screened against placebo for their hair growth-promoting efficacy. The administration regimen was 4 weeks (5 days / week), followed by a 1-week observation period. During the study, skin color changes from pink skin (terminal growth phase) to black skin (initial growth phase) and the appearance of new hair regrowth were observed in all animals. At the end of the observation period, the FOL-005 formulations were observed to induce hair growth in a dose-responsive manner. Faster induction of initial growth was observed at the high dose (3 / 7 animals), followed by the medium dose (2 / 7 animals) and the low dose (1 / 7 animals). Hair growth was observed at the high dose (3 / 7 animals) and the medium dose (1 / 7 animals). No hair growth was observed at the low dose. Visible melanin production was also observed in the shed skin of 3 / 7, 2 / 7, and 1 / 7 animals at the high, medium, and low doses, respectively.

[0787] Minoxidil solution (5%) was used as a control and applied topically (50 μL / cm). 2 The treatment was applied to shaved skin on the backs of mice. The administration regimen was twice daily for 4 weeks, followed by a 1-week observation period. Initial growth induction, followed by hair regrowth, was observed in 4 / 5 of the animals in this group. Visible melanin production was also observed in the shaved skin of 4 / 5 of the animals.

[0788] in conclusion

[0789] All three topical formulations of FOL-005 (high, medium, and low doses) exhibited hair growth promoting efficacy in a dose-dependent manner, with the high dose (0.5%) showing the highest hair growth promoting efficacy, followed by the medium dose (0.05%), and then the low dose (0.005%).

[0790] The data is shown in Figure 5.

[0791] Example 7. Preparation method

[0792] In short, the preparation process is as follows:

[0793] Sodium FOL-005 was freeze-dried together with sucrose. The freeze-dried particles were then mixed with dried isopropyl myristate and sorbitol laurate, followed by a ball milling step.

[0794] Three excipients (sorbitol laurate, glyceryl behenate, and petrolatum) were added to the reactor at ambient temperature. The reactor was equipped with a stirrer. The excipients were mixed at room temperature until a homogeneous viscous gel was formed. The reactor was then heated to 75°C with stirring and then cooled to room temperature. Subsequently, a ball-milled suspension of FOL-005 / sucrose-isopropyl myristate was added to the reactor, and the mixture was stirred until a homogeneous mixture was obtained.

[0795] Example 8. A composition containing peptides

[0796] In this study, compositions containing a number of representative peptides (see Table 16) were prepared. Furthermore, the compositions were stored at 20°C for 4 weeks to investigate the stability of the peptides within the compositions.

[0797] Table 16. Peptides.

[0798]

[0799] preparation

[0800] Each peptide was lyophilized with sucrose at a w / w ratio of 2:1 (sucrose / peptide) according to standard low-pressure lyophilization methods. Span20 was mixed with IPM to obtain a 4% (w / w) homogeneous solution.

[0801] Peptide-sucrose was added to a Span20-IPM mixture to obtain a suspension with a peptide content of 0.4%. The peptide-sucrose particles were micronized in the Span20-IPM suspension using a standardized wet bead milling method.

[0802] The ointment base was prepared by mixing 89.5% petrolatum, 4.2% Span20, and 6.3% glyceryl behenate (w / w%). The mixture was heated to 75°C while stirring. Stirring was continued until the glyceryl behenate dissolved. The ointment base was then cooled to room temperature with gentle stirring.

[0803] Once the ointment base has cooled to room temperature, it is added to a separate peptide suspension to obtain an ointment with a peptide concentration of 0.2%. The mixture is stirred at ambient temperature for 2 hours. The total composition is given in Table 17.

[0804] Table 17. Overall Components.

[0805]

[0806]

[0807] Stability Study

[0808] Samples of the individual formulations were stored at 20°C. Additionally, PBS solutions of oxytocin and FOL-004 were prepared separately and stored at 20°C.

[0809] Peptide purity in ointments and PBS solutions was analyzed using standard HPLC-UV-DA methods when samples were freshly prepared (time 0) and at 1, 2, and 4 weeks later. The data are shown in Figure 6.

[0810] sequence

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819] sequence list <110> Fuli Kam Co., Ltd. <120> Peptides for treating diabetes <130> P4428EP00 <160> 187 <170> PatentIn version 3.5 <210> 1 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> Peptide, FOL-005 <400> 1Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 2 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 2Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Ser1 5 10 15 <210> 3 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> Peptide, FOL-025 <400> 3Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu1 5 10 <210> 4 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 4Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 5 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 5Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 10 <210> 6 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222>(1)..(13) <223> Peptide, FOL-024 <400> 6Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly1 5 10 <210> 7 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 7Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu1 5 10 <210> 8 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 8Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 9 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 9Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 10 <210> 10 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 10Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr1 5 10 <210> 11 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 11Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly1 5 10 <210> 12 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 12Thr Tyr Asp GlyAsp Ile Ser Val Val Tyr Gly Leu1 5 10 <210> 13 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 13Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 14 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 14Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 10 <210> 15 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 15Val Asp Thr Tyr Asp Gly Asp Ile Ser Val Val1 5 10 <210> 16 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 16Asp Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr1 5 10 <210> 17 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 17Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly1 5 10 <210> 18 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 18Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu1 5 10 <210> 19 <211> 11 <212> PRT <213>Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 19Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 20 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 20Gly Asp Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 10 <210> twenty one <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 21Val Asp Thr Tyr Asp Gly Asp Ile Ser Val1 5 10 <210> twenty two <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 22Asp Thr Tyr Asp Gly Asp Ile Ser Val Val1 5 10 <210> twenty three <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 23Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr1 5 10 <210> twenty four <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 24Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 25Asp Gly Asp Ile Ser ValVal Tyr Gly Leu1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> Peptide, FOL-009h <400> 26Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 27 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 27Asp Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 10 <210> 28 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> Peptide, FOL-019h <400> 28Val Asp Thr Tyr Asp Gly Asp Ile Ser1 5 <210> 29 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 29Asp Thr Tyr Asp Gly Asp Ile Ser Val1 5 <210> 30 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 30Thr Tyr Asp Gly Asp Ile Ser Val Val1 5 <210> 31 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 31Tyr Asp Gly Asp Ile Ser Val Val Tyr1 5 <210> 32 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400>32Asp Gly Asp Ile Ser Val Val Tyr Gly1 5 <210> 33 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 33Gly Asp Ile Ser Val Val Tyr Gly Leu1 5 <210> 34 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 34Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 <210> 35 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 35Ile Ser Val Val Tyr Gly Leu Arg Ser1 5 <210> 36 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 36Val Asp Thr Tyr Asp Gly Asp Ile1 5 <210> 37 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 37Asp Thr Tyr Asp Gly Asp Ile Ser1 5 <210> 38 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 38Thr Tyr Asp Gly Asp Ile Ser Val1 5 <210> 39 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 39Tyr Asp Gly Asp Ile Ser ValVal1 5 <210> 40 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 40Asp Gly Asp Ile Ser Val Val Tyr1 5 <210> 41 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 41Gly Asp Ile Ser Val Val Tyr Gly1 5 <210> 42 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 42Asp Ile Ser Val Val Tyr Gly Leu1 5 <210> 43 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 43Ile Ser Val Val Tyr Gly Leu Arg1 5 <210> 44 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 44Val Asp Thr Tyr Asp Gly Asp1 5 <210> 45 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 45Asp Thr Tyr Asp Gly Asp Ile1 5 <210> 46 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 46Thr Tyr Asp Gly Asp Ile Ser1 5 <210> 47 <211> 7 <212> PRT <213> Artificial sequence <220> <223>Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 47Tyr Asp Gly Asp Ile Ser Val1 5 <210> 48 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 48Asp Gly Asp Ile Ser Val Val1 5 <210> 49 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 49Gly Asp Ile Ser Val Val Tyr1 5 <210> 50 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 50Asp Ile Ser Val Val Tyr Gly1 5 <210> 51 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 51Ile Ser Val Val Tyr Gly Leu1 5 <210> 52 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 52Asp Thr Tyr Asp Gly Asp1 5 <210> 53 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 53Thr Tyr Asp Gly Asp Ile1 5 <210> 54 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 54Tyr Asp Gly Asp Ile Ser15 <210> 55 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 55Asp Gly Asp Ile Ser Val1 5 <210> 56 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 56Gly Asp Ile Ser Val Val1 5 <210> 57 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 57Asp Ile Ser Val Val Tyr1 5 <210> 58 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 58Ile Ser Val Val Tyr Gly1 5 <210> 59 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 59Thr Tyr Asp Gly Asp1 5 <210> 60 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 60Tyr Asp Gly Asp Ile1 5 <210> 61 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 61Asp Gly Asp Ile Ser1 5 <210> 62 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 62Gly Asp IleSer Val1 5 <210> 63 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 63Asp Ile Ser Val Val1 5 <210> 64 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 64Ile Ser Val Val Tyr1 5 <210> 65 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 65Ser Val Val Tyr Gly1 5 <210> 66 <211> 300 <212> PRT <213> Homo sapiens <220> <221> MISC_FEATURE <222> (1)..(300) <223> Wild-type human osteopontin <400> 66Met Arg Ile Ala Val Ile Cys Phe Cys Leu Leu Gly Ile Thr Cys Ala1 5 10 15Ile Pro Val Lys Gln Ala Asp Ser Gly Ser Ser Glu Glu Lys Gln Leu20 25 30Tyr Asn Lys Tyr Pro Asp Ala Val Ala Thr Trp Leu Asn Pro Asp Pro35 40 45Ser Gln Lys Gln Asn Leu Leu Ala Pro Gln Thr Leu Pro Ser Lys Ser50 55 60Asn Glu Ser His Asp His Met Asp Asp Met Asp Asp Glu Asp Asp Asp65 70 75 80Asp His Val Asp Ser Gln Asp Ser Ile Asp Ser Asn Asp Ser Asp Asp85 90 95Val Asp Asp Thr Asp Asp Ser His Gln Ser Asp Glu Ser His His Ser100 105 110Asp Glu Ser Asp GluLeu Val Thr Asp Phe Pro Thr Asp Leu Pro Ala 115 120 125 Thr Glu Val Phe Thr Pro Val Val Pro Thr Val Asp Thr Tyr Asp Gly 130 135 140 Arg Gly Asp Ser Val Val Tyr Gly Leu Arg Ser Lys Ser Lys Lys Phe 145 150 155 160 Arg Arg Pro Asp Ile Gln Tyr Pro Asp Ala Thr Asp Glu Asp Ile Thr 165 170 175 Ser His Met Glu Ser Glu Glu Leu Asn Gly Ala Tyr Lys Ala Ile Pro 180 185 190 Val Ala Gln Asp Leu Asn Ala Pro Ser Asp Trp Asp Ser Arg Gly Lys 195 200 205 Asp Ser Tyr Glu Thr Ser Gln Leu Asp Asp Gln Ser Ala Glu Thr His 210 215 220 Ser His Lys Gln Ser Arg Leu Tyr Lys Arg Lys Ala Asn Asp Glu Ser 225 230 235 240 Asn Glu His Ser Asp Val Ile Asp Ser Gln Glu Leu Ser Lys Val Ser 245 250 255 Arg Glu Phe His Ser His Glu Phe His Ser His Glu Asp Met Leu Val 260 265 270 Val Asp Pro Lys Ser Lys Glu Glu Asp Lys His Leu Lys Phe Arg Ile 275 280 285 Ser His Glu Leu Asp Ser Ala Ser Ser Glu Val Asn 290 295 300 <210> 67 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> Synthetic Sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> Peptide, FOL-002 <400> 67 Val Asp Thr Tyr Asp Gly ArgGly Asp Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 68 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (3)..(3) <223> X is T or V <220> <221> MISC_FEATURE <222> (4)..(4) <223> X is Y or P <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is D or N <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is D or G <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is I or G <220> <221> MISC_FEATURE <222> (10)..(10) <223> X is V or L <220> <221> MISC_FEATURE <222> (11)..(11) <223> X is V or A <400> 68Val Asp Xaa Xaa Xaa Gly Xaa Xaa Ser Xaa Xaa Tyr Gly Leu Arg1 5 10 15 <210> 69 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> Peptide, FOL-004 <400> 69Val Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 15 <210> 70 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 70Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 15 <210> 71 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222>(1)..(14) <223> peptides <400> 71Val Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 10 <210> 72 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 72Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 <210> 73 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 73Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 <210> 74 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> Peptide, FOL-017 <400> 74Val Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly1 5 10 <210> 75 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 75Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 10 <210> 76 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 76Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 <210> 77 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222>(1)..(13) <223> peptides <400> 77Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 <210> 78 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 78Val Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr1 5 10 <210> 79 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 79Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly1 5 10 <210> 80 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 80Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 10 <210> 81 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 81Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 <210> 82 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 82Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 <210> 83 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 83Val Asp Val Pro Asn Gly AspIle Ser Leu Ala1 5 10 <210> 84 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 84Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr1 5 10 <210> 85 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 85Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly1 5 10 <210> 86 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 86Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 10 <210> 87 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 87Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 <210> 88 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 88Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 <210> 89 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 89Val Asp Val Pro Asn Gly Asp Ile Ser Leu1 5 10 <210> 90 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221>MISC_FEATURE <222> (1)..(10) <223> peptides <400> 90Asp Val Pro Asn Gly Asp Ile Ser Leu Ala1 5 10 <210> 91 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 91Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr1 5 10 <210> 92 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 92Pro Asn Gly Asp Ile Ser Leu Ala Tyr Gly1 5 10 <210> 93 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 93Asn Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 10 <210> 94 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> Peptide, FOL-009 <400> 94Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 <210> 95 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 95Asp Ile Ser Leu Ala Tyr Gly Leu Arg Ser1 5 10 <210> 96 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <220> <221> MISC_FEATURE <222> (1)..(9) <223> Peptide, FOL-019 <400> 96ValAsp Val Pro Asn Gly Asp Ile Ser1 5 <210> 97 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 97Asp Val Pro Asn Gly Asp Ile Ser Leu1 5 <210> 98 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 98Val Pro Asn Gly Asp Ile Ser Leu Ala1 5 <210> 99 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 99Pro Asn Gly Asp Ile Ser Leu Ala Tyr1 5 <210> 100 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 100Asn Gly Asp Ile Ser Leu Ala Tyr Gly1 5 <210> 101 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 101Gly Asp Ile Ser Leu Ala Tyr Gly Leu1 5 <210> 102 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 102Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 <210> 103 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <400> 103Ile Ser Leu AlaTyr Gly Leu Arg Ser1 5 <210> 104 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 104Val Asp Val Pro Asn Gly Asp Ile1 5 <210> 105 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 105Asp Val Pro Asn Gly Asp Ile Ser1 5 <210> 106 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 106Val Pro Asn Gly Asp Ile Ser Leu1 5 <210> 107 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 107Pro Asn Gly Asp Ile Ser Leu Ala1 5 <210> 108 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 108Asn Gly Asp Ile Ser Leu Ala Tyr1 5 <210> 109 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 109Gly Asp Ile Ser Leu Ala Tyr Gly1 5 <210> 110 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 110Asp Ile Ser Leu Ala Tyr Gly Leu1 5 <210>111 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 111Ile Ser Leu Ala Tyr Gly Leu Arg1 5 <210> 112 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 112Val Asp Val Pro Asn Gly Asp1 5 <210> 113 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 113Asp Val Pro Asn Gly Asp Ile1 5 <210> 114 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 114Val Pro Asn Gly Asp Ile Ser1 5 <210> 115 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 115Pro Asn Gly Asp Ile Ser Leu1 5 <210> 116 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 116Asn Gly Asp Ile Ser Leu Ala1 5 <210> 117 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 117Gly Asp Ile Ser Leu Ala Tyr1 5 <210> 118 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221>MISC_FEATURE <222> (1)..(7) <223> peptides <400> 118Asp Ile Ser Leu Ala Tyr Gly1 5 <210> 119 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <400> 119Ile Ser Leu Ala Tyr Gly Leu1 5 <210> 120 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 120Asp Val Pro Asn Gly Asp1 5 <210> 121 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 121Val Pro Asn Gly Asp Ile1 5 <210> 122 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 122Pro Asn Gly Asp Ile Ser1 5 <210> 123 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 123Asn Gly Asp Ile Ser Leu1 5 <210> 124 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 124Gly Asp Ile Ser Leu Ala1 5 <210> 125 <211> 6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 125Asp Ile Ser Leu Ala Tyr1 5 <210> 126 <211>6 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(6) <223> peptides <400> 126Ile Ser Leu Ala Tyr Gly1 5 <210> 127 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 127Val Pro Asn Gly Asp1 5 <210> 128 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 128Pro Asn Gly Asp Ile1 5 <210> 129 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 129Asn Gly Asp Ile Ser1 5 <210> 130 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 130Gly Asp Ile Ser Leu1 5 <210> 131 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 131Asp Ile Ser Leu Ala1 5 <210> 132 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 132Ile Ser Leu Ala Tyr1 5 <210> 133 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(5) <223> peptides <400> 133Ser Leu Ala Tyr Gly15<210> 134<211> 294<212> PRT<213> Mus musculus<220><221> MISC_FEATURE<222> (1)..(294)<223> Wild-type murine osteopontin<400> 134Met Arg Leu Ala Val Ile Cys Phe Cys Leu Phe Gly Ile Ala Ser Ser1 5 10 15Leu Pro Val Lys Val Thr Asp Ser Gly Ser Ser Glu Glu Lys Leu Tyr20 25 30Ser Leu His Pro Asp Pro Ile Ala Thr Trp Leu Val Pro Asp Pro Ser35 40 45Gln Lys Gln Asn Leu Leu Ala Pro Gln Asn Ala Val Ser Ser Glu Glu50 55 60Lys Asp Asp Phe Lys Gln Glu Thr Leu Pro Ser Asn Ser Asn Glu Ser65 70 75 80His Asp His Met Asp Asp Asp Asp Asp Asp Asp Asp Asp Asp Gly Asp85 90 95His Ala Glu Ser Glu Asp Ser Val Asp Ser Asp Glu Ser Asp Glu Ser100 105 110His His Ser Asp Glu Ser Asp Glu Thr Val Thr Ala Ser Thr Gln Ala115 120 125Asp Thr Phe Thr Pro Ile Val Pro Thr Val Asp Val Pro Asn Gly Arg130 135 140Gly Asp Ser Leu Ala Tyr Gly Leu Arg Ser Lys Ser Arg Ser Phe Gln145 150 155 160Val Ser Asp Glu Gln Tyr Pro Asp Ala Thr Asp Glu Asp Leu Thr Ser165 170 175His Met Lys Ser Gly Glu Ser Lys Glu Ser Leu Asp Val Ile Pro Val180 185 190Ala Gln Leu Leu Ser MetPro Ser Asp Gln Asp Asn Asn Gly Lys Gly195 200 205Ser His Glu Ser Ser Gln Leu Asp Glu Pro Ser Leu Glu Thr His Arg210 215 220Leu Glu His Ser Lys Glu Ser Gln Glu Ser Ala Asp Gln Ser Asp Val225 230 235 240Ile Asp Ser Gln Ala Ser Ser Lys Ala Ser Leu Glu His Gln Ser His245 250 255Lys Phe His Ser His Lys Asp Lys Leu Val Leu Asp Pro Lys Ser Lys260 265 270Glu Asp Asp Arg Tyr Leu Lys Phe Arg Ile Ser His Glu Leu Glu Ser275 280 285Ser Ser Ser Glu Val Asn290 <210> 135 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> Peptide, FOL-001 <400> 135Val Asp Val Pro Asn Gly Arg Gly Asp Ser Leu Ala Tyr Gly Leu Arg1 5 10 15 <210> 136 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> Peptide, FOL-014 <400> 136Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 137 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> Peptide, FOL-003 <400> 137Gly Asp Pro Asn Asp Gly Arg Gly Asp Ser Val Val Tyr Gly LeuArg1 5 10 15 <210> 138 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> Peptide, FOL-026 <400> 138Val Asp Thr Tyr Asp Gly Gly Ile Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 139 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> Peptide, FOL-027 <400> 139Val Asp Thr Tyr Asp Gly Asp Gly Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 140 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <220> <221> MISC_FEATURE <222> (2)..(2) <223> X is C, P, or G. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is E or G <220> <221> MISC_FEATURE <222> (6)..(6) <223> X is C, D, or I. <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is D, I, S, or G. <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is S, D, or G. <220> <221> MISC_FEATURE <222> (10)..(10) <223> X is E or G <220> <221> MISC_FEATURE <222> (12)..(12) <223> X is S or T <400> 140Lys Xaa Leu Ala Xaa Xaa Xaa Xaa Ile Xaa Leu Xaa Tyr Gly Ile Lys1 5 10 15 <210> 141 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222>(1)..(16) <223> peptides <400> 141Lys Cys Leu Ala Glu Cys Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 142 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 142Cys Leu Ala Glu Ile Asp Ser Cys1 5 <210> 143 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(18) <223> peptides <400> 143Cys Phe Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Cys Ser Tyr Gly1 5 10 15Ile Lys <210> 144 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 144Lys Pro Leu Ala Glu Asp Ile Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 145 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 145Lys Pro Leu Ala Glu Ile Ser Asp Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 146 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 146Lys Pro Leu Ala Glu Ile Gly Asp Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 147 <211> 15 <212> PRT <213> Artificial sequence <220> <223>Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 147Lys Pro Leu Ala Glu Gly Asp Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 148 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 148Lys Pro Leu Ala Glu Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 149 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 149Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu Thr Tyr Gly Ile Lys1 5 10 15 <210> 150 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 150Lys Pro Leu Ala Glu Ile Asp Gly Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 151 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 151Lys Pro Leu Ala Glu Ile Asp Gly Ile Glu Leu Thr Tyr Gly Ile Lys1 5 10 15 <210> 152 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 152Lys Pro Leu Ala Glu Ile Gly Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 1015 <210> 153 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 153Lys Gly Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 154 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 154Lys Pro Leu Ala Gly Ile Asp Ser Ile Gly Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 155 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <400> 155Lys Cys Leu Ala Glu Ile Asp Ser Cys Glu Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 156 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 156Cys Phe Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Cys1 5 10 <210> 157 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 157Val Asp Val Pro Glu Gly Asp Ile Ser Leu Ala Tyr Gly Leu Arg1 5 10 15 <210> 158 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 158Leu Asp Gly Leu ValArg Ala Tyr Asp Asn Ile Ser Pro Val Gly1 5 10 15 <210> 159 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 159Gly Asp Pro Asn Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 <210> 160 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 160Val Asp Val Pro Asn Gly Asp Ile Ser Leu Ala Tyr Arg Leu Arg1 5 10 15 <210> 161 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 161Val Asp Val Pro Glu Gly Asp Ile Ser Leu Ala Tyr Arg Leu Arg1 5 10 15 <210> 162 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(16) <223> peptides <220> <221> MISC_FEATURE <222> (2)..(2) <223> X is C, P, or G. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is E or G <220> <221> MISC_FEATURE <222> (6)..(6) <223> X is C, I, or does not exist. <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is D, G, or does not exist. <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is S, G, or does not exist. <220> <221> MISC_FEATURE <222> (10)..(10) <223> X is E or G <400> 162Lys Xaa Leu Ala Xaa XaaXaa Xaa Ile Xaa Leu Ser Tyr Gly Ile Lys1 5 10 15 <210> 163 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <220> <221> MISC_FEATURE <222> (2)..(2) <223> X is C, P, or G. <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is E or G <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is E or G <400> 163Lys Xaa Leu Ala Xaa Ile Xaa Leu Ser Tyr Gly Ile Lys1 5 10 <210> 164 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is E or N <220> <221> MISC_FEATURE <222> (13)..(13) <223> X is R or G <400> 164Val Asp Val Pro Xaa Gly Asp Ile Ser Leu Ala Tyr Xaa Leu Arg1 5 10 15 <210> 165 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is D or G <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is I or G <400> 165Val Asp Thr Tyr Asp Gly Xaa Xaa Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 166 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(16) <223>peptides <220> <221> MISC_FEATURE <222> (5)..(5) <223> Z is either D or G <220> <221> MISC_FEATURE <222> (6)..(6) <223> X is D or G <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is I or R <220> <221> MISC_FEATURE <222> (8)..(8) <223> X is G or does not exist. <220> <221> MISC_FEATURE <222> (9)..(9) <223> X is D or does not exist. <400> 166Gly Asp Pro Asn Xaa Xaa Xaa Xaa Xaa Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 167 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (2)..(2) <223> X is β D <400> 167Val Xaa Thr Tyr Asp Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 168 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is β D <400> 168Val Asp Thr Tyr Xaa Gly Asp Ile Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210> 169 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic peptides <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <220> <221> MISC_FEATURE <222> (7)..(7) <223> X is β D <400> 169Val Asp Thr Tyr Asp Gly Xaa Ile Ser Val Val Tyr Gly Leu Arg1 5 10 15 <210>170 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 170Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 171 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> Peptide, FOL-056 <400> 171Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 172 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> Peptide, FOL-057 <400> 172Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 173 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> Peptide, FOL-058 <400> 173Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 174 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> Peptide, FOL-059 <400> 174Asp Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 10 <210> 175 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> Peptide, FOL-060 <400> 175Ser Ile Glu Leu Ser Tyr Gly Ile Lys1 5 <210> 176 <211> 8 <212>PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(8) <223> peptides <400> 176Ile Glu Leu Ser Tyr Gly Ile Lys1 5 <210> 177 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(7) <223> peptides <220> <221> MISC_FEATURE <222> (1)..(1) <223> X is E or G <220> <221> MISC_FEATURE <222> (3)..(3) <223> X is S or T <400> 177Xaa Leu Xaa Tyr Gly Ile Lys1 5 <210> 178 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptides <220> <221> MISC_FEATURE <222> (1)..(1) <223> X is D or G <220> <221> MISC_FEATURE <222> (2)..(2) <223> X is I or G <220> <221> MISC_FEATURE <222> (4)..(4) <223> X is V or L <220> <221> MISC_FEATURE <222> (5)..(5) <223> X is V or A <400> 178Xaa Xaa Ser Xaa Xaa Tyr Gly Leu Arg1 5 <210> 179 <211> 15 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(15) <223> peptides <400> 179Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr Gly Ile1 5 10 15 <210> 180 <211> 14 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(14) <223> peptides <400> 180Lys Pro Leu Ala Glu Ile Asp Ser Ile GluLeu Ser Tyr Gly1 5 10 <210> 181 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(13) <223> peptides <400> 181Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser Tyr1 5 10 <210> 182 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(12) <223> peptides <400> 182Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu Ser1 5 10 <210> 183 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(11) <223> peptides <400> 183Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu Leu1 5 10 <210> 184 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(10) <223> peptides <400> 184Lys Pro Leu Ala Glu Ile Asp Ser Ile Glu1 5 10 <210> 185 <211> 25 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(25) <223> Peptide, FOL-199 <400> 185Gly Lys Tyr Gly Phe Tyr Thr His Val Phe Arg Leu Lys Lys Trp Ile1 5 10 15Gln Lys Val Ile Asp Gln Phe Gly Glu20 25 <210> 186 <211> 9 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(9) <223> peptide, oxytocin <400> 186Cys TyrIle Gln Asn Cys Pro Leu Gly1 5 <210> 187 <211> 37 <212> PRT <213> Artificial sequence <220> <223> Synthetic sequence <220> <221> MISC_FEATURE <222> (1)..(37) <223> Peptide, LL-37 <400> 187Leu Leu Gly Asp Phe Phe Arg Lys Ser Lys Glu Lys Ile Gly Lys Glu1 5 10 15Phe Lys Arg Ile Val Gln Arg Ile Lys Asp Phe Leu Arg Asn Leu Val20 25 30Pro Arg Thr Glu Ser35

Claims

1. A composition comprising: a. 0.01-2% by weight of a peptide, wherein the peptide comprises the following amino acid sequence: VDTYDGDISVVYGLR (SEQ ID NO: 1; FOL-005), or VDTYDGGISVVYGLR (SEQ ID NO: 138; FOL-026); b. 0.01-4% by weight of sugar or modified sugar; c. 35-50% by weight of petrolatum; d. 40-60% by weight of isopropyl myristate, and e. 1-8% by weight of thickener, provided that the total number of components in the total composition does not exceed 100% by weight.

2. The composition of claim 1, wherein the composition comprises particles, the particles comprising the peptide and the sugar or modified sugar, or consisting of the peptide and the sugar or modified sugar.

3. The composition according to claim 1, wherein the thickener is selected from the group consisting of glyceryl behenate and carnauba wax.

4. The composition according to any one of claims 1-3, wherein the composition further comprises 2-10% by weight of a surfactant.

5. The composition according to claim 4, wherein the surfactant is sorbitol laurate.

6. The composition according to any one of claims 1-3, wherein the modified sugar is a sugar alcohol.

7. The composition according to any one of claims 1-3, wherein the sugar or modified sugar is selected from sucrose, mannitol and glucose.

8. The composition according to any one of claims 1-3, wherein the composition comprises or is composed of the following substances: a. 0.01-2% by weight of peptides; b. 0.01-4% by weight of sucrose, mannitol, or glucose; c. 1-8% by weight of behenicol or carnauba wax; d. 35-45% by weight of petrolatum; e. 40-60% by weight of isopropyl myristate; and f. 2-10% by weight of surfactants.

9. The composition according to any one of claims 1-3, wherein the weight ratio of sugar or modified sugar to peptide in the composition is 5:1 to 1:

5.

10. The composition according to any one of claims 1-3, wherein the composition comprises isopropyl myristate and petrolatum in a weight ratio of 2:1 to 1:

2.

11. The composition according to claim 8, wherein the surfactant is sorbitol laurate.

12. The composition according to claim 9, wherein the weight ratio of sugar or modified sugar to peptide in the composition is 2:1 or 1:

1.

13. The composition of claim 10, wherein the composition comprises isopropyl myristate and petrolatum in a weight ratio of 3:2 to 2:

3.

14. The composition of claim 10, wherein the composition comprises isopropyl myristate and petrolatum in a 1:1 weight ratio.

15. The composition according to any one of claims 1-3, wherein the composition comprises or is composed of the following substances: a. 0.01-2% by weight of peptides; b. 0.01-4% by weight of sucrose; c. 3% by weight of behenicol glyceride; d. 42.4% by weight of petrolatum; e. 50% by weight of isopropyl myristate; and f. 4% by weight of sorbitol laurate.

16. The composition according to any one of claims 1-3, wherein the composition comprises or is composed of the following substances: a. 0.2% by weight peptides; b. 0.4% by weight sucrose; c. 3% by weight glyceryl behenate; d. 42.4% by weight petrolatum; e. 50% by weight isopropyl myristate; and f. 4% by weight sorbitol laurate.

17. The composition according to any one of claims 1-3, wherein the composition is water-free.

18. The composition according to any one of claims 1-3, wherein at least 50% of the particles have an average particle size between 0.1 and 50 µm.

19. The composition according to any one of claims 1-3, wherein the peptide is conjugated to a portion, wherein the portion is selected from the group consisting of polyethylene glycol (PEG), monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides.

20. The composition according to any one of claims 1-3, wherein the peptide is modified by glycosylation or by polyethylene glycolation, esterification, acylation and / or alkylation.

21. The composition according to any one of claims 1-3, wherein the peptide is modified by acetylation.

22. The composition according to any one of claims 1-3, wherein the peptide is modified by amidation.

23. The composition according to any one of claims 1-3, wherein the composition is in the form of an ointment, powder, spray, lotion, gel, foam or cream.

24. The composition according to any one of claims 1-3, wherein the composition is in the form of a cosmetic.

25. The composition according to any one of claims 1-3, wherein the composition is in the form of a shampoo.

26. Use of the composition according to any one of claims 1-25 in the preparation of a medicament for treating or preventing diseases or conditions related to hair loss.

27. A method for preparing a composition according to any one of claims 4, 5, 8, 11, 15, and 16, the method comprising the steps of: a) Mix the peptide with sugar or modified sugar; b) freeze-dry the mixture of a); c) mix b) with petrolatum, isopropyl myristate and surfactant; d) grind the mixture of c); and e) mix the mixture of d) with thickener.

28. A method for preparing a composition according to any one of claims 4, 5, 8, 11, 15, and 16, the method comprising the steps of: a) Mix the peptide with sugar or modified sugar; b) Freeze-dry the mixture of a); c) Mix b) with petrolatum and surfactant; d) Grind the mixture of c); e) Mix the mixture of d) with thickener; f) Mix the mixture from e) with isopropyl myristate.

29. A method for preparing a composition according to any one of claims 4, 5, 8, 11, 15, and 16, the method comprising the steps of: a) Mix the peptide with sugar or modified sugar; b) Freeze-dry the mixture of a); c) Mix b) with isopropyl myristate and surfactant; d) Grind the mixture of c); e) Mix the mixture of d) with thickener; f) Mix the mixture from e) with the petrolatum.

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