Compositions and methods for treating alopecia or promoting hair growth

Abstract

A method of treating or preventing alopecia or promoting hair growth or regeneration is provided. In particular to a composition for preventing or treating alopecia and / or promoting hair growth of the scalp and / or skin of a subject in need thereof. The composition comprises an effective amount of a polypeptide or a nucleic acid molecule encoding the polypeptide, and the polypeptide comprises an amino acid sequence having an EGF-like domain of clotting regulatory or a conservative variant thereof.

Description

[0001] Sequence Listing

[0002] This application contains a computer-readable sequence listing, filed electronically in XML format, pursuant to 37 CFR §1.831-835, and incorporated herein by reference in its entirety. The XML file was created on February 13, 2023, is named 211140US-SequenceListing-20230213, and is 4.75 kb in size. Technical Field

[0003] The present disclosure relates to hair maintenance and growth, and more particularly to preventing and / or slowing hair loss and promoting hair growth and / or regrowth on the scalp and / or skin of a mammal. Existing technology

[0004] Hair loss, also known as baldness, is caused by a disruption in the physiological cycle of hair production. Mammalian hair grows in three cycles:

[0005] (i) Anagen phase: The activation phase, during which the hair follicle penetrates deep into the dermis and the cells of the hair bulb rapidly divide and differentiate to form hair;

[0006] (ii) Catagen: The catagen phase, during which the hair follicle retracts upward through the dermis and hair growth ceases; and

[0007] (iii) Telogen: The resting stage, in which the involuted hair follicle contains a small secondary hair germ with a tightly packed ball of dermal papilla cells underneath.

[0008] The rapid proliferation of the hair germ, the expansion of the dermal papilla, and the development of basement membrane components indicate the onset of a new growth phase. The hair cycle repeats multiple times until male pattern baldness develops, with most follicles spending an increasing proportion of their resting phase and the hair produced becoming thinner, shorter, and less noticeable; this process is called the terminal to vellus transformation.

[0009] Hair loss can occur anywhere on the body, but it most commonly affects the scalp. The average human scalp has 100,000 hairs, which go through a cycle of growth, rest, shedding, and regrowth. Signs and symptoms of hair loss on the scalp may include gradual thinning on the crown, circular or patchy bald spots, sudden hair loss, and scaly patches scattered across the scalp. Excessive hair loss can often be the result of genetics, hormonal changes, medical conditions (such as cancer chemotherapy), or normal aging.

[0010] With an aging population and the pressures of modern life, more and more people are facing the crisis of hair loss. It's estimated that 40% of 35-year-old men in the United States experience some noticeable hair loss. This condition worsens as men age, reaching 65% of adult men by the age of 60. Women also experience hair loss. Unlike men, hair loss in women typically involves noticeable thinning across the entire head and hairline. The American Academy of Dermatology reports that 40% of women experience noticeable hair loss by the age of 40. While excessive scalp hair loss is mostly medically benign, it has significant cosmetic consequences, placing significant emotional and psychosocial strain on individuals and potentially impacting their self-confidence and social life. For example, hair loss can be considered abnormal or unacceptable for women, partly due to societal norms that pressure women to present their best appearance. Even slight hair thinning, if noticeable, can negatively impact a woman's self-image and the way others perceive her.

[0011] Current treatments for hair loss and / or baldness include medications and hair transplantation; however, they are generally unsatisfactory in that they are insufficient to activate hair that is in a relatively degenerate and / or resting state, possibly due to the diversity of causes of hair loss and the complexity of hair growth mechanisms.

[0012] Medication, such as: (Rogains), (Propecia) and (Avodart) are approved hair loss treatments. However, these medications have drawbacks, as they require daily use for effectiveness. Furthermore, they only work long-term if patients continue taking them. Any interruption could result in loss of any increased hair. Furthermore, some of these medications are not approved for use in women due to safety concerns.

[0013] Available invasive hair loss treatments include surgical procedures such as follicular unit transplantation, scalp reduction, or scalp flaps. These surgical procedures may risk necrosis of the skin in the donor area or the formation of keloid tissue. These surgical procedures also often produce unsatisfactory results, such as unnatural-looking hair growth due to the direction of hair growth and a limited number of hair follicles that can be safely transplanted (a patient can undergo a maximum of three surgeries in their lifetime, with each procedure transplanting fewer than 4,000 follicles). This surgical treatment is also inconvenient for the patient because it usually requires a 3 to 4 hour surgery, postoperative care, and immediate disruption to normal daily life for up to about 2 weeks after the surgery (even if there are no complications).

[0014] There are also several different types of injections available, such as single injections of platelet-rich plasma (PRP) for hair loss treatment. A large literature has documented the use of PRP in sports medicine, orthopedic surgery, dental surgery, and many other medical and surgical specialties to enhance tissue repair and healing after surgery or injury. However, the results of these injections vary greatly. While existing injections can restore hair in some individuals, they lack consistency and are not applicable to the large number of other people suffering from hair loss.

[0015] As mentioned above, despite various attempts, current hair loss treatments do not necessarily provide adequate hair care, i.e., preventing hair loss and promoting hair growth in all areas of the scalp. Finasteride and minoxidil treatments, while claimed to be effective for both the vertex and forehead areas, are only relatively successful in the vertex area. Furthermore, most baldness treatments require a long time, e.g., four to six months of treatment before significant results are seen. The only method that has achieved some success in growing hair in individuals who are already bald or experiencing balding may be to transplant hair to the bald areas, a procedure that is often painful and not always successful. Furthermore, it is immediately apparent to the casual observer that individuals who undergo hair transplants may require months or even years after surgery for hair to regrow in an appearance similar to the original, naturally grown hair.

[0016] Therefore, there is a need to provide a novel composition that effectively prevents hair loss and promotes hair growth and / or regeneration on the scalp and / or skin. Summary of the Invention

[0017] In view of the foregoing, the present disclosure provides a composition that has hair loss prevention, hair growth promotion, and hair care effects in humans and other mammals, and can be used as a pharmaceutical, quasi-pharmaceutical, or cosmetic composition for hair care. The composition comprises an effective amount of a polypeptide comprising the amino acid sequence of the EGF-like domain of thrombomodulin or a conservative variant thereof.

[0018] Thrombomodulin is an anticoagulant (endothelial membrane glycoprotein). Recombinant thrombomodulins TMD2 (containing an EGF-like structure) and TMD23 (containing TMD2 and a serine-threonine rich domain) exhibited partial cellular behavioral activity.

[0019] In at least one embodiment of the present disclosure, the composition comprises an effective amount of a recombinant polypeptide comprising an amino acid sequence of an EGF-like domain of thrombomodulin or a conservative variant thereof. In other embodiments, the polypeptide is a recombinant polypeptide comprising an amino acid sequence of an EGF-like structure of thrombomodulin or a conservative variant thereof operably linked to a serine-threonine-rich domain of thrombomodulin. In at least one embodiment, the number of the EGF-like structures is 1 to 6. In some embodiments, the number of the EGF-like structures is 6.

[0020] The present invention provides a method for preventing or treating hair loss or promoting hair growth or regeneration, comprising administering to an individual in need thereof a therapeutically effective amount of a polypeptide or a nucleic acid molecule encoding the polypeptide, wherein the polypeptide comprises an amino acid sequence having an EGF-like domain of thrombomodulin or a conservative variant thereof.

[0021] In a preferred embodiment, the polypeptide is a recombinant polypeptide comprising an amino acid sequence having an EGF-like structure of thrombomodulin or a conservative variant thereof operably linked to a serine-threonine-rich domain of thrombomodulin. In some embodiments, the number of such EGF-like structures is 6. In another embodiment, the recombinant polypeptide consists essentially of an amino acid sequence having 6 EGF-like structures of thrombomodulin or a conservative variant thereof operably linked to a serine-threonine-rich domain of thrombomodulin.

[0022] In at least one embodiment, the polypeptide is at least 35% identical to TMD23, ​​which has the amino acid sequence of SEQ ID NO: 1 as follows:

[0023] AWDCSVENGGCEHACNAIPGAPRCQCPAGAALQADGRSCTASATQSCNDL

[0024] CEHFCVPNPDQPGSYSCMCETGYRLAADQHRCEDVDDCILEPSPCPQRCV

[0025] NTQGGFECHCYPNYDLVDGECVEPVDPCFRANCEYQCQPLNQTSYLCVCA

[0026] EGFAPIPHEPHRCQMFCNQTACPADCDPNTQASCECPEGYILDDGFICTDID

[0027] ECENGGFCSGVCHNLPGTFECICGPDSALARHIGTDCDSGKVDGGDSGSGE

[0028] PPPSPTPGSTLTPPAVGLVHS

[0029] In some embodiments, the polypeptide consists essentially of TMD23. In some embodiments, the polypeptide is TMD23.

[0030] In at least one embodiment, the polypeptide consists essentially of BB101, which has the amino acid sequence of SEQ ID NO: 2 as follows:

[0031] AWDCSVENGGCEHACNAIPGAPRCQCPAGAALQADGRSCTASATQSCNDL

[0032] CEHFCVPNPDQPGSYSCMCETGYRLAADQHRCEDVDDCILEPSPCPQRCV

[0033] NTQGGFECHCYPNYDLVDGECVEPVDPCFRANCEYQCQPLAQTSYLCVCA

[0034] EGFAPIPHEPHRCQMFCAQTACPADCDPNTQASCECPEGYILDDGFICTDID

[0035] ECENGGFCSGVCHNLPGTFECICGPDSALARHIGTDCDSGKVDGGDSGSGE

[0036] PPPSPTPGSTLTPPAVGLVHS

[0037] In at least one embodiment, the polypeptide comprises a TME5 structure having an amino acid sequence that is at least 35% identical to SEQ ID NO: 3, wherein the sequence of SEQ ID NO: 3 is as follows:

[0038] QMFCNQTACPADCDPNTQASCECPEGYILDDGFICTDIDE

[0039] In some embodiments, the polypeptide comprises a TME5 structure having an amino acid sequence consisting essentially of SEQ ID NO: 3. In some embodiments, the TME5 structure has an amino acid sequence of SEQ ID NO: 3.

[0040] In at least one embodiment, the polypeptide comprises a TME5C structure having an amino acid sequence that is at least 35% identical to SEQ ID NO: 4, wherein the sequence of SEQ ID NO: 4 is as follows:

[0041] ECPEGYILDDGFICTDIDE

[0042] In some embodiments, the polypeptide comprises a TME5C structure having an amino acid sequence consisting essentially of SEQ ID NO: 4. In some embodiments, the TME5C structure has an amino acid sequence of SEQ ID NO: 4.

[0043] In at least one embodiment, the nucleic acid molecule is an exogenously introduced polynucleic acid that increases the expression of the polypeptide in a subject. In some embodiments, the nucleic acid molecule encoding the polypeptide is mRNA.

[0044] In further embodiments, the composition further comprises a pharmaceutically or cosmetically acceptable carrier.

[0045] In one aspect, the present disclosure provides a method for treating hair loss, comprising administering to an individual in need thereof a composition comprising: a) a recombinant polypeptide comprising an amino acid sequence having an EGF-like structure of thrombomodulin or a conservative variant thereof operably linked to a serine-threonine-rich domain of thrombomodulin; and b) a pharmaceutically or cosmetically acceptable carrier.

[0046] Common types of hair loss include male-pattern baldness, female-pattern baldness, alopecia areata, and thinning hair (called telogen effluvium). Male-pattern baldness is caused by a combination of genetics and androgen factors; the cause of female-pattern baldness is unknown; alopecia areata is caused by autoimmunity; and telogen effluvium is often caused by physical or psychological stress. Telogen effluvium is common after pregnancy.

[0047] Less common causes of hair loss without inflammation or scarring include hair plucking, certain medications (including chemotherapy, HIV / AIDS, hypothyroidism), and nutritional deficiencies (including iron deficiency). Causes of hair loss with scarring or inflammation include fungal infections, lupus erythematosus, radiation therapy, and sarcoidosis. The diagnosis of hair loss depends in part on the affected area.

[0048] In at least one embodiment of the present disclosure, the hair loss is selected from the group consisting of involutional alopecia, androgenic alopecia, male-pattern hair loss, female-pattern hair loss, alopecia areata, traction alopecia, anagen effluvium, telogen effluvium, cicatricial (scarring) alopecia, hair loss caused by infectious diseases, hair loss caused by chemotherapy, hair loss caused by radiation, hair loss caused by hormonal imbalance, hair loss caused by drugs, hair loss caused by chemical exposure, hair loss caused by stress, and any combination thereof.

[0049] In at least one embodiment of the present disclosure, the hair loss is menopausal alopecia.

[0050] In at least one embodiment of the present disclosure, the hair loss is androgenetic alopecia (male pattern baldness or female pattern baldness).

[0051] In some embodiments, the composition promotes hair growth and / or regeneration in a subject. In at least one embodiment of the present disclosure, administering the composition of the present invention produces one or more of the following results: cell growth, hair follicle regeneration, strong and robust hair follicles, increased hair shaft size, and hair regrowth.

[0052] The composition of the present invention may be formulated in any form, as long as it is applicable to the skin, particularly the scalp. Examples include gels, creams, pastes, emulsions, sprays, suspensions, solutions, dispersion salve, hydrogels, liquids, emulsions, ointments, films, oral creams, powders, and liniments. Furthermore, the composition of the present invention may be in any form, such as hair tonics, hair cleansing lotions, hair creams, hair gels, hair mousses, and shampoos.

[0053] The composition of the present invention comprises a pharmaceutically or cosmetically acceptable carrier as a diluent, dispersant, or carrier for the recombinant thrombomodulin of the present invention to facilitate its distribution when the composition is applied to the skin and / or scalp. In addition to water, the carrier may include liquid or solid emollients, solvents, humectants, thickeners, and powders.

[0054] In at least one embodiment, the pharmaceutically or cosmetically acceptable carrier is between 0.001% and 99.999%, for example, but not limited to, 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, 0.2%, 0.3%, 0.4%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.10%, 0.11%, 0.12%, 0.13%, 0.14%, 0.15%, 0.16%, 0.17%, 0.18%, 0.19%, 0.20%, 0.21%, 0.22%, 0.23%, 0.24%, 0.25%, 0.26%, 0.27%, 0.28%, 0.29%, 0.30%, 0.31%, 0.32%, 0.33%, 0.34%, 0.35%, 0.36%, 0.37%, 0.38%, 0.39%, 0.40%, 0.41%, 0.42%, 0.43%, 0.44%, 0.45%, 0.46%, 0.47%, 0.48%, 0.49%, 0.50%, 0.51%, 0.52%, 0.53%, 0.54%, 0.55%, 0.56%, 0.57%, 0.58%, 0.59%, 0.6 0.09%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.9999%, and the balance of the composition can be maintained in the absence of other pharmaceutical or cosmetic adjuvants.

[0055] In at least one embodiment of the present application, the composition can be in the form of an aqueous solution, an aqueous / alcoholic solution, or an oily solution; a dispersion of the emulsion or serum type; an anhydrous or lipophilic gel; an emulsion of liquid or semi-liquid consistency obtained by dispersing a fat phase in an aqueous phase (O / W) or vice versa (W / O); or a suspension or emulsion of smooth, semi-solid, or solid consistency of the cream or gel type. These compositions can be formulated according to conventional techniques known in the art.

[0056] In at least one embodiment of the present application, the composition of the present disclosure may also contain additives and adjuvants commonly used in the fields of cosmetics, medicine, or dermatology, such as hydrophilic or lipophilic gelling agents, hydrophilic or lipophilic active agents, preservatives, antioxidants, solvents, fragrances, fillers, bactericides, odor absorbers, and dyes or colorants. In at least one embodiment, the composition of the present disclosure is delivered to an individual topically or systemically.

[0057] In at least one embodiment, the compositions of the present disclosure can be administered via a route including subcutaneous and intradermal injection. In some embodiments, the compositions are administered to the individual's scalp. In at least one embodiment, the method further comprises heating the individual's skin using infrared light or a heat compress. In other embodiments, the compositions are administered to the individual's scalp. In yet other embodiments, the compositions are administered to the individual topically, intradermally, or subcutaneously. Preferably, the compositions of the present disclosure are administered via intradermal injection.

[0058] In at least one embodiment, the method of the present disclosure further comprises administering a physical intervention, a chemical intervention, or a combination thereof. In some embodiments, the physical intervention can be performed by applying any device to increase skin penetration. In some embodiments, the physical intervention is selected from the group consisting of a needle, a microneedle, a microneedle patch, a microneedle roller, a microneedle stamp, a meso gun, a microsurgical device, a superficial injection device, a needle-free intradermal injection, a razor, temperature elevation, electroporation, ultrasound conduction, ultrasound-conducted microbubble cavitation, and any combination thereof.

[0059] In at least one embodiment, the compositions of the present disclosure can be administered topically, intradermally, or subcutaneously to a target site, such as the scalp, using various injection tools. In some embodiments, the compositions of the present disclosure can be administered to an individual via a transdermal delivery system, including: needles, microneedles, solid microneedles, coated microneedles, dissolving microneedles, hollow microneedles, microneedle patches with attached microneedles, microneedle (dermal) rollers, microneedle (dermal) stamps, mesotherapy guns, microsurgical devices, razors, superficial injection devices, electroporation, ultrasound-mediated microbubble cavitation (which involves administering cavitation-enhanced nanoparticles or microparticles to the skin and then irradiating the skin with ultrasound energy), needle-free intradermal injection, and any combination thereof, but the present disclosure is not limited thereto.

[0060] In at least one embodiment, the compositions of the present invention can be administered topically, intradermally, or subcutaneously to the target area, for example, by direct application or spraying onto the skin.

[0061] In at least one embodiment of the present disclosure, the polypeptide is at least 35% identical to TMD23 having the amino acid sequence of SEQ ID NO: 1. In some embodiments, the polypeptide of the present disclosure is at least 35% to 99%, 40% to 90%, 55% to 80%, or 50% to 75% identical to the amino acid sequence of SEQ ID NO: 1. In some embodiments, the polypeptide is at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 99.5% identical to the amino acid sequence of SEQ ID NO: 1.

[0062] In at least one embodiment, the polypeptide comprises a TME5 structure having an amino acid sequence that is at least 35% to 99%, 40% to 90%, 55% to 80%, or 50% to 75% identical to the amino acid sequence of SEQ ID NO: 3. In some embodiments, the polypeptide is at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% identical to the amino acid sequence of SEQ ID NO: 3.

[0063] In at least one embodiment, the polypeptide comprises a TME5C structure having an amino acid sequence that is at least 35% to 99%, 40% to 90%, 55% to 80%, or 50% to 75% identical to the amino acid sequence of SEQ ID NO: 4. In some embodiments, the polypeptide is at least 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 99.5% identical to the amino acid sequence of SEQ ID NO: 4.

[0064] The dosage of the composition of the present invention varies depending on age, individual differences, disease state, form of the composition, administration method, etc., and cannot be specifically specified. The effective amount of TMD23, ​​BB101, or a variant thereof varies depending on age, individual differences, individual disease state, form of the composition, administration method, etc., and is not particularly limited. Generally speaking, when administered to humans, the effective amount of TMD23, ​​BB101, or a variant thereof can be applied to the skin surface of the hair growth target per cm2. 2 An amount of 0.05 μg to 1 mg of TMD23, ​​BB101 or a variant thereof is administered, for example, per cm of skin surface. 2 An amount of about 0.05, 0.1, 0.5, 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900 or 1000 μg, but the present disclosure is not limited thereto. In some embodiments, the amount of the hair growth target skin surface per cm 2 An amount of 0.05 μg to 100 μg, 0.1 μg to 50 μg, or 10 μg to 200 μg of TMD23, ​​BB101, or a variant thereof is administered. In further embodiments, TMD23, ​​BB101, or a variant thereof can be used at a concentration of 0.05 μg / mL to 200 μg / mL when administered to an individual in need thereof.

[0065] The frequency of application of the composition of the present invention is not particularly limited. In some embodiments, the composition of the present invention is preferably applied to the affected area several times regularly (e.g., every 2 to 6 weeks or every 3 to 5 weeks) to maintain a good effect. In other words, the composition can be applied repeatedly. The frequency of application can be adjusted based on the individual's hair condition and the desired treatment outcome.

[0066] In other embodiments, the methods of the present disclosure further comprise administering a second active agent, wherein the second active agent is administered sequentially, simultaneously, or separately with the composition of the present invention.

[0067] Other objects and features of the present invention will become readily understood by considering the following detailed description in conjunction with the accompanying drawings. However, it should be understood that the drawings are designed for illustrative purposes only and are not intended to limit the present invention, for which reference should be made to the appended claims. It should be further understood that the drawings are not necessarily drawn to scale and, unless otherwise indicated, are intended merely to conceptually illustrate the structures and processes described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The present disclosure may be more fully understood by reading the following description of embodiments in conjunction with the accompanying drawings.

[0069] Figure 1 Figures show the effects of BB101 or TMD23 treatment on cell viability.

[0070] Figure 2 Figures show the effects of BB101 or TMD23 on hair growth in mice from day 1 to day 11 after administration compared to finasteride.

[0071] Figure 3 Figures show the effects of BB101 or TMD23 on hair growth in mice from day 13 to day 17 after administration compared to finasteride. DETAILED DESCRIPTION

[0072] The technical solutions described in the embodiments of the present disclosure will be described more clearly and completely. Obviously, the embodiments described are only a part of the embodiments of the present disclosure and are not exhaustive. The present disclosure can also be implemented or applied according to the different embodiments. All other embodiments obtained by those skilled in the art without inventive work are within the scope of the present disclosure.

[0073] It should be further noted that, as used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless expressly and unequivocally limited to one referent. The term "or" is used interchangeably with the term "and / or," unless the context clearly dictates otherwise.

[0074] As used herein, the terms "comprises," "includes," "has," "contains," and any other variations thereof are intended to cover a non-exclusive inclusion. For example, when an object is described as "comprising" an element, unless otherwise stated, it may also include other components, elements, components, structures, regions, parts, devices, systems, steps, or connections, and other elements should not be excluded.

[0075] As used herein, the term "prevention" refers to measures to prevent or avoid a disease, symptom, or condition, including, but not limited to, applying or administering one or more active agents to an individual who has not yet been diagnosed with the disease, symptom, or condition but may be susceptible or prone to the disease, symptom, or condition. The present disclosure provides preventative measures to avoid, prevent, or delay a disease, symptom, or condition, such as hair loss.

[0076] As used herein, the term "treating" refers to obtaining a desired pharmacological, physiological, and / or cosmetic effect, e.g., restoration of hair growth. The effect can be prophylactic, i.e., complete or partial prevention of a condition, appearance, disease, or symptom, and / or can be therapeutic, i.e., partial or complete cure of a condition and / or side effects attributable to a condition or disease.

[0077] As used herein, the term "administering" refers to placing an active agent into an individual by a method or route that results in the active agent being at least partially localized at a desired site to produce a desired effect. The active agents described herein can be administered by any suitable route known in the art. For example, the compositions of the present disclosure are administered intradermally to an individual.

[0078] As used herein, the term "effective amount" refers to a sufficient amount of a composition to provide a hair growth promoting effect at a reasonable beneficial-harmful ratio. The amount and ratio of the active ingredient will be determined within the scope of appropriate medical judgment, depending on the condition of the affected area, the severity of the symptoms, the cause of the disease, the duration of treatment, the specific active ingredient contained, the concentration, the method of administration, and the overall health of the patient. These may vary depending on various factors, such as the condition, the individual's tolerance to administration, and other drugs administered to the individual.

[0079] As described herein, the term "recombinant" may refer to changes in genetic material that are made by human intervention. For example, recombinant may refer to manipulation of DNA or RNA in a cell or virus or expression vector by molecular biology (recombinant DNA technology), including replication and rearrangement. Recombinant may also refer to manipulation of DNA or RNA in a cell or virus by random or positional mutagenesis. "Recombinant" nucleic acids may be described with reference to differences from naturally occurring counterparts (wild type). Recombinant protein may refer to a protein expressed via recombinant DNA technology. A recombinant protein has an amino acid sequence similar to that of its parent protein and maintains the same activity or function.

[0080] As used herein, the term "intradermal" refers to within the dermal tissue of the skin, and "subcutaneous" refers to application of the composition to the fatty tissue of the skin.

[0081] The numerical ranges used herein are inclusive and combinable, and any numerical value falling within the numerical range herein can be regarded as a maximum or minimum value to derive a subrange therefrom. For example, it should be understood that the numerical range "0.05 μg to 1 mg" includes any subrange between the minimum value 0.05 μg and the maximum value 1 mg, such as subranges from 0.05 μg to 0.1 μg, 0.3 μg to 5 μg, 1 μg to 10 μg, 15 μg to 500 μg, 10 μg to 1000 μg, 30 μg to 80 μg, etc. In addition, multiple numerical values ​​used herein can be selectively selected as maximum and minimum values ​​to derive a numerical range. For example, the numerical ranges of 0.1 μg to 50 μg, 0.1 μg to 100 μg, and 50 μg to 100 μg can be derived from the numerical values ​​of 0.1 μg, 50 μg, and 100 μg.

[0082] As used herein, the term "about" generally refers to a value that varies by ±20%, ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from a given value or range. Such variation in the value may occur due to, for example, experimental error, typical errors in the measurement or processing procedures used to prepare the compounds, compositions, concentrates, or formulations, differences in the source, manufacture, or purity of the starting materials or ingredients used in the present disclosure, or similar considerations. Alternatively, the term "about" means falling within an acceptable standard error of the mean when considered by one of ordinary skill in the art. Unless expressly stated otherwise, all numerical ranges, amounts, values, and percentages disclosed herein, such as amounts of material, duration of time periods, temperatures, operating conditions, ratios of quantities, and the like, should be understood in all instances to be modified by the term "about."

[0083] As described herein, the term "hair" in this disclosure is not limited to hair growing on the scalp, but includes eyelashes, eyebrows, beards, ears, nose, chest hair, pubic hair, etc., and refers to any hair on the scalp, head, face and body.

[0084] As used herein, the term "hair growth" refers to inducing new hair growth cycles, extending the growth phase, increasing the rate of hair growth, and increasing hair thickness.

[0085] As used herein, the terms "hair loss" and "thinning hair" refer to a loss of hair density, a shortened anagen phase, a decrease in hair shaft thickness, and a decrease in the number of hairs that may be due to aging, genetic factors, or other causes and may occur in and occur in men and women of all ages.

[0086] As used herein, the terms "patient" and "subject" are used interchangeably. The term "subject" refers to a human or other animal. Examples of subjects include, but are not limited to, humans, monkeys, mice, rats, woodchucks, ferrets, rabbits, hamsters, cows, horses, pigs, deer, dogs, cats, foxes, wolves, chickens, emus, and ostriches. In at least one embodiment of the present disclosure, the subject is a mammal, such as a primate (e.g., a human).

[0087] As used herein, the term "nucleic acid molecule" refers to a sequence of deoxyribonucleotides or ribonucleotides in double-stranded or single-stranded form, and generally includes naturally occurring nucleotides or artificial chemical mimics, without limitation to their origin. As used herein, the term "nucleic acid" includes natural or non-natural genes, polynucleotides, oligonucleotides, RNA, mRNA, DNA, cDNA, or nucleic acid analogs, but the disclosure is not limited thereto.

[0088] As used herein, the term "nucleic acid analog" refers to a compound or artificial nucleic acid that is structurally or functionally equivalent to natural RNA or DNA. In some embodiments, the nucleic acid analog may have at least a portion of the nucleotides (e.g., nucleobases, phosphate backbones, or pentoses) modified to alter the nucleic acid structure.

[0089] A number of examples have been used to illustrate the present disclosure. The following examples should not be considered as limiting the scope of the present disclosure.

[0090] Example

[0091] In order to describe the present disclosure in more detail, the disclosed method will be described in detail with reference to the following examples. Materials used in the present disclosure but not specified are commercially available.

[0092] Example 1: Effects of TMD23 and BB101 on cell viability

[0093] In a 96-well plate, 1x10 4Hair follicle dermal papilla cells (HFDPCs) were cultured for 12 hours and exposed to 1 mM testosterone. Cells were then treated with varying concentrations of BB101 and TMD23. Cell viability was assessed 24 hours after treatment using MTT assay and expressed as a percentage of the DMSO control group.

[0094] like Figure 1 As shown, the results showed that treatment with BB101 or TMD23 significantly increased cell survival compared with the control group.

[0095] Example 2: TMD23 accelerates hair growth in mice

[0096] Six-week-old male C57BL / 6 mice were purchased from the Laboratory Animal Center. The space allocated for each 10 animals was 29x18x13cm. 3 All animals were maintained in a controlled temperature (22°C to 24°C) and humidity (50% to 60%) environment with a 12-h light-dark cycle for at least one week. Mice were ensured to have free access to standard laboratory chow and RO water. All aspects of this operation, including animal husbandry, experiments, and handling, were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (National Academy Press, Washington, DC, 1996).

[0097] The animals were housed and acclimated to the laboratory environment for 1 week, after which 7-week-old mice were divided into 5 groups, with 3 mice in each group: a 50 μg / mL BB101-treated group, a 200 μg / mL BB101-treated group, a 50 μg / mL TMD23-treated group, and a 200 μg / mL TMD23-treated group.

[0098] To evaluate the effect of hair growth, the back of each mouse was shaved using animal electric clippers one day before the start of the experiment. The back was divided into two areas, and testosterone was topically applied to the two areas once a day on the shaved skin of each mouse throughout the experiment. In the lower area, the test drugs TMD23, ​​BB101 and finasteride were topically applied to the shaved skin through a transdermal delivery system (dermal stamp) once a day, with 2 stamps (volume of about 20 μL) each time. Water was given as a solution control group through the delivery system in the upper area. Mice were photographed with a digital camera under ether anesthesia to evaluate the darkening of skin color on days 1, 9, 11, 13, 15 and 17. The animal care and procedures of this study were in accordance with IACUC (Institutional Animal Care and Use Committee LAC-2022-0137) guidelines.

[0099] The results showed that on day 17 after application, the darkening of skin color between the test group and the positive treatment group (finasteride) was comparable, indicating that TMD23 and BB101 are effective in accelerating hair growth and treating hair loss ( Figure 2 and Figure 3 ).

[0100] Although some embodiments of the present disclosure have been described in detail above, various modifications and variations may be made to the illustrated embodiments by those skilled in the art without departing substantially from the teachings and advantages of the present disclosure. Therefore, such modifications and variations are intended to be within the scope of the present disclosure as set forth in the appended claims.

Claims

1. A method for preventing or treating hair loss or promoting hair growth or regeneration, characterized in that: The invention comprises administering a composition to an individual in need thereof, wherein the composition comprises an effective amount of a polypeptide or a nucleic acid molecule encoding the polypeptide, and the polypeptide comprises an amino acid sequence having an EGF-like domain of thrombomodulin or a conservative variant thereof.

2. The method according to claim 1, wherein The polypeptide is a recombinant polypeptide comprising an amino acid sequence having the EGF-like structure of the thrombomodulin or a conservative variant thereof, which is operably linked to the serine-threonine-rich domain of the thrombomodulin.

3. The method according to claim 2, wherein The number of the EGF-like structures is 1 to 6.

4. The method according to claim 3, wherein The recombinant polypeptide is substantially composed of an amino acid sequence having six EGF-like structures of the thrombomodulin or a conservative variant thereof, which is operably linked to the serine-threonine-rich domain of the thrombomodulin.

5. The method according to claim 1, wherein The polypeptide is at least 35% identical to TMD23 having the amino acid sequence of SEQ ID NO:

1.

6. The method according to claim 1, wherein The polypeptide consists essentially of BB101 having the amino acid sequence of SEQ ID NO:

2.

7. The method according to claim 1, wherein The polypeptide comprises a TME5 structure having an amino acid sequence that is at least 35% identical to SEQ ID NO:

3.

8. The method according to claim 1, wherein The polypeptide comprises a TME5C structure having an amino acid sequence at least 35% identical to SEQ ID NO:

4.

9. The method according to claim 1, wherein The nucleic acid molecule is an exogenously introduced polynucleic acid used to increase the expression of the polypeptide in the individual.

10. The method according to claim 1, wherein The hair loss is selected from the group consisting of baldness, menopausal baldness, androgenetic alopecia, male pattern baldness, female pattern baldness, alopecia areata, traction alopecia, anagen effluvium, telogen effluvium, cicatricial alopecia, hair loss caused by infectious diseases, hair loss caused by chemotherapy, hair loss caused by radiation, hair loss caused by hormonal imbalance, hair loss caused by drugs, hair loss caused by chemical exposure, hair loss caused by stress, and any combination thereof.

11. The method according to claim 1, wherein The composition is applied to the skin of the individual.

12. The method according to claim 1, wherein The composition is administered to the subject topically, intradermally, or subcutaneously.

13. The method according to claim 1, wherein Further included is the administration of physical intervention, chemical intervention, or a combination thereof.

14. The method according to claim 13, wherein The physical intervention is selected from the group consisting of needles, microneedles, microneedle patches, microneedle rollers, microneedle stamps, mesotherapy guns, microsurgical devices, razors, superficial injection devices, needle-free intradermal injections, temperature elevation, electroporation, ultrasound conduction, ultrasound-conducted microbubble cavitation, and any combination thereof.

15. The method according to claim 1, wherein The composition further comprises a pharmaceutically or cosmetically acceptable carrier.

16. The method according to claim 1, wherein The composition is formulated in a form selected from the group consisting of gel, cream, paste, emulsion, spray, suspension, solution, dispersion, hydrogel, liquid, emulsion, ointment, film, oral cream, powder and liniment.

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