Compositions comprising finasteride and uses thereof

Abstract

The application belongs to the field of medicine, and discloses a composition containing finasteride and use thereof. The composition contains finasteride, graphene and one or more pharmaceutically acceptable excipients. The composition of the application can be used to prevent and / or treat alopecia, seborrheic alopecia, androgenic alopecia, alopecia areata, or promote hair growth, and the amount of active ingredient is greatly reduced compared with finasteride tablets, thereby reducing the side effects associated therewith, and the composition has fast onset, long duration of action and good efficacy.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically relating to a topical composition comprising finasteride and graphene, which can be used as a medicine to prevent and / or treat hair loss, seborrheic alopecia, androgenetic alopecia or alopecia areata, or to promote hair growth. Background Technology

[0002] Each hair follicle in an individual undergoes a recurring cyclical growth process, including an active growth phase (anagen phase), which can last approximately 2 to 6 years; a transitional phase (catagen phase), lasting only one to two weeks; and a resting phase (telogen phase), lasting 3 to 4 months. Hair falls out at the end of the telogen phase, and new hair grows with each cycle. The human scalp contains approximately 100,000 hair follicles, with about 86% typically in the anagen phase, 1% in the catagen phase, and 13% in the telogen phase. Therefore, in a normal adult, approximately 100 hairs fall out of the scalp every day. Statistics show that approximately 252 million people in China experience hair loss, of which 164 million are men. Currently, the available drugs in China are oral finasteride tablets and topical minoxidil solution. The domestic market size for androgen-related hair loss drugs was approximately 1.69 billion yuan in 2020 and is expected to reach 4.73 billion yuan by 2028.

[0003] Excessive hair loss or alopecia can be divided into two types: non-scarring alopecia and scarring alopecia, and can be caused by a variety of factors. For example, non-scarring alopecia is usually attributed to genetics and advanced age; the use of medications such as chemotherapy drugs for cancer, birth control pills, etc.; topical chemotherapy, such as hair dyes, perms, and straighteners; diseases such as leprosy or syphilis; pathological conditions; allergies; and hair follicle infections. Scarring alopecia, on the other hand, may be caused by burns, such as accidental or postoperative burns from cryotherapy or laser surgery, or other types of trauma, which usually lead to the destruction of hair follicles.

[0004] The most common type of hair loss in humans is androgenetic alopecia, a non-scarring loss of telogen effluvium caused by excessive androgen activity in genetically susceptible men and women. Androgenetic alopecia is the most common hair loss disease in men, with an incidence rate as high as 20%. Clinically, it manifests as progressive thinning and reduction of hair on the crown of the head, with some patients experiencing baldness, accompanied by seborrheic dermatitis of the scalp. The pathogenesis of androgenetic alopecia involves the metabolism of testosterone to dihydrotestosterone (DHT) by 5-α-reductase (SRD5A2). DHT activates androgen receptors in hair follicles. After binding to androgen receptors, DHT enters the cell nucleus, activates androgen receptor coactivator, and initiates a multi-step molecular pathway involving target gene transcription and protein translation, thereby exerting its biological effects. The skin contains all the enzymes required for androgen metabolism and can be considered a peripheral organ that locally synthesizes large amounts of androgens with endocrine or paracrine functions. The autonomous formation of androgens allows the human skin to adjust androgen levels according to local needs, resulting in different responses in hair follicles. Testosterone is the main circulating androgen. It reaches the skin through capillaries and is converted into the more active androgen DHT (dihydrotestosterone, mainly found in the prostate, seminal vesicles, epididymis, hair follicles, and liver) by 5α-reductase (5αR) in the cytoplasm (Lolli F, Pallotti F, Rossi A, et al. Androgenetic alopecia: a review. Endocrine. 2017; 57(1):9-17.). DHT enters the cell nucleus, which leads to the inhibition of hair protein synthesis, causing hair matrix cells to lose vitality and gradually begin to keratinize, resulting in hair follicle atrophy and necrosis. In addition to affecting hair follicle growth and differentiation, DHT also promotes the proliferation, differentiation, and secretion of sebaceous gland cells, accelerating scalp oil production.

[0005] Finasteride is a competitive and specific inhibitor of type II 5α-reductase. It inhibits this enzyme, blocking the conversion of testosterone to DHT, reducing scalp DHT levels to those found in hairy scalps, lowering serum DHT, thereby increasing hair regrowth and slowing hair loss. In 1998, the FDA first approved oral finasteride tablets (1 mg) for androgenetic alopecia (male). However, systemic administration of finasteride can cause adverse reactions such as decreased libido, erectile dysfunction, and ejaculatory dysfunction. Since type II 5α-reductase is mainly distributed in scalp hair follicles, topical administration of finasteride can minimize systemic adverse reactions and improve efficacy compared to oral administration. However, finasteride's hydrophobic nature and poor transdermal efficiency pose a significant challenge to topical administration.

[0006] Several topical compositions containing finasteride are known in the art. Difa Cooper SpA developed a topical spray containing 0.25% w / w finasteride and employing hydroxypropyl chitosan (HPCH) film-forming technology, which reduces the systemic side effects of finasteride compared to oral tablets. However, this product is prone to leakage when administered via spray, leading to absorption through the mouth and nose and increasing side effects. Additionally, the spray device is too bulky and inconvenient to carry. CN117883361A discloses a chitosan-finasteride nanocrystalline microneedle formulation that enhances skin retention and reduces systemic side effects; however, microneedle administration easily induces skin inflammation, and the preparation process is complex, making commercialization difficult. US11786466B2 discloses a finasteride liposome topical formulation that uses a specific water-soluble organosilicon to provide a local reservoir effect and barrier function, but it also suffers from a complex preparation process. Summary of the Invention

[0007] This invention overcomes the shortcomings of existing technologies by providing a composition containing finasteride and its uses. The composition can be used as a medicine in the treatment of hair loss, seborrheic alopecia, androgenetic alopecia, alopecia areata, or to promote hair growth.

[0008] The objective of this invention is achieved by at least one of the following technical solutions.

[0009] On one hand, the present invention provides a composition comprising: finasteride, graphene, and one or more pharmaceutically acceptable excipients.

[0010] In some embodiments, the graphene is monolayer graphene and / or (including both "and" and "or") oligolayer graphene. In some embodiments, the monolayer graphene comprises 60 wt% or more. In another embodiment, the monolayer graphene comprises 80 wt% or more. In yet another embodiment, the monolayer graphene comprises 90 wt% or more.

[0011] In some embodiments, the graphene has a nanostructure with an average diameter of 100 nm to 1000 nm, preferably 300 nm to 600 nm.

[0012] In some embodiments, the graphene content in the composition is 0.05% to 0.20% by mass, preferably 0.023% to 0.20%, more preferably 0.15% to 0.20%; and the finasteride content in the composition is 0.01 wt% to 0.5 wt%, preferably 0.23 wt%.

[0013] In some embodiments, the one or more pharmaceutically acceptable excipients comprise one or more of a solubilizer, diluent, humectant, suspending agent, and film-forming agent.

[0014] Furthermore, the co-solvent is selected from one of ethanol, polyethylene glycol, isopropanol, or propylene glycol.

[0015] Furthermore, the diluent is selected from water.

[0016] Furthermore, the moisturizer is selected from one or more of sodium hyaluronate and panthenol.

[0017] Furthermore, the suspending agent is selected from one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

[0018] In some embodiments, the amount of ethanol, polyethylene glycol, water, or a combination thereof is 50 wt% to 70 wt% based on the total weight of the composition. In another embodiment, the amount of ethanol, polyethylene glycol, water, or a combination thereof is 40 wt% to 80 wt% based on the total weight of the composition. In yet another embodiment, the amount of ethanol, polyethylene glycol, water, or a combination thereof is 20 wt% to 95 wt% based on the total weight of the composition.

[0019] In some embodiments, the amount of sodium hyaluronate is from 0.05 wt% to 10 wt% based on the total weight of the composition. In another embodiment, the amount of sodium hyaluronate is from 0.1 wt% to 5 wt% based on the total weight of the composition. In yet another embodiment, the amount of panthenol is 0.1 wt% based on the total weight of the composition.

[0020] In some embodiments, the amount of panthenol is from 0.5 wt% to 20 wt% based on the total weight of the composition. In another embodiment, the amount of panthenol is from 1 wt% to 10 wt% based on the total weight of the composition. In yet another embodiment, the amount of panthenol is from 3 wt% to 8 wt% based on the total weight of the composition.

[0021] In some embodiments, the composition is in the form of a topical solution, emulsion, ointment, suspension, or gel.

[0022] On the other hand, the present invention provides the use of the compositions described herein in the preparation of medicaments for the prevention and / or treatment of hair loss, seborrheic alopecia, androgenetic alopecia, or alopecia areata.

[0023] On the other hand, the present invention provides the use of the composition described herein in the preparation of a medicament for promoting hair growth.

[0024] In the composition described in this invention, the components have good compatibility.

[0025] In this invention, graphene can emit low-temperature far-infrared rays of the same wavelength as the human body, which can increase the local temperature of the scalp and promote local blood circulation in the scalp, thereby reducing hair loss and assisting hair growth. In addition, graphene can adsorb active pharmaceutical ingredients, deliver drugs and make them continuously released, making the combination of finasteride and graphene a truly synergistic combination for the prevention and treatment of hair loss, which can significantly reduce the dosage and toxic side effects of finasteride.

[0026] The method of using the pharmaceutical composition of this invention is as follows:

[0027] The compositions of this invention can be administered in topical or transdermal dosage forms, including but not limited to ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalers, and patches. Furthermore, this invention particularly considers the use of emulsions, gels, transdermal patches, or sprays, which offer numerous advantages in controlling the delivery of the composition into the body. Such dosage forms can be prepared by dispersing the compositions of this invention in a suitable medium. Absorption enhancers or penetration enhancers can increase the flow of the active ingredient through the skin, and the rate can be controlled by using rate-controlled films or by dispersing the composition in a polymer matrix or gelatin.

[0028] The compositions of the present invention are preferably formulated in dosage units to reduce dosage and ensure uniformity of administration. The term "dosage unit" refers to a physical dispersion of the drug required to provide adequate treatment to the patient. However, it should be understood that the total daily dosage of the compositions of the present invention will be determined by the attending physician based on reliable medical judgment. For any given patient or organism, the specific effective dosage level will depend on numerous factors, including the disease or condition to be treated and its severity, the specific composition used, the patient's age, weight, health status, sex, and dietary habits, the time of administration, the route of administration, and the absorption and excretion rates of the active ingredients involved, the duration of treatment, the use of the drug in combination therapy, and other factors known in the pharmaceutical field. Variations in the dosage of a single dosage form composition will depend on the treatment and the specific administration method. In some embodiments, the composition may be formulated as finasteride at a dosage of 0.001-0.1 mg / kg body weight / day, administered by means of the amount of composition received by the patient.

[0029] The composition of this invention can effectively prevent and / or treat hair loss, seborrheic alopecia, androgenetic alopecia, or alopecia areata, or promote hair growth. Compared with finasteride tablets, the dosage of its active ingredient is greatly reduced, alleviating its related side effects. It has a rapid onset of action, a long duration of effect, and excellent efficacy. The pharmaceutical composition of this invention can also be used in combination with other adjunctive therapeutic agents, including but not limited to minoxidil, dutasteride, JAK inhibitors, caffeine, and other plant extracts.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] The therapeutic composition of this invention comprises finasteride and graphene. Because graphene emits low-temperature far-infrared rays of the same wavelength as the human body, it increases the local temperature of the scalp, promotes local blood circulation in the scalp, thereby reducing hair loss and promoting hair growth. Furthermore, graphene can adsorb the active pharmaceutical ingredient, delivering the drug and allowing for its sustained release. This makes the combination of finasteride and graphene a truly synergistic combination for the prevention and treatment of hair loss, addressing both internal and external factors. It significantly reduces the dosage and toxic side effects of finasteride. The therapeutic composition of this invention effectively prevents and / or treats hair loss, seborrheic alopecia, androgenetic alopecia, alopecia areata, or promotes hair growth. Compared to finasteride tablets, it significantly reduces the dosage of its active ingredient, alleviates related side effects, and offers rapid onset of action, long-lasting efficacy, and excellent therapeutic effect. Attached Figure Description

[0032] Figure 1 This is the finasteride drug penetration-time curve. Detailed Implementation

[0033] To better understand the present invention, the following embodiments further illustrate the content of the present invention, but the content of the present invention is not limited to the following embodiments.

[0034] In the examples described below, all temperatures are in Celsius unless otherwise stated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Alfa Chemical Company, Aladdin, and Xilong Scientific. Unless otherwise stated, the reagents used in this invention are ready for use without further processing. Commonly used solvents were purchased from Aladdin, Xiya Reagent, Guangzhou Chemical Reagent Factory, and Nanjing Chemical Reagent Co., Ltd., all of AR or HPLC grade. Gas chromatography was performed using an Agilent 789013 column: a capillary column with bonded polyethylene glycol as the stationary phase (Agilent DB-Wax Ultra Inert, 30m × 0.25mm, 0.25μm). Water bath: Tianjin Tester Instrument Co., Ltd., DK-98-II. Centrifuge: Hunan Xiangyi Laboratory Instrument Development Co., Ltd., TG16-WS. 0.0001% balance: Mettler XSE105.

[0035] Unless otherwise specified, all reagents and materials used in the following examples are commercially available. For example, Aldrich Chemical Company, Alfa Chemical Company, Aladdin, and Xilong Scientific. Unless otherwise stated, the reagents used in this invention can be used without further processing. Commonly used solvents were purchased from Aladdin, West Asia Reagent, Guangzhou Chemical Reagent Factory, and Nanjing Chemical Reagent Co., Ltd., all of AR or HPLC grade. Gas chromatography detection was performed using an Agilent 789013 column: a capillary column with bonded polyethylene glycol as the stationary phase (Agilent DB-Wax Ultra Inert, 30m × 0.25mm, 0.25μm). Water bath: Tianjin Tester Instrument Co., Ltd., DK-98-II. Centrifuge: Hunan Xiangyi Laboratory Instrument Development Co., Ltd., TG16-WS. 0.0001% balance: Mettler XSE105.

[0036] Preparation methods of pharmaceutical compositions in Examples 1-4

[0037] 1. Weigh out the solvent ethanol, purified water, humectant propylene glycol, sodium hyaluronate or panthenol, and film-forming agent hydroxypropyl methylcellulose or povidone according to the proportions of Examples 1 to 4 in Table 1 below, and stir until a clear and transparent solution is formed (the humectant can be any one of propylene glycol, sodium hyaluronate or panthenol, or any two of them, or all three at the same time).

[0038] 2. Weigh finasteride and graphene according to the proportions of Examples 1 to 4, and stir to mix evenly to obtain a uniform suspension.

[0039] Table 1. Prescription ratios for Examples 1-4

[0040]

[0041]

[0042] In the above embodiments, the graphene includes monolayer graphene and oligolayer graphene.

[0043] Example 5

[0044] The pharmaceutical compositions of Examples 1 to 4 are filled into 15 ml to 25 ml unit dose or multi-dose containers.

[0045] Comparative Example 1

[0046] This embodiment does not contain graphene. The specific composition is: finasteride 0.23%, ethanol 48.3%, purified water 48.37%, sodium hyaluronate 0.1%, and hydroxypropyl methylcellulose E3 3%.

[0047] Comparative Example 2

[0048] The mass ratio of finasteride to graphene is 1:0.1, and the specific composition is as follows: finasteride 0.23%, graphene 0.023%, ethanol 48.3%, purified water 48.347%, sodium hyaluronate 0.1%, and hydroxypropyl methylcellulose E3 3%.

[0049] Comparative Example 3

[0050] The mass ratio of finasteride to graphene is 1:0.2, and the specific composition is as follows: finasteride 0.23%, graphene 0.046%, ethanol 48.3%, purified water 48.324%, sodium hyaluronate 0.1%, and hydroxypropyl methylcellulose E3 3%.

[0051] In Comparative Examples 2 and 3, the graphene contained monolayer graphene and oligolayer graphene; the ratio of monolayer graphene to graphene was 60 wt%.

[0052] Test Example 1: Permeability Study and Retention Test

[0053] 1. Ex vivo skin permeability test

[0054] In vitro drug penetration was performed using isolated hairless rat skin on a Franz diffusion cell with a contact surface area of ​​approximately 5 cm². The skin was washed repeatedly with PBS (pH 5.8) to remove adhering fat and subcutaneous tissue. 2 The sample was fixed between the donor and recipient compartments, with the stratum corneum in contact with the sample formulation and the dermis facing the recipient area. The drug composition of Example 2 was used as the treatment group, and the drug compositions of Comparative Examples 1, 2, and 3 were used as the control groups, with 1 ml of each placed in the donor compartment. PBS (pH 7.4) was used as the release medium to maintain the water bath conditions. The buffer temperature was stabilized at 32°C and stirred at 600 rpm. At predetermined time intervals (0, 2, 4, 6, 8, 12, 16, and 24 hours), 5 mL of sample was removed from the recipient compartment and replaced with the same volume of fresh buffer. The active substance was simultaneously quantified by HPLC-MS / MS. This experiment was repeated three times.

[0055] 2. Skin drug retention research

[0056] For the skin drug retention study, the skin was separated from the diffusion cell 24 hours after the ex vivo skin permeability study. The epidermal sample was recovered, and any residual formulation was removed from the epidermal surface. Subsequently, the skin was washed with 10 mL of methanol to remove any additional residual formulation. Afterward, the skin was homogenized with 5 mL of methanol, sonicated for 30 min, and finally centrifuged (15 min, 10000 rpm). The supernatant was analyzed by HPLC-MS / MS. The amount of drug retained from the skin was determined. This experiment was repeated three times.

[0057] Table 2. Permeability and Drug Retention Data

[0058]

[0059] The results are shown in Table 2 and Figure 1 As shown, the addition of graphene to the drug combination significantly reduces the permeation and flux of finasteride, resulting in extremely low drug concentrations entering the bloodstream and avoiding systemic drug effects. Permeation and drug retention data indicate that the finasteride-graphene combination can release slowly and act locally, exhibiting an ideal "drug reservoir" effect.

[0060] However, the concentration of graphene affects the above effects. Based on the concentrations of finasteride and graphene in Comparative Examples 1-3, the effect is not significantly different from that without graphene; the effect is not obvious. In Example 2, the concentrations of finasteride and graphene were 0.23% and 0.20% respectively, i.e., a mass ratio of 1:0.9, which showed a significant effect. Exceeding this ratio affected the properties of the drug solution and resulted in poor suspension. Therefore, the optimal ratio of finasteride to graphene is 0.23% and 0.023%–0.20%.

[0061] Test Example 2: Pharmacodynamic Test

[0062] Twelve male mice were randomly divided into groups A and B, with six mice in each group. Approximately 5 cm² of the back of mice in group A were scraped off. 2 For hair, the drug composition of Example 2 was used for in vitro application, with 0.2 mL (0.46 mg) applied evenly to the hair removal area once a day for 3 consecutive weeks. Group B was given finasteride tablets (1 mg) orally once a day for 3 consecutive weeks. The hair growth on the back of the mice was observed and the hair growth coverage rate was calculated. The results are shown in Table 3.

[0063] Table 3 Results of mouse hair growth coverage

[0064] Group Test sample Average coverage of mouse fur growth (n=3) 1 Example 2 83.4％ 2 Finasteride tablets 71.3％

[0065] As shown in Table 3, the finasteride-graphene composition of Example 2 exhibited significantly higher dorsal hair growth rate in mice after 3 weeks of topical application compared to the finasteride tablet group. Preliminary pharmacodynamic studies suggest that finasteride-graphene requires a lower dosage and provides better efficacy than finasteride tablets.

[0066] Test Example 3: Skin Irritation Assessment

[0067] The skin irritation of the finasteride and graphene composition prepared in Example 2 was evaluated and compared with that of a commercially available finasteride spray as a comparative example. One male rabbit weighing 2.0 ± 0.2 kg was used. 24 hours before administration, the hair on both sides of the rabbit's spine was removed with sodium sulfide, with a hair removal area of ​​50 cm² on each side. 2A left-right control was used. 1 mL of the finasteride and graphene combination was applied to the left side of the rabbits, while 1 mL of finasteride spray was applied to the right side. The skin was covered with gauze, and after 24 hours, the skin was washed off with warm water to remove any drug residue. The presence of erythema and edema was observed and recorded. The treatment was repeated once daily for one week. The skin condition of the rabbits was observed at 0, 12, 24, and 48 hours after the last application. The presence of erythema and edema, or other skin irritation, was visually assessed. The results are shown in Table 5.

[0068] Table 4 Results of skin irritation

[0069]

[0070] As shown in Table 4, the skin irritation of finasteride combined with graphene is significantly less than that of finasteride spray, indicating that the combination of finasteride and graphene can significantly reduce skin irritation and has higher safety and patient compliance.

[0071] Finally, it should be noted that there are other ways to implement this invention. Accordingly, the embodiments of the invention are described as examples, but are not limited to the content described herein, and may include modifications made within the scope of the invention or equivalent content added to the claims. All publications or patents cited in this invention are to be used as references in this invention.

Claims

1. A composition characterized in that, It is composed of the following ingredients: 0.23% finasteride, 0.2% graphene, 48.3% ethanol, 48.17% purified water, 0.1% sodium hyaluronate, and 3% hydroxypropyl methylcellulose E3; The graphene comprises monolayer graphene and oligolayer graphene; the ratio of monolayer graphene to oligolayer graphene is 60 wt%. The graphene has a nanostructure with an average diameter of 100 nm to 1000 nm. Use of the composition in the preparation of medicaments for the prevention and / or treatment of hair loss, seborrheic alopecia, androgenetic alopecia, alopecia areata, or the promotion of hair growth; The composition is in the form of a topical solution, emulsion, ointment, suspension, or gel.

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