Compositions comprising finasteride and uses thereof

Abstract

The invention belongs to the field of medicines, and discloses a finasteride-containing composition and application thereof. The composition comprises finasteride, graphene and more than one pharmaceutically acceptable auxiliary material. The composition can well prevent and / or treat alopecia, alopecia seborrhoeica, androgenetic alopecia and alopecia areata or promote hair growth, compared with finasteride tablets, the dosage of active ingredients of the composition is greatly reduced, related side effects of the active ingredients are relieved, and the composition is quick in effect taking, long in drug effect lasting time and good in curative effect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and particularly relates to an external composition containing finasteride and graphene, which can be used as a medicine for preventing and / or treating hair loss, seborrheic alopecia, androgenic alopecia or alopecia areata, or promoting hair growth. Background Art

[0002] In an individual, each hair follicle undergoes a repetitive cyclical growth cycle, including an active growth phase (anagen), which can last approximately 2 to 6 years; a transitional phase (catagen), which lasts only one or two weeks; and a resting phase (telogen) that lasts 3 to 4 months. Hair falls out at the end of the telogen phase, and as the cycle repeats, new hair grows. The human scalp contains approximately 100,000 hair follicles. Typically, about 86% of the follicles are in the anagen phase, 1% are in the catagen phase, and 13% are in the telogen phase. Therefore, in normal adults, approximately 100 hairs fall out from the scalp every day. According to statistics, approximately 252 million people in China experience hair loss, of which 164 million are male. Currently, the marketed drugs in China are oral finasteride tablets and topical minoxidil solutions. The market size of androgen-related hair loss drugs in China in 2020 was approximately 1.69 billion yuan, and is expected to reach 4.73 billion yuan in 2028.

[0003] Excessive hair loss or alopecia can be divided into two types, namely non-scarring alopecia and scarring alopecia, and can be caused by various factors. For example, non-scarring alopecia is usually attributed to genetics and advanced age; drug administration such as anticancer chemotherapy drugs and contraceptives; local chemotherapy, such as hair dyes, perming agents, and straightening irons; diseases, such as leprosy or syphilis; morbidity; allergies; and follicular infections. Scarring alopecia may be caused by burns, such as accidental or post-operative burns caused by cryosurgery or laser surgery, or other types of trauma, which usually result in follicular damage.

[0004] The most common type of hair loss in humans is androgenic alopecia, which is a non-scarring hair loss of telogen induced by excessive androgen action in genetically susceptible men and women. Androgenic alopecia is the most common hair loss disease in men, with an incidence rate of up to 20%. The clinical manifestations are progressive hair loss and thinning on the top of the head of the patient, and some patients will have baldness, accompanied by seborrheic dermatitis of the scalp. The pathogenesis of androgenic alopecia is induced by the metabolism of testosterone into dihydrotestosterone (DHT) under the action of 5-α reductase (SRD5A2), and dihydrotestosterone activates the androgen receptors of the hair follicles. After binding to the androgen receptor, dihydrotestosterone enters the cell nucleus, activates androgen receptor coactivators, and initiates a multi-step molecular pathway such as target gene transcription and protein translation, thereby exerting biological effects. The skin contains all the enzymes required for androgen metabolism and can be regarded as a peripheral organ that locally synthesizes a large amount of androgens with endocrine or paracrine effects. The autonomous formation of androgens enables the human skin to adjust the level of androgens according to local needs and causes different responses in the 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 will lead to the blockage of hair protein synthesis, causing hair matrix cells to lose vitality and slowly begin to keratinize, thus leading to hair follicle atrophy and necrosis. In addition to affecting the growth and differentiation of hair follicles, DHT also promotes the proliferation, differentiation and secretion of sebaceous gland cells, accelerating the oil production of the scalp.

[0005] Finasteride is a competitive and specific inhibitor of type II 5α-reductase, which can inhibit type II 5α-reductase, block the conversion of testosterone to DHT, reduce the scalp DHT concentration to the level in the hairy scalp, reduce serum DHT, thereby increasing hair regeneration and slowing hair loss. In 1998, the FDA first approved finasteride oral tablets (1mg) for androgenetic alopecia (male), but systemic administration of finasteride can cause adverse reactions, such as decreased libido, erectile dysfunction, and ejaculation disorders. Since type II 5α-reductase is mainly distributed in the scalp hair follicles, local administration of finasteride can minimize systemic adverse reactions and improve efficacy compared to oral administration. However, finasteride is hydrophobic and has poor transdermal efficiency, which poses a great challenge to local administration.

[0006] Some topical compositions containing finasteride are known in the art. Difa Cooper S.p.A. has developed a topical spray containing 0.25% w / w finasteride and using hydroxypropyl chitosan (HPCH) film-forming technology, which can reduce the systemic side effects of finasteride compared to oral tablets. However, when this product is administered by spraying, it is prone to leakage, and thus is absorbed through the mouth and nose, increasing side effects. In addition, the spray device is too large and inconvenient to carry. CN117883361A discloses a chitosan-finasteride nanocrystal microneedle preparation that can enhance the skin retention of finasteride and reduce systemic side effects, but microneedle administration is prone to cause skin inflammatory reactions, and the preparation process is complex, making it difficult to commercialize. US11786466B2 discloses a finasteride liposome topical preparation that uses a specific water-soluble silicone to provide a local depot effect and barrier function, but it also has a complex preparation process. Summary of the Invention

[0007] The present invention overcomes the defects of the prior art and provides a composition containing finasteride and its uses. The composition can be used as a drug in the treatment of hair loss, seborrheic alopecia, androgenetic alopecia, alopecia areata or promoting hair growth.

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

[0009] On the one hand, the present invention provides a composition, which comprises: 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" cases) few-layer graphene. In some embodiments, the proportion of monolayer graphene is more than 60 wt%. In another embodiment, the proportion of monolayer graphene is more than 80 wt%. In another embodiment, the proportion of monolayer graphene is more than 90 wt%.

[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 mass content of graphene in the composition is 0.05% to 0.20%, preferably 0.023% to 0.20%, more preferably 0.15% to 0.20%; the mass content of finasteride 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 include one or more of a co-solvent, a diluent, a humectant, a suspending agent and a film-forming agent.

[0014] Further, the cosolvent is selected from one of ethanol, polyethylene glycol, isopropanol or propylene glycol.

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

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

[0017] Further, the suspending agent is selected from one or more of hypromellose, sodium carboxymethylcellulose, polyvinylpyrrolidone and polyvinyl alcohol.

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

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

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

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

[0022] On the other hand, the present invention provides the use of the composition of the present invention in the preparation of a medicament for preventing and / or treating hair loss, seborrheic alopecia, androgenetic alopecia or alopecia areata.

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

[0024] In the composition of the present invention, the components have good compatibility with each other.

[0025] In the present invention, since graphene can emit low-temperature far-infrared rays with the same wavelength as that of the human body, it can increase the local temperature of the scalp, promote local blood circulation of the scalp, thereby reducing hair loss and assisting hair growth. Moreover, graphene can adsorb the active ingredients of drugs, deliver the drugs and enable their sustained release, making the combination of finasteride and graphene a truly synergistic combination for preventing and treating hair loss both internally and externally. It can significantly reduce the dosage and side effects of finasteride.

[0026] The usage method of the pharmaceutical composition in the present invention is as follows:

[0027] The composition of the present invention can be administered through local or transdermal dosage forms, including but not limited to ointments, pastes, emulsions, lotions, gels, powders, solutions, sprays, inhalants, patches. Additionally, the present invention particularly contemplates the application of emulsions, gels, transdermal patches or sprays, which have many advantages in controlling the delivery of the composition to the body. Such dosage forms can be prepared by dispersing the composition of the present invention in a suitable medium. Absorption promoters or penetration enhancers can increase the flux of the active ingredient through the skin, and the rate can be controlled by a rate-controlling membrane or by dispersing the composition in a polymeric matrix or gelatin.

[0028] The composition of the present invention is preferably prepared into dosage unit forms according to the formulation to reduce the dosage and ensure the uniformity of the dosage. The term "dosage unit form" refers to the physical dispersion unit of the drug required for a patient to receive appropriate treatment. However, it should be understood that the total daily usage of the composition of the present invention will be determined by the attending physician based on a reliable medical range judgment. For any particular patient or organism, the specific effective dosage level will depend on many factors, including the disease or disorder to be treated and the severity of the disease or disorder, the specific composition used, the patient's age, weight, health status, gender and eating habits, the time of administration, the administration route, and the absorption and excretion rates of the active ingredient involved, the duration of treatment, the application of the drug in combination with other drugs, and other factors well-known in the pharmaceutical field. The change in the dosage of the single-dose form composition will depend on the attending physician and the specific administration mode. In some embodiments, the composition can be prepared into a dosage of finasteride at 0.001 - 0.1 mg / kg body weight / day according to the formulation method and administered according to the amount of the composition received by the patient.

[0029] The composition of the present invention can well prevent and / or treat hair loss, seborrheic alopecia, androgenetic alopecia, or alopecia areata, or in the preparation of promoting hair growth. Compared with finasteride tablets, the dosage of its active ingredient is greatly reduced, reducing its related side effects, with a fast onset, a long duration of drug effect, and good curative effects. The pharmaceutical composition of the present invention can also be used in combination with other additional therapeutic agents, including but not limited to minoxidil, dutasteride, JAK inhibitors, caffeine, other plant extracts, etc.

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

[0031] The therapeutic composition of the present invention is composed of finasteride and graphene. Since graphene can emit low-temperature far-infrared rays with the same wavelength as the human body, it can increase the local temperature of the scalp, promote local blood circulation in the scalp, thereby reducing hair loss and assisting hair growth. Moreover, graphene can adsorb the active ingredients of drugs, deliver drugs and enable their sustained release, making the composition of finasteride and graphene a truly synergistic combination for preventing and treating hair loss both internally and externally. It can significantly reduce the dosage and side effects of finasteride. The therapeutic composition of the present invention can effectively prevent and / or treat hair loss, seborrheic alopecia, androgenic alopecia, alopecia areata, or promote hair growth. Compared with finasteride tablets, the dosage of its active ingredients is greatly reduced, reducing its related side effects, with a fast onset, a long duration of efficacy, and good curative effects. Brief Description of the Drawings

[0032] Figure 1 It is the finasteride drug penetration amount-time curve. Detailed Embodiments

[0033] To better understand the present invention, the content of the present invention will be further clarified below in conjunction with embodiments, but the content of the present invention is not limited to the following embodiments.

[0034] Unless otherwise indicated, all temperatures in the following-described embodiments are in degrees Celsius. Reagents are purchased from commercial suppliers, such as Aldrich Chemical Company, Alfa Chemical Company, aladdin, Xilong Scientific. Unless otherwise specified, the reagents used in the present invention can be used without further treatment. Common solvents are purchased from aladdin, West Asia Reagents, Guangzhou Chemical Reagent Factory, and Nanjing Chemical Reagent Co., Ltd., all of which are of AR grade or HPLC grade. Gas chromatography detection is carried out using Agilent 789013, chromatographic column: capillary column with bonded polyethylene glycol as the stationary liquid (Agilent DB-WaxUltra Inert, 30m×0.25mm, 0.25μm). Water bath: Tianjin Test Instrument Co., Ltd., DK-98-II. Centrifuge: Hunan Xiangyi Laboratory Instrument Development Co., Ltd., TG16-WS. One-hundred-thousandth balance: Mettler XSE105.

[0035] Unless otherwise specified, the reagents and materials used in the following examples are commercially available. For example, Aldrich Chemical Company, Alfa Chemical Company, aladdin, Xilong Scientific. Unless otherwise stated, the reagents used in the present invention can be used without further treatment. Common solvents are purchased from aladdin, Xiya Reagent, Guangzhou Chemical Reagent Factory and Nanjing Chemical Reagent Co., Ltd., all of which are of AR grade or HPLC grade. Gas chromatography detection is carried out using Agilent 789013, chromatographic column: capillary column with bonded polyethylene glycol as the stationary liquid (Agilent DB-Wax Ultra Inert, 30m×0.25mm, 0.25μm). Water bath: Tianjin Test Instrument Co., Ltd., DK-98-II. Centrifuge: Hunan Xiangyi Laboratory Instrument Development Co., Ltd., TG16-WS. One in one hundred thousand balance: Mettler XSE105.

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

[0037] 1. Weigh the solvent ethanol, purified water, the humectants propylene glycol, sodium hyaluronate or panthenol, and the film-forming agents hypromellose or polyvinylpyrrolidone according to the ratios 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 are used simultaneously).

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

[0039] Table 1 Prescription ratios of Examples 1-4

[0040]

[0041]

[0042] In the above examples, the graphene includes single-layer graphene and few-layer graphene.

[0043] Example 5

[0044] Fill the pharmaceutical compositions of Examples 1-4 into 15 ml - 25 ml unit-dose or multi-dose containers.

[0045] Comparative Example 1

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

[0047] Comparative Example 2

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

[0049] Control Example 3

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

[0051] In Control Example 2 and Control Example 3, the graphene contains single-layer graphene and few-layer graphene; the ratio of single-layer graphene to graphene is: 60 wt%.

[0052] Test Example 1 Permeability Study and Retention Test

[0053] 1. Ex vivo Skin Permeability Test

[0054] In vitro drug permeation was carried out using ex vivo hairless rat skin on a Franz diffusion cell with a contact surface area. The skin was washed several times with PBS (pH 5.8) to remove adherent fat and subcutaneous tissue. The skin (about 5 cm 2 ) was fixed between the donor and receptor compartments, with the stratum corneum in contact with the sample preparation and the dermis facing the receptor compartment. The drug composition of Example 2 was used as the treatment group, and the drug combinations of Control Example 1, Control Example 2, and Control Example 3 were used as the control groups. 1 ml of each was placed in the donor compartment. PBS (pH 7.4) was used as the release medium to maintain the sink 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 the sample was taken from the receptor compartment and replaced with the same volume of fresh buffer. The active substance was synchronously quantified by HPLC-MS / MS method. This experiment was repeated three times.

[0055] 2. Skin Drug Retention Study

[0056] For the skin drug retention study, after 24 hours of the ex vivo skin permeability study, the skin was separated from the diffusion cell, the epidermal sample was recovered and any residual preparation was removed from the epidermal surface. Subsequently, it was washed with 10 mL of methanol to remove any additional residual preparation. Thereafter, the skin was homogenized with 5 mL of methanol, the sample was sonicated for 30 min, and finally the sample was centrifuged (15 minutes, 10000 rpm) and the supernatant was analyzed by HPLC-MS / MS method. The amount of drug retained extracted 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, when graphene is added to the drug combination, the penetration amount and flux of finasteride are significantly reduced, resulting in a very low drug concentration entering the blood, avoiding the systemic effect of the drug. The data of the penetration amount and drug retention amount show that the finasteride-graphene composition can release slowly and act locally, showing an ideal "drug depot" effect.

[0060] However, the concentration of graphene will affect the above effects. According to the concentrations of finasteride and graphene in Comparative Examples 1-3, the effects are not much different from those without graphene addition, and the effects are not obvious. The respective concentrations of finasteride and graphene in Example 2 are: 0.23% and 0.20%, that is, the mass ratio of 1:0.9 has obvious effects. Exceeding this ratio will affect the properties of the liquid medicine and the suspension effect is not good. Therefore, the optimal ratio of finasteride to graphene is 0.23% and 0.023% - 0.20%.

[0061] Test Example 2 Pharmacodynamic Test

[0062] Take 12 male mice and randomly divide them into groups A and B, with 6 mice in each group. In group A, the hair on the back of the mice with an area of about 5 cm 2 is shaved off, and the drug combination in Example 2 is used for external application. It is applied once a day, 0.2 mL (0.46 mg) each time, evenly on the depilated area, and continuously applied for 3 weeks. In group B, finasteride tablets (1 mg) are taken orally, once a day, and continuously applied for 3 weeks. Observe the hair growth on the back of the mice and calculate the hair growth coverage rate. The results are shown in Table 3.

[0063] Table 3 Results of Hair Growth Coverage Rate of Mouse Hair

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

[0065] As can be seen from Table 3, the back hair growth rate of the finasteride-graphene composition in Example 2 is significantly higher than that of the finasteride tablet group after 3 weeks of local use. Through the preliminary study of pharmacodynamics, it can be preliminarily judged that finasteride-graphene has a lower dose and better efficacy than finasteride tablets.

[0066] Test Example 3 Evaluation of Skin Irritation

[0067] Evaluate the skin irritation of the finasteride and graphene composition prepared in Example 2 and compare it with the commercially available finasteride spray in the comparative example. Take 1 male rabbit weighing 2.0 ± 0.2 kg. 24 hours before drug administration, the hair on both sides of the back spine of the rabbit is removed with sodium sulfide, and the hair removal area on both sides is 50 cm 2Using a left-right comparison, 1 mL of the finasteride and graphene composition was applied to the left side of the rabbits, and 1 mL of the finasteride spray was applied to the right side of the rabbits. The skin was covered with gauze. After 24 hours, the drug residues on the skin were washed off with warm water, and the presence of erythema and edema on the skin was observed and recorded. It was applied once a day for 1 week continuously. The skin conditions of the rabbits were observed at 0, 12, 24, and 48 hours after the last removal of the drug. The local skin was observed macroscopically for skin irritation reactions such as erythema and edema. The results are shown in Table 5.

[0068] Table 4 Results of Skin Irritation

[0069]

[0070] As can be seen from Table 4, the skin irritation of finasteride and graphene is significantly less than that of the finasteride spray, indicating that the finasteride and graphene drug combination 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 the present invention. Accordingly, the embodiments of the present invention are illustrative, but not limited to the content described in the present invention, and may also be modifications made within the scope of the present invention or equivalent content added in the claims. All publications or patents cited by the present invention will be used as references for the present invention.

Claims

1. A composition, characterized in that Contains finasteride, graphene and one or more pharmaceutically acceptable excipients.

2. The composition according to claim 1, characterized in that The graphene is single-layer graphene and / or few-layer graphene; the ratio of the single-layer graphene to the graphene is: more than 60wt%, more than 80wt% or more than 90wt%.

3. The composition according to claim 1, characterized in that Based on the total weight of the composition, the mass content of the graphene in the composition is 0.05% to 0.20%; the mass content of the finasteride in the composition is 0.01wt% to 0.5wt%.

4. The composition according to claim 1, characterized in that The graphene has a nanostructure, and its average diameter is 100nm-1000nm.

5. The composition according to claim 1, characterized in that The pharmaceutically acceptable excipients include one or more of a solubilizing agent, a diluent, a humectant, a suspending agent and a film-forming agent.

6. The composition according to claim 5, characterized in that The cosolvent is selected from one of ethanol, polyethylene glycol, isopropanol or propylene glycol; and the diluent is selected from water.

7. The composition according to claim 5, characterized in that The moisturizing agent is selected from at least one of sodium hyaluronate and panthenol.

8. The composition according to claim 5, characterized in that The suspending agent is selected from one or more of hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and polyvinyl alcohol.

9. Use of the composition according to any one of claims 1 to 9 in the preparation of a medicament for preventing and / or treating alopecia, seborrheic alopecia, androgenic alopecia, alopecia areata or promoting hair growth.

10. The use according to claim 9, characterized in that The composition is in the form of an external solution, emulsion, ointment, suspension or gel.

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