Application of coniferyl aldehyde and derivatives thereof in promoting hair regeneration and preventing alopecia

Abstract

The invention belongs to the technical field of medicines, cosmetics and scalp care, and particularly relates to application of coniferaldehydes and derivatives or salts of the coniferaldehydes to preparation of medicines and cosmetics for promoting hair regeneration and treating chemotherapy-induced alopecia (CIA, CIA) and other types of alopecia, in particular to application of the coniferaldehydes and the derivatives or salts of the coniferaldehydes to preparation of the medicines and the cosmetics. Experimental results show that coniferyl aldehyde can promote hair regeneration of mice, accelerate hair growth of the mice and effectively relieve alopecia symptoms of the mice after chemotherapy, and the effect of coniferyl aldehyde is better than that of minoxidil. According to the application, coniferyl aldehyde or a composition thereof is given to a subject, so that the vigor of hair follicles is remarkably enhanced, the stationary period of the hair follicles is shortened, and the hair loss process is inhibited. The coniferyl aldehyde provided by the invention has the industrial application advantages of reliable biological safety, controllable preparation cost and high raw material accessibility, can be obtained by a plant extraction or chemical synthesis method, is suitable for an external solution, gel or a scalp care preparation, and provides a natural, safe and effective solution for alopecia patients.

Description

Technical Field

[0001] The present invention belongs to the technical fields of medicine, cosmetics and scalp care, and particularly relates to the use of coniferaldehyde and its derivatives or salts in the preparation of medicines or cosmetics for promoting hair regeneration and alleviating hair loss. Background Art

[0002] Continuous healthy hair growth relies on the precise regulation of the hair follicle cycle on the scalp—approximately 90%-95% of follicles are in the anagen phase (lasting 2-6 years), 5%-10% are in the telogen phase (approximately 3 months), and only 1% undergoes a brief catagen phase. This dynamic balance ensures that the physiological daily loss of 50-100 hair follicles is balanced by new hair growth. However, stress, hormonal fluctuations, or external stimuli can significantly disrupt the follicle cycle, leading to an abnormally shortened anagen phase (to several months) and a prolonged telogen phase, disrupting the follicle balance. Pathological hair loss occurs when daily hair loss exceeds 100 hairs for more than three months. Long-term abnormalities in the follicle cycle can cause miniaturization, reducing the hair shaft diameter by more than 60%, and fibrosis around the follicles, ultimately leading to irreversible follicular atrophy.

[0003] The number of people suffering from hair loss worldwide has exceeded 2.1 billion, with men accounting for over 70%. A recent multinational epidemiological survey revealed that among 47 countries, Spain has the highest male hair loss rate (44.50%), while the incidence in Chinese men reaches 30.81%. The total number of patients nationwide exceeds 100 million, with approximately 7 million women affected, and the annual growth rate is as high as 15%. The accelerated pace of modern life and psychological stress have been identified as key drivers. Among the various types of hair loss, androgenic alopecia (AGA) and alopecia areata (AA) account for over 90% of clinical cases. To date, the US FDA has approved only two medications: minoxidil (topical / oral) and finasteride for the systemic treatment of hair loss. While these medications have demonstrated clinical efficacy, they carry significant safety risks and limitations. Minoxidil, a vasodilator, is used topically or at low doses orally to promote hair growth, but it can cause contact dermatitis (12%-15% incidence), hirsutism, and recurrence of hair loss after discontinuation. Finasteride, a 5α-reductase inhibitor, while effectively blocking key pathways in androgenic alopecia, can cause erectile dysfunction in men (3.8%-5.8%) and is contraindicated in women of childbearing age due to the risk of teratogenicity. Currently, many hair loss treatments under development have entered clinical trials, including new anti-androgenic drugs (dutasteride / flurodil), JAK inhibitors (ruxolitinib / tofacitinib), and anti-inflammatory therapies (glucocorticoids / tacrolimus). While these drugs hold potential as targeted therapies, they face safety challenges such as hepatotoxicity, hematologic abnormalities, and systemic side effects. Therefore, the search for safer, more effective, and targeted new hair loss treatments has become a hot topic.

[0004] Coniferaldehyde is a natural monomeric component derived from plants such as Acanthopanax senticosus, Platycladus orientalis, and Vitex rotundifolia. Related studies have reported that coniferaldehyde is a potent inducer of heme oxygenase 1, inhibits LPS-induced apoptosis, and exhibits antioxidant properties. In applications, coniferaldehyde can be used as a plant growth regulator and, due to its pleasant pine aroma, is also used as a flavoring agent in foods and spices.

[0005] The application of coniferaldehyde as a hair growth promoting product has the following advantages: First, coniferaldehyde has been put into industrial production and has a ready-made mature extraction process, and the quality and production costs are relatively controllable; second, coniferaldehyde can be used as a food additive, which has a certain guarantee of safety for the human body; third, coniferaldehyde has a fresh and attractive smell and has been specifically used to add fragrance to products, which helps to enhance the product experience. Summary of the Invention

[0006] In view of the deficiencies of the prior art, the present invention provides a new application of coniferaldehyde and its derivatives for effectively promoting hair growth and preventing hair loss.

[0007] In order to achieve the above technical objectives, the present invention mainly adopts the following technical solutions: The present invention discloses a new use of coniferaldehyde and its derivatives in promoting hair growth and preventing hair loss, wherein the objects include mammals, such as humans, pets and the like.

[0008] The coniferaldehyde can be purchased commercially or prepared from the following raw materials: one or more of Vitex rotundifolia, Platycladus orientalis, Selaginella, Aralia arborvitae, Pinus tabulaeformis, Pinus massoniana, Picea australis, Cypress, Angelica sinensis, Ligusticum chuanxiong, and Eucommia ulmoides.

[0009] In the present invention, the structural formula of coniferaldehyde is:

[0010] In one embodiment of the present invention, coniferaldehyde and its derivatives can be used alone or in combination with traditional Chinese medicines having hair growth and hair loss prevention effects.

[0011] The medicinal materials include: one or more of ginger, ginseng, ganoderma lucidum, rhubarb, polygonum multiflorum, pepper, pinellia, psoralea corylifolia, black sesame, gastrodia elata, cypress leaves, mint, mugwort, siler, vitex rotundifolia, wolfberry, safflower, angelica, salvia miltiorrhiza, bergamot, astragalus, glossy privet fruit, hibiscus, wild hawthorn, polyporus, red sandalwood, ginkgo, ligustrum lucidum, black beans or licorice.

[0012] The coniferaldehyde and its derivatives can be used in combination with chemical drugs for hair growth or hair loss prevention.

[0013] The compound drug comprises one or more of minoxidil, finasteride, dutasteride, fluoxetine, ruxolitinib, tofacitinib, glucocorticoids, tacrolimus, cyclosporine, and anthocyanin.

[0014] In one embodiment of the present invention, the subject exhibits symptoms such as abnormal hair loss, thinning hair or stagnation of hair growth, and miniaturization of hair follicles.

[0015] In one embodiment of the present invention, the abnormal hair loss symptoms include but are not limited to alopecia areata, androgenic alopecia, neurotic alopecia, seborrheic alopecia, senile alopecia, chemotherapy-induced alopecia, scarring alopecia, etc.

[0016] In one embodiment of the present invention, coniferyl aldehyde and its derivatives can be combined with a pharmaceutically acceptable carrier to prepare an external dosage form or an oral dosage form.

[0017] The topical dosage form used is selected from shampoo preparations, hair dye preparations, conditioners, gels, freeze-dried powders, topical solutions, ointments, gels, patches, tinctures or sprays; the oral dosage form is selected from tablets, capsules, granules, pills or oral liquid preparations.

[0018] In one embodiment of the present invention, the coniferyl aldehyde and its derivatives can be used to prepare medicines, cosmetics, nursing products, beauty products, foods or health products.

[0019] In a preferred embodiment of the present invention, coniferaldehyde promotes hair follicle cell proliferation, enhances cell viability, stimulates hair follicle growth and alleviates hair loss, and is used to promote hair regeneration and treat hair loss.

[0020] Compared with the prior art, the present invention has the following beneficial effects: The present invention provides a new application of coniferyl aldehyde and its derivatives for promoting hair regeneration and preventing hair loss, and improving symptoms such as hair growth stagnation. Coniferyl aldehyde has a significant effect in alleviating hair loss and is highly safe, and is suitable for use in the fields of medicine, cosmetics, and care products. In addition, the application of coniferyl aldehyde as a hair regeneration-promoting product has the following advantages: first, coniferyl aldehyde has been put into industrial production and has a ready-made mature extraction process, and the quality and cost are relatively controllable; second, coniferyl aldehyde can be used as a food additive, which has a certain guarantee of safety for the human body; third, coniferyl aldehyde has a fresh and attractive smell and has been specifically used to add fragrance to products, which helps to enhance the user experience of the product. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is a schematic diagram of the results of coniferaldehyde promoting the proliferation activity of hair follicle cells; Figure 2 This is a diagram showing the results of coniferaldehyde improving hair follicle cell vitality and the statistical results; Figure 3 This is a schematic diagram showing the results of coniferaldehyde promoting the growth of vibrissa hair follicles in cultured mice in vitro and the statistical results; Figure 4 This is a schematic diagram of the results of coniferaldehyde promoting hair regeneration in shaved mice; Figure 5 This is the HE staining result of the back skin of mice on the 7th day after treatment with coniferyl aldehyde; Figure 6 Schematic diagram of the effect of coniferaldehyde in alleviating cyclophosphamide-induced chemical alopecia in mice DETAILED DESCRIPTION

[0022] The following is a combination of specific embodiments and experimental examples to further illustrate the present invention. However, these embodiments are intended to illustrate the application and are not intended to limit the scope. If experimental conditions are not specified, conventional methods were used.

[0023] Aiming at various existing hair loss problems, the present invention has discovered a plant monomer compound, coniferaldehyde, which can promote hair regeneration and prevent hair loss.

[0024] First, to determine the appropriate concentration of coniferaldehyde, its toxicity to primary dermal papilla cells (DP cells) was evaluated. DP cells were isolated from the whisker hair follicles of C57BL / 6 mice and treated with different concentrations of coniferaldehyde for 48 hours, and then analyzed using a cell proliferation / toxicity assay kit. Figure 1 As shown in the results, 12.5–100 μM coniferaldehyde showed no toxicity to DP cells and significantly enhanced cell proliferation activity (P<0.05). Given that DP cell activity is positively correlated with hair follicle growth ability, coniferaldehyde may promote hair growth by enhancing DP cell activity. In addition, if Figure 2 As shown in the results of cell immunofluorescence staining experiments, at concentrations of 25μM and 50μM, coniferyl aldehyde significantly increased the expression level of alkaline phosphatase (ALP) protein in a concentration-dependent manner. Coniferyl aldehyde treatment significantly increased the expression of ALP in DP cells. These results indicate that coniferyl aldehyde treatment upregulates the levels of DP cell activity markers, helping to enhance their hair-inducing function.

[0025] In the in vitro hair follicle model, the hair follicles were photographed under a microscope every 3 days, and the length of the hair shaft growth was quantitatively counted and plotted into a line graph. The results are shown in the figure below. Figure 3 As shown. The hair follicles treated with coniferyl aldehyde not only had longer hair shaft elongation, but also started growing faster. On the third day, the hair shafts of the blank control group and the minoxidil group had barely elongated, while the hair follicles in the coniferyl aldehyde group had already grown significantly. On the 12th day, the total length of the hair shafts of the hair follicles in the coniferyl aldehyde group was also longer than those in the other two groups. Figure 3 ).

[0026] Secondly, in order to evaluate the promoting effect of coniferyl aldehyde on hair growth, this study conducted experiments by constructing a synchronized hair regeneration model in mice. First, the back hair of seven-week-old C57BL / 6 mice was treated with depilatory cream. At this time, the skin on the back of the mice was pink, and the hair follicles were in the resting phase. The stimulation of the depilatory cream will cause the entire back hair removal area to synchronously begin to enter the growth phase. After hair removal, basic cream (blank control group), 2% minoxidil (positive control group) and 2 mM concentration of coniferyl aldehyde (CFA group) were applied to the hair removal area respectively. Each mouse was applied 0.2 g per day, and then the hair growth of the mice was observed and photographed regularly. The results are as follows. Figure 4 As shown, on the day of hair removal, the hair follicles on the backs of all three groups of mice were in the telogen phase. By day 7, the coniferaldehyde group showed a significant increase in grayscale (an early sign of the anagen phase), while the blank and minoxidil groups remained in the telogen phase. On day 10, the grayscale in the coniferaldehyde group further deepened. Furthermore, the coniferaldehyde group achieved >80% regional conversion to the anagen phase on day 13, while the minoxidil group delayed this conversion until day 19. By day 22, all three groups had fully entered the anagen phase, confirming that coniferaldehyde treatment can shorten the telogen phase of hair follicles and significantly advance the process of hair regeneration by 6 days.

[0027] Finally, a chemically induced hair loss model was successfully established in mice by intraperitoneal injection of cyclophosphamide. The experimental results showed that the mice treated with coniferaldehyde were able to significantly alleviate the symptoms of hair loss induced by cyclophosphamide and effectively promote hair growth under the stress environment of cyclophosphamide. In addition, the hair growth-promoting effect of coniferaldehyde was better than that of the group treated with 2% minoxidil ( Figure 6 ).

[0028] The following is a detailed description through examples.

[0029] Example 1. Coniferaldehyde promotes the proliferation of hair follicle cells and improves their vitality Experimental methods: Dermal papilla cells (DP cells) were isolated from vibrissae follicles of C57BL / 6J mice, digested with 0.2% collagenase I (37°C for 1 h), and then cultured in DMEM medium containing 15% FBS. The cells were plated at 1×10 4 / well density seeded 96-well plate, when the confluence reached 80%, the cells were treated with gradient concentrations of coniferaldehyde for 24 h, and then MTS solution was added to each well for incubation for 0.5-2 h. The absorbance at 450 nm was measured to assess cell viability. In immunofluorescence assay, cells were plated at 3×10 4The cells were seeded at a density of 1 / well in a 24-well plate and treated with coniferyl aldehyde (25 / 50 μM) for 24 h. The cells were fixed with 4% PFA (15 min), permeabilized with 0.1% Triton X-100, and blocked with 1% FBS (30 min). The cells were then incubated with anti-ALP primary antibody at 4°C overnight, fluorescent secondary antibody at room temperature for 2 h, and nuclei stained with DAPI for 5 min. The cells were then imaged using an Olympus fluorescence microscope.

[0030] like Figure 1 and Figure 2 As shown, coniferaldehyde can significantly promote the proliferation ability of hair follicle cells and significantly enhance their activity.

[0031] 2. The promoting effect of coniferaldehyde on the growth of isolated mouse hair follicles Experimental methods: Vibrissae hair follicles from 7-week-old mice were isolated and cultured in WE medium in vitro. The experimental groups included a control group, a minoxidil group, and a coniferyl aldehyde group (25 / 50 μM), with 6 hair follicles in each group. Hair follicle length was measured by microscopy on the first and 14th days of culture, and statistical analysis was performed using GraphPad Prism software (significance levels set: *P<0.05, **P<0.01, ***P<0.001).

[0032] Depend on Figure 3 As shown in the results, coniferaldehyde at concentrations of 25 and 50 μM could significantly promote the growth of hair shafts of mouse hair follicles cultured in vitro.

[0033] 3. Experiment on promoting hair regeneration in mice with coniferaldehyde Experimental Methods: Seven-week-old mice were treated with a chemical depilatory agent on their backs to induce synchronous telogen follicle entry. The mice were then randomly divided into three groups (n=3): a blank control group, a minoxidil (2%) group, and a coniferyl aldehyde (2 mM) group. Coniferyl aldehyde was mixed with a base cream to create a 2 mM formulation. Each group received 0.2 g of the corresponding formulation daily: control group (pure base), minoxidil group (containing 2% minoxidil), and coniferyl aldehyde group (containing 2 mM coniferyl aldehyde).

[0034] Depend on Figure 4 It can be seen that coniferaldehyde can quickly start the experimental mice's hair from the resting phase to the growth phase, accelerating the mice's hair regeneration and growth.

[0035] 3. HE staining experiment of the back skin of mice treated with coniferaldehyde on the 7th day Experimental Methods: Seven days after treatment, dorsal skin of mice was collected and fixed in 4% paraformaldehyde (PFA) for 24 hours. The skin was then dehydrated with graded ethanol (50%, 75%, 85%, 95%, and 100%), cleared with xylene, and embedded in paraffin. Sections were then sectioned at 5 μm thickness. After dewaxing with xylene and rehydrating with graded ethanol, the sections were stained with hematoxylin for 5 minutes and eosin for 30 seconds. Hair follicle morphology was observed under an Olympus microscope (Olympus, Tokyo, Japan). Statistical significance was set at *P < 0.05, **P < 0.01, and ***P < 0.001.

[0036] Depend on Figure 4 and Figure 5 As we know, on the seventh day, the coniferaldehyde-treated group accelerated the transition of hair growth from the resting phase to the growing phase on the backs of mice, while the control group remained in the resting phase. The difference was particularly significant on the tenth day. Furthermore, coniferaldehyde treatment significantly increased the number of hair follicles in the back skin of mice. Compared with minoxidil, coniferaldehyde was significantly more effective in promoting hair regeneration in mice.

[0037] 4. Coniferaldehyde alleviates cyclophosphamide-induced chemotherapy-induced alopecia in mice Experimental Methods: Seven-week-old C57BL / 6 male mice (SPF environment, 12-h light / dark cycle) were randomly divided into groups (4-5 mice per group). After depilation of the backs of mice in each group, the corresponding medication (blank / 2% minoxidil / CFA) was applied daily. On day 9, the model and treatment groups received an intraperitoneal injection of 200 μL of cyclophosphamide (12.5 mg / mL) to induce hair loss, while the blank group received an equal volume of saline. Hair growth was continuously observed and recorded until complete recovery.

[0038] Depend on Figure 6 As we know, the results on the 17th day showed that coniferyl aldehyde treatment could significantly alleviate the symptoms of hair loss induced by cyclophosphamide in a concentration-dependent manner; the results from the 19th to 30th day showed that the hair regeneration rate in the cyclophosphamide group was very slow, but coniferyl aldehyde treatment effectively promoted hair regeneration under the cyclophosphamide stress environment, and the effect was better than that of the minoxidil group.

[0039] Finally, it should be noted that the above preferred embodiments are intended only to illustrate the technical solutions of the present invention and do not limit its scope of application. Although the present invention has been described in detail through the above examples, it should be understood by those skilled in the art that various changes in form and details may be made without departing from the scope of the present invention as defined in the claims.

Claims

1. Use of coniferaldehyde and its derivatives in the preparation of a composition for promoting hair growth and preventing hair loss, characterized in that: The composition includes coniferyl aldehyde and its derivatives or salts.

2. The composition of coniferyl aldehyde and its derivatives for promoting hair growth and preventing hair loss according to claim 1, characterized in that: The coniferaldehyde can be obtained through plant extraction and chemical synthesis.

3. The composition comprising coniferyl aldehyde and its derivatives is suitable for individuals suffering from symptoms such as abnormal hair loss, thinning hair or stagnation of hair growth.

4. The use according to claim 3, characterized in that The abnormal hair loss symptoms include alopecia areata, androgenic alopecia, neurotic alopecia, seborrheic alopecia, chemotherapy-induced alopecia, scarring alopecia, senile alopecia and other types.

5. The use according to any one of claims 1 to 4, characterized in that: The coniferaldehyde and its derivatives or salts can be used as a single active ingredient, or used in combination with a traditional Chinese medicine composition or chemical drug having hair growth effect. The use according to any one of claims 1 to 4, characterized in that the coniferaldehyde is prepared from the following raw materials: one or more of Vitex rotundifolia, Platycladus orientalis, Selaginella truncatula, Cypress, Pinus tabulaeformis, Pinus massoniana, Picea australis, Cypress, Angelica sinensis, Ligusticum chuanxiong, and Eucommia ulmoides.

6. The use according to any one of claims 1 to 4, characterized in that: The coniferaldehyde and its derivatives or salts can be used as a single active ingredient, or used in combination with a traditional Chinese medicine composition or chemical drug having hair growth effect.

7. The use according to any one of claims 1 to 4, characterized in that: The coniferyl aldehyde and its derivatives or salts can be prepared with at least one pharmaceutically acceptable carrier into an oral dosage form or an external preparation or a cosmetic.

8. The use according to claim 7, characterized in that The external preparation is selected from shampoo preparations, hair dye preparations, conditioners, gels, freeze-dried powders, external solutions, ointments, gels, patches, tinctures or sprays; the oral dosage form is selected from tablets, capsules, granules, pills or oral liquid preparations.

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