A composition containing a peripheral vasodilator and a 5 alpha-reductase inhibitor

Abstract

The application discloses a composition containing a peripheral vasodilator and a 5alpha-reductase inhibitor, effectively solves the transdermal inhibition of the peripheral vasodilator on the 5alpha-reductase inhibitor by adding a specific penetration enhancer, improves the transdermal rate of the active ingredients in the pharmaceutical composition by proportion adjustment, greatly improves the synergistic effect of local combined medication, avoids the side effects brought by oral 5alpha-reductase inhibitor, and improves the safety of the medicine.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a composition containing a peripheral vasodilator and a 5α-reductase inhibitor. Background Technology

[0002] Androgenetic alopecia (AGA) is the most common type of hair loss, formerly known as seborrheic alopecia or premature baldness. It is a progressive hair loss disorder that occurs during and after puberty. AGA is characterized by follicle miniaturization, resulting from increased sensitivity of localized scalp follicles to androgens, altering the hair growth cycle, causing follicle atrophy, and the gradual transformation and disappearance of terminal follicles into vellus hair. In men, it primarily manifests as a receding hairline and / or progressive thinning and thinning of hair on the crown, also known as male pattern alopecia. In women, it primarily manifests as progressive thinning and thinning of hair on the crown, with a smaller percentage experiencing diffuse hair thinning without a receding hairline, known as female pattern alopecia.

[0003] In treating androgenetic alopecia, the combined use of peripheral vasodilators and 5α-reductase inhibitors can exert a synergistic effect. Peripheral vasodilators primarily focus on improving blood supply to hair follicles, providing a favorable nutritional environment. They can directly stimulate the proliferation and differentiation of follicular epithelial cells, accelerate angiogenesis, thereby increasing local blood supply. Simultaneously, they can open potassium ion channels, facilitating the transition of hair follicles from the resting phase to the anagen phase. 5α-reductase inhibitors primarily target androgen metabolism, inhibiting the conversion of testosterone into the more potent dihydrotestosterone (DHT), thus reducing DHT damage to hair follicles.

[0004] Currently, the most commonly used drugs for treating AGA include peripheral vasodilators (such as minoxidil) and 5α-reductase inhibitors (such as finasteride). The commercially available topical solution of minoxidil (6-(1-piperidinyl)-2,4-pyrimidinediamine 3-oxide) is Rogaine, available in 2% and 5% concentrations. However, this topical minoxidil solution requires consistent application several times daily; irregular use or arbitrary discontinuation will lead to poor efficacy. This cumbersome procedure hinders user adherence.

[0005] Finasteride ((5α,17β)-N-(1,1-dimethylethyl)-3-oxo-4-azaandrost-1-ene-17-carboxamide) is a synthetic androgen inhibitor. Its commercial product, Propecla, was developed by Merck & Co., and was approved by the U.S. Food and Drug Administration (FDA) in December 1997 as a treatment for hair loss due to its efficacy and safety. However, oral finasteride has significant side effects. For example, women using it may have a high risk of birth defects, while men may experience decreased libido, erectile dysfunction, and ejaculatory dysfunction.

[0006] Previous studies have shown that patients benefit more from the combined use of topical minoxidil and oral finasteride compared to using either drug alone, indicating a synergistic effect. However, the side effects and inconvenience of oral finasteride hinder patient adherence. Therefore, topical formulations of minoxidil and finasteride are currently one area of ​​research.

[0007] CN103596550A discloses a topical composition for preventing hair loss and promoting hair growth. In Examples 1-6, it discloses a mixed solution containing 5% minoxidil and 0.001%-0.002% finasteride or dutasteride, thereby reducing its side effects by reducing the content of finasteride or dutasteride.

[0008] During the experiments, the inventors discovered that minoxidil, finasteride, dutasteride, or iristaride, when used as single agents, all have a certain transdermal penetration rate. However, when minoxidil, finasteride, dutasteride, or iristaride are used in combination, they exhibit an inhibitory effect. Specifically, minoxidil affects the transdermal penetration rate of finasteride, dutasteride, or iristaride, thereby reducing the effectiveness of the combined medication. Improving the efficacy, safety, and compliance of minoxidil-finasteride-dutasteride-or iristaride combinations is an urgent problem to be solved. Summary of the Invention

[0009] The purpose of this invention is to provide a composition containing a peripheral vasodilator and a 5α-reductase inhibitor. By adding a specific penetration enhancer, the transdermal inhibition of finasteride / dutasteride / iristaride by minoxidil in the compound is solved. This composition has the advantages of high transdermal efficiency, good therapeutic effect on hair loss, and few side effects.

[0010] The present invention provides a composition comprising a peripheral vasodilator and a 5α-reductase inhibitor, comprising an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a peripheral vasodilator and a 5α-reductase inhibitor, and the excipients comprise a penetration enhancer.

[0011] Further, the peripheral vasodilator is selected from one or more of minoxidil, buprodil, cetiridil, and their salts or derivatives, preferably minoxidil or its salts or derivatives; wherein the salt is an addition salt or onium salt formed by the reaction of the compound with an acid, wherein the acid includes, but is not limited to: formic acid, acetic acid, propionic acid, butyric acid, caprylic acid, adipic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid, valeric acid, hexanoic acid, decanoic acid, stearic acid, palmitic acid, acrylic acid, citric acid, citric acid, sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid; preferably minoxidil or minoxidil onium sulfate (2,6-diamino-4-(piperidin-1-yl)pyrimidin-1-onium-1-yl sulfate).

[0012] Furthermore, the 5α-reductase inhibitor is selected from finasteride, dutasteride, iridarone, or combinations thereof; preferably finasteride or dutasteride.

[0013] Furthermore, the penetration enhancer is selected from diethylene glycol monoethyl ether, sodium sulfobutyl betacyclodextrin, polyethylene glycol succinate, oleic acid, oleyl alcohol, menthol, propylene glycol monolaurate, methyl salicylate, caprylic / capric acid mono- and diglycerides, propylene glycol monocaprylate, propylene glycol dicaprylate, caprylic acid, capric acid, lauric acid, sorbic acid, polyglycerol oleate, medium-chain triglycerides, caprylic / capric acid polyethylene glycol glyceride, Tween, sodium lauryl sulfate, urea, laurocapranolone, isopropyl myristate, propylene glycol, ethanol, or combinations thereof;

[0014] The preferred penetration enhancers are diethylene glycol monoethyl ether, sodium sulfobutyl betacyclodextrin, polyethylene glycol succinate, oleic acid, oleyl alcohol, menthol, propylene glycol monolaurate, methyl salicylate, propylene glycol, ethanol, or combinations thereof; more preferably, a combination of diethylene glycol monoethyl ether, oleic acid and methyl salicylate, oleyl alcohol and methyl salicylate, propylene glycol, and ethanol.

[0015] Further, by weight percentage, the content of the peripheral vasodilator is 1.5%-6.5%, preferably 2%-5%; the content of the 5α-reductase inhibitor is 0.001%-0.5%, preferably 0.005%-0.3%; the content of the penetration enhancer is 0.05%-20%, preferably 0.1%-15%, and even more preferably 0.15%-10%; the balance being pharmaceutically acceptable excipients.

[0016] Furthermore, the compositions provided by the present invention include solutions, sprays, liniments, foams, gels, lotions, or tinctures.

[0017] Furthermore, when the dosage form is a solution, spray, or liniment, pharmaceutically acceptable excipients also include low molecular weight alcohols and water as solvents; the low molecular weight alcohols include one or more of propylene glycol and ethanol; preferably a combination of propylene glycol and ethanol; when the low molecular weight alcohols are a combination of propylene glycol and ethanol, the mass fraction of propylene glycol in the composition is 40%-55% and the mass fraction of ethanol is 20%-30%.

[0018] Furthermore, when the dosage form is a solution, spray, or liniment, pharmaceutically acceptable excipients also include surfactants, which are selected from one or more of sodium dodecyl sulfate, sodium dodecyl sulfonate, and Tween 80; the mass fraction of the surfactant in the composition is 1%-3%.

[0019] Furthermore, when the dosage form is a foaming agent, pharmaceutically acceptable excipients also include 1 wt%-3 wt% glycerol, 0.5 wt%-2 wt% lactic acid, 0.2 wt%-1.0 wt% polysorbate 80, 0.05 wt%-0.2 wt% anhydrous citric acid, 0.5 wt%-1.0 wt% butylated hydroxytoluene, 1.0 wt%-1.5 wt% cetyl alcohol, 0.2 wt%-1.0 wt% octadecyl alcohol, 1 wt%-3 wt% propane, 0.5 wt%-1.5 wt% butane, 0.5 wt%-1.5 wt% isobutane, and the balance being purified water.

[0020] Furthermore, when the dosage form is a gel, pharmaceutically acceptable excipients also include 25wt%-3wt% glycerol, 1.0wt%-2.0wt% carbomer, and the balance being purified water.

[0021] The present invention also provides the use of the composition in the treatment or prevention of hair loss.

[0022] The present invention also provides an application of the composition in the treatment of alopecia areata and androgenetic alopecia.

[0023] The beneficial effects of this invention are as follows: The inventors unexpectedly discovered that adding a specific penetration enhancer can effectively solve the transdermal inhibition of minoxidil against finasteride, dutasteride, and iridarone, thereby increasing the transdermal permeability of finasteride, dutasteride, and iridarone in the compound formulation. This significantly improves the synergistic effect of topical combined medication, while avoiding the in vivo side effects of finasteride / dutasteride / iridarone in oral formulations, thus improving drug safety. Furthermore, the compound combined medication method of this invention reduces the frequency of topical application of single agents and the inconvenience of separate application, improving patient compliance. Detailed Implementation

[0024] The present invention will be further described in detail below with reference to specific embodiments. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] Examples 1-9: Minoxidil + Finasteride / Dutasteride / Iridostroginide + Penetration Enhancer Solution

[0026] The formulations of solutions containing minoxidil, finasteride, dutasteride, iristrolide, and penetration enhancers are shown in Table 1.

[0027] Table 1 Prescriptions for Examples 1-9

[0028]

[0029] Preparation methods of Examples 1-9:

[0030] According to Table 1, mix the prescribed amounts of propylene glycol and ethanol evenly. Add minoxidil, finasteride / dutasteride / iristaride, and the prescribed amount of penetration enhancer (diethylene glycol monoethyl ether, oleic acid / oleyl alcohol + methyl salicylate) according to the prescription amounts of each embodiment. Stir and mix evenly. Finally, add purified water to dilute to the prescription amount and fill into the solution.

[0031] Examples 10-12: Foaming agents containing minoxidil + finasteride / dutasteride / iristaride + penetration enhancer

[0032] The formulations of foaming agents consisting of minoxidil + finasteride / dutasteride / iristaride + penetration enhancer are shown in Table 2.

[0033] Table 2 Prescriptions for Examples 10-12

[0034] Element Example 10 (wt%) Example 11 (wt%) Example 12 (wt%) Minoxidil 5 5 5 Dutasteride 0.02 / / Finasteride / 0.02 / Iridosterone / / 0.02 Diethylene glycol monoethyl ether 5 5 5 ethanol 45 45 45 glycerin 2 2 2 lactic acid 1 1 1 Polysorbate 80 0.5 0.5 0.5 Anhydrous citric acid 0.1 0.1 0.1 Butylated hydroxytoluene 0.9 0.9 0.9 cetyl alcohol 1.1 1.1 1.1 Stearyl alcohol 0.5 0.5 0.5 propane 3 3 3 butane 1 1 1 Isobutane 1 1 1 Purified water Appropriate amount up to 100 Appropriate amount up to 100 Appropriate amount up to 100

[0035] Preparation methods of Examples 10-12:

[0036] Step 1: Take the prescribed amounts of ethanol, glycerin, polysorbate 80, butylated hydroxytoluene, anhydrous citric acid, cetyl alcohol, and octadecyl alcohol and stir at 60°C until completely dissolved;

[0037] Step 2: Add the prescribed amount of minoxidil, finasteride / dutasteride / iristaride, and the prescribed amount of penetration enhancer (diethylene glycol monoethyl ether) to Step 1, and continue stirring until the raw materials are evenly dispersed;

[0038] Step 3: Add purified water to the prescribed volume as in Step 2;

[0039] Step 4: Add the prescribed amounts of propane, butane, and isobutane to Step 3 and mix thoroughly to obtain the foaming agent.

[0040] Examples 13-15: Gel formulation of minoxidil + finasteride / dutasteride / iristaride + penetration enhancer

[0041] The formulation of a gel containing minoxidil, finasteride, dutasteride, iristride, and a penetration enhancer is shown in Figure 3.

[0042] Table 3 Prescriptions for Examples 13-15

[0043]

[0044]

[0045] Preparation methods of Examples 13-15:

[0046] Step 1: Take the prescribed amount of carbomer and purified water and mix them thoroughly at room temperature;

[0047] Step 2: Take the prescribed amounts of minoxidil, finasteride / dutasteride / iristaride, diethylene glycol monoethyl ether, and glycerin, and stir at room temperature until completely dissolved;

[0048] Step 3: Mix the substances obtained in Step 1 and Step 2 thoroughly to obtain the gel.

[0049] Experimental Example 1

[0050] 1. Experimental Objective: To test the transdermal effects of single-ingredient and compound preparations.

[0051] 2. Experimental Methods: Minoxidil monotherapy (solution), finasteride monotherapy (solution), dutasteride monotherapy (solution), iridarone monotherapy (solution), minoxidil and finasteride combination (solution), minoxidil and dutasteride combination (solution), and minoxidil and iridarone combination (solution) were prepared separately for transdermal efficacy evaluation. The solutions contained 25% ethanol, 50% propylene glycol, and the remainder purified water by mass percentage. Transdermal efficacy was evaluated using the keratinocytes of Bama miniature pigskin, measuring the cumulative permeation per unit area over 24 hours, the cumulative permeation over 24 hours, the drug residue in the skin, and the drug residue on the skin surface for each formulation. Experimental Method: A 30mm diameter, 1mm thick pigskin was installed on a France vertical diffusion cell with an inner diameter of 20mm and a radial diameter. Six portions of the product, approximately 1ml each, were transferred, and the average value was calculated.

[0052] 3. Experimental design: The experimental grouping and dosage design are shown in Table 4.

[0053] Table 4. Trial grouping and dosage design

[0054]

[0055]

[0056] 4. Experimental results: The experimental results for each group are shown in Table 5.

[0057] Table 5. Experimental results for each group

[0058]

[0059] The results above show that the transdermal penetration rates of finasteride, dutasteride, and iridrone in the combination were significantly lower than those of the single-ingredient formulations.

[0060] Experimental Example 2

[0061] 1. Experimental objective: To screen the types and dosages of penetration enhancers to improve the transdermal permeability of finasteride, dutasteride, or iridrone in compound preparations.

[0062] 2. Experimental methods: Minoxidil + finasteride formulations (solutions), minoxidil + dutasteride formulations (solutions), and minoxidil and iridarone combination formulations (solutions) containing different types of penetration enhancers were prepared. Other components in the solutions were the same as in Experimental Example 1. The transdermal effects were compared. The transdermal effects were evaluated by using isolated skin of miniature pigs to measure the cumulative permeation per unit area, the cumulative permeation per 24 hours, and the amount of drug residue in the skin for each formulation.

[0063] 3. Experimental design: The experimental grouping and dosage design are shown in Table 6.

[0064] Table 6. Grouping and Dosage Design of Penetration Enhancer Screening Tests

[0065]

[0066]

[0067] 4. Experimental results: The experimental results of each prescription are shown in Tables 7-1, 7-2 and 7-3.

[0068] Table 7-1 Results of Minoxidil + Dutasteride + Different Penetration Enhancers

[0069]

[0070] Table 7-2 Results of Minoxidil + Finasteride + Different Penetration Enhancers

[0071]

[0072] Table 7-3 Results of Minoxidil + Iridostigmine + Different Penetration Enhancers

[0073]

[0074] The results in Tables 7-1, 7-2, and 7-3 show that the following ingredients have different effects on the concentration of the compound: diethylene glycol monoethyl ether (1%-5%), sodium sulfobutyl betacyclodextrin (5%), oleic acid (5%), oleyl alcohol (5%), oleic acid (5%) + methyl salicylate (0.05%), oleyl alcohol (5%) + methyl salicylate (0.05%), polyethylene glycol succinate (3%), and menthol (3%). Dutasteride, finasteride, or iridarone all have varying degrees of penetration-enhancing effects; minoxidil in the isopropyl myristate (5% concentration) compound has a penetration-enhancing effect, but no effect on dutasteride, finasteride, or iridarone; while methyl salicylate (0.05% concentration), sodium dodecyl sulfate (1.5% concentration), and diethylene glycol monoethyl ether (0.5% concentration) have no significant penetration-enhancing effect on minoxidil, dutasteride, finasteride, or iridarone.

[0075] Experimental Example 3: Animal Stimulation Experiment

[0076] 1. Experimental objective: To observe whether different penetration enhancers cause irritation at the administration site by administering samples of these agents to the skin of mice and rabbits.

[0077] 2. Test samples: Prescriptions 1 to 1-15, 2 to 2-15, and 3 to 3-15 mentioned above.

[0078] 3. Experimental animals: C57BL / 6J mice; Japanese white rabbits.

[0079] 4. Experimental Methods: One rabbit and one mouse were tested for each prescription. After shaving the hair, the prescribed medication was applied to the affected area. For mice: 100 μL / time, twice a day for 7 consecutive days; for rabbits: 0.5 mL / time, twice a day for 7 consecutive days. Before each administration, the presence of erythema, edema, or other irritants at the application site was observed and recorded to determine if there was any irritation.

[0080] 5. Experimental results: The experimental results of each prescription are shown in Table 8.

[0081] Table 8. Results of animal irritation tests for each prescription.

[0082]

[0083]

[0084] Note: "None" means that no erythema or edema appeared in rabbits or mice within 7 days; "Mild irritation" means that erythema appeared in rabbits or mice within 7 days; "Moderate irritation" means that erythema and edema appeared in rabbits or mice within 7 days; " / " means that no experiment was conducted.

[0085] As shown in Table 8, the compound formulations containing oleic acid (5%), oleic acid (5%), and menthol (3%) all exhibited significant irritation. Combined with Tables 7-1, 7-2, and 7-3, it can be seen that diethylene glycol monoethyl ether (1%-5%), sodium sulfobutyl betacyclodextrin (5%), oleic acid (5%) + methyl salicylate (0.05%), oleyl alcohol (5%) + methyl salicylate (0.05%), and polyethylene glycol succinate (3%) not only enhanced the penetration of dutasteride or finasteride in the compound formulations to varying degrees but also showed no irritation to animals.

[0086] Experimental Example 4: Pharmacodynamic Experiment

[0087] 1. Experimental objective: To establish an androgenetic alopecia model by subcutaneous injection of testosterone propionate (5 mg / kg) into the back of male C57BL / 6J mice, and to compare the therapeutic effects of different formulations on the androgenetic alopecia model.

[0088] 2. Test samples: Blank control group, model control group, Example 1 group, Example 2 group, Example 4 group, Example 5 group, Example 8 group, Example 10 group, Example 11 group, Example 12 group, Example 13 group, Example 14 group, Example 15 group, Positive control group 1 (5% minoxidil + 0.02% dutasteride solution), Positive control group 2 (5% minoxidil + 0.02% finasteride solution), Positive control group 3 (5% minoxidil + 0.02% eriasteride solution), Positive control group 4 (CN118384170A Example 1 liniment), Positive control group 5 (CN118384170A Example 2 aerosol foam), Positive control group 6 (CN118384170A Example 3 gel).

[0089] 3. Experimental animals: C57BL / 6J mice, weighing 18-22g.

[0090] 4. Experimental Methods: 190 C57BL / 6J mice, weighing 18-22g, were used. Five mice were selected as the blank control group. The remaining mice were injected subcutaneously along the spine with testosterone propionate solution (5mg / kg, 10mL / kg) to induce the hair loss model, once daily for 6 weeks. After obvious hair loss areas formed on the backs of the mice, they were randomly divided into 18 groups: model control group, Example 1 group, Example 2 group, Example 4 group, Example 5 group, Example 8 group, Example 10 group, Example 11 group, Example 12 group, Example 13 group, Example 1... Group 4, Example 15, Positive Control Group 1 (5% minoxidil + 0.02% dutasteride solution), Positive Control Group 2 (5% minoxidil + 0.02% finasteride solution), Positive Control Group 3 (5% minoxidil + 0.02% eriasteride solution), Positive Control Group 4 (CN118384170A Example 1 liniment), Positive Control Group 5 (CN118384170A Example 2 aerosol foam), Positive Control Group 6 (CN118384170A Example 3 gel), with 5 model mice in each group.

[0091] According to the prescriptions for each group, the bald areas of the mice after the modeling process were treated with topical medication, with an application area of ​​1 cm². 2 The dosage was 50 μL per mouse, administered twice daily at 12-hour intervals for two consecutive weeks. After the onset of the model, the hair loss in mice was observed and recorded weekly. Following administration, the skin and hair growth at the bald areas were observed weekly, and the hair growth score was recorded. The scoring criteria were: 0 points: no growth, pink skin in the bald area; 1 point: gray skin in the bald area (less than 20% hair growth); 2 points: black skin in the bald area (more than 20% but less than 40% hair growth); 3 points: black skin in the bald area with some hair growth (more than 40% but less than 60% hair growth); 4 points: black skin in the bald area with some hair growth (60%–80% hair growth); 5 points…

[0092] After the last administration, mice were euthanized by cervical dislocation. Skin around the administration site, along with the attached back muscle tissue and spine, was harvested and fixed from each group of mice. The skin tissue at the center of the administration site (the center of the spine and nearby skin tissue) was selected for HE staining. The morphological changes of hair follicles and skin irritation of each group of mice were observed under a microscope. The classification of hair growth stages at the center of the administration site under 100x magnification and the number of hair follicles at each stage under 200x magnification were observed and recorded. The ratio of terminal hair to vellus hair was calculated.

[0093] 5. Dosage design

[0094] The experimental grouping and dosage design are shown in Table 9.

[0095] Table 9. Trial grouping and dosage design

[0096]

[0097]

[0098] 6. Experimental results: The statistical results of animal hair growth scores are shown in Table 10; the effects of the compound preparation on the average number of hair follicles and the ratio of terminal hair to vellus hair in mice with baldness after 2 weeks of administration are shown in Table 11.

[0099] Table 10 Statistical Results of Animal Hair Growth Scores

[0100]

[0101]

[0102] Note: Compared with the blank control group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0103] Table 11 Effects of the compound preparation on the average number of hair follicles and the ratio of terminal hair to vellus hair in mice with baldness after 2 weeks of administration.

[0104]

[0105] Note: Compared with the blank control group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0106] The results above show that the composition of minoxidil (5%) + dutasteride / finasteride / iristaride (0.02%-0.05%) + diethylene glycol monoethyl ether (3%-5%) in this invention has a significant therapeutic effect on testosterone propionate-induced androgenic alopecia model mice.

[0107] Test Example 5: Safety Test

[0108] 1. Experimental objective: To establish an androgenetic alopecia model by subcutaneous injection of testosterone propionate (5 mg / kg) into the back of male C57BL / 6J mice, to compare the drug concentration in vivo 2 hours after administration of different formulations, and to evaluate the safety of the compound preparation.

[0109] 2. Test samples: Example 1 group, Example 4 group, Positive control group 1 (5% minoxidil + 0.02% dutasteride solution), Positive control group 4 (CN118384170A Example 1 liniment).

[0110] 3. Experimental animals: C57BL / 6J mice, weighing 18-22g.

[0111] 4. Experimental Methods: The prescribed formulations were applied to the bald areas of the mice after modeling, with each application covering an area of ​​1 cm². 2 The dosage was 50 μL per animal. Two hours after administration, 200 μL of blood was collected from the orbital cavity and placed in a centrifuge tube moistened with heparin sodium. The tube was centrifuged at 4000 rpm for 10 min, and 50 μL of plasma was collected, processed, and tested.

[0112] 5. Experimental Results

[0113] The experimental groups and results are shown in Table 12.

[0114] Table 12 Drug concentrations in vivo 2 hours after administration of different formulations

[0115]

[0116] As shown in Table 12, the drug concentration in the blood of the embodiment with the added penetration enhancer was basically the same as that of the control group without the added penetration enhancer. Combined with the results in Tables 10-11, it can be seen that the drug of the present invention mainly acts locally and has no safety risks.

Claims

1. A composition, characterized in that, It includes an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient includes peripheral vasodilators and 5α-reductase inhibitors, and the excipients include penetration enhancers.

2. The composition according to claim 1, characterized in that, The peripheral vasodilator is selected from one or more of minoxidil, buprodil, cetiridil and their salts or derivatives, preferably minoxidil or its salts or derivatives; The 5α-reductase inhibitor is selected from finasteride, dutasteride, iridarone, or combinations thereof; preferably finasteride or dutasteride. The penetration enhancer is selected from diethylene glycol monoethyl ether, sodium sulfobutyl betacyclodextrin, polyethylene glycol eurovis succinate, oleic acid, oleyl alcohol, menthol, propylene glycol monolaurate, methyl salicylate, caprylic / capric acid mono- and diglycerides, propylene glycol monocaprylate, propylene glycol dicaprylate, caprylic acid, capric acid, lauric acid, sorbic acid, polyglycerol oleate, medium-chain triglycerides, polyethylene glycol eurovis succinate, Tween, sodium lauryl sulfate, urea, laurocapranolone, isopropyl myristate, propylene glycol, ethanol, or combinations thereof, preferably diethylene glycol monoethyl ether, sodium sulfobutyl betacyclodextrin, polyethylene glycol eurovis succinate, oleic acid, oleyl alcohol, menthol, propylene glycol monolaurate, methyl salicylate, propylene glycol, ethanol, or combinations thereof.

3. The composition according to claim 1 or 2, characterized in that, The peripheral vasodilator contains 1.5%-6.5% by weight, preferably 2%-5%; The content of the 5α-reductase inhibitor is 0.001%-0.5%, preferably 0.005%-0.3%; The penetration enhancer content is 0.05%-20%, preferably 0.1%-15%, and even more preferably 0.15%-10%.

4. The composition according to any one of claims 1-3, characterized in that, The topical preparations include solutions, sprays, liniments, foams, gels, lotions, or tinctures.

5. The composition according to claim 4, characterized in that, When the dosage form is a solution, spray, or liniment, pharmaceutically acceptable excipients also include low molecular weight alcohols and water; the low molecular weight alcohols include one or more of propylene glycol and ethanol; preferably a combination of propylene glycol and ethanol; When the low molecular weight alcohol is a combination of propylene glycol and ethanol, the mass fraction of propylene glycol in the composition is 40%-55% and the mass fraction of ethanol is 20%-30%.

6. The composition according to claim 5, characterized in that, The pharmaceutically acceptable excipients also include surfactants selected from one or more of sodium dodecyl sulfate, sodium dodecyl sulfonate, and Tween 80; the surfactant in the composition has a mass fraction of 0.1%-3%.

7. The composition according to claim 4, characterized in that, When the dosage form is a foaming agent, pharmaceutically acceptable excipients also include 1 wt%-3 wt% glycerol, 0.5 wt%-2 wt% lactic acid, 0.2 wt%-1.0 wt% polysorbate 80, 0.05 wt%-0.2 wt% anhydrous citric acid, 0.5 wt%-1.0 wt% butylated hydroxytoluene, 1.0 wt%-1.5 wt% cetyl alcohol, 0.2 wt%-1.0 wt% octadecyl alcohol, 1 wt%-3 wt% propane, 0.5 wt%-1.5 wt% butane, 0.5 wt%-1.5 wt% isobutane, and the balance being purified water.

8. The composition according to claim 4, characterized in that, When the dosage form is a gel, pharmaceutically acceptable excipients also include 25wt%-3wt% glycerol, 1.0wt%-2.0wt% carbomer, and the balance being purified water.

9. The use of the composition according to any one of claims 1-8 in the treatment or prevention of hair loss.

10. The use of the composition according to any one of claims 1-8 in the treatment of alopecia areata and androgenetic alopecia.

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