A minoxidil liniment as well as a preparation method and application thereof

Abstract

The application belongs to the technical field of pharmacy, and particularly relates to a minoxidil liniment as well as a preparation method and application thereof. The minoxidil liniment comprises the following components: minoxidil, alcohol solution, stabilizer, oat extract and water, wherein the stabilizer comprises EDTA-tetrasodium, panthenol and hydroxypropyl cellulose. The synergistic effect of EDTA-tetrasodium, panthenol and hydroxypropyl cellulose is utilized to optimize the preparation process, so that the effectiveness and stability of the raw drug minoxidil can be effectively improved, the effective period is prolonged, and the medication compliance is improved. The oat extract is used as the auxiliary material of the liniment, the side effects of minoxidil are reduced, the redness, itching and discomfort possibly caused by minoxidil can be effectively reduced, the damaged scalp skin barrier is helped to repair, the micro-inflammation around the hair follicle is reduced, and a healthier environment for hair growth is created.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a minoxidil liniment, its preparation method, and its application. Background Technology

[0002] Minoxidil is an aminopyridine potassium channel opener that causes vasodilation and premature entry of resting hair follicles into the anagen phase, increasing follicle size. Its positive effect on hair growth is mainly due to its metabolite, minoxidil sulfate. Due to the poor solubility of minoxidil raw material, current preparation techniques mostly involve direct dissolution in solvents, typically requiring the addition of high concentrations of organic reagents, such as propylene glycol and ethanol. Propylene glycol, acting as a penetration enhancer and solubilizer, is often used at concentrations as high as 30-50%. Without propylene glycol, the solubility of minoxidil is difficult to reach above 2%. However, high concentrations of propylene glycol can easily cause allergic reactions such as rashes in users. To achieve a good therapeutic effect, multiple applications are required, but repeated use may worsen adverse reactions in patients.

[0003] For example, Chinese invention patent publication number CN119280151A discloses a method for preparing minoxidil liniment. The preparation method first mixes propylene glycol, anhydrous ethanol, and about 40% purified water until there is no obvious layering, and finally adds minoxidil and stirs to dissolve it to obtain minoxidil liniment. The preparation process provided by this invention allows purified water and anhydrous ethanol to form a cosolvent, which greatly improves the solubility of minoxidil in a single excipient.

[0004] Another Chinese invention patent publication, CN121102179A, discloses a minoxidil film-forming agent, its preparation method, and its application. This minoxidil film-forming agent comprises 40-60% propylene glycol, 3-7% polyvinyl alcohol, 20-30% ethanol, 1-7% minoxidil, and the balance being water. This invention uses propylene glycol as a solvent, plasticizer, and transdermal absorption enhancer; polyvinyl alcohol as the film-forming material; and ethanol as a volatile agent. After administration, ethanol evaporation promotes polyvinyl alcohol film formation, and propylene glycol enhances the plasticity of the film, thereby reducing drug loss, increasing local drug concentration, and improving bioavailability. This minoxidil film-forming agent exhibits excellent skin permeability, effectively delivering the drug to the desired site. Furthermore, during drug release, it ensures precise drug delivery at a fixed location on the skin, reducing irritation to other areas caused by drug flow, thus achieving a good therapeutic effect.

[0005] However, the minoxidil formulation prepared by the aforementioned invention patent is still unsatisfactory in terms of efficacy and stability. Therefore, there is an urgent need in the field to provide a minoxidil topical formulation with better efficacy and stability, which can improve patient medication compliance and reduce side effects. Summary of the Invention

[0006] This invention addresses the problems existing in the prior art by providing a minoxidil liniment, its preparation method, and its application.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] A minoxidil topical solution comprises the following components: minoxidil, an alcoholic solution, a stabilizer, oat extract, and water, wherein the stabilizer comprises EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose.

[0009] Preferably, the mass ratio of EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose is 0.5-1.5:1.5-2:1-1.5.

[0010] More preferably, the mass ratio of EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose is 0.8-1.2:1.8-2:1-1.2.

[0011] More preferably, the mass ratio of EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose is 1:2:1.

[0012] Preferably, the alcohol solution is a mixture of anhydrous ethanol and propylene glycol in a volume ratio of 4-6:2-4.

[0013] More preferably, the alcohol solution is a mixture of anhydrous ethanol and propylene glycol in a volume ratio of 5:3.

[0014] Preferably, by weight percentage, it comprises the following components: 5-8% minoxidil, 60-80% alcohol solution, 3-5% stabilizer, 1-2% oat extract, and the balance to 100% water.

[0015] More preferably, by weight percentage, it comprises the following components: 5-7% minoxidil, 65-70% alcohol solution, 4-5% stabilizer, 1.5-2% oat extract, and the balance to 100% water.

[0016] More preferably, by weight percentage, it comprises the following components: 6% minoxidil, 70% alcohol solution, 4% stabilizer, 2% oat extract, and the balance to 100% water.

[0017] This invention provides a method for preparing the above-mentioned minoxidil liniment, comprising the following steps: (1) First, mix EDTA-tetrasodium, panthenol and hydroxypropyl cellulose in water, then add oat extract to obtain an aqueous phase; (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, add the alcohol phase to the aqueous phase, adjust the pH, stir well, and you will get minoxidil liniment.

[0018] Preferably, the mixing process in step (1) includes: first dissolving EDTA-tetrasodium and panthenol in water, and then adding hydroxypropyl cellulose at a speed of 500-1000 rpm.

[0019] Preferably, after adding oat extract in step (1), ultrasonic treatment is performed, wherein the ultrasonic temperature is 20-30℃, the ultrasonic time is 15-25 min, and the ultrasonic frequency is 50-100 kHz.

[0020] More preferably, after adding oat extract in step (1), ultrasonic treatment is performed, wherein the ultrasonic temperature is 24-26°C, the ultrasonic time is 18-22 min, and the ultrasonic frequency is 70-90 kHz.

[0021] Preferably, the pH adjustment process in step (3) is as follows: the pH is adjusted to 4-6 using citric acid.

[0022] Preferably, in step (3), the stirring speed is 500-1000 rpm and the stirring time is 30-60 min.

[0023] This invention provides the application of the above-mentioned minoxidil liniment or the minoxidil liniment prepared by the above preparation method in the preparation of anti-hair loss drugs.

[0024] Compared with the prior art, the present invention has the following beneficial effects: (1) This invention provides a minoxidil topical solution, which can effectively improve the efficacy and stability of the raw material minoxidil, extend its shelf life, and improve medication compliance by utilizing the synergistic effect of EDTA-tetrasodium, panthenol and hydroxypropyl cellulose.

[0025] (2) The present invention uses oat extract as an excipient of the liniment, which reduces the side effects of minoxidil and can effectively alleviate the redness, swelling, itching and discomfort that minoxidil may cause, help repair the damaged scalp skin barrier, reduce micro-inflammation around hair follicles, and create a healthier environment for hair growth. Detailed Implementation

[0026] It is worth noting that all raw materials used in this invention are commercially available products. Specifically, minoxidil (CAS No.: 38304-91-5, purity 99.99%), oat extract (content 90%), were purchased from Shaanxi Kehong Health Industry Co., Ltd.; panthenol (CAS No.: 81-13-0), purchased from Aladdin; hydroxypropyl cellulose (CAS No.: 9004-64-2), purchased from Aladdin; scutellaria baicalensis extract (content 98%), purchased from Shaanxi Kehong Health Industry Co., Ltd.; and commercially available minoxidil topical solution (5%), purchased from Jiangsu Wango Pharmaceutical Co., Ltd.

[0027] Example 1 A minoxidil topical solution, by weight percentage, comprises the following components: 6% minoxidil, 70% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 5:3), 4% stabilizer (composed of tetrasodium EDTA, panthenol, and hydroxypropyl cellulose in a mass ratio of 1:2:1), 2% oat extract, and the balance to 100% water.

[0028] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve EDTA-tetrasodium and panthenol in water, then add hydroxypropyl cellulose at 800 rpm, and continue to add oat extract. Sonicate at 25℃ and 80 kHz for 20 min to obtain an aqueous phase. (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 5 with citric acid, and the mixture is stirred at 800 rpm for 50 min to obtain minoxidil liniment.

[0029] Example 2 A minoxidil topical solution, by weight percentage, comprises the following components: 5% minoxidil, 60% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 1:1), 5% stabilizer (composed of EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose in a mass ratio of 0.5:2:1.5), 1% oat extract, and the balance to 100% water.

[0030] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve EDTA-tetrasodium and panthenol in water, then add hydroxypropyl cellulose at 500 rpm, and continue to add oat extract. Sonicate at 20℃ and 100 kHz for 15 min to obtain an aqueous phase. (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 4 with citric acid, and the mixture is stirred at 1000 rpm for 60 min to obtain minoxidil liniment.

[0031] Example 3 A minoxidil topical solution, by weight percentage, comprises the following components: 8% minoxidil, 80% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 3:1), 3% stabilizer (composed of tetrasodium EDTA, panthenol, and hydroxypropyl cellulose in a mass ratio of 1.5:1.5:1), 2% oat extract, and the balance to 100% water.

[0032] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve EDTA-tetrasodium and panthenol in water, then add hydroxypropyl cellulose at 1000 rpm, and continue to add oat extract. Sonicate at 30℃ and 50 kHz for 25 min to obtain an aqueous phase. (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 6 with citric acid, and the mixture is stirred at 500 rpm for 30 minutes to obtain minoxidil liniment.

[0033] Comparative Example 1 Compared to Example 1, the only difference is that the stabilizer consists of EDTA-tetrasodium and panthenol in a mass ratio of 1:2, resulting in a minoxidil liniment. Details are as follows: A minoxidil topical solution, by weight percentage, comprises the following components: 6% minoxidil, 70% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 5:3), 4% stabilizer (composed of tetrasodium EDTA and panthenol in a mass ratio of 1:2), 2% oat extract, and the balance to 100% water.

[0034] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve EDTA-tetrasodium and panthenol in water, then add oat extract, and sonicate at 25℃ and 80 kHz for 20 min to obtain an aqueous phase; (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 5 with citric acid, and the mixture is stirred at 800 rpm for 50 min to obtain minoxidil liniment.

[0035] Comparative Example 2 Compared to Example 1, the only difference is that the stabilizer is composed of EDTA-tetrasodium and hydroxypropyl cellulose in a mass ratio of 1:1, resulting in a minoxidil liniment. Details are as follows: A minoxidil topical solution, by weight percentage, comprises the following components: 6% minoxidil, 70% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 5:3), 4% stabilizer (composed of EDTA-tetrasodium and hydroxypropyl cellulose in a mass ratio of 1:1), 2% oat extract, and the balance to 100% water.

[0036] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve EDTA-tetrasodium in water, then add hydroxypropyl cellulose at 800 rpm, and then add oat extract. Sonicate at 25℃ and 80 kHz for 20 min to obtain an aqueous phase. (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 5 with citric acid, and the mixture is stirred at 800 rpm for 50 min to obtain minoxidil liniment.

[0037] Comparative Example 3 Compared to Example 1, the only difference is that the stabilizer consists of panthenol and hydroxypropyl cellulose in a mass ratio of 2:1, resulting in a minoxidil liniment. Details are as follows: A minoxidil topical solution, by weight percentage, comprises the following components: 6% minoxidil, 70% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 5:3), 4% stabilizer (composed of panthenol and hydroxypropyl cellulose in a mass ratio of 2:1), 2% oat extract, and the balance to 100% water.

[0038] The preparation method of the above minoxidil liniment is as follows: (1) First, dissolve panthenol in water, then add hydroxypropyl cellulose at 800 rpm, and then add oat extract. Sonicate at 25℃ and 80 kHz for 20 min to obtain an aqueous phase. (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, the alcohol phase is added to the aqueous phase, the pH is adjusted to 5 with citric acid, and the mixture is stirred at 800 rpm for 50 min to obtain minoxidil liniment.

[0039] Comparative Example 4 Compared with Example 1, the only difference is that the oat extract was replaced with Scutellaria baicalensis extract to obtain minoxidil liniment.

[0040] Comparative Example 5 Compared with Example 1, the only difference is that the frequency of the ultrasound is 150 kHz, resulting in minoxidil liniment.

[0041] Comparative Example 6 Compared to Example 1, the only difference is the component content, resulting in a minoxidil topical solution. Details are as follows: A minoxidil topical solution, by weight percentage, comprises the following components: 12% minoxidil, 50% alcohol solution (composed of anhydrous ethanol and propylene glycol in a volume ratio of 5:3), 8% stabilizer (composed of tetrasodium EDTA, panthenol, and hydroxypropyl cellulose in a mass ratio of 1:2:1), 5% oat extract, and the balance to 100% water.

[0042] Test Example 1 Accelerated stability tests were conducted on the minoxidil liniments prepared in Examples 1-3 and Comparative Examples 1-6, respectively. The method was as follows: the minoxidil liniments were sealed in glass spray bottles and left to stand in the dark for 24 months at 60°C and 50% humidity. Samples were taken at different time points, and the total impurity content was determined using high-performance liquid chromatography (HPLC). The total impurity content was determined according to HPLC (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512).

[0043] The experimental results are shown in Table 1. As can be seen from Table 1, the stability of Examples 1-3 is better than that of Comparative Examples 1-6 and commercially available minoxidil topical solution. In particular, the experimental data of Examples 1 and Comparative Examples 1-3 show that by utilizing the synergistic effect of EDTA-tetrasodium, panthenol and hydroxypropyl cellulose, the stability of the active pharmaceutical ingredient minoxidil can be effectively improved and its shelf life extended.

[0044] Table 1 Total impurity content (%)

[0045] Note: Total impurity content below 0.01% is counted as 0.

[0046] Test Example 2 Animal experiments were conducted on the minoxidil liniments prepared in Examples 1-3 and Comparative Examples 1-6, respectively. The experimental methods were as follows: ICR male mice weighing 20-23 g were selected, and a 3 cm × 3 cm area was marked on the back of the mice as the experimental area. The mice were injected subcutaneously with the androgen testosterone propionate at a dose of 5 mg / kg every day for 30 consecutive days. The model was considered successful when the hair on the back of the mice became sparse, fell out, or partially fell out.

[0047] Mice were randomly divided into 11 groups, with 5 mice in each group. These were the positive control group, blank control group, Examples 1-3 groups, and Comparative Examples 1-6 groups. Except for the blank control group, the other groups underwent modeling. The blank control group was treated with physiological saline; the positive control group was treated with commercially available minoxidil ointment; and Examples 1 and Comparative Examples 1-6 groups were treated with the corresponding prepared minoxidil ointment. The dosage was 0.2 g per mouse per day, administered once daily for 15 consecutive days. During the treatment period, testosterone propionate was continuously injected daily to maintain hormone levels. Hair growth in the experimental areas of the mice was observed, as were adverse reactions such as rashes, desquamation, and redness. Hair follicle morphology was observed, and the total number of hair follicles in each group was counted, with the average value taken for each group.

[0048] The results are shown in Table 2. As can be seen from Table 2, the therapeutic effects of Examples 1-3 on androgenetic alopecia are superior to those of Comparative Examples 1-6 and commercially available minoxidil topical solution, while reducing the scalp irritation of minoxidil and minimizing adverse reactions during minoxidil use.

[0049] Table 2 Experimental Results

[0050] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A minoxidil topical solution, characterized in that, The product comprises, by weight percentage, the following components: 5-8% minoxidil, 60-80% alcohol solution, 3-5% stabilizer, 1-2% oat extract, and the balance to 100% water; wherein the stabilizer comprises tetrasodium EDTA, panthenol, and hydroxypropyl cellulose.

2. The minoxidil topical solution according to claim 1, characterized in that, The mass ratio of EDTA-tetrasodium, panthenol, and hydroxypropyl cellulose is 0.5-1.5:1.5-2:1-1.

5.

3. The minoxidil topical solution according to claim 1, characterized in that, The alcohol solution is a mixture of anhydrous ethanol and propylene glycol in a volume ratio of 4-6:2-4.

4. The minoxidil topical solution according to claim 1, characterized in that, By weight percentage, it comprises the following components: minoxidil 5-7%, alcohol solution 65-70%, stabilizer 4-5%, oat extract 1.5-2%, and the balance to 100% water.

5. A method for preparing a minoxidil liniment as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) First, mix EDTA-tetrasodium, panthenol and hydroxypropyl cellulose in water, then add oat extract to obtain an aqueous phase; (2) Minoxidil is then dissolved in an alcohol solution to obtain the alcohol phase; (3) Finally, add the alcohol phase to the aqueous phase, adjust the pH, stir well, and you will get minoxidil liniment.

6. The preparation method according to claim 5, characterized in that, The mixing process described in step (1) includes: first dissolving EDTA-tetrasodium and panthenol in water, and then adding hydroxypropyl cellulose at a speed of 500-1000 rpm.

7. The preparation method according to claim 5, characterized in that, After adding oat extract in step (1), ultrasonic treatment is performed. The ultrasonic temperature is 20-30℃, the ultrasonic time is 15-25 min, and the ultrasonic frequency is 50-100kHz.

8. The preparation method according to claim 5, characterized in that, In step (3), the pH adjustment process is as follows: the pH is adjusted to 4-6 using citric acid; the stirring speed is 500-1000 rpm and the stirring time is 30-60 min.

9. The use of a minoxidil liniment as described in any one of claims 1-4 or a minoxidil liniment prepared by the preparation method described in any one of claims 5-8 in the preparation of a hair loss prevention drug.

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