A kind of minoxidil foam and preparation method thereof

Abstract

The present invention relates to a minoxidil foam and a preparation method thereof, which comprises, by weight percentage, 5-6% minoxidil, 4% foam carrier, 5% surfactant, 0.08%-0.12% butylated hydroxytoluene, 0.1% buffer, 50%-60% anhydrous ethanol, 5%-15% glycerol, 0.5%-1% disodium edetate, 0.3%-0.5% white beeswax, the remainder being purified water, and the propellant being 8%-10% of the total weight of the raw materials. The foam of the present invention has relatively higher penetration and retention than the tincture, and the relevant quality indicators of the minoxidil foam are basically consistent with those of the tincture, and its 24h cumulative penetration amount and the drug residue in the skin are significantly greater than those of the tincture, that is, its transdermal absorption effect is better, and the compliance of the application is better at the same time.

Description

Technical Field

[0001] The invention relates to a minoxidil foam and a preparation method thereof, and belongs to the field of anti-hair loss products. Background Art

[0002] Minoxidil can prolong the growth period of hair and make the miniaturized hair follicles grow larger. According to experimental studies, adding minoxidil to the in vitro culture of hair follicles can increase the growth time of the cultured hair follicles. Hair follicle hepatocyte growth factor and vascular endothelial cell growth factor are two main growth factors of the hair papilla, which have an important regulatory effect on the growth cycle of hair. Currently, the minoxidil dosage forms available in China include tinctures, solutions, sprays and lotions for the treatment of male pattern baldness and alopecia areata.

[0003] The solubility of minoxidil is almost insoluble, and it is difficult to achieve complete dissolution in the process of preparing tincture, and the stability of minoxidil will deteriorate with the increase of temperature. The process of preparing minoxidil tincture in the prior art usually adopts propylene glycol to dissolve the minoxidil raw material first, and then adds ethanol and water to make up the volume in sequence. In addition to promoting the dissolution of minoxidil in the prescription, propylene glycol can also play a certain role in promoting transdermal and moisturizing. However, high concentrations of propylene glycol easily cause allergic reactions such as rashes in users. To achieve good therapeutic effects, it is necessary to spray the medicine several times, and repeated use may make the adverse reactions of patients more serious.

[0004] At the same time, the existing minoxidil tincture has a slow steady-state transdermal rate of minoxidil, a low cumulative permeation amount and a low drug residue in the skin, and a poor transdermal effect, resulting in a poor effect. Summary of the invention

[0005] The invention provides a minoxidil foam and a preparation method thereof, which solve the problems of poor stability, low penetration and retention of minoxidil in existing minoxidil products.

[0006] The technical solution adopted by the present invention is:

[0007] A minoxidil foam comprises, by weight percentage, 5-6% minoxidil, 4% foam carrier, 5% surfactant, 0.08%-0.12% butylated hydroxytoluene, 0.1% buffer, 50%-60% anhydrous ethanol, 5%-15% glycerol, 0.5%-1% disodium edetate, 0.3%-0.5% white beeswax, and the balance is purified water. The propellant accounts for 8%-10% of the total weight of the raw materials.

[0008] Furthermore, a preferred embodiment is that the glycerol content is 5% to 10%.

[0009] Furthermore, a preferred embodiment is that the foam carrier is octadecyl alcohol and hexadecanol in a weight ratio of 1:1.

[0010] Furthermore, a preferred embodiment is that the buffer is one or more of lactic acid, acetic acid and tartaric acid.

[0011] Furthermore, a preferred embodiment is that the buffer is lactic acid.

[0012] Furthermore, a preferred embodiment is that the surfactant is polysorbate 80.

[0013] Furthermore, a preferred embodiment is that the propellant is HFC-134a.

[0014] A method for preparing a minoxidil foam of the present invention comprises the following steps:

[0015] (1) Preparation of alcohol phase: minoxidil, octadecyl alcohol, cetyl alcohol, polysorbate 80, white beeswax, butylated hydroxytoluene and anhydrous ethanol were mixed and heated to dissolve, and kept at 60°C for later use;

[0016] (2) Preparation of aqueous phase: Combine purified water, glycerol, disodium edetate and lactic acid, adjust the pH to 4-6 with citric acid, then heat to dissolve, and keep at 60°C for later use;

[0017] (3) Total mixing: Add the water phase to the alcohol phase, stir for 5 to 10 minutes at a speed of 200-300 r / min, and cool to 50°C while stirring;

[0018] (4) Filling and filling: Fill the liquid medicine obtained in step (3) into a medicinal aerosol can, cap it, and add the propellant.

[0019] Beneficial effects of the present invention:

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] The present invention adopts disodium edetate, white beeswax and minoxidil to compound, the fatty alcohol components in the white beeswax can effectively improve the foam stability, and the antioxidant and enzyme in the white beeswax can slow down the oxidation process of minoxidil, thereby improving its stability; when the white beeswax is combined with disodium edetate, the antioxidant in the white beeswax can further enhance the antioxidant effect of disodium edetate, and this synergistic effect can effectively improve the stability of the drug, prolong its validity period, and reduce the oxidation reaction that may occur in the drug during storage and use, thereby increasing the stability and effectiveness of the drug. The foam of the present invention has relatively higher penetration and retention relative to the tincture, and the relevant quality indicators of the minoxidil foam are basically the same as those of the tincture, and its 24h cumulative penetration amount and the drug residue in the skin are significantly greater than those of the tincture, that is, its transdermal absorption effect is better, and the compliance of the application is better. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] In order to more clearly illustrate the technical solutions of the embodiments of the present application, the following is a brief introduction to the drawings required for use in the embodiments of the present application. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without creative work.

[0023] Figure 1 It is a flow chart of the in vitro transdermal experiment operation of the present invention. DETAILED DESCRIPTION

[0024] The technical solution of the present invention will be clearly and completely described below in combination with the embodiments of the present invention and the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Minoxidil (raw material quality indicators and sources): Properties: white or off-white crystalline powder, related substances: impurity A ≤ 0.10%, impurity E ≤ 0.2%, single substance ≤ 0.10%, total impurities ≤ 0.3%, content: not less than 99.0% calculated on the basis of dry product, source: Tianjin Institute of Pharmaceutical Research Pharmaceutical Co., Ltd.

[0026] The white beeswax can be natural white beeswax. In the embodiment of the present invention, western beeswax is used, and the acid value is 16.0-23.0 and the iodine value is 8.0-13.0.

[0027] The remaining raw materials are commercially available and meet relevant requirements.

[0028] Example 1-3 Effect of pH on the stability of minoxidil (5%)

[0029] A minoxidil foam comprises, by weight percentage, 5% minoxidil, 4% foam carrier, 5% surfactant, 0.10% butylated hydroxytoluene, 0.1% buffer, 50% anhydrous ethanol, 10% glycerol, 0.6% disodium edetate, 0.3% white beeswax, and the balance is purified water. The propellant accounts for 10% of the total weight of the raw materials.

[0030] The foam carrier is octadecyl alcohol and hexadecanol, with a weight ratio of 1:1; the buffer is lactic acid; the surfactant is polysorbate 80; and the propellant is HFC-134a.

[0031] The preparation method thereof comprises the following steps:

[0032] (1) Preparation of alcohol phase: minoxidil, octadecyl alcohol, cetyl alcohol, polysorbate 80, butylated hydroxytoluene and anhydrous ethanol were mixed and heated to dissolve, and kept at 60°C for later use;

[0033] (2) Preparation of aqueous phase: Combine purified water, glycerin, disodium edetate, white beeswax and lactic acid, adjust the pH to 4, 5 and 6 respectively with citric acid, then heat to dissolve, and keep at 60°C for later use;

[0034] (3) Total mixing: Add the water phase to the alcohol phase, stir at 200 r / min for 5 minutes, and cool to 50°C with stirring;

[0035] (4) Filling and filling: Fill the liquid medicine obtained in step (3) into a medicinal aerosol can, cap it, and add the propellant.

[0036] Determination of the total impurity content and foam properties of the minoxidil foam prepared in Examples 1-3

[0037] The total impurity content of minoxidil foam is determined according to the high performance liquid chromatography method (General Rules 0512 of Part IV of the Chinese Pharmacopoeia 2020 Edition).

[0038] Table 1: Stability of minoxidil solution at different pH

[0039]

[0040] It can be seen that the pH of minoxidil foam is adjusted to 4-6 by citric acid, and the impurities of minoxidil foam (5%) solution are unchanged after being stored at 40°C for one month, and the stability is good.

[0041] Example 4-7 Screening of the amount of anhydrous ethanol and glycerol

[0042] According to the prescription ratio in Table 2, the preparation method is the same as that in Example 1, and the foam properties are used as the evaluation basis to examine the dosage of anhydrous ethanol and glycerol.

[0043] Table 2: Prescription composition percentage (%)

[0044]

[0045] The results in Table 2 show that judging from the properties of the foam, 50% to 60% anhydrous ethanol and 5% to 15% glycerol have better foam formability, and the preferred amount of anhydrous ethanol is 50% and the preferred amount of glycerol is 15%.

[0046] Example 8-13 Screening of the dosage of butylated hydroxytoluene

[0047] According to the prescription ratio in Table 3, the preparation method is the same as that in Example 1, and the foam properties and preparation-related substances are used as the evaluation basis to examine the amount of butylated hydroxytoluene.

[0048] Table 3: Prescription composition percentage (%)

[0049]

[0050] Table 4 Related substances in prescription studies

[0051]

[0052] The results in Table 4 show that when minoxidil is exposed to high temperature or oxidative environment, free radicals will be generated, which may cause oxidation reaction of minoxidil molecules, making them inactive or producing harmful substances. Butylated hydroxytoluene has the ability to capture free radicals and can effectively inhibit the activity of free radicals, thereby preventing the oxidation process of minoxidil, effectively protecting the stability and activity of its molecular structure, and extending the service life and effectiveness of minoxidil, thereby ensuring the quality and stability of the product.

[0053] Example 14-27 Screening of Disodium Edetate and White Beeswax

[0054] According to the prescription ratio in Table 5, the preparation method is the same as that in Example 1, and the foam properties, preparation-related substances and transdermal absorption performance are used as evaluation criteria to examine the screening amounts of disodium edetate and white beeswax.

[0055] Table 5: Prescription composition percentage (%)

[0056]

[0057] As shown in Table 5, the disodium edetate and white beeswax of the present invention have a certain influence on the foam properties, and the addition of disodium edetate and white beeswax can effectively improve the foam state.

[0058] Table 6 Related substances in prescription studies

[0059]

[0060] As shown in Table 6, the disodium edetate and white beeswax of the present invention have a significant effect on the stability of minoxidil. The addition of disodium edetate and white beeswax can effectively reduce the effect of high temperature on minoxidil, especially for reducing impurity E. After the disodium edetate of the present invention is replaced by rose essential oil or citronella essential oil, the effect is significantly reduced.

[0061] In vitro transdermal test:

[0062] like Figure 1 As shown, the back skin of Bama miniature pigs was used as the ex vivo skin. The details are as follows:

[0063] Table 7 Experimental parameters

[0064]

[0065] 1. Transdermal Devices and Methods

[0066] The Franz diffusion cell method was used.

[0067] 2. Transdermal test

[0068] 2.1 Skin integrity test before transdermal operation

[0069] Place 0.9% sodium chloride solution into the diffusion cell and then into the skin, and measure the resistance before and after the skin is placed. If the resistance value of the skin is 3 times or more than the background value, it means the skin is intact.

[0070] 2.2 Transdermal operation process

[0071] The skin was placed between the receiving chamber and the supply chamber of the LOGAN Franz diffusion cell, and the products of Examples 14-27 and 5% minoxidil tincture were evenly applied to the skin, and an appropriate amount of receiving solution was added to the receiving cell, and the receiving solution was tested. Samples were taken at the sampling time points to determine the API.

[0072] 2.3 Skin residue samples

[0073] Take the skin after 1h, 2h, 4h, 6h, 12h, and 24h of transdermal test. If there are crystals on the skin surface, gently scrape it three times in one direction with a small spoon, place it in a certain volume of receiving medium, and rinse it with the medium three times to obtain the solution residual on the skin for testing.

[0074] 2.4 Skin retention samples

[0075] Cut the skin into pieces and place them in the homogenization cup of the smart homogenizer. Use a pipette to transfer 40 ml of 1 pH 7.4 phosphate buffer solution to the homogenization cup of the smart homogenizer for homogenization at 20,000 rpm / min for 1 min, repeat twice. Place the homogenate in a 50 ml centrifuge tube and centrifuge at 10,000 rpm / min for 5 min. Place the supernatant in a 5 ml centrifuge tube for testing.

[0076] See Table 8 for specific results.

[0077] Table 8 Evaluation of transdermal effect

[0078]

[0079] As shown in Table 8, the cumulative penetration of minoxidil in 24 hours and the drug residue in the skin of the present invention have a significant impact on the stability of minoxidil, and the addition of disodium edetate and white beeswax can effectively promote the transdermal effect of minoxidil. After disodium edetate of the present invention is replaced by rose essential oil or citronella essential oil, the effect is significantly reduced.

[0080] Examples 28-32: Propellant dosage screening

[0081] According to the prescription ratio in Table 9, the preparation method is the same as that in Example 1, and the amount of propellant is examined based on the evaluation of foam properties, etc.

[0082] Table 9: Prescription composition percentage (%)

[0083]

[0084] It can be seen from Table 9 that the amount of propellant has a significant effect on the foam properties. When the amount of propellant increases from 5% to 12%, the foam density decreases from 0.133g / ml to 0.075g / ml, and the defoaming time at 33°C increases from 69.7s to 89.3s. When the amount of propellant is between 8% and 10%, the foam appearance is beautiful and the defoaming time is appropriate.

[0085] Example 33 Quality Index Evaluation of Minoxidil Tincture

[0086] A minoxidil foam comprises, by weight percentage, 5% minoxidil, 4% foam carrier, 5% surfactant, 0.10% butylated hydroxytoluene, 0.1% buffer, 50% anhydrous ethanol, 10% glycerol, 0.6% disodium edetate, 0.4% white beeswax, the balance being purified water, and the propellant being 10% of the total weight of the raw materials. The preparation method is similar to that of Example 1. The quality indicators of the sample of Evaluation Example 33 and the minoxidil tincture are specifically shown in Table 10.

[0087] Table 10 Minoxidil foam related quality index detection

[0088]

[0089] It can be seen from Tables 9 and 10 that the relevant quality indicators of the minoxidil foam prepared by the present invention are basically consistent with those of the tincture, indicating that the penetration and retention of the foam are relatively higher than those of the tincture. The relevant quality indicators of the minoxidil foam are basically consistent with those of the tincture, but its 24h cumulative penetration amount and the drug residue in the skin are significantly greater than those of the tincture, that is, its transdermal absorption effect is better, and the compliance of the application is better.

[0090] Although the embodiments of the present invention have been described above, it will be apparent to those skilled in the art that modifications and substitutions made without departing from the principles and spirit of the present invention are intended to fall within the scope of protection claimed by the present invention.

Claims

1. A minoxidil foam, characterized in that: According to the weight percentage, the liquid medicine includes 5-6% minoxidil, 4% foam carrier, 5% surfactant, 0.08%-0.12% butylated hydroxytoluene, 0.1% buffer, 50%-60% anhydrous ethanol, 5%-10% glycerol, 0.5%-1% disodium edetate, 0.3%-0.5% white beeswax, the pH is adjusted to 4-6 with citric acid, and the balance is purified water; It also includes a propellant, the amount of which is 8% to 10% of the total weight of the liquid medicine; The foam carrier is octadecyl alcohol and hexadecanol in a weight ratio of 1:1; The buffer is lactic acid; The surfactant is polysorbate 80; The propellant is HFC-134a.

2. A method for preparing the minoxidil foam according to claim 1, characterized in that: The following steps are involved: (1) Preparation of alcohol phase: minoxidil, octadecyl alcohol, cetyl alcohol, polysorbate 80, white beeswax, butylated hydroxytoluene and anhydrous ethanol were mixed and heated to dissolve, and kept at 60°C for later use; (2) Preparation of aqueous phase: Combine purified water, glycerol, disodium edetate and lactic acid, adjust the pH to 4-6 with citric acid, then heat to dissolve, and keep at 60°C for later use; (3) Total mixing: Add the water phase to the alcohol phase, stir for 5 to 10 minutes at a speed of 200 to 300 r / min, and cool to 50°C while stirring; (4) Filling and filling: Fill the liquid medicine obtained in step (3) into a medicinal aerosol can, cap it, and add the propellant.

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