Foaming agent containing minoxidil and finasteride and preparation method thereof

Abstract

According to the foaming agent containing minoxidil and finasteride provided by the invention, micronization of raw material medicines and complicated preparation procedures such as homogenization are not needed in the preparation process, liquid medicine liquid is directly prepared and then is filled, and a propellant is added to prepare the foaming agent, so that the foaming agent has the advantages of few impurities, uniform medicine liquid and high stability; the invention has the advantages of strong foam adhesiveness, prolonged action time of the medicament on the scalp, uniform and non-greasy application, quick defoaming to enhance the curative effect, strong permeability, effective penetration of the medicament into the skin or mucous membrane to improve the bioavailability of the medicament, and the like. The preparation method is simple and easy to operate, time and cost can be greatly saved, meanwhile, the dosage form of the foaming agent has the advantages of being easy to smear, few in residue, capable of being smeared in a large area and the like, patient compliance is improved, use is convenient, the two active ingredients with different action mechanisms are in synergistic interaction, and the clinical effect is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a foam containing minoxidil and finasteride and a preparation method thereof. Background Art

[0002] Currently, hair loss has been a hot topic, and hair loss treatment is no longer a new topic. Androgenetic alopecia (AGA) is a common type of hair loss that seriously affects the patient's mental health and quality of life.

[0003] Finasteride and minoxidil are currently the most popular hair loss treatments worldwide, with more than half of hair restoration experts recommending topical minoxidil and more than two-thirds recommending oral finasteride. But a growing number of studies suggest that a combination of minoxidil and finasteride actually works best for male pattern baldness.

[0004] Minoxidil is a vasodilator. In the treatment of hair loss, it mainly dilates blood vessels in the scalp, opens potassium ion channels, improves blood circulation in the hair follicles, and provides more nutrients and oxygen to the hair follicles, thereby controlling hair cell death and promoting the growth of new hair.

[0005] The hair growth cycle includes three different periods: growth phase, regression phase and resting phase. Relevant studies have found that minoxidil helps to prolong the growth phase of hair and stimulate hair growth. In terms of mechanism of action, minoxidil cannot prevent the problem of hair loss. On the contrary, it stimulates the shedding of hair in the resting phase and replaces these hair in the resting phase by promoting the regrowth of new hair in the growth phase, thereby achieving the effect of improving hair volume. Simply put, it improves hair loss by accelerating the fall of aging hair and the rapid growth of new hair. Minoxidil affects the normal growth cycle of hair, so in the first few months of use, accelerated hair loss may occur, but over time, the hair in the resting phase is replaced by the hair in the growth phase, and the hair will become thicker.

[0006] Minoxidil has no effect on male hormone levels, so it will not protect hair from the effects of DHT.

[0007] Male pattern hair loss is caused by the conversion of testosterone into the male sex hormone dihydrotestosterone (DHT) via the 5α-reductase enzyme. DHT is a major androgen, and high DHT levels can cause hair follicles to shrink and decrease, leading to baldness. Finasteride is a 5α-reductase inhibitor drug that inhibits the conversion of testosterone into dihydrotestosterone, reducing or even further controlling male pattern hair loss.

[0008] Finasteride is generally more effective at preventing male pattern baldness from getting worse and protecting existing hair, compared to minoxidil, which promotes new hair growth.

[0009] Therefore, given that minoxidil and finasteride address hair loss through two different mechanisms of action, the combination of these two drugs will lead to better therapeutic effects.

[0010] At present, there are no minoxidil-finasteride combination preparations on the market in China. The main dosage forms of minoxidil are foams, sprays, solutions, gels, tinctures, and ointments. The main dosage forms of finasteride are tablets and capsules. The results of clinical trials show that the combination of finasteride and minoxidil can control the side effects of combined use to ensure its safety and effectiveness. However, finasteride is not easy to dissolve in water and has a small dosage form. The difficulty of its conventional oral solid preparation process lies in the fact that its therapeutic effect is affected by solubility and content uniformity. Therefore, topical minoxidil and topical finasteride have higher application prospects.

[0011] Chinese patent CN105434352A discloses a minoxidil foam and its preparation method and application, and the stability of the obtained product is poor. During the preparation, the hydrophobic phase and the aqueous phase are prepared separately, and the two phases are mixed and homogenized with a homogenizer. The homogenization process is complicated, the homogenizer equipment is expensive, prone to failure, and the maintenance cost is high. In addition, minoxidil has no effect on male androgen levels, and its use alone will not protect hair from the phenomenon of hair follicle shrinkage and reduction caused by high levels of dihydrotestosterone, which leads to baldness.

[0012] Chinese patent CN115089594A discloses a minoxidil finasteride nanoemulsion and its preparation method and application. Before preparing the nanoemulsion, the raw materials finasteride and minoxidil need to be micronized. Micronization generally adopts mechanical grinding, which is costly, complex and dusty. The raw materials are easily adsorbed on the surface of the equipment after micronization, and dust is easily generated during the transfer process, thereby causing the loss of the raw materials. In addition, the nanoemulsion has a short shelf life, and long-term storage may cause stratification, flocculation and other phenomena, and the transdermal absorption effect is not good.

[0013] Therefore, it is very necessary to develop a topical preparation that has low cost, simple process, good stability, few side effects, high bioavailability, and can combine minoxidil and finasteride with different mechanisms of action to treat hair loss, and a pharmaceutical composition and preparation method suitable for large-scale commercial production. Summary of the invention

[0014] The purpose of the present invention is to provide a foam containing minoxidil and finasteride on the basis of the prior art, with minoxidil and finasteride as active ingredients, and no need to micronize the raw materials in the preparation process, nor to perform complex preparation processes such as homogenization, and directly prepare the liquid medicine for filling, and add the propellant to prepare the foam. The foam of the present invention has the advantages of less impurities, uniform medicine, high stability, strong foam adhesion, prolonged drug action time on the scalp, uniform and non-greasy application, rapid defoaming and enhanced efficacy, and strong permeability, the drug effectively penetrates into the skin or mucous membrane to improve the bioavailability of the drug, etc. The whole preparation process is simple and easy to operate, which can greatly save time and cost. At the same time, the dosage form of the foam has the advantages of easy application, less residue and large-area application, high patient compliance, convenient use, and easier for patients to accept and continue to use, so that the active ingredients of two different mechanisms of action can synergize and improve the clinical effect.

[0015] Another object of the present invention is to provide a method for preparing the foam containing minoxidil and finasteride.

[0016] The technical solution of the present invention is as follows:

[0017] A foam containing minoxidil and finasteride, wherein the foam is prepared from the following components in parts by weight: 1-10 parts of minoxidil, 0.01-1 parts of finasteride, 40-85 parts of solvent, 1-5 parts of foam adjuvant, 1-6 parts of surfactant, 1-10 parts of moisturizer, 1-10 parts of penetration enhancer, 0.001-0.02 parts of antioxidant and 3-7 parts of propellant.

[0018] In the present invention, the solvent is anhydrous ethanol, which is a common organic solvent, widely used in cosmetics, medicines, and alcoholic beverages. The main function of ethanol is solvent, and it also has the functions of sterilization, anti-inflammatory, antiseptic, giving the product a cool feeling, astringency, etc. Ethanol is a commonly used solvent for foaming agents. Foaming agents containing ethanol are called "fast-breaking foams" and can be broken quickly at skin temperature, so that the drug can reach an effective concentration on the skin in a short time, forming a supersaturated drug solution, which is beneficial to the penetration of the drug and achieves rapid onset. Therefore, it is safe and effective for suitable people to use foaming agents containing ethanol under the correct usage and dosage.

[0019] In the present invention, minoxidil and finasteride are used as active ingredients, wherein the foam adjuvant is a mixture of cetyl alcohol and octadecanol, wherein the weight ratio of cetyl alcohol to octadecanol is 1.5-3:1, and may be but not limited to 1.5:1, 1.8:1, 2:1, 2.5:1 or 3:1; in a preferred embodiment, the weight ratio of cetyl alcohol to octadecanol is 1.8-2.5:1, and further, the weight ratio of cetyl alcohol to octadecanol is 2:1.

[0020] In the present invention, the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 40-50:25-35:20-30, preferably, the weight ratio of propane, butane and isobutane is 45:30:25.

[0021] In the present invention, during its preparation process, minoxidil, finasteride, solvent, foam adjuvant, surfactant, humectant, penetration enhancer, antioxidant and part of purified water are stirred at 40-60°C until dissolved, the pH of the obtained mixed solution is adjusted to 5.0-6.0, the remaining purified water is added to make up the volume, and the drug solution is stirred to obtain a drug solution. After the drug solution is prepared, it is sterilized and filtered, filled, and pressed into a propellant to obtain a finished product.

[0022] In a preferred embodiment, the foam containing minoxidil and finasteride provided by the present invention is made of the following components in parts by weight: 4-6 parts of minoxidil, 0.05-0.2 parts of finasteride, 45-65 parts of anhydrous ethanol, 2-3 parts of foam adjuvant, 2-5 parts of poloxamer 188, 2-5 parts of sorbitol, 1-3 parts of isopropyl myristate, 0.005-0.015 parts of butylated hydroxyanisole, and 4-6 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8-2.5:1; and the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25.

[0023] In a more preferred embodiment, the foam containing minoxidil and finasteride provided by the present invention is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 50-60 parts of anhydrous ethanol, 2.2-2.6 parts of foam adjuvant, 2.5-3.5 parts of poloxamer 188, 2.5-3.5 parts of sorbitol, 1.5-2.5 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8-2.5:1; and the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25.

[0024] In a particularly preferred embodiment, the foam containing minoxidil and finasteride provided by the present invention is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of poloxamer 188, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8:1, that is, the hexadecanol is 1.54 parts and the octadecanol is 0.86 parts; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25.

[0025] In a particularly preferred embodiment, the foam containing minoxidil and finasteride provided by the present invention is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of poloxamer 188, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 2:1, that is, hexadecanol is 1.6 parts and octadecanol is 0.8 parts; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25.

[0026] In a particularly preferred embodiment, the foam containing minoxidil and finasteride provided by the present invention is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of poloxamer 188, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 2.5:1, that is, the hexadecanol is 1.71 parts and the octadecanol is 0.69 parts; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25.

[0027] The present invention also provides a method for preparing the foam containing minoxidil and finasteride, which comprises the following steps:

[0028] (1) stirring minoxidil, finasteride, solvent, foam adjuvant, surfactant, humectant, penetration enhancer, antioxidant and partially purified water at 40-60° C. until dissolved;

[0029] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.0-6.0, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0030] (3) After the preparation of the liquid medicine, it is sterilized and filtered, filled, and pressed into the propellant to obtain the finished product.

[0031] In the present invention, in step (1), minoxidil, finasteride, solvent, foam adjuvant, surfactant, humectant, penetration enhancer, antioxidant and partially purified water are stirred at 40-60°C until dissolved. Preferably, the solution preparation temperature is 50-60°C.

[0032] In the present invention, in step (2), the pH value of the mixed solution obtained in step (1) is adjusted to 5.0-6.0, preferably, the pH value of the mixed solution obtained in step (1) is adjusted to 5.5.

[0033] In the present invention, in step (3), the filter membrane material is PES when filtering the liquid medicine; during the filling process, the filling volume is 60.0-62.0 g.

[0034] In the present invention, after the filling process, the propellant is pressed into the finished product, wherein the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 40-50:25-35:20-30, preferably, the weight ratio of propane, butane and isobutane is 45:30:25.

[0035] The foam containing minoxidil and finasteride provided by the present invention realizes the combined use of minoxidil and finasteride, two active ingredients for treating hair loss with different action mechanisms, and is applied in the treatment of male androgenic alopecia.

[0036] Adopt the technical scheme of the present invention, the advantages are as follows:

[0037] (1) The present invention provides a foam containing minoxidil and finasteride that can be absorbed on the surface of the scalp. The foam contains minoxidil and finasteride as active ingredients. During the preparation process, there is no need to micronize the raw materials, nor is there any need to perform complex preparation steps such as homogenization. The foam can be directly prepared into a liquid solution and then filled. A propellant is added to obtain the foam. The entire preparation method is simple and easy to operate, which can greatly save time and cost and has high industrial application value.

[0038] (2) The foam containing minoxidil and finasteride provided by the present invention has the advantages of less impurities, uniform drug solution, high stability, strong foam adhesion, prolonged drug action time on the scalp, uniform and non-greasy application, rapid defoaming to enhance therapeutic effect, and strong permeability, so that the drug can effectively penetrate into the skin or mucous membrane to improve the bioavailability of the drug. At the same time, the dosage form of the foam has the advantages of easy application, less residue and large-area application, high patient compliance, convenient use, and patients are more likely to accept and continue to use it, so that the two active ingredients with different action mechanisms synergize and improve the clinical effect.

[0039] (3) The present invention combines minoxidil and finasteride to form a compound preparation, which has good synergistic effects, improves clinical effects, reduces side effects, and solves the problem of hair loss through two different mechanisms, thus having higher clinical application value. DETAILED DESCRIPTION

[0040] The present invention is further explained below by specific examples and comparative examples, but this is not intended to limit the present invention. Professionals and technicians in this field can make any modifications, equivalent substitutions or improvements based on the basic ideas of the present invention, which should all be included in the scope of the present invention.

[0041] Example 1

[0042] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, with 1.6 parts of hexadecanol and 0.8 parts of octadecanol, and the weight ratio of hexadecanol to octadecanol is 2:1; the propellant is a mixture of propane, butane and isobutane, and the weight ratio of propane, butane and isobutane is 45:30:25, as follows:

[0043] Recipe composition Weight (parts) Minoxidil 5 Finasteride 0.1 Anhydrous ethanol 55 Cetyl Alcohol 1.6 Octadecanol 0.8 Poloxamer 188 3 Sorbitol 3 Isopropyl myristate 2 Butylated Hydroxyanisole 0.01 Propellant 5.5

[0044] The preparation method of the foam containing minoxidil and finasteride comprises the following steps:

[0045] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and partially purified water into a liquid preparation tank, and stir at 50-60° C. until dissolved;

[0046] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.5, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0047] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 5.5 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0048] Example 2

[0049] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, with 1.54 parts of hexadecanol and 0.86 parts of octadecanol, and the weight ratio of hexadecanol to octadecanol is 1.8:1; the propellant is a mixture of propane, butane and isobutane, and the weight ratio of propane, butane and isobutane is 45:30:25, as follows:

[0050] Recipe composition Weight (parts) Minoxidil 5 Finasteride 0.1 Anhydrous ethanol 55 Cetyl Alcohol 1.54 Octadecanol 0.86 Poloxamer 188 3 Sorbitol 3 Isopropyl myristate 2 Butylated Hydroxyanisole 0.01 Propellant 5.5

[0051] The preparation method of the foam containing minoxidil and finasteride comprises the following steps:

[0052] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and partially purified water into a liquid preparation tank, and stir at 50-60° C. until dissolved;

[0053] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.5, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0054] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 5.5 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0055] Example 3

[0056] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, with 1.71 parts of hexadecanol and 0.69 parts of octadecanol, and the weight ratio of hexadecanol to octadecanol is 2.5:1; the propellant is a mixture of propane, butane and isobutane, and the weight ratio of propane, butane and isobutane is 45:30:25, as follows:

[0057]

[0058]

[0059] The preparation method of the foam containing minoxidil and finasteride comprises the following steps:

[0060] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and partially purified water into a liquid preparation tank, and stir at 50-60° C. until dissolved;

[0061] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.5, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0062] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 5.5 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0063] Example 4

[0064] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, with 1.6 parts of hexadecanol and 0.8 parts of octadecanol, and the weight ratio of hexadecanol to octadecanol is 2:1; the propellant is a mixture of propane, butane and isobutane, and the weight ratio of propane, butane and isobutane is 45:30:25, as follows:

[0065] Recipe composition Weight (parts) Minoxidil 5 Finasteride 0.1 Anhydrous ethanol 55 Cetyl Alcohol 1.6 Octadecanol 0.8 Poloxamer 188 3 Sorbitol 3 Isopropyl myristate 2 Butylated Hydroxyanisole 0.01 Propellant 5.5

[0066] The preparation method of the foam containing minoxidil and finasteride comprises the following steps:

[0067] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and part of purified water into the liquid preparation tank, stir until dissolved at room temperature (18-25℃), 40℃, 50℃ and 60℃ respectively; observe and record the dissolution of each component, and the results are shown in Table 1. At the same time, take part of the drug solution for sample stability test, and place it at room temperature (18-25℃), 40℃, 50℃ and 60℃ for 24h to test the stability of the drug solution, and the results are shown in Table 2.

[0068] (2) adjusting the pH value of the mixed solution obtained under different temperature conditions in step (1) to 5.5, adding the remaining purified water to make up the volume, and stirring to obtain a drug solution;

[0069] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 5.5 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0070] Table 1 Dissolution of raw materials and auxiliary materials at different preparation temperatures

[0071]

[0072] Table 2 Stability test data of different solution temperatures

[0073]

[0074] Conclusion: When the preparation temperature is room temperature (18-25°C), the raw and auxiliary materials are milky white suspension and cannot be completely dissolved. When the preparation temperature is 40°C, 50°C, and 60°C, the raw and auxiliary materials can be completely dissolved, and the dissolution is significantly better than room temperature. The dissolution time at 40°C is slightly longer. When the preparation temperature is 40°C, 50°C, and 60°C, the sample has good stability when placed for 24 hours. Combined with actual production conditions, the preferred preparation temperature is 50-60°C.

[0075] Comparative Example 1-2

[0076] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, the hexadecanol is 1.2 parts and 1.2 parts respectively, the octadecanol is 2.0 parts and 0.4 parts respectively, the weight ratio of hexadecanol to octadecanol is 1:1 and 5:1, and the propellant is a mixture of propane, butane and isobutane, the weight ratio of propane, butane and isobutane is 45:30:25, specifically as follows:

[0077]

[0078] The preparation methods of Comparative Examples 1 and 2 are as follows, comprising the following steps:

[0079] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and partially purified water into a liquid preparation tank, and stir at 50-60° C. until dissolved;

[0080] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.5, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0081] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 5.5 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0082] Comparative Examples 3-4

[0083] A foam containing minoxidil and finasteride is prepared from the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of solvent anhydrous ethanol, 2.4 parts of foam adjuvant, 3 parts of surfactant poloxamer 188, 3 parts of moisturizer sorbitol, 2 parts of penetration enhancer isopropyl myristate, 0.01 parts of antioxidant butylated hydroxyanisole, and 1 part or 10 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, the hexadecanol is 1.6 parts, the octadecanol is 0.8 parts, and the weight ratio of the hexadecanol to the octadecanol is 2:1; the propellant is a mixture of propane, butane and isobutane, and the weight ratio of the propane, butane and isobutane is 45:30:25, as follows:

[0084]

[0085] The preparation methods of Comparative Examples 3 and 4 are as follows, comprising the following steps:

[0086] (1) Add minoxidil, finasteride, solvent, foam adjuvant, surfactant, moisturizer, penetration enhancer, antioxidant and partially purified water into a liquid preparation tank, and stir at 50-60° C. until dissolved;

[0087] (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.5, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution;

[0088] (3) After the preparation of the drug solution, it is sterilized and filtered through a PES filter membrane, and 60.0 to 62.0 g of the drug solution is poured into a container bottle at 40 to 50° C., and 1 or 10 parts of a propellant (the weight ratio of propane, butane and isobutane is 45:30:25) is pressed into the container bottle, and the bottle is capped, sealed, leak tested, and packaged to obtain the finished product.

[0089] Comparative Example 5

[0090] A minoxidil foam was prepared according to the formula and preparation method disclosed in Example 1 of Chinese Patent CN105434352A.

[0091] Comparative Example 6

[0092] A finasteride minoxidil nanoemulsion was prepared according to the formula and preparation method disclosed in Example 6 of Chinese patent CN115089594A.

[0093] The foaming agents prepared in Example 1, Example 2, Example 3 and Comparative Examples 1, Comparative Example 2, Comparative Example 3 and Comparative Example 4 are compared, that is, the defoaming time, spray rate, touch, etc. of the foaming agents prepared by comparing different proportions of hexadecanol, octadecyl alcohol and different propellant dosages are compared. The results are shown in Table 3.

[0094] Table 3 Test data of different proportions of hexadecanol and octadecyl alcohol and different propellant dosages

[0095]

[0096]

[0097] Conclusion: The appropriate defoaming time of the foaming agent is no more than 120s at 33°C, and the average injection rate should be no less than 2.0g / s. The data in Table 3 show that when the weight ratio of hexadecanol and octadecanol in the foam adjuvant in Comparative Example 1 is 1:1, the defoaming time of the prepared sample is longer, and the excessive defoaming time seriously affects the patient's use experience. When the weight ratio of hexadecanol and octadecanol in the foam adjuvant in Comparative Example 2 is 5:1, the injection rate of the prepared sample is lower, which also affects the patient's use experience. When the weight ratio of hexadecanol and octadecanol is 2:1, 1.8:1 and 2.5:1, the defoaming time and injection rate of the prepared sample are appropriate and the feel is good. It can be seen that the weight ratio of hexadecanol and octadecanol in the foam adjuvant also needs to be controlled within the protection scope of the present invention. In addition, in Comparative Example 3, when the amount of propellant is low, the injection rate is slow; in Comparative Example 5, when the amount of propellant is high, the injection rate is significantly increased, but the excessively high injection rate makes the sprayed foam sparsely expanded, the foam is unstable, melts at the touch, and part of it is sprayed in liquid form, which is not suitable for uniform transdermal application. Therefore, the amount of propellant needs to be controlled within the scope of the present invention.

[0098] The effectiveness of the minoxidil and finasteride foams prepared in Example 1 was evaluated and compared with the minoxidil foam of Comparative Example 5. The animal experiment was as follows: 18 male mice aged 6-8 weeks were randomly divided into 3 groups, all of which were depilated, and the depilatory area on the back of the mice was 2 cm×3 cm. The model group simulated the pathological state of hair loss caused by excessive androgen by injecting dihydrotestosterone androgen into the depilated mice to construct an androgenic alopecia model. The drug group was injected with dihydrotestosterone androgen, and the foams of Example 1 and Comparative Example 5 were applied twice a day. Photos were taken at different time points to compare and observe the hair condition on the back of the mice. The results are shown in Table 4.

[0099] Table 4 Effectiveness test data

[0100]

[0101]

[0102] Conclusion: It can be seen from the test results that the minoxidil finasteride foam of Example 1 has a significantly higher hair growth rate in the hair loss area than the minoxidil foam of Comparative Example 5 after 3 weeks of treatment of mice with hair loss caused by injection of dihydrotestosterone. Therefore, the combined use of minoxidil and finasteride has a better effect.

[0103] The stability of the samples obtained in Example 1 and Comparative Example 5 is further compared, and the results are shown in Table 5.

[0104] Table 5 Sample stability test data

[0105]

[0106] Conclusion: It can be seen from the test results that during the accelerated test, the antioxidant butylated hydroxyanisole was added to the sample prepared in Example 1 to ensure the stability of the sample, and its properties, defoaming time, injection rate, and total impurities did not change significantly, and the stability was good. The stability of the sample prepared in Comparative Example 5 was poor, and the properties changed under the accelerated test, and the total impurities were large and increased significantly.

[0107] The property stability of the minoxidil and finasteride foams prepared in Example 1 was evaluated and compared with the finasteride minoxidil nanoemulsion of Comparative Example 6. Five samples prepared in Example 1 and Comparative Example 6 were placed in an accelerated stability box, and the property changes were observed simultaneously. The results are shown in Table 6.

[0108] Table 6 Property stability data

[0109]

[0110]

[0111] Conclusion: From the test results, it can be seen that the foam sample prepared in Example 1 has good stability and its properties have not changed. The nanoemulsion prepared in Comparative Example 6 has poor stability and is prone to aggregation, merging and stratification after long-term storage. Therefore, the dosage form of the foam exhibits strong stability and is easier to store and use for a long time.

[0112] The in vitro transdermal effect of the minoxidil finasteride foam prepared in Example 1 was evaluated and compared with the finasteride minoxidil nanoemulsion of Comparative Example 6. The skin of the ventral and dorsal areas of 1-month-old male Bama miniature pigs was used for the test to investigate the permeation rate, 24h cumulative permeation amount, and intradermal retention of the samples. The results are shown in Table 7.

[0113] Table 7 In vitro skin permeation test data

[0114]

[0115] Conclusion: The transdermal amount reflects the ability of the drug to exert a therapeutic effect through the stratum corneum of the skin, and the intradermal retention amount reflects the distribution and action time of the drug in the skin. An appropriate intradermal retention amount can increase the retention of the drug in the stratum corneum, thereby improving the therapeutic effect. The above data show that the foam containing minoxidil and finasteride prepared in Example 1 has a penetration rate, a penetration amount and an intradermal retention amount that are significantly greater than the finasteride minoxidil nanoemulsion prepared in Comparative Example 6. Therefore, Example 1 has a better transdermal absorption effect.

[0116] In summary, the foam containing minoxidil and finasteride provided by the present invention has the advantages of less impurities, uniform liquid medicine, high stability, strong foam adhesion, prolonged drug action time on the scalp, uniform and non-greasy application, rapid defoaming and enhanced efficacy, strong permeability, and effective drug penetration into the skin or mucous membrane to improve the bioavailability of the drug. The entire preparation method is simple and easy to operate, which can greatly save time and cost. At the same time, the dosage form of the foam has the advantages of easy application, less residue, high permeability and large-area application, high patient compliance, convenient use, and patients are more likely to accept and continue to use it, so that the active ingredients with two different action mechanisms synergize and improve the clinical effect.

[0117] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A foam containing minoxidil and finasteride, characterized in that: The foam is prepared from the following components in parts by weight: 1-10 parts of minoxidil, 0.01-1 parts of finasteride, 40-85 parts of solvent, 1-5 parts of foam adjuvant, 1-6 parts of surfactant, 1-10 parts of moisturizing agent, 1-10 parts of penetration enhancer, 0.001-0.02 parts of antioxidant and 3-7 parts of propellant.

2. The foam containing minoxidil and finasteride according to claim 1, characterized in that: During the preparation process, minoxidil, finasteride, solvent, foam adjuvant, surfactant, humectant, penetration enhancer, antioxidant and part of purified water are stirred at 40-60°C until dissolved, the pH of the obtained mixed solution is adjusted to 5.0-6.0, the remaining purified water is added to make up the volume, and the drug solution is stirred to obtain a drug solution. After the drug solution is prepared, it is sterilized and filtered, filled, and the propellant is pressed into the finished product.

3. The foam containing minoxidil and finasteride according to claim 2, characterized in that: The solvent is anhydrous ethanol; the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.5-3:1; the surfactant is poloxamer 188; the moisturizer is sorbitol; the penetration enhancer is isopropyl myristate; the antioxidant is butylated hydroxyanisole; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 40-50:25-35:20-30.

4. The foam containing minoxidil and finasteride according to claim 3, characterized in that: The foam is made of the following components in parts by weight: 4-6 parts of minoxidil, 0.05-0.2 parts of finasteride, 45-65 parts of anhydrous ethanol, 2-3 parts of foam adjuvant, 2-5 parts of poloxamer 188, 2-5 parts of sorbitol, 1-3 parts of isopropyl myristate, 0.005-0.015 parts of butylated hydroxyanisole, and 4-6 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8-2.5:1; and the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:

25.

5. The foam containing minoxidil and finasteride according to claim 4, characterized in that: The foam is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 50-60 parts of anhydrous ethanol, 2.2-2.6 parts of foam adjuvant, 2.5-3.5 parts of poloxamer 188, 2.5-3.5 parts of sorbitol, 1.5-2.5 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8-2.5:1; and the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:

25.

6. The foam containing minoxidil and finasteride according to claim 5, characterized in that: The foaming agent is made of the following components in parts by weight: 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 1883 parts of poloxamer, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8:1; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25; 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 1883 parts of poloxamer, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 2:1; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:25; 5 parts of minoxidil, 0.1 parts of finasteride, 55 parts of anhydrous ethanol, 2.4 parts of foam adjuvant, 1883 parts of poloxamer, 3 parts of sorbitol, 2 parts of isopropyl myristate, 0.01 parts of butylated hydroxyanisole, and 5.5 parts of propellant; wherein the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 2.5:1; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:

25.

7. The method for preparing the foam containing minoxidil and finasteride according to claim 1, characterized in that: It includes the following steps: (1) stirring minoxidil, finasteride, solvent, foam adjuvant, surfactant, humectant, penetration enhancer, antioxidant and partially purified water at 40-60° C. until dissolved; (2) adjusting the pH value of the mixed solution obtained in step (1) to 5.0-6.0, adding the remaining purified water to make up to volume, and stirring to obtain a drug solution; (3) After the drug solution is prepared, it is sterilized and filtered, filled, and pressed into the propellant to obtain the finished product.

8. The method for preparing the foam containing minoxidil and finasteride according to claim 7, characterized in that: The solvent is anhydrous ethanol; the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.5-3:1; the surfactant poloxamer 188; the moisturizer is sorbitol; the penetration enhancer is isopropyl myristate; the antioxidant is butylated hydroxyanisole; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 40-50:25-35:20-30.

9. The method for preparing the foam containing minoxidil and finasteride according to claim 8, characterized in that: The foam is prepared from the following components in parts by weight: 4-6 parts of minoxidil, 0.05-0.2 parts of finasteride, 45-65 parts of anhydrous ethanol, 2-3 parts of foam adjuvant, 2-5 parts of poloxamer 188, 2-5 parts of sorbitol, 1-3 parts of isopropyl myristate, 0.005-0.015 parts of butylated hydroxyanisole, and 4-6 parts of propellant; the foam adjuvant is a mixture of hexadecanol and octadecanol, wherein the weight ratio of hexadecanol to octadecanol is 1.8-2.5:1; the propellant is a mixture of propane, butane and isobutane, wherein the weight ratio of propane, butane and isobutane is 45:30:

25.

10. The method for preparing the foam containing minoxidil and finasteride according to claim 9, characterized in that: The foam adjuvant is a mixture of cetyl alcohol and octadecanol, wherein the weight ratio of cetyl alcohol to octadecanol is 2:1.

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