Pharmaceutical formulation for treating alopecia, preparation method therefor and use thereof

Abstract

The present invention provides a pharmaceutical formulation for treating alopecia, a preparation method therefor and the use thereof. Specifically, the present invention provides a formulation or composition for treating alopecia, comprising the following active components on the basis of the mass percentage (w / w) or mass / volume percentage (w / v): (a) 5% of minoxidil and (b) 0.07-0.095% of finasteride; the formulation or the composition is a foaming agent or a liniment; and when the formulation is a foaming agent, the total mass in the mass percentages does not contain the mass of a propellant. The foaming agent and liniment of the present invention take effect quickly and have good effects and few side effects.

Description

Pharmaceutical preparation for treating hair loss, preparation method and use thereof Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and in particular, relates to a pharmaceutical preparation for treating hair loss, a preparation method thereof, and uses thereof. Background Art

[0002] Currently, hair loss is becoming a growing concern for people of all ages. Besides affecting the patient's appearance, hair loss can also have a significant negative impact on their psychological and social well-being.

[0003] Take androgenetic alopecia (AGA), for example. It's the most common type of hair loss, a progressive hair follicle miniaturization disorder that begins during or after puberty. It affects both men and women, but with varying patterns and prevalence. While AGA doesn't affect physical health, it can severely impact patients' mental health and quality of life. Early diagnosis and treatment can significantly slow the progression of hair loss and improve patients' quality of life.

[0004] Because AGA progressively worsens until baldness sets in, the importance of early and long-term treatment is emphasized. Generally speaking, the earlier treatment is initiated, the better the outcome. Treatment options include systemic medications, topical medications, hair transplantation, mesotherapy, and low-intensity laser therapy.

[0005] However, the current main drugs for treating hair loss still have many shortcomings, such as slow onset, unsatisfactory results or side effects.

[0006] Therefore, it is of great significance to the art to develop a drug or compound preparation for treating hair loss with rapid onset, good effect and few side effects.

[0007] Summary of the Invention

[0008] The present invention provides a medicine for treating hair loss with rapid onset, good effect and small side effects.

[0009] In a first aspect of the present invention, a preparation or composition having a hair loss treatment effect is provided, wherein the preparation or composition comprises the following active ingredients:

[0010] (a) minoxidil 5%; and

[0011] (b) finasteride 0.07-0.095%;

[0012] Calculated as mass percentage (w / w) or mass volume percentage (w / v).

[0013] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0014] (a) minoxidil 5%; and

[0015] (b) finasteride 0.07-0.09%;

[0016] Measured by mass percentage or mass volume percentage.

[0017] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0018] (a) minoxidil 5%; and

[0019] (b) finasteride 0.07-0.085%;

[0020] Measured by mass percentage or mass volume percentage.

[0021] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0022] (a) minoxidil 5%; and

[0023] (b) finasteride 0.07-0.08%;

[0024] Measured by mass percentage or mass volume percentage.

[0025] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0026] (a) minoxidil 5%; and

[0027] (b) finasteride 0.07-0.075%;

[0028] Measured by mass percentage or mass volume percentage.

[0029] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0030] (a) minoxidil 5%; and

[0031] (b) finasteride 0.075%;

[0032] Measured by mass percentage or mass volume percentage.

[0033] In another preferred embodiment, the preparation or composition further comprises a pharmaceutically acceptable carrier.

[0034] In another preferred embodiment, the dosage form of the preparation or composition is selected from the following group: foam, liniment, tincture, spray, gel.

[0035] In another preferred embodiment, the preparation or composition is in the form of a foam or a liniment.

[0036] In another preferred embodiment, the preparation or composition is a foam.

[0037] In another preferred embodiment, the preparation or composition is a liniment.

[0038] In another preferred embodiment, the preparation or composition contains or does not contain propylene glycol and isopropyl alcohol.

[0039] In another preferred embodiment, when the preparation or composition is a foam, the preparation or composition does not contain propylene glycol and isopropyl alcohol.

[0040] In another preferred embodiment, when the preparation or composition is a foam, the active ingredient is calculated as a percentage by mass (w / w).

[0041] In another preferred embodiment, when the preparation or composition is a liniment, the active ingredient is calculated as mass volume percentage (w / v).

[0042] In another preferred embodiment, the preparation is a laboratory preparation.

[0043] In another preferred embodiment, the preparation is a pharmaceutical preparation.

[0044] In another preferred embodiment, the composition is a pharmaceutical composition.

[0045] In another preferred embodiment, the preparation or composition further contains additional ingredients that promote hair growth.

[0046] In a second aspect of the present invention, there is provided a foam for treating hair loss, the foam comprising the following active ingredients:

[0047] (a) minoxidil 5%; and

[0048] (b) finasteride 0.07-0.095%;

[0049] Calculated as mass percentage (w / w).

[0050] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0051] (a) minoxidil 5%; and

[0052] (b) finasteride 0.07-0.09%;

[0053] Measured by mass percentage.

[0054] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0055] (a) minoxidil 5%; and

[0056] (b) finasteride 0.07-0.085%;

[0057] Measured by mass percentage.

[0058] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0059] (a) minoxidil 5%; and

[0060] (b) finasteride 0.07-0.08%;

[0061] Measured by mass percentage.

[0062] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0063] (a) minoxidil 5%; and

[0064] (b) finasteride 0.07-0.075%;

[0065] Measured by mass percentage.

[0066] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0067] (a) minoxidil 5%; and

[0068] (b) finasteride 0.075%;

[0069] Measured by mass percentage;

[0070] The total mass in the mass percentage does not include the mass of the propellant.

[0071] In another preferred example, the mass percentage is the percentage of the mass of the active ingredient to the total mass of the foaming agent, and the total mass of the foaming agent does not include the mass of the propellant.

[0072] In another preferred embodiment, the foam further comprises a pharmaceutically acceptable carrier.

[0073] In another preferred embodiment, the foam further comprises an ingredient selected from the group consisting of a moisturizer, a solubilizer, a pH regulator, an antioxidant, a support agent, a diluent, a complexing agent, a propellant, or a combination thereof.

[0074] In another preferred embodiment, the moisturizing agent is selected from the following group: glycerin, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, or a combination thereof.

[0075] In another preferred embodiment, the moisturizing agent is glycerin.

[0076] In another preferred embodiment, the mass percentage of the moisturizing agent in the foaming agent is 1 to 10 wt %; preferably 1 to 5 wt %; more preferably 2 to 3 wt %; and even more preferably 2 to 2.5 wt %.

[0077] In another preferred embodiment, the solubilizing agent is selected from the group consisting of Tween 40, Tween 60, Tween 80, sodium lauryl sulfate, docusate sodium, or a combination thereof.

[0078] In another preferred embodiment, the solubilizing agent is Tween 60.

[0079] In another preferred embodiment, the mass percentage of the solubilizer in the foaming agent is 0.1 to 5.0 wt %; preferably 0.1 to 1.0 wt %; more preferably 0.1 to 0.5 wt %; and even more preferably 0.3 to 0.5 wt %.

[0080] In another preferred embodiment, the pH adjuster is selected from the group consisting of lactic acid, hydrochloric acid, sodium hydroxide, acetic acid, or a combination thereof.

[0081] In another preferred embodiment, the pH adjuster is lactic acid.

[0082] In another preferred embodiment, the mass percentage of the pH regulator in the foaming agent is 0.1 to 5.0 wt %; preferably 0.5 to 2.5 wt %; more preferably 1.0 to 2.0 wt %; and even more preferably 1.0 to 1.5 wt %.

[0083] In another preferred embodiment, the antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or a combination thereof.

[0084] In another preferred embodiment, the antioxidant is butylated hydroxytoluene.

[0085] In another preferred embodiment, the mass percentage of the antioxidant in the foaming agent is 0.01 to 1 wt %; preferably 0.05 to 0.5 wt %; more preferably 0.1 to 0.2 wt %.

[0086] In another preferred embodiment, the proppant is selected from the group consisting of hexadecanol, octadecanol, or a combination thereof.

[0087] In another preferred embodiment, the proppant is hexadecanol and octadecanol.

[0088] In another preferred embodiment, the mass percentage of the proppant in the foaming agent is 0.5-10 wt %; preferably 0.5-5 wt %; more preferably 1.5-2.5 wt %; and even more preferably 1.5-2.0 wt %.

[0089] In another preferred embodiment, the diluent is selected from the following group: purified water, anhydrous ethanol, n-propanol, or a combination thereof.

[0090] In another preferred embodiment, the diluent is selected from the following group: purified water, anhydrous ethanol, or a combination thereof.

[0091] In another preferred embodiment, the diluent is a mixture of purified water and anhydrous ethanol.

[0092] In another preferred embodiment, the complexing agent is selected from the group consisting of lactic acid, anhydrous citric acid, acetic acid, malic acid, maleic acid, or a combination thereof.

[0093] In another preferred embodiment, the complexing agent is anhydrous citric acid.

[0094] In another preferred embodiment, the mass percentage of the complexing agent in the foaming agent is 0.1-5.0 wt %; preferably 0.1-1.0 wt %; more preferably 0.1-0.5 wt %; more preferably 0.1-0.3 wt %; more preferably 0.1-0.2 wt %.

[0095] In another preferred embodiment, the propellant is selected from the group consisting of propane, butane, isobutane, or a combination thereof.

[0096] In another preferred embodiment, the propellant contains: a mixture of 48% propane, 30% butane and 22% isobutane, calculated by mass percentage (w / w).

[0097] In another preferred embodiment, the mass percentage of the propellant in the foaming agent is 1.5-8.5 wt %; preferably 2.5-7.5 wt %; more preferably 3.5-6.5 wt %; and even more preferably 4.5-5.5 wt %.

[0098] In another preferred embodiment, the foaming agent does not contain propylene glycol and isopropyl alcohol.

[0099] In another preferred embodiment, the foaming agent further comprises: glycerin, Tween 60, lactic acid, butylated hydroxytoluene, cetyl alcohol, octadecyl alcohol, anhydrous citric acid, anhydrous ethanol, purified water and a propellant.

[0100] In another preferred embodiment, based on the absence of propellant, the foaming agent further comprises: 2.11% glycerol, 0.42% Tween 60, 1.05% lactic acid, 0.1% butylated hydroxytoluene, 1.16% hexadecanol, 0.53% octadecyl alcohol, 0.11% anhydrous citric acid, 56.46% anhydrous ethanol, and 32.985% purified water, calculated by mass percentage (w / w).

[0101] In another preferred embodiment, the foaming agent further comprises: 5.00% propellant, calculated by mass percentage (w / w).

[0102] In another preferred embodiment, the foam further contains additional ingredients that promote hair growth.

[0103] In a third aspect of the present invention, there is provided a liniment for treating hair loss, the liniment comprising the following active ingredients:

[0104] (a) minoxidil 5%; and

[0105] (b) finasteride 0.07-0.095%;

[0106] Calculated as mass volume percentage (w / v).

[0107] In another preferred embodiment, the liniment comprises the following active ingredients:

[0108] (a) minoxidil 5%; and

[0109] (b) finasteride 0.07-0.09%;

[0110] Measured by mass volume percentage.

[0111] In another preferred embodiment, the liniment comprises the following active ingredients:

[0112] (a) minoxidil 5%; and

[0113] (b) finasteride 0.07-0.085%;

[0114] Measured by mass volume percentage.

[0115] In another preferred embodiment, the liniment comprises the following active ingredients:

[0116] (a) minoxidil 5%; and

[0117] (b) finasteride 0.07-0.08%;

[0118] Measured by mass volume percentage.

[0119] In another preferred embodiment, the liniment comprises the following active ingredients:

[0120] (a) minoxidil 5%; and

[0121] (b) finasteride 0.07-0.075%;

[0122] Measured by mass volume percentage.

[0123] In another preferred embodiment, the liniment comprises the following active ingredients:

[0124] (a) minoxidil 5%; and

[0125] (b) finasteride 0.075%;

[0126] Measured by mass volume percentage.

[0127] In another preferred embodiment, the mass volume percentage is the percentage of the mass of the active ingredient (g) to the total volume (ml) of the liniment.

[0128] In another preferred embodiment, the liniment further comprises a pharmaceutically acceptable carrier.

[0129] In another preferred embodiment, the liniment further contains a penetration enhancer, a solubilizing agent, a solvent, or a combination thereof.

[0130] In another preferred embodiment, the penetration enhancer is selected from the following group: propylene glycol, laurocapram, cyclohexanol, decyl methyl sulfoxide, or a combination thereof.

[0131] In another preferred embodiment, the penetration enhancer is propylene glycol.

[0132] In another preferred embodiment, the volume percentage (v / v) of the penetration enhancer in the liniment is 35% to 60% (v / v), preferably 45% to 55% (v / v), and more preferably 50% to 55% (v / v).

[0133] In another preferred embodiment, the co-solvent is selected from the group consisting of anhydrous ethanol, glycerol, isopropyl alcohol, polyethylene glycol, liquid paraffin, or a combination thereof.

[0134] In another preferred embodiment, the co-solvent is anhydrous ethanol.

[0135] In another preferred embodiment, the volume percentage (v / v) of the co-solvent in the liniment is 15% to 45% (v / v), preferably 20% to 40% (v / v), and more preferably 25% to 35% (v / v).

[0136] In another preferred embodiment, the solvent is purified water.

[0137] In another preferred embodiment, the liniment further comprises: propylene glycol, anhydrous ethanol and purified water.

[0138] In another preferred embodiment, the liniment further comprises: 50% (v / v) propylene glycol and 30% (v / v) anhydrous ethanol.

[0139] In another preferred embodiment, the liniment further comprises: purified water adjusted to a specified volume.

[0140] In another preferred embodiment, the liniment further contains additional ingredients for promoting hair growth.

[0141] In a fourth aspect of the present invention, there is provided the use of the preparation or composition of the first aspect of the present invention, the foam of the second aspect of the present invention, or the liniment of the third aspect of the present invention for preparing a medicament for treating hair loss.

[0142] In another preferred embodiment, the treatment includes promoting hair growth and preventing further hair loss.

[0143] In another preferred embodiment, the hair loss is androgenic alopecia, hair loss caused by drugs (such as chemotherapy drugs), hair loss caused by radiotherapy, hair loss caused by age, hair loss caused by autoimmune diseases, hair loss caused by hormones, hair loss caused by infection, or a combination thereof.

[0144] In another preferred embodiment, the hair loss is androgenic alopecia.

[0145] In another preferred embodiment, the hair loss is male androgenic alopecia or female postmenopausal alopecia.

[0146] In a fifth aspect of the present invention, a method for preparing the foaming agent according to the second aspect of the present invention is provided, comprising the following steps:

[0147] (s1) Take the following active ingredient raw materials by mass percentage:

[0148] (a) minoxidil 5%; and

[0149] (b) finasteride 0.07-0.095%;

[0150] (s2) mixing and dissolving the active ingredient and the pharmaceutically acceptable carrier, and then filling and sealing the container; and

[0151] (s3) adding a propellant into the sealed solution to prepare the foaming agent.

[0152] In another preferred embodiment, when preparing the foaming agent, the following sub-steps are further included in step (s2) by mass percentage:

[0153] (s2a) Water phase: dissolve the complexing agent in purified water;

[0154] (s2b) alcohol phase: dissolving the finasteride in a small amount of anhydrous ethanol, then adding a moisturizer, a solubilizer, a pH adjuster, a finasteride solution, an antioxidant, and a support agent to the anhydrous ethanol to dissolve, and then adding the minoxidil, stirring, and dispersing; and

[0155] (s2c) Mix the complexing agent aqueous solution with (s2b), stir until the minoxidil is completely dissolved, and then fill and seal.

[0156] In another preferred embodiment, when preparing the foaming agent, the following sub-steps are further included in step (s2) by mass percentage:

[0157] (s2a) Aqueous phase: Dissolve anhydrous citric acid in purified water;

[0158] (s2b) alcohol phase: dissolving the finasteride in a small amount of anhydrous ethanol, then adding glycerol, Tween 60, lactic acid, finasteride ethanol solution, butylated hydroxytoluene, cetyl alcohol, and octadecanol to the anhydrous ethanol to dissolve, and then adding the minoxidil, stirring, and dispersing; and

[0159] (s2c) Mixing the aqueous phase (s2a) and the alcohol phase (s2b), stirring until the minoxidil is completely dissolved, and then filling and sealing.

[0160] In a sixth aspect of the present invention, there is provided a method for preparing the liniment according to the third aspect of the present invention, characterized in that it comprises the following steps:

[0161] (s1) Take the following active ingredient raw materials according to mass volume percentage and set aside;

[0162] (a) minoxidil 5%; and

[0163] (b) finasteride 0.07-0.095%;

[0164] (s2) mixing the active ingredient and the pharmaceutically acceptable carrier uniformly, fixing the volume, and filtering; and

[0165] (s3) filling the filtered solution to obtain the liniment.

[0166] In another preferred embodiment, when preparing the liniment, the following sub-steps are further included in step (s2) based on the mass volume percentage:

[0167] (s2a) dissolving the finasteride in a small amount of a cosolvent;

[0168] (s2b) after uniformly mixing the penetration enhancer, cosolvent and part of the solvent, adding the minoxidil and finasteride solution and stirring to dissolve; and

[0169] (s2c) The resulting solution is diluted with the remaining solvent and filtered.

[0170] In another preferred embodiment, when preparing the liniment, the following sub-steps are further included in step (s2) based on the mass volume percentage:

[0171] (s2a) dissolving the finasteride in a small amount of anhydrous ethanol;

[0172] (s2b) mixing the propylene glycol, anhydrous ethanol and partially purified water, adding the minoxidil and finasteride ethanol solution, and stirring to dissolve; and

[0173] (s2c) The resulting solution is made up to volume with the remaining purified water and filtered.

[0174] In the seventh aspect of the present invention, a method for treating hair loss is provided, comprising administering to a subject in need thereof a therapeutically effective amount of the preparation or composition of the first aspect of the present invention, or the foam of the second aspect of the present invention, or the liniment of the third aspect of the present invention.

[0175] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0176] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0177] Figures 1 to 3 show the hair growth score results of each group of experimental mice after administration of the foam of the present invention.

[0178] FIG4 shows the hair growth scoring results of each group of experimental mice after application of the liniment of the present invention. DETAILED DESCRIPTION

[0179] After extensive and in-depth research and extensive screening, the inventors unexpectedly discovered that a specific ratio of the active ingredient combination of minoxidil and finasteride (for example, 5% minoxidil and 0.075% finasteride, measured by mass percentage or by mass volume percentage) has a significantly superior effect in treating hair loss compared to other ratios, with a shorter onset of action and better efficacy. Based on this, the present invention was completed.

[0180] Specifically, the present invention conducted multiple comparative experiments, setting up single minoxidil and finasteride preparations and compound preparations with specific proportions to conduct experiments on mice with constructed hair loss models. The experimental results showed that when the minoxidil content was 5% and the finasteride content was 0.075%, the foam and ointment of the present invention had unexpectedly excellent effects, and their effect in treating hair loss was better than when the finasteride content was 0.1%. And when the finasteride content was 0.15%, its effect in treating hair loss was also better than when the finasteride content was 0.1%, that is, two effect peaks appeared at finasteride contents of about 0.075% and 0.15%, respectively.

[0181] the term

[0182] In order to more easily understand the present disclosure, some terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms should have the meaning given below. Other definitions are set forth throughout the application.

[0183] The term "about" can refer to a value or composition that is within an acceptable error range for a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined. For example, as used herein, the expression "about 100" includes all values ​​between 99 and 101 (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0184] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0185] As used herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the range and, where appropriate, fractional values ​​thereof (e.g., tenths and hundredths of an integer).

[0186] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the associated listed items.

[0187] As used herein, the terms "specification 5%-0.075%" and "5%-0.075%" have the same meaning, meaning that in a foam, the mass percentage of minoxidil is 5% and the mass percentage of finasteride is 0.075%; and in a liniment, the mass volume percentage of minoxidil is 5% and the mass volume percentage of finasteride is 0.075%. Other equivalent expressions herein have the same meaning, i.e., in a foam, the first (left) percentage value is the mass percentage of minoxidil, and the second (right) percentage value is the mass percentage of finasteride; in a liniment, the first percentage value is the mass volume percentage of minoxidil, and the second percentage value is the mass volume percentage of finasteride.

[0188] The main advantages of the present invention include:

[0189] (a) Compared with single preparations of minoxidil and finasteride, and compound preparations of minoxidil and finasteride with other ratios and dosage forms, the pharmaceutical preparation or composition provided by the present invention exhibits the characteristics of rapid onset of action, good effect, and few side effects, and has better clinical application prospects.

[0190] (b) When the pharmaceutical preparation provided by the present invention is a foam, it has the following advantages compared to other dosage forms: it does not contain propylene glycol and isopropyl alcohol, reducing irritation and allergic reactions; the foam is evenly dispersed, easily spreads, has a wide coating surface, and has a significant local therapeutic effect; the foam has a low density and a soft structure; after the foam breaks, it can easily enter the stratum corneum through the hair follicles and is easily absorbed; the foam is easy to use, is odorless, non-sticky, and has little residue, so patients are generally more willing to accept it and have a high compliance rate.

[0191] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which no specific conditions are specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight percentages and parts by weight or parts by volume.

[0192] Example 1 Pharmacodynamic Study 1

[0193] 1.1 Experimental reagents and materials

[0194] The experimental materials of this embodiment are shown in Table 1.

[0195] Table 1 Experimental materials

[0196] Preparation of testosterone propionate solution:

[0197] Accurately weigh 80 mg of testosterone propionate and dissolve it in 26.133 ml of corn oil for injection. Vortex and ultrasonically mix to obtain a uniform solution with a concentration of 3 mg / ml.

[0198] Preparation of finasteride suspension:

[0199] Accurately weigh 0.542 mg of finasteride and add it to 5.420 ml of 0.5% CMC-Na. Vortex and sonicate to obtain a uniform suspension with a concentration of 0.1 mg / ml.

[0200] Preparation of 5% minoxidil foam:

[0201] 1) The composition of the prescription is shown in Table 2.

[0202] Table 2 Prescription composition

[0203] The propellant formulation composition and filling formulation composition are shown in Tables 3 and 4.

[0204] Table 3 Propellant prescription composition

[0205] Table 4 Filling prescription composition

[0206] 2) The preparation process is as follows:

[0207] ①Preparation of liquid

[0208] Aqueous phase: Weigh purified water according to the prescribed amount, add anhydrous citric acid, and stir until completely dissolved to obtain an aqueous phase;

[0209] Alcohol phase: Add glycerol, Tween 60, lactic acid, butylated hydroxytoluene, cetyl alcohol, and octadecanol to anhydrous ethanol according to the prescribed amount, stir at 35°C to 60°C, then add minoxidil, stir, and disperse to obtain an alcohol phase;

[0210] Mixing: Add the aqueous phase to the alcohol phase and stir until the minoxidil is completely dissolved and the two phases are mixed evenly;

[0211] ② Filter

[0212] Filter the mixed solution through a filter element;

[0213] ③Filling

[0214] The filtrate was filled into aluminum spray cans, 57 g / can;

[0215] ④Seal

[0216] Add valve and seal;

[0217] ⑤Inflation

[0218] Fill the mixed alkanes, the filling amount per tank is 3g;

[0219] ⑥ Cover the mousse nozzle cover and outer cover, package and you are done.

[0220] Preparation of blank foam:

[0221] The process steps are the same as those for minoxidil foam (5%), except that minoxidil is removed from the alcohol phase and added. The minoxidil is removed from the formulation, and the amount of anhydrous ethanol is adjusted to 34.34 g / bottle, resulting in a formula volume of 60.24% (excluding propellant). The amount of purified water is adjusted to 19.54 g / bottle, resulting in a formula volume of 34.28% (excluding propellant). The contents of the other components remain unchanged.

[0222] Preparation of minoxidil finasteride foam (specification 5%-0.075%):

[0223] 1) Prescription composition is shown in Table 5

[0224] Table 5 Prescription composition

[0225] The propellant formulation composition and filling formulation composition are shown in Tables 6 and 7.

[0226] Table 6 Propellant prescription composition

[0227] Table 7 Filling prescription composition

[0228] 2) The preparation process is as follows:

[0229] ①Preparation of liquid

[0230] Aqueous phase: Weigh purified water according to the prescribed amount, add anhydrous citric acid, and stir until completely dissolved to obtain an aqueous phase;

[0231] Alcohol phase:

[0232] Weigh anhydrous ethanol according to the prescribed amount;

[0233] Dissolve finasteride in a small amount of anhydrous ethanol;

[0234] Add glycerol, Tween 60, lactic acid, finasteride ethanol solution, butylated hydroxytoluene, cetyl alcohol, and octadecanol to the remaining anhydrous ethanol according to the prescribed amount, stir at 35°C to 60°C, then add minoxidil, stir, and disperse to obtain an alcohol phase;

[0235] Mixing: Add the aqueous phase to the alcohol phase and stir until the minoxidil is completely dissolved and the two phases are mixed evenly;

[0236] ② Filter

[0237] Filter the mixed solution through a filter element;

[0238] ③Filling

[0239] The filtrate was filled into aluminum spray cans, 57 g / can;

[0240] ④Seal

[0241] Add valve and seal;

[0242] ⑤Inflation

[0243] Fill the mixed alkanes, the filling amount per tank is 3g;

[0244] ⑥ Cover the mousse nozzle cover and outer cover, package and you are done.

[0245] Preparation of minoxidil finasteride foam (specification 5%-0.008%):

[0246] The process is the same as that of minoxidil finasteride foam (specification 5%-0.075%), wherein the dosage of finasteride is 0.005g / bottle, and the weight content without propellant is 0.008%. The dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0247] Preparation of minoxidil finasteride foam (specification 5%-0.025%):

[0248] The process is the same as that of minoxidil finasteride foam (specification 5%-0.075%), wherein the dosage of finasteride is 0.014g / bottle, and the weight content without propellant is 0.025%. The dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0249] 1.2 Experimental process and results

[0250] C57BL / 6J male mice were housed in a single cage in an SPF-grade constant temperature and humidity laminar flow clean room. After one week of adaptation, hair removal cream was used to remove approximately 3 × 4 cm hair from the back. 2 The skin was pink and undamaged, confirming that the mouse hair follicles were in the resting phase. The mice were randomly divided into 7 groups, as shown in Table 8 below.

[0251] Table 8 Experimental groups

[0252] In addition to the blank control group, which received multiple daily injections of corn oil, mice in each group received 30 mg / kg / day of testosterone propionate solution subcutaneously injected into the depilated area on the back (creating an androgenic alopecia model). Half an hour after the testosterone propionate injection, mice in each foam group received 200 mg of the foam applied to the depilated area on the back once daily for 30 days. The blank control and model groups received blank foam once daily for 30 days.

[0253] Finasteride group was orally administered, with an initial dosage of 0.1 ml / mouse. The dosage was adjusted weekly according to body weight changes, initial body weight / 0.1=weekly body weight / finasteride dosage, once a day for 30 consecutive days.

[0254] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0255] Hair growth score

[0256] The skin and hair growth of the depilatory sites of each group of mice were observed every day. The scores were scored once a week for the first two weeks and twice a week after the third week. During the scoring process, photos of each group were taken and the hair growth score results were recorded.

[0257] The scoring criteria are shown in Table 9.

[0258] Table 9 Hair growth scoring criteria

[0259] The scoring results are shown in Table 10 and Figure 1.

[0260] Table 10 Hair growth score results of each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group; &p<0.05 compared with the minoxidil group, +p<0.05, ++p<0.01 compared with the oral finasteride group.

[0261] The results showed that there was no significant difference in the score results between the finasteride group and the model group; the score results of the experimental group III were not only significantly higher than those of the minoxidil group, but also significantly higher than those of the experimental groups I and II.

[0262] Unexpectedly, Experiment III group had an extremely excellent effect.

[0263] On the one hand, the score results increased rapidly after the 18th day of administration, and on the 21st day, they were significantly different from the experimental group I and experimental group II. Taking the data on day 21 as an example, the difference between the experimental group III and the model group was 1.7, while the differences between the minoxidil group, finasteride group, experimental group I and experimental group II and the model group were 0.7, 0.2, 0.5 and 1 respectively. Therefore, the difference (or effect) between the experimental group III and the model group was more than 2.4 times, 8.5 times, 3.4 times and 1.7 times that of the minoxidil group, finasteride group, experimental group I and experimental group II, respectively.

[0264] On the other hand, this significant difference persisted until the end of this experiment (30 days after administration).

[0265] It can be seen that the onset time of minoxidil finasteride foam in experimental group III was significantly better than that in experimental group I, experimental group II and minoxidil single foam group.

[0266] Hair weight evaluation

[0267] After the experiment, the mice were euthanized, the hair on the skin surface of the depilatory area was removed, and the mice were weighed. The experimental results are shown in Table 11.

[0268] Table 11 Statistical results of hair weight in each group of experiments Note: One-way ANOVA, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group; +p<0.05, ++p<0.01 compared with the oral finasteride group.

[0269] The results showed that the hair weight of the finasteride group was not significantly different from that of the model group. Unexpectedly, the hair weight of the experimental group III was significantly greater than not only the minoxidil group, but also the experimental groups I and II.

[0270] The difference between the minoxidil group and the model group showed that hair weight increased significantly in the minoxidil group, while hair weight in the finasteride group did not increase but decreased slightly. The effect of Experiment I group was worse than that of the minoxidil group.

[0271] Unexpectedly, Experiment II achieved significantly improved results compared to the minoxidil group. Even more surprisingly, Experiment III (Δ = 32.4) achieved approximately 2.3 times the hair growth effect of the minoxidil group. Furthermore, its hair weight growth effect was significantly greater than that of the finasteride group alone, the minoxidil group alone, and the combined effects of the minoxidil and finasteride groups alone (i.e., Δ = 14.3 + (-0.8)).

[0272] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0273] Hair follicle number assessment

[0274] Skin samples were obtained from the depilated area parallel to the spine and trimmed into 1 cm wide strips. The skin was fixed in 10% neutral formalin for 24-36 hours, dehydrated in a gradient of ethanol, embedded in paraffin, trimmed, and sectioned. After H&E staining, the skin was observed under a light microscope and the number of hair follicles was counted. The results are shown in Table 12.

[0275] Table 12 Statistical results of hair follicle numbers in each experimental group Note: One-way ANOVA, **p<0.01 compared with the model group; T-test, ##p<0.01 compared with the model group; +p<0.05, ++p<0.01 compared with the oral finasteride group.

[0276] The results showed that the number of hair follicles in the finasteride group was not significantly different from that in the model group, and even decreased slightly; there was no significant difference between the experimental group I, experimental group II and minoxidil group, and the number of hair follicles in the experimental group I and experimental group II was less than that in the minoxidil group.

[0277] Unexpectedly, the number of hair follicles in Experiment III (Δ=10) was higher than that in the minoxidil group, and significantly higher than that in Experiment I and Experiment II. Its effect on increasing the number of hair follicles was significantly better than that of the finasteride group alone, the minoxidil group alone, and the combined effect of the minoxidil and finasteride groups alone (Δ=7+(-3)).

[0278] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0279] Example 2 Pharmacodynamic Study 2

[0280] 2.1 Experimental reagents and materials

[0281] The experimental materials of this example are shown in Table 13.

[0282] Table 13 Experimental materials

[0283] Preparation of testosterone propionate solution:

[0284] Accurately weigh 80.65 mg of testosterone propionate and dissolve it in 26.346 ml of corn oil for injection. Vortex and ultrasonically mix to obtain a uniform solution with a concentration of 3 mg / ml.

[0285] Preparation of 5% minoxidil foam:

[0286] The preparation method is the same as that of the 5% minoxidil foam in Example 1.

[0287] Preparation of blank foam:

[0288] The preparation method is the same as that of the blank foaming agent in Example 1.

[0289] Preparation of minoxidil finasteride foam (specification 5%-0.05%):

[0290] The process was the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride was 0.029 g / bottle, and the mass content was 0.05% when the propellant was not included. The amount of purified water was adjusted accordingly, and the contents of other components remained unchanged.

[0291] Preparation of minoxidil finasteride foam (specification 5%-0.06%):

[0292] The process was the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride was 0.034 g / bottle, and the mass content was 0.06% when the propellant was not included. The amount of purified water was adjusted accordingly, and the contents of other components remained unchanged.

[0293] Preparation of minoxidil finasteride foam (specification 5%-0.07%):

[0294] The process was the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride was 0.04 g / bottle, and the mass content was 0.07% when the propellant was not included. The amount of purified water was adjusted accordingly, and the contents of other components remained unchanged.

[0295] 2.2 Experimental process and results

[0296] C57BL / 6J male mice were housed in a single cage in an SPF-grade constant temperature and humidity laminar flow clean room. After one week of adaptation, hair removal cream was used to remove approximately 3 × 4 cm hair from the back. 2 The skin was pink and undamaged, confirming that the mouse hair follicles were in the resting phase. The mice were randomly divided into 6 groups, as shown in Table 14.

[0297] Table 14 Experimental groups

[0298] In addition to the blank control group, which received multiple daily injections of corn oil, mice in each group received 30 mg / kg / day of testosterone propionate solution subcutaneously injected into the depilated area on the back (creating an androgenic alopecia model). Half an hour after the testosterone propionate injection, mice in each foam group received 200 mg of the foam applied to the depilated area on the back once daily for 30 days. The blank control and model groups received blank foam once daily for 30 days.

[0299] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0300] Hair growth score

[0301] The skin and hair growth of the depilated areas of each group of mice were observed daily. Scoring was performed weekly for the first two weeks and twice weekly thereafter. During scoring, photos were taken of each group and the hair growth scores were recorded. The scoring criteria are shown in Table 8.

[0302] The scoring results are shown in Table 15 and Figure 2.

[0303] Table 15 Hair growth score results of each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0304] The results showed that the scores of all groups were significantly higher than those of the model group; the score of experimental group III was significantly higher not only than that of the minoxidil group, but also significantly higher than that of experimental groups I and II.

[0305] Unexpectedly, Experiment III group had an extremely excellent effect.

[0306] On the one hand, the scores increased rapidly after the 14th day of administration, and by the 18th day, they were significantly different from those of Experimental Groups I and II. Taking the data from Day 18 as an example, the difference between Experimental Group III and the model group was 1.2, the difference between the minoxidil group and Experimental Group I and the model group was 0.6, and the difference between Experimental Group II and the model group was 0.7; therefore, the difference (or effect) between Experimental Group III and the model group was twice that of the minoxidil group and Experimental Group I alone, and more than 1.7 times that of Experimental Group II.

[0307] On the other hand, this significant trend continued until the end of this experiment (30 days after administration).

[0308] It can be seen that the onset time of minoxidil finasteride foam in experimental group III was significantly better than that in experimental group I, experimental group II and minoxidil single foam group.

[0309] Hair weight evaluation

[0310] After the experiment, the mice were euthanized, the hair on the skin surface of the depilatory area was removed, and the mice were weighed. The experimental results are shown in Table 16.

[0311] Table 16 Statistical results of hair weight in each group of experiments Note: **p<0.01 compared with the model group by one-way ANOVA; ##p<0.01 compared with the model group by T test.

[0312] The results showed that the hair weight of the minoxidil group, experimental groups I, II, and III was significantly greater than that of the model group; among them, the hair weight of the experimental group III was not only significantly greater than that of the minoxidil group, but also significantly greater than that of the experimental groups I and II.

[0313] The difference between the minoxidil group and the model group showed that the minoxidil group significantly increased hair weight compared to the model group. The experimental effects of the experimental groups I and II were comparable to those of the minoxidil group.

[0314] Unexpectedly, the experimental group III showed significant improvement compared with the minoxidil group, experimental group I and experimental group II, and the hair growth effect of the experimental group III was about 1.5 times that of the minoxidil group.

[0315] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.07%) can achieve extremely excellent effect improvement and has a synergistic effect.

[0316] Hair follicle number assessment

[0317] Skin samples were obtained from the depilated area parallel to the spine and trimmed into 1 cm wide strips. The skin was fixed in 10% neutral formalin for 24-36 hours, dehydrated in a gradient of ethanol, embedded in paraffin, trimmed, and sectioned. After H&E staining, the skin was observed under a light microscope and the number of hair follicles was counted. The results are shown in Table 17.

[0318] Table 17 Statistical results of hair follicle numbers in each experimental group Note: **p<0.01 compared with the model group by one-way ANOVA; ##p<0.01, #p<0.05 by T test.

[0319] The results showed that the number of hair follicles in the minoxidil group, experimental groups I, II, and III was higher than that in the model group; among them, the number of hair follicles in experimental group III was higher not only than that in the minoxidil group, but also higher than that in experimental groups I and II.

[0320] According to the difference with the model group, the minoxidil group can significantly increase hair weight compared with the model group. Experimental group I also has an improvement effect, but the effect is slightly weaker than that of the minoxidil group; the effect of experimental group II is equivalent to that of the minoxidil group.

[0321] Unexpectedly, the effect of Experiment III group was further improved compared with the minoxidil group, and its hair growth effect was about 1.3 times that of the minoxidil group.

[0322] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.07%) can achieve extremely excellent effect improvement.

[0323] Example 3 Pharmacodynamics Experiment 3

[0324] 3.1 Experimental reagents and materials

[0325] The experimental materials of this example are shown in Table 18.

[0326] Table 18 Experimental materials

[0327] Preparation of testosterone propionate solution:

[0328] Accurately weigh 92.29 mg of testosterone propionate and dissolve it in 30.148 ml of corn oil for injection. Vortex and ultrasonically mix to obtain a uniform solution with a concentration of 3 mg / ml.

[0329] Preparation of minoxidil finasteride foam (specification 5%-0.075%):

[0330] The preparation method is the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1.

[0331] Preparation of blank foam:

[0332] The preparation method is the same as that of the blank foaming agent in Example 1.

[0333] Preparation of minoxidil finasteride foam (specification 5%-0.1%):

[0334] The process was the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride was 0.057 g / bottle, and the mass content was 0.1% when the propellant was not included. The amount of purified water was adjusted accordingly, and the contents of other components remained unchanged.

[0335] Preparation of minoxidil finasteride foam (specification 5%-0.15%):

[0336] The process was the same as that of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride was 0.086 g / bottle, and the mass content was 0.15% when the propellant was not included. The amount of purified water was adjusted accordingly, and the contents of other components remained unchanged.

[0337] 3.2 Test process and results

[0338] C57BL / 6J male mice were housed in a single cage in an SPF-grade constant temperature and humidity laminar flow clean room. After one week of adaptation, hair removal cream was used to remove approximately 3 × 4 cm hair from the back. 2 The skin was pink and undamaged, confirming that the mouse hair follicles were in the resting phase. The mice were randomly divided into 5 groups, as shown in Table 19.

[0339] Table 19 Experimental groups

[0340] In addition to the blank control group, which received multiple daily injections of corn oil, each group received a 30 mg / kg / day subcutaneous injection of testosterone propionate solution into the depilated area on the back of mice (creating an androgenic alopecia model). Half an hour after the testosterone propionate injection, 200 mg of the foam was applied to the depilated area on the back of each mouse once daily for 30 days. The blank control and model groups were also given the foam once daily for 30 days.

[0341] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0342] Hair growth score

[0343] The skin and hair growth of the depilated areas of each group of mice were observed daily. Scoring was performed weekly for the first two weeks and twice weekly thereafter. During scoring, photos were taken of each group and the hair growth scores were recorded. The scoring criteria are shown in Table 8.

[0344] The scoring results are shown in Table 20 and Figure 3.

[0345] Table 20 Hair growth scoring results of each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0346] The results showed that the scores of all groups were significantly higher than those of the model group; the score of experimental group I was higher than that of experimental group II and experimental group III.

[0347] Unexpectedly, Experimental Group I had an extremely excellent effect.

[0348] On the one hand, when the dosage of finasteride decreased, the score results increased rapidly after the 14th day of administration, and on the 18th day, there was a significant difference with the experimental group II and the experimental group III; taking the data on the 14th day as an example, the difference between the experimental group I and the model group was 0.8, while the difference between the experimental group II and the experimental group III and the model group was 0.5, so the difference (or effect) between the experimental group I and the model group was 1.6 times that of the experimental group II and the experimental group III.

[0349] On the other hand, this significant trend continued until administration day 21. From day 25 to day 30, the increasing trends of experimental group I and experimental group III were similar and higher than that of experimental group II.

[0350] It can be seen that the onset time of minoxidil finasteride foam in experimental group I was significantly better than that in experimental groups II and III.

[0351] Hair weight evaluation

[0352] After the experiment, the mice were euthanized, the hair on the skin surface of the depilatory area was removed, and the mice were weighed. The experimental results are shown in Table 21.

[0353] Table 21 Statistical results of hair weight in each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0354] The results showed that the hair weights of experimental groups I, II, and III were significantly greater than those of the model group; among them, the hair weight of experimental group I was greater than that of experimental groups II and III.

[0355] According to the difference with the model group, the hair weight of experimental groups I-III was significantly increased compared with the model group.

[0356] Unexpectedly, when the dosage of finasteride decreased, the experimental group I showed significant improvement compared with the experimental groups II and III, and its growth effect was more than 1.2 times that of the experimental groups II and III.

[0357] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0358] Hair follicle number assessment

[0359] Skin samples were obtained from the depilated area parallel to the spine and trimmed into 1 cm wide strips. The skin was fixed in 10% neutral formalin for 24-36 hours, dehydrated in a gradient of ethanol, embedded in paraffin, trimmed, and sectioned. After H&E staining, the skin was observed under a light microscope and the number of hair follicles was counted. The results are shown in Table 22.

[0360] Table 22 Statistical results of the number of hair follicles in each experimental group Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0361] The results showed that the number of hair follicles in experimental groups I, II, and III was significantly greater than that in the model group.

[0362] Unexpectedly, with the decrease in finasteride dosage, the number of hair follicles in Experimental Group I was significantly higher than that in Experimental Group II and Experimental Group III, and even significantly higher than that in the blank control group.

[0363] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has an excellent effect.

[0364] Example 4 Pharmacodynamic Study 4

[0365] 4.1 Experimental preparations and materials

[0366] The experimental materials of this example are shown in Table 23.

[0367] Table 23 Experimental materials

[0368] Preparation of testosterone propionate solution:

[0369] Accurately weigh 66.42 mg of testosterone propionate and dissolve it in 21.697 ml of corn oil for injection. Vortex and ultrasonically mix to obtain a uniform solution with a concentration of 3 mg / ml.

[0370] Preparation of minoxidil finasteride liniment (specification 5%-0.075%):

[0371] 1) The prescription composition is shown in Table 24

[0372] Table 24 Prescription composition

[0373] 2) The preparation process is as follows:

[0374] ① According to the above formula, weigh minoxidil, finasteride, propylene glycol, and anhydrous ethanol;

[0375] ②Dissolve finasteride in a small amount of anhydrous ethanol;

[0376] ③Stir and mix the prescribed amount of propylene glycol, the remaining anhydrous ethanol and part of the purified water evenly;

[0377] ④ Add minoxidil and finasteride ethanol solution to the mixed solution obtained in ③, respectively, and stir at room temperature until the solution becomes clear and transparent;

[0378] ⑤ Add purified water and dilute to the prescribed volume to obtain the drug solution;

[0379] ⑥ Filter the obtained liquid medicine using a 0.45 μm microporous filter membrane;

[0380] ⑦ Fill and package the liquid medicine into 60ml / bottle.

[0381] Preparation of blank liniment:

[0382] The process is the same as that of minoxidil and finasteride liniment (specifications 5%-0.075%) except that minoxidil and finasteride are removed from the formulation, while the contents of the other components remain unchanged.

[0383] Preparation of minoxidil finasteride liniment (specification 5%-0.05%):

[0384] The process is the same as that for preparing minoxidil finasteride liniment (specification 5%-0.075%), wherein the proportion of finasteride is 0.05% (w / v), the dosage is 0.03 g / bottle, the dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0385] Preparation of minoxidil finasteride liniment (specification 5%-0.1%):

[0386] The process is the same as that for preparing minoxidil finasteride liniment (specification 5%-0.075%), wherein the proportion of finasteride is 0.1% (w / v), the dosage is 0.06 g / bottle, the dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0387] 4.2 Experimental process and results

[0388] C57BL / 6J male mice were housed in a single cage in an SPF-grade constant temperature and humidity laminar flow clean room. After one week of adaptation, hair removal cream was used to remove approximately 3 × 4 cm hair from the back. 2 The skin was pink and undamaged, confirming that the mouse hair follicles were in the resting phase. The mice were randomly divided into 5 groups, as shown in Table 25.

[0389] Table 25 Experimental groups

[0390] In addition to the blank control group, which received multiple daily injections of corn oil, all other groups received multiple subcutaneous injections of testosterone propionate solution (30 mg / kg / day) into the depilated areas on the backs of mice. Half an hour after the testosterone propionate injection, 0.2 ml of the liniment was applied to the depilated areas on the backs of mice in each group once daily for 30 days. The blank control group and the model group were given a blank liniment once daily for 30 days.

[0391] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0392] Hair growth score

[0393] The skin and hair growth at the depilated area of ​​each group of mice were observed daily to evaluate the effect of the drug on the mice's hair growth cycle. Scoring was performed weekly for the first two weeks and twice weekly for the next two weeks. During scoring, each group was photographed and the hair growth score was recorded. The scoring criteria are shown in Table 8.

[0394] The scoring results are shown in Table 26 and Figure 4

[0395] Table 26 Hair growth score results of each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0396] The results showed that the scores of all groups were significantly higher than those of the model group; the scores of experimental group II were significantly higher than those of experimental group I and experimental group III.

[0397] Unexpectedly, Experiment II group had an extremely excellent effect.

[0398] On the one hand, as the dosage of finasteride decreased, the score increased rapidly after the 14th day of administration, and by the 18th day, it had already shown significant differences from the experimental groups I and III. Taking the data on day 18 as an example, the difference between the experimental group II and the model group was 1.1, the difference between the experimental group I and the model group was 0.3, and the difference between the experimental group III and the model group was 0.5; therefore, the difference (or effect) between the experimental group II and the model group was more than 3.6 times that of the experimental group I and 2.2 times that of the experimental group III.

[0399] On the other hand, this trend continued until day 21 of administration, after which the three groups showed similar increasing trends.

[0400] It can be seen that the onset time of minoxidil finasteride ointment in experimental group II was significantly better than that in experimental group I and experimental group III.

[0401] Hair weight evaluation

[0402] After the experiment, the mice were euthanized, the hair on the skin of the depilatory area was removed, and the mice were weighed. The experimental results are shown in Table 27.

[0403] Table 27 Statistical results of hair weight in each group of experiments Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0404] The results showed that the hair weights of experimental groups I, II, and III were significantly greater than those of the model group. Among them, the hair weight of experimental group II was greater than that of experimental groups I and III.

[0405] The difference between the two groups showed that hair weight increased significantly in Experimental Groups I-III compared to the Model Group. Surprisingly, although the dosage of finasteride in Experimental Group II was lower than that in Experimental Group III, its effect was 1.3 times greater than that of Experimental Group III.

[0406] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0407] Hair follicle number assessment

[0408] At the end of the experiment, the animal skin was collected, fixed with formalin, and then stained with H&E. Four visual fields were selected for hair follicle counting. The experimental results are shown in Table 28.

[0409] Table 28 Statistical results of hair follicle numbers in each experimental group Note: One-way ANOVA, *p<0.05, **p<0.01 compared with the model group; T-test, #p<0.05, ##p<0.01 compared with the model group.

[0410] The results showed that the number of hair follicles in Experimental Groups I, II, and III was significantly higher than that in the model group. Among them, the number of hair follicles in Experimental Group II was greater than that in Experimental Groups I and III.

[0411] According to the difference between the experimental groups I and III and the model group, the number of hair follicles in experimental groups I to III was significantly increased compared with the model group. The effect of experimental group II was better than that of experimental group I.

[0412] Unexpectedly, although the dosage of finasteride in Experimental Group II was lower than that in Experimental Group III, its effect was more than 1.1 times that of Experimental Group III.

[0413] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0414] discuss

[0415] Minoxidil is a potassium channel agonist that dilates local capillaries, increases blood supply, and stimulates hair growth in the affected area. Available products include minoxidil solution (2% and 5%) and minoxidil foam (5%). If you experience allergic symptoms such as recurrent local itching and redness while using minoxidil solution, you can try switching to a propylene glycol-free minoxidil foam formulation, the internationally recommended formulation, to reduce or eliminate allergic reactions. Topical minoxidil is associated with a "shrinkage phase," leading to poor patient compliance. This so-called "shrinkage phase" refers to the temporary, extensive hair loss experienced by approximately 20% of hair loss patients after approximately 2-4 weeks of minoxidil use. This excessive shedding can last for approximately 1.5 months. Clinical studies have shown that after this "shrinkage phase," most patients experience anxiety, and some may stop taking the medication, which can worsen the hair loss.

[0416] Finasteride is a specific 5α-reductase inhibitor. 5α-reductase catalyzes the conversion of testosterone (T) to dihydrotestosterone (DHT). When DHT accumulates to high levels in the skin, it can cause AGA. Finasteride treats androgenic alopecia by inhibiting the conversion of testosterone to DHT. Available products include finasteride tablets (1 mg) and finasteride spray (2.275 mg / mL). Finasteride's adverse reactions significantly impact patient acceptance. Finasteride is generally well tolerated, with adverse reactions generally being mild and generally not requiring treatment discontinuation. Its main adverse events are decreased libido (1.9%), impotence (1.3%), and decreased ejaculation (1%), all with an incidence of less than 2%. Most adverse events gradually resolve with continued treatment. Although finasteride has relatively few adverse reactions, the potential for sexual dysfunction significantly limits its use in most male patients. Finasteride spray, which converts oral administration to topical administration, has similar effects to oral finasteride, but with significantly lower systemic exposure, less impact on serum dihydrotestosterone concentrations, and is well tolerated. In a pivotal Phase III study, after topical administration of finasteride at the intended dose (i.e., up to 200 microliters = up to four sprays per day), the mean maximum plasma finasteride concentrations were >100-fold lower than those following oral administration of 1 mg finasteride per day at all sampling times over the six-month treatment period.

[0417] Existing clinical trials have demonstrated the effectiveness of topical minoxidil solution, topical minoxidil foam, oral finasteride tablets, and topical finasteride spray for androgenic alopecia. However, drug treatments still have numerous shortcomings, primarily manifested in slow onset and low efficacy. Currently, the average onset of minoxidil's effect is 6-9 months, with an efficacy rate of only 60%. Finasteride tablets have an overall efficacy rate of 68%-77% in the treatment of mild and moderate AGA, with efficacy rates of 38.04%, 23.37%, and 13.59% for mild improvement, moderate improvement, and significant improvement, respectively. Overall, treatment efficacy lasts 6-9 months, and efficacy is positively correlated with duration of treatment.

[0418] Minoxidil promotes hair growth, while finasteride stops hair loss, forming a complementary relationship in terms of pharmacological mechanisms. According to the "2023 Chinese Clinical Practice Guidelines: Diagnosis and Treatment of Androgenic Alopecia", the combined treatment of finasteride and minoxidil scored 0.80 points higher than that of minoxidil alone. The compound preparation minoxidil finasteride topical lipid solution (3% minoxidil + 0.1% finasteride, 5% minoxidil + 0.1% finasteride, 10% minoxidil + 0.1% finasteride) is available in India. There is no minoxidil finasteride foam available globally.

[0419] Finasteride is not recommended for women. The specification of minoxidil used by men is 5%. The present invention reduces the amount of finasteride and reduces side effects under a fixed minoxidil specification of 5%. At the same time, under a specific ratio, it has a fast onset and good effect.

[0420] The experimental results of the present invention fully demonstrate that when the minoxidil content is 5% and the finasteride content is 0.075%, it has an extremely excellent hair growth promoting effect, can effectively treat hair loss, and has a synergistic effect at this specific ratio.

[0421] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A preparation or composition for treating hair loss, characterized in that: The preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.095%; Measured as mass percentage (w / w) or mass volume percentage (w / v).

2. The preparation or composition according to claim 1, characterized in that The preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; By mass percentage or mass volume percentage; Preferably, the preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; By mass percentage or mass volume percentage; Preferably, the preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; By mass percentage or mass volume percentage; More preferably, the preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass percentage or mass volume percentage.

3. The preparation or composition according to claim 1, characterized in that The preparation or composition comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.075%; Measured by mass percentage or mass volume percentage.

4. The preparation or composition according to any one of claims 1 to 3, characterized in that The preparation or composition is in the form of a foam or an ointment.

5. A foam for treating hair loss, characterized in that: The foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.095%; Measured as mass percentage (w / w). Preferably, the foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; Measured by mass percentage. Preferably, the foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; Measured by mass percentage. Preferably, the foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; Measured by mass percentage. Preferably, the foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass percentage. More preferably, the foam comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.075%; By mass percentage; The total mass in the mass percentage does not include the mass of the propellant.

6. The foaming agent according to claim 5, characterized in that The foaming agent further comprises an ingredient selected from the group consisting of a humectant, a solubilizer, a pH adjuster, an antioxidant, a proppant, a diluent, a complexing agent, a propellant, or a combination thereof; Furthermore, the moisturizing agent is selected from the group consisting of glycerin, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, or a combination thereof; The solubilizing agent is selected from the group consisting of Tween 40, Tween 60, Tween 80, sodium lauryl sulfate, docusate sodium, or a combination thereof; The pH adjuster is selected from the group consisting of lactic acid, hydrochloric acid, sodium hydroxide, acetic acid, or a combination thereof; The antioxidant is selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or a combination thereof; The proppant is selected from the group consisting of hexadecanol, octadecanol, or a combination thereof; The diluent is selected from the group consisting of purified water, anhydrous ethanol, n-propanol, or a combination thereof; The complexing agent is selected from the group consisting of lactic acid, anhydrous citric acid, acetic acid, malic acid, maleic acid, or a combination thereof; The propellant is selected from the group consisting of propane, butane, isobutane, or a combination thereof.

7. The foaming agent according to claim 6, characterized in that The mass percentage of the moisturizing agent in the foaming agent is 1 to 10 wt % without propellant; preferably 1 to 5 wt %; more preferably 2 to 3 wt %; more preferably 2 to 2.5 wt %; The mass percentage of the solubilizer in the foaming agent is 0.1-5.0wt% without propellant; preferably 0.1-1.0wt%; more preferably 0.1-0.5wt%; more preferably 0.3-0.5wt%; The mass percentage of the pH regulator in the foaming agent is 0.1-5.0 wt % without propellant; preferably 0.5-2.5 wt %; more preferably 1.0-2.0 wt %; more preferably 1.0-1.5 wt %; The antioxidant has a mass percentage of 0.01 to 1 wt% in the foaming agent without propellant, preferably 0.05 to 0.5 wt% and more preferably 0.1 to 0.2 wt%; Based on the calculation without propellant, the mass percentage of the proppant in the foaming agent is 0.5-10wt%; preferably 0.5-5wt%; more preferably 1.5-2.5wt%; more preferably 1.5-2.0wt%. The mass percentage of the complexing agent in the foaming agent is 0.1-5.0wt% without propellant; preferably 0.1-1.0wt%; more preferably 0.1-0.5wt%; more preferably 0.1-0.3wt%; more preferably 0.1-0.2wt%; The mass percentage of the propellant in the foaming agent is 1.5-8.5wt%; preferably 2.5-7.5wt%; more preferably 3.5-6.5wt%; and more preferably 4.5-5.5wt%.

8. The foaming agent according to claim 6, characterized in that The foaming agent comprises: glycerin, Tween 60, lactic acid, butylated hydroxytoluene, hexadecanol, octadecyl alcohol, anhydrous citric acid, anhydrous ethanol, purified water and a propellant.

9. A liniment for treating hair loss, characterized in that: The liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.095%; Measured in mass volume percentage (w / v). Preferably, the liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; Measured by mass volume percentage. Preferably, the liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; Measured by mass volume percentage. Preferably, the liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; Measured by mass volume percentage. Preferably, the liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass volume percentage. More preferably, the liniment comprises the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.075%; Measured by mass volume percentage.

10. The liniment according to claim 9, characterized in that The liniment further comprises a penetration enhancer, a solubilizing agent, a solvent, or a combination thereof; Furthermore, the penetration enhancer is selected from the group consisting of propylene glycol, laurocapram, cyclohexanehexol, decylmethyl Sulfone, or a combination thereof; The co-solvent is selected from the group consisting of anhydrous ethanol, glycerol, isopropanol, polyethylene glycol, liquid paraffin, or a combination thereof.

11. The liniment according to claim 10, characterized in that The volume percentage (v / v) of the penetration enhancer in the liniment is: 35% to 60% (v / v), preferably 45% to 55% (v / v), more preferably 50% to 55% (v / v); The volume percentage (v / v) of the co-solvent in the liniment is 15% to 45% (v / v), preferably 20% to 40% (v / v), and more preferably 25% to 35% (v / v).

12. The liniment according to claim 10, characterized in that The ointment comprises propylene glycol, anhydrous ethanol and purified water.

13. Use of the preparation or composition according to claim 1, or the foam according to claim 5, or the liniment according to claim 9, characterized in that: For preparing a medicament for treating hair loss; Among other things, the treatment includes promoting hair growth and preventing further hair loss.

14. The use according to claim 13, characterized in that The hair loss is male androgenic alopecia or female postmenopausal alopecia.

15. The method for preparing the foaming agent according to claim 5, characterized in that: The following steps are involved: (s1) Take the following active ingredient raw materials by mass percentage for later use: (a) minoxidil 5%; and (b) finasteride 0.07-0.095%; (s2) mixing and dissolving the active ingredient and the pharmaceutically acceptable carrier, filtering, filling and sealing; and (s3) adding a propellant into the sealed solution to obtain the foaming agent.

16. The method according to claim 15, characterized in that In step (s2), the following sub-steps are also included: (s2a) aqueous phase: dissolve the complexing agent in purified water; (s2b) Alcohol phase: dissolving the finasteride in a small amount of anhydrous ethanol, then adding a moisturizer, a solubilizer, a pH adjuster, a finasteride solution, an antioxidant, and a support agent to the anhydrous ethanol to dissolve, and then adding the minoxidil, stirring, and dispersing; and (s2c) Mix the aqueous phase (s2a) and the alcohol phase (s2b), stir until the API is completely dissolved, filter, fill and seal.

17. The method according to claim 15, characterized in that In step (s2), the following sub-steps are also included: (s2a) Aqueous phase: dissolve anhydrous citric acid in purified water; (s2b) Alcohol phase: dissolving the finasteride in a small amount of anhydrous ethanol, then adding glycerol, Tween 60, lactic acid, finasteride ethanol solution, butylated hydroxytoluene, hexadecanol, and octadecyl alcohol to the anhydrous ethanol to dissolve, and then adding the minoxidil, stirring, and dispersing; and (s2c) Mix the aqueous phase (s2a) and the alcohol phase (s2b), stir until the minoxidil is completely dissolved, filter, fill and seal.

18. The method for preparing the liniment according to claim 9, characterized in that: The following steps are involved: (s1) Take the following active ingredient raw materials according to mass volume percentage for later use; (a) Minoxidil 5%; and (b) finasteride 0.07-0.095%; (s2) mixing the active ingredient and the pharmaceutically acceptable carrier uniformly, fixing the volume, and filtering; and (s3) filling the filtered solution to obtain the liniment.

19. The method according to claim 18, characterized in that In step (s2), the following sub-steps are also included: (s2a) dissolving the finasteride in a small amount of a solvent; (s2b) after the penetration enhancer, the cosolvent and part of the solvent are uniformly mixed, the minoxidil and finasteride solution are added, and the mixture is stirred to dissolve; and (s2c) The solution obtained after dissolution is made up to volume with the remaining solvent and filtered.

20. The method of claim 18, wherein: In step (s2), the following sub-steps are also included: (s2a) dissolving the finasteride in a small amount of anhydrous ethanol; (s2b) after uniformly mixing the propylene glycol, anhydrous ethanol and partially purified water, adding the minoxidil and finasteride ethanol solution, stirring to dissolve; and (s2c) The solution obtained after dissolution is made up to volume with the remaining purified water and filtered.

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