Pharmaceutical preparation for treating hair loss and its preparation method and use

Abstract

The present invention provides a pharmaceutical preparation for treating hair loss, and a preparation method and use thereof. Specifically, the present invention provides a preparation or composition for treating hair loss, comprising the following active ingredients: (a) minoxidil 5%; and (b) finasteride 0.07-0.095%; measured by mass percentage (w / w) or mass volume percentage (w / v), and the preparation or composition is a foam or liniment; when the preparation is a foam, the total mass in the mass percentage does not include the mass of the propellant. The foam and liniment of the present invention have fast onset, good effect and small side effects.

Description

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, and a preparation method and use thereof. Background Art

[0002] At present, hair loss is becoming a growing problem for people of all ages. In addition to affecting the patient's appearance, hair loss also has a significant negative impact on the patient's psychology and social life.

[0003] Take androgenetic alopecia (AGA) as an example. It is the most common type of hair loss. It is a progressive hair follicle miniaturization disease that starts in adolescence or late adolescence. Both men and women can suffer from it, but they show different hair loss patterns and prevalence rates. Although AGA does not affect physical health, it seriously affects the patient's mental health and quality of life. If it can be diagnosed and treated early, it can significantly delay the progression of hair loss and improve the patient's quality of life.

[0004] Since AGA is a progressive process that worsens until baldness occurs, the importance of early and long-term treatment should be emphasized. Generally speaking, the earlier the treatment, the better the effect. Treatment methods include systemic medication, topical medication, hair transplantation, mesotherapy, and low-energy laser therapy.

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

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

[0007] The invention provides a medicine for treating hair loss with rapid onset, good effect and small side effects.

[0008] 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:

[0009] (a) minoxidil 5%; and

[0010] (b) finasteride 0.07-0.095%;

[0011] Measured as mass percentage (w / w) or mass volume percentage (w / v).

[0012] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0013] (a) minoxidil 5%; and

[0014] (b) finasteride 0.07-0.09%;

[0015] Measured by mass percentage or mass volume percentage.

[0016] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0017] (a) minoxidil 5%; and

[0018] (b) finasteride 0.07-0.085%;

[0019] Measured by mass percentage or mass volume percentage.

[0020] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0021] (a) minoxidil 5%; and

[0022] (b) finasteride 0.07-0.08%;

[0023] Measured by mass percentage or mass volume percentage.

[0024] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0025] (a) minoxidil 5%; and

[0026] (b) finasteride 0.07-0.075%;

[0027] Measured by mass percentage or mass volume percentage.

[0028] In another preferred embodiment, the preparation or composition comprises the following active ingredients:

[0029] (a) minoxidil 5%; and

[0030] (b) finasteride 0.075%;

[0031] Measured by mass percentage or mass volume percentage.

[0032] In another preferred embodiment, the preparation or composition further comprises a pharmaceutically acceptable carrier.

[0033] In another preferred embodiment, the dosage form of the preparation or composition is selected from the following group: foam, ointment, tincture, spray, gel.

[0034] In another preferred embodiment, the preparation or composition is in the form of a foam or an ointment.

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

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

[0037] In another preferred example, the preparation or composition contains or does not contain propylene glycol and isopropyl alcohol.

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

[0039] In another preferred embodiment, when the preparation or composition is a foam, the active ingredient is calculated by mass percentage (w / w).

[0040] In another preferred embodiment, when the preparation or composition is an ointment, the active ingredient is calculated by mass volume percentage (w / v).

[0041] In another preferred embodiment, the preparation is a laboratory preparation.

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

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

[0044] In another preferred embodiment, the preparation or composition further contains additional ingredients that promote hair growth.

[0045] In a second aspect of the present invention, there is provided a foam for treating hair loss, the foam comprising the following active ingredients:

[0046] (a) minoxidil 5%; and

[0047] (b) finasteride 0.07-0.095%;

[0048] Measured as mass percentage (w / w).

[0049] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0050] (a) minoxidil 5%; and

[0051] (b) finasteride 0.07-0.09%;

[0052] Measured by mass percentage.

[0053] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0054] (a) minoxidil 5%; and

[0055] (b) finasteride 0.07-0.085%;

[0056] Measured by mass percentage.

[0057] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0058] (a) minoxidil 5%; and

[0059] (b) finasteride 0.07-0.08%;

[0060] Measured by mass percentage.

[0061] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0062] (a) minoxidil 5%; and

[0063] (b) finasteride 0.07-0.075%;

[0064] Measured by mass percentage.

[0065] In another preferred embodiment, the foaming agent comprises the following active ingredients:

[0066] (a) minoxidil 5%; and

[0067] (b) finasteride 0.075%;

[0068] By mass percentage;

[0069] The total mass in the mass percentage does not include the mass of the propellant.

[0070] In another preferred embodiment, 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.

[0071] In another preferred embodiment, the foam further comprises a pharmaceutically acceptable carrier.

[0072] In another preferred embodiment, the foam further comprises an ingredient selected from the following group: a moisturizer, a solubilizer, a pH regulator, an antioxidant, a proppant, a diluent, a complexing agent, a propellant, or a combination thereof.

[0073] 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.

[0074] In another preferred embodiment, the humectant is glycerin.

[0075] 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 more preferably 2 to 2.5 wt %.

[0076] In another preferred embodiment, the solubilizing agent is selected from the following group: Tween 40, Tween 60, Tween 80, sodium lauryl sulfate, docusate sodium, or a combination thereof.

[0077] In another preferred embodiment, the solubilizing agent is Tween 60.

[0078] In another preferred embodiment, the mass percentage of the solubilizer in the foaming agent is 0.1-5.0wt%; preferably 0.1-1.0wt%; more preferably 0.1-0.5wt%; more preferably 0.3-0.5wt%.

[0079] In another preferred embodiment, the pH adjuster is selected from the following group: lactic acid, hydrochloric acid, sodium hydroxide, acetic acid, or a combination thereof.

[0080] In another preferred embodiment, the pH adjuster is lactic acid.

[0081] In another preferred embodiment, the mass percentage of the pH regulator in the foaming agent is 0.1-5.0wt%; preferably 0.5-2.5wt%; more preferably 1.0-2.0wt%; more preferably 1.0-1.5wt%.

[0082] In another preferred embodiment, the antioxidant is selected from the following group: butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E, or a combination thereof.

[0083] In another preferred embodiment, the antioxidant is butylated hydroxytoluene.

[0084] In another preferred embodiment, the mass percentage of the antioxidant in the foaming agent is 0.01-1wt%; preferably 0.05-0.5wt%; more preferably 0.1-0.2wt%.

[0085] In another preferred example, the proppant is selected from the following group: hexadecanol, octadecyl alcohol, or a combination thereof.

[0086] In another preferred embodiment, the proppant is hexadecanol and octadecanol.

[0087] In another preferred embodiment, 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%.

[0088] In another preferred embodiment, the diluent is selected from the following group: purified water, anhydrous ethanol, n-propanol, or a combination thereof.

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

[0090] In another preferred embodiment, the diluent is selected as a mixture of purified water and anhydrous ethanol.

[0091] In another preferred embodiment, the complexing agent is selected from the following group: lactic acid, anhydrous citric acid, acetic acid, malic acid, maleic acid, or a combination thereof.

[0092] In another preferred embodiment, the complexing agent is anhydrous citric acid.

[0093] In another preferred embodiment, the mass percentage of the complexing agent in the foaming agent is 0.1-5.0wt%; preferably 0.1-1.0wt%; more preferably 0.1-0.5wt%; more preferably 0.1-0.3wt%; more preferably 0.1-0.2wt%.

[0094] In another preferred embodiment, the propellant is selected from the following group: propane, butane, isobutane, or a combination thereof.

[0095] In another preferred embodiment, the propellant contains: a mixture of 48% propane, 30% butane and 22% isobutane, calculated by mass percentage (w / w).

[0096] In another preferred embodiment, 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%.

[0097] In another preferred embodiment, the foaming agent does not contain propylene glycol and isopropyl alcohol.

[0098] In another preferred embodiment, the foaming agent further comprises: glycerin, Tween 60, lactic acid, butylated hydroxytoluene, hexadecanol, octadecyl alcohol, anhydrous citric acid, anhydrous ethanol, purified water and a propellant.

[0099] In another preferred embodiment, based on the absence of propellant, the foaming agent further includes: 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).

[0100] In another preferred embodiment, the foaming agent further comprises: 5.00% propellant, calculated by mass percentage (w / w).

[0101] In another preferred embodiment, the foam further contains additional ingredients that promote hair growth.

[0102] In a third aspect of the present invention, there is provided a liniment for treating hair loss, the liniment comprising the following active ingredients:

[0103] (a) minoxidil 5%; and

[0104] (b) finasteride 0.07-0.095%;

[0105] Measured in mass volume percentage (w / v).

[0106] In another preferred embodiment, the liniment comprises the following active ingredients:

[0107] (a) minoxidil 5%; and

[0108] (b) finasteride 0.07-0.09%;

[0109] Measured by mass volume percentage.

[0110] In another preferred embodiment, the liniment comprises the following active ingredients:

[0111] (a) minoxidil 5%; and

[0112] (b) finasteride 0.07-0.085%;

[0113] Measured by mass volume percentage.

[0114] In another preferred embodiment, the liniment comprises the following active ingredients:

[0115] (a) minoxidil 5%; and

[0116] (b) finasteride 0.07-0.08%;

[0117] Measured by mass volume percentage.

[0118] In another preferred embodiment, the liniment comprises the following active ingredients:

[0119] (a) minoxidil 5%; and

[0120] (b) finasteride 0.07-0.075%;

[0121] Measured by mass volume percentage.

[0122] In another preferred embodiment, the liniment comprises the following active ingredients:

[0123] (a) minoxidil 5%; and

[0124] (b) finasteride 0.075%;

[0125] Measured by mass volume percentage.

[0126] 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 ointment.

[0127] In another preferred embodiment, the ointment further comprises a pharmaceutically acceptable carrier.

[0128] In another preferred embodiment, the ointment further contains a penetration enhancer, a solubilizing agent, a solvent, or a combination thereof.

[0129] In another preferred embodiment, the penetration enhancer is selected from the following group: propylene glycol, laurocapram, cyclohexanehexol, decyl methyl sulfoxide, or a combination thereof.

[0130] In another preferred embodiment, the penetration enhancer is propylene glycol.

[0131] In another preferred embodiment, the volume percentage (v / v) of the penetration enhancer in the ointment is 35% to 60% (v / v), preferably 45% to 55% (v / v), and more preferably 50% to 55% (v / v).

[0132] In another preferred embodiment, the co-solvent is selected from the following group: anhydrous ethanol, glycerol, isopropanol, polyethylene glycol, liquid paraffin, or a combination thereof.

[0133] In another preferred embodiment, the co-solvent is anhydrous ethanol.

[0134] In another preferred embodiment, the volume percentage (v / v) of the co-solvent in the ointment is 15% to 45% (v / v), preferably 20% to 40% (v / v), and more preferably 25% to 35% (v / v).

[0135] In another preferred embodiment, the solvent is purified water.

[0136] In another preferred embodiment, the ointment further comprises: propylene glycol, anhydrous ethanol and purified water.

[0137] In another preferred embodiment, the ointment further comprises: 50% (v / v) propylene glycol and 30% (v / v) anhydrous ethanol.

[0138] In another preferred embodiment, the ointment further comprises: purified water adjusted to a specified volume.

[0139] In another preferred embodiment, the ointment further contains additional ingredients for promoting hair growth.

[0140] In the fourth aspect of the present invention, there is provided the use of the preparation or composition as described in the first aspect of the present invention, the foam as described in the second aspect of the present invention, or the ointment as described in the third aspect of the present invention for preparing a medicament for treating hair loss.

[0141] In another preferred embodiment, the treatment includes promoting hair growth and preventing further hair loss.

[0142] 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.

[0143] In another preferred embodiment, the hair loss is androgenic alopecia.

[0144] In another preferred embodiment, the hair loss is male androgenic alopecia or female postmenopausal alopecia.

[0145] 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:

[0146] (s1) Take the following active ingredient raw materials by mass percentage for later use:

[0147] (a) minoxidil 5%; and

[0148] (b) finasteride 0.07-0.095%;

[0149] (s2) mixing and dissolving the active ingredient and the pharmaceutically acceptable carrier, and then filling and sealing; and

[0150] (s3) adding a propellant into the sealed solution to obtain the foaming agent.

[0151] In another preferred embodiment, when preparing the foaming agent, by mass percentage, and in step (s2), the following sub-steps are also included:

[0152] (s2a) aqueous phase: dissolve the complexing agent in purified water;

[0153] (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 proppant to the anhydrous ethanol to dissolve, and then adding the minoxidil, stirring, and dispersing; and

[0154] (s2c) Mix the complexing agent aqueous solution with (s2b), stir until the minoxidil is completely dissolved, and then fill and seal.

[0155] In another preferred embodiment, when preparing the foaming agent, by mass percentage, and in step (s2), the following sub-steps are also included:

[0156] (s2a) Aqueous phase: dissolve anhydrous citric acid in purified water;

[0157] (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, then adding the minoxidil, stirring, and dispersing; and

[0158] (s2c) Mix the aqueous phase (s2a) and the alcohol phase solution (s2b), stir until the minoxidil is completely dissolved, and then fill and seal.

[0159] In a sixth aspect of the present invention, a method for preparing the liniment according to the third aspect of the present invention is provided, characterized in that it comprises the following steps:

[0160] (s1) Taking the following active ingredient raw materials according to mass volume percentage for later use;

[0161] (a) minoxidil 5%; and

[0162] (b) finasteride 0.07-0.095%;

[0163] (s2) mixing the active ingredient and the pharmaceutically acceptable carrier uniformly, fixing the volume, and filtering; and

[0164] (s3) filling the filtered solution to obtain the liniment.

[0165] In another preferred embodiment, when preparing the liniment, the liniment is calculated by mass volume percentage, and in step (s2), the following sub-steps are also included:

[0166] (s2a) dissolving the finasteride in a small amount of a solvent;

[0167] (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

[0168] (s2c) The solution obtained after dissolution is made up to volume with the remaining solvent and filtered.

[0169] In another preferred embodiment, when preparing the liniment, the liniment is calculated by mass volume percentage, and in step (s2), the following sub-steps are also included:

[0170] (s2a) dissolving the finasteride in a small amount of anhydrous ethanol;

[0171] (s2b) after uniformly mixing the propylene glycol, anhydrous ethanol and partially purified water, adding the minoxidil and finasteride ethanol solution, stirring to dissolve; and

[0172] (s2c) The solution obtained after dissolution is made up to volume with the remaining purified water and filtered.

[0173] In the seventh aspect of the present invention, a method for treating hair loss is provided, wherein a therapeutically effective amount of the preparation or composition described in the first aspect of the present invention, or the foam described in the second aspect of the present invention, or the ointment described in the third aspect of the present invention is administered to a subject in need thereof.

[0174] In another preferred embodiment, the method is non-diagnostic and non-therapeutic.

[0175] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0176] Figure 1-Figure 3 The results of hair growth scores of each group of experimental mice after application of the foam of the present invention are shown.

[0177] Figure 4 The results of hair growth scores after each group of experimental mice were administered the ointment of the present invention are shown. DETAILED DESCRIPTION

[0178] After extensive and in-depth research and a large number of screenings, the inventor unexpectedly discovered that a specific ratio of the active ingredient combination of minoxidil and finasteride (for example, minoxidil 5%, finasteride 0.075%, by mass percentage or by mass volume percentage) has a very excellent effect in treating hair loss compared to other ratios, and can take effect in a shorter time and with good effect. The present invention was completed on this basis.

[0179] Specifically, the present invention has conducted multiple comparative experiments, and set up single minoxidil and finasteride and compound preparations with specific proportions to conduct experiments on the constructed hair loss model mice. The experimental results show that when the minoxidil content is 5% and the finasteride content is 0.075%, the foam and ointment of the present invention have unexpectedly excellent effects, and the effect of treating hair loss is better than when the finasteride content is 0.1%. And when the finasteride content is 0.15%, its effect on treating hair loss is also better than when the finasteride content is 0.1%, that is, two effect peaks appear when the finasteride content is about 0.075% and 0.15%, respectively.

[0180] the term

[0181] 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.

[0182] The term "about" can refer to a value or composition that is within an acceptable error range for a particular value or composition 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.).

[0183] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0184] As used herein, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the range and fractional values ​​thereof (e.g., one tenth and one hundredth of an integer) where appropriate.

[0185] 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.

[0186] As used herein, the terms "specification 5%-0.075%" and "5%-0.075%" have the same meaning, both referring to if in the foam, the mass percentage of minoxidil is 5%, and the mass percentage of finasteride is 0.075%; if in the liniment, the mass volume percentage of minoxidil is 5%, and the mass volume percentage of finasteride is 0.075%. Other identical expressions in this article have the same meaning, that is, in the 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 the liniment, the first percentage value is the mass volume percentage of minoxidil, and the second percentage value is the mass volume percentage of finasteride.

[0187] The main advantages of the present invention include:

[0188] (a) Compared with single preparations of minoxidil and finasteride and compound preparations of minoxidil and finasteride with other proportions and dosage forms, the pharmaceutical preparation or composition provided by the present invention exhibits the characteristics of rapid onset of action, good effect and small side effects, and has better clinical application prospects.

[0189] (b) When the pharmaceutical preparation provided by the present invention is a foam, compared with other dosage forms, it has the following advantages: it does not contain propylene glycol and isopropanol, reducing irritation and allergy; the foam is evenly dispersed, easy to spread, with a wide coating surface, and obvious local treatment effect; the foam density is small and the structure is soft; 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, odorless, non-sticky, and has little residue, so patients are generally more willing to accept it and have a high compliance with medication.

[0190] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended only to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods for the unrecorded specific conditions in the following examples are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise indicated, percentages and parts are weight percentages and weight parts or volume parts.

[0191] Example 1 Pharmacodynamic Study 1

[0192] 1.1 Experimental reagents and materials

[0193] The experimental materials of this example are shown in Table 1.

[0194] Table 1 Experimental materials

[0195]

[0196]

[0197] Preparation of testosterone propionate solution:

[0198] 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.

[0199] Preparation of finasteride suspension:

[0200] Accurately weigh 0.542 mg of finasteride and add 5.420 ml of 0.5% CMC-Na. Vortex and sonicate to obtain a uniform suspension with a concentration of 0.1 mg / ml.

[0201] Preparation of 5% Minoxidil Foam:

[0202] 1) The composition of the prescription is shown in Table 2.

[0203] Table 2 Prescription composition

[0204] Prescription composition Dosage / bottle(g) Proportion (wt%) (excluding propellant) Minoxidil 2.850 5.00 Anhydrous ethanol 32.182 56.46 Purified water 18.844 33.06 Butylated Hydroxytoluene 0.057 0.10 lactic acid 0.599 1.05 Anhydrous citric acid 0.063 0.11 glycerin 1.203 2.11 Cetyl Alcohol 0.661 1.16 Octadecanol 0.302 0.53 Twain 60 0.239 0.42 Propellant 3.000 N / A total 60.000 100.00

[0205] The propellant formulation composition and filling formulation composition are shown in Table 3 and Table 4.

[0206] Table 3 Propellant prescription composition

[0207] Propellant (mixed alkanes) composition Proportion(%) Propane 48 Butane 30 Isobutane 22

[0208] Table 4 Filling prescription composition

[0209] Propellant canning prescription effect Prescription ratio (wt%) Dosage per bottle (g) Contents Contents 95 57 Mixed Alkanes Propellant 5 3

[0210] 2) The preparation process is as follows:

[0211] ①Preparation of liquid

[0212] Water phase: Weigh purified water according to the prescription amount, add anhydrous citric acid, and stir until completely dissolved to obtain a water phase;

[0213] Alcohol phase: add glycerol, Tween 60, lactic acid, butylated hydroxytoluene, hexadecanol and octadecyl alcohol into 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;

[0214] Mixing: Add the water phase to the alcohol phase and stir until the minoxidil is completely dissolved and the two phases are mixed evenly;

[0215] ② Filter

[0216] Filter the mixed solution through a filter element;

[0217] ③Filling

[0218] Fill the filtrate into aluminum spray cans, 57g / can;

[0219] ④Sealing

[0220] Add valve and seal;

[0221] ⑤Inflation

[0222] Fill the mixed alkane with 3g per tank;

[0223] ⑥ Put the mousse nozzle cover and outer cover on it, package it, and you are done.

[0224] Preparation of blank foam:

[0225] The process steps are the same as those of minoxidil foam (specification 5%), but minoxidil is removed from the alcohol phase and added. Minoxidil is removed from the prescription, the amount of anhydrous ethanol is 34.34 g / bottle, the prescription amount is adjusted to 60.24% (without propellant), the amount of purified water is 19.54 g / bottle, the prescription amount is adjusted to 34.28% (without propellant), and the contents of other components remain unchanged.

[0226] Preparation of minoxidil finasteride foam (specification 5%-0.075%):

[0227] 1) The prescription composition is shown in Table 5

[0228] Table 5 Prescription composition

[0229] Prescription composition Dosage / bottle(g) Proportion (wt%) (excluding propellant) Minoxidil 2.850 5.00 Finasteride 0.043 0.075 Anhydrous ethanol 32.182 56.46 glycerin 1.203 2.11 Twain 60 0.239 0.42 lactic acid 0.599 1.05 Butylated Hydroxytoluene 0.057 0.10 Cetyl Alcohol 0.661 1.16 Octadecanol 0.302 0.53 Anhydrous citric acid 0.063 0.11 Purified water 18.801 32.985 Propellant 3.000 N / A total 60.000 100.00

[0230] The propellant formulation composition and filling formulation composition are shown in Table 6 and Table 7.

[0231] Table 6 Propellant prescription composition

[0232] Propellant (mixed alkanes) composition Proportion(%) Propane 48 Butane 30 Isobutane 22

[0233] Table 7 Filling prescription composition

[0234] Propellant canning prescription effect Prescription ratio (wt%) Dosage per bottle (g) Contents Contents 95 57 Mixed Alkanes Propellant 5 3

[0235] 2) The preparation process is as follows:

[0236] ①Preparation of liquid

[0237] Water phase: Weigh purified water according to the prescription amount, add anhydrous citric acid, and stir until completely dissolved to obtain a water phase;

[0238] Alcohol phase:

[0239] Weigh anhydrous ethanol according to the prescription amount;

[0240] Dissolve finasteride in a small amount of anhydrous ethanol;

[0241] Add glycerol, Tween 60, lactic acid, finasteride ethanol solution, butylated hydroxytoluene, hexadecanol, and octadecyl alcohol 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;

[0242] Mixing: Add the water phase to the alcohol phase and stir until the minoxidil is completely dissolved and the two phases are mixed evenly;

[0243] ② Filter

[0244] Filter the mixed solution through a filter element;

[0245] ③Filling

[0246] Fill the filtrate into aluminum spray cans, 57g / can;

[0247] ④Sealing

[0248] Add valve and seal;

[0249] ⑤Inflation

[0250] Fill the mixed alkane with 3g per tank;

[0251] ⑥ Put the mousse nozzle cover and outer cover on it, package it, and you are done.

[0252] Preparation of minoxidil finasteride foam (specification 5%-0.008%):

[0253] The process is the same as that of minoxidil finasteride foam (specification 5%-0.075%), wherein the dosage of finasteride is 0.005 g / bottle, and the weight content is 0.008% without propellant, the dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0254] Preparation of minoxidil finasteride foam (specification 5%-0.025%):

[0255] The process is the same as that of minoxidil finasteride foam (specification 5%-0.075%), wherein the dosage of finasteride is 0.014 g / bottle, and the weight content is 0.025% without propellant, the dosage of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0256] 1.2 Experimental process and results

[0257] 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, a depilatory cream was used to remove hair from the back of the mice (approximately 3 × 4 cm). 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.

[0258] Table 8 Experimental groups

[0259] Group Drug administration Blank control group Corn oil + blank foaming agent Model Group Testosterone propionate solution + blank foam Minoxidil group Testosterone Propionate Solution + 5% Minoxidil Foam Finasteride group Testosterone propionate solution + oral 0.01% finasteride (0.1 mg / kg) Experimental Group I Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.008%) Experiment II group Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.025%) Experimental Group III Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.075%)

[0260] In addition to the blank control group, corn oil was injected at multiple points every day. Testosterone propionate solution was injected subcutaneously at multiple points on the hair removal area on the back of mice in each group (to construct an androgenic alopecia model) at 30 mg / kg / day. 0.5 hours after the injection of testosterone propionate, 200 mg of foam was applied to the hair removal area on the back of mice in each foam group once a day for 30 consecutive days. The blank control group and the model group were given blank foam once a day for 30 consecutive days.

[0261] The finasteride group was given the drug orally, 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.

[0262] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0263] Hair growth score

[0264] The skin and hair growth conditions of the depilatory sites of each group of mice were observed every day. The scores were scored once a week in the first two weeks and twice a week after the third week. During the scoring, each group was photographed and the hair growth score results were recorded.

[0265] The scoring criteria are shown in Table 9.

[0266] Table 9 Hair growth scoring criteria

[0267]

[0268]

[0269] The scoring results are shown in Table 10 and Figure 1 shown.

[0270] Table 10 Hair growth scoring results of each group of experiments

[0271]

[0272] 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.

[0273] The results showed that there was no significant difference between the score results of 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.

[0274] Unexpectedly, Experimental Group III had an extremely excellent effect.

[0275] 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 the 21st day 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.

[0276] On the other hand, this significant difference persisted until the end of this experiment (30 days after administration).

[0277] 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.

[0278] Hair weight evaluation

[0279] After the experiment, the experimental mice were euthanized, the hair on the skin surface of the depilatory area of ​​the mice was removed, and the mice were weighed. The experimental results are shown in Table 11.

[0280] Table 11 Statistical results of hair weight in each group of experiments

[0281]

[0282] 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.

[0283] 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.

[0284] According to the difference with the model group, the minoxidil group can significantly increase hair weight compared with the model group, while the hair weight of the finasteride group not only did not increase but slightly decreased. The effect of experimental group I was worse than that of the minoxidil group.

[0285] Unexpectedly, the effect of Experiment II group was significantly improved compared with that of minoxidil group. Even more unexpectedly, the hair growth effect of Experiment III group (Δ=32.4) was about 2.3 times that of minoxidil group. And its effect on hair weight growth was significantly better than that of finasteride alone group, minoxidil alone group, and the combined effect of minoxidil alone group and finasteride alone group (i.e. Δ=14.3+(-0.8)).

[0286] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0287] Hair follicle count assessment

[0288] The skin was cut into 1 cm wide strips parallel to the spine in the hair removal area, fixed in 10% neutral formalin solution for 24-36 hours, dehydrated with gradient alcohol, embedded in paraffin, cut into pieces, stained with H&E, and observed under an optical microscope to count the number of hair follicles. The experimental results are shown in Table 12.

[0289] Table 12 Statistical results of hair follicle numbers in each group

[0290]

[0291] 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.

[0292] 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.

[0293] Unexpectedly, the number of hair follicles in Experiment III group (Δ=10) was higher than that in the minoxidil group, and significantly higher than that in Experiment I and Experiment II groups. Its effect on the increase of hair follicle number was significantly better than that of the finasteride group alone, the minoxidil group alone, and the combined effect of the minoxidil group alone and the finasteride group alone (Δ=7+(-3)).

[0294] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0295] Example 2 Pharmacodynamic Study 2

[0296] 2.1 Experimental reagents and materials

[0297] The experimental materials of this example are shown in Table 13.

[0298] Table 13 Experimental materials

[0299]

[0300]

[0301] Preparation of testosterone propionate solution:

[0302] 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.

[0303] Preparation of 5% Minoxidil Foam:

[0304] The preparation method is the same as that of the 5% minoxidil foam in Example 1.

[0305] Preparation of blank foam:

[0306] The preparation method is the same as that of the blank foaming agent in Example 1.

[0307] Preparation of minoxidil finasteride foam (specification 5%-0.05%):

[0308] The process is the same as the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride is 0.029 g / bottle, and the mass content is 0.05% when the propellant is not included, the amount of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0309] Preparation of minoxidil finasteride foam (specification 5%-0.06%):

[0310] The process is the same as the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride is 0.034 g / bottle, and the mass content is 0.06% when the propellant is not included, the amount of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0311] Preparation of minoxidil finasteride foam (specification 5%-0.07%):

[0312] The process is the same as the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride is 0.04 g / bottle, and the mass content is 0.07% when the propellant is not included, the amount of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0313] 2.2 Experimental process and results

[0314] 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, a depilatory cream was used to remove hair from the back of the mice (approximately 3 × 4 cm). 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.

[0315] Table 14 Experimental groups

[0316] Group Drug administration Blank control group Corn oil + blank foaming agent Model Group Testosterone propionate solution + blank foam Minoxidil group Testosterone Propionate Solution + 5% Minoxidil Foam Experimental Group I Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.05%) Experiment II group Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.06%) Experimental Group III Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.07%)

[0317] In addition to the blank control group, corn oil was injected at multiple points every day. Testosterone propionate solution was injected subcutaneously at multiple points on the hair removal area on the back of mice in each group (to construct an androgenic alopecia model) at 30 mg / kg / day. 0.5 hours after the injection of testosterone propionate, 200 mg of foam was applied to the hair removal area on the back of mice in each foam group once a day for 30 consecutive days. The blank control group and the model group were given blank foam once a day for 30 consecutive days.

[0318] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0319] Hair growth score

[0320] The skin and hair growth of the depilatory sites of each group of mice were observed every day, and the scores were scored once a week in the first two weeks, and twice a week after the third week. During the scoring, each group was photographed and the hair growth score was recorded. The scoring criteria are shown in Table 8.

[0321] The scoring results are shown in Table 15 and Figure 2 shown.

[0322] Table 15 Hair growth scoring results of each group of experiments

[0323]

[0324]

[0325] 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.

[0326] The results showed that the scores of all groups were significantly higher than those of the model group; the score of the experimental group III was not only significantly higher than that of the minoxidil group, but also significantly higher than that of the experimental groups I and II.

[0327] Unexpectedly, Experimental Group III had an extremely excellent effect.

[0328] On the one hand, the score results increased rapidly after the 14th day of administration, and on the 18th day, they were significantly different from the experimental group I and the experimental group II. Taking the data on the 18th day as an example, the difference between the experimental group III and the model group was 1.2, the difference between the minoxidil group and the experimental group I and the model group was 0.6, and the difference between the experimental group II and the model group was 0.7; therefore, the difference (or effect) between the experimental group III and the model group was twice that of the minoxidil group and the experimental group I alone, and more than 1.7 times that of the experimental group II.

[0329] On the other hand, this significant trend continued until the end of this experiment (30 days after administration).

[0330] 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.

[0331] Hair weight evaluation

[0332] After the experiment, the experimental mice were euthanized, the hair on the skin surface of the depilatory area of ​​the mice was removed, and the mice were weighed. The experimental results are shown in Table 16.

[0333] Table 16 Statistical results of hair weight in each group of experiments

[0334]

[0335] Note: **p<0.01 compared with the model group by one-way ANOVA; ##p<0.01 compared with the model group by T test.

[0336] 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.

[0337] According to the difference with the model group, the minoxidil group can significantly increase hair weight compared with the model group. The experimental effects of the experimental groups I and II are comparable to those of the minoxidil group.

[0338] 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.

[0339] 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.

[0340] Hair follicle count assessment

[0341] The skin was cut into 1 cm wide strips parallel to the spine in the hair removal area, fixed in 10% neutral formalin solution for 24-36 hours, dehydrated with gradient alcohol, embedded in paraffin, cut into pieces, stained with H&E, and observed under an optical microscope to count the number of hair follicles. The experimental results are shown in Table 17.

[0342] Table 17 Statistical results of hair follicle numbers in each group

[0343]

[0344] Note: One-way ANOVA, **p<0.01 compared with the model group; T-test, ##p<0.01, #p<0.05.

[0345] 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 not only higher than that in the minoxidil group, but also higher than that in experimental groups I and II.

[0346] According to the difference with the model group, compared with the model group, the minoxidil group can significantly increase hair weight, and the experimental group I also has an improvement effect, but the effect is slightly weaker than the minoxidil group; the experimental group II has an effect equivalent to the minoxidil group.

[0347] 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.

[0348] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.07%) can achieve extremely excellent effect improvement.

[0349] Example 3 Pharmacodynamics Experiment 3

[0350] 3.1 Experimental reagents and materials

[0351] The experimental materials of this example are shown in Table 18.

[0352] Table 18 Experimental materials

[0353] Preparation of testosterone propionate solution:

[0354] Accurately weigh 92.29 mg of testosterone propionate and dissolve it in 30.148 ml of corn oil for injection. Vortex and mix by ultrasonic mixing to obtain a uniform solution with a concentration of 3 mg / ml.

[0355] Preparation of minoxidil finasteride foam (specification 5%-0.075%):

[0356] The preparation method is the same as the preparation of the minoxidil finasteride foam (specification 5%-0.075%) in Example 1.

[0357] Preparation of blank foam:

[0358] The preparation method is the same as that of the blank foaming agent in Example 1.

[0359] Preparation of minoxidil finasteride foam (specification 5%-0.1%):

[0360] The process is the same as the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride is 0.057 g / bottle, the mass content is 0.1% when the propellant is not included, the amount of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0361] Preparation of minoxidil finasteride foam (specification 5%-0.15%):

[0362] The process is the same as the minoxidil finasteride foam (specification 5%-0.075%) in Example 1, wherein the amount of finasteride is 0.086 g / bottle, the mass content is 0.15% when the propellant is not included, the amount of purified water is adjusted accordingly, and the contents of other components remain unchanged.

[0363] 3.2 Test process and results

[0364] 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, a depilatory cream was used to remove hair from the back of the mice (approximately 3 × 4 cm). 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.

[0365] Table 19 Experimental groups

[0366] Group Drug administration Blank control group Corn oil + blank foaming agent Model Group Testosterone propionate solution + blank foam Experimental Group I Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.075%) Experiment II group Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.1%) Experimental Group III Testosterone propionate solution + minoxidil finasteride foam (specification 5%-0.15%)

[0367] In addition to the blank control group, which was injected with corn oil at multiple points every day, each group of mice was subcutaneously injected with testosterone propionate solution (to construct an androgenic alopecia model) at multiple points on the back hair removal area of ​​the mice. 0.5 hours after the injection of testosterone propionate, 200 mg of foam was applied to the hair removal area on the back of each group of mice, once a day for 30 consecutive days. The blank control group and the model group were given blank foam once a day for 30 consecutive days.

[0368] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0369] Hair growth score

[0370] The skin and hair growth of the depilatory sites of each group of mice were observed every day, and the scores were scored once a week in the first two weeks, and twice a week after the third week. During the scoring, each group was photographed and the hair growth score was recorded. The scoring criteria are shown in Table 8.

[0371] The scoring results are shown in Table 20 and Figure 3 shown.

[0372] Table 20 Hair growth scoring results of each group of experiments

[0373]

[0374]

[0375] 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.

[0376] 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 groups II and III.

[0377] Unexpectedly, Experimental Group I had an extremely excellent effect.

[0378] On the one hand, with the decrease in the dosage of finasteride, the score results increased rapidly after the 14th day of administration, and on the 18th day, there was a significant difference with Experimental Group II and Experimental Group III; taking the 14th day data as an example, the difference between Experimental Group I and the model group was 0.8, while the difference between Experimental Group II and Experimental Group III and the model group was 0.5. Therefore, the difference (or effect) between Experimental Group I and the model group is 1.6 times that of Experimental Group II and Experimental Group III.

[0379] On the other hand, this significant trend continued until the 21st day of administration. From the 25th day to the 30th day, the increasing trends of the experimental group I and the experimental group III were similar and higher than that of the experimental group II.

[0380] 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.

[0381] Hair weight evaluation

[0382] After the experiment, the experimental mice were euthanized, the hair on the skin surface of the depilatory area of ​​the mice was removed, and the mice were weighed. The experimental results are shown in Table 21.

[0383] Table 21 Statistical results of hair weight in each group of experiments

[0384]

[0385]

[0386] 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.

[0387] 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.

[0388] According to the difference with the model group, the hair weight of experimental groups I-III was significantly increased compared with the model group.

[0389] 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.

[0390] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0391] Hair follicle number assessment

[0392] The skin was cut into 1 cm wide strips parallel to the spine in the hair removal area, fixed in 10% neutral formalin solution for 24-36 hours, dehydrated with gradient alcohol, embedded in paraffin, cut into pieces, stained with H&E, and observed under an optical microscope to count the number of hair follicles. The experimental results are shown in Table 22.

[0393] Table 22 Statistical results of the number of hair follicles in each group of experiments

[0394]

[0395] 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 number of hair follicles in experimental groups I, II, and III was significantly greater than that in the model group.

[0397] Unexpectedly, with the decrease in the dosage of finasteride, the number of hair follicles in Experimental Group I was significantly higher than that in Experimental Groups II and III, and even significantly higher than that in the blank control group.

[0398] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has an excellent effect.

[0399] Example 4 Pharmacodynamic Study 4

[0400] 4.1 Experimental preparations and materials

[0401] The experimental materials of this example are shown in Table 23.

[0402] Table 23 Experimental materials

[0403]

[0404] Preparation of testosterone propionate solution:

[0405] 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.

[0406] Preparation of minoxidil finasteride liniment (specification 5%-0.075%):

[0407] 1) The prescription composition is shown in Table 24

[0408] Table 24 Prescription composition

[0409] Prescription composition Dosage / bottle Proportion Minoxidil 3.00g 5%(w / v) Finasteride 0.45g 0.075%(w / v) Propylene glycol 30ml 50%(v / v) Anhydrous ethanol 18ml 30%(v / v) Purified water Moderate N / A total 60ml N / A

[0410] 2) The preparation process is as follows:

[0411] ① According to the above formula, weigh minoxidil, finasteride, propylene glycol and anhydrous ethanol;

[0412] ②Dissolve finasteride in a small amount of anhydrous ethanol;

[0413] ③Stir and mix the prescribed amount of propylene glycol, the remaining anhydrous ethanol and part of the purified water evenly;

[0414] 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;

[0415] ⑤ Add purified water and dilute to the prescribed volume to obtain the drug solution;

[0416] ⑥ Filter the obtained liquid medicine using a 0.45 μm microporous filter membrane;

[0417] ⑦ Fill and package the liquid medicine into 60ml / bottle.

[0418] Preparation of blank liniment:

[0419] The process is to remove the operation process of minoxidil and finasteride, and the rest is the same as the preparation of minoxidil finasteride lotion (specification 5%-0.075%). Minoxidil and finasteride are removed from the prescription, and the contents of other components remain unchanged.

[0420] Preparation of minoxidil finasteride liniment (specification 5%-0.05%):

[0421] The process is the same as the preparation of minoxidil finasteride ointment (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.

[0422] Preparation of minoxidil finasteride liniment (specification 5%-0.1%):

[0423] The process is the same as the preparation of minoxidil finasteride ointment (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.

[0424] 4.2 Experimental process and results

[0425] 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, a depilatory cream was used to remove hair from the back of the mice (approximately 3 × 4 cm). 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.

[0426] Table 25 Experimental groups

[0427]

[0428]

[0429] In addition to the blank control group, which was injected with corn oil at multiple points every day, the mice in each group were injected with testosterone propionate solution at multiple points on the skin of the depilatory area on the back of the mice at 30 mg / kg / day. 0.5 hours after the injection of testosterone propionate, the depilatory area on the back of the mice in each group was smeared with 0.2 ml of the ointment once a day for 30 consecutive days. The blank control group and the model group were given blank ointment once a day for 30 consecutive days.

[0430] The active ingredient combination with a specific content of the present invention has a fast onset and good effect

[0431] Hair growth score

[0432] The skin and hair growth of the depilatory sites of each group of mice were observed every day to evaluate the effect of the drug on the hair growth cycle of mice. The scores were scored once a week in the first two weeks and twice a week in the last two weeks. During the scoring, each group was photographed and the hair growth score was recorded. The scoring criteria are shown in Table 8.

[0433] The scoring results are shown in Table 26 and Figure 4

[0434] Table 26 Hair growth score results of each group of experiments

[0435]

[0436] 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.

[0437] 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.

[0438] Unexpectedly, the experimental II group had an extremely excellent effect.

[0439] 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 I and the experimental group III. Taking the data on the 18th day 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.

[0440] On the other hand, this trend continued until the 21st day of administration. After that, the three groups showed similar increasing trends.

[0441] It can be seen that the onset time of minoxidil finasteride ointment in experimental group II was significantly better than that in experimental groups I and III.

[0442] Hair weight evaluation

[0443] After the experiment, the experimental mice were euthanized, the hair on the skin surface of the depilatory area of ​​the mice was removed, and the mice were weighed. The experimental results are shown in Table 27.

[0444] Table 27 Statistical results of hair weight in each group of experiments

[0445]

[0446] 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.

[0447] The results showed that the hair weight of experimental group I, group II and group III was significantly greater than that of the model group. Among them, the hair weight of experimental group II was greater than that of experimental group I and experimental group III.

[0448] According to the difference with the model group, compared with the model group, the experimental groups I-III can significantly increase the hair weight. Unexpectedly, although the amount of finasteride used in the experimental group II was lower than that in the experimental group III, its effect was 1.3 times that of the experimental group III.

[0449] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0450] Hair follicle number assessment

[0451] At the end of the experiment, the animal skin was collected, fixed with formalin, and then stained with H&E, and 4 fields of view were selected for hair follicle counting. The experimental results are shown in Table 28.

[0452] Table 28 Statistical results of the number of hair follicles in each group of experiments

[0453]

[0454]

[0455] 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.

[0456] 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.

[0457] According to the difference with the model group, the number of hair follicles in experimental groups I-III was significantly increased compared with the model group. The effect of experimental group II was better than that of experimental group I.

[0458] 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.

[0459] It can be seen that a specific ratio of minoxidil and finasteride (eg, 5%-0.075%) has a synergistic effect.

[0460] discuss

[0461] Minoxidil is a potassium channel agonist that can dilate local capillaries, increase local blood supply, and stimulate hair growth in the affected area. The varieties that have been launched on the market include minoxidil solution (2%, 5%) and minoxidil foam (5%). When using minoxidil solution, if allergic symptoms such as local repeated itching and skin redness occur, you can try to switch to minoxidil without propylene glycol, which is the internationally recommended foam preparation, to reduce or eliminate allergic adverse reactions. There is a "crazy shedding period" for topical minoxidil, and patients have poor compliance. The so-called crazy shedding period refers to the phenomenon that about 20% of hair loss patients experience temporary hair loss when using minoxidil for about 2-4 weeks, and excessive shedding can last for about 1.5 months. Clinical studies have shown that after the "crazy shedding period" occurs, most patients become anxious, and some patients will stop taking the medication, which in turn aggravates the symptoms of hair loss.

[0462] Finasteride is a specific 5α-reductase inhibitor. 5α-reductase catalyzes the conversion of testosterone (T) into dihydrotestosterone (DHT), which causes AGA when dihydrotestosterone accumulates to high levels in the skin. Finasteride treats androgenic alopecia by inhibiting the conversion of testosterone into dihydrotestosterone. The varieties that have been launched on the market include finasteride tablets (1mg) and finasteride spray (2.275mg / mL). The adverse reactions of finasteride greatly affect the psychological compliance of patients. Finasteride is well tolerated overall, and adverse reactions are usually mild, and treatment generally does not need to be discontinued. Its main adverse events are decreased libido (1.9%), impotence (1.3%), and decreased ejaculation (1%), and their incidence is less than 2%. Most adverse events gradually disappear after continued treatment. Although finasteride has fewer adverse reactions, it may affect sexual dysfunction, which greatly limits the use of this drug for most male patients. Finasteride spray changes oral administration to topical administration, and its effect is similar to oral finasteride, but the systemic exposure is significantly reduced, the effect on serum dihydrotestosterone concentration is small, and it is well tolerated. In the pivotal Phase III study, after topical administration of finasteride at the intended dose (i.e., up to 200 microliters = up to 4 sprays per day), the average maximum plasma finasteride concentration was >100 times lower than the concentration after oral administration of 1 mg finasteride per day at all sampling times within 6 months of treatment.

[0463] Existing clinical trials have proven that topical minoxidil solution, topical minoxidil foam, oral finasteride tablets, and topical finasteride spray are effective for androgenic alopecia. However, drug treatment still has many shortcomings, mainly manifested in slow onset and low efficacy. At present, the average onset time of minoxidil is 6-9 months, and the efficacy is only 60%. The overall efficacy of finasteride tablets in the treatment of mild and moderate AGA can reach 68%-77%, among which the efficacy of mild improvement, moderate improvement and significant improvement are 38.04%, 23.37% and 13.59% respectively. The overall treatment takes 6-9 months to take effect, and the efficacy is positively correlated with the duration of medication.

[0464] Minoxidil promotes hair growth, while finasteride stops hair loss, complementing each other in terms of pharmacological mechanisms. According to the 2023 China Clinical Practice Guidelines: Diagnosis and Treatment of Androgenic Alopecia, finasteride is combined with minoxidil, and the combined treatment regimen scores 0.80 points higher than that after treatment with 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, and there is no minoxidil finasteride foam available globally.

[0465] Finasteride is not recommended for women, and the specification of minoxidil used by men is 5%. The present invention reduces the amount of finasteride and the side effects under the fixed specification of minoxidil 5%, and at the same time, under a specific ratio, it takes effect quickly and has a good effect.

[0466] The experimental results of the present invention fully show that when the minoxidil content is 5% and the finasteride content is 0.075%, it has an extremely excellent effect of promoting hair growth, can effectively treat hair loss, and has a synergistic effect at this specific ratio.

[0467] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A preparation or composition for treating hair loss, characterized in that: The active ingredients of the preparation or composition consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; 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 active ingredients of the preparation or composition consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; Measured by mass percentage or mass volume percentage.

3. The preparation or composition according to claim 1, characterized in that The active ingredients of the preparation or composition consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; Measured by mass percentage or mass volume percentage.

4. The preparation or composition according to claim 1, characterized in that The active ingredients of the preparation or composition consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass percentage or mass volume percentage.

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

6. The preparation or composition according to any one of claims 1 to 5, characterized in that The preparation or composition is in the form of a foam or an ointment.

7. A foam for treating hair loss, characterized in that: The active ingredients of the foam are composed of: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; Measured by mass percentage (w / w); The total mass in the mass percentage does not include the mass of the propellant.

8. The foaming agent according to claim 7, characterized in that The active ingredients of the foam are composed of: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; Measured by mass percentage.

9. The foaming agent according to claim 7, characterized in that The active ingredients of the foam are composed of: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; Measured by mass percentage.

10. The foaming agent according to claim 7, characterized in that The active ingredients of the foam are composed of: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass percentage.

11. The foaming agent according to claim 7, characterized in that The active ingredients of the foam are composed of: (a) minoxidil 5%; and (b) finasteride 0.075%; Measured by mass percentage.

12. The foaming agent according to claim 7, 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.

13. The foaming agent according to claim 12, characterized in that The mass percentage of the moisturizing agent in the foaming agent is 1 to 10 wt % without propellant; The mass percentage of the solubilizer in the foaming agent is 0.1 to 5.0 wt % without propellant; The mass percentage of the pH regulator in the foaming agent is 0.1 to 5.0 wt % without propellant; The mass percentage of the antioxidant in the foaming agent is 0.01 to 1 wt % without propellant; The mass percentage of the proppant in the foaming agent is 0.5 to 10 wt % without propellant; The mass percentage of the complexing agent in the foaming agent is 0.1 to 5.0 wt % without propellant; The mass percentage of the propellant in the foaming agent is 1.5 to 8.5 wt %.

14. The foaming agent according to claim 13, characterized in that The mass percentage of the moisturizing agent in the foaming agent is 1 to 5 wt % without propellant.

15. The foaming agent according to claim 13, characterized in that The mass percentage of the moisturizing agent in the foaming agent is 2-3wt% based on the calculation without propellant.

16. The foaming agent according to claim 13, characterized in that The mass percentage of the moisturizing agent in the foaming agent is 2 to 2.5 wt % without propellant.

17. The foaming agent according to claim 13, characterized in that The mass percentage of the solubilizer in the foaming agent is 0.1-1.0 wt % without propellant.

18. The foaming agent according to claim 13, characterized in that The mass percentage of the solubilizer in the foaming agent is 0.1-0.5wt% based on the propellant not included.

19. The foaming agent according to claim 13, characterized in that The mass percentage of the solubilizer in the foaming agent is 0.3-0.5wt% based on the propellant not included.

20. The foaming agent according to claim 13, characterized in that The mass percentage of the pH adjuster in the foaming agent is 0.5-2.5wt% without propellant.

21. The foaming agent according to claim 13, characterized in that The mass percentage of the pH adjuster in the foaming agent is 1.0-2.0 wt % without propellant.

22. The foaming agent according to claim 13, characterized in that The mass percentage of the pH adjuster in the foaming agent is 1.0 to 1.5 wt % without propellant.

23. The foaming agent according to claim 13, characterized in that The mass percentage of the antioxidant in the foaming agent is 0.05-0.5wt% without propellant.

24. The foaming agent according to claim 13, characterized in that The mass percentage of the antioxidant in the foaming agent is 0.1-0.2 wt % without propellant.

25. The foaming agent according to claim 13, characterized in that The mass percentage of the proppant in the foaming agent is 0.5-5wt% without propellant.

26. The foaming agent according to claim 13, characterized in that The mass percentage of the proppant in the foaming agent is 1.5-2.5wt% without propellant.

27. The foaming agent according to claim 13, characterized in that The mass percentage of the proppant in the foaming agent is 1.5-2.0wt% without propellant.

28. The foaming agent according to claim 13, characterized in that The mass percentage of the complexing agent in the foaming agent is 0.1-1.0wt% without propellant.

29. The foaming agent according to claim 13, characterized in that The mass percentage of the complexing agent in the foaming agent is 0.1-0.5wt% without propellant.

30. The foaming agent according to claim 13, characterized in that The mass percentage of the complexing agent in the foaming agent is 0.1-0.3wt% without propellant.

31. The foaming agent according to claim 13, characterized in that The mass percentage of the complexing agent in the foaming agent is 0.1-0.2wt% without propellant.

32. The foaming agent according to claim 13, characterized in that The mass percentage of the propellant in the foaming agent is 2.5-7.5wt%.

33. The foaming agent according to claim 13, characterized in that The mass percentage of the propellant in the foaming agent is 3.5-6.5wt%.

34. The foaming agent according to claim 13, characterized in that The mass percentage of the propellant in the foaming agent is 4.5-5.5wt%.

35. The foaming agent according to claim 12, 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.

36. A liniment for treating hair loss, characterized in that: The active ingredients of the liniment consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.09%; Measured in mass volume percentage (w / v).

37. The liniment according to claim 36, characterized in that The active ingredients of the liniment consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.085%; Measured by mass volume percentage.

38. The liniment according to claim 36, characterized in that The active ingredients of the liniment consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.08%; Measured by mass volume percentage.

39. The liniment according to claim 36, characterized in that The active ingredients of the liniment consist of: (a) minoxidil 5%; and (b) finasteride 0.07-0.075%; Measured by mass volume percentage.

40. The liniment according to claim 36, characterized in that The active ingredients of the liniment consist of: (a) minoxidil 5%; and (b) finasteride 0.075%; Measured by mass volume percentage.

41. The liniment according to claim 36, 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, decyl methyl sulfoxide, 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.

42. The liniment according to claim 41, characterized in that The volume percentage (v / v) of the penetration enhancer in the liniment is: 35% to 60% (v / v); The volume percentage (v / v) of the co-solvent in the liniment is 15% to 45% (v / v).

43. The liniment according to claim 41, characterized in that The volume percentage (v / v) of the penetration enhancer in the liniment is 45% to 55% (v / v).

44. The liniment according to claim 41, characterized in that The volume percentage (v / v) of the penetration enhancer in the liniment is 50% to 55% (v / v).

45. The liniment according to claim 41, characterized in that The volume percentage (v / v) of the co-solvent in the liniment is 20% to 40% (v / v).

46. ​​The liniment according to claim 41, characterized in that The volume percentage (v / v) of the co-solvent in the liniment is 25% to 35% (v / v).

47. The liniment according to claim 41, characterized in that The ointment comprises propylene glycol, anhydrous ethanol and purified water.

48. Use of the preparation or composition of claim 1, or the foam of claim 7, or the liniment of claim 36, 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.

49. The use according to claim 48, characterized in that The hair loss is male androgenic alopecia or female postmenopausal alopecia.

50. The method for preparing the foaming agent according to claim 7, 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 0.07-0.09%; (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.

51. The method of claim 50, wherein: 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.

52. The method of claim 50, wherein: 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.

53. The method for preparing the liniment according to claim 36, 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 0.07-0.09%; (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.

54. The method of claim 53, wherein: 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.

55. The method of claim 53, wherein: In step (s2), the following sub-steps are also included: (s2a) dissolving the finasteride in a small amount of anhydrous ethanol; (s2b) mixing propylene glycol, anhydrous ethanol and partially purified water, adding the minoxidil and finasteride ethanol solution, and 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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