CN118384171A - Minoxidil-dutasteride compound external preparation and preparation method thereof - Google Patents
Minoxidil-dutasteride compound external preparation and preparation method thereof Download PDFInfo
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Abstract
The invention provides a minoxidil-dutasteride compound external preparation and a preparation method thereof, belonging to the technical field of medicines. The minoxidil-dutasteride compound external preparation provided by the invention comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is minoxidil and dutasteride; the minoxidil-dutasteride compound external preparation is in a local external preparation form. The minoxidil-dutasteride compound external preparation provided by the invention is a compound external preparation for treating alopecia by local application, and has small side effect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a minoxidil-dutasteride compound external preparation and a preparation method thereof.
Background
Alopecia refers to the phenomenon of hair loss. The hair which is normally shed is the hair in the withdrawal phase and the resting phase, and the hair which enters the withdrawal phase and the hair which newly enters the growing phase are in dynamic balance continuously, so that the normal quantity of hair can be maintained. The pathological alopecia refers to abnormal or excessive hair loss, and can be classified into diffuse alopecia, focal alopecia and androgenetic alopecia. Diffuse hair loss is temporary and can be completely recovered. Alopecia areata and scarring alopecia belong to focal alopecia. Androgenetic alopecia (AGA) is one of the most common types of alopecia, a progressive hair follicle miniaturization that begins at puberty or post puberty. Epidemiological investigation shows that the family genetic history of AGA patients accounts for 53.3-63.9%, and the father line is obviously higher than the mother line; and it was shown by survey data that androgenic alopecia men were more afflicted than women.
Minoxidil is a potassium channel activator that prevents the influx of calcium. Because the EGF inhibits the hair growth in the presence of calcium, minoxidil can relieve the growth inhibition induced by EGF, accelerate the hair growth, dilate blood vessels and reduce peripheral resistance. Because of the strong effect on small vessel dilation, the Chinese medicinal preparation can improve local microcirculation of skin, increase blood supply of skin, prolong survival time of epithelial cells, eliminate infiltration of peripheral lymphocytes, promote hair growth and change vellus hair into terminal hair. When used topically, normal and untreated hypertensive patients show no systemic effect due to minoxidil absorption.
Testosterone is the major androgen in the blood, which is converted to dihydrotestosterone (dihydrotestosterone, DHT), the major pathogenic androgen of AGA, under the catalysis of 5α -reductase. Thus, inhibition of 5α -reductase is a major target for AGA treatment. The 5 a-reductase in human body is classified into 3 types, and among them, type ii 5 a-reductase is widely distributed among the prostate, the inside of hair follicle (the innermost layer of outer root sheath) and the tissues around hair follicle, and is most related to AGA. Many drugs achieve the goal of treating alopecia by inhibiting the action of 5 alpha-reductase. Studies have shown that plants and substances resistant to 5α -reductase activity are also capable of promoting hair growth, such as Myrica rubra bark, white cedar seed, epigallocatechin gallate (EGCG) in green tea, and the like.
Finasteride is a type II 5 alpha-reductase inhibitor capable of competitively inhibiting the activity of type II 5 alpha-reductase. By reducing the activity of the type II 5 alpha-reductase to reduce the expression level of DHT, the alopecia can be obviously improved, and the traditional Chinese medicine composition is also used for treating the prostatic hyperplasia. The side effects are mainly male sexual dysfunction, including erectile dysfunction, reduced ejaculation, decreased libido, and gynecomastia. DHT reduction is a partial cause of these symptoms, but the conversion of additional testosterone to estradiol also leads to the above-mentioned side effects. After the finasteride is stopped, the treatment effect can be reversed, and the side effect can be gradually reduced after the drug is stopped for a few years.
Dutasteride is an analogue of finasteride and is also a generation 25 alpha-reductase inhibitor, and can inhibit type I and type II 5 alpha-reductase, and compared with finasteride, the dutasteride has the effect of inhibiting type I5 alpha-reductase enhanced by 3 times and the effect of inhibiting type II 5 alpha-reductase enhanced by 100 times. Clinical trials show that dutasteride is superior to finasteride in increasing hair number and improving hair follicle microminiaturization, and similar in side effects, as well as sexual dysfunction.
At present, systemic drugs or topical drugs can be adopted for alopecia treatment, and among Chinese approved drugs, the systemic drugs are oral drugs prepared from finasteride (1 mg) and are stopped by a trade name retaining methodSales, which act as blockers of DHT; the topical drug is minoxidil-based drug, and is known by the trade nameSales, containing 2% minoxidil (for females) and 5% minoxidil (for males). At present, the clinical treatment for the patient suffering from alopecia is usually minoxidil for external use, and the finasteride or dutasteride is orally taken, but the finasteride or dutasteride has larger side effects, such as hyposexuality, impotence or small ejaculation liquid amount for men.
Disclosure of Invention
The invention aims to provide a minoxidil-dutasteride compound external preparation and a preparation method thereof.
In order to achieve the above object, the present invention provides the following technical solutions:
The invention provides a minoxidil-dutasteride compound external preparation, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is minoxidil and dutasteride; the minoxidil-dutasteride compound external preparation is in a local external preparation form.
Preferably, the mass ratio of minoxidil to dutasteride is 100: 0.06-2; the mass fraction of the dutasteride in the minoxidil-dutasteride compound external preparation is 0.003% -0.1%.
Preferably, the topical preparation comprises a liniment, an aerosol foam or a gel.
Preferably, when the dosage form is a liniment, the pharmaceutically acceptable excipients include a polyhydric alcohol, ethanol, and water; the polyol includes one or more of propylene glycol, isopropanol, and glycerin.
Preferably, when the dosage form is an aerosol foam, the pharmaceutically acceptable excipients include ethanol, glycerol, lactic acid, polysorbate 60, citric acid, dibutyl hydroxytoluene, cetyl alcohol, stearyl alcohol, water, propane, butane, and isobutane.
Preferably, when the dosage form is a gel, the pharmaceutically acceptable excipients include glycerin, acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate, and water.
The invention provides a preparation method of minoxidil-dutasteride compound external preparation, which comprises the following steps: mixing the active ingredient with pharmaceutically acceptable auxiliary materials to obtain the minoxidil-dutasteride compound external preparation.
Preferably, when the dosage form is a liniment, the preparation method of the minoxidil-dutasteride compound external preparation comprises the following steps:
carrying out first mixing on pharmaceutically acceptable auxiliary materials except water to obtain a first mixture;
performing second mixing on the mixed auxiliary materials and the active ingredients to obtain a second mixture;
and thirdly mixing the second mixture with water to obtain the minoxidil-dutasteride compound external preparation.
Preferably, when the dosage form is an aerosol foam, the preparation method of the minoxidil-dutasteride compound external preparation comprises the following steps:
Mixing ethanol, glycerol, lactic acid, polysorbate 60, dibutyl hydroxy toluene, citric acid, cetyl alcohol and stearyl alcohol to obtain a mixture I;
mixing the first mixed material with the active ingredient in the second step to obtain a second mixed material;
Mixing the II mixture with water to obtain a III mixture;
And IV mixing the III mixture, propane, butane and isobutane to obtain the minoxidil-dutasteride compound external preparation.
Preferably, when the dosage form is a gel, the preparation method of the minoxidil-dutasteride compound external preparation comprises the following steps:
Mixing the acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture with water for the 1 st step to obtain a1 st mixture;
Mixing glycerol with the active ingredients in the 2 nd step to obtain a2 nd mixture;
and (3) mixing the 1 st mixture with the 2 nd mixture to obtain the minoxidil-dutasteride compound external preparation.
The invention provides a minoxidil-dutasteride compound external preparation, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is minoxidil and dutasteride; the minoxidil-dutasteride compound external preparation is in a local external preparation form. The minoxidil-dutasteride compound external preparation provided by the invention is a compound external preparation for treating alopecia by local application, and compared with an oral drug such as dutasteride preparation, the blood concentration can be obviously reduced, and the corresponding side effect is small.
Detailed Description
The invention provides a minoxidil-dutasteride compound external preparation, which comprises an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient is minoxidil and dutasteride; the minoxidil-dutasteride compound external preparation is in a local external preparation form.
The invention adopts minoxidil and dutasteride as active ingredients, and the mass ratio of minoxidil to dutasteride is preferably 100:0.06 to 2, more preferably 100:0.2 to 1.2, more preferably 100:0.6 to 0.8; the mass fraction of the dutasteride in the minoxidil-dutasteride compound external preparation is preferably 0.003% -0.1%, more preferably 0.01% -0.06%, and even more preferably 0.03% -0.04%.
In the invention, the minoxidil-dutasteride compound external preparation is in a form of a topical external preparation, and the topical external preparation preferably comprises a liniment, an aerosol foam or a gel. The present invention preferably selects suitable pharmaceutically acceptable excipients according to the type of dosage form, as will be described in detail below. In the present invention, when water is used as a pharmaceutically acceptable adjuvant, it is specifically purified water unless otherwise specified.
In the present invention, when the dosage form is a liniment, the pharmaceutically acceptable excipients preferably include a polyhydric alcohol, ethanol, and water; the polyol preferably comprises one or more of propylene glycol, isopropanol and glycerin, and may be propylene glycol, or may be isopropanol+glycerin (the volume ratio of isopropanol to glycerin is preferably 1:0.1-10, more preferably 0.5-5, and even more preferably 1:1), and is preferably propylene glycol. In the invention, the proportion of each pharmaceutically acceptable auxiliary material is preferably as follows in parts by volume: 18-168 parts of polyol, 28-63 parts of ethanol and 15-30 parts of water, more preferably: 40-80 parts of polyalcohol, 30-40 parts of ethanol and 18-20 parts of water; still more preferably: 45-50 parts of polyalcohol, 30-35 parts of ethanol and 19-20 parts of water. In the embodiment of the invention, 100mL is taken as a reference, and when the dosage form is a liniment, the minoxidil-dutasteride compound external preparation comprises the following specific formula: 5g of minoxidil, 0.03g of dutasteride, 50mL of propylene glycol, 30mL of ethanol and the balance of water.
In the present invention, when the dosage form is an aerosol foam, the pharmaceutically acceptable excipients include ethanol, glycerol, lactic acid, polysorbate 60, citric acid (preferably anhydrous citric acid), dibutyl hydroxytoluene, cetyl alcohol, stearyl alcohol, water, propane, butane, and isobutane. In the invention, the proportion of each pharmaceutically acceptable auxiliary material is preferably as follows in parts by weight: 48.0 to 62.0 parts of ethanol, 1.5 to 2.5 parts of glycerin, 0.5 to 3.0 parts of lactic acid, 600.05 to 1.0 parts of polysorbate, 0.01 to 2.0 parts of citric acid, 0.1 to 1.0 parts of dibutyl hydroxy toluene, 0.5 to 3.0 parts of hexadecanol, 0.1 to 1.0 parts of stearyl alcohol, 28.0 to 38.0 parts of water, 1.0 to 5.0 parts of propane, 0.1 to 5.0 parts of butane and 0.1 to 5.0 parts of isobutane, more preferably: 50.0 to 52.37 parts of ethanol, 1.8 to 2.0 parts of glycerin, 1.0 to 1.5 parts of lactic acid, 600.1 to 0.5 part of polysorbate, 0.1 to 1.0 part of citric acid, 0.5 to 0.9 part of dibutyl hydroxy toluene, 1.1 to 2.0 parts of cetyl alcohol, 0.3 to 0.5 part of stearyl alcohol, 31.5 to 34.0 parts of water, 2.5 to 3.0 parts of propane, 1.0 to 2.0 parts of butane and 1.0 to 2.0 parts of isobutane. In the embodiment of the invention, 100g is taken as a reference, and when the dosage form is an aerosol foam, the minoxidil-dutasteride compound external preparation comprises the following specific formula: minoxidil 5g, dutasteride 0.03g, ethanol 52.37g, glycerin 2g, lactic acid 1g, polysorbate 600.5g, citric acid 0.1g, dibutyl hydroxy toluene 0.9g, cetyl alcohol 1.1g, stearyl alcohol 0.5g, water 31.5g, propane 3g, butane 1g, and isobutane 1g.
In the present invention, when the dosage form is a gel, the pharmaceutically acceptable excipients include glycerin, acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80, sorbitan oleate, and water. In the invention, the acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate are compounded in advance and are marked as an acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture; in the examples of the present invention, a compounded commercial product, commercially available from Siemens (France) Co., ltd, under the name SIMULGEL 600PHA, was used. In the invention, the proportion of each pharmaceutically acceptable auxiliary material is preferably as follows in parts by weight: 25-40 parts of glycerin, 0.5-2 parts of acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture and 50-70 parts of water; more preferably: 30-35 parts of glycerin, 1-1.5 parts of acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture and 55-63.97 parts of water. In the embodiment of the invention, 100g is taken as a reference, and when the dosage form is gel, the minoxidil-dutasteride compound external preparation specifically comprises the following formula: 5g of minoxidil, 0.03g of dutasteride, 30g of glycerin, 1g of an acrylamide/sodium acryloyldimethyl taurate copolymer, 1g of an isohexadecane polysorbate 80 and sorbitan oleate mixture and 63.97g of water.
The invention provides a preparation method of minoxidil-dutasteride compound external preparation, which comprises the following steps: mixing the active ingredient with pharmaceutically acceptable auxiliary materials to obtain the nodil-dutasteride compound external preparation. The present invention preferably selects an appropriate preparation process according to the type of dosage form, and will be described in detail below.
In the present invention, when the formulation is a liniment, the preparation method of the minoxidil-dutasteride compound external preparation preferably comprises the following steps:
carrying out first mixing on pharmaceutically acceptable auxiliary materials except water to obtain a first mixture;
performing second mixing on the mixed auxiliary materials and the active ingredients to obtain a second mixture;
and thirdly mixing the second mixture with water to obtain the minoxidil-dutasteride compound external preparation.
The invention can be directly used in the form of raw materials without crushing and sieving the active ingredients. In the present invention, the temperatures of the first mixing, the second mixing and the third mixing are preferably 20 to 30 ℃, and specifically may be 20 ℃, 25 ℃ or 30 ℃; the first, second and third mixing are preferably performed under stirring conditions, and the rotation speed of the stirring is independently preferably 200 to 400rpm, and may specifically be 200rpm, 300rpm or 400rpm.
In the present invention, when the formulation is an aerosol foam, the preparation method of the minoxidil-dutasteride compound external preparation preferably comprises the following steps:
Mixing ethanol, glycerol, lactic acid, polysorbate 60, dibutyl hydroxy toluene, citric acid, cetyl alcohol and stearyl alcohol to obtain a mixture I;
mixing the first mixed material with the active ingredient in the second step to obtain a second mixed material;
Mixing the II mixture with water to obtain a III mixture;
And IV mixing the III mixture, propane, butane and isobutane to obtain the minoxidil-dutasteride compound external preparation.
The invention can be directly used in the form of raw materials without crushing and sieving the active ingredients. In the invention, the temperature of the first mixture, the second mixture and the third mixture is preferably 40-60 ℃, and can be specifically 40 ℃,50 ℃ or 60 ℃; the mixing I, II and III is preferably performed under stirring conditions, and the stirring speed is preferably independently 400-500 rpm, and may be 400rpm, 450rpm or 500rpm. The IV mixing is not particularly limited, and the components can be fully and uniformly mixed.
In the present invention, when the dosage form is a gel, the preparation method of the minoxidil-dutasteride compound external preparation preferably comprises the following steps:
Mixing the acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture with water for the 1 st step to obtain a1 st mixture;
Mixing glycerol with the active ingredients in the 2 nd step to obtain a2 nd mixture;
and (3) mixing the 1 st mixture with the 2 nd mixture to obtain the minoxidil-dutasteride compound external preparation.
The invention can be directly used in the form of raw materials without crushing and sieving the active ingredients. In the present invention, the temperature of the 1 st mixture, the 2 nd mixture and the 3 rd mixture is preferably 20 to 30 ℃, and specifically may be 20 ℃,25 ℃ or 30 ℃; the 1 st mixing is preferably carried out under stirring conditions, and the stirring speed is preferably 500-600 rpm, and can be specifically 500rpm, 550rpm or 600rpm; the 2 nd mixing is preferably carried out under stirring conditions, and the stirring speed is preferably 200-400 rpm, and can be 200rpm, 300rpm or 400rpm in particular; the 3 rd mixing is preferably carried out under homogeneous or stirred conditions, the stirring speed being preferably 500 to 600rpm, in particular 500rpm, 550rpm or 600rpm.
The technical solutions of the present invention will be clearly and completely described in the following in connection with the embodiments of the present invention. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Preparation of minoxidil-dutasteride liniment:
Prescription composition: minoxidil 5g, dutasteride 0.03g, propylene glycol 50mL, ethanol 30mL, and purified water was added to dilute to 100mL.
The preparation method comprises the following steps: mixing propylene glycol and ethanol at room temperature and 350rpm, adding minoxidil and dutasteride, stirring, and diluting with purified water to obtain stable liniment.
After 6 months of storage at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75%.+ -. 5%, the minoxidil content and dutasteride content and related substances were determined.
1. Characterization of the liniments:
A. Traits (3)
Taking a proper amount of the product, placing the product into a transparent glass container, placing the transparent glass container on white paper, and visually observing the appearance of the product under natural light.
B. Determination of the pH value
The pH value of the liniment was directly measured by a pH meter, and the average value of three replicates was taken.
C. Determination of viscosity
The viscosity of the liniment was measured using a DVNXABCBG cone-plate viscometer (CP-40, BROOKFIELD, USA), specifically at 25.+ -. 1 ℃ and 20rpm for 60s, with data collected every 10 s.
D. Determination of minoxidil content
High Performance Liquid Chromatography (HPLC) was used to determine minoxidil content: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
E. analysis of minoxidil related substances
Analysis of minoxidil related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; a sample injection volume of 20 mu L; the equipment is Agilent 1260vwd high performance liquid chromatograph; the run time was 3 times the main peak retention time.
F. Determination of dutasteride content
The dutasteride content was determined by HPLC: an ultraviolet-visible light detector was used, and Agilent Zorbax SB-Phenyl chromatography column was used; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is trifluoroacetic acid aqueous solution with the volume fraction of 0.1%, the mobile phase B is acetonitrile, and the volume ratio of the mobile phase A to the mobile phase B is 62:38; the flow rate is 1mL/min; column temperature is 30 ℃; the detection wavelength is 240nm; sample injection volume 80. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
G. analysis of dutasteride related substances
Analysis of dutasteride related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is acetonitrile, the mobile phase B is sodium dihydrogen phosphate solution with the concentration of 10mmol/L, and the volume ratio of the mobile phase A to the mobile phase B is 45:55; the flow rate is 1mL/min; column temperature 20 ℃; the detection wavelength is 210nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
H. Determination of Density
The density of the liniment was directly measured using a densitometer, and the average of three replicates was taken.
I. Checking for the presence of crystals
And observing whether crystals are precipitated in the liniment under a polarizing microscope.
The characterization results of the liniments are shown in Table 1.
TABLE 1 characterization results of liniments prepared in example 1
| Traits (3) | Colorless to pale yellow clear liquid |
| PH value of | 7.8 |
| Viscosity (cp) | 8.8 |
| Minoxidil content (%) | 4.99 |
| Minoxidil related substance content (%) | Impurity A:0.01, total impurities: 0.01 |
| Dutasteride content (%) | 0.03 |
| Dutasteride related substance content (%) | Not detected |
| Density (g/mL) | 0.99 |
| Microscopic birefringence | No crystal |
2. The preparation process of the liniment is examined:
a) Investigation of granularity of crude drug
Because the product system is a true solution, the raw material medicine is completely dissolved, and the granularity of the raw material medicine can influence the preparation dissolution time, so that raw materials with different granularities are selected to prepare the liniment under the room temperature condition, and the influence of the liniment on the raw material dissolution time is examined, and the specific results are shown in table 2. As is clear from Table 2, the dissolution time of the raw material mixture after pulverization and sieving through the 80-mesh sieve is not significantly different from the dissolution time of the raw material mixture after pulverization and sieving, and therefore, the raw material mixture is directly dissolved without pulverization and sieving.
TABLE 2 Effect of drug substance particle size on dissolution time in Liniment preparation
| Minoxidil | Not sieved | Pulverizing, sieving with 60 mesh sieve | Pulverizing, sieving with 80 mesh sieve |
| Finasteride | Not sieved | Not sieved | Not sieved |
| Dissolution time | 30min | 26min | 23min |
B) Rotation speed investigation
Liniments were prepared at room temperature, and the effect of the liniments on the dissolution phenomenon and time of the solution during the preparation of the liniments was examined by setting different rotational speeds (100 to 600 rpm), and the specific results are shown in Table 3. As is clear from Table 3, the stirring speed was preferably in the range of 200 to 400rpm for the dissolution of the liquid. The stirring speed during the formulation was thus determined to be between 200 and 400rpm.
TABLE 3 influence of rotational speed on dissolution phenomena and dissolution time in the preparation of liniments
C) Temperature investigation
Liniments are prepared at 20 ℃, 25 ℃ and 30 ℃ respectively, and the influence of temperature on the properties, color and pH value of the liniments is examined. The results are shown in Table 4. As is clear from Table 4, the liniments prepared at different temperatures were confirmed to have a formulation temperature of 20 to 30℃because there was no significant difference in the properties, color, and pH.
TABLE 4 influence of temperature on Liniment Properties, color and pH values in Liniment preparation
Example 2
Preparation of minoxidil-dutasteride aerosol foam:
prescription composition: minoxidil 5g, dutasteride 0.03g, ethanol 52.37g, glycerin 2g, lactic acid 1g, polysorbate 600.5g, anhydrous citric acid 0.1g, dibutyl hydroxy toluene 0.9g, cetyl alcohol 1.1g, stearyl alcohol 0.5g, purified water 31.5g, propane 3g, butane 1g, and isobutane 1g.
The preparation method comprises the following steps:
1. Preparation of a pre-foaming liquid: (1) Taking the prescription amount of ethanol, glycerol, lactic acid, polysorbate 60, dibutyl hydroxy toluene, anhydrous citric acid, cetyl alcohol and stearyl alcohol, and completely dissolving at 60 ℃ and 500 rpm; (2) Adding minoxidil and dutasteride in the prescription amount, and continuously stirring at 60 ℃ and 500rpm until the raw materials are uniformly dispersed; (3) Adding purified water, mixing, and stirring at 60deg.C and 500rpm to completely dissolve the raw materials to obtain pre-foaming liquid.
2. Preparation of aerosol foam: and uniformly mixing the pre-foaming liquid with the prescribed amount of propane, butane and isobutane to obtain the aerosol foaming agent.
After 6 months of storage at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75%.+ -. 5%, the minoxidil content and dutasteride content and related substances were determined.
1. Characterization of aerosol foam:
A. Traits (3)
And (5) spraying out the foam, and observing the foam property.
B. Determination of the pH value
A proper amount of foam is sprayed out, foam is removed under 40 ℃ water bath to form a solution, the pH value of the solution is measured by a pH meter, and the average value of three repetitions is taken.
C. Viscosity of the mixture
An appropriate amount of foam was sprayed, defoamed into a solution in a 40℃water bath, the viscosity of the solution was measured using a DVNXABCBG cone-plate viscometer (CP-40, BROOKFIELD, USA), specifically, the viscosity was measured at 25.+ -. 1 ℃ and 20rpm for 60 seconds, and data were collected every 10 seconds.
D. Injection rate
Taking a sample 4, removing caps, spraying for a few seconds, cleaning, precisely weighing, immersing in a constant-temperature water bath (25+/-1 ℃) for 30min, taking out, cleaning, continuously spraying for 5s unless otherwise specified, cleaning, precisely weighing, placing in a constant-temperature water bath (25+/-1 ℃) and calculating the spraying rate (g/s) of each tank.
E. Total amount of ejection
Taking 4 cans of the test sample, removing caps, precisely weighing, respectively continuously spraying the cans into a container added with a proper amount of absorption liquid in a fume hood until the cans are completely sprayed, precisely weighing the cans, and ensuring that the spraying amount of each can is not less than 85% of the marked loading amount.
F. determination of minoxidil content
High Performance Liquid Chromatography (HPLC) was used to determine minoxidil content: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
G. analysis of minoxidil related substances
Analysis of minoxidil related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; a sample injection volume of 20 mu L; the equipment is Agilent 1260vwd high performance liquid chromatograph; the run time was 3 times the main peak retention time.
H. Determination of dutasteride content
The dutasteride content was determined by HPLC: an ultraviolet-visible light detector was used, and Agilent Zorbax SB-Phenyl chromatography column was used; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is trifluoroacetic acid aqueous solution with the volume fraction of 0.1%, the mobile phase B is acetonitrile, and the volume ratio of the mobile phase A to the mobile phase B is 62:38; the flow rate is 1mL/min; column temperature is 30 ℃; the detection wavelength is 240nm; sample injection volume 80. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
I. analysis of dutasteride related substances
Analysis of dutasteride related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is acetonitrile, the mobile phase B is sodium dihydrogen phosphate solution with the concentration of 10mmol/L, and the volume ratio of the mobile phase A to the mobile phase B is 45:55; the flow rate is 1mL/min; column temperature 20 ℃; the detection wavelength is 210nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
J. determination of the Dibutylhydroxytoluene content
Dibutyl hydroxy toluene is used as an antioxidant, and the content is measured by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is methanol, the mobile phase B is water, and the volume ratio of the mobile phase A to the mobile phase B is 9:1; the flow rate is 1mL/min; column temperature is 40 ℃; the detection wavelength is 278nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
K. checking for the presence of crystals
And observing whether crystals are separated out in the foam collapse process under a polarizing microscope.
The results of the characterization of the aerosol foam are shown in table 5.
Table 5 characterization results of aerosol foams
| Traits (3) | White foam |
| PH value of | 5.4 |
| Viscosity (cp) | 15.6 |
| Injection rate (g/s) | 6.8 |
| Total amount of ejection (%) | 97.3 |
| Minoxidil content (%) | 5.01 |
| Minoxidil related substance content (%) | Impurity A:0.01, total impurities: 0.01 |
| Dutasteride content (%) | 0.03 |
| Dutasteride related substance content (%) | Unknown list of impurities: 0.02, total impurities: 0.02 |
| Dibutyl hydroxy toluene content (%) | 0.10 |
| Microscopic birefringence | No crystal precipitation |
2. Inspection of preparation process of aerosol foaming agent
A) The results of examining the particle size of the crude drug are shown in Table 6, wherein the "dispersing step" in Table 6 corresponds to the step (2) of preparing the pre-foaming liquid, and the "mixing step" corresponds to the step (3) of preparing the pre-foaming liquid. As can be seen from table 6, the dispersion speed of minoxidil raw material before and after sieving in the dispersion process was not significantly changed; the dissolution rate of the raw materials which are not sieved is slower than that of the raw materials which are sieved in the mixing process, but the raw materials can be completely dissolved in a shorter time, so that the granularity of the raw materials does not need to be controlled.
TABLE 6 Effect of drug substance particle size on dissolution time results for preparation of aerosol foamer
B) The results of the rotation speed examination, specifically, the influence of the rotation speed on the liquid preparation phenomenon and the time during the preparation process of the aerosol foaming agent under different rotation speed conditions (300 rpm, 400rpm and 500 rpm) are shown in table 7, wherein the "dissolving process" in table 7 corresponds to the step (1) of preparing the pre-foaming liquid, the "dispersing process" corresponds to the step (2) of preparing the pre-foaming liquid, and the "mixing process" corresponds to the step (3) of preparing the pre-foaming liquid. As is clear from Table 7, the raw materials were not completely dispersed at 300rpm, and the mixing process time was long, so that the rotation speed was controlled at 400 to 500rpm.
TABLE 7 influence of rotational speed on liquid formulation and time results for the preparation of aerosol foams
C) The temperature was examined, specifically, the effect of the aerosol foaming agent on the phenomenon and time of each step of the liquid preparation was examined at 40℃and 50℃and 60℃respectively, and the results of the detection of the relevant substances on the final product were shown in Table 8, wherein the "dissolving step" in Table 8 corresponds to the step (1) of preparing the pre-foaming liquid, the "dispersing step" corresponds to the step (2) of preparing the pre-foaming liquid, and the "mixing step" corresponds to the step (3) of preparing the pre-foaming liquid. As shown in Table 8, the temperature of the liquid preparation is within the range of 40-60 ℃, the raw materials and auxiliary materials can be completely dissolved in a short time, the related substances have no obvious difference, and the temperature of the liquid preparation can be controlled within the range of 40-60 ℃.
TABLE 8 influence of temperature on liquid formulation and time and related substances in the preparation of aerosol foam
Example 3
Preparation of minoxidil-dutasteride gel:
Prescription composition: 5g of minoxidil, 0.03g of dutasteride, 30g of glycerol, 1g of an acrylamide/sodium acryloyldimethyl taurate copolymer, 1g of an isohexadecane polysorbate 80 and sorbitan oleate mixture and 63.97g of purified water; wherein the acrylamide/sodium acryloyldimethyl taurate copolymer & isohexadecane & polysorbate 80& sorbitan oleate mixture was purchased from Sai-Bico (France) under the trade name SIMULGEL 600PHA.
The preparation method comprises the following steps:
(1) Preparing a matrix phase: under the stirring condition of room temperature and 500rpm, uniformly mixing a prescribed amount of acrylamide/sodium acryloyldimethyl taurate copolymer, isohexadecane, polysorbate 80 and sorbitan oleate mixture and purified water to obtain a matrix phase;
(2) Active phase preparation: adding minoxidil and dutasteride into the glycerol with the prescription amount to be completely dissolved at room temperature under the stirring condition of 300rpm, so as to obtain an active phase;
(3) Mixing: and adding the active phase into the matrix phase at room temperature under the stirring condition of 500rpm, and uniformly mixing to obtain the stable gel.
After 6 months of storage at a temperature of 40.+ -. 2 ℃ and a relative humidity of 75%.+ -. 5%, the minoxidil content and dutasteride content and related substances were determined.
1. Characterization of the gel:
A. Traits (3)
The gel was extruded and observed for behavior.
B. Determination of the pH value
The pH value of the gel is directly measured by a pH meter, and the average value of three repetitions is taken.
C. Viscosity of the mixture
The viscosity of the gels was measured using a DVNXABCBG cone-plate viscometer (CP-51, BROOKFIELD, USA), specifically at 25.+ -. 1 ℃ and 50rpm for 120s, and data was collected every 10 seconds.
D. Determination of minoxidil content
High Performance Liquid Chromatography (HPLC) was used to determine minoxidil content: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
E. analysis of minoxidil related substances
Analysis of minoxidil related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; sodium heptanesulfonate-methanol-water-trifluoroacetic acid mixture is used as a mobile phase, and the volume ratio of methanol, water and trifluoroacetic acid in the mobile phase is 450:550:1, the content of sodium heptanesulfonate is 2g/L; the flow rate is 0.8mL/min; column temperature 40 ℃; the detection wavelength is 230nm; a sample injection volume of 20 mu L; the equipment is Agilent 1260vwd high performance liquid chromatograph; the run time was 3 times the main peak retention time.
F. Determination of dutasteride content
The dutasteride content was determined by HPLC: an ultraviolet-visible light detector was used, and Agilent Zorbax SB-Phenyl chromatography column was used; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is trifluoroacetic acid aqueous solution with the volume fraction of 0.1%, the mobile phase B is acetonitrile, and the volume ratio of the mobile phase A to the mobile phase B is 62:38; the flow rate is 1mL/min; column temperature is 30 ℃; the detection wavelength is 240nm; sample injection volume 80. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
G. analysis of dutasteride related substances
Analysis of dutasteride related substances by HPLC: using ultraviolet-visible light detector, using octadecylsilane chemically bonded silica as filler of chromatographic column; the mobile phase comprises a mobile phase A and a mobile phase B, wherein the mobile phase A is acetonitrile, the mobile phase B is sodium dihydrogen phosphate solution with the concentration of 10mmol/L, and the volume ratio of the mobile phase A to the mobile phase B is 45:55; the flow rate is 1mL/min; column temperature 20 ℃; the detection wavelength is 210nm; sample volume 10. Mu.L; the equipment is Agilent 1260vwd high performance liquid chromatograph.
H. Checking for the presence of crystals
The gel was observed under a polarizing microscope for the precipitation of crystals.
The characterization results of the gels are shown in Table 9.
Table 9 characterization results of gels
| Traits (3) | White gel |
| PH value of | 5.5 |
| Viscosity (cp) | 180 |
| Minoxidil (%) | 5.00 |
| Minoxidil related substance content (%) | Impurity A:0.01, total impurities: 0.01 |
| Dutasteride content (%) | 0.03 |
| Dutasteride related substance content (%) | Not detected |
| Microscopic birefringence | No crystal precipitation |
2. Examination of gel preparation process
A) The particle size of the crude drug was examined and the results are shown in table 9. As is clear from Table 9, the dissolution time of the raw material preparation after pulverization and sieving with the 80 mesh sieve is not significantly different from the dissolution time of the raw material preparation after pulverization and sieving at room temperature, and therefore, the raw material preparation is selected to be directly dissolved without pulverization and sieving.
TABLE 9 Effect of drug size on dissolution time results for gel preparation
| Minoxidil | Not sieved | Pulverizing, sieving with 60 mesh sieve | Pulverizing, sieving with 80 mesh sieve |
| Finasteride | Not sieved | Not sieved | Not sieved |
| Dissolution time | 35min | 23min | 20min |
B) The rotational speed of the matrix phase is examined, specifically, the matrix phase is prepared under the condition of room temperature, different rotational speeds (100-600 rpm) are set, the influence of the rotational speeds on the phenomenon and the time in the matrix phase preparation process is examined, and the results are shown in Table 10. As is clear from Table 10, the stirring speed was preferably in the range of 500 to 600rpm for the dissolution of the liquid. The stirring speed during the formulation was thus determined to be between 500 and 600rpm.
TABLE 10 results of influence of the rotational speed on the swelling time in the matrix phase of the gel preparation
| Stirring speed | 100rpm | 200rpm | 300rpm | 400rpm | 500rpm | 600rpm |
| Matrix swelling time | 4h | 3h | 2h | 2h | 1h | 1h |
C) The active phase is prepared under room temperature condition, different rotation speeds (100-600 rpm) are set, the influence of the rotation speeds on the phenomenon and time in the active phase preparation process is examined, and the results are shown in Table 11. As is clear from Table 11, the stirring speed was preferably in the range of 200 to 400rpm for the dissolution of the liquid. The stirring speed during the formulation was thus determined to be between 200 and 400rpm.
TABLE 11 influence of the rotational speed on the dissolution of the formulations and the time during the preparation of the active phase of the gels
D) The two-phase mixing rotation speed is examined, specifically, the active phase and the matrix phase are mixed under the room temperature condition to prepare the gel, different rotation speeds (100-600 rpm) are set, the influence of the gel on the phenomenon and the time in the two-phase mixing preparation process is examined, and the results are shown in Table 12. As is clear from Table 12, the stirring speed was 500 to 600rpm, and the dissolution process of the liquid formulation was good. The stirring speed during the formulation was thus determined to be between 500 and 600rpm.
TABLE 12 influence of two-phase mixing speed on mixing phenomenon during gel preparation
| Stirring speed | 100rpm | 200rpm | 300rpm | 400rpm | 500rpm | 600rpm |
| Mixing phenomenon | Layering | Layering | Mixing uniformly | Mixing uniformly | Mixing uniformly | Mixing uniformly |
| Mixing for a uniform time | — | — | 1.5h | 1.5h | 1h | 1h |
E) The effect of the gel preparation on the properties, viscosity and pH of the gel preparation prepared at 20℃and 25℃at 30℃was examined, and the results are shown in Table 13. As is clear from Table 13, the gel prepared at different temperatures had no significant difference in properties, viscosity and pH, and thus the formulation temperature was determined to be 20 to 30 ℃.
TABLE 13 influence of temperature on properties, viscosity and pH of gels when gels were prepared
| Temperature (temperature) | 20℃ | 25℃ | 30℃ |
| Traits (3) | Colorless transparent gel | Colorless transparent gel | Colorless transparent gel |
| Viscosity of the product | 3873cp | 3638cp | 3412cp |
| PH value of | 7.21 | 7.28 | 7.22 |
Test example 1
The liniments prepared in example 1, the aerosol foamer prepared in example 2 and the gel prepared in example 3 were subjected to performance tests by the following specific test methods:
1. Purpose of test
A male C57 mouse is adopted to subcutaneously inject testosterone propionate (5 mg/kg) into the back of the mouse to establish an androgenetic alopecia model, and the treatment effect of the compound external preparation on the androgenetic alopecia model is compared and studied.
2. Test materials
2.1 Test article
Blank auxiliary material (I), blank auxiliary material (II), blank auxiliary material (III), 5% minoxidil liniment, 0.03% dutasteride liniment, (5% minoxidil+0.03% dutasteride) liniment aerosol foamer and (5% minoxidil+0.03% dutasteride gel.
2.2 Test animals
SPF-class male C57 mice, body weight 18.0-22.0 g, supplied by Hunan Stokes Sedan test animals Co., ltd., test animal production license number: SCXK (xiang) 2019-0004, test animal quality eligibility number: no.430727221101445228.
2.3 Major reagents
Testosterone propionate injection, lot number: 20220101, a product of the Haerbin three-horse veterinary drug industry Co., ltd; testosterone propionate injection, lot number: 20220501 Sichuan Jin Ke products of pharmaceutical industry Co.Ltd; soybean oil (for injection), lot number: 20220403, 20220602, 20220604, zhejiang Tian Yushan pharmaceutical oil Co., ltd; 0.9% sodium chloride injection, lot number: 22031401D, 22051401D, hunan Conyuan pharmaceutical Co., ltd; isoflurane, lot number: 20211201, jiangsu Hengfeng strength biotechnology limited company.
2.4 Main instruments
ME 2002E-type electronic balance, product of Shimadzu corporation; ME 2002E-type electronic balance, product of Shimadzu corporation; ASP200S type full-automatic tissue dehydrator, ASP300S type full-automatic tissue dehydrator, TP1020 type full-automatic dehydrator, HI1210 type sheet spreading machine, HI1220 type sheet baking machine, RM2235 type paraffin slicer, EG1150H+C type tissue embedding machine, autoStainerXL automatic slide staining machine+CV 5030 automatic cover plate machine, BX53 type biological microscope+MD 50 type digital imaging system, CX31 type biological microscope, leica company product, germany.
3. Test content
3.1 Test methods
130 SPF-class male C57 mice, the weight of which is 18.0-22.0 g,10 mice are selected as a normal control group, testosterone propionate solution (5 mg/kg,10 mL/kg) is subcutaneously injected in parallel along the spinal column for molding, the molding is carried out for 1 time a day for 10 consecutive weeks, after the skin on the back of the mice forms obvious alopecia areas, 90 mice with successful molding are selected and randomly divided into 9 groups according to the alopecia scores and the weights of the mice, wherein the three groups are as follows: model control group, blank auxiliary material group (I), blank auxiliary material group (II), blank auxiliary material group (III), 5% minoxidil liniment group, 0.03% dutasteride liniment group, (5% minoxidil+0.03% dutasteride) aerosol foam agent group, (5% minoxidil+0.03% dutasteride) gel agent group, 10 each. The alopecia area of 1cm×1cm was selected for application, the volume of application was 50 μl/dose, 2 times daily, 6h intervals, and administration was continued for 30 days. The hair loss sites were scored each week before and after the administration, and after the last administration, skin tissues of the hair loss sites were stained with hematoxylin and eosin (hematoxylin and eosin, H & E) for each group of mice, and the number of hair follicles, the number of final hairs and the number of vellus hair of the skin tissues were observed.
3.2 Dose design
The test groupings and dose designs are shown in Table 14.
Table 14 test group and dose design
3.3 Detection index
3.3.1 Skin histopathological detection
After D30 administration, a part of the skin of the hair loss part of the mouse is taken and stored at-80 ℃ for preservation (to be detected), and the other part is subjected to histopathological detection, and the hair follicle number, the final hair number and the hair number are recorded.
3.3.2 Data processing and statistical analysis
The significant digital modification of the test data was performed by rounding and statistical analysis according to the SOP specification, with the software used for statistics being SPSS23.0. Standard error of average value + -average value of metering dataThe normal and variance alignment were examined using Leven's test method. The normal and variance alignment data were met and statistical analysis was performed using one-way analysis of variance (ANOVA). If ANOVA is statistically significant (P.ltoreq.0.05), then further analysis of the group comparisons is performed using LSD test (parametric method). The normal distribution is not met, or the variance of each group is not uniform, the Kruskal-Wallis test is used. If the Kruskal-Wallis Test is statistically significant (P.ltoreq.0.05), a comparative analysis is performed using Dunnett's Test (nonparametric method). The statistical result takes alpha=0.05 as a checking limit, wherein p.ltoreq.0.05 represents a statistical significance and p.ltoreq.0.01 represents a very significant significance of the checked differences.
4 Test results
As can be seen from Table 14, the number of hair follicles, the number of hair, and the hair/vellus of the model control group were all significantly reduced (P.ltoreq.0.05 or P.ltoreq.0.01) in the mice D30 compared with the normal control group; the number of hair follicles, the number of hair and the hair/hair of the mice D30 are obviously reduced (P is less than or equal to 0.05 or P is less than or equal to 0.01).
Compared with the model control group, the numbers of hair follicles and vellus of the 5% minoxidil liniment group and the 0.03% dutasteride liniment group D30 are obviously increased (P is less than or equal to 0.05 or P is less than or equal to 0.01); the (5% minoxidil+0.03% dutasteride) linimentum group, (5% minoxidil+0.03% dutasteride) aerosol foamer group, (5% minoxidil+0.03% dutasteride) gel group the number of hair follicles, the number of hair/hair of mice D30 were all significantly increased (p.ltoreq.0.05 or p.ltoreq.0.01).
The (5% minoxidil+0.03% dutasteride) liniment group, (5% minoxidil+0.03% dutasteride) aerosol foam group, (5% minoxidil+0.03% dutasteride) gel group D30 hair follicle number, number of hair, hair/hair number were all significantly increased (p.ltoreq.0.05 or p.ltoreq.0.01) compared to the 5% minoxidil liniment group.
Compared with the 0.03% dutasteride liniment group, the (5% minoxidil+0.03% dutasteride) aerosol foam group, the (5% minoxidil+0.03% dutasteride) gel group D30 hair follicle number, the final hair number and the final hair/hairiness were all significantly increased (P is less than or equal to 0.05 or P is less than or equal to 0.01), and the rest groups have no significant difference.
TABLE 15 influence of Compound external preparation on testosterone propionate-induced androgenetic alopecia model mice D30 skin hair follicle number, final hair number, and vellus numbern＝10)
Note that: compared with a normal control group, +P≤0.05,++ P is less than or equal to 0.01; p.ltoreq.0.05, p.ltoreq.0.01 compared to the model control group; compared with 5% minoxidil liniment group, #P≤0.05,## P is less than or equal to 0.01; compared with 0.03% of the dutasteride liniment group, &P≤0.05,&& P is less than or equal to 0.01.
From the results, the compound external preparation has remarkable treatment effect on testosterone propionate-induced androgenetic alopecia model mice, and the effects of the (5% minoxidil+0.03% dutasteride) linimentum, (5% minoxidil+0.03% dutasteride) aerosol foamer and the (5% minoxidil+0.03% dutasteride) gel are superior to those of the 5% minoxidil linimentum.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
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| CN120392772A (en) * | 2025-06-12 | 2025-08-01 | 睿铼医药科技(北京)有限公司 | A compound preparation for treating hair loss and its preparation technology |
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| CN120392772A (en) * | 2025-06-12 | 2025-08-01 | 睿铼医药科技(北京)有限公司 | A compound preparation for treating hair loss and its preparation technology |
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