A minoxidil mixture and a preparation method thereof

Abstract

The application discloses a kind of minoxidil mixed solution and preparation method thereof, it is related to pharmaceutical preparation field.The application is prepared when minoxidil mixed solution, dialdehyde cellulose, minoxidil, diethylene triamine are reacted by emulsion method to obtain cellulose microspheres;Methyl bromide, iodomethane are reacted to obtain modified cellulose microspheres by cellulose microspheres;Octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane are reacted to obtain polysiloxane;Polysiloxane, allyl polyether, chloroplatinic acid are reacted to obtain modified polysiloxane;Modified polysiloxane, modified cellulose microspheres, deionized water are uniformly mixed to obtain minoxidil mixed solution.The minoxidil mixed solution prepared by the application has good bacteriostasis, fat-soluble release, foam stability and low irritation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, in particular to a minoxidil mixed solution and a preparation method thereof. BACKGROUND

[0002] Androgenetic alopecia, also known as pattern baldness, is a genetically determined, patterned and progressive hair loss. Male patients show sparse hair on the temples, and the hair loss gradually progresses to involve the vertex. Female patients show sparse hair on the vertex, and the hairline on the forehead is not obvious, sometimes forming a "Christmas tree" pattern of hair loss. Currently, this disease cannot be cured, and as the disease progresses, the patient's hair density gradually decreases. When the hair loss symptoms progress to the late stage, the hair follicles that have completely lost their growth ability are irreversible.

[0003] Minoxidil is a drug widely used to treat androgenetic alopecia and hypertension. Its main mechanism of action is to dilate blood vessels and promote hair growth. Minoxidil solution usually contains high concentrations of ethanol and other solvents, which can cause dry skin, itching and irritation; minoxidil is easily degraded in solution, especially under light and high temperature conditions, affecting the efficacy and stability of the drug. The minoxidil mixed solution prepared by the present application has good bacteriostatic property, liposoluble release property, foam stability and low irritation. SUMMARY

[0004] The purpose of the present application is to provide a preparation method of a minoxidil mixed solution to solve the problems in the prior art.

[0005] In order to solve the above technical problems, the present application provides the following technical solutions:

[0006] A minoxidil mixed solution, the minoxidil mixed solution is prepared by reacting dialdehyde cellulose, minoxidil and diethylenetriamine by emulsion method to obtain cellulose microspheres; the cellulose microspheres, bromohexane and iodomethane are reacted to obtain modified cellulose microspheres; octamethylcyclotetrasiloxane and tetramethylcyclotetrasiloxane are reacted to obtain polysiloxane; the polysiloxane, allyl polyether and chloroplatinic acid are reacted to obtain modified polysiloxane; and the modified polysiloxane, modified cellulose microspheres and deionized water are uniformly mixed to obtain the minoxidil mixed solution.

[0007] A preparation method of a minoxidil mixed solution, comprising the following preparation steps:

[0008] (1) The dialdehyde cellulose and deionized water are mixed in a mass ratio of 1: (80-120), and a 0.1 mol / L sodium hydroxide solution is used to adjust the pH to 9, and then the mixture is stirred at a room temperature and a speed of 350-450 r / min for 1-2 h to prepare a dialdehyde cellulose solution; Span-80, sodium dodecyl sulfate and paraffin are mixed in a mass ratio of 1: (0.8-1.2) : (8-12), and the mixed solution with a mass of 0.5-0.7 times that of the paraffin is added at a rate of 20 ml / min, and then the mixture is stirred at a room temperature and a speed of 300-400 r / min for 20-30 min, and then 0.01-0.02 times the mass of diethylenetriamine is added, and the stirring is continued for 1-2 h, and then the precipitate is obtained by centrifugal separation, and then the precipitate is washed with petroleum ether for 3-5 times, and then the precipitate is dried at 45-55℃ for 20-24 h to prepare cellulose microspheres; the cellulose microspheres, bromohexane and anhydrous ethanol are mixed, and then the mixture is stirred at 75-85℃ and a speed of 200-300 r / min for 10-14 h, and then 0.7-0.8 times the mass of iodomethane is added, and the stirring is continued for 10-14 h, and then the precipitate is obtained by centrifugal separation, and then the precipitate is washed with deionized water for 3-5 times, and then the precipitate is dried under vacuum at 75-85℃ for 10-14 h to prepare modified cellulose microspheres;

[0009] (2) Octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid are mixed, and then the mixture is stirred at 60-70℃ and a speed of 200-300 r / min for 4-6 h, and then the temperature is lowered to a room temperature, and then sodium bicarbonate is added to adjust the pH to 7, and then the mixture is filtered, and then the filtrate is polysiloxane;

[0010] (3) Polysiloxane, allyl polyether and chloroplatinic acid are mixed, and then the mixture is stirred at 105-115℃ and a speed of 300-400 r / min for 2-3 h, and then the temperature is lowered to a room temperature, and then the mixture is filtered, and then the filtrate is modified polysiloxane;

[0011] (4) 1-2 parts of the modified cellulose microspheres, 1-2 parts of the modified polysiloxane and 5-7 parts of deionized water are mixed, and then the mixture is stirred at a room temperature and a speed of 500-600 r / min for 20-30 min to prepare a minoxidil mixed solution.

[0012] As an optimization, the preparation method of the dialdehyde cellulose in step (1) is as follows: anhydrous zinc chloride and deionized water are mixed in a mass ratio of 1:125 to prepare a zinc chloride solution; nanocellulose, sodium periodate and the zinc chloride solution are mixed in a mass ratio of 1: (1.5-2) : (200-300), and then the pH is adjusted to 3-4 with dilute hydrochloric acid, and then the mixture is stirred at 65-75℃ and a speed of 150-250 r / min for 2-3 h in the dark, and then the mixture is filtered with a filter membrane with a pore size of 0.45 μm, and then the solid is washed with deionized water for 3-5 times, and then the solid is freeze-dried to prepare the dialdehyde cellulose.

[0013] As optimization, the preparation method of the mixed solution in step (1) is as follows: minoxidil and dialdehyde cellulose solution are uniformly mixed at a mass ratio of 1: (60-70), ultrasonic dispersion is carried out for 5-10 min, and the preparation is obtained.

[0014] As optimization, the mass ratio of the cellulose microspheres, bromohexane and anhydrous ethanol in step (1) is 1: (0.5-0.7): (30-40).

[0015] As optimization, the mass ratio of octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid in step (2) is 1: (0.2-0.4): (0.001-0.002).

[0016] As optimization, the allyl polyether in step (3) is an allyl polyether with a molecular weight of 1000.

[0017] As optimization, the mass ratio of polysiloxane, allyl polyether and chloroplatinic acid in step (3) is 1: (1.3-1.5): (0.00001-0.00003).

[0018] As optimization, the minoxidil mixed solution is packaged by using a press-type foaming bottle.

[0019] Compared with the prior art, the present application has the following beneficial effects:

[0020] In the preparation of the minoxidil mixed solution, the cellulose microspheres are prepared by emulsion method reaction of dialdehyde cellulose, minoxidil and diethylenetriamine; the modified cellulose microspheres are prepared by reaction of the cellulose microspheres, bromohexane and iodomethane; the polysiloxane is prepared by reaction of octamethylcyclotetrasiloxane and tetramethylcyclotetrasiloxane; the modified polysiloxane is prepared by reaction of the polysiloxane, allyl polyether and chloroplatinic acid; and the minoxidil mixed solution is prepared by uniformly mixing the modified polysiloxane, the modified cellulose microspheres and deionized water.

[0021] Firstly, the cellulose microspheres are prepared by emulsion method through reaction of dialdehyde cellulose, minoxidil and diethylene triamine. The cellulose coats minoxidil. Since minoxidil is not soluble in water, it cannot be dissolved and released in the solution environment of deionized water. After the minoxidil mixture is sprayed on the scalp, it can be automatically dissolved and released after contacting the oil secreted by the hair follicle, so that the minoxidil mixture has good liposoluble release performance. Diethylene triamine is used as a crosslinking agent to introduce a secondary amine structure on the cellulose microspheres, and undergoes quaternary ammonium reaction with bromohexane and iodomethane to make the cellulose microspheres have quaternary ammonium salt. On the one hand, the quaternary ammonium salt, as a cationic antibacterial agent, effectively improves the bacteriostatic property of the minoxidil mixture. On the other hand, the quaternary ammonium salt has good hydrophilicity, which effectively improves the dispersibility of minoxidil in deionized water, so that the modified cellulose microspheres coated with minoxidil can be uniformly dispersed in deionized water without using a mixed solution of anhydrous ethanol and propylene glycol as a solvent. The mixed solution of anhydrous ethanol and propylene glycol has great irritation to the scalp. Replacing the solvent with deionized water can effectively reduce the irritation of the minoxidil mixture.

[0022] Secondly, the modified polysiloxane is prepared by reacting polysiloxane with allyl polyether. The polyether segment is a hydrophilic segment, and the siloxane segment is a hydrophobic segment. After the reaction, the hydrophilic-lipophilic property of the modified polysiloxane is improved, so that the modified polysiloxane has good surface activity and the stability of the foam is improved. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0024] The allyl polyether used in the following examples and comparative examples has a molecular weight of 1000.

[0025] Example 1: A preparation method of a minoxidil mixture, comprising the following preparation steps:

[0026] (1) Anhydrous zinc chloride and deionized water were mixed at a mass ratio of 1:125 to prepare a zinc chloride solution; nanocellulose, sodium periodate, and zinc chloride solution were mixed at a mass ratio of 1:1.5:200, the pH was adjusted to 3 with dilute hydrochloric acid, and stirred at 150 r / min for 2 h at 65 °C under light-protected conditions. The mixture was filtered through a 0.45 μm filter membrane, and the solid was washed three times with deionized water and freeze-dried to obtain dialdehyde cellulose; dialdehyde cellulose and deionized water were mixed at a mass ratio of 1:80, the pH was adjusted to 9 with 0.1 mol / L sodium hydroxide solution, and stirred at 350 r / min for 1 h at room temperature to prepare a dialdehyde cellulose solution; minoxidil and dialdehyde cellulose solution were mixed at a mass ratio of 1:60 and ultrasonically dispersed for 5 min to obtain a mixed solution; Span -80, sodium dodecyl sulfate, and paraffin were mixed at a mass ratio of 1:0.8:8. 0.5 times the mass of paraffin was added to the mixture at a rate of 20 ml / min. The mixture was stirred at 300 r / min for 20 min at room temperature. 0.01 times the mass of diethylenetriamine was added, and stirring continued for 1 h. The precipitate was separated by centrifugation. The precipitate was washed three times with petroleum ether and dried at 45 °C for 20 h to obtain cellulose microspheres. Cellulose microspheres, bromohexane, and anhydrous ethanol were mixed at a mass ratio of 1:0.5:30. The mixture was stirred at 200 r / min for 10 h at 75 °C. 0.7 times the mass of bromohexane was added, and stirring continued for 10 h. The precipitate was separated by centrifugation. The precipitate was washed three times with deionized water and dried under vacuum at 75 °C for 10 h to obtain modified cellulose microspheres.

[0027] (2) Mix octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid in a mass ratio of 1:0.2:0.001, stir at 200r / min for 4h at 60℃, cool to room temperature, add sodium bicarbonate to adjust the pH to 7, filter, and the filtrate is polysiloxane.

[0028] (3) Mix polysiloxane, allyl polyether and chloroplatinic acid in a mass ratio of 1:1.3:0.00001, stir at 300 r / min for 2 h at 105 °C, cool to room temperature, filter, and take the filtrate as modified polysiloxane.

[0029] (4) Weigh 1 part of modified cellulose microspheres, 1 part of modified polysiloxane, and 5 parts of deionized water, mix them well, and stir at 500 r / min for 20 min at room temperature to obtain minoxidil mixture.

[0030] Example 2: A method for preparing a minoxidil mixture, comprising the following preparation steps:

[0031] (1) Anhydrous zinc chloride and deionized water were mixed at a mass ratio of 1:125 to prepare a zinc chloride solution; nanocellulose, sodium periodate, and zinc chloride solution were mixed at a mass ratio of 1:1.75:250, the pH was adjusted to 3.5 with dilute hydrochloric acid, and stirred at 70℃ and 200r / min for 2.5h under light-protected conditions, filtered through a 0.45μm filter membrane, and the solid was washed 4 times with deionized water and freeze-dried to obtain dialdehyde cellulose; dialdehyde cellulose and deionized water were mixed at a mass ratio of 1:100, the pH was adjusted to 9 with 0.1mol / L sodium hydroxide solution, and stirred at 400r / min for 1.5h at room temperature to prepare a dialdehyde cellulose solution; minoxidil and dialdehyde cellulose solution were mixed at a mass ratio of 1:65 and ultrasonically dispersed for 7.5min to obtain a mixed solution; S Pan-80, sodium dodecyl sulfate, and paraffin were mixed in a mass ratio of 1:1:10. A 0.6 times mass ratio of the paraffin solution was added at a rate of 20 ml / min. The mixture was stirred at 350 rpm for 25 min at room temperature. Then, 0.015 times the mass ratio of the mixed solution of diethylenetriamine was added, and stirring continued for 1.5 h. The precipitate was separated by centrifugation, washed four times with petroleum ether, and dried at 50 °C for 22 h to obtain cellulose microspheres. Cellulose microspheres, hexane, and anhydrous ethanol were mixed in a mass ratio of 1:0.6:35 and stirred at 250 rpm for 12 h at 80 °C. Then, 0.75 times the mass ratio of the hexane of iodomethane was added, and stirring continued for 12 h. The precipitate was separated by centrifugation, washed four times with deionized water, and dried under vacuum at 80 °C for 12 h to obtain modified cellulose microspheres.

[0032] (2) Mix octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid in a mass ratio of 1:0.3:0.0015, stir at 250 r / min for 5 h at 65 °C, cool to room temperature, add sodium bicarbonate to adjust the pH to 7, filter, and the filtrate is polysiloxane.

[0033] (3) Mix polysiloxane, allyl polyether and chloroplatinic acid in a mass ratio of 1:1.4:0.00002, stir at 350 r / min for 2.5 h at 110 °C, cool to room temperature, filter, and take the filtrate as modified polysiloxane.

[0034] (4) Weigh 1.5 parts of modified cellulose microspheres, 1.5 parts of modified polysiloxane, and 6 parts of deionized water, mix them well, and stir at 550 r / min for 25 min at room temperature to obtain minoxidil mixture.

[0035] Example 3: A method for preparing a minoxidil mixture, comprising the following preparation steps:

[0036] (1) Anhydrous zinc chloride and deionized water were mixed at a mass ratio of 1:125 to prepare a zinc chloride solution; nanocellulose, sodium periodate, and zinc chloride solution were mixed at a mass ratio of 1:2:300, the pH was adjusted to 4 with dilute hydrochloric acid, and stirred at 75°C and 250 r / min for 3 h under light-protected conditions, filtered through a 0.45 μm filter membrane, and the solid was washed 5 times with deionized water and freeze-dried to obtain dialdehyde cellulose; dialdehyde cellulose and deionized water were mixed at a mass ratio of 1:120, the pH was adjusted to 9 with 0.1 mol / L sodium hydroxide solution, and stirred at 450 r / min for 2 h at room temperature to prepare a dialdehyde cellulose solution; minoxidil and dialdehyde cellulose solution were mixed at a mass ratio of 1:70, and ultrasonically dispersed for 10 min to prepare a mixed solution; Span- 80. Sodium dodecyl sulfate and paraffin were mixed at a mass ratio of 1:1.2:12. 0.7 times the mass of paraffin was added to the mixture at a rate of 20 ml / min. The mixture was stirred at 400 r / min for 30 min at room temperature. 0.02 times the mass of diethylenetriamine was added, and stirring continued for 2 h. The precipitate was separated by centrifugation. The precipitate was washed 5 times with petroleum ether and dried at 55 °C for 24 h to obtain cellulose microspheres. Cellulose microspheres, bromohexane, and anhydrous ethanol were mixed at a mass ratio of 1:0.7:40. The mixture was stirred at 300 r / min for 14 h at 85 °C. 0.8 times the mass of bromohexane was added, and stirring continued for 14 h. The precipitate was separated by centrifugation. The precipitate was washed 5 times with deionized water and dried under vacuum at 85 °C for 14 h to obtain modified cellulose microspheres.

[0037] (2) Mix octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid in a mass ratio of 1:0.4:0.002, stir at 300r / min for 6h at 70℃, cool to room temperature, add sodium bicarbonate to adjust the pH to 7, filter, and the filtrate is polysiloxane.

[0038] (3) Mix polysiloxane, allyl polyether and chloroplatinic acid in a mass ratio of 1:1.5:0.00003, stir at 400 r / min for 3 h at 115 °C, cool to room temperature, filter, and take the filtrate as modified polysiloxane.

[0039] (4) Weigh 2 parts of modified cellulose microspheres, 2 parts of modified polysiloxane, and 7 parts of deionized water, mix them well, and stir at 600 r / min for 30 min at room temperature to obtain minoxidil mixture.

[0040] Comparative Example 1:

[0041] The difference between the preparation method of the minoxidil mixture in Comparative Example 1 and Example 2 lies in the different step (1). Step (1) is modified as follows: anhydrous zinc chloride and deionized water are mixed at a mass ratio of 1:125 to obtain a zinc chloride solution; nanocellulose, sodium periodate, and zinc chloride solution are mixed at a mass ratio of 1:1.75:250, the pH is adjusted to 3.5 with dilute hydrochloric acid, and stirred at 70°C and 200 r / min for 2.5 h under light-protected conditions, filtered through a 0.45 μm filter membrane, the solid is washed 4 times with deionized water, and freeze-dried to obtain dialdehyde cellulose; dialdehyde cellulose and deionized water are mixed at a mass ratio of 1:100, and then mixed with 0.1 mol / L sodium hydroxide solution. The pH of the solution was adjusted to 9, and the mixture was stirred at 400 rpm for 1.5 h at room temperature to obtain a dialdehyde cellulose solution. Minoxidil and the dialdehyde cellulose solution were mixed at a mass ratio of 1:65 and ultrasonically dispersed for 7.5 min to obtain a mixed solution. Span-80, sodium dodecyl sulfate, and paraffin were mixed at a mass ratio of 1:1:10. 0.6 times the mass of paraffin in the mixed solution was added at a rate of 20 ml / min, and the mixture was stirred at 350 rpm for 25 min at room temperature. 0.015 times the mass of the mixed solution of diethylenetriamine was added, and stirring continued for 1.5 h. The precipitate was separated by centrifugation, washed four times with petroleum ether, and dried at 50 °C for 22 h to obtain modified cellulose microspheres. The remaining steps were the same as in Example 2.

[0042] Comparative Example 2:

[0043] The preparation method of the minoxidil mixture in Comparative Example 2 differs from that in Example 2 in that step (1) is omitted, and step (4) is modified as follows: deionized water, anhydrous ethanol, and propylene glycol are mixed in a mass ratio of 1:7:2 to obtain a mixed solvent. 1.5 parts of modified cellulose microspheres, 1.5 parts of modified polysiloxane, and 6 parts of the mixed solvent are weighed, mixed, and stirred at 550 r / min for 25 min at room temperature to obtain the minoxidil mixture. The remaining steps are the same as in Example 2.

[0044] Comparative Example 3:

[0045] The preparation method of the minoxidil mixture in Comparative Example 2 differs from that in Example 2 in that steps (2) and (3) are omitted, and step (4) is modified as follows: Weigh 1.5 parts of modified cellulose microspheres, 1.5 parts of sodium lauryl ether sulfate, and 6 parts of deionized water, mix them well, and stir at 550 r / min for 25 min at room temperature to obtain the minoxidil mixture. The remaining steps are the same as in Example 2.

[0046] Test Example 1:

[0047] Lipid-soluble release performance test:

[0048] Control group: 20 ml of the minoxidil mixture prepared in Example 2 was dried at room temperature, the dried solid was dissolved in deionized water, filtered after 1 h, and the cumulative release of minoxidil in deionized water was detected.

[0049] Test group: 20 ml of minoxidil mixtures prepared in each example and comparative example were dried at room temperature. The dried solids were dissolved in glycerol, filtered after 1 hour, and the cumulative release of minoxidil in glycerol was measured. The results are shown in Table 1.

[0050] Table 1

[0051]

[0052] A comparison of the experimental data from Examples 1-3 and the control and comparative examples 1-3 in Table 1 shows that the minoxidil mixture prepared by the present invention has good lipid-soluble release performance.

[0053] Compared with the control group, the minoxidil mixture in Example 2 was prepared using the same method as in Example 2. The difference was that the solid obtained after drying at room temperature in the control group was placed in deionized water instead of glycerin for dissolution and release testing. By comparison, the release amount in Example 2 was greater than that in the control group, indicating that cellulose-coated minoxidil, because minoxidil itself is insoluble in water, will not dissolve and release in a deionized water solution environment. Compared with Comparative Example 2, the minoxidil in Comparative Example 2 was not coated with cellulose microspheres. By comparison, the release amount in Examples 1-3 was greater than that in Comparative Example 2, indicating that the minoxidil mixture can automatically dissolve and release after contact with the sebum secreted by the hair follicles when sprayed onto the scalp, giving the minoxidil mixture good lipid-soluble release performance.

[0054] Test Example 2:

[0055] Antibacterial performance test: The minoxidil mixtures prepared in each example and comparative example were tested for their antibacterial rate against Escherichia coli using the plate count method. The results are shown in Table 2.

[0056] Table 2

[0057]

[0058] A comparison of the experimental data from Examples 1-3 and Comparative Examples 1-3 in Table 2 reveals that the minoxidil mixture prepared in this invention exhibits good antibacterial properties.

[0059] Compared with Example 1, the cellulose microspheres in Comparative Example 1 did not react with bromohexane or iodomethane. By comparison, the antibacterial rates of Examples 1-3 were greater than those of Comparative Example 2, indicating that diethylenetriamine, as a crosslinking agent, introduced a secondary amine structure into the cellulose microspheres, which underwent a quaternization reaction with bromohexane and iodomethane, resulting in quaternary ammonium salts on the cellulose microspheres. As a cationic antibacterial agent, this effectively improved the antibacterial activity of the minoxidil mixture.

[0060] Test Example 3:

[0061] Foam stability test: The minoxidil mixtures prepared in each example and comparative example were foamed using a press-type foaming bottle. Ten pumps of foam were placed in a 100ml graduated cylinder, and the foam was gently shaken to allow it to settle. The 80% liquefaction time of the foam was recorded. The results are shown in Table 3.

[0062] Table 3

[0063]

[0064] A comparison of the experimental data from Examples 1-3 and Comparative Examples 1-3 in Table 3 reveals that the minoxidil mixture prepared in this invention exhibits good foam stability.

[0065] Compared with Example 2, Comparative Example 3 replaced the modified polysiloxane with sodium lauryl ether sulfate. By comparison, the 80% liquefaction time of Examples 1-3 was significantly longer than that of Comparative Example 3, indicating that the modified polysiloxane has better surface activity than sodium lauryl ether sulfate. The modified polysiloxane is prepared by reacting polysiloxane with allyl polyether. The polyether segment is a hydrophilic segment and the siloxane segment is a hydrophobic segment. After the reaction, the hydrophilic and oleophilic properties of the modified polysiloxane are improved, thereby exhibiting good surface activity and improving the stability of the foam.

[0066] Test Example 4:

[0067] Stimulation tests:

[0068] Thirty-two male mice of similar weight were selected, and a 3cm × 3cm area was designated on the backs of each mouse as the experimental area. These 32 male mice were randomly divided into 8 groups of 4 mice each: Examples 1-3, Comparative Examples 1-3, Positive Control Group, and Negative Control Group. The mice in Examples 1-3 and Comparative Examples 1-3 were treated with a mixture of minoxidil prepared in Examples 1-3 and Comparative Examples 1-3, respectively. The positive control group was treated with a mixture of deionized water, anhydrous ethanol, and propylene glycol in a mass ratio of 1:7:2. The negative control group was treated with deionized water. Each mouse received 200 μl of the mixture once daily for 15 consecutive days. The skin condition of the experimental area was observed for adverse reactions such as rash, desquamation, and redness. The results are shown in Table 4.

[0069] Table 4

[0070]

[0071] A comparison of the experimental data from Examples 1-3, Comparative Examples 1-3, Positive Control Group, and Negative Control Group in Table 4 reveals that the minoxidil mixture prepared in this invention has low irritation.

[0072] Compared with Example 2, the solvent in Comparative Example 2 was changed from deionized water to a mixed solvent prepared by mixing deionized water, anhydrous ethanol, and propylene glycol in a mass ratio of 1:7:2. By comparison, the adverse reactions in Examples 1-3 were significantly better than those in Comparative Example 2. This indicates that the reaction of dialdehyde cellulose with diethylenetriamine to coat minoxidil, followed by quaternization modification with hexane and iodomethane, effectively improves the dispersibility of minoxidil in deionized water, enabling minoxidil to be uniformly dispersed in deionized water. This eliminates the need to use a mixed solution of anhydrous ethanol and propylene glycol as a solvent, as the mixed solution of anhydrous ethanol and propylene glycol has a high degree of irritation to the scalp. Replacing the solvent with deionized water can effectively reduce the irritation of the minoxidil mixture.

[0073] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A minoxidil mixed solution agent, characterized by, The minoxidil mixed solution is prepared by mixing modified cellulose microspheres, modified polysiloxane and deionized water and stirring; The modified cellulose microspheres are prepared by reacting dialdehyde cellulose, minoxidil and diethylene triamine by emulsion method to obtain cellulose microspheres, and by reacting the cellulose microspheres, bromohexane and iodomethane. The modified polysiloxane is prepared by reacting octamethylcyclotetrasiloxane and tetramethylcyclotetrasiloxane to obtain polysiloxane, and by reacting the polysiloxane, allyl polyether and chloroplatinic acid.

2. A method for preparing a minoxidil mixed solution, characterized by, The preparation comprises the following steps: (1) Mix dialdehyde cellulose and deionized water according to a mass ratio of 1: (80-120), adjust the pH to 9 with 0.1 mol / L sodium hydroxide solution, stir at room temperature at 350-450 r / min for 1-2 h to obtain a dialdehyde cellulose solution; mix Span-80, sodium dodecyl sulfate and paraffin according to a mass ratio of 1: (0.8-1.2): (8-12), add the mixed solution with a mass of 0.5-0.7 times of paraffin at a rate of 20 ml / min, stir at room temperature at 300-400 r / min for 20-30 min, add diethylene triamine with a mass of 0.01-0.02 times of the mixed solution, continue to stir for 1-2 h, centrifugally separate the precipitate, wash the precipitate with petroleum ether for 3-5 times, dry at 45-55℃ for 20-24 h to obtain cellulose microspheres; mix the cellulose microspheres, bromohexane and anhydrous ethanol, stir at 75-85℃ at 200-300 r / min for 10-14 h, add iodomethane with a mass of 0.7-0.8 times of bromohexane, continue to stir for 10-14 h, centrifugally separate the precipitate, wash the precipitate with deionized water for 3-5 times, dry at 75-85℃ under vacuum for 10-14 h to obtain modified cellulose microspheres; (2) Mix octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid, stir at 60-70℃ at 200-300 r / min for 4-6 h, cool to room temperature, add sodium bicarbonate to adjust the pH to 7, filter, and take the filtrate as polysiloxane; (3) Mix polysiloxane, allyl polyether and chloroplatinic acid, stir at 105-115℃ at 300-400 r / min for 2-3 h, cool to room temperature, filter, and take the filtrate as modified polysiloxane; (4) Take 1-2 parts of modified cellulose microspheres, 1-2 parts of modified polysiloxane and 5-7 parts of deionized water, mix, stir at room temperature at 500-600 r / min for 20-30 min to obtain a minoxidil mixed solution.

3. The method for preparing a minoxidil mixture according to claim 2, characterized in that, In step (1), the dialdehyde cellulose is prepared by mixing anhydrous zinc chloride and deionized water according to a mass ratio of 1:125 to obtain a zinc chloride solution, mixing nanocellulose, sodium periodate and the zinc chloride solution according to a mass ratio of 1: (1.5-2): (200-300), adjusting the pH to 3-4 with dilute hydrochloric acid, stirring at 65-75℃ at 150-250 r / min for 2-3 h in the dark, filtering with a filter membrane with a pore size of 0.45 μm, washing the solid with deionized water for 3-5 times, and freeze-drying.

4. The method for preparing a minoxidil mixture according to claim 2, characterized in that, The preparation method of the mixed solution in step (1) is as follows: uniformly mixing minoxidil and a dialdehyde cellulose solution at a mass ratio of 1:(60-70), and ultrasonic dispersion for 5-10 min to obtain the mixed solution.

5. The method for preparing a minoxidil mixture according to claim 2, characterized in that, The mass ratio of the cellulose microspheres, bromohexane and anhydrous ethanol in step (1) is 1:(0.5-0.7):(30-40).

6. The method for preparing a minoxidil mixture according to claim 2, characterized in that, The mass ratio of octamethylcyclotetrasiloxane, tetramethylcyclotetrasiloxane and concentrated sulfuric acid in step (2) is 1:(0.2-0.4):(0.001-0.002).

7. The method for preparing a minoxidil mixture according to claim 2, characterized in that, The allyl polyether in step (3) is an allyl polyether with a molecular weight of 1000.

8. The method for preparing a minoxidil mixture according to claim 2, characterized in that, The mass ratio of polysiloxane, allyl polyether and chloroplatinic acid in step (3) is 1:(1.3-1.5):(0.00001-0.00003).

9. The minoxidil mixture agent according to claim any one of claims 2 to 8, wherein the minoxidil mixture agent is prepared by the preparation method of the minoxidil mixture agent. The minoxidil mixed solution is packaged by using a press-type foaming bottle.

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