Minoxidil external solution and one-pot preparation method thereof

Abstract

The invention discloses a minoxidil topical solution and a one-pot preparation method thereof, and belongs to the technical field of pharmaceutical solutions. The method for preparing a minoxidil topical solution in a one-pot method in the present invention comprises the following steps: mixing minoxidil, a low eutectic solvent, sesamol, sodium alginate and water in a mass ratio of 2-8:5-15:1-5:1-5:100 at 20-40°C and 100-1000rpm to obtain a minoxidil topical solution; wherein the low eutectic solvent is citric acid and panthenol in a molar ratio of 1-2:1-2 at 75-85°C and heated and stirred for 1-3h, and cooled to obtain the minoxidil topical solution prepared by the present invention. The raw materials used in the minoxidil topical solution prepared by the present invention are few, the concentration is low, and the minoxidil topical solution has stable storage under high temperature environment, maintains drug efficacy, and can well alleviate the side effects such as skin itching, allergy, and redness and swelling when the patient takes the medicine.

Description

Technical Field

[0001] The invention relates to a minoxidil external solution and a one-pot preparation method thereof, belonging to the technical field of medical solutions. Background Art

[0002] Minoxidil is a drug that promotes hair growth. It was originally used as a drug for the treatment of hypertension and was later approved by the FDA for the treatment of seborrheic alopecia and alopecia areata. Minoxidil solution is unstable and is prone to oxidation and discoloration during storage and use.

[0003] At present, there are some related literatures that use some methods to improve the problems of easy oxidation and discoloration; for example:

[0004] CN1280507A discloses that discoloration during storage can be prevented by adding amino acids, especially taurine;

[0005] CN109431996A discloses that the problem of solution discoloration can be improved by adding phosphate buffer to the solution, but does not explain the mechanism of solution discoloration. Adding phosphate buffer only stabilizes the pH of the solution and alleviates the instability of the solution caused by pH change. Simply adding phosphate buffer cannot solve the problem of discoloration of the drug solution due to oxidation and the increase of related substances.

[0006] CN 115531304A discloses that the addition of antioxidants and metal ion chelators can prevent the liquid preparation containing minoxidil from oxidative discoloration during storage and use, and keep the related substances at a low level.

[0007] However, these methods have many ingredients and are complicated to operate, and there are still oxidation and discoloration phenomena during storage and use, especially at high temperatures for a long time.

[0008] Moreover, during the use of minoxidil topical solution, the user needs to open the bottle cap every morning and evening to take out the solution for application, which greatly increases the frequency and time of the solution's contact with air, accelerates the solution's oxidation reaction, and makes the solution less stable and discolored.

[0009] In addition, the preparation of minoxidil topical solution involves a filtration operation, which causes the filter membrane to adsorb more or less active ingredients in the solution, thereby reducing the content of the active ingredients and increasing the time of further contact with air. Summary of the invention

[0010] To solve the above problems, the present invention provides a minoxidil topical solution and a one-pot preparation method thereof. Specifically, the present invention selects panthenol and citric acid to form a low eutectic solvent, which increases the solubility of minoxidil; and adds sesamol and sodium alginate, both of which can improve the antioxidant properties of the minoxidil solution; at the same time, citric acid also helps to improve the antioxidant effect of sesamol and sodium alginate, and can also play its own chelating effect; in addition, panthenol is beneficial to improve its inflammation, allergy and other problems. The minoxidil topical solution of the present invention has good stability under high temperature environment, and the preparation method is a one-pot preparation, which is simpler to operate and more suitable for industrial use.

[0011] The first object of the present invention is to provide a minoxidil topical solution, which is composed of minoxidil, a deep eutectic solvent, sesamol, sodium alginate and water;

[0012] The deep eutectic solvent is composed of panthenol and citric acid, and the molar ratio of panthenol to citric acid is 1-2:1-2;

[0013] The mass ratio of minoxidil, deep eutectic solvent, sesamol, sodium alginate and water is 2-8:5-15:1-5:1-5:100;

[0014] The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

[0015] A second object of the present invention is to provide a method for preparing a minoxidil topical solution by a one-pot process, comprising the steps of:

[0016] Mix minoxidil, a low eutectic solvent, sesamol, sodium alginate and water in a mass ratio of 2-8:5-15:1-5:1-5:100 at 20-40° C. and 100-1000 rpm to obtain a minoxidil topical solution;

[0017] The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

[0018] The third object of the present invention is to provide the use of the minoxidil topical solution of the present invention in the preparation of hair growth medicines.

[0019] The fourth object of the present invention is to provide a medicine, which contains the minoxidil external solution of the present invention.

[0020] A fifth object of the present invention is to provide a method for improving the oxidation and discoloration properties of a minoxidil topical solution, comprising the steps of:

[0021] Mix minoxidil, a low eutectic solvent, sesamol, sodium alginate and water in a mass ratio of 2-8:5-15:1-5:1-5:100 at 20-40° C. and 100-1000 rpm to obtain a minoxidil topical solution;

[0022] The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

[0023] The beneficial effects of the present invention are as follows:

[0024] The present invention prepares a minoxidil topical solution based on a low eutectic solvent (panthenol-citric acid). The minoxidil topical solution prepared by the present invention uses less raw materials and has a low concentration, is stable in storage under different environments, maintains drug efficacy, and can well alleviate side effects such as skin itching, allergies, and redness and swelling when patients take the medicine.

[0025] Specific:

[0026] (1) The minoxidil topical solution of the present invention was stored at 60° C. for 24 months (opened for 15 min each in the morning and evening), and the solution was clear, did not change color, and had no precipitation.

[0027] (2) The present invention can effectively alleviate the side effects such as skin itching, allergy, redness and swelling when patients take the medicine.

[0028] (3) The present invention selects panthenol and citric acid to form a low eutectic solvent, which increases the solubility of minoxidil and simplifies its preparation process.

[0029] (4) The present invention adds sesamol and sodium alginate, both of which can enhance the antioxidant properties of the minoxidil solution; at the same time, citric acid also helps to enhance the antioxidant effects of sesamol and sodium alginate, and can also exert its own chelating effect; further improving the storage stability of the minoxidil topical solution under different environments.

[0030] (5) The present invention can realize the one-pot method for preparing minoxidil topical solution, which is simple to operate, more suitable for industrial use, and has broad application prospects. DETAILED DESCRIPTION

[0031] The preferred embodiments of the present invention are described below. It should be understood that the embodiments are for better explaining the present invention and are not used to limit the present invention.

[0032] The raw materials used in the embodiment:

[0033] Minoxidil: CAS: 38304-91-5, 99%;

[0034] Citric acid: anhydrous citric acid, CAS: 77-92-9, 99.5%;

[0035] Panthenol: D-panthenol, CAS: 81-13-0, 98%;

[0036] Sesamol: CAS: 533-31-3, 98%;

[0037] Sodium alginate: CAS: 9005-38-3, 98%;

[0038] The above raw materials are all pharmaceutical agents.

[0039] Example 1

[0040] A method for preparing a minoxidil topical solution in one pot comprises the following steps:

[0041] 6 g of minoxidil, 10 g of a deep eutectic solvent, 3 g of sesamol, 3 g of sodium alginate and 100 g of water were stirred and mixed at 25° C. and 500 rpm to obtain a minoxidil topical solution;

[0042] The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1:1 at 80° C. and 500 rpm for 2 hours, and then cooling.

[0043] Example 2

[0044] The amount of minoxidil in Example 1 was adjusted to 3 g; the rest was kept consistent with Example 1 to obtain a minoxidil topical solution.

[0045] Example 3

[0046] The amount of sesamol in Example 1 was adjusted to 4 g, and the amount of sodium alginate was adjusted to 1 g; the other ingredients were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0047] Example 4

[0048] The amount of sesamol in Example 1 was adjusted to 1 g, and the amount of sodium alginate was adjusted to 4 g; the other ingredients were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0049] Comparative Example 1

[0050] The sesamol in Example 1 was omitted, the amount of sodium alginate was adjusted to 6 g, and the other contents were kept the same as in Example 1 to obtain a minoxidil topical solution.

[0051] Comparative Example 2

[0052] The sodium alginate in Example 1 was omitted, the amount of sesamol was adjusted to 6 g, and the other ingredients were kept consistent with Example 1 to obtain a minoxidil external solution.

[0053] Comparative Example 3

[0054] The panthenol in Example 1 was adjusted to choline chloride, and the other parts were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0055] Comparative Example 4

[0056] The citric acid in Example 1 was adjusted to lactic acid, and the other aspects were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0057] Comparative Example 5

[0058] The sodium alginate in Example 1 was adjusted to chitosan (commercially available, CAS: 9012-76-4, deacetylation degree 95%), and the other ingredients were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0059] Comparative Example 6

[0060] The sesamol in Example 1 was adjusted to paeonol (commercially available, CAS: 552-41-0, 98%), and the other ingredients were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0061] Comparative Example 7

[0062] The sodium alginate in Example 1 was adjusted to guar gum (commercially available), and the other contents were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0063] Comparative Example 8

[0064] The sesamol in Example 1 was adjusted to tea polyphenols (commercially available, CAS: 84650-60-2, 98%), and the other contents were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0065] Comparative Example 9

[0066] The sesamol in Example 1 was adjusted to quercetin (CAS: 117-39-5, 97%), and the other ingredients were kept consistent with Example 1 to obtain a minoxidil topical solution.

[0067] The minoxidil external-use solutions prepared in Examples 1-4 and Comparative Examples 1-9 were taken to test their properties.

[0068] (1) The minoxidil topical solutions prepared in Examples 1-4 and Comparative Examples 1-9 were sealed in spray bottles (glass) and kept in the dark at a temperature of 60° C. and a humidity of 50% for 24 months (opened for 15 min each in the morning and evening). The bottles were observed every 3 months for any discoloration or precipitation.

[0069] The results are shown in Table 1.

[0070] Table 1 Storage stability

[0071]

[0072] The results showed that the minoxidil topical solutions prepared in Examples 1-4 had good stability when placed in the dark for 24 months at a temperature of 60° C. and a humidity of 50%. However, the stability of Comparative Examples 1-9 was only 12 months at most, and all of them had problems such as discoloration and precipitation.

[0073] (2) The minoxidil topical solutions prepared in Examples 1-4 and Comparative Examples 1-9 were sealed in spray bottles (glass) and kept in the dark at a temperature of 60° C. and a humidity of 50% for 24 months (opened for 15 min each in the morning and evening). Samples were taken every 3 months and related substances were detected by high performance liquid chromatography.

[0074] The results are shown in Tables 2 and 3.

[0075] Table 2 Total impurity content during storage (%) (those below 0.01% are counted as 0)

[0076] example 0 months 3 months 6 months 9 months 12 months 24 months Example 1 0 0 0 0 0.02 0.06 Example 2 0 0 0 0 0.01 0.04 Example 3 0 0 0 0.02 0.05 0.10 Example 4 0 0 0 0.03 0.06 0.13 Comparative Example 1 0 0 0.03 0.09 0.14 0.23 Comparative Example 2 0 0 0.01 0.04 0.08 0.15 Comparative Example 3 0 0 0.01 0.06 0.12 0.17 Comparative Example 4 0 0 0.02 0.05 0.15 0.22 Comparative Example 5 0 0 0.01 0.03 0.11 0.16 Comparative Example 6 0 0 0.01 0.04 0.09 0.18 Comparative Example 7 0 0 0.04 0.10 0.20 0.32 Comparative Example 8 0 0 0.05 0.14 0.21 0.37 Comparative Example 9 0 0 0.04 0.14 0.19 0.42

[0077] Table 3 Number of single impurities in storage (pieces)

[0078] example 0 months 3 months 6 months 9 months 12 months 24 months Example 1 0 0 0 1 3 3 Example 2 0 0 0 0 2 5 Example 3 0 0 0 4 6 10 Example 4 0 0 0 3 6 12 Comparative Example 1 0 0 8 10 33 44 Comparative Example 2 0 0 7 15 28 34 Comparative Example 3 0 0 5 11 19 25 Comparative Example 4 0 0 4 10 16 21 Comparative Example 5 0 0 7 12 20 41 Comparative Example 6 0 0 8 14 24 35 Comparative Example 7 0 5 12 23 38 69 Comparative Example 8 0 8 17 26 35 52 Comparative Example 9 0 9 19 29 41 58

[0079] The results show that the minoxidil topical solutions prepared in Examples 1-4 have good stability and few impurities when placed in the dark for 24 months at a temperature of 60° C. and a humidity of 50%. However, the stability of Comparative Examples 1-9 was poor, and impurities appeared at most in 6 months.

[0080] (3) In vitro skin permeability test of minoxidil topical solution

[0081] The in vitro skin permeability of minoxidil topical solution was tested as follows:

[0082] A vertical Franz transdermal diffusion cell (effective area 1.13 cm 2 , volume 15mL), fix the mouse skin (mouse abdominal skin) after drug application between the dosing chamber and the receiving pool of the diffusion cell, and keep the dermis side (the mouse skin has two sides, the upper side is the epidermis, that is, the dosing side, and the lower side is the dermis) in close contact with the receiving solution (glacial acetic acid), exhaust all bubbles, place it in the intelligent transdermal absorption instrument, keep it warm and balanced for 10 minutes, then turn on the magnetic stirrer (300rpm), maintain a constant speed and temperature (37℃), and permeate for 16 hours. Take 1mL of sample solution at regular intervals, filter it with a 0.45μm microporous filter membrane to obtain the permeate, and detect the minoxidil concentration in the permeate by liquid phase.

[0083] Cumulative permeability = minoxidil concentration in permeate / minoxidil concentration in dosing chamber × 100%

[0084] The results are shown in Table 4.

[0085] Table 4 Transmittance (%)

[0086] example 0.5h 1h 2h 4h 6h 8h 12h 16h Example 1 5.1 7.3 10.8 13.9 15.6 18.7 20.1 21.3 Example 2 4.9 6.8 10.0 13.1 14.2 15.2 18.7 19.8 Example 3 4.2 6.6 8.9 11.5 12.1 13.5 15.2 16.5 Example 4 4.2 7.0 8.2 10.2 11.8 12.1 15.7 17.2 Comparative Example 1 0.5 1.4 2.2 2.7 3.2 3.5 3.8 4.1 Comparative Example 2 0.5 1.5 1.9 2.4 2.7 3.0 3.1 3.3 Comparative Example 3 0.4 1.2 1.8 2.3 2.9 3.5 4.3 4.7 Comparative Example 4 0.5 1.8 2.4 3.1 3.5 3.7 4.4 4.9 Comparative Example 5 0.4 0.9 1.6 2.3 2.7 3.1 3.9 4.4 Comparative Example 6 0.4 0.8 1.6 2.3 2.6 3.0 3.9 4.3 Comparative Example 7 0.6 1.4 2.3 3.2 3.9 4.1 4.6 5.1 Comparative Example 8 0.3 0.9 1.5 1.9 2.4 2.9 3.4 3.8 Comparative Example 9 0.4 1.1 1.7 2.1 2.8 3.0 3.6 4.0

[0087] It can be seen from Table 4 that the transmittance of Example 1-4 is relatively high within 16 hours, reaching more than 16.5%, and its effect is much higher than that of Comparative Example 1-9, that is, it has better efficacy.

[0088] Although the present invention has been disclosed as above in the form of a preferred embodiment, it is not intended to limit the present invention. Anyone familiar with this technology can make various changes and modifications without departing from the spirit and scope of the present invention. Therefore, the scope of protection of the present invention should be based on the definition of the claims.

Claims

1. A minoxidil topical solution, characterized in that: The minoxidil topical solution is composed of minoxidil, a low eutectic solvent, sesamol, sodium alginate and water; The low eutectic solvent is composed of panthenol and citric acid; the molar ratio of panthenol to citric acid is 1-2:1-2; The mass ratio of minoxidil, low eutectic solvent, sesamol, sodium alginate and water is 2-8:5-15:1-5:1-5:

100.

2. The minoxidil topical solution according to claim 1, characterized in that The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

3. A one-pot method for preparing the minoxidil topical solution according to claim 1 or 2, characterized in that: The steps include: Mix minoxidil, a low eutectic solvent, sesamol, sodium alginate and water in a mass ratio of 2-8:5-15:1-5:1-5:100 at 20-40° C. and 100-1000 rpm to obtain a minoxidil topical solution; The low eutectic solvent consists of panthenol and citric acid; the molar ratio of panthenol to citric acid is 1-2:1-2.

4. The method according to claim 3, characterized in that The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

5. Use of the minoxidil external solution according to claim 1 or 2 in the preparation of hair growth medicines.

6. A medicine, characterized in that: The medicine contains the minoxidil external solution according to claim 1 or 2.

7. A method for improving the oxidation and discoloration properties of minoxidil topical solution, characterized in that: The steps include: Mix minoxidil, a low eutectic solvent, sesamol, sodium alginate and water in a mass ratio of 2-8:5-15:1-5:1-5:100 at 20-40° C. and 100-1000 rpm to obtain a minoxidil topical solution; The low eutectic solvent consists of panthenol and citric acid; the molar ratio of panthenol to citric acid is 1-2:1-2.

8. The method according to claim 7, characterized in that The low eutectic solvent is prepared by heating and stirring citric acid and panthenol at a molar ratio of 1-2:1-2 at 75-85° C. for 1-3 hours, and then cooling.

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