A formulation containing minoxidil and process thereof
The hydrogel formulation made by combining minoxidil microcapsules with hyaluronic acid and L-lysine solves the problems of low drug utilization and temperature sensitivity of minoxidil formulations during application, achieving sustained release and enhanced stability for therapeutic effects.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- CHINA PHARM UNIV PHARM CO LTD
- Filing Date
- 2023-12-20
- Publication Date
- 2026-07-24
Smart Images
Figure BDA0004617729110000061
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical formulation technology, specifically to a formulation containing minoxidil and its manufacturing process. Background Technology
[0002] Currently, commercially available minoxidil formulations for treating hair loss can be categorized into solutions, foams, and gels based on their dosage form. Solutions are prone to flow, making application inconvenient and difficult to maintain at the application site, resulting in incomplete absorption of the active ingredient and reduced drug utilization. While foams are easy to apply, they are temperature-sensitive; excessively high temperatures will cause them to liquefy, affecting their effectiveness. Furthermore, foams are flammable and explosive, making them inconvenient to carry. Gels are easy to apply and can remain on the affected area, but due to minoxidil's poor solubility, gels often fail to achieve effective drug concentrations, impacting absorption and therapeutic efficacy. Developing new minoxidil formulations is of great significance for hair loss treatment.
[0003] Therefore, this invention studies and prepares a formulation containing minoxidil, which has a sustained-release effect and uses a hydrogel as a carrier to achieve better therapeutic effects. Summary of the Invention
[0004] The purpose of this invention is to provide a formulation containing minoxidil and its process to solve the problems mentioned in the background art.
[0005] To solve the above-mentioned technical problems, the present invention provides the following technical solution: a formulation containing minoxidil, wherein the formulation containing minoxidil is a hydrogel formulation prepared by minoxidil microcapsules with hyaluronic acid and L-lysine.
[0006] Preferably, the minoxidil microcapsules are prepared by combining polysalicylic acid, minoxidil and β-cyclodextrin.
[0007] Preferably, the polysalicylic acid is obtained by ring-opening polymerization of salicylic acid anhydride.
[0008] Preferably, the preparation process of the formulation containing minoxidil includes the following specific steps:
[0009] (1) Mix crude salicylic acid anhydride with tetrahydrofuran at a mass ratio of 1:1.5-3 and stir to dissolve to obtain salicylic acid anhydride solution; mix diethyl ether and n-hexane in equal volumes to obtain diethyl ether solution; add the salicylic acid anhydride solution dropwise to a diethyl ether solution with a mass of 3-5 times that of the salicylic acid anhydride solution at a rate of 1-3 mL / min, cool to -18--20℃, let stand for 10-12 h, filter and wash with diethyl ether 3-5 times, and dry to obtain salicylic acid anhydride.
[0010] (2) Polysalicylic acid was prepared by polymerizing salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran at room temperature for 3-5 min and then rotary evaporating.
[0011] (3) Mix polysalicylic acid, minoxidil and ethanol in a mass ratio of 1:1:8-10, place them in a homogenizer and emulsify them at 8000-10000 rpm and 45-55℃, add them to 10-20 times the mass of polysalicylic acid in a 20-30% β-cyclodextrin aqueous solution, stir evenly, and spray dry to obtain minoxidil microcapsules;
[0012] (4) Hyaluronic acid, L-lysine and deionized water are mixed in a mass ratio of 10:0.5~2:80~100 and stirred at 2000~4000rpm for 30~50min. Minoxidil microcapsules are added and stirred evenly. The pH is adjusted to 7~8 with triethylamine to obtain a preparation containing minoxidil.
[0013] Preferably, in step (1) above, the preparation method of crude salicylic acid intracyclic anhydride is as follows: triphosgene, activated carbon and diethyl ether are mixed in a mass ratio of 1.5 to 1.8:30:30 and placed in an ice-cold ethanol bath at -18 to -20°C. A salicylic acid diethyl ether solution with a mass fraction of 8 to 8 times the mass of triphosgene is added dropwise at a rate of 1 to 3 mL / min. After reacting for 2 to 3 hours, a triethylamine diethyl ether solution with a mass fraction of 2 to 4% is added dropwise at a rate of 10 to 15 times the mass of triphosgene. The mixture is then transferred to room temperature and reacted for 2 to 3 hours. An equal volume of ethyl acetate is added, and the mixture is stirred evenly, filtered, and rotary evaporated to obtain crude salicylic acid intracyclic anhydride.
[0014] Preferably, in step (2) above, the mass ratio of salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran is 30-50:0.1:0.1:5-8.
[0015] Preferably, in step (3) above: during spray drying, the inlet temperature is 150-170℃ and the feed rate is 4-8 mL / min.
[0016] Preferably, in step (4) above, the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.2 to 1.5:1.
[0017] Compared with the prior art, the beneficial effects achieved by the present invention are:
[0018] The formulation containing minoxidil prepared in this invention is a hydrogel formulation made from minoxidil microcapsules, hyaluronic acid, and L-lysine.
[0019] Minoxidil microcapsules are made from a complex of polysalicylic acid and minoxidil. Polysalicylic acid is obtained by ring-opening polymerization of salicylic acid anhydride. Polysalicylic acid with a high degree of polymerization, when combined with minoxidil and then coated with β-cyclodextrin, produces minoxidil microcapsules. This allows high-concentration minoxidil formulations to have a sustained-release effect, preventing skin damage caused by excessively high concentrations of minoxidil and achieving a continuous effect. The minoxidil microcapsules are then combined with hyaluronic acid and L-lysine to form a hydrogel formulation. This not only uniformly disperses minoxidil in the formulation but also enhances its efficacy. The carboxyl groups on hyaluronic acid and L-lysine form hydrogen bonds with the hydroxyl groups on the surface of the minoxidil microcapsules, forming a hydrogel formulation with a three-dimensional cross-linked structure, which enhances storage stability. Detailed Implementation
[0020] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.
[0021] To more clearly illustrate the method provided by the present invention, the following examples are provided for detailed description. The test methods for various indicators of the minoxidil-containing formulations prepared in the examples and comparative examples are as follows:
[0022] Sustained effect: The duration of sustained release in vivo was tested for the minoxidil-containing formulations prepared in the examples and comparative examples according to the pharmacopoeia testing standards.
[0023] Storage stability: After the minoxidil-containing formulations prepared in the examples and comparative examples were placed under the same ambient light for one week, the continuous effect was tested again.
[0024] Hair follicle regeneration: Eighteen male Kunming mice were selected, anesthetized with ether, and their backs were shaved and then waxed. The mice were randomly divided into three groups: blank group, control group, and experimental group. The blank group was not coated, the control group was coated with commercially available minoxidil gel, and the experimental group was coated with the minoxidil-containing preparations prepared in the examples and comparative examples. The drugs were administered twice a day for three consecutive weeks, and the ability to clearly distinguish the shaved areas on the back was observed and recorded.
[0025] Example 1
[0026] (1) Mix triphosgene, activated carbon, and diethyl ether in a mass ratio of 1.5:30:30 and place in an ice-ethanol bath at -18℃. Add 8% salicylic acid diethyl ether solution at a mass ratio of 6 times that of triphosgene at a rate of 1 mL / min. After reacting for 2 h, add 2% triethylamine diethyl ether solution at a mass ratio of 10 times that of triphosgene at a rate of 1 mL / min. Transfer to room temperature and react for 2 h. Add an equal volume of ethyl acetate to the diethyl ether solution, stir well, filter, and rotary evaporate. A crude salicylic acid anhydride was prepared. The crude salicylic acid anhydride was mixed with tetrahydrofuran at a mass ratio of 1:1.5 and stirred to dissolve, thus obtaining a salicylic acid anhydride solution. Diethyl ether and n-hexane were mixed in equal volumes to prepare an ether solution. The salicylic acid anhydride solution was added dropwise to an ether solution with a mass of 3 times that of the salicylic acid anhydride solution at a rate of 1 mL / min. The mixture was cooled to -18℃, allowed to stand for 10 h, filtered, washed 3 times with ether, and dried under vacuum to obtain the salicylic acid anhydride.
[0027] (2) The salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran were mixed in a mass ratio of 30:0.1:0.1:5 and polymerized at room temperature for 3 min. The mixture was then rotary evaporated to obtain polysalicylic acid.
[0028] (3) Polysalicylic acid, minoxidil and ethanol were mixed in a mass ratio of 1:1:8 and placed in a homogenizer. The mixture was homogenized and emulsified at 8000 rpm and 45°C. The mixture was then added to a 20% β-cyclodextrin aqueous solution, which was 10 times the mass of polysalicylic acid. The mixture was stirred evenly and then spray-dried at an inlet temperature of 150°C and a feed rate of 4 mL / min to obtain minoxidil microcapsules.
[0029] (4) Hyaluronic acid, L-lysine and deionized water are mixed in a mass ratio of 10:0.5:80 and stirred at 2000 rpm for 30 min. Minoxidil microcapsules are added, and the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.2:1. The mixture is stirred evenly and the pH is adjusted to 7 with triethylamine to obtain a preparation containing minoxidil.
[0030] Example 2
[0031] (1) Triphosgene, activated carbon, and diethyl ether were mixed in a mass ratio of 1.65:30:30 and placed in an ice-cold ethanol bath at -19℃. A 9% salicylic acid diethyl ether solution, seven times the mass of triphosgene, was added dropwise at a rate of 2 mL / min. After reacting for 2.5 h, a 3% triethylamine diethyl ether solution, thirteen times the mass of triphosgene, was added dropwise at a rate of 2 mL / min. The mixture was then transferred to room temperature and reacted for another 2.5 h. An equal volume of ethyl acetate was added, and the mixture was stirred until homogeneous before filtration. Rotary evaporation was used to obtain crude salicylic acid anhydride; the crude salicylic acid anhydride was mixed with tetrahydrofuran at a mass ratio of 1:2.25 and stirred to dissolve, thus obtaining a salicylic acid anhydride solution; diethyl ether and n-hexane were mixed in equal volumes to obtain an ether solution; the salicylic acid anhydride solution was added dropwise to an ether solution with a mass of 4 times that of the salicylic acid anhydride solution at a rate of 2 mL / min, cooled to -19℃, allowed to stand for 11 h, filtered, washed 4 times with diethyl ether, and dried under vacuum to obtain salicylic acid anhydride;
[0032] (2) The salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran were mixed in a mass ratio of 40:0.1:0.1:6.5 and polymerized at room temperature for 4 min. The mixture was then rotary evaporated to obtain polysalicylic acid.
[0033] (3) Polysalicylic acid, minoxidil and ethanol were mixed in a mass ratio of 1:1:9 and placed in a homogenizer. The mixture was homogenized and emulsified at 9000 rpm and 50°C. The mixture was then added to a β-cyclodextrin aqueous solution with a mass fraction of 25% at 15 times the mass of polysalicylic acid. The mixture was stirred evenly and then spray-dried at an inlet temperature of 160°C and a feed rate of 6 mL / min to obtain minoxidil microcapsules.
[0034] (4) Hyaluronic acid, L-lysine and deionized water are mixed in a mass ratio of 10:1.4:90 and stirred at 3000 rpm for 40 min. Minoxidil microcapsules are added, and the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.35:1. The mixture is stirred evenly and the pH is adjusted to 7.5 with triethylamine to obtain a preparation containing minoxidil.
[0035] Example 3
[0036] (1) Triphosgene, activated carbon, and diethyl ether were mixed in a mass ratio of 1.8:30:30 and placed in an ice-cold ethanol bath at -20°C. A 10% salicylic acid diethyl ether solution, with a mass ratio of 8 times that of triphosgene, was added dropwise at a rate of 3 mL / min. After reacting for 3 h, a 4% triethylamine diethyl ether solution, with a mass ratio of 15 times that of triphosgene, was added dropwise at a rate of 3 mL / min. The mixture was then transferred to room temperature and reacted for 3 h. An equal volume of ethyl acetate was added, and the mixture was stirred until homogeneous. The mixture was then filtered and vortexed. The crude salicylic acid anhydride was obtained by steaming. The crude salicylic acid anhydride was mixed with tetrahydrofuran at a mass ratio of 1:3 and stirred to dissolve, thus obtaining a salicylic acid anhydride solution. Diethyl ether and n-hexane were mixed in equal volumes to obtain an ether solution. The salicylic acid anhydride solution was added dropwise to an ether solution with a mass of 5 times that of the salicylic acid anhydride solution at a rate of 3 mL / min. The mixture was cooled to -20℃, allowed to stand for 12 h, filtered, washed 5 times with ether, and dried under vacuum to obtain the salicylic acid anhydride.
[0037] (2) The salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran were mixed in a mass ratio of 50:0.1:0.1:8 and polymerized at room temperature for 5 min. The mixture was then rotary evaporated to obtain polysalicylic acid.
[0038] (3) Polysalicylic acid, minoxidil and ethanol were mixed in a mass ratio of 1:1:10 and placed in a homogenizer. The mixture was homogenized and emulsified at 10,000 rpm and 55°C. The mixture was then added to a β-cyclodextrin aqueous solution with a mass fraction of 30% at 20 times the mass of polysalicylic acid. The mixture was stirred evenly and then spray-dried at an inlet temperature of 170°C and a feed rate of 8 mL / min to obtain minoxidil microcapsules.
[0039] (4) Hyaluronic acid, L-lysine and deionized water are mixed in a mass ratio of 10:2:100 and stirred at 4000 rpm for 50 min. Minoxidil microcapsules are added, and the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.5:1. The mixture is stirred evenly and the pH is adjusted to 8 with triethylamine to obtain a preparation containing minoxidil.
[0040] Comparative Example 1
[0041] The composition of Comparative Example 1 is the same as that of Example 2. The difference between the preparation process of this minoxidil-containing formulation and Example 2 is that step (2) is omitted, and step (3) is modified as follows: the salicylic acid cyclic anhydride, minoxidil and ethanol are mixed in a mass ratio of 1:1:10, placed in a homogenizer, and homogenized at 10000 rpm and 55°C. The mixture is then added to a 30% β-cyclodextrin aqueous solution, which is 20 times the mass of the salicylic acid cyclic anhydride. The mixture is stirred evenly and spray-dried at an inlet temperature of 170°C and a feed rate of 8 mL / min to obtain minoxidil microcapsules.
[0042] Comparative Example 2
[0043] (1) Minoxidil and ethanol were mixed at a mass ratio of 1:1:9 and placed in a homogenizer. The mixture was homogenized at 9000 rpm and 50°C. The mixture was then added to a β-cyclodextrin aqueous solution with a mass fraction of 25% at 15 times the mass of minoxidil. The mixture was stirred evenly and then spray-dried at an inlet temperature of 160°C and a feed rate of 6 mL / min to obtain minoxidil microcapsules.
[0044] (2) Hyaluronic acid, L-lysine and deionized water were mixed in a mass ratio of 10:1.4:90 and stirred at 3000 rpm for 40 min. Minoxidil microcapsules were added, and the mass ratio of minoxidil microcapsules to hyaluronic acid was 1.35:1. The mixture was stirred evenly and the pH was adjusted to 7.5 with triethylamine to obtain a preparation containing minoxidil.
[0045] Comparative Example 3
[0046] (1) Salicylic acid, minoxidil and ethanol were mixed in a mass ratio of 1:1:9 and placed in a homogenizer. The mixture was homogenized and emulsified at 9000 rpm and 50°C. The mixture was then added to a 25% β-cyclodextrin aqueous solution, which was 15 times the mass of salicylic acid. The mixture was stirred evenly and then spray-dried at an inlet temperature of 160°C and a feed rate of 6 mL / min to obtain minoxidil microcapsules.
[0047] (2) Hyaluronic acid, L-lysine and deionized water were mixed in a mass ratio of 10:1.4:90 and stirred at 3000 rpm for 40 min. Minoxidil microcapsules were added, and the mass ratio of minoxidil microcapsules to hyaluronic acid was 1.35:1. The mixture was stirred evenly and the pH was adjusted to 7.5 with triethylamine to obtain a preparation containing minoxidil.
[0048] Comparative Example 4
[0049] The composition of Comparative Example 4 is the same as that of Example 2. The difference between the preparation process of this minoxidil-containing formulation and that of Example 2 lies in step (4). Step (4) is modified as follows: Hyaluronic acid and deionized water are mixed at a mass ratio of 10:90 and stirred at 3000 rpm for 40 min. Minoxidil microcapsules are added, and the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.35:1. The mixture is stirred evenly, and the pH is adjusted to 7.5 with triethylamine to obtain the minoxidil-containing formulation.
[0050] Example of effect
[0051] Table 1 below presents the performance analysis results of the minoxidil-containing formulations prepared using Examples 1 to 3 and Comparative Examples 1 to 4 of this invention:
[0052] Table 1
[0053]
[0054] By comparing the experimental data of the examples and comparative examples in Table 1, it can be clearly seen that the formulations containing minoxidil prepared using Examples 1, 2, and 3 have better sustained effects, storage stability, and sustained-release pharmacological effects.
[0055] A comparison of the experimental data from Examples 1, 2, and 3 and Comparative Examples 1, 2, and 3 reveals that polysalicylic acid with a high degree of polymerization, when combined with minoxidil and coated with β-cyclodextrin to form minoxidil microcapsules, enables high-concentration minoxidil formulations to have a sustained-release effect, preventing skin damage caused by excessively high concentrations of minoxidil and achieving a continuous effect.
[0056] A comparison of the experimental data from Examples 1, 2, 3 and Comparative Example 4 reveals that the hydrogel formulation prepared by combining minoxidil microcapsules with hyaluronic acid and L-lysine not only uniformly disperses minoxidil in the formulation but also enhances its efficacy. Furthermore, hydrogen bonds are formed between the carboxyl groups on hyaluronic acid and L-lysine and the hydroxyl groups on the surface of the minoxidil microcapsules, resulting in a hydrogel formulation with a three-dimensional cross-linked structure, thus enhancing storage stability.
[0057] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, all variations falling within the meaning and scope of equivalents of the claims are intended to be included within the present invention. No markings in the claims should be construed as limiting the scope of the claims.
Claims
1. A formulation containing minoxidil, characterized in that: The formulation containing minoxidil is a hydrogel formulation made of minoxidil microcapsules, hyaluronic acid, and L-lysine. The minoxidil microcapsules are prepared by combining polysalicylic acid, minoxidil and β-cyclodextrin. The polysalicylic acid is obtained by ring-opening polymerization of salicylic acid anhydride within the salicylic acid ring. The mass ratio of minoxidil microcapsules, hyaluronic acid, and L-lysine is 12–15:10:0.5–2.
2. A preparation process for a formulation containing minoxidil, applied to the formulation containing minoxidil as described in claim 1, characterized in that: The preparation process of the formulation containing minoxidil includes the following specific steps: (1) Mix crude salicylic acid anhydride with tetrahydrofuran at a mass ratio of 1:1.5-3 and stir to dissolve to obtain salicylic acid anhydride solution; mix diethyl ether and n-hexane in equal volumes to obtain diethyl ether solution; add the salicylic acid anhydride solution dropwise to a diethyl ether solution with a mass of 3-5 times that of the salicylic acid anhydride solution at a rate of 1-3 mL / min, cool to -18--20℃, let stand for 10-12 h, filter and wash with diethyl ether 3-5 times, and dry to obtain salicylic acid anhydride. (2) Polysalicylic acid was prepared by polymerizing salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran at room temperature for 3-5 min and then rotary evaporating. (3) Mix polysalicylic acid, minoxidil and ethanol in a mass ratio of 1:1:8-10, place them in a homogenizer and emulsify them at 8000-10000 rpm and 45-55℃, add them to 10-20 times the mass of polysalicylic acid in a 20-30% β-cyclodextrin aqueous solution, stir evenly, and spray dry to obtain minoxidil microcapsules; (4) Hyaluronic acid, L-lysine and deionized water are mixed in a mass ratio of 10:0.5~2:80~100 and stirred at 2000~4000rpm for 30~50min. Minoxidil microcapsules are added and stirred evenly. The pH is adjusted to 7~8 with triethylamine to obtain a preparation containing minoxidil.
3. The preparation process of the formulation containing minoxidil according to claim 2, characterized in that: In step (1) above, the preparation process of crude salicylic acid intracyclic anhydride is as follows: triphosgene, activated carbon and diethyl ether are mixed in a mass ratio of 1.5 to 1.8:30:30 and placed in an ice-cold ethanol bath at -18 to -20°C. A salicylic acid diethyl ether solution with a mass fraction of 8 to 8 times the mass of triphosgene is added dropwise at a rate of 1 to 3 mL / min. After reacting for 2 to 3 hours, a triethylamine diethyl ether solution with a mass fraction of 2 to 4% is added dropwise at a rate of 10 to 15 times the mass of triphosgene. The mixture is then transferred to room temperature and reacted for 2 to 3 hours. An equal volume of ethyl acetate is added, and the mixture is stirred evenly, filtered, and rotary evaporated to obtain crude salicylic acid intracyclic anhydride.
4. The preparation process of the formulation containing minoxidil according to claim 2, characterized in that: In step (2) above, the mass ratio of salicylic acid anhydride, catalyst DBU, benzyl alcohol and tetrahydrofuran is 30-50:0.1:0.1:5-8.
5. The preparation process of the formulation containing minoxidil according to claim 4, characterized in that: In step (3) above: during spray drying, the inlet temperature is 150-170℃ and the feed rate is 4-8 mL / min.
6. The preparation process of the formulation containing minoxidil according to claim 2, characterized in that: In step (4) above, the mass ratio of minoxidil microcapsules to hyaluronic acid is 1.2 to 1.5:1.