Polymer microneedle of minoxidil as well as preparation method and application of polymer microneedle

Abstract

The invention discloses a minoxidil polymer microneedle as well as a preparation method and application thereof, and belongs to the technical field of medicines. The method comprises the following steps: uniformly mixing a double-bond monomer, a cross-linking agent and a photoinitiator to obtain a mixture A; minoxidil and an effervescing agent component are added into the mixture A and evenly mixed, a mixture B is obtained, the mixture B is added into a microneedle mold, vacuum degassing and centrifugation are conducted, and the needle tip part of the microneedle mold is filled with the mixture B; and pre-crosslinking the mixture B in the micro-needle mold, adding the mixture B into the pre-crosslinked micro-needle mold again until the residual cavity of the micro-needle mold is completely filled, then crosslinking the mixture B in the micro-needle mold, and taking the micro-needle patch out of the micro-needle mold after the crosslinking is finished to obtain the minoxidil polymer micro-needle. The minoxidil micro-needle can quickly release minoxidil after being applied, and the drug onset time is shortened when the minoxidil micro-needle is used for treating androgenetic alopecia.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and in particular relates to a minoxidil polymer microneedle and a preparation method and application thereof. Background Art

[0002] Androgenetic Alopecia (AGA), also known as pattern hair loss, is one of the most common forms of hair loss, affecting millions of men and women worldwide. AGA is a multifactorial disease involving genetic predisposition and the effects of androgens (such as dihydrotestosterone, DHT), which shrink hair follicles in certain areas, causing hair to become thinner, shorter, and eventually stop growing. Male patients usually present with an M-shaped receding hairline and thinning hair on the top of the head, while female patients show gradual thinning of hair in the center of the head.

[0003] Currently, the main drugs for the treatment of AGA include minoxidil and finasteride. Minoxidil is a topical drug that was originally used to treat hypertension. Later, it was found to have the side effect of promoting hair growth, so it was developed for the treatment of hair loss. However, minoxidil has a low transdermal absorption rate, which means that most drugs cannot effectively penetrate the skin barrier to reach the targeted hair follicles, resulting in limited bioavailability, requiring patients to use it multiple times a day to maintain efficacy. Long-term use may also cause side effects such as skin irritation, itching, and erythema, and sometimes even systemic adverse reactions such as hypotension and increased heart rate.

[0004] Existing minoxidil solutions or foams need to penetrate the stratum corneum of the scalp to reach the hair follicles, but the natural barrier function of the skin will limit the effective penetration of the drug, resulting in low absorption efficiency; and minoxidil in liquid or foam form is easily lost due to evaporation after use, especially under high temperature or air-drying conditions, which may cause the drug to fail to fully act on the target area; solvents commonly used in minoxidil solutions, such as propylene glycol, may cause skin irritation or allergic reactions, such as redness, itching, burning sensation, etc., especially for users with sensitive skin. Solutions or foams may be inconvenient to use, and need to be applied by hand or spray, which is easy to stain hands or clothes, and the foam may deform in certain circumstances (such as high temperature), affecting use; especially foam-formed minoxidil, which needs to be stored at a specific temperature, and the pressure tank packaging restricts its carrying, such as being unable to pass the security check of public transportation; and when using solutions or foams, it is difficult for users to accurately control the dosage used each time, which may affect the treatment effect or lead to drug waste. Once the solution or foam dries, the sustained release capacity of the drug is limited, and frequent reapplication may be required to maintain the efficacy. When using other hair care products, minoxidil solution or foam may react chemically with other products and affect their effectiveness.

[0005] On the other hand, finasteride reduces the production of DHT (Dihydrotestosterone) by inhibiting 5α-reductase, but its use is limited by its potential side effects, including sexual dysfunction, which is particularly sensitive in young men and is not suitable for female and pediatric patients.

[0006] Given the limitations of existing therapies, developing new and more effective AGA treatment strategies has become a research focus. The ideal new method should be able to overcome the problem of low transdermal absorption, improve the bioavailability of the drug, while reducing the incidence of side effects and enhancing patient compliance. In addition, new therapies should also take into account individual differences, such as age, gender, severity of hair loss, etc., to achieve personalized treatment. Summary of the invention

[0007] In order to solve the problems in the prior art, the present invention provides a minoxidil polymer microneedle and a preparation method and application thereof.

[0008] The technical solution adopted by the present invention is as follows:

[0009] In a first aspect, the present invention provides a minoxidil polymer microneedle and a preparation method thereof, comprising the following steps:

[0010] 1) uniformly mixing a double bond monomer, a cross-linking agent ethylene glycol dimethacrylate and a photoinitiator I2959 to obtain a mixture A, wherein the mass ratio of the double bond monomer: the cross-linking agent ethylene glycol dimethacrylate: the photoinitiator I2959 is 95-98: 1-2.5: 1-2.5;

[0011] 2) adding minoxidil and the effervescent component to the mixture A and mixing them evenly to obtain a mixture B; wherein the mass ratio of the minoxidil: the effervescent component: the mixture A is 4-8: 1-3: 90-95, adding the mixture B to the microneedle mold, vacuum degassing and centrifuging, so that the mixture B fills the needle tip part of the microneedle mold;

[0012] 3) pre-crosslinking the mixture B in the microneedle mold, adding the mixture B to the pre-crosslinked microneedle mold until the mixture B completely fills the remaining cavity of the microneedle mold, and then crosslinking the mixture B in the microneedle mold. After the crosslinking is completed, the microneedle patch is removed from the microneedle mold to obtain a minoxidil polymer microneedle;

[0013] The double bond monomer comprises one or more of vinyl pyrrolidone, acrylamide, acrylic acid, dimethylaminoethyl acrylate, m-aminophenylboronic acid, ethylene glycol dimethacrylate, dimethylaminoethyl methacrylate, methacrylic acid, glycidyl acrylate, and polyethylene glycol diacrylate; the effervescent component is a mixture of an acid source and an alkali source, and the mass ratio of the acid source to the alkali source in the effervescent component is 0.1-3:1.

[0014] Furthermore, in the step 1), uniform mixing is performed by vortexing to obtain a mixture A.

[0015] Furthermore, in step 1), the photoinitiator I2959 is 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone.

[0016] Furthermore, in step 2), the acid source of the effervescent component is one or more of citric acid, malic acid, boric acid, tartaric acid, fumaric acid, and hydrochloric acid;

[0017] The alkali source of the effervescent component is one or more of sodium bicarbonate and sodium carbonate.

[0018] Furthermore, in the step 2), the vacuum degassing time is 10 min-1 h, the centrifugal speed is 1000-5000 rpm, and the centrifugal time is 1-30 min.

[0019] Furthermore, in step 3), the pre-crosslinking method is: at an ultraviolet intensity of 150-600mW / cm 2 The cross-linking method is: irradiate for 30s-10min under the conditions of ultraviolet intensity 150-600mW / cm 2 Irradiate for 5-20 minutes under the conditions.

[0020] Furthermore, in step 3), the shape of the minoxidil polymer microneedle is a cone or a quadrangular pyramid; the height of the microneedle is 500-2000 microns; and the distance between the microneedle tips is 100-1000 microns.

[0021] In a second aspect, the present invention provides a minoxidil polymer microneedle prepared by the preparation method.

[0022] In a third aspect, the present invention proposes an application of the microneedle in the preparation of a drug for treating androgenic alopecia.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] 1) The present invention uses microneedles as drug delivery carriers to directly penetrate the stratum corneum, opening up a "fast lane" for drug delivery, thereby overcoming the problem that minoxidil solutions or foams in the prior art cannot penetrate the skin barrier, and greatly improving the transdermal absorption efficiency of minoxidil;

[0025] 2) The present invention controls the dosage of minoxidil by using a microneedle patch, thereby overcoming the problem that the dosage of the existing minoxidil liquid or foam can only be calculated by the number of spraying times when using the minoxidil, and achieving more accurate dosage control;

[0026] 3) The present invention adopts a microneedle patch as the final preparation type of the drug, which is simple, convenient and safe to use, and overcomes the problems of the existing minoxidil tincture, ointment, spray and foam, which are complicated to operate and require frequent and multiple administrations, and the residue will remain on the hands during the application and massage process, thereby improving the patient's comfort and compliance;

[0027] 4) The present invention uses microneedle technology to encapsulate minoxidil, which overcomes the problem that solvents (such as propylene glycol) in traditional minoxidil preparations may cause skin irritation or allergic reactions, making it easier to use on sensitive skin;

[0028] 5) The present invention loads minoxidil inside the microneedle, which overcomes the problem that minoxidil liquid or foam preparations are easily lost due to evaporation after use (especially under high temperature or air-drying conditions). The microneedle patch protects minoxidil from the influence of external environmental factors such as oxygen and light, thereby prolonging the drug's action time and sustained release ability;

[0029] 6) The present invention uses an effervescent ingredient to accelerate the release of minoxidil, thereby overcoming the problem of long onset time of existing minoxidil preparations and allowing the minoxidil to act on the lesion site more quickly;

[0030] 7) The present invention uses microneedles to deliver minoxidil, which overcomes the problem that existing minoxidil preparations may chemically react with other hair care products, affecting their effects, and improves their drug compatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 The scanning electron microscope images of minoxidil microneedle and minoxidil microneedle (containing effervescent agent);

[0032] Figure 2 It is the mechanical strength diagram of minoxidil microneedle and minoxidil microneedle (containing effervescent agent);

[0033] Figure 3 The in vitro release curves of minoxidil microneedle and minoxidil microneedle (containing effervescent agent);

[0034] Figure 4 The graph shows the therapeutic effects of blank, minoxidil, minoxidil microneedle and minoxidil microneedle (containing effervescent agent) on androgenic alopecia in mice. DETAILED DESCRIPTION

[0035] The present invention is further described and illustrated below in conjunction with specific embodiments. The embodiments are merely exemplary of the present disclosure and do not define the scope of limitation. The technical features of each embodiment of the present invention may be combined accordingly without conflicting with each other.

[0036] Comparative Example 1 Preparation of a Minoxidil Polymer Microneedle Patch (without Effervescent Agent)

[0037] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the proportions of vinyl pyrrolidone monomer, initiator and crosslinker refer to their mass percentages in the total mass of the monomer, initiator and crosslinker (i.e., the total mass of the mixture A);

[0038] (2) Adding minoxidil to the polymer cross-linking system (mixture A), wherein minoxidil accounts for 5% (w / w%) and the polymer cross-linking system (mixture A) accounts for 95%, and mixing thoroughly by vortexing to obtain a mixture C, adding the mixture C to the microneedle mold, and using a vacuum degassing method to fill the needle tip of the microneedle mold with the mixture C, and the vacuum degassing time is 30 minutes. The excess polymer cross-linking system (mixture C) on the surface of the mold is removed, and the mixture is dried under ultraviolet conditions (ultraviolet intensity is 600mW / cm 2 ) for 30 seconds for pre-crosslinking.

[0039] (3) Add a small amount of mixture C to the pre-crosslinked microneedle mold and evenly cover the surface of the microneedle. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be taken out from the mold to obtain a polymer microneedle patch of minoxidil (without effervescent agent).

[0040] Example 1 Preparation of a Minoxidil Polymer Microneedle Patch (Containing Effervescent Agent)

[0041] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the proportions of vinyl pyrrolidone monomer, photoinitiator and crosslinker respectively refer to their mass percentages in the total mass of monomer, initiator and crosslinker (i.e., the total mass of mixture A).

[0042] (2) Add minoxidil and a medicinal effervescent component (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent component is 3:1) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent agent accounts for 1.5% (w / w%), and the polymer cross-linking system (mixture A) accounts for 93.5%. Mix well by vortexing to obtain a mixture B, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0043] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2 ) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0044] The scanning electron microscope images of the microneedles obtained in Comparative Example 1 and Example 1 are as follows: Figure 1 As shown, Figure 1 The left image is a scanning electron microscope image of the microneedle of Comparative Example 1. Figure 1 The picture on the right in the middle is a scanning electron microscope picture of the microneedle of Example 1.

[0045] The mechanical properties of the microneedles obtained in Comparative Example 1 and Example 1 are shown in the figure Figure 2 As shown in the figure, the green curve is the mechanical property of Example 1, and the black curve is the mechanical property of Comparative Example 1. The mechanical properties of the two are similar. Under the action of the same force, Example 1 can produce a larger displacement, which proves that the microneedle of Example 1 can better penetrate the skin tissue.

[0046] Example 2 Preparation of a Minoxidil Polymer Microneedle Patch (2% Effervescent)

[0047] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the ratios of vinyl pyrrolidone monomer, initiator and crosslinker respectively refer to their mass percentages in the total mass of the monomer, initiator and crosslinker (i.e., the total mass of the mixture A).

[0048] (2) Add minoxidil and a medicinal effervescent component (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent component is 3:1) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent agent accounts for 2% (w / w%), and the polymer cross-linking system (mixture A) accounts for 93%. Mix well by vortexing to obtain a mixture B, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0049] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2 ) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0050] Example 3 Preparation of a Minoxidil Polymer Microneedle Patch (3% Effervescent)

[0051] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the ratios of vinyl pyrrolidone monomer, initiator and crosslinker respectively refer to their mass percentages in the total mass of the monomer, initiator and crosslinker (i.e., the total mass of the mixture A).

[0052] (2) Add minoxidil and a medicinal effervescent component (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent component is 3:1) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent agent accounts for 3% (w / w%), and the polymer cross-linked system (mixture A) accounts for 92%. Mix well by vortexing to obtain a mixture B, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0053] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0054] Example 4 Comparison of total in vitro release of effervescent preparations with different contents within 1 hour

[0055] The microneedle patches prepared in Comparative Example 1, Example 1, Example 2 and Example 3 were immersed in a PBS buffer solution with the needle tip facing downward to simulate the release in vitro, and the release amount of minoxidil was detected by ultraviolet spectrophotometry.

[0056] Table 1 Total release of different effervescent contents within 1 hour

[0057] Group Effervescent content Total release of minoxidil within 1 hour Comparative Example 1 0％ 45.4％ Example 1 1.5％ 77.1％ Example 2 2％ 77.8％ Example 3 3％ 78.3％

[0058] The results showed that the introduction of effervescent ingredients could significantly promote the release of minoxidil compared with the microneedles without effervescent agents (0%). Within 1 hour, as the effervescent content increased from 0% to 1.5%, the total release of minoxidil increased from 45% to 77%, and the release rate increased significantly, indicating that the introduction of effervescent ingredients could promote the release of minoxidil from microneedles and improve its drug utilization. On the basis of the effervescent content of 1.5%, the minoxidil release rate reached saturation when the effervescent content was further increased, and there was no significant increase.

[0059] Example 5 Preparation of Minoxidil Polymer Microneedle Patch (Effervescent Ratio is 1 (i.e., Acid Source: Alkaline Source = 1:1))

[0060] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the proportions of vinyl pyrrolidone monomer, photoinitiator and crosslinker respectively refer to their mass percentages in the total mass of monomer, initiator and crosslinker (i.e., the total mass of mixture A).

[0061] (2) Add minoxidil and a medicinal effervescent component (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent component is 1:1) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent accounts for 1.5% (w / w%), and the polymer cross-linking system (mixture A) accounts for 93.5%. Mix well by vortexing to obtain a mixture B, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0062] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2 ) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0063] Example 6 Preparation of Minoxidil Polymer Microneedle Patch (Effervescent Ratio of 4 (i.e., Acid Source: Alkaline Source = 4:1))

[0064] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the proportions of vinyl pyrrolidone monomer, photoinitiator and crosslinker respectively refer to their mass percentages in the total mass of monomer, initiator and crosslinker (i.e., the total mass of mixture A).

[0065] (2) Add minoxidil and a medicinal effervescent component (citric acid + sodium bicarbonate) (the mass ratio of the acid source to the base source in the effervescent component is) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent accounts for 1.5% (w / w%), and the polymer cross-linked system (mixture A) accounts for 93.5%. Mix the mixture B by vortexing, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0066] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0067] Example 7 Comparison of total in vitro release of microneedles with different effervescent ratios within 1 hour

[0068] The microneedle patches prepared in Example 1, Example 5 and Example 6 were immersed in a PBS buffer solution with the needle tip facing downward to simulate the release in vitro, and the release amount of minoxidil was detected by ultraviolet spectrophotometry.

[0069] Table 2 Total release of different effervescent ratios within 1 hour

[0070] Group Effervescent agent ratio (acid source: alkali source) Total release of minoxidil within 1 hour Example 1 3:1 77.1％ Example 5 1:1 74.8％ Example 6 4:1 77.4％

[0071] The results show that compared with Example 1, reducing the acid source of the effervescent agent in Example 5 has no significant effect on the release of minoxidil, and increasing the acid source ratio in Example 6 cannot accelerate the release of minoxidil, and the ratio of the acid source to the alkaline source reaches saturation at 3:1.

[0072] Example 8 Preparation of a Minoxidil Polymer Microneedle Patch (Different Effervescent Ingredients)

[0073] (1) Vinyl pyrrolidone monomer (97 w / w%), crosslinker ethylene glycol dimethacrylate (1.5 w / w%) and photoinitiator I2959 (2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone) (1.5 w / w%) were uniformly mixed by vortexing to obtain a mixture A, wherein the proportions of vinyl pyrrolidone monomer, photoinitiator and crosslinker respectively refer to their mass percentages in the total mass of monomer, initiator and crosslinker (i.e., the total mass of mixture A).

[0074] (2) Add minoxidil and a medicinal effervescent component (malic acid + sodium carbonate) (the mass ratio of the acid source to the base source in the effervescent component is 3:1) to the mixed mixture A, wherein minoxidil accounts for 5% (w / w%), the effervescent accounts for 1.5% (w / w%), and the polymer cross-linking system (mixture A) accounts for 93.5%. Mix the mixture B by vortexing, add the obtained mixture B to the microneedle mold, and use a vacuum degassing method to fill the needle tip part of the microneedle mold (vacuum degassing for 20 minutes), and then pre-centrifuge at 4000 rpm for 2 minutes.

[0075] (3) Remove the excess polymer mixed cross-linking system (mixture B) on the surface of the mold and irradiate it under ultraviolet conditions (ultraviolet intensity of 600mW / cm 2) for 30 seconds for pre-crosslinking. Then, a small amount of mixture B was added to the pre-crosslinked microneedle mold and evenly spread over the surface of the microneedles. 2 ) for 5 minutes for cross-linking. After the reaction is completed, the microneedles can be removed from the mold.

[0076] Example 9 Comparison of total in vitro release of different effervescent ingredients from microneedles within 1 hour

[0077] The microneedle patches prepared in Example 1 and Example 8 were immersed in a PBS buffer solution with the needle tip facing downward to simulate the release in vitro, and the release amount of minoxidil was detected by ultraviolet spectrophotometry.

[0078] Table 3 Total release of different effervescent microneedles within 1 hour

[0079] Group Effervescent Total release of minoxidil within 1 hour Example 1 Citric acid + sodium bicarbonate 77.1％ Example 8 Malic acid + sodium carbonate 76.6％

[0080] The results show that there is no significant difference between Example 8 and Example 1, and different effervescent ingredients have no effect on the release of minoxidil.

[0081] Example 10 The in vitro release of minoxidil from the polymer microneedle patch and its efficacy in the androgenic alopecia mouse model are as follows:

[0082] (1) The microneedles of Comparative Example 1 and Example 1 were immersed in a PBS buffer solution with their tips facing downward to simulate their release in vitro, and the amount of minoxidil released was detected by ultraviolet spectrophotometry.

[0083] (2) Figure 3 As shown, the in vitro release results show that the microneedles of Comparative Example 1 cumulatively release about 40% within 1 hour, while the microneedles of Example 1 cumulatively release about 80% within the same time.

[0084] (3) Efficacy test: 7-week-old C57BL / 6 male mice were used to prepare an androgenic alopecia model. The hair in the central part of the back of the experimental animals was first shaved. The back skin area of ​​each mouse was about 2*3 cm. The back skin area was depilated with a depilatory cream. The dilution of testosterone propionate was injected subcutaneously at multiple points in the depilated area on the back of the mouse. The total dose was 1 mg / mouse / day. The drug was administered continuously every day to establish the model. Figure 4As shown, the mice were divided into 4 groups, the first group was a blank group: only subcutaneous injection of testosterone propionate was performed every day, the second group was a minoxidil group: subcutaneous injection of testosterone propionate was performed every day and minoxidil was applied on the back, the third group was a minoxidil microneedle group: subcutaneous injection of testosterone propionate was performed every day and the microneedle patch of Comparative Example 1 was pasted on the back, and one patch was changed every 12 hours; the fourth group was a minoxidil microneedle (containing effervescent) group: subcutaneous injection of testosterone propionate was performed every day and the microneedle patch of Example 1 was pasted on the back, and one patch was changed every 12 hours, and photos were taken on the 0th, 5th, 9th, 13th, and 17th days to observe the hair growth.

[0085] Efficacy results: the first group of blank control group had no hair growth until the 17th day, indicating that the androgenic alopecia model was successfully established; the second group of topical minoxidil began to grow hair on the 13th day, and the hair was luxuriant on the 17th day; the results of the third group of minoxidil microneedle group were similar to those of the second group; the fourth group of minoxidil microneedle (containing effervescent) group had a large amount of hair starting to grow on the 13th day, and the effect was significantly better than the second and third groups, indicating that the minoxidil microneedle (containing effervescent) of the present invention can treat androgenic alopecia faster.

[0086] The above-mentioned embodiments only express several implementation modes of the present invention, and the description is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. For those of ordinary skill in the art, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing a polymer microneedle of minoxidil, characterized in that: The following steps are involved: 1) uniformly mixing a double bond monomer, a cross-linking agent ethylene glycol dimethacrylate and a photoinitiator I2959 to obtain a mixture A, wherein the mass ratio of the double bond monomer: the cross-linking agent ethylene glycol dimethacrylate: the photoinitiator I2959 is 95-98: 1-2.5: 1-2.5; 2) adding minoxidil and the effervescent component to the mixture A and mixing them evenly to obtain a mixture B; wherein the mass ratio of the minoxidil: the effervescent component: the mixture A is 4-8: 1-3: 90-95, adding the mixture B to the microneedle mold, vacuum degassing and centrifuging, so that the mixture B fills the needle tip part of the microneedle mold; 3) pre-crosslinking the mixture B in the microneedle mold, adding the mixture B to the pre-crosslinked microneedle mold until the mixture B completely fills the remaining cavity of the microneedle mold, and then crosslinking the mixture B in the microneedle mold. After the crosslinking is completed, the microneedle patch is removed from the microneedle mold to obtain a minoxidil polymer microneedle; The double bond monomer comprises one or more of vinyl pyrrolidone, acrylamide, acrylic acid, dimethylaminoethyl acrylate, m-aminophenylboronic acid, ethylene glycol dimethacrylate, dimethylaminoethyl methacrylate, methacrylic acid, glycidyl acrylate, and polyethylene glycol diacrylate; the effervescent component is a mixture of an acid source and an alkali source, and the mass ratio of the acid source to the alkali source in the effervescent component is 0.1-3:

1.

2. The method according to claim 1, characterized in that In the step 1), uniform mixing is performed by vortexing to obtain a mixture A.

3. The method according to claim 1, characterized in that In step 1), the photoinitiator I2959 is 2-hydroxy-4-(2-hydroxyethoxy)-2-methylpropiophenone.

4. The method according to claim 1, characterized in that: In the step 2), the acid source of the effervescent component is one or more of citric acid, malic acid, boric acid, tartaric acid, fumaric acid, and hydrochloric acid; The alkali source of the effervescent component is one or more of sodium bicarbonate and sodium carbonate.

5. The method according to claim 1, characterized in that In the step 2), the vacuum degassing time is 10 min-1 h, the centrifugal speed is 1000-5000 rpm, and the centrifugal time is 1-30 min.

6. The method according to claim 1, characterized in that In step 3), the pre-crosslinking method is: under a UV intensity of 150-600 mW / cm 2 The cross-linking method is: irradiate for 30s-10min under the conditions of ultraviolet intensity of 150-600mW / cm 2 Irradiate for 5-20 minutes under the conditions.

7. The method according to claim 1, characterized in that In step 3), the shape of the minoxidil polymer microneedle is a cone or a quadrangular pyramid; the height of the microneedle is 500-2000 microns; and the distance between the microneedle tips is 100-1000 microns.

8. A minoxidil polymer microneedle prepared by the preparation method according to any one of claims 1 to 7.

9. Use of the microneedle according to claim 8 in preparing a drug for treating androgenic alopecia.

Images