A sustained-release microneedle containing minoxidil, its preparation method and application

Abstract

The present invention discloses a sustained-release microneedle containing minoxidil, and a preparation method and application thereof. The method includes: dissolving PLGA in a mixed solution of chloroform and ethyl acetate with a volume ratio of (10-20):1 to obtain a PLGA solution; mixing a minoxidil solution with a volume ratio of 1:(4-6) and the PLGA solution to obtain an oil-phase solution; dissolving polyvinyl alcohol in ultrapure water to obtain an aqueous-phase solution; dropping the oil-phase solution with a volume ratio of 1:(2-10) into the aqueous-phase solution, and through stirring, centrifuging, washing and drying, obtaining a drug-loaded PLGA microsphere powder; dispersing polyvinyl alcohol and sucrose in ultrapure water and dissolving them, then adding the drug-loaded PLGA microsphere powder and mixing evenly to obtain a tip matrix solution; adding it to a microneedle mold, evacuating and centrifuging, and demolding the microneedle after drying to obtain a sustained-release microneedle containing minoxidil, so as to improve the bioavailability of the therapeutic drug minoxidil.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a sustained-release microneedle containing minoxidil, a preparation method thereof, and an application thereof. Background Art

[0002] The exact cause of androgenetic alopecia has not been clearly defined, but it is certain that genetic factors and the action of androgens are related to the onset. In addition to genetic factors, the action of androgens is mainly manifested in that after testosterone binds to androgen receptors in hair follicles, it will be converted into dihydrotestosterone by 5α-reductase in the cytoplasm. Dihydrotestosterone enters the cell nucleus and affects metabolism, and can produce toxic effects on hair follicles, causing hair follicles to atrophy. At present, there are only two treatment methods approved by the U.S. Food and Drug Administration (FDA) for the treatment of androgenetic alopecia: oral finasteride and topical minoxidil solution. Oral drugs will enter the systemic circulation, and some drugs will be metabolized due to the first-pass effect, thus affecting their bioavailability. The drugs in the systemic circulation will also cause side effects on other organs of the body. Topical application of drugs is convenient to use and belongs to local administration. However, due to the existence of the skin-stratum corneum barrier, the transdermal absorption rate of drugs is low. Therefore, patients need to administer drugs frequently and repeatedly, which is likely to cause side effects such as skin allergies and skin inflammation.

[0003] In summary, the deficiencies in the treatment of androgenetic alopecia in the prior art are as follows: (1) Avoid frequent and repeated drug administration and achieve long-term release of drugs. (2) Effectively improve the bioavailability of drugs. Therefore, in order to solve the above problems, it is necessary to develop a new treatment product for androgenetic alopecia. Summary of the Invention

[0004] The object of the present invention is to provide a blend matrix of polyvinyl alcohol-PLGA, a preparation method thereof, and an application thereof, which can achieve long-term and slow release of the therapeutic drug minoxidil and improve the bioavailability of the therapeutic drug minoxidil.

[0005] In order to achieve the above object, the present invention adopts the following technical solutions:

[0006] In the first aspect of the present invention, a preparation method of a sustained-release microneedle containing minoxidil is provided, and the method includes:

[0007] Dissolve PLGA in a mixed solution of chloroform and ethyl acetate with a volume ratio of (10-20):1 to obtain PLGA

[0008] Solution: Minoxidil was dissolved in glacial acetic acid to obtain a minoxidil solution; the minoxidil solution was added to the PLGA solution to obtain an oil-phase solution; wherein, the volume ratio of the minoxidil solution to the PLGA solution was 1:(4 - 6);

[0009] Polyvinyl alcohol was dissolved in ultrapure water to obtain an aqueous-phase solution;

[0010] The oil-phase solution was dropped into the aqueous-phase solution to obtain a white emulsion, which was then stirred to obtain drug-loaded PLGA microspheres. After centrifugation, washing, and drying, drug-loaded PLGA microsphere powder was obtained; wherein, the volume ratio of the oil-phase solution to the aqueous-phase solution was 1:(2 - 10);

[0011] Polyvinyl alcohol and sucrose were dispersed and dissolved in ultrapure water to obtain a mixed solution; the drug-loaded PLGA microsphere powder was added to the mixed solution and mixed evenly to obtain a tip matrix solution;

[0012] The tip matrix solution was added to a microneedle mold, evacuated, and centrifuged. After drying, the microneedles were demolded to obtain sustained-release microneedles containing minoxidil.

[0013] In a second aspect of the present invention, there is provided a sustained-release microneedle containing minoxidil obtained by the method described above.

[0014] In a third aspect of the present invention, there is provided the application of the sustained-release microneedle containing minoxidil in the preparation of a product for treating androgenetic alopecia.

[0015] One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

[0016] 1. A sustained-release microneedle containing minoxidil and its preparation method and application provided by the present invention. The drug-loaded sustained-release microneedle of the present invention can achieve the long-term and slow release of the therapeutic drug minoxidil. Combining with the application of microneedle technology, the bioavailability of the therapeutic drug minoxidil is improved. When the microneedles penetrate the skin, along with the dissolution of the microneedles, the PLGA microspheres can stably remain under the skin to achieve long-term slow drug release. The released minoxidil dilates vascular smooth muscle, increases local blood flow, and promotes hair follicle regeneration in the subcutaneous tissue, so as to significantly promote hair regeneration and effectively increase the effect of hair regeneration. The drug-loaded sustained-release microneedle invented by us mainly improves the safety of medication and the compliance of patients by reducing the dosing frequency and increasing the bioavailability of the drug.

[0017] 2. The technical difficulty of this application lies in how to control the particle size of the drug-loaded PLGA microspheres between 10 - 20 µm so that they can be smoothly loaded into the microneedles. If the particle size of the drug-loaded microspheres is too large, they cannot be loaded into the microneedles. If the particle size is too small, due to the resistance of the microneedle matrix, they cannot be well filled to the tip of the microneedle. The inventor of this application found through experiments that by using the single emulsion method and controlling the parameters: dissolving PLGA in a mixed solution of chloroform and ethyl acetate with a volume ratio of (10 - 20):1; the volume ratio of the minoxidil solution to the PLGA solution is 1:(4 - 6); the volume ratio of the oil phase solution to the water phase solution is 1:(2 - 10); the particle size of the microspheres can be controlled between 10 - 20 µm, enabling them to be better loaded into the microneedles.

[0018] 3. In this invention, it was determined that the drug-loaded PLGA microspheres have a very good drug release efficiency of up to 28 days in phosphate buffer solution, and the cumulative drug release rate can reach nearly 100%. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0020] Figure 1 It is the particle size distribution diagram of the drug-loaded PLGA sustained-release microspheres.

[0021] Figure 2 It is the in vitro drug release of minoxidil in the microspheres within 28 days.

[0022] Figure 3 It is the comparison diagram of loading PLGA microspheres into the tip of the microneedle by single method and composite method.

[0023] Figure 4 It is the in vitro skin puncture diagram of the microneedle loaded with microspheres.

[0024] Figure 5 It is the quantitative result diagram of the gradual release of the fluorescent dye Nile red encapsulated in the microspheres in vivo.

[0025] Figure 6 It is the quantitative diagram of the fluorescence intensity in the subcutaneous tissue after different administration methods.

[0026] Figure 7 It is the diagram of the promoted hair regeneration area after the drug-loaded sustained-release microneedles are applied to the androgenetic alopecia mouse model.

[0027] Figure 8Quantification diagram of the promoting effect of drug-loaded sustained-release microneedles on hair regeneration density after application to an androgenetic alopecia mouse model.

[0028] Figure 9 Quantification diagram of the promoting effect of drug-loaded sustained-release microneedles on the diameter of regenerated hair after application to an androgenetic alopecia mouse model.

[0029] Figure 10 Quantification diagram of the promoting effect of drug-loaded sustained-release microneedles on the length of regenerated hair follicles after application to an androgenetic alopecia mouse model.

[0030] Figure 11 Quantification diagram of the promoting effect of drug-loaded sustained-release microneedles on the thickness of the dermis after application to an androgenetic alopecia mouse model. Detailed implementation manners

[0031] The present invention will be specifically described below in combination with the detailed implementation manners and examples, and the advantages and various effects of the present invention will be presented more clearly therefrom. Those skilled in the art should understand that these detailed implementation manners and examples are used to illustrate the present invention, rather than to limit the present invention.

[0032] Throughout the specification, unless otherwise specifically stated, the terms used herein should be understood as having the meanings commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which the present invention pertains. In case of any conflict, this specification shall prevail.

[0033] Unless otherwise specifically stated, various raw materials, reagents, instruments, and equipment used in the present invention can be obtained through market purchase or by existing methods.

[0034] The sustained-release microneedles containing minoxidil and its preparation method and application of the present application will be described in detail below in combination with examples, comparative examples, and experimental data.

[0035] Example 1, Sustained-release microneedles containing minoxidil and its preparation method

[0036] 1. Preparation of PLGA sustained-release microspheres encapsulating minoxidil

[0037] This example includes the following raw materials by mass percentage:

[0038] Minoxidil 150 mg

[0039] Glacial acetic acid 200 μL

[0040] PLGA (50:50, molecular weight 5k - 30k) 180 mg

[0041] Chloroform 950 μL

[0042] 50 µL of ethyl acetate

[0043] 100 mg of polyvinyl alcohol (molecular weight 12k - 15k)

[0044] 5 mL of ultrapure water

[0045] Preparation method of this example:

[0046] A. According to the prescription ratio, at 40 °C, dissolve PLGA (50:50, molecular weight 5k - 30k) in chloroform and ethyl acetate through magnetic stirring to form a transparent and clear solution (PLGA solution); dissolve the prescribed amount of minoxidil in glacial acetic acid and then add it to the above PLGA solution to obtain an oil-phase solution;

[0047] B. According to the prescription ratio, at room temperature, dissolve 2% polyvinyl alcohol (molecular weight 12k - 15k) in ultrapure water to form a polyvinyl alcohol solution, which is the aqueous phase;

[0048] C. At room temperature, dropwise add the solution of step A into the solution described in step B, then use a vortex mixer to vortex for 90 s to form a stable white emulsion. After stirring with a magnetic stirrer at 800 revolutions for 4 - 5 h to fully volatilize the organic solvent, the drug-loaded PLGA microspheres are obtained. After centrifugation and washing three times, they are dried by a freeze dryer to obtain the drug-loaded microsphere powder. It can be seen that the particle size distribution of the microspheres is between 10 - 20 µm, and the average particle size is 15 µm. Figure 1 It can be seen that the particle size distribution of the microspheres is between 10 - 20 µm, and the average particle size is 15 µm.

[0049] In this example, the volume ratio of chloroform to ethyl acetate is 19:1. The volume ratio of the minoxidil solution to the PLGA solution is 1:5; the volume ratio of the oil-phase solution to the aqueous-phase solution is 1:5;

[0050] 2. Preparation of drug-loaded sustained-release microsphere microneedles

[0051] 20 mg of PLGA sustained-release microsphere powder encapsulating minoxidil

[0052] 18% of polyvinyl alcohol (molecular weight 12k - 15k)

[0053] 18% of sucrose

[0054] 1 mL of ultrapure water

[0055] Preparation method of this example:

[0056] A. Take the white powder of the drug-loaded PLGA microspheres prepared in Example 1;

[0057] B. Weigh 180 mg of polyvinyl alcohol (molecular weight 12k - 15k) and 180 mg of sucrose according to the prescription ratio, disperse them in 1 mL of water, stir until fully dissolved, add the lyophilized powder of drug-loaded PLGA microspheres in the prescription ratio, and stir until evenly mixed. Take 100 µL of the above needle tip matrix and spread it on the microneedle mold. After evacuating on the vacuum plate for 20 min, use a centrifuge at 4200 rpm for 5 min, and repeat the operation until the excess matrix solution on the backing is removed and the drug-loaded microspheres are fully filled into the needle tip part of the mold;

[0058] C. Weigh 180 mg of polyvinyl alcohol (molecular weight 12k - 15k) and 180 mg of sucrose according to the prescription ratio, disperse them in 1 mL of water, and stir until fully dissolved. Do not add the drug-loaded microsphere powder as the blank matrix solution. Subsequently, add 100 µL of the blank matrix solution to the centrifuged mold. After evacuating on the vacuum plate for 2 h, place it on a magnetic stirrer and dry at 40 °C for 24 h. After demolding with an acrylic plate, the sustained-release microneedles containing minoxidil are obtained.

[0059] Example 2

[0060] In this example, the volume ratio of chloroform to ethyl acetate is 10:1. The volume ratio of the minoxidil solution to the PLGA solution is 1:4; the volume ratio of the oil phase solution to the water phase solution is 1:2; other steps are the same as in Example 1.

[0061] Specifically, this example includes the following raw materials by mass percentage:

[0062] Minoxidil 150 mg

[0063] Glacial acetic acid 275 µL

[0064] PLGA (50:50, molecular weight 5k - 30k) 180 mg

[0065] Chloroform 1000 µL

[0066] Ethyl acetate 100 µL

[0067] Polyvinyl alcohol (molecular weight 12k - 15k) 100 mg

[0068] Ultra-pure water 2.2 mL.

[0069] Example 3

[0070] In this example, the volume ratio of chloroform to ethyl acetate is 20:1. The volume ratio of the minoxidil solution to the PLGA solution is 1:6; the volume ratio of the oil phase solution to the water phase solution is 1:10; other steps are the same as in Example 1.

[0071] Specifically, this embodiment includes the following raw materials by mass percentage:

[0072] Minoxidil 150 mg

[0073] Glacial acetic acid 175 µL

[0074] PLGA (50:50, molecular weight 5k – 30k) 180 mg

[0075] Chloroform 1000 µL

[0076] Ethyl acetate 50 µL

[0077] Polyvinyl alcohol (molecular weight 12k-15k) 100 mg

[0078] Ultra-pure water 10.5 mL

[0079] Comparative Example 1

[0080] In this comparative example, the solvent of PLGA is 100% chloroform, and other steps are the same as those in Example 1.

[0081] Comparative Example 2

[0082] In this comparative example, the solvent of PLGA is 100% ethyl acetate, and other steps are the same as those in Example 1.

[0083] Comparative Example 3

[0084] In this comparative example, the volume ratio of the minoxidil solution to the PLGA solution is 1:2, and other steps are the same as those in Example 1.

[0085] Comparative Example 4

[0086] In this comparative example, the volume ratio of the minoxidil solution to the PLGA solution is 1:1, and other steps are the same as those in Example 1.

[0087] Comparative Example 5

[0088] In this comparative example, the volume ratio of the oil phase solution to the water phase solution is 1:2, and other steps are the same as those in Example 1.

[0089] Comparative Example 6

[0090] In this comparative example, the volume ratio of the oil phase solution to the water phase solution is 1:1, and other steps are the same as those in Example 1.

[0091] Experimental Example 1. Determination of the particle size of the drug-loaded PLGA microspheres

[0092] The particle sizes of the drug-loaded PLGA microspheres in Example 1 and Comparative Examples 1-6 were measured as shown in Table 1.

[0093] Table 1

[0094]

[0095] As can be seen from Table 1,

[0096] In Comparative Example 1, the PLGA solvent was 100% chloroform, which was not within the range of (10 - 20):1 in the examples of the present invention. The microsphere particle size was 500 µm - 1 mm and could not be loaded into the microneedle;

[0097] In Comparative Example 2, the PLGA solvent was 100% ethyl acetate, which was not within the range of (10 - 20):1 in the examples of the present invention. The microsphere particle size was 500 µm - 1 mm and could not be loaded into the microneedle;

[0098] In Comparative Example 3, the volume ratio of the minoxidil solution to the PLGA solution was 1:2, which was greater than the range of 1:(2 - 10) in Example 1 of the present invention. The microsphere particle size was 5 µm - 1 µm and could not be filled into the tip of the microneedle;

[0099] In Comparative Example 4, the volume ratio of the minoxidil solution to the PLGA solution was 1:1, which was less than the range of 1:(2 - 10) in Example 1 of the present invention. The microsphere particle size was 500 nm - 1000 nm and could not be filled into the tip of the microneedle;

[0100] In Comparative Example 5, the volume ratio of the oil - phase solution to the water - phase solution was 1:2, which was greater than the range of 1:(2 - 10) in Example 1 of the present invention. The microsphere particle size was 200 µm - 500 µm and could not be filled into the tip of the microneedle;

[0101] In Comparative Example 6, the volume ratio of the oil - phase solution to the water - phase solution was 1:1, which was less than the range of 1:(2 - 10) in Example 1 of the present invention. The microsphere particle size was 500 µm - 800 µm and could not be loaded into the microneedle;

[0102] In Example 1, by the single - emulsion method and controlling the parameters: dissolving PLGA in a mixed solution of chloroform and ethyl acetate with a volume ratio of (10 - 20):1; the volume ratio of the minoxidil solution to the PLGA solution was 1:(4 - 6); the volume ratio of the oil - phase solution to the water - phase solution was 1:(2 - 10); it was possible to control the particle size of the microspheres between 10 - 20 µm, enabling them to be better loaded into the microneedle. If any one of the parameters was not within the range of the examples of the present invention, they could not be loaded into the microneedle.

[0103] In Experimental Example 2, the in vitro drug release of the drug - loaded microspheres prepared in Example 1 was measured

[0104] In vitro release experiment method: Dissolve the entire microsphere-loaded microneedle in 1 mL of deionized water. After the microspheres are dissolved, centrifuge and wash three times, then freeze-dry to obtain the amount of loaded spheres in one microneedle. Subsequently, add the microsphere powder to 2 mL of phosphate buffer solution with a pH of 7.2 - 7.4 and incubate in a shaker at 37 ◦ °C. Centrifuge at regular time intervals, collect the supernatant, and replace it with an equal volume of fresh buffer. Use a UV spectrophotometer to measure the concentration of minoxidil in the supernatant.

[0105] Results: As can be seen from Figure 2 it, the drug release rate is relatively fast in the initial release stage. After 14 days, the drug release rate gradually slows down. By the 28th day, the drug is basically released completely. The final cumulative release amount of the drug can reach almost 100%, indicating that PLGA microspheres can achieve drug sustained release for about one month and have good drug release efficiency.

[0106] Experimental Example 3: Perform in vitro skin puncture experiment on the microsphere-loaded microneedle prepared in Example 1

[0107] In vitro skin puncture experiment method: Use the fluorescent dye Nile red as a simulated drug to prepare microsphere-loaded microneedles. Subsequently, take the excised dorsal skin of a rat and fix the skin on the anvil with rivets. Start timing when pressing a dry microneedle into the skin with the thumb. After pressing for 50 s and leaving it on the skin for 20 min, remove the microneedle. Use a fluorescence microscope to observe the skin puncture situation.

[0108] Results: As can be seen from Figure 4 it, clear fluorescent spots of a 10 × 10 microneedle array are left on the skin. The results show that almost 100% of the microneedles can penetrate into the skin.

[0109] Experimental Example 4: Drug release kinetics of microsphere-loaded microneedles loaded with the fluorescent dye Nile red in rats

[0110] Experimental method: After anesthetizing adult SD rats with sodium pentobarbital, use a hair clipper to shave the hair on the rats' backs and use Veet hair removal cream to remove fine hair. During this process, ensure that the dorsal skin of the rats is not damaged. Use microneedles loaded with Nile red microspheres to simulate the dynamic release process of the drug in vivo. After inserting the microneedles into the dorsal skin of SD rats, press for 50 s. After the microneedles stay for 20 min, remove the backing part of the microneedles. All experimental animals are raised under light-proof conditions. Use a fluorescence microscope to record the release of the fluorescent dye with the degradation of microspheres in rats within 1, 4, 7, 10, 14, 17, 20, 25, 30, and 35 days. All shooting conditions are the same. Then, use ImageJ to quantify the fluorescence intensity of Nile red, and calculate the subsequent fluorescence intensity after normalizing the fluorescence intensity on the first day.

[0111] Result: From Figure 5 the quantification result of the fluorescence intensity, it can be seen that after the 25th day, most of the fluorescence has basically disappeared. During the entire release process, the fluorescence shows a stable attenuation trend, indicating that the drug is released slowly over a long period of time.

[0112] Experimental Example 5: Percutaneous penetration comparison experiment of the drug after different administration methods using the fluorescent dye Nile red as a simulated drug

[0113] Experimental method: Using Nile red as a simulated drug, microspheres encapsulating Nile red, Nile red solution, and drug-loaded microsphere microneedles loaded with Nile red were prepared respectively. After anesthetizing male C57BL / 6 mice with sodium pentobarbital, their backs were depilated, taking care to avoid damaging the back skin. Subsequently, the microspheres encapsulating Nile red, Nile red solution, and microsphere microneedles encapsulating Nile red were applied to their back skin respectively. After 24 h, the mice were sacrificed, and the skin at the application site and the needle insertion site was embedded and then cryosectioned. The in vivo percutaneous penetration of each group was photographed using an inverted fluorescence microscope. And the fluorescence intensity at different depths in the subcutaneous tissue was quantified to reflect the percutaneous penetration of the drug.

[0114] Result: From Figure 6 it can be seen that the fluorescence in the microsphere application group and the solution application group only stays on the skin surface, and there is no fluorescence as the depth in the subcutaneous tissue increases. However, in the microneedle application group, the fluorescence intensity in the subcutaneous tissue is higher. Through the above comparative experiments, it can be fully demonstrated that the use of the microneedle dosage form can effectively deliver the drug-loaded microspheres to the subcutaneous tissue for long-term drug release, effectively improving the percutaneous absorption rate of the drug minoxidil.

[0115] Experimental Example 6: Evaluation of the in vivo therapeutic effect of the microsphere microneedles

[0116] Experimental method: Establishment of an androgenetic alopecia model: After 5-week-old male C57BL / 6 mice were adapted for one week, the hair on their backs was removed using a hair clipper, and then the fine hair on the backs of the mice was removed using Veet depilatory cream. After the mice were allowed to adapt for one day. One day later, a 0.2% testosterone solution with a solvent of 50% ethanol was applied to the backs of the mice. According to 0.1 mL / cm 2The amount was topically applied to the depilated area on the back of mice. Subsequently, the mice were randomly grouped into a control group, a group with microneedles loaded with blank microspheres, a group with microneedles loaded with drug-loaded microspheres (administered once within 28 days), a group with microneedles loaded with drug-loaded microspheres (administered once a week within 28 days), and a group applying 5% minoxidil solution topically every day. The mice in each group were topically applied with 0.2% testosterone solution every day for 42 days. In addition, the group with microneedles loaded with blank microspheres and the group with microneedles loaded with drug-loaded microspheres (administered once) were given microneedles once on the first day when testosterone solution was applied. The group with microneedles loaded with drug-loaded microspheres (administered once a week) was given microneedles once on the first day when testosterone solution was applied, and then given microneedles again after one week for four consecutive weeks. The 5% minoxidil group applied once a day with the same application size as the microneedle array. The mice in each group were observed until the 42nd day. After 42 days, the hair regeneration area and regeneration density were quantified, and the diameter of the regenerated hair in each group was quantified to evaluate the therapeutic effect of the microneedles loaded with drug-loaded microspheres. Finally, the skin tissue at the hair growth site was stained with HE to evaluate the regeneration of hair follicles in the subcutaneous tissue.

[0117] Results: As Figure 7 can be seen, the group with microneedle treatment once a week promoted the hair regeneration area significantly better than the group applying 5% minoxidil solution topically every day, and compared with the control group, it could significantly promote hair regeneration; while the treatment group administered once a month had a similar effect to the group applying 5% minoxidil solution topically every day. As Figure 8 can be seen, by the 42nd day, the group with microneedle treatment once a week also promoted the hair regeneration density significantly better than the group applying 5% minoxidil solution topically every day. Secondly, by quantifying the diameter of the regenerated hair in each group, as Figure 9 can be seen, the group with microneedle treatment once a week promoted the diameter of the regenerated hair significantly higher than the group applying 5% minoxidil solution topically every day. Subsequently, by quantifying the length of the regenerated hair follicles in the subcutaneous tissue, as Figure 10 can be seen, the group with microneedle treatment once a week promoted the length of the hair follicle regrowth in the subcutaneous tissue significantly better than the group applying 5% minoxidil solution topically every day. Finally, as Figure 11 can be seen, the group with microneedle treatment once a week significantly increased the thickness of the dermis because it had the best effect on promoting the length of hair follicle regrowth.

[0118] From the treatment experiment results of androgenetic alopecia model mice, it can be seen that compared with other drug administration groups, the drug-loaded sustained-release microneedles of the present invention can achieve a treatment effect similar to that of daily application of minoxidil solution by administering once a month, and the best treatment effect is obtained after microneedle treatment once a week. Compared with the minoxidil solution topical application treatment group, the microneedles can not only administer drugs safely and conveniently but also effectively improve the drug bioavailability. The microneedles act on the alopecia area and directly deliver the drug-loaded sustained-release microspheres into the skin. The drug-loaded sustained-release microspheres can directly release drugs slowly for a long time near the hair follicles, avoiding frequent drug administration by patients and improving the compliance of patients. The minoxidil released from the microspheres can dilate vascular smooth muscle and increase local blood flow, effectively promoting hair follicle regeneration, so as to achieve the purpose of promoting hair regeneration, which is of great significance for hair growth.

[0119] Finally, it should also be noted that the term "comprising", "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device.

[0120] Although the preferred embodiments of the present invention have been described, those skilled in the art can make additional changes and modifications to these embodiments once they know the basic creative concept. Therefore, the appended claims are intended to be construed as including the preferred embodiments and all changes and modifications falling within the scope of the present invention.

[0121] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these modifications and variations.

Claims

1. A preparation method of minoxidil-containing sustained-release microneedles, characterized in that, The method includes: Dissolve PLGA in a mixed solution of chloroform and ethyl acetate with a volume ratio of (10 - 20):1 to obtain a PLGA solution; dissolve minoxidil in glacial acetic acid to obtain a minoxidil solution; add the minoxidil solution to the PLGA solution to obtain an oil-phase solution; wherein, the volume ratio of the minoxidil solution to the PLGA solution is 1:(4 - 6); Dissolve polyvinyl alcohol in ultrapure water to obtain an aqueous-phase solution; Drop the oil-phase solution into the aqueous-phase solution to obtain a white emulsion, and then obtain drug-loaded PLGA microspheres through stirring, and obtain drug-loaded PLGA microsphere powder through centrifugation, washing and drying; wherein, the volume ratio of the oil-phase solution to the aqueous-phase solution is 1:(2 - 10); Disperse polyvinyl alcohol and sucrose in ultrapure water and dissolve them to obtain a mixed solution; add the drug-loaded PLGA microsphere powder to the mixed solution and mix evenly to obtain a tip matrix solution; Add the tip matrix solution to a microneedle mold, evacuate and centrifuge, and demold the microneedles after drying to obtain sustained-release microneedles containing minoxidil; The concentration range of PLGA in the PLGA solution is 10% - 20%; The concentration range of the minoxidil solution is (500 - 1000) mg / ml.

2. The preparation method of a sustained-release microneedle containing minoxidil according to claim 1, wherein The concentration range of polyvinyl alcohol in the aqueous-phase solution is 10% - 50%.

3. The preparation method of a sustained-release microneedle containing minoxidil according to claim 1, wherein, In the mixed solution, the concentration range of polyvinyl alcohol is (178 - 182) mg / ml, and the concentration range of sucrose is (178 - 182) mg / ml.

4. The preparation method of a sustained-release microneedle containing minoxidil according to claim 1, wherein In the tip matrix solution, the ratio of the volume of the mixed solution to the mass of the drug-loaded PLGA microsphere powder is 1 mL:(10 - 50) mg.

5. A sustained-release microneedle containing minoxidil prepared by the method according to any one of claims 1 - 4.

6. Use of the sustained-release microneedle containing minoxidil according to claim 5 in the preparation of a product for treating androgenetic alopecia.

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