Preparation method and application of flexible soluble microneedle patch

Abstract

The present invention discloses a preparation method and application of a flexible soluble microneedle patch, and belongs to the technical field of microneedle patches. The microneedle patch prepared by the preparation method provided by the present invention has a high backing water content, good adhesion to the skin, and is tightly attached to skin of various curvatures, and the active ingredients therein are easily absorbed by the skin; the storage time of the microneedle patch can be effectively extended, and the microneedles of the microneedle patch can be ensured to have sufficient strength, and can effectively pierce the stratum corneum of the skin to obtain the corresponding patch effect; the materials used are all soluble, and can be dissolved after penetrating the stratum corneum, and the dissolved components have no toxic side effects on the human body; the microneedles and the backing are made of different materials, which can effectively reduce the preparation cost, and can also realize the graded delivery of active ingredients.

Description

Technical Field

[0001] The invention relates to the technical field of microneedle patches, and in particular to a preparation method and application of a flexible soluble microneedle patch. Background Art

[0002] Microneedle (MN) is a micron-sized array that can pierce the stratum corneum of the skin, forming micron-sized channels, and deliver drugs to the subcutaneous tissue through the skin barrier. The drugs are then absorbed through the subcutaneous blood vessels and enter the systemic circulation to exert their effects. The concept of using microneedles for drug delivery was first proposed in 1976, but due to limitations in preparation technology, microneedle transdermal drug delivery technology only gradually attracted attention in the 1990s. Henry et al. first used solid silicon microneedles to deliver calcein in 1998, which promoted the penetration of calcein into the skin. As a result, the feasibility of microneedle transdermal drug delivery technology has been confirmed and has attracted extensive research.

[0003] At present, microneedle transdermal drug delivery technology has been applied and widely studied in the fields of blood sugar regulation, vaccine delivery, tissue fluid extraction, cancer treatment, and beauty. According to the structure and use of microneedles, microneedles can be divided into five types: solid microneedles, coated microneedles, hollow microneedles, soluble microneedles, and hydrogel microneedles.

[0004] Solid microneedles are mainly made of silicon, ceramics, metals and polymer materials. After use, microchannels are formed on the skin. After the drug solution is applied to the skin surface, it penetrates downward through the microchannels to achieve transdermal drug delivery. It is mainly used with creams and ointments for the treatment of skin diseases. The operation is relatively cumbersome. There is a risk of microneedle breakage during use, which can easily cause skin damage. Coated microneedles fix the drug on the surface of the microneedle by dipping, spraying, dripping, etc. After the coated microneedle penetrates the skin tissue, the drug quickly diffuses from the surface of the microneedle into the skin tissue. Too much coating will affect the sharpness of the microneedle tip, thereby reducing the penetration performance of the microneedle. Limited by the drug loading, it can only be used to deliver very small amounts of drugs such as potent drugs.

[0005] Hollow microneedles are designed based on solid microneedles with microchannels that run through them. Drugs are delivered through the microchannels. The materials used to prepare hollow microneedles include ceramics, metals, silicon, and glass. There are also problems with microneedles being prone to breakage in the skin, causing irritation, and micropores being easily clogged by the microenvironment of the skin tissue, affecting delivery.

[0006] After piercing the skin, the hydrogel microneedle absorbs tissue fluid and swells but does not dissolve, thus achieving controlled release of the drug. The swelling degree of the hydrogel microneedle is related to the degree of cross-linking of the material, which affects the release rate of the drug and the efficiency of extracting tissue fluid. After the drug is administered, the hydrogel microneedle can be removed from the skin without any material remaining under the skin, making it the latest form of delivery.

[0007] Soluble microneedles are made of water-soluble or biodegradable polymers. The drug-carrying forms include drug enrichment at the needle tip and uniform distribution in the needle body. The drug enrichment at the needle tip has higher drug delivery efficiency and is the main option for preparing drug-carrying soluble microneedles. CN113713088A and Jinqiang Wang et al. (Core-Shell Microneedle Gel for Self-Regulated Insulin Delivery, 2018) also disclose a soluble hollow microneedle.

[0008] At present, the soluble microneedles on the market mainly have the following problems: 1. The backing of the soluble microneedle patch is made of water-soluble material. In order to ensure the strength of the microneedle, the existing microneedle preparation technology adopts measures to fully dry the microneedle patch. However, the backing has low water content after drying, and the adhesion to the skin is poor, and the human skin is not easy to absorb the active ingredients in the backing material; 2. In order to ensure the absorbability of the microneedle tip, the needle tip has a certain water content, which will also lead to low strength of the needle body. In order to ensure the strength of the needle tip and maintain the shape of the needle body, insoluble or high molecular excipients are added during the production process, resulting in poor absorption performance of the soluble material; 3. The needle tip and the backing are not prepared in layers, and hydrogel materials are used entirely, resulting in high material costs for the microneedle patch and the inability to carry out targeted graded delivery of active ingredients. Summary of the invention

[0009] The purpose of the present invention is to provide a method for preparing a flexible soluble microneedle patch and its application, so as to solve the problems of insufficient microneedle strength, low water content, poor adhesion to the skin, difficult absorption and utilization of active ingredients, high preparation cost and non-graded delivery of the microneedle patch.

[0010] To achieve the above object, the present invention provides a method for preparing a flexible soluble microneedle patch, the steps of which are as follows:

[0011] S1. Weigh the microneedle body powder raw material, add deionized water, stir until the powder is completely dissolved, and centrifuge to remove bubbles to obtain the needle tip preparation solution;

[0012] S2. Weigh the base preparation powder and add it to deionized water. Stir it in a 90-100°C water bath or oil bath until it is completely dissolved. After cooling to room temperature, centrifuge to remove bubbles to obtain a base preparation solution.

[0013] S3, stirring and mixing the ecoflex A solution and the ecoflex B solution to obtain an isolation preparation solution;

[0014] S4, adding the base preparation powder into deionized water, stirring in a 90-100°C water bath or oil bath until completely dissolved, adding glycerol after cooling to room temperature, and centrifuging to remove bubbles to obtain a gel preparation solution;

[0015] S5, pouring the needle tip making liquid into the groove of the microneedle mold to cover the entire microneedle area, evacuating the vacuum, replenishing the needle tip making liquid, and then scraping off the excess needle tip making liquid;

[0016] S6, pour the base making liquid to cover the entire needle tip area, dry for a certain time, and then quickly pour the prepared isolation making liquid to cover the entire needle tip area, and dry for a certain time;

[0017] S7. Pour the gel making liquid into the mold to cover the groove of the female mold. Repeat the freezing and thawing of the mold containing the above-mentioned making liquid three times, and then demold it.

[0018] Preferably, in step S1, the raw material of the microneedle body powder is sodium hyaluronate, and the mass ratio of the raw material of the microneedle body powder to deionized water is 1:2.

[0019] Preferably, the centrifugation conditions for removing bubbles in steps S1, S2, and S4 are 2000-5000 rpm and centrifugation for 5-10 min.

[0020] Preferably, the base making powder is one of PVA, gelatin and polysaccharide materials.

[0021] Preferably, in step S3, the volume ratio of ecoflex A solution to ecoflex B solution is 3:2.

[0022] Preferably, the mass ratio of the base preparation powder to deionized water in steps S2 and S4 is 1:9, and the glycerol in step S4 accounts for 20% of the total mass of the gel preparation solution.

[0023] Preferably, the vacuuming condition in step S5 is 0.05-0.5 MPa, and maintained for 1-10 min.

[0024] Preferably, the amount of the substrate preparation liquid in step S6 is 1.4-1.6 mL, the amount of the isolation preparation liquid is 0.2-0.3 mL, and the amount of the gel preparation liquid in step S7 is 4-5 mL.

[0025] Preferably, in step S6, drying for a certain period of time after pouring the base making liquid refers to drying at 40°C for 30-60 minutes, and when the base making liquid is dried to a water content of 5-15%, drying for a certain period of time after pouring the isolation making liquid refers to drying at 70°C for 20-40 seconds; and repeated freezing and thawing in step S7 refers to freezing at -80°C and thawing at room temperature.

[0026] The flexible soluble microneedle patch prepared by the preparation method as described above is used in transdermal drug delivery or skin care products, wherein the required drug is applied to the surface of the microneedle, dispersed in the microneedle and the backing matrix, or coated in the center of the microneedle.

[0027] Therefore, the present invention provides a method for preparing a flexible soluble microneedle patch and its application, and its specific technical effects are as follows:

[0028] 1. The microneedle patch prepared by the preparation method provided by the present invention has a backing with a high water content and good adhesion to the skin. The microneedle patch can also be closely attached to skin of various curvatures, so that the active ingredients in the microneedles and the backing are easily absorbed by the skin, thereby ensuring the treatment effect of the skin of various parts under the microneedle patch and improving the utilization rate of the microneedle patch;

[0029] 2. The isolation layer of the microneedle patch prepared by the method provided by the present invention has a complete water-isolating function, which can effectively prevent the moisture in the backing from diffusing to the needle tip and destroying the strength of the needle tip. Therefore, the storage time of the microneedle patch can be effectively extended, and the microneedles of the microneedle patch can be ensured to have sufficient strength to effectively pierce the stratum corneum of the skin and obtain the corresponding patch effect;

[0030] 3. The microneedle patch prepared by the preparation method provided by the present invention has microneedle tip materials, microneedle base layer materials, and backing gel layer materials that are all soluble and can be dissolved after penetrating the stratum corneum, and the dissolved components have no toxic side effects on the human body;

[0031] 4. The microneedle patch prepared by the preparation method provided by the present invention has microneedles and a backing made of different materials, which can effectively reduce the preparation cost and realize the graded delivery of active ingredients.

[0032] The technical solution of the present invention is further described in detail below through the accompanying drawings and embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings required for use in the description of the embodiments of the present invention will be briefly introduced below. Obviously, the accompanying drawings in the following description are only some embodiments of the present invention. For ordinary technicians in this field, other accompanying drawings can be obtained based on these accompanying drawings without paying creative labor.

[0034] Figure 1 Schematic diagram of the microneedle hydrogel patch prepared in Example 2 of the present invention.

[0035] Reference numerals

[0036] 1. Gel layer; 2. Isolation layer; 3. Basal layer; 4. Needle tip; 5. Pig skin. DETAILED DESCRIPTION

[0037] The technical solution of the present invention is further described below through the accompanying drawings and embodiments.

[0038] In order to make the purpose, technical scheme and advantages of the present application clearer, more thorough and more complete, the technical scheme of the present invention is clearly and completely described below through the accompanying drawings and examples. The following detailed descriptions are all descriptions of the embodiments, and are intended to provide further detailed descriptions of the present invention. Unless otherwise specified, all technical terms used in the present invention have the same meaning as those generally understood by those skilled in the art to which the present application belongs.

[0039] The instruments, equipment, reagents and materials used in the examples were all obtained through commercial channels.

[0040] Embodiment 1

[0041] Prepare the required production solution:

[0042] S1.1. Preparation of needle tip preparation solution

[0043] Weigh 5 g of hyaluronic acid, add 10 mL of deionized water, stir until the hyaluronic acid is completely dissolved, centrifuge at 1000 rpm for 10 min, and remove bubbles.

[0044] S1.2. Preparation of substrate preparation solution

[0045] Add 10 mL of deionized water (PVA mass percentage is 10%) to 1 g of PVA powder, stir at 100° C. until PVA is completely dissolved, cool to room temperature, place in a centrifuge, centrifuge at 3000 rpm, centrifuge for 10 min, and remove bubbles.

[0046] S1.3. Preparation of Isolation Solution

[0047] Weigh 3 mL of ecoflex A solution and 1 mL of ecoflex B solution, and stir to mix.

[0048] S1.4. Preparation of gel making solution

[0049] Add 1 g of PVA powder to 10 mL of deionized water (the mass percentage of PVA is 10%), stir in a 90°C water bath until the PVA powder is completely dissolved, cool to room temperature, add 2 mL of glycerol (the mass percentage of glycerol is 20%), place in a centrifuge, 3000 rpm, centrifuge for 10 min, and remove bubbles.

[0050] Embodiment 2

[0051] A flexible soluble microneedle patch is prepared as follows:

[0052] 1) Pour the needle tip preparation liquid prepared in Example 1 into the groove of the microneedle mold to cover the entire microneedle area, place it in a vacuum drying oven and evacuate it at 0.5 MPa for 1 min, then add the needle tip preparation liquid prepared in Example 1 until it covers the groove of the mold.

[0053] 2) After scraping off the excess needle tip preparation liquid, pour in 1.5 mL of base preparation liquid to cover the entire area of ​​the needle tip, and then place it in a 40°C static drying oven for 0.5 h. When the base preparation liquid is about to dry completely, quickly pour in 0.1-0.2 mL of the prepared isolation preparation liquid to cover the needle tip area, and place it in a 70°C drying oven for 50 s.

[0054] 3) Quickly pour 4 mL of gel-making solution to cover the groove of the negative mold, then place the mold containing the gel solution in a -80°C refrigerator for 0.5 h, then thaw it at room temperature, repeat the above freeze-thaw operation three times, and then place it in a 25°C forced air drying oven for 4 h to obtain a soluble microneedle hydrogel patch with a smooth and moist surface, high needle tip strength, as shown in the schematic diagram. Figure 1 shown.

[0055] Embodiment 3

[0056] A flexible soluble microneedle patch was prepared in the same manner as in Example 2, except that:

[0057] In step 1), 4% nicotinamide material is added to the needle tip material;

[0058] Step 3) is dried in a forced air drying oven for 6 hours.

[0059] Embodiment 4

[0060] A flexible soluble microneedle patch was prepared in the same manner as in Example 2, except that:

[0061] Step 1) adding 8% nicotinamide material to the needle tip material;

[0062] In step 2), the mixture is dried in a forced air drying oven for 12 hours.

[0063] Experimental Test 1

[0064] The microneedle strength of the flexible soluble microneedle patches prepared in Examples 2 to 4 was examined by the following method:

[0065] The microneedle patch was fixed on the horizontal test bench of the Shimadzu universal material testing machine with the needle tip facing upwards, and a P / 6 flat-head stainless steel cylindrical probe was used to apply vertical pressure along the microneedle axis at a constant rate of 0.1 mm / s and an excitation force of 0.01 N. This process can record in detail the entire mechanical response from the probe contacting the needle tip until reaching the predetermined end height (i.e., the full length of the microneedle of 400 μm) to evaluate the mechanical properties and deformation characteristics of the microneedle.

[0066] The results are shown in Table 1.

[0067] Table 1

[0068] Experimental Case Strength (N) Embodiment 2 8.14±1.9 Embodiment 3 6.8±1.8 Embodiment 4 2.3±0.91

[0069] It can be seen that the maximum strength of the microneedle can reach 8.14±1.9N. When nicotinamide is added to a 10% sodium hyaluronate solution, the mechanical strength of the microneedle structure is weakened. This discovery reveals the unique interaction of nicotinamide as a functional additive in the modified sodium hyaluronate matrix, which may affect the intermolecular interaction force or crystallization behavior, thereby adjusting the physical properties of the microneedle material.

[0070] Experimental Test 2

[0071] The solubility of the flexible soluble microneedle patches prepared in Examples 2 to 4 was investigated by the following method:

[0072] The microneedle patch was immersed in a constant temperature water bath at 37±0.5℃ to simulate the physiological temperature environment of the human skin surface to ensure the physiological relevance of the experimental conditions. The timing program was started to closely monitor the progress of the experiment. Using the side-mounted electron microscope technology, the dissolution dynamics of the microneedle patch were imaged and recorded with high resolution at preset time intervals, aiming to capture and analyze the morphological changes of the microneedle structure over time in detail.

[0073] This observation process continues until the microneedle structure can no longer be identified as a clear morphological feature by the naked eye, and this node is defined as the "dissolution end point". Subsequently, the sample is taken out of the water bath and an in-depth morphological verification is performed under a high-power microscope to accurately determine and record the final complete dissolution time point.

[0074] The results are shown in Table 2. The microneedle patch prepared by the present invention is soluble. As the drying time increases, although the dissolution rate of the microneedles is initially accelerated, the reduction in the water content of the gel layer leads to an increase in its water absorption capacity. This enhanced water absorption performance delays the overall dissolution process of the microneedle patch in water. Even if the microneedles themselves dissolve quickly, the higher water absorption of the gel layer still prolongs the overall complete dissolution time.

[0075] Table 2

[0076] Experimental Case Dissolution time Embodiment 2 3min Embodiment 3 3.25min Embodiment 4 6.45min

[0077] Experimental Test 3

[0078] The degree of fit between the flexible soluble microneedle patches prepared in Examples 2 to 4 and the skin was investigated as follows:

[0079] The pig skin samples were cleaned with water, and a microneedle mask was applied and inverted to monitor and record the mask shedding time and evaluate the relationship between the moisture content of the gel layer and the adhesion performance.

[0080] The results are shown in Table 3. The increase in gel drying time leads to a decrease in moisture, which reduces the adhesion to pig skin. After comprehensive consideration, 4h was selected as the optimal drying time, which can maintain an appropriate moisture level and ensure good adhesion of the mask to the skin.

[0081] Table 3

[0082] Implementation Cases Drop Time Embodiment 2 3h Embodiment 3 2h Experimental Example 4 10min

[0083] Therefore, the microneedle patch prepared by the preparation method provided by the present invention has a high backing water content, good adhesion to the skin, and fits tightly to skin of various curvatures, and the active ingredients therein are easily absorbed by the skin; the storage time of the microneedle patch can be effectively extended, and the microneedles of the microneedle patch can be ensured to have sufficient strength to effectively pierce the stratum corneum of the skin to obtain the corresponding patch effect; the materials used are all soluble and can be dissolved after penetrating the stratum corneum, and the dissolved components have no toxic side effects on the human body; the microneedles and the backing are made of different materials, which can effectively reduce the preparation cost and realize the graded delivery of the active ingredients.

[0084] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that they can still modify or replace the technical solution of the present invention with equivalents, and these modifications or equivalent replacements cannot cause the modified technical solution to deviate from the spirit and scope of the technical solution of the present invention.

Claims

1. A method for preparing a flexible soluble microneedle patch, characterized in that: Here are the steps: S1. Weigh the microneedle body powder raw material, add deionized water, stir until the powder is completely dissolved, and centrifuge to remove bubbles to obtain the needle tip preparation solution; S2. Weigh the base preparation powder and add it to deionized water. Stir it in a 90-100°C water bath or oil bath until it is completely dissolved. After cooling to room temperature, centrifuge to remove bubbles to obtain a base preparation solution. S3, stirring and mixing the ecoflex A solution and the ecoflex B solution to obtain an isolation preparation solution; S4, adding the base preparation powder into deionized water, stirring in a 90-100°C water bath or oil bath until completely dissolved, adding glycerol after cooling to room temperature, and centrifuging to remove bubbles to obtain a gel preparation solution; S5, pouring the needle tip making liquid into the groove of the microneedle mold to cover the entire microneedle area, evacuating the vacuum, replenishing the needle tip making liquid, and then scraping off the excess needle tip making liquid; S6, pour the base making liquid to cover the entire needle tip area, dry for a certain time, and then quickly pour the prepared isolation making liquid to cover the entire needle tip area, and dry for a certain time; S7, pour the gel making liquid into the mold to cover the groove of the female mold, freeze and thaw the mold containing the making liquid three times, and then demold it; In step S1, the raw material of the microneedle body powder is sodium hyaluronate, and the mass ratio of the raw material of the microneedle body powder to deionized water is 1:2; The base making powder is one of PVA, gelatin and polysaccharide materials; In step S3, the volume ratio of ecoflex A solution to ecoflex B solution is 3:2; The mass ratio of the base preparation powder to deionized water in steps S2 and S4 is 1:9, and the glycerol in step S4 accounts for 20% of the total mass of the gel preparation solution; In the step S6, drying for a certain time after pouring the base making liquid refers to drying at 40° C. for 30-60 minutes. When the base making liquid is dried to a water content of 5-15%, drying for a certain time after pouring the isolation making liquid refers to drying at 70° C. for 20-40 seconds. In the step S7, repeated freezing and thawing refers to freezing at -80° C. and thawing at room temperature.

2. The method for preparing a flexible soluble microneedle patch according to claim 1, characterized in that: The centrifugal conditions for removing bubbles in steps S1, S2, and S4 are 2000-5000 rpm and centrifugation for 5-10 min.

3. The method for preparing a flexible soluble microneedle patch according to claim 1, characterized in that: The vacuum condition in step S5 is 0.05-0.5 MPa, and is maintained for 1-10 minutes.

4. The method for preparing a flexible soluble microneedle patch according to claim 1, characterized in that: The amount of the substrate preparation liquid in step S6 is 1.4-1.6 mL, the amount of the isolation preparation liquid is 0.2-0.3 mL, and the amount of the gel preparation liquid in step S7 is 4-5 mL.

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