Soluble Microneedles and Their Preparation Methods

Abstract

The present invention discloses a preparation method of soluble microneedles. The preparation method includes the following steps: S1. Prepare a silicon microneedle array on the surface of a silicon wafer; S2. Spread a soluble microneedle material solution on the silicon microneedle array and the surface of the silicon wafer, and obtain a soluble microneedle membrane after curing; S3. Strip the soluble microneedle membrane from the silicon microneedle array and the surface of the silicon wafer by pickling. The back surface of the soluble microneedle membrane has a microgroove array; S4. Pour a soluble microneedle material solution and / or a support material solution into the microgroove array of the soluble microneedle membrane, and obtain soluble microneedles after curing. The preparation method of the soluble microneedles of the present invention is relatively simple, the service life of the silicon wafer template is long, the process cost is low, large-area preparation can be realized, it is suitable for mass industrial production, and the prepared microneedles have relatively high mechanical strength.

Description

Technical Field

[0001] The present invention belongs to the technical field of microneedles, and particularly relates to a soluble microneedle and a preparation method thereof. Background Art

[0002] Microneedle transdermal drug delivery is a new technology for delivering drugs in a minimally invasive manner on the skin, and has always been a research hotspot in the fields of biotechnology and medicine. This technology loads drugs or active ingredients into a micron-scale microneedle array, forms micron-sized channels on the skin surface, and directly guides the drugs or active ingredients through the stratum corneum barrier into the epidermis or the upper layer of the dermis, so that the drugs or active ingredients can directly participate in microcirculation through capillaries to achieve local precise treatment. In addition, since microneedles do not touch the pain nerves in the dermis layer, microneedle drug delivery does not cause pain to the human body and does not cause skin damage.

[0003] The preparation of microneedle arrays is the core of microneedle transdermal drug delivery technology. As a new physical penetration enhancement technology, it is composed of micro-needle tips with lengths ranging from dozens of microns to several millimeters and tip diameters less than dozens of microns arranged in an array on a base. Microneedles can be classified into two major categories according to the types of manufacturing materials: solid microneedles and soluble microneedles. Solid microneedles usually have two types of drug delivery methods: one is to pierce the skin with a solid microneedle array to generate micron-sized channels on the skin surface, and the drug penetrates into the skin layer through these channels to achieve the purpose of transdermal drug delivery; the other is to coat the drug on the surface of the microneedle (i.e., coated microneedles) or place the drug in the holes of the perforated microneedles (i.e., hollow microneedles), and deliver the drug to the epidermis of the skin while piercing the skin. Soluble microneedles are usually made of biodegradable polymers to form a soluble microneedle array and encapsulate drugs or active ingredients. After the microneedles penetrate the skin, they dissolve and release the drugs or active ingredients. Compared with solid microneedles, the whole of soluble microneedles is a drug-loading area, and has obvious advantages in drug loading capacity. In addition, soluble microneedles also have no risk of broken needles remaining in the body like solid microneedles, and the cost is relatively low, having better commercial prospects.

[0004] In the prior art, soluble microneedles are usually prepared by adding a solution of soluble microneedle raw materials to a PDMS microneedle female mold. After the solution of soluble microneedle raw materials is fully cured, it is peeled off from the mold. For example, in Chinese Patent CN111603435A, first, a microneedle male mold is prepared by using laser direct writing technology, then a PDMS microneedle female mold is obtained by casting with this male mold, and finally, the prepared mixed solution of soluble microneedle raw materials is added to the PDMS female mold, and soluble microneedles are obtained by demolding; in Chinese Patent CN111544758A, first, a PDMS mold plate is prepared by using PDMS and a curing agent, then a microneedle female mold is etched on the PDMS mold plate by using an integrated fiber optic carbon dioxide laser marking machine, and finally, the prepared mixed solution of soluble microneedle raw materials is added to the PDMS female mold prepared by this method, and soluble microneedles are obtained by demolding; in Chinese Patent CN113069683A, similarly, a PDMS microneedle female mold is first prepared by casting with an ETPTA microneedle template, then the solution of soluble microneedle raw materials is filled into the microneedle female mold by high-speed centrifugation and cured by ultraviolet light, and finally, soluble microneedles are obtained by demolding after full curing; it is mentioned in Patent CN114681604A that first, a mixed solution of PDMS and a curing agent is poured into a rectangular container with a single-crystalline silicon microneedle male mold, and a PDMS microneedle female mold is cured, and then a soluble microneedle for hand, foot and mouth disease vaccine is prepared by using the vacuum molding method. In addition, it is mentioned in other patents such as CN115363992A, CN110897996A, and CN111558128A that a soluble microneedle array is prepared by using a microneedle female mold template.

[0005] Basically in the prior art, a microneedle array female mold made of easily curable materials such as PDMS is first prepared, and then a solution of soluble microneedle raw materials is injected into the female mold for curing, and soluble microneedles are obtained by demolding. The above preparation method is relatively complex; there is a problem that the PDMS female mold is not completely demolded, and usually special treatment (such as plasma treatment) is required before use. Even after treatment, there are still problems such as incomplete demolding of microneedles and low yield of microneedle products, and the service life is relatively low; in addition, since the prepared soluble microneedles need to take into account functionality, the mechanical strength is relatively poor.

[0006] Therefore, in view of the above technical problems, it is necessary to provide a soluble microneedle and a preparation method thereof. Summary of the Invention

[0007] In view of this, the purpose of the present invention is to provide a soluble microneedle and a preparation method thereof.

[0008] In order to achieve the above purpose, the technical solution provided by an embodiment of the present invention is as follows:

[0009] A preparation method of a soluble microneedle, the preparation method comprising the following steps:

[0010] S1. Prepare a silicon microneedle array on the surface of a silicon wafer;

[0011] S2. Spread a soluble microneedle material solution on the silicon microneedle array and the surface of the silicon wafer, and obtain a soluble microneedle membrane after curing;

[0012] S3. Strip the soluble microneedle membrane from the silicon microneedle array and the surface of the silicon wafer by pickling. The back surface of the soluble microneedle membrane has a microgroove array;

[0013] S4. Pour a soluble microneedle material solution and / or a support material solution into the microgroove array of the soluble microneedle membrane, and obtain soluble microneedles after curing.

[0014] In one embodiment, step S1 includes:

[0015] Prepare a patterned mask on the surface of the silicon wafer;

[0016] Etch the surface of the silicon wafer through a wet chemical etching process;

[0017] Remove the mask to form a silicon microneedle array on the surface of the silicon wafer.

[0018] In one embodiment, preparing a patterned mask on the surface of the silicon wafer specifically includes:

[0019] Prepare a silicon oxide layer with a thickness of 0.5 μm to 2 μm on the silicon wafer;

[0020] Coat a photoresist layer with a thickness of 5 μm to 10 μm on the surface of the silicon oxide layer and bake it for curing;

[0021] Perform photolithography, exposure, and development to transfer the mask pattern on the mask template to the photoresist layer. The diameter of the circular spots in the mask pattern is 200 μm to 600 μm, and the center distance between adjacent circular spots is 500 μm to 2000 μm.

[0022] In one embodiment, in the silicon microneedle array, the height of the silicon microneedles is 0.1 mm to 1 mm, the bottom size of the silicon microneedles is 0.1 mm to 1 mm, and the spacing between adjacent silicon microneedles is 0.3 mm to 2 mm.

[0023] In one embodiment, step S1 further includes:

[0024] Prepare a silicon oxide layer and / or a silicon nitride layer on the silicon microneedle array and the surface of the silicon wafer.

[0025] In one embodiment, preparing a silicon oxide layer on the silicon microneedle array and the surface of the silicon wafer specifically includes:

[0026] At a temperature of 600°C to 1200°C, an oxidation gas is introduced to oxidize the surface of the silicon wafer. The oxidation time is 0.5 h to 24 h, and a silicon oxide layer with a thickness of 0.02 μm to 2 μm is prepared. Among them, the oxidation gas is oxygen, or water vapor, or a mixed gas of oxygen and water vapor.

[0027] In one embodiment, the preparation of the silicon nitride layer on the silicon micro-needle array and the silicon wafer surface is specifically as follows:

[0028] Ammonia gas and silane gas are introduced into a tubular vacuum furnace tube in a ratio of 2:1 to 10:1, and a silicon nitride thin film is deposited by PECVD process. The discharge pressure is 150 Pa to 300 Pa, the discharge power is 1000 W to 3000 W, the substrate temperature is 300°C to 500°C, and the deposition time is 0.5 h to 12 h. A silicon nitride layer with a thickness of 0.05 μm to 1 μm is prepared.

[0029] In one embodiment, the specific step S3 is as follows:

[0030] The silicon wafer with the soluble micro-needle film is placed in a fluorine-containing acidic solution for reaction. The reaction temperature is 0°C to 50°C, and the reaction time is 5 s to 5000 s.

[0031] In one embodiment, the fluorine-containing acidic solution is an aqueous solution containing hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride, and the mass concentration of hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride is 0.1% to 20%.

[0032] In one embodiment, the soluble micro-needle material includes at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen, collagen tripeptide, polylactic acid, polyethylene, polypropylene, polymethyl acrylate, polyvinyl alcohol or polymethyl methacrylate.

[0033] In one embodiment, the support material includes at least one of gelatin, silicone rubber, polyacrylamide polymers, polymethyl methacrylate, poly-p-dioxanone, polydimethylsiloxane.

[0034] The technical solution provided by another embodiment of the present invention is as follows:

[0035] A soluble micro-needle, which is prepared by the above preparation method.

[0036] The present invention has the following beneficial effects:

[0037] The preparation method of the soluble micro-needle of the present invention is relatively simple, the service life of the silicon wafer template is long, the process cost is low, large-area preparation can be realized, it is suitable for mass industrial production, and the prepared micro-needles have relatively high mechanical strength. Description of the Drawings

[0038] To more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the accompanying drawings required for the description of the embodiments or the prior art. Obviously, the accompanying drawings in the following description are only some embodiments recorded in the present application. For those of ordinary skill in the art, without creative efforts, other accompanying drawings can also be obtained based on these drawings.

[0039] Figure 1 It is a schematic flow chart of the preparation method of soluble microneedles in the present invention;

[0040] Figures 2a - 2f It is a process flow chart of the preparation method of soluble microneedles in the present invention;

[0041] Figure 3a 、 3b It is a scanning electron microscope image of soluble microneedles at different magnification ratios in a specific embodiment of the present invention. Detailed implementation manners

[0042] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0043] Refer Figure 1 As shown, the preparation method of soluble microneedles in the present invention includes the following steps:

[0044] S1. Refer Figure 2a As shown, a silicon microneedle array 20 is prepared on the surface of a silicon wafer 10.

[0045] The silicon microneedle array can be prepared by using a photolithography method to prepare a mask and a wet chemical etching process, or by using a laser or water jet mask scribing and wet chemical etching process.

[0046] Exemplarily, the preparation of the silicon microneedle array by using a photolithography method to prepare a mask and a wet chemical etching process includes:

[0047] Preparing a patterned mask on the surface of the silicon wafer;

[0048] Etching the surface of the silicon wafer through a wet chemical etching process;

[0049] Removing the mask to form a silicon microneedle array on the surface of the silicon wafer.

[0050] Preferably, the preparation process of the patterned mask is specifically:

[0051] Prepare a silicon oxide layer with a thickness of 0.5 μm to 2 μm on a silicon wafer;

[0052] Coat a photoresist layer with a thickness of 5 μm to 10 μm on the surface of the silicon oxide layer, and bake and cure it. Preferably, the photoresist layer is a negative photoresist;

[0053] Perform photolithography, exposure, and development to transfer the mask pattern on the mask to the photoresist layer. The diameter of the circular spots in the mask pattern is 200 μm to 600 μm, and the center distance between adjacent circular spots is 500 μm to 2000 μm.

[0054] Preferably, in the silicon microneedle array of the present invention, the height of the silicon microneedles is 0.1 mm to 1 mm, the bottom size of the silicon microneedles is 0.1 mm to 1 mm, and the spacing between adjacent silicon microneedles is 0.3 mm to 2 mm.

[0055] Furthermore, step S1 further includes:

[0056] Refer Figure 2b As shown, prepare a silicon oxide layer 30 and / or a silicon nitride layer (not shown) on the surface of the silicon microneedle array 20 and the silicon wafer 10.

[0057] Among them, the silicon oxide layer 30 is prepared by a thermal oxidation process. Specifically:

[0058] At a temperature of 600 °C to 1200 °C, introduce an oxidation gas to oxidize the surface of the silicon wafer. The oxidation time is 0.5 h to 24 h to prepare a silicon oxide layer with a thickness of 0.02 μm to 2 μm. Among them, the oxidation gas is oxygen, or water vapor, or a mixed gas of oxygen and water vapor.

[0059] The silicon nitride layer is prepared by a PECVD process. Specifically:

[0060] Introduce ammonia gas and silane gas into the tube of a tube-type vacuum furnace in a ratio of 2:1 to 10:1, and deposit a silicon nitride thin film by the PECVD process. The discharge pressure is 150 Pa to 300 Pa, the discharge power is 1000 W to 3000 W, the substrate temperature is 300 °C to 500 °C, and the deposition time is 0.5 h to 12 h to prepare a silicon nitride layer with a thickness of 0.05 μm to 1 μm.

[0061] The advantages of preparing the silicon oxide layer or the silicon nitride layer are as follows:

[0062] On the one hand, preparing the silicon oxide layer or the silicon nitride layer as a stripping material facilitates the stripping of soluble microneedles;

[0063] On the other hand, the porous silicon oxide layer or silicon nitride layer can make the soluble microneedle material conformal on the surface of the silicon microneedles.

[0064] S2. Refer to Figure 2c As shown, spread the soluble microneedle material solution evenly on the surfaces of the silicon microneedle array 20 and the silicon wafer 10, and after curing, obtain the soluble microneedle film 40.

[0065] Among them, the soluble microneedle material includes at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen, collagen tripeptide, polylactic acid, polyethylene, polypropylene, methyl polyacrylate, polyvinyl alcohol, or polymethyl methacrylate, etc.

[0066] Furthermore, in this step, other drugs or active ingredients can also be added according to the function of the microneedles.

[0067] S3. Refer to Figure 2d As shown, strip the soluble microneedle film 40 from the surfaces of the silicon microneedle array 20 and the silicon wafer 10 by pickling. The back surface of the soluble microneedle film 40 has a microgroove array 41.

[0068] The stripping process of the soluble microneedle film 40 is specifically as follows:

[0069] Place the silicon wafer with the soluble microneedle film prepared in an acidic solution containing fluorine and react. The reaction temperature is 0°C to 50°C, and the reaction time is 5s to 5000s.

[0070] Among them, the acidic solution containing fluorine is an aqueous solution containing hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride, etc. The mass concentration of hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride, etc. is 0.1% to 20%.

[0071] S4. Refer to Figure 2e As shown, pour the soluble microneedle material solution and / or the support material solution into the microgroove array 41 of the soluble microneedle film 40, and after curing, obtain Figure 2f the soluble microneedles as shown.

[0072] Among them, the soluble microneedle material includes at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen, collagen tripeptide, polylactic acid, polyethylene, polypropylene, methyl polyacrylate, polyvinyl alcohol, or polymethyl methacrylate, etc.;

[0073] The support material includes at least one of gelatin, silicone rubber, polyacrylamide polymers, polymethyl methacrylate, poly(p-dioxanone), polydimethylsiloxane, etc.

[0074] In a specific embodiment of the present invention, the preparation method of the soluble microneedles includes the following steps:

[0075] 1. Use photolithography to prepare a mask and wet chemical etching process to prepare an array-distributed silicon microneedle array on a single-crystalline silicon wafer. The height dimension of the silicon microneedles is about 200μm, the bottom dimension of the silicon microneedles is about 150μm, and the spacing between adjacent silicon microneedles is about 450μm.

[0076] 2. Place the monocrystalline silicon wafer with the silicon microneedle array prepared therein into an oxidation furnace, and introduce water vapor carried by O2 with a flow rate of 2500 sccm into the furnace as the oxidation source gas for oxidation. The oxidation temperature is 1000 °C, and the oxidation time is 1 h. The thickness of the obtained silicon oxide layer is about 250 nm.

[0077] 3. Prepare a soluble microneedle material solution, including by mass: 30 parts of hyaluronic acid, 20 parts of collagen tripeptide, 10 parts of hyaluronic acid, 10 parts of glutathione, 5 parts of ascorbic acid, 5 parts of niacinamide, 3 parts of salicylic acid, 2 parts of other active substances, and 15 parts of deionized water.

[0078] Then place the monocrystalline silicon wafer with the silicon microneedle array prepared therein into a sterile rectangular groove container, add the prepared soluble microneedle material solution thereto, and make it evenly spread on the surface of the silicon microneedle array. Then place the container into a vacuum and sterile reaction chamber for curing. The curing temperature is 200 °C, the pressure is 50 - 100 Pa, and the curing time is 10 min to obtain a soluble microneedle membrane.

[0079] 4. Place the monocrystalline silicon wafer with the soluble microneedle membrane prepared therein into a hydrofluoric acid solution with a mass concentration of 2% and react for 10 min to peel the soluble microneedle membrane from the surface of the silicon microneedle array and the silicon wafer.

[0080] 5. Flip the peeled soluble microneedle membrane and spread it flat on a fixing device, inject the above-prepared soluble microneedle material solution into the microgroove array on the back, and place it into a vacuum and sterile reaction chamber for curing again. The curing temperature is 200 °C, the pressure is 50 - 100 Pa, and the curing time is 10 min, thereby preparing a soluble microneedle for freckle removal. Its scanning electron microscope images are as Figure 3a 、 3b shown (the magnification factors are 60 times and 300 times respectively).

[0081] In the present invention, the outer layer of the soluble microneedle is subjected to two curing treatments, and has a higher compressive yield strength than conventional soluble microneedles, that is, has higher mechanical strength. In addition, this soluble microneedle can also avoid the problem of sacrificing mechanical strength due to considering the functionality of the absorption layer. Through the hierarchical curing control of the inner and outer layers in the present invention, while ensuring the functionality of the microneedle, the mechanical properties of the microneedle are also taken into account.

[0082] It should be understood that the above embodiments are exemplary descriptions of the soluble microneedle preparation method. In other embodiments, other types of soluble microneedles can be prepared by other soluble microneedle material solutions or support material solutions, and no further examples will be given here for illustration.

[0083] From the above technical solutions, it can be seen that the present invention has the following advantages:

[0084] The preparation method of the soluble microneedles of the present invention is relatively simple, the silicon wafer template has a long service life, the process cost is low, large-area preparation can be achieved, it is suitable for mass industrial production, and the prepared microneedles have relatively high mechanical strength.

[0085] For those skilled in the art, it is obvious that the present invention is not limited to the details of the above exemplary embodiments, and without departing from the spirit or basic characteristics of the present invention, the present invention can be implemented in other specific forms. Therefore, from any point of view, the embodiments should be regarded as exemplary and non-limiting. The scope of the present invention is defined by the appended claims rather than the above description. Therefore, all changes falling within the meaning and scope of the equivalent elements of the claims are intended to be included in the present invention. Any reference signs in the claims should not be construed as limiting the claimed invention.

[0086] In addition, it should be understood that although this specification is described according to embodiments, not every embodiment only contains an independent technical solution. This narrative way of the specification is only for clarity. Those skilled in the art should regard the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A preparation method of soluble microneedles, characterized in that, The preparation method includes the following steps: S1. Prepare a silicon micro-needle array on the surface of a silicon wafer, and prepare a silicon oxide layer and / or a silicon nitride layer on the silicon micro-needle array and the surface of the silicon wafer; S2. Spread a soluble micro-needle material solution on the silicon micro-needle array and the surface of the silicon wafer, and obtain a soluble micro-needle membrane after curing; S3. Strip the soluble micro-needle membrane from the silicon micro-needle array and the surface of the silicon wafer by pickling. The back surface of the soluble micro-needle membrane has a micro-groove array; S4. Pour a soluble micro-needle material solution and a support material solution into the micro-groove array of the soluble micro-needle membrane, and obtain soluble micro-needles after curing; The step S1 further includes: preparing a silicon oxide layer and / or a silicon nitride layer on the silicon micro-needle array and the surface of the silicon wafer; The step S3 specifically is: placing the silicon wafer with the soluble micro-needle membrane prepared thereon in an acidic solution containing fluorine for reaction, the reaction temperature is 0°C to 50°C, and the reaction time is 5 s to 5000 s.

2. The preparation method according to claim 1, characterized in that, The step S1 includes: Preparing a patterned mask on the surface of the silicon wafer; Etching the surface of the silicon wafer by a wet chemical etching process; Removing the mask to form a silicon micro-needle array on the surface of the silicon wafer.

3. The preparation method according to claim 2, characterized in that, Preparing a patterned mask on the surface of the silicon wafer specifically is: Preparing a 0.5 µm to 2 µm thick silicon oxide layer on the silicon wafer; Coating a 5 µm to 10 µm thick photoresist layer on the surface of the silicon oxide layer and baking and curing it; Performing photolithography, exposure, and development to transfer the mask pattern on the mask plate to the photoresist layer. The diameter of the circular spots in the mask pattern is 200 µm to 600 µm, and the center distance between adjacent circular spots is 500 µm to 2000 µm.

4. The preparation method according to claim 1, wherein, In the silicon micro-needle array, the height of the silicon micro-needles is 0.1 mm to 1 mm, the bottom size of the silicon micro-needles is 0.1 mm to 1 mm, and the distance between adjacent silicon micro-needles is 0.3 mm to 2 mm.

5. The preparation method according to claim 1, characterized in that, Preparing a silicon oxide layer on the silicon micro-needle array and the surface of the silicon wafer specifically is: At a temperature of 600°C to 1200°C, introducing an oxidation gas to oxidize the surface of the silicon wafer, the oxidation time is 0.5 h to 24 h, and a silicon oxide layer with a thickness of 0.02 µm to 2 µm is prepared. Among them, the oxidation gas is oxygen, or water vapor, or a mixed gas of oxygen and water vapor; And / or Preparing a silicon nitride layer on the silicon micro-needle array and the surface of the silicon wafer specifically is: Introducing ammonia gas and silane gas into a tubular vacuum furnace tube in a ratio of 2:1 to 10:1, depositing a silicon nitride thin film by PECVD process, the discharge pressure is 150 Pa to 300 Pa, the discharge power is 1000 W to 3000 W, the substrate temperature is 300°C to 500°C, and the deposition time is 0.5 h to 12 h, and a silicon nitride layer with a thickness of 0.05 µm to 1 µm is prepared.

6. The preparation method according to claim 1, characterized in that, The acidic solution containing fluorine is an aqueous solution containing hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride, and the mass concentration of hydrofluoric acid, or ammonium fluoride, or ammonium bifluoride is 0.1% to 20%.

7. The preparation method according to claim 1, wherein, The soluble micro-needle material includes at least one of sodium hyaluronate, hyaluronic acid, sodium alginate, collagen, polylactic acid, polyethylene, polypropylene, methyl polyacrylate, polyvinyl alcohol, or polymethyl methacrylate; and / or The supporting material includes at least one of gelatin, silicone rubber, polyacrylamide polymers, polymethyl methacrylate, poly(p-dioxanone), and polydimethylsiloxane.

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