Soluble drug-loaded microneedle patch and manufacturing process therefor

Abstract

Provided are a soluble drug-loaded microneedle patch and a manufacturing process therefor. The manufacturing process comprises the following steps: S1, injecting a soluble microneedle solution into microneedle grooves of a microneedle female mold to form microneedles, the soluble microneedle solution forming protruding liquid droplets on surfaces of the corresponding microneedle grooves in the microneedle female mold; S2, sequentially performing semi-curing drying treatment and semi-curing humidification treatment on the microneedle female mold containing the protruding liquid droplets to obtain pre-treated protrusions; and S3, press-bonding a spacer to the pre-treated protrusions, followed by drying and demolding to obtain the final product. By replacing an adhesive layer with the spacer and performing semi-curing drying treatment and semi-curing humidification treatment on the microneedle female mold containing the protruding liquid droplets, the process improves the adhesion performance between the spacer and the soluble microneedle solution, enables detachment of the microneedles formed in the microneedle female mold from the microneedle grooves, achieves manufacture of the soluble microneedle patch, and avoids adverse effects of adhesive material penetration on microneedle safety and drug efficacy stability.

Description

A soluble drug-loaded microneedle patch and its preparation process

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims priority to Chinese patent application number 202311870215.4 filed with the Chinese Patent Office on December 29, 2023, entitled “A Process for Preparing Soluble Drug-Loaded Microneedle Patches,” the entire contents of which are incorporated by reference into this disclosure. Technical Field

[0003] The present application relates to the field of medical and cosmetic microneedle technology, and in particular to a soluble drug-loaded microneedle patch and a preparation process thereof. Background Art

[0004] At present, the preparation process of soluble microneedle patches in related technologies is mainly as follows: injecting the microneedle solution into the microneedle female mold (the microneedle female mold is generally made of silicone, and microneedle grooves in the shape of microneedles are formed on the silicone, which are used to fill the microneedle solution and form microneedles after solidification. The microneedle grooves include the needle tip groove and the root groove, and the root groove is close to one end of the surface of the microneedle mold female mold), and then covering the microneedle female mold filled with the microneedle solution with a sticky layer. The sticky layer is used to bond the microneedles formed in the microneedle female mold, so that the microneedles are fixedly bonded to the sticky layer, which facilitates the demolding and separation of the solidified microneedles from the microneedle female mold to form a soluble microneedle patch.

[0005] The main component of the viscose material in the viscous layer of related art is generally a rubber or resin colloid. This viscose material easily penetrates into the interior of the microneedles, resulting in the microneedles containing the viscose material components. During use, the microneedles penetrate the human body, and the viscose material that has penetrated the microneedles enters the body through the channel formed by the microneedles puncturing the skin, which can easily cause adverse effects on the human body. Furthermore, since the components of the viscose material penetrate into the microneedles, they can affect the effectiveness of the microneedle components. Different viscose materials have different effects on different microneedle components.

[0006] Dissolvable microneedle patches prepared using the prior art pose potential safety and efficacy risks due to the penetration of adhesive into the microneedles. Therefore, preventing the effects of adhesive penetration on the microneedles and improving the safety and efficacy of dissolvable microneedle patches are pressing technical challenges in the industry.

[0007] In view of this, this application is hereby filed. Summary of the Invention

[0008] In order to solve the above technical problems, the present application provides a soluble drug-loaded microneedle patch and a preparation process thereof, which uses a gasket instead of a sticky layer, and improves the adhesion performance between the gasket and the soluble microneedle solution by semi-curing drying and semi-curing wetting treatments on the microneedle female mold containing raised droplets. The microneedles formed in the microneedle female mold can be separated from the microneedle grooves, thereby realizing the preparation of a soluble microneedle patch and avoiding the influence of the penetration of adhesive materials in the existing microneedle patch preparation process on the safety of the microneedles and the stability of the drug efficacy.

[0009] In order to achieve the above objectives, this application adopts the following technical solutions:

[0010] In a first aspect, the present application provides a process for preparing a soluble drug-loaded microneedle patch, comprising the following steps:

[0011] S1. Injecting a soluble microneedle solution into the microneedle grooves of the microneedle negative mold, so that the soluble microneedle solution fills the microneedle grooves to form microneedles, and the soluble microneedle solution forms protruding droplets on the surface of the corresponding microneedle grooves of the microneedle negative mold;

[0012] S2, sequentially performing a semi-curing drying treatment and a semi-curing wetting treatment on the microneedle female mold containing the protruding droplets in step S1, so that the protruding droplets form pre-treated protrusions;

[0013] S3. Pressing the gasket onto the pre-treated protrusions described in step S2, drying, and demolding to obtain the soluble drug-loaded microneedle patch.

[0014] In an optional embodiment, the concentration of the soluble microneedle preparation in the soluble microneedle solution in step S1 of the present application only needs to meet the conventional processing requirements in the art, and the mass percentage of the soluble microneedle preparation in the soluble microneedle solution is higher than 30%, preferably 30%-50%.

[0015] Further optionally, the soluble microneedle preparation is a conventional preparation in the art, including a soluble microneedle skeleton material.

[0016] In an optional embodiment, the soluble microneedle skeleton material is polyester, polyhydroxyalkanoate, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate, polyacrylamide, modified polypropylene, polyhydroxyalkanoate-polyethylene glycol, poly α-hydroxy acid, poly β-hydroxy acid, polyhydroxybutyrate, polyesteramide, polycaprolactone, polylactide, polyglycolic acid, polydioxanone, polyorthoester, polyetherester, polyanhydride, glycolic acid-trimethylene carbonate copolymer, polyphosphate, polyphosphate carbamate, At least one of polyamino acid, polycyanoacrylate, polytrimethylene carbonate, polycarbonate, polycreatine polyphosphate, chitosan, dextran, heparin, hyaluronic acid, sucrose, trehalose, mannitol, chondroitin sulfate, Tween 80, gelatin, polylactic acid-co-glycolic acid, polyvinyl pyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, maltose, hydroxypropyl-β-cyclodextrin, polylactic acid, polyethylene glycol, glycerol, sodium chloride, inulin, starch and glycogen.

[0017] In an optional embodiment, the soluble microneedle solution further contains a drug.

[0018] In an optional embodiment, the drug is doxorubicin, triamcinolone acetonide, teriparatide, abalaparatide, GLP-1 analogs, growth factors, insulin, acetyl hexapeptide, pilocarpine, hyaluronic acid, tranexamic acid, glutathione, nicotinamide, calcipotriol & betamethasone, monoclonal antibodies, influenza vaccine and measles rubella inactivated vaccine, pilocarpine, adenosine, horse oil, doxorubicin, ascorbic acid, ferulic acid, retinyl retinoate, ascorbic acid, zolmitriptan, tilibon, 4-n-butylresorcinol, lidocaine, aminocaine, encephalitis vaccine, mitomycin, semaglutide, inactivated split influenza virus hemagglutinin vaccine, glucagon, parathyroid hormone (1-34), At least one of 15T vaccine, platelet-rich fibrin (I-PRF), C19-A3 GNP (gold nanoparticles), polio vaccine, adalimumab, IVT aflibercept, tuberculin (purified protein derivative), sumatriptan succinate, ipilimumab, nivolumab, indocyanine green, hepatitis B vaccine, S-OIV influenza A (H1N1) intradermal vaccine, levodopa, recombinant plasmin, platelet-rich plasma (PRP), botulinum toxin type A, Staphylococcal enterotoxin B vaccine, scrub typhus vaccine, SARS-CoV-2 vaccine, malaria vaccine, HIV vaccine, inactivated rotavirus vaccine, tuberculosis vaccine, porcine circovirus type 2 vaccine, rabies vaccine, HPV vaccine, melanoma vaccine, porcine reproductive and respiratory syndrome virus (PRRSV) vaccine, Ebola virus vaccine, Zika vaccine, respiratory syncytial virus (RSV) vaccine, and acute respiratory syndrome coronavirus vaccine.

[0019] The injection described in step S1 of the present application is a conventional method in the art, including but not limited to injection of the soluble microneedle solution by spraying or filling, and this injection method is not specifically limited here.

[0020] The raised droplets described in step S1 of the present application can be increased in mass based on the density and viscosity of the soluble microneedle solution used, based on the mass of the soluble microneedle solution required to be injected into the microneedles, so that the soluble microneedle solution forms suitable raised droplets on the surface of the microneedle female mold. In the present application, if the raised droplets are too large, the microneedle solution can easily overflow the space between the gasket and the female mold surface when laminating with the gasket, causing different microneedle patches to adhere to each other or partially connect into pieces. During the subsequent drying process, due to different drying degrees, the needle body is easily broken during demolding. At the same time, when the microneedle solution overflowing the space between the gasket and the female mold surface spreads and adheres to form a sheet or partially forms a sheet, the solution tension causes the solution to aggregate, causing the microneedle solution filled in the root groove to escape from the root groove and flow to the connection area outside the gasket, resulting in the root solution being unable to completely fill the microneedle groove. The prepared microneedle patch has new problems such as bubbles, incomplete needle shape, and missing needles in the microneedles, which causes the microneedle body to fall off the gasket after demolding, reducing the yield of the microneedle patch product and increasing the cost. Technicians in this field can also use the following experience to obtain raised droplets. Based on a microneedle female mold with a volume of 5-95nl, the mass of the raised droplets is 0.01-0.40mg.

[0021] In an optional embodiment, the pre-treated protrusions in step S2 of the present application are soft-glue protrusions with a sticky surface, which are obtained by semi-curing drying and semi-curing wetting treatments of protrusion droplets.

[0022] Specifically, the present application can reduce the fluidity of the solution and fix the shape of the droplets by semi-curing and drying the raised droplets, thereby avoiding the generation of bubbles due to backlog during bonding. At the same time, the semi-curing and wetting treatment of the raised droplets that have undergone semi-curing and drying treatment can increase the viscosity of the solution surface, which is beneficial to the bonding of the gasket. There is no need for additional adhesives, thus avoiding the impact of chemical substances on the safety and efficacy stability of soluble microneedles.

[0023] In an optional embodiment, the semi-curing drying treatment in step S2 is carried out under the following conditions: humidity of 30%-70%, temperature greater than 10°C, and placement for 3-60 minutes. Furthermore, the temperature is 10-40°C.

[0024] The semi-cured drying treatment of the present invention does not cause adhesion between the protrusions and the gasket, and the protrusions do not deform. Further semi-curing wet treatment is performed to obtain soft-gel protrusions, which will adhere to the gasket when in contact and will deform.

[0025] Those skilled in the art can select the appropriate humidity and temperature for wet treatment of the semi-cured protrusions based on the semi-curing humidity and temperature conditions. At the same temperature, the wet treatment humidity should be higher than the dry treatment humidity. When the wet treatment temperature is higher than the dry treatment temperature at different temperatures, the wet treatment humidity can be slightly lower than the dry treatment humidity, but preferably, it should be higher than the dry treatment humidity. Optionally, the semi-curing wet treatment conditions are: 40%-90% humidity, 20-45°C temperature, and 2-5 minutes of standing.

[0026] In an optional embodiment, the material of the gasket in step S3 of the present application is any one of thermoplastic polyurethane, polypropylene (PP), polycarbonate (PC) and acrylonitrile-butadiene-styrene copolymer (ABS). Preferably, the gasket is a thermoplastic polyurethane elastomer rubber (TPU) gasket.

[0027] In an optional embodiment, after the pre-treated protrusions described in step S3 of the present application are pressed together, a microneedle soft gel layer is formed between the surface of the microneedle female mold and the gasket, and no adhesion occurs between the microneedle soft gel layers formed corresponding to each pre-treated protrusion, which can better achieve uniform drying and further improve the peeling integrity.

[0028] In an optional embodiment, the area of ​​the microneedle soft gel layer is larger than the bottom area of ​​the microneedle root in the microneedle female mold, which can achieve pressing support and simultaneously realize the adhesion area of ​​the gasket, thereby improving the demolding stability of the gasket.

[0029] Further optionally, the pressing pressure is 1-5N per square centimeter.

[0030] In an optional embodiment, the drying in step S3 of the present application is: drying at a humidity of 10%-90% and room temperature (20-25° C.) for 15-72 hours.

[0031] In an optional embodiment, the microneedles in step S1 of the present application are formed by injecting a soluble microneedle solution at least once, and thus the formed microneedles may be one-piece, two-stage, or multi-stage.

[0032] In some optional embodiments, the microneedles in the present application can be formed into two-segment microneedles by injecting a soluble microneedle solution twice. Specifically, the method for forming the two-segment microneedles includes the following steps:

[0033] S11, injecting a soluble microneedle solution into the tip groove of the microneedle groove of the microneedle female mold, and letting it stand to dry to form a microneedle tip;

[0034] S12, injecting a soluble microneedle solution into the root groove of the microneedle groove in step S11 until the soluble microneedle solution forms raised droplets on the surface of the microneedle female mold, and standing to dry to form the microneedle root.

[0035] In a second aspect, the present invention provides a soluble drug-loaded microneedle patch, which is prepared using the preparation process for a soluble drug-loaded microneedle patch described in any of the above embodiments. The beneficial effects of this application are:

[0036] (1) The preparation process of the present application utilizes a gasket instead of an adhesive layer. By subjecting the microneedle female mold containing raised droplets to a semi-curing drying treatment and a semi-curing wetting treatment, the adhesion performance between the gasket and the raised droplets of the soluble microneedle solution is improved. The microneedles formed in the microneedle female mold can be peeled off from the microneedle grooves, thereby realizing the preparation of a soluble microneedle patch and avoiding the influence of the penetration of the adhesive material on the safety and drug stability of the microneedles.

[0037] (2) The semi-curing drying treatment and semi-curing wetting treatment of the present application enable the soluble microneedle solution to be cured more evenly inside and outside during drying, avoiding uneven curing or over-drying, and effectively preventing the needle body from breaking during demolding.

[0038] (3) The present application can effectively control the size of the protruding droplets by optimizing the relationship between the volume of the microneedle female mold and the mass of the soluble microneedle solution, so that the pre-treated protrusions after semi-curing drying treatment and semi-curing wetting treatment can meet the contact adhesion when pressed with the gasket, and at the same time prevent the adjacent pre-treated protrusions on the microneedle patch from adhering when the gasket is pressed, avoiding the problem of different drying degrees of the external and internal solutions of the adhesion due to the inability to ventilate the adhesion area during subsequent drying treatment, and then causing the needle body to break during demolding; at the same time, it can also effectively prevent the solution from aggregating due to the action of solution tension, causing the microneedle solution filled in the root groove to escape from the root groove and flow to the microneedle groove adjacent to the gasket or the connection area outside the gasket, resulting in the root solution being unable to completely fill the microneedle groove, thereby improving the yield rate of the microneedle patch product. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] In order to more clearly illustrate the specific embodiments of the present disclosure or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the specific embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0040] FIG1 is a soluble drug-loaded microneedle patch prepared in an embodiment of the present application;

[0041] FIG2 is a soluble drug-loaded microneedle patch prepared in Comparative Example 1 of the present application;

[0042] FIG3 is a soluble drug-loaded microneedle patch prepared in Comparative Example 2 of the present application;

[0043] FIG4 is a soluble drug-loaded microneedle patch prepared in Comparative Example 3 of the present application;

[0044] FIG5 is a soluble drug-loaded microneedle patch prepared in Comparative Example 8 of the present application. DETAILED DESCRIPTION

[0045] The following describes the embodiments of the present application through specific examples. Those skilled in the art will readily understand the other advantages and benefits of the present application from the disclosure herein. The present application may also be implemented or applied through various other specific embodiments, and the details in this specification may be modified or altered based on different viewpoints and applications without departing from the spirit of the present application.

[0046] Before further describing the specific embodiments of the present application, it should be understood that the scope of protection of the present application is not limited to the specific specific embodiments described below; it should also be understood that the terms used in the examples of the present application are for describing specific specific embodiments, rather than for limiting the scope of protection of the present application.

[0047] When numerical ranges are given in the Examples, it should be understood that, unless otherwise specified herein, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this application belongs.

[0048] This application does not limit the sources of the raw materials used. Unless otherwise specified, the raw materials used in this application are common commercial products in this technical field.

[0049] Basic Example

[0050] A process for preparing a soluble drug-loaded microneedle patch comprises the following steps:

[0051] S1. Injecting a soluble microneedle solution into the microneedle grooves of the microneedle negative mold so that the soluble microneedle solution fills the microneedle grooves to form microneedles, and the soluble microneedle solution forms protruding droplets on the surface of the microneedle negative mold.

[0052] S2. The microneedle negative mold containing the protruding droplets in step S1 is subjected to a semi-curing drying treatment and a semi-curing wetting treatment in sequence to obtain pre-treated protrusions in a soft gel state.

[0053] S3. Press the TPU gasket onto the pretreated protrusion described in step S2 with a force of 2N per square centimeter. After pressing, a microneedle soft adhesive layer is formed between the surface of the microneedle female mold and the gasket. The area of ​​the microneedle soft adhesive layer is larger than the bottom area of ​​the microneedle root in the microneedle female mold, and there is no adhesion between the microneedle soft adhesive layers formed corresponding to each pretreated protrusion. Dry at room temperature (20°C) for 44 hours at a humidity of 50%, and demold to obtain a soluble drug-loaded microneedle patch.

[0054] Examples 1-9 and Comparative Examples 1-3

[0055] Specific parameters of the semi-curing drying treatment and the semi-curing wetting treatment in the preparation processes described in Examples 1-9 and Comparative Examples 1-3 are shown in Table 1.

[0056] Table 1

[0057] The yield rates of the soluble microneedle patches prepared in Examples 1-9 and Comparative Examples 1-3 are shown in Table 2.

[0058] Table 2

[0059] It can be seen from Examples 1-9 that the use of the specific semi-curing drying treatment and semi-curing wetting treatment processes of the present application can improve the adhesion performance between the TPU gasket and the soluble microneedle solution, successfully peel off the microneedles formed in the negative mold from the microneedle grooves, and realize the preparation of the soluble microneedle patch. The prepared soluble microneedle patch has no bubbles, complete needle shape, and no missing needles, which avoids the microneedle body from falling off the TPU gasket after demolding, thereby improving the yield rate of the microneedle patch product, as shown in Figure 1 and Table 2.

[0060] Comparative Examples 1 and 2 differed from Example 1 only in the humidity conditions used for semi-curing and drying. In Comparative Example 1, the semi-curing drying temperature was 20%. Due to the low humidity, the protruding droplets dried rapidly, preventing the air inside from being expelled in time, leading to bubbles in the microneedle cavities and substrate, as shown in Figure 2. In Comparative Example 2, the semi-curing drying temperature was 80%. Due to the high humidity, the water in the polymer solution in the substrate could not evaporate, resulting in a drying failure, as shown in Figure 3.

[0061] Comparative Example 3 differs from Example 1 only in the semi-curing drying temperature. In Comparative Example 3, the semi-curing drying temperature was 8°C. This low temperature increased the viscosity of the soluble microneedle solution, accelerating the solidification of the protruding droplets. The air inside was not expelled in time, resulting in bubbles in the microneedle cavities and substrate, as shown in Figure 4.

[0062] Examples 10-18 and Comparative Examples 4-11

[0063] The specific parameters of the semi-curing drying treatment and the semi-curing wetting treatment in the preparation processes described in Examples 10-18 and Comparative Examples 4-11 are shown in Table 3.

[0064] Table 3

[0065] The yield rates of the soluble microneedle patches prepared in Examples 10-18 and Comparative Examples 4-10 are shown in Table 4.

[0066] Table 4

[0067] It can be seen from Examples 10-18 that the use of the specific semi-curing drying treatment and semi-curing wetting treatment processes of the present application can improve the adhesion performance between the TPU gasket and the soluble microneedle solution, successfully peel off the microneedles formed in the negative mold from the microneedle grooves, and realize the preparation of the soluble microneedle patch. The prepared soluble microneedle patch has no bubbles, complete needle shape, and no missing needles, which avoids the microneedle body from falling off the TPU gasket after demolding, thereby improving the yield rate of the microneedle patch product, as shown in Figure 1 and Table 4.

[0068] Comparative Examples 4 and 5 differed from Example 10 solely in the different humidity conditions for semi-curing. The semi-curing humidity in Comparative Example 4 was low, at 35%, preventing the solid-surface projections from being wetted, thus preventing fixed adhesion between the projections and the TPU gasket. The semi-curing humidity in Comparative Example 5 was 95%, resulting in the solid-surface projections dissolving too quickly, preventing timely application of the TPU gasket during the experimental operation. The product obtained in Comparative Example 5 was similar to that obtained in Comparative Example 2. The specific structure can also be seen in Figure 3.

[0069] Comparative Example 6 differs from Example 10 solely in the semi-curing humidification temperature. Due to the higher humidification temperature in Comparative Example 6, the protruding droplets dissolved too quickly, preventing timely application of the TPU gasket during the experimental procedure. The product obtained in Comparative Example 6 is similar to that obtained in Comparative Example 2. The detailed structure can also be found in Figure 3.

[0070] Comparative Examples 7 and 8 differed from Example 10 only in the semi-curing and wetting time conditions. In Comparative Example 7, the time was shorter, and the solid protrusions on the surface did not fully dissolve, failing to adhere to the TPU backing. In Comparative Example 8, the protrusions completely dissolved, and the microneedle bases became a single piece after TPU coating. However, after demolding, the outer ring of microneedles dried excessively, resulting in breakage, as shown in Figure 5.

[0071] Comparative Example 9 differs from Example 10 in that the semi-curing drying and semi-curing wetting steps are omitted. Comparative Example 9 exhibits phenomena such as the base spreading and bonding together, excessive drying of the outer ring of microneedles after demolding, and needle breakage. Furthermore, the needle cavity solution is empty, bubbles form, and the needle body falls off after demolding. The product obtained in Comparative Example 9 is similar to the product obtained in Comparative Example 8, both exhibiting excessive drying. For details on the structure, see Figure 5.

[0072] Comparative Example 10 differs from Example 10 in that the semi-curing wetting step is omitted. The microneedles in Comparative Example 10 were over-dried, resulting in weak adhesion between the microneedles and the TPU gasket, and some microneedles detached. The product obtained in Comparative Example 10 is similar to the product obtained in Comparative Example 8, both of which were over-dried. The specific structure can also be seen in Figure 5.

[0073] In summary, the preparation process for soluble drug-loaded microneedle patches provided by the present application utilizes a gasket instead of an adhesive layer, and improves the adhesion performance between the gasket and the protruding droplets of the soluble microneedle solution by performing a semi-curing drying treatment and a semi-curing wetting treatment on the microneedle female mold containing protruding droplets. The microneedles formed in the microneedle female mold can be peeled off from the microneedle grooves, thereby realizing the preparation of soluble microneedle patches and avoiding the impact of the penetration of adhesive materials on the safety and drug stability of the microneedles. At the same time, the semi-curing drying treatment and semi-curing wetting treatment of the present application enable the soluble microneedle solution to be cured more evenly inside and outside during drying, avoiding uneven curing or over-drying, and effectively preventing the breakage of the needle body during demolding. Furthermore, the present application can effectively control the size of the protruding droplets by optimizing the relationship between the volume of the microneedle female mold and the mass of the soluble microneedle solution, so that the pretreated protrusions after semi-curing drying treatment and semi-curing wetting treatment can meet the contact adhesion when pressed with the gasket, and at the same time prevent the adjacent pretreated protrusions on the microneedle patch from adhering when the gasket is pressed, avoiding the problem of different drying degrees of the external and internal solutions of the adhesion due to the inability to ventilate the adhesion area during subsequent drying treatment, and then the needle body breaking during demolding; at the same time, it can also effectively prevent the solution from aggregating due to the action of solution tension, so that the microneedle solution filled in the root groove escapes from the root groove and flows to the microneedle groove adjacent to the gasket or the connection area outside the gasket, resulting in the root solution being unable to completely fill the microneedle groove, thereby improving the yield rate of the microneedle patch product.

[0074] The above further describes the present application in conjunction with specific embodiments, but these embodiments are merely exemplary and do not constitute any limitation on the scope of the present application. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present application may be modified or replaced without departing from the spirit and scope of the present application, and such modifications and replacements shall fall within the scope of protection of the present application. Industrial Applicability

[0075] In summary, the present application provides a soluble drug-loaded microneedle patch and a preparation process thereof, which uses a gasket instead of a sticky layer, and improves the adhesion performance between the gasket and the soluble microneedle solution by semi-curing drying and semi-curing wetting treatments on the microneedle female mold containing raised droplets. The microneedles formed in the microneedle female mold can be separated from the microneedle grooves, thereby realizing the preparation of a soluble microneedle patch and avoiding the influence of the penetration of adhesive materials in the existing microneedle patch preparation process on the safety of the microneedles and the stability of the drug efficacy.

Claims

1. A preparation process for a soluble drug-loaded microneedle patch, characterized in that, It includes the following steps: S1. Inject a soluble microneedle solution into the microneedle grooves of the microneedle female mold, so that the soluble microneedle solution fills the microneedle grooves to form microneedles, and the soluble microneedle solution forms raised droplets on the surface of the corresponding microneedle grooves of the microneedle female mold; S2. Sequentially perform semi-curing drying treatment and semi-curing humidifying treatment on the microneedle female mold containing raised droplets in step S1, so that the raised droplets form pre-treated protrusions; S3. Press a gasket onto the pre-treated protrusions in step S2, dry and demold to obtain the soluble drug-loaded microneedle patch.

2. The preparation process of the soluble drug-loaded microneedle patch according to claim 1, wherein The pre-treated protrusions in step S2 are soft rubber-like protrusions with sticky surfaces.

3. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-2, characterized in that, The conditions for the semi-curing drying treatment in step S2 are: humidity is 30%-70%, temperature is not lower than 10°C, and it is placed for 3-60 min; And / or, the conditions for the semi-curing humidifying treatment are: humidity is 40%-90%, temperature is 20-45°C, and it is placed for 2-5 min.

4. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-3, characterized in that, The number of the microneedle grooves in step S1 is not less than 1. After the pre-treated protrusions are pressed in step S3, a microneedle soft rubber layer is correspondingly formed between the surface of the microneedle female mold and the gasket, and there is no adhesion between the microneedle soft rubber layers corresponding to each pre-treated protrusion.

5. The preparation process of the soluble drug-loaded microneedle patch according to claim 4, characterized in that, The area of the microneedle soft rubber layer is larger than the bottom area of the microneedle roots in the microneedle female mold.

6. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-5, characterized in that, The material of the gasket in step S3 is any one of thermoplastic polyurethane, polypropylene, polycarbonate, and acrylonitrile-butadiene-styrene copolymer.

7. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-6, characterized in that, The soluble microneedle solution in step S1 contains a soluble microneedle skeleton material.

8. The preparation process for the soluble drug-loaded microneedle patch according to claim 7, characterized in that, The soluble microneedle skeleton material is at least one of polyester, polyhydroxyalkanoate, copolymer of 3-hydroxybutyrate and 3-hydroxyvalerate, polyacrylamide, modified polypropylene, polyhydroxyalkanoate-polyethylene glycol, poly-α-hydroxy acid, poly-β-hydroxy acid, polyhydroxybutyrate, polyester amide, polycaprolactone, polylactide, polyglycolic acid, polydioxanone, polyorthoester, polyether ester, polyanhydride, glycolic acid-trimethylenecarbonate copolymer, polyphosphate, polyphosphate urethane, polyamino acid, polycyanoacrylate, polytrimethylene carbonate, polycarbonate, creatine phosphate, chitosan, dextran, heparin, hyaluronic acid, sucrose, trehalose, mannitol, chondroitin sulfate, Tween 80, gelatin, poly(lactic-co-glycolic acid), polyvinylpyrrolidone, polyvinyl alcohol, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, sodium alginate, maltose, hydroxypropyl-β-cyclodextrin, polylactic acid, polyethylene glycol, glycerol, sodium chloride, inulin, starch, and glycogen.

9. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 7-8, characterized in that, The soluble microneedle solution further contains a drug.

10. The preparation process for the soluble drug-loaded microneedle patch according to claim 9, characterized in that, The drugs are doxorubicin, triamcinolone acetonide, teriparatide, abaloparatide, GLP-1 analogues, growth factors, insulin, acetyl hexapeptide, pilocarpine, hyaluronic acid, tranexamic acid, glutathione, niacinamide, calcipotriol & betamethasone, monoclonal antibodies, influenza vaccine and measles-rubella inactivated vaccine, pilocarpine, adenosine, horse oil, doxorubicin, ascorbic acid, ferulic acid, retinyl retinoate, ascorbic acid, zolmitriptan, tilibang, 4-n-butylresorcinol, lidocaine, amethocaine, encephalitis vaccine, mitomycin, semaglutide, inactivated split influenza virus hemagglutinin vaccine, glucagon, parathyroid hormone, at least one of the 15T vaccine, platelet-rich fibrin, C19-A3 GNP, polio vaccine, adalimumab, IVT aflibercept, tuberculin, sumatriptan succinate, ipilimumab, nivolumab, indocyanine green, hepatitis B vaccine, S-OIV influenza A H1N1 intradermal vaccine, levodopa, recombinant fibrinolytic enzyme, platelet-rich plasma, botulinum toxin type A, staphylococcal enterotoxin B vaccine, scrub typhus vaccine, SARS-CoV-2 vaccine, malaria vaccine, HIV vaccine, rotavirus inactivated virus vaccine, tuberculosis vaccine, porcine circovirus type 2 vaccine, rabies vaccine, HPV vaccine, melanoma vaccine, porcine reproductive and respiratory syndrome virus vaccine, Ebola virus vaccine, Zika vaccine, respiratory syncytial virus vaccine, acute respiratory syndrome coronavirus vaccine.

11. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-10, characterized in that, The pressure for pressing in step S3 is 1-5 N per square centimeter; And / or, the drying is: humidity is 10%-90%, and it is dried at room temperature for 15-72 h.

12. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-11, characterized in that, The microneedles in step S1 are formed by injecting the soluble microneedle solution at least once.

13. The preparation process of the soluble drug-loaded microneedle patch according to claim 12, characterized in that, The microneedles in step S1 are formed by injecting the soluble microneedle solution twice to form two-stage microneedles. The formation method of the two-stage microneedles includes the following steps: S11. Inject a soluble microneedle solution into the tip groove of the microneedle groove of the microneedle female mold, let it stand and dry to form microneedle tips. S12. Inject a soluble microneedle solution into the root groove of the microneedle groove in step S11 until the soluble microneedle solution forms a raised droplet on the surface of the microneedle female mold, let it stand and dry to form microneedle roots.

14. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-13, characterized in that, The mass percentage of the soluble microneedle preparation in the soluble microneedle solution is 30%-50%.

15. The preparation process for the soluble drug-loaded microneedle patch according to any one of claims 1-13, characterized in that, The volume of the microneedle female mold and the mass ratio of the raised droplet are 5-95 nl: 0.01-0.40 mg.

16. A soluble drug-loaded microneedle patch, characterized in that, It is prepared by using the preparation process for soluble drug-loaded microneedle patches described in any one of claims 1-15.

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