A solid cavity microneedle patch and a preparation method thereof

Abstract

This application discloses a solid cavity microneedle patch and its preparation method, relating to the field of transdermal drug delivery technology. The solid microneedles in the microneedle patch can effectively penetrate the skin, and after penetration, the needle tip layer dissolves rapidly, allowing the drug within the cavity structure to be slowly released through the degradation of the non-water-soluble needle body layer, thereby achieving long-acting transdermal drug delivery. The microneedle patch includes a bottom encapsulation layer and a plurality of solid microneedles distributed on the bottom encapsulation layer; each solid microneedle includes a needle tip layer and a needle body layer; the needle tip layer is made of a water-soluble polymer material; both the needle body layer and the bottom encapsulation layer are made of a non-water-soluble polymer material; a closed cavity structure is formed inside the needle body layer. This application also discloses a method for preparing the above-mentioned solid cavity microneedle patch.

Description

Technical Field

[0001] This application relates to the field of transdermal drug delivery technology, and in particular to a solid cavity microneedle patch and its preparation method. Background Technology

[0002] Transdermal drug delivery technology has significant advantages, such as avoiding the first-pass effect of oral medications, reducing pain associated with injections, and enabling long-term, controllable drug release, making it a promising field for clinical treatment and the delivery of biological agents. However, traditional transdermal drug delivery methods are limited by the skin's stratum corneum barrier, allowing only the penetration of small-molecule, lipid-soluble drugs. This makes it difficult to meet the delivery needs of large-molecule drugs such as proteins, nucleic acids, and peptides, greatly restricting its application scope.

[0003] Microneedle technology, as a novel transdermal drug delivery carrier, uses an array of microneedles to pierce the stratum corneum of the skin, creating tiny channels that effectively overcome the skin barrier and achieve highly efficient drug penetration. Furthermore, due to their micron-sized dimensions, they significantly reduce pain during administration, making them a key technological direction for solving transdermal drug delivery problems. Based on structural and functional differences, microneedles are mainly classified into solid microneedles, hollow microneedles, soluble microneedles, and hydrogel microneedles. Amidst the continuous innovation of microneedle technology, solid and soluble microneedles, primarily made of biodegradable materials, have become research hotspots in the field due to their excellent biocompatibility and safety, providing innovative solutions for transdermal drug delivery in pharmaceuticals and other areas.

[0004] Biodegradable solid microneedles are primarily made from non-water-soluble biodegradable materials such as polylactic acid (PLA) and polycaprolactone (PCL). Their sharp needles possess good mechanical strength, enabling them to effectively penetrate the skin's stratum corneum barrier and form tiny channels on the skin's surface. The mechanism of action of solid microneedles mainly involves two steps: first, the solid microneedles puncture the skin surface to create temporary microchannels; second, after removing the microneedles, solutions, gels, or patches containing drugs or other active ingredients are applied to the skin surface, effectively enhancing the transdermal absorption efficiency of the active ingredients. Unlike solid microneedles, biodegradable soluble microneedles are mainly prepared from water-soluble polymers such as sodium hyaluronate (HA) and polyvinyl alcohol (PVA) in combination with drugs or active ingredients. After insertion into the subcutaneous tissue, they dissolve directly, delivering the drug directly to the subcutaneous layer. Soluble microneedles are very convenient to use and do not produce sharp medical waste, and have been widely studied for transdermal delivery research of vaccines, analgesics, and diabetes treatments.

[0005] However, existing biodegradable microneedles still have the following limitations: 1. While solid biodegradable microneedles possess excellent mechanical properties, their operation is cumbersome, and the microchannels created after skin pretreatment close rapidly, severely affecting the absorption of active ingredients. 2. Biodegradable soluble microneedles, due to their water-soluble base material, require storage in a dry, sealed environment; otherwise, they are prone to moisture absorption, leading to premature dissolution or ineffectiveness. Furthermore, they are typically only suitable for loading water-soluble active ingredients. 3. Existing biodegradable microneedles have limited loading capacity; their small size and the need to ensure solubility make them unsuitable for scenarios requiring large-dose drug delivery. Summary of the Invention

[0006] The embodiments of this application provide a solid cavity microneedle patch and its preparation method. The solid microneedles in the microneedle patch can effectively penetrate the skin, and after penetrating the skin, the needle tip layer can dissolve rapidly. The drug in the cavity structure is slowly released through the degradation of the non-water-soluble needle body layer, thereby achieving long-term transdermal drug delivery.

[0007] To achieve the above objectives, in one aspect, embodiments of this application provide a solid cavity microneedle patch, including a bottom encapsulation layer and a plurality of solid microneedles distributed on the bottom encapsulation layer; the solid microneedles include a tip layer and a body layer; the tip layer is made of a water-soluble polymer material; the body layer and the bottom encapsulation layer are both made of a non-water-soluble polymer material; a closed cavity structure is formed inside the body layer.

[0008] Furthermore, the solid microneedle has a conical or near-conical structure; the height of the solid microneedle is 100~1000μm, the bottom diameter is 150~500μm, and the height ratio of the tip layer to the body layer of the solid microneedle is less than 0.5.

[0009] Furthermore, the cavity structure is oval, ellipsoidal, or a combination of cylinder and hemisphere; the volume ratio of the cavity structure to the needle layer is greater than 0.2.

[0010] Furthermore, the water-soluble polymer material is one or more of polyvinyl alcohol, polyvinylpyrrolidone, sodium hyaluronate, carboxymethyl cellulose, and chondroitin sulfate; the non-water-soluble polymer material is one or more of polylactic acid, polycaprolactone, and polylactic-glycolic acid copolymer.

[0011] Furthermore, the mass concentration of the water-soluble polymer solution is 5% to 30%; the mass concentration of the non-water-soluble polymer solution is 5% to 25%; and the solvent is dichloromethane, chloroform, or acetone.

[0012] On the other hand, embodiments of this application also provide a method for preparing the above-mentioned solid cavity microneedle patch, comprising the following steps: preparing a water-soluble polymer solution and an insoluble polymer solution; coating the surface of a microneedle template with the water-soluble polymer solution, and using a first external force to fill the microneedle template groove tip with the water-soluble polymer solution to form a needle tip layer; coating the surface of the microneedle template with the needle tip layer with an insoluble polymer solution, and using a second external force to partially fill the microneedle template groove with the insoluble polymer solution, and after the solvent evaporates, forming a needle body layer with an internal cavity structure; coating the surface of the microneedle template with an insoluble polymer solution, and after the solvent evaporates, forming a bottom encapsulation layer; demolding to obtain a solid cavity microneedle patch.

[0013] Furthermore, the step of coating a non-water-soluble polymer solution on the surface of the microneedle template with the needle tip layer, using a second external force to partially fill the groove of the microneedle template with the non-water-soluble polymer solution, and forming a needle body layer with an internal cavity structure after the solvent evaporates, further includes coating a drug on the microneedle template with the needle tip layer and the needle body layer, and using a third external force to load the drug into the cavity structure.

[0014] Furthermore, the volume ratio of the cavity structure to the needle layer is greater than 0.2, and the volume ratio is determined by controlling the intensity and duration of the first external force and the second external force.

[0015] Furthermore, the first, second, and third external forces are all centrifugal or vacuum treatments; the centrifugal treatment is performed at a speed of 2000 rpm to 8000 rpm for a holding time of 0.5 min to 5 min; the vacuum treatment is performed at a vacuum level of -60 kPa to -100 kPa for a holding time of 10 to 30 min.

[0016] This application has the following advantages over the prior art: 1. Compared to the traditional two-step process of puncturing the skin and then applying additional medication, the solid cavity microneedle patch of this application integrates puncture and drug delivery. The puncture and drug release can be completed in one application, which significantly simplifies the drug delivery process and avoids the problem of reduced drug absorption efficiency caused by rapid closure of microchannels. It is easy to operate and highly efficient.

[0017] 2. The solid cavity microneedle patch of this application can achieve a higher drug loading capacity through the cavity structure set inside, and the cavity volume ratio can be flexibly controlled by adjusting the external force parameters. It breaks through the bottleneck of insufficient loading capacity of traditional soluble microneedles due to volume and material limitations, and is more suitable for the transdermal delivery of large doses or high concentrations of drugs.

[0018] 3. In the embodiments of this application, both the needle body layer and the bottom encapsulation layer of the solid cavity microneedle patch are made of non-water-soluble biodegradable materials such as polylactic acid. This allows the microneedles to not only carry water-soluble drugs, but also to be compatible with drug formulations in various forms such as solutions, gels, or powders. At the same time, the non-water-soluble materials make the microneedles less prone to moisture absorption and denaturation during storage, improving the stability and shelf life of the product. This overcomes the shortcomings of soluble microneedles, which have stringent requirements for storage environment, and has broad drug compatibility and storage stability.

[0019] 4. In the embodiments of this application, the needle tip layer of the solid cavity microneedle patch is made of water-soluble polymer material, which maintains the sharpness of the microneedle tip and can dissolve rapidly after being inserted into the subcutaneous tissue. The needle body layer relies on the slow degradation of non-water-soluble materials to achieve continuous drug release. By adjusting the ratio of the soluble layer of the needle tip to the non-water-soluble part of the needle body, long-term controllable release from several hours to several weeks can be achieved to meet the long-term drug delivery needs in different treatment scenarios. Attached Figure Description

[0020] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0021] Figure 1 This is a schematic diagram of the solid microneedles in the solid cavity microneedle patch prepared in Example 1 of this application.

[0022] Figure 2 This is a flowchart illustrating the preparation process of the solid cavity microneedle patch in Example 1 of this application.

[0023] Figure 3 These are microscope images of soluble needle tip layers of different heights in the embodiments of this application.

[0024] Figure 4 These are microscope images of non-water-soluble needle layers with different cavity sizes in the embodiments of this application.

[0025] Figure 5 This is a microscope image of the morphology of the solid cavity microneedle patch prepared in Example 1 of this application.

[0026] Figure 6 This is a scanning electron microscope image of the morphology of the solid cavity microneedle patch prepared in Example 1 of this application.

[0027] Figure 7 This is a scanning electron microscope image of the cavity structure of the solid cavity microneedle prepared in Example 1 of this application.

[0028] Figure 8Force-displacement curve of the solid cavity microneedle prepared in Example 1 of this application.

[0029] Figure 9 This is a microscope image of the morphology of the solid cavity microneedle patch prepared in Example 2 of this application.

[0030] Figure 10 This is a flowchart illustrating the preparation process of the solid cavity microneedle patch in Embodiment 2 of this application. Detailed Implementation

[0031] The technical solutions of the embodiments of this application will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0032] In the description of this application, it should be understood that the terms "center", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc., indicate the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing this application and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of this application.

[0033] In the description of this application, it should be noted that, unless otherwise expressly specified and limited, the terms "installation", "connection" and "joining" should be interpreted broadly, for example, they can refer to fixed connections, detachable connections, or integral connections; those skilled in the art can understand the specific meaning of the above terms in this application based on the specific circumstances.

[0034] The terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of technical features indicated. Thus, a feature defined as "first" or "second" can explicitly or implicitly include one or more of that feature. In the description of this application, unless otherwise stated, "a plurality of" means two or more.

[0035] Example 1 Reference Figure 2 Example 1 provides a method for preparing a solid cavity microneedle patch, comprising the following steps: Step 1. Mix sodium hyaluronate with a molecular weight of 1-100,000 and sodium hyaluronate with a molecular weight of 200,000-400,000 at a mass ratio of 1:1 to prepare a 10% sodium hyaluronate mixed aqueous solution.

[0036] Step 2. Dissolve polylactic acid particles in dichloromethane solution and prepare polylactic acid solutions with mass concentrations of 10% and 20% using glass sample bottles.

[0037] Step 3. After cleaning and drying the microneedle template, place it in a clean bench and coat it with a 10% sodium hyaluronate aqueous solution under a vacuum of -80 kPa. After 10 minutes, scrape off all the surface solution and dry it under vacuum conditions in natural wind for 1.5 hours to obtain a water-soluble needle tip layer.

[0038] The microneedle template is a PDMS microneedle template with a height of 500 μm, a bottom diameter of 300 μm, a center-to-center distance of 800 μm between two adjacent microneedles, and an array of 10×10.

[0039] Step 4. Add 150 μL of 10% polylactic acid solution to the surface of the microneedle template, then transfer it to a centrifuge and centrifuge at 5000 rpm for 3 min at room temperature. After solidification, a non-water-soluble needle layer is obtained.

[0040] Step 5. Remove the microneedle template with solid microneedles from the centrifuge, place it on a clean bench, coat the surface of the microneedle template with 20% polylactic acid solution, and then allow it to air dry at room temperature for 6-8 hours.

[0041] Step 6. Demold to obtain solid cavity microneedle patch.

[0042] Step 7. Transfer the demolded solid cavity microneedle patch to a dryer and use it after it has dried.

[0043] Reference Figure 1 , Figure 5 and Figure 6 The solid cavity microneedle patch prepared by the above method includes a bottom encapsulation layer 1 and 100 solid microneedles 2 distributed on the bottom encapsulation layer 1. The solid microneedles 2 have a conical structure with a height of approximately 500 μm, a base diameter of approximately 300 μm, a center-to-center distance of 800 μm between two adjacent microneedles, and a cavity height of approximately 150 μm. The solid microneedles 2 include a tip layer 21 and a body layer 22, with a closed cavity structure 23 formed inside the body layer 22 that can be used for drug loading.

[0044] In Example 1, the coating time of the sodium hyaluronate aqueous solution and the mass concentration of the polylactic acid solution were both controllable variables. By controlling the coating time of the sodium hyaluronate aqueous solution to 10 min, 20 min, and 30 min, soluble needle tip layers of different heights could be prepared, such as... Figure 3As shown. Meanwhile, by adjusting the mass concentration of polylactic acid solution to 5%, 8%, 10%, and 12%, non-water-soluble needle layers with different cavity sizes and distribution locations can be prepared, such as... Figure 4 As shown.

[0045] Example 2 Reference Figure 10 Example 2 provides another method for preparing a (drug-loaded) solid cavity microneedle patch, comprising the following steps: Step 1. Mix sodium hyaluronate with a molecular weight of 1-100,000 and sodium hyaluronate with a molecular weight of 200,000-400,000 at a mass ratio of 1:1 to prepare a 10% sodium hyaluronate mixed aqueous solution.

[0046] Step 2. Dissolve polylactic acid particles in dichloromethane solution and prepare polylactic acid solutions with mass concentrations of 10% and 20% using glass sample bottles.

[0047] Step 3. After cleaning and drying the microneedle template, place it in a clean bench and coat it with a 10% sodium hyaluronate aqueous solution under a vacuum of -80 kPa. After 10 minutes, scrape off all the surface solution and dry it under vacuum conditions in natural wind for 1.5 hours to obtain a water-soluble needle tip layer.

[0048] The microneedle template is a PDMS microneedle template with a height of 500 μm, a bottom diameter of 300 μm, a center-to-center distance of 800 μm between two adjacent microneedles, and an array of 10×10.

[0049] Step 4. Add 150 μL of 10% polylactic acid solution to the surface of the microneedle template, then transfer it to a centrifuge and centrifuge at 5000 rpm for 3 min at room temperature. After the solvent has completely evaporated, a non-water-soluble needle layer is obtained.

[0050] Step 5. Remove the microneedle template with solid microneedles from the centrifuge, add liquid or powdered drug, and continue centrifuging for 5 minutes to allow the drug to fill the cavity structure.

[0051] Step 6. Transfer the microneedle template to a clean bench, coat the template surface with 100 μL of 20% polylactic acid solution, and then allow it to air dry at room temperature for 6-8 hours.

[0052] Step 7. Demold to obtain solid cavity microneedle patch.

[0053] Step 8. Transfer the demolded solid cavity microneedle patch to a dryer and use it after it has dried.

[0054] Reference Figure 9The difference between the (drug-loaded) solid cavity microneedle patch prepared by the above method and the solid cavity microneedle patch prepared in Example 1 is only that the drug is loaded in the cavity structure 23. It should be noted that an adhesive backing layer can also be provided on the side of the solid cavity microneedle patch prepared in Examples 1 and 2 near the bottom encapsulation layer 1, and the solid cavity microneedle patch is adhered to the adhesive backing layer.

[0055] Effect verification The cavity structure was verified using a solid cavity microneedle prepared in Example 1.

[0056] Figure 7 This is a cross-sectional image of a microneedle after being randomly cut in the middle, as seen under a scanning electron microscope. The SEM image provides a clearer view of the cavities within the microneedles, and the size and wall thickness of these cavities support subsequent drug loading.

[0057] The mechanical properties of microneedles are crucial for their effective barrier function in drug delivery over the stratum corneum. This invention applies a force along the central axis to the microneedles using a Mark-10 force gauge, causing the microneedles to bend. For example... Figure 8 As shown, as the displacement increases from 0 μm to 250 μm, the force borne by the 10×10 array microneedle patch increases from 0 N to 30 N, and the force-displacement curve changes abruptly, indicating that the microneedles bend at the cavity. At this time, the force borne by a single microneedle is 300 mN, which is much higher than the minimum skin penetration force, proving that the solid cavity microneedles have good mechanical properties.

[0058] The above are merely specific embodiments of this application, but the scope of protection of this application is not limited thereto. Any variations or substitutions within the technical scope disclosed in this application should be included within the scope of protection of this application. Therefore, the scope of protection of this application should be determined by the scope of the claims.

Claims

1. A solid cavity microneedle patch, characterized by, It includes a bottom encapsulation layer and several solid microneedles distributed on the bottom encapsulation layer; the solid microneedles include a tip layer and a body layer; the tip layer is made of a water-soluble polymer material; the body layer and the bottom encapsulation layer are both made of a non-water-soluble polymer material; a closed cavity structure is formed inside the body layer.

2. The solid cavity microneedle patch of claim 1, wherein, The solid microneedle has a conical or near-conical structure; the height of the solid microneedle is 100~1000μm, the bottom diameter is 150~500μm, and the height ratio of the tip layer to the body layer of the solid microneedle is less than 0.

5.

3. The solid cavity microneedle patch of claim 1, wherein, The cavity structure is oval, ellipsoidal, or a combination of cylinder and hemisphere; the volume ratio of the cavity structure to the needle layer is greater than 0.

2.

4. The solid cavity microneedle patch of claim 1, wherein, The water-soluble polymer material is one or more of polyvinyl alcohol, polyvinylpyrrolidone, sodium hyaluronate, carboxymethyl cellulose, and chondroitin sulfate; the non-water-soluble polymer material is one or more of polylactic acid, polycaprolactone, and polylactic-glycolic acid copolymer.

5. The solid cavity microneedle patch according to claim 1, characterized in that, The water-soluble polymer solution has a mass concentration of 5% to 30%; the non-water-soluble polymer solution has a mass concentration of 5% to 25%; and the solvent is dichloromethane, chloroform, or acetone.

6. The solid cavity microneedle patch according to claim 1, characterized in that, The cavity structure is loaded with a drug; the drug is in the form of a solution, gel, or lyophilized powder.

7. A method for preparing a solid cavity microneedle patch according to any one of claims 1 to 6, characterized in that, Includes the following steps: Prepare water-soluble polymer solutions and insoluble polymer solutions; A water-soluble polymer solution is coated on the surface of the microneedle template. The water-soluble polymer solution is then filled into the tip of the groove of the microneedle template by the application of a first external force to form a needle tip layer. A non-water-soluble polymer solution is coated on the surface of a microneedle template with a needle tip layer. A second external force is used to partially fill the grooves of the microneedle template with the non-water-soluble polymer solution. After the solvent evaporates, a needle layer with an internal cavity structure is formed. A non-water-soluble polymer solution is coated on the surface of the microneedle template, and the bottom encapsulation layer is formed after the solvent evaporates; Demolding yields a solid cavity microneedle patch.

8. The preparation method according to claim 7, characterized in that, The steps include coating a non-water-soluble polymer solution onto the surface of a microneedle template with a needle tip layer, using a second external force to partially fill the grooves in the microneedle template with the non-water-soluble polymer solution, and forming a needle body layer with an internal cavity structure after the solvent evaporates. The steps also include coating a drug onto the microneedle template with the needle tip layer and the needle body layer, and using a third external force to load the drug into the cavity structure.

9. The preparation method according to claim 8, characterized in that, The volume ratio of the cavity structure to the needle layer is greater than 0.2, and the volume ratio is determined by controlling the intensity and duration of the first and second external forces.

10. The preparation method according to claim 9, characterized in that, The first, second, and third external forces are all centrifugal or vacuum treatments; the centrifugal speed is 2000 rpm ~ 8000 rpm, and the holding time is 0.5 min ~ 5 min; the vacuum degree of the vacuum treatment is -60 kPa ~ -100 kPa, and the vacuum holding time is 10 ~ 30 min.

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