Microneedle for improving drug utilization

Abstract

The application discloses a microneedle for improving drug utilization, which comprises a substrate and a plurality of needle bodies arranged in an array on the substrate; the needle body comprises a base, a needle tip part, and a support connecting part connecting the base and the needle tip part; the base is a circular truncated cone, the bottom of the circular truncated cone is inclined at an angle of 15-50 degrees; the needle tip part is a circular cone, the top angle of the circular cone is 15-40 degrees; and the side surface of the support connecting part is a concave curved surface. The microneedle is suitable for 3D printing, and can solve the problems that the conventional method for increasing the drug loading capacity by increasing the height and array density of the microneedle is difficult to penetrate into the skin due to the increase of the microneedle density, and the high height of the microneedle increases the pain degree.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology. More specifically, it relates to a microneedle for improving drug utilization. Background Technology

[0002] Microneedles are a minimally invasive drug delivery method that allows for self-administration; they are inexpensive to manufacture, store, and transport; and they do not generate biohazardous sharps waste, making them popular choices. Currently, microneedles are widely studied for delivering various drugs, including small molecules, proteins, nucleic acids, vaccines, and nanoparticles. Microneedles used for transdermal drug delivery have a characteristic shape, typically conical or pyramidal. The needle tip pierces the skin, and the needle body carries the drug. Due to the small size of microneedles, the drug loading capacity at the tip is very low, and increasing the drug loading capacity is one of the main factors limiting their application. Increasing the microneedle height and array density is commonly used to improve drug loading, but increasing the density makes it more difficult to insert the microneedle into the skin, requiring greater force to penetrate. Increasing the microneedle height increases the depth of skin penetration, increasing pain; and because dissolving microneedles use soluble polymers as a matrix, longer needle tips pose safety risks. Therefore, designing the geometry of microneedles to improve drug loading capacity while ensuring user compliance and safety remains a challenge.

[0003] Designing the geometry of microneedles can increase drug loading capacity while maintaining compliance and safety. It has been reported that designing the geometry of microneedles can increase the depth of skin penetration, thereby improving percutaneous penetration efficiency. However, increased penetration depth can decrease user compliance.

[0004] In addition, since 3D printing is one of the important methods for microneedle forming, how to make microneedle structures suitable for 3D printing is also one of the issues that technicians need to consider. Summary of the Invention

[0005] Based on the above facts, the purpose of this invention is to provide a microneedle that improves drug utilization. This microneedle is suitable for 3D printing and can solve the problems of conventional methods that increase drug loading by increasing microneedle height and array density, but which make it difficult to penetrate the skin due to the increased microneedle density, and the problem that excessively high microneedle height increases pain and may penetrate the dermis.

[0006] The present invention provides a microneedle for improving drug utilization, the microneedle comprising a base and a plurality of needles arranged in an array on the base;

[0007] The needle body includes a base, a needle tip, and a support connection portion connecting the base and the needle tip;

[0008] The base is a frustum of a cone, and the bottom of the frustum has an inclination angle of 15° to 50°.

[0009] The tip of the needle is a cone with an angle of 15° to 40°.

[0010] The side of the support connection is a concave surface.

[0011] Further, the angle of the bottom of the circular table is 25° to 40°.

[0012] Further, the angle of the cone is 20° to 35°.

[0013] Further, the ratio between the height of the base and the height of the tip is 1:3 to 1:15.

[0014] Further, the ratio between the height of the base and the height of the tip is 1:5 to 1:11.

[0015] Further, the ratio between the height of the base and the height of the support connection is 1:0.5 to 1:2.5.

[0016] Further, the ratio between the height of the base and the height of the support connection is 1:1.5 to 1:2.5.

[0017] Further, the side of the support connection is a streamlined surface, and the support connection connects the base and the tip along a tangent. That is, the side of the support connection is a streamlined surface.

[0018] Further, the upper surface of the support connection matches the bottom surface of the tip, and the lower surface of the support connection matches the upper surface of the base.

[0019] The specific structure of the support connection can improve the strength of the needle body and make it easier for the drug solution before needle formation to enter the micro-needle mold cavity, thereby increasing the drug loading capacity of the micro-needle. Finally, the overall design of the circular table and the cone makes the micro-needle particularly suitable for 3D molding.

[0020] It can be understood that in the technical solution, the sizes, dimensions, and heights of the needle bodies are the same. They are arranged uniformly perpendicular to the base to form an array structure.

[0021] Further, the distance between the tops of adjacent needle tips is 200-800 microns, and the height of the needle body is 200-800 microns. This solves the safety and use compliance of the micro-needle.

[0022] Further, the distance between the tops of adjacent needle tips is 200-300 microns.

[0023] Further, the distance between the tops of adjacent needle tips is the same as the height of the needle body.

[0024] Further, the bases are arranged in a hexagonal close packing on the substrate. This can reduce the area of blank regions on the patch without microneedles, so that more drugs are concentrated in the microneedle bodies. In combination with the design of the sizes and positions of the support connecting portions and the tip portions, the microneedle patch still has the performance of easily penetrating the skin under the condition of having a large microneedle density.

[0025] Further, the edges of each adjacent base are tangent.

[0026] In the technical solution of the present application, the material of the microneedles has no special requirements, and a person skilled in the art can select it according to actual needs.

[0027] Further, the material of the microneedle bodies is a soluble polymer material or a degradable polymer material.

[0028] Further, the soluble polymer material is selected from polysaccharides and derivatives thereof, collagen, silk protein, sodium alginate, polyglutamic acid, polyvinyl alcohol and derivatives thereof, polyacrylic acid and derivatives thereof, polyvinylpyrrolidone and derivatives thereof, and polylactic acid derivatives. The degradable polymer material is selected from polysaccharides and derivatives thereof, polylactic acid and derivatives thereof, polyglycolide and derivatives thereof, and polyglycolic acid and derivatives thereof.

[0029] Further, the polysaccharide is selected from dextran, hyaluronic acid, chitosan, cellulose and derivatives thereof, and plant polysaccharides.

[0030] Further, the microneedle body, the substrate or the microneedle as a whole contains a molding additive.

[0031] Further, the microneedle body, the substrate or the microneedle as a whole contains a drug or a skin care active ingredient.

[0032] Further, the molding additive is selected from sucrose, trehalose, polyhydric alcohol and lecithin.

[0033] Further, the solution, the nanoparticle or the microparticle suspension can be used to make the microneedle.

[0034] The beneficial effects of the present application are as follows:

[0035] The present application optimizes the geometry of the microneedle, and designs a microneedle which is especially suitable for 3D printing technology and can efficiently utilize drugs, and is suitable for epidermis application. The sharp tip of the microneedle can pierce the stratum corneum, weaken the barrier function of the stratum corneum, and provide a channel for drug transdermal penetration. The expanded base can make the drug easily enriched in the microneedle body. The array arrangement of the microneedle array is preferably a hexagonal close-packed array arrangement, the edges of the microneedle base are circularly tangent, and the design of the support connecting part further maximizes the concentration of the drug in the tip of the microneedle, and minimizes the residual drug on the base of the microneedle. The microneedle not only has high microneedle density and high microneedle drug loading, but also has good puncture performance. The microneedle overcomes the problems that the conventional method of increasing the height and array density of the microneedle to improve the drug loading capacity is difficult to pierce the skin due to the increase of the microneedle density, and the high height of the microneedle increases the pain and may pierce the dermis. At the same time, the design of the structure, the size relationship of the base, the tip and the support connecting part makes the needle body especially suitable for 3D printing. BRIEF DESCRIPTION OF DRAWINGS

[0036] The specific embodiments of the present application will be further described in detail below with reference to the accompanying drawings.

[0037] Figure 1 A side view of the microneedle structure schematic diagram of the present embodiment is shown.

[0038] Figure 2 A top view of the microneedle structure schematic diagram of the present embodiment is shown.

[0039] Figure 3 A side view of the microneedle of Example 1 is shown.

[0040] Figure 4 A top view of the microneedle of Example 1 is shown.

[0041] Figure 5 A top view of the microneedle structure schematic diagram of Example 2 is shown in a, and a side view of the microneedle structure schematic diagram of Example 2 is shown in b.

[0042] Figure 6 A side view of the microneedle of Example 2 is shown.

[0043] Figure 7 A top view of the microneedle of Example 2 is shown.

[0044] Figure 8 A and B are fluorescence imaging of the microneedle of Example 2 piercing the skin (scale = 200 microns) and three-dimensional reconstruction image of the microneedle piercing the skin (scale = 200 microns) respectively; C and D are fluorescence imaging of the microneedle of Example 3 piercing the skin (scale = 200 microns) and three-dimensional reconstruction image of the microneedle piercing the skin (scale = 200 microns) respectively.

[0045] Figure 9 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0046] Figure 10 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0047] Figure 11 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0048] Figure 12 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0049] Figure 13 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0050] Figure 14 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0051] Figure 15 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3.

[0052] Figure 16 Figure 3a shows a top view of the microneedle structure of Example 3, and Figure 3b shows a side view of the microneedle patch structure of Example 3. DETAILED DESCRIPTION

[0053] In order to illustrate the application more clearly, the application will be described further in conjunction with preferred embodiments and the accompanying drawings. Like components are denoted by like reference numerals in the drawings. Those skilled in the art will understand that the specific details described below are illustrative and not restrictive and are not intended to limit the scope of the application.

[0054] As shown in Figures 1a and 1b, the microneedle of the present embodiment comprises a base 1 and a plurality of needle bodies 2 arranged in an array on the base 1. The needle bodies 2 comprise a base 201, a tip 203, and a support connecting portion 202 connecting the base 201 and the tip 203. The base 201 is a circular truncated cone with a bottom inclined angle of 15° to 50°, preferably 25° to 40°. The tip 203 is a circular cone with an apex angle of 15° to 40°, preferably 20° to 35°. The side surface of the support connecting portion 202 is a concave curved surface. Figure 1 As shown in Figures 1a and 1b, the microneedle of the present embodiment comprises a base 1 and a plurality of needle bodies 2 arranged in an array on the base 1. The needle bodies 2 comprise a base 201, a tip 203, and a support connecting portion 202 connecting the base 201 and the tip 203. The base 201 is a circular truncated cone with a bottom inclined angle of 15° to 50°, preferably 25° to 40°. The tip 203 is a circular cone with an apex angle of 15° to 40°, preferably 20° to 35°. The side surface of the support connecting portion 202 is a concave curved surface. Figure 2 As shown in Figures 1a and 1b, the microneedle of the present embodiment comprises a base 1 and a plurality of needle bodies 2 arranged in an array on the base 1. The needle bodies 2 comprise a base 201, a tip 203, and a support connecting portion 202 connecting the base 201 and the tip 203. The base 201 is a circular truncated cone with a bottom inclined angle of 15° to 50°, preferably 25° to 40°. The tip 203 is a circular cone with an apex angle of 15° to 40°, preferably 20° to 35°. The side surface of the support connecting portion 202 is a concave curved surface. Figure 1 As shown in Figures 1a and 1b, the microneedle of the present embodiment comprises a base 1 and a plurality of needle bodies 2 arranged in an array on the base 1. The needle bodies 2 comprise a base 201, a tip 203, and a support connecting portion 202 connecting the base 201 and the tip 203. The base 201 is a circular truncated cone with a bottom inclined angle of 15° to 50°, preferably 25° to 40°. The tip 203 is a circular cone with an apex angle of 15° to 40°, preferably 20° to 35°. The side surface of the support connecting portion 202 is a concave curved surface. Figure 2 As shown in Figures 1a and 1b, the microneedle of the present embodiment comprises a base 1 and a plurality of needle bodies 2 arranged in an array on the base 1. The needle bodies 2 comprise a base 201, a tip 203, and a support connecting portion 202 connecting the base 201 and the tip 203. The base 201 is a circular truncated cone with a bottom inclined angle of 15° to 50°, preferably 25° to 40°. The tip 203 is a circular cone with an apex angle of 15° to 40°, preferably 20° to 35°. The side surface of the support connecting portion 202 is a concave curved surface.

[0055] Exemplarily, the ratio between the height of the base 201 and the height of the needle tip 203 is 1:3 to 1:15, preferably in the range of 1:5 to 1:11; the ratio between the height of the base 201 and the height of the support connecting part 202 is 1:0.5 to 1:2.5, preferably in the range of 1:1.5 to 1:2.5.

[0056] Exemplarily, the side of the support connecting part 202 is streamlined, and the support connecting part 202 connects the base 201 and the needle tip 203 along a tangent.

[0057] The distance between the top of adjacent needle tips 203 is 200-800 microns; the height of the needle body 2 is 200-800 microns.

[0058] Exemplarily, the distance between the top of adjacent needle tips 203 is the same as the height of the needle body 2.

[0059] Exemplarily, the bases 201 are arranged in a hexagonal close-packed arrangement on the substrate 1.

[0060] Embodiment 1

[0061] As shown in Figure 1 , the base micro-needle array designed in this embodiment is an array formed by micro-needles arranged uniformly perpendicularly to the substrate. The height of the micro-needle body 2 is 200 microns, and the height of the needle tip 203, the middle layer (the support connecting part 202), and the bottom (the base 201) is 125 microns, 50 microns, and 25 microns, respectively. The distance between the top of adjacent needle tips 203 is about 200 microns, and a hexagonal close-packed arrangement is adopted. Each square centimeter of the patch contains 1942 micro-needles. The top angle of the needle tip 203 is 30°. The inclination of the micro-needle bottom circular cone (the base 201) is 37.5°, and the maximum diameter is 200 microns. The volume of a single micro-needle is 0.968 nL, and the total volume of the micro-needles per square centimeter of the patch is 1.88 microliters. The area of the blank area without micro-needles is 12.087%. The side view of the micro-needle is shown in Figure 3 , and the top view is shown in Figure 4 .

[0062] The micro-needle is obtained by using a 3D printing forming process. The needle tip is sharp and uniform, and the needle shape is intact.

[0063] Embodiment 2

[0064] As shown in Figure 5 , wherein, Figure 5Figure a is a top view of the microneedle, and figure b is a side view of the microneedle. The base-type microneedle array designed in this embodiment is an array of microneedles uniformly arranged perpendicular to the substrate. The height of the microneedle body 2 is 250 μm, and the heights of the tip 203, support connection 202, and base 201 are 175 μm, 50 μm, and 25 μm, respectively. The microneedle spacing is approximately 250 μm, using a hexagonal close-packed arrangement, with 1651 microneedles per square centimeter patch. The apex angle of the tip 203 is 30°. The inclination angle of the base 201 is 35°, and the maximum diameter is 250 μm. The volume of a single microneedle is 1.950 nL, and the total volume of microneedles per square centimeter patch is 3.220 μL. The area of ​​the blank region without microneedles is 12.521%. The side view of the microneedle is shown below. Figure 6 As shown, the top view is as follows Figure 7 As shown.

[0065] Figure 8 In the image, A and B represent the fluorescence imaging (scale bar = 200 μm) and the three-dimensional reconstruction image (scale bar = 200 μm) of the skin punctured by the microneedles, respectively, in this embodiment. The depth of the microneedles puncturing the skin is 90 μm.

[0066] The microneedle was obtained using 3D printing technology, and the needle tip was sharp and uniform with a perfect shape.

[0067] Example 3

[0068] like Figure 9 As shown, where, Figure 9 Figure a shows a top view of the microneedle, and figure b shows a side view of the microneedle. The base-type microneedle array designed in this embodiment is an array of microneedles uniformly arranged perpendicular to the substrate. The height of the microneedle body 2 is 300 μm, and the heights of the tip 203, support connection 202, and base 201 are 225 μm, 50 μm, and 25 μm, respectively. The microneedle spacing is approximately 300 μm, using a hexagonal close-packed arrangement, with 1237 microneedles per square centimeter patch. The apex angle of the tip 203 is 30°. The inclination angle of the base 201 is 31°, and the maximum diameter is 300 μm. The volume of a single microneedle is 3.164 nL, and the total volume of microneedles per square centimeter patch is 3.914 μL. The area of ​​the blank region without microneedles is 12.658%. Compared to the comparative example, the total volume of the microneedles per square centimeter increased by 2.243 times, and the area of ​​the blank region without microneedles decreased by 55.369%. A side view of the microneedle is shown below. Figure 10 As shown, the top view is as follows Figure 11 As shown.

[0069] Figure 8In the middle, C and D are fluorescence images of microneedle penetrating skin (scale = 200 microns) and three-dimensional reconstruction images of microneedle penetrating skin (scale = 200 microns) of the present embodiment, respectively. The depth of microneedle penetrating skin is 130 microns.

[0070] The microneedle is obtained by using a 3D printing forming process, the needle tip is sharp and uniform, and the needle shape is intact.

[0071] Example 4

[0072] As shown in Figure 1 , the base type microneedle array designed in the present embodiment is an array formed by microneedles uniformly arranged perpendicular to the substrate. The height of the microneedle body is 345 μm, the height of the needle tip part, the support connecting part and the base is 270 μm, 50 μm and 25 μm, respectively. The microneedle spacing is about 345 μm, and the hexagonal close-packed arrangement is adopted. Each square centimeter of the patch contains 925 microneedles. The top angle of the needle tip part is 30°. The inclination is 27.5°, and the maximum diameter is 345 μm. The volume of a single microneedle is 4.610 nL, and the total volume of microneedles per square centimeter of the patch is 4.264 μL. The area of the blank area without microneedles is 13.624%. The side view of the microneedle is shown in Figure 12 , and the top view is shown in Figure 13 .

[0073] The microneedle is obtained by using a 3D printing forming process, the needle tip is sharp and uniform, and the needle shape is intact.

[0074] Comparative Example

[0075] Taking the conical microneedle commonly used for transdermal drug delivery as an example, the height of the microneedle body is 300 μm, the spacing of the needle tip part is 300 μm, and the hexagonal close-packed arrangement is adopted. Each square centimeter of the patch contains 1237 microneedles. The top angle of the needle tip part is 30°, the maximum diameter is 160.770 μm, the volume of a single microneedle is 1.411 nL, and the total volume of microneedles per square centimeter of the patch is 1.745 μL. The area of the blank area without microneedles is 68.027%. The side view of the microneedle is shown in Figure 14 , and the top view is shown in Figure 15 .

[0076] The same solution was used to make two kinds of microneedles of the comparative example and Example 3, specifically: 15% polyvinyl alcohol was dissolved in 22.5% water at 90°C. 20% aspirin and 10% polyvinylpyrrolidone were dissolved in 32.5% N,N-dimethylacetamide. The two solutions were mixed to obtain the microneedle tip solution. 15% polyvinyl alcohol was dissolved in 22.5% water at 90°C. 10% polyvinylpyrrolidone was dissolved in 52.5% N,N-dimethylacetamide. The two solutions were mixed to obtain the microneedle base solution. The aspirin was loaded on the tip of the microneedle using an ex vivo pig ear skin model. The effect of the microneedle on promoting the transdermal penetration of aspirin was evaluated by the cumulative release amount in vitro. In 12 hours, the comparative example microneedle accumulated 155.09 μg / cm 2 , and the Example 3 microneedle accumulated 289.01 μg / cm 2 . Compared with the comparative example, the Example 3 microneedle improved the transdermal penetration of the drug by 1.86 times. The experimental results show that, when the needle height and needle spacing are the same, the Example 3 microneedle can better promote the transdermal penetration of the drug. The specific results are shown in Figure 16 .

[0077] Obviously, the above examples of the present application are only examples for clearly illustrating the present application, and are not intended to limit the embodiments of the present application. For those skilled in the art, other different forms of changes or variations can be made on the basis of the above description, and it is impossible to enumerate all the embodiments here. Any obvious changes or variations derived from the technical solutions of the present application are still within the protection scope of the present application.

Claims

1. A microneedle for improving drug utilization, characterized by, The microneedle comprises a base and a plurality of needle bodies arranged in an array on the base; The needle body comprises a base, a tip, and a support connecting portion connecting the base and the tip; The base is a circular truncated cone with a bottom inclination angle of 15° to 50°; The tip is a circular cone with an apex angle of 15° to 40°; The side surface of the support connecting portion is a concave curved surface; The base is arranged in a hexagonal close-packed arrangement on the base; The ratio between the height of the base and the height of the tip is 1:3 to 1:15; the ratio between the height of the base and the height of the support connecting portion is 1:0.5 to 1:2.5; The side surface of the support connecting portion is streamlined, and the support connecting portion connects the base and the tip along a tangent.

2. The microneedle of claim 1, wherein, The upper surface of the support connecting portion matches the bottom surface of the tip; the lower surface of the support connecting portion matches the upper surface of the base.

3. The microneedle of claim 1, wherein, The distance between the top of adjacent tips is 200-800 microns; the height of the needle body is 200-800 microns.

4. The microneedle of claim 1, wherein, The bottom inclination angle of the circular truncated cone is 25° to 40°.

5. The microneedle of claim 1, wherein, The apex angle of the circular cone is 20° to 35°.

6. The microneedle of claim 1, wherein, The ratio between the height of the base and the height of the tip is 1:5 to 1:

11.

7. The microneedle of claim 1, wherein, The ratio between the height of the base and the height of the support connecting portion is 1:1.5 to 1:2.5.

Images