CN116474254A - Hierarchical microneedle patch and processing method - Google Patents
Hierarchical microneedle patch and processing method Download PDFInfo
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- CN116474254A CN116474254A CN202310501510.6A CN202310501510A CN116474254A CN 116474254 A CN116474254 A CN 116474254A CN 202310501510 A CN202310501510 A CN 202310501510A CN 116474254 A CN116474254 A CN 116474254A
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y80/00—Products made by additive manufacturing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M2207/00—Methods of manufacture, assembly or production
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Manufacturing & Machinery (AREA)
- Materials Engineering (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
The invention relates to the technical field of medical materials, in particular to a grading microneedle patch which comprises a back patch and a microneedle, wherein the microneedle is provided with three parts of a needle tip part, an extending part and a needle base part which are sequentially connected, a first dividing line or a first dividing surface is arranged between the outer wall of the needle tip part and the outer wall of the extending part in a ring mode, and a second dividing line or a second dividing surface is arranged between the outer wall of the extending part and the outer wall of the needle base part in a ring mode, namely the positions of the needle tip part, the extending part and the needle base part can be clearly distinguished. Through setting up every part into different functions, for example set up to some carry medicine, some are as supporting, just can clearly discern the position of microneedle on carrying medicine part, be convenient for grasp the degree of depth of dosing, facilitate the use. The invention also provides a processing method for processing the grading microneedle patch.
Description
Technical Field
The invention relates to the technical field of medical materials, in particular to a grading microneedle patch and a processing method.
Background
The microneedle can effectively penetrate the skin barrier, and the drug utilization rate is improved. In contrast to conventional hypodermic needles, microneedles can penetrate the outermost stratum corneum of the skin through their sharp tips, facilitating penetration of therapeutic agents into the epidermis and dermis, resulting in a local or systemic drug effect. The existing microneedle patch is provided with a plurality of conical microneedles on the back patch, and the size of the microneedles is small, and the microneedles are conical, so that the positions of medicine loading parts on the microneedles cannot be clearly identified, the medicine feeding depth is required to be grasped, whether the medicine feeding amount is sufficient or not is required to be checked after the microneedle patch is used, and the use inconvenience is brought. Meanwhile, the projection taper of each part of the existing integrated conical microneedle on the second plane is the same, once the microneedle is stressed in the use process, the microneedle is broken and uncontrollable, the position of the broken position cannot be effectively predicted, and the accuracy of delivering the drug dose by the microneedle cannot be ensured. Finally, the integral conical microneedle structure makes it difficult to achieve accurate multi-drug delivery because of the lack of distinct positional discrimination of the various portions, and the difficulty in achieving multiple drug components or multiple drug dosage forms at different locations of the microneedle.
Therefore, there is a need for a hierarchical microneedle patch and method of processing to address the above-mentioned issues.
Disclosure of Invention
One object of the present invention is to: the grading microneedle patch can clearly identify the position of a drug loading part of a microneedle, and is convenient to use.
To achieve the purpose, the invention adopts the following technical scheme:
there is provided a hierarchical microneedle patch comprising:
backing;
the micro needle comprises a needle tip, an extension portion and a needle base portion which are sequentially connected, a first parting line or a first parting plane is arranged between the outer wall of the needle tip and the outer wall of the extension portion in a ring mode, a second parting line or a second parting plane is arranged between the outer wall of the extension portion and the outer wall of the needle base portion in a ring mode, the needle base portion is connected to the back portion, the micro needle is parallel to any first section and any second section of the back portion, the first section is closer to the back portion than the second section, projections of the second section on a plane where the first section is located coincide with the first section or are in the first section, the shapes and the conicity of projections of the needle tip portion, the extension portion and the needle base portion on the second plane are different, and the second plane is perpendicular to the back portion.
As a preferred scheme of the grading micro-needle patch, the projection of the first top surface of the needle tip part, which is projected on the back patch, is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex inner concave shape, and the first top surface is positioned at the end part of the needle tip part, which is far away from the extension part;
and/or the projection of the first bottom surface of the needle tip part, which is projected on the back patch, is a combination of a circumferential symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or an outer convex inner concave shape, and the first bottom surface is positioned at the end part of the needle tip part, which is contacted with the extension part;
and/or the projection of the second top surface of the extension part, which is projected on the back patch, is a combination of a circumferential symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or an outer convex inner concave shape, and the second top surface is positioned at the end part of the extension part, which is contacted with the needle tip part;
and/or the projection of the second bottom surface of the extension part, which is projected on the back patch, is a combination of a circumferential symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or an outer convex inner concave shape, and the second bottom surface is positioned at the end part of the extension part, which is contacted with the needle base part;
And/or the projection of the third top surface of the needle base part, which is projected on the back patch, is a combination of a circumferential symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or an outer convex inner concave shape, and the third top surface is positioned at the end part of the needle base part, which is contacted with the extension part;
and/or the projection of the third bottom surface of the needle base part on the back patch is in a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex-concave combination shape, and the third bottom surface is positioned at the end part of the needle base part, which is contacted with the back patch.
As a preferable scheme of the grading microneedle patch, the projection of the first top surface projected on the back patch is a first area, and the value range of the ratio of the length to the width of the smallest rectangle capable of accommodating the first area is 1.1-10;
and/or the projection of the first bottom surface projected on the back patch is a second area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the second area is 1.1-10;
and/or the projection of the second top surface projected on the back patch is a third area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the third area is 1.1-10;
And/or the projection of the second bottom surface projected on the back patch is a fourth area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the fourth area is 1.1-10;
and/or the projection of the third top surface projected on the back patch is a fifth area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the fifth area is 1.1-10;
and/or the projection of the third bottom surface projected on the back patch is a sixth area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the sixth area is 1.1-10.
As a preferable scheme of the grading microneedle patch, the projection of the needle tip part projected on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid;
and/or the projection of the extension part projected on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid;
and/or the projection of the needle base on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid.
As a preferred mode of the grading micro-needle patch, a plurality of the extending parts are arranged on one needle base, and the end part of each extending part far away from the needle base is provided with the needle tip part.
As a preferred embodiment of the hierarchical microneedle patch, a plurality of the extensions on one of the needle bases are uniformly spaced.
As a preferable scheme of the grading micro-needle patch, the joint of the needle tip part and the extension part is provided with a first step surface;
and/or the connection part of the extension part and the needle base part is provided with a second step surface.
As a preferable scheme of the grading micro-needle patch, a notch is formed in the side wall of the needle tip part, the extending part or the needle base part, or a notch is formed in the joint of the needle tip part and the extending part, or a notch is formed in the joint of the extending part and the needle base part.
As a preferred scheme of the grading microneedle patch, a breaking groove is annularly arranged on the side wall of the needle tip part, the extending part or the needle base part.
Another object of the invention is: a method for manufacturing a hierarchical microneedle patch is provided, which can manufacture a hierarchical microneedle patch in which the position of a drug-loading portion of a microneedle can be recognized more easily.
To achieve the purpose, the invention adopts the following technical scheme:
the processing method is used for processing the grading microneedle patch and comprises the following steps of:
s1, preparing a male die of a microneedle array by adopting 3D printing, wherein the 3D printing material is photosensitive resin, the male die comprises a substrate and a plurality of microneedle parts, a molding groove is formed in the substrate, an annular groove is formed in the bottom of the molding groove, and the microneedle parts are arranged in the groove bottom and are positioned in an area surrounded by the annular groove;
S2, adding PDMS into the molding groove, curing at a preset temperature T1 for a preset time period T1, and realizing crosslinking between chains to obtain a PDMS female mold, wherein the PDMS female mold is provided with an annular edge;
s3, pouring the matrix material solution into a groove surrounded by the annular edge, or directly placing the PDMS female die into a container filled with the matrix material solution, and continuously preserving for a preset time period T2 at a preset temperature T2 so as to reduce the fluidity of the solution;
s4, placing the PDMS female die filled with the matrix material solution into a vacuum dryer, vacuumizing at room temperature for a preset time period t3, or placing the PDMS female die into a centrifuge tube filled with the matrix material solution, and continuously placing the PDMS female die into a needle-shaped groove of the PDMS female die at a rotating speed r1 for a preset time period t 4;
s5, placing the PDMS female die at a preset temperature T3 for curing and forming.
The invention has the beneficial effects that:
the invention provides a grading micro-needle patch which comprises a back patch and a micro-needle, wherein the micro-needle is provided with three parts of a needle tip part, an extending part and a needle base part which are sequentially connected, a first dividing line or a first dividing surface is arranged between the outer wall of the needle tip part and the outer wall of the extending part in a ring mode, and a second dividing line or a second dividing surface is arranged between the outer wall of the extending part and the outer wall of the needle base part in a ring mode, so that the positions of the needle tip part, the extending part and the needle base part can be clearly distinguished. Through setting up every part into different functions, for example set up to some carry medicine, some are as supporting, just can clearly discern the position of microneedle on carrying medicine part, be convenient for grasp the degree of depth of dosing, facilitate the use. And because the microneedle is parallel to the arbitrary first cross section and the second cross section that the back was pasted all satisfy, first cross section is closer to the back than the second cross section, and the projection of second cross section on the plane that first cross section was located coincides with first cross section or in first cross section, can guarantee to conveniently pull out the mould and take out in the course of working. Meanwhile, as the projection shapes and the taper of the needle tip part, the extension part and the needle base part of the three-stage micro-needle structure on the second plane are different, namely the mechanical properties of the three parts bearing the external force load are different, the difficulty level of structural fracture under the action of the external force is different, the difficulty level of structural fracture of the corresponding part under the action of the external force can be improved or reduced through the projection shapes and the taper setting of the second plane of the three parts, the position of the micro-needle fracture can be effectively predicted, the micro-needle fracture is regulated and controlled, and the precision of the micro-needle for delivering the medicine dosage is ensured. The number and the positions of the segments after the micro-needle is broken are different according to the different applied external forces. Finally, the needle tip, the extension and the needle base of the three-stage microneedle structure are clearly demarcated, and the three parts can be respectively loaded with two or even three drug components or drug dosage forms, so that a product with multiple drugs for accurate delivery can be conveniently designed and processed.
The invention also provides a processing method for processing the grading microneedle patch, which comprises the following steps: s1, preparing a male die of a microneedle array by adopting 3D printing, wherein the 3D printing material is photosensitive resin, the male die comprises a substrate and a plurality of microneedle parts, a molding groove is formed in the substrate, an annular groove is formed in the bottom of the molding groove, and the microneedle parts are arranged at the bottom of the groove and are positioned in an area surrounded by the annular groove; s2, adding PDMS into the molding groove, curing at a preset temperature T1 for a preset time period T1, and realizing crosslinking between chains to obtain a PDMS female mold, wherein the PDMS female mold is provided with an annular edge; s3, pouring the matrix material solution into a groove surrounded by the annular edge, or directly placing the PDMS female die into a container filled with the matrix material solution, and continuously presetting the duration T2 at the preset temperature T2 to reduce the fluidity of the solution; s4, placing the PDMS female die filled with the matrix material solution into a vacuum dryer, and vacuumizing at room temperature for a preset time period t3, or placing the PDMS female die into a centrifuge tube filled with the matrix material solution, and continuously placing the PDMS female die into a needle-shaped groove of the PDMS female die at a rotating speed r1 for a preset time period t 4; s5, placing the PDMS female die at a preset temperature T3 for curing and forming. The grading microneedle patch which can easily identify the position of the drug loading part of the microneedle can be obtained by the processing method.
Drawings
FIG. 1 is a partial cross-sectional view of a hierarchical microneedle patch provided by an embodiment of the present invention;
FIG. 2 is a schematic view of a structure of a microneedle according to an embodiment of the present invention (the projections of the first top surface and the first bottom surface are both circular, and the projection of the microneedle onto the second plane is isosceles trapezoid);
FIG. 3 is a schematic view of a structure of a microneedle according to an embodiment of the present invention (the projections of the first top surface and the first bottom surface are both circular, the projections of the second top surface and the second bottom surface are both positive directions, and the projection of the second top surface and the second bottom surface on the second plane is isosceles trapezoid);
FIG. 4 is a schematic structural view of a microneedle according to an embodiment of the present invention (the projection of the first bottom surface is crescent and the projection of the first bottom surface on the second plane is rectangular trapezoid);
FIG. 5 is a schematic view of a structure of a microneedle according to an embodiment of the present invention (the projection of the first bottom surface is elliptical, and the projection of the first bottom surface on the second plane is rectangular trapezoid);
FIG. 6 is a schematic view of a structure of a microneedle according to an embodiment of the present invention (the projection of the first top surface is a regular hexagon, the projection of the first bottom surface is a regular hexagon, and the projection of the first bottom surface on the second plane is an isosceles trapezoid);
FIG. 7 is a schematic view of a structure of a microneedle according to an embodiment of the present invention (the projection of the first top surface is rectangular, the projection of the first bottom surface is rectangular, and the projection of the first bottom surface on the second plane is rectangular trapezoid);
FIG. 8 is a schematic view of a microneedle (with a notch and a breaking groove) according to an embodiment of the present invention;
FIG. 9 is a schematic diagram of the structure of a microneedle (sea anemone-like) according to an embodiment of the present invention;
FIG. 10 is a schematic view showing the structure of a microneedle (first comparative example) provided in an embodiment of the present invention;
FIG. 11 is a schematic view showing the structure of a microneedle (second comparative example) according to an embodiment of the present invention;
FIG. 12 is a schematic diagram of the structure of a microneedle (linear multi-tip design) according to an embodiment of the present invention;
FIG. 13 is a graphical illustration of axisymmetric double male external shapes and single male external shapes provided by embodiments of the present invention;
FIG. 14 is an example of an axisymmetric double concave-in to convex-concave combined shape provided by an embodiment of the present invention;
FIG. 15 is a schematic view of a structure of a microneedle (the projection of the first top surface is circular, the projection of the first bottom surface is diamond, and the projection of the first bottom surface on the second plane is isosceles trapezoid) according to an embodiment of the present invention;
FIG. 16 is a schematic view of a structure of a microneedle (a projection of a first top surface is square, a projection of a first bottom surface is rectangular, and a projection of the first bottom surface on a second plane is isosceles trapezoid) according to an embodiment of the present invention;
FIG. 17 is a graphical illustration of the projection of the tip and extension of a microneedle onto a second plane provided by an embodiment of the present invention;
FIG. 18 is a graphical illustration of the projection of the tip and extension (step transition therebetween) of a microneedle onto a second plane provided by an embodiment of the present invention;
FIG. 19 is a graphical illustration of the projection of the tip and extension (smooth transition therebetween) of a microneedle onto a second plane provided by an embodiment of the present invention;
fig. 20 is a force diagram of a microneedle (having a first notch and a second notch) according to an embodiment of the present invention.
In the figure:
1. backing;
2. a microneedle; 21. a needle tip; 211. a first top surface;
22. an extension; 221. a second top surface; 2211. a first step surface;
23. a needle base; 231. a third top surface; 2311. a second step surface;
201. a notch; 2011. a first opening; 2012. a second opening; 202. breaking the groove;
300. the position easy to break;
4. a main body arc; 5. and (5) adducting an arc.
Detailed Description
Advantages and features of the present invention and methods of accomplishing the same may become apparent with reference to the following detailed description of embodiments taken in conjunction with the accompanying drawings. However, the present invention is not limited to the embodiments disclosed below, but may be embodied in various different forms, which are provided only for the purpose of completing the disclosure of the present invention and fully understanding the scope of the present invention by those skilled in the art, and the present invention is limited only by the scope of the claims. Like reference numerals denote like constituent elements throughout the specification.
As shown in fig. 1, the hierarchical microneedle patch of the present embodiment includes a back patch 1 and a microneedle 2, and since the microneedle 2 has three portions of a needle tip 21, an extension portion 22 and a needle base 23 that are sequentially connected, and a first dividing line or a first dividing plane is provided between the outer wall of the needle tip 21 and the outer wall of the extension portion 22 in a ring, and a second dividing line or a second dividing plane is provided between the outer wall of the extension portion 22 and the outer wall of the needle base 23 in a ring, that is, the positions of the three portions of the needle tip 21, the extension portion 22 and the needle base 23 can be clearly distinguished. As shown in fig. 2, when there is a smooth transition between two adjacent portions, there is a division plane that is looped. As shown in fig. 3, when a step structure or a fold line transition is formed between two adjacent portions, there is a division line which is looped. And the shape and taper of the projections of the needle tip 21, the extension 22 and the needle base 23 on the second plane are different from each other, the second plane being perpendicular to the backing 1.
Through setting up every part to different functions, for example set up to some carry medicine, some are as the support, just can clearly discern the position of microneedle 2 on the portion of carrying medicine, be convenient for grasp the degree of depth of dosing, facilitate the use. Meanwhile, the projection shapes and the taper angles of the needle tip 21, the extension 22 and the needle base 23 of the three-stage structure on the second plane are different, namely the mechanical properties of the three parts bearing the external force load are different, the difficulty level of structural fracture under the action of the external force is different, the difficulty level of structural fracture of the corresponding part under the action of the external force can be improved or reduced through the projection shapes and the taper angles of the second plane of the three parts, the fracture occurrence position of the micro needle 2 is effectively predicted, the fracture of the micro needle 2 is regulated and controlled, and the accuracy of drug dosage delivery of the micro needle 2 is ensured. For example, when the first dividing line and the second dividing line are the same and the heights of the extension portion 22 and the needle tip portion 21 are the same, the more gradually the taper of the extension portion 22 and the needle tip portion 21 is, the less the material of the tip end of the extension portion 22 and the tip end of the needle tip portion 21 is, the more the risk of cracking due to an external force and the greater the risk of structural fracture. In addition, the number and positions of the segments after the breakage of the microneedle 2 are different according to the magnitude of the applied external force. When the external force is small, the material of the tip 21 is small, the breakage is easy to occur, and when the external force is large, even if the material of the extension part 22 is large, the structural breakage is possible to occur under the action of large deformation and large stress. At the first dividing line or the second dividing line, due to the smooth or step transition area between the needle base 23 and the extension 22, and between the extension 22 and the needle tip 21, the projected cross section in the direction parallel to the back plate 1 changes more severely, and is a potential stress concentration area, and when an external force acts, the risk of structural fracture is higher. Finally, the three-stage structure needle tip 21, extension 22 and needle base 23 are clearly demarcated from one another, and the three sections can be loaded with two or even three drug components or drug dosage forms, respectively, facilitating the design and processing of multi-drug delivery products. And because the microneedle 2 is parallel to the arbitrary first cross section and the second cross section of back subsides 1 all satisfy, first cross section is closer to back subsides 1 than the second cross section, and the projection of second cross section on the plane that first cross section was located coincides with first cross section or in first cross section, can guarantee to conveniently pull out the mould and take out in the course of working. Preferably, the tip 21 is in a needle-punched structure, and the tip of the tip 21 is sharp to successfully pierce a physical barrier such as skin or mucous membrane.
Preferably, the minimum width of the projection of the first top surface 211 of the needle tip 21 onto the backing 1 is in the range of 1 μm to 100 μm, the first top surface 211 being located at the end of the needle tip 21 remote from the extension 22. When the processing method is used, the possibility of industrialization is realized when the minimum width is larger than 1 mu m, and the processing precision is required to be too high when the minimum width is smaller than 1 mu m, so that the difficulty is too high and the rejection rate is too high. According to p=f/S, under the condition that the static force F of the puncture barrier is unchanged, the smaller the projection minimum width is, the smaller the projection area S is, the greater the pressure P of the puncture barrier is, and the difficulty of the puncture of the physical barrier is reduced. In summary, 1 μm was chosen as the lower limit of the minimum width of the projection. With the increase of the minimum projection width, the processing difficulty is reduced, the qualification rate is improved, and the cost is reduced. As the minimum width increases, the projected area increases, and according to p=f/S, when the static force F of the barrier piercing is unchanged, the projected area S increases, so that the pressure P of the barrier piercing decreases, and the difficulty of the barrier piercing increases. So to maintain a balance between processing costs and the difficulty of puncturing the barrier, 100 μm is chosen as the upper limit of the minimum width of the projection.
Further, the minimum width of the projection of the first top surface 211 of the needle tip 21 onto the backing 1 is in the range of 20 μm to 40 μm.20 μm is the minimum width of projection of the first top surface 211 of the needle tip 21 of the existing conventional high-precision 3D printer printing photosensitive resin matrix mold onto the back patch 1. 40 μm is the minimum width projected by the first top surface 211 that is deliberately reduced to enhance the barrier penetration capability of the needle tip 21. Preferably, the minimum width of the projection of the first bottom surface of the needle tip 21 onto the backing sheet 1 is greater than or equal to the minimum width of the projection of the first top surface 211 of the needle tip 21 onto the backing sheet 1, so as to form a draft angle, facilitating complete draft removal of the needle tip 21, the first bottom surface being at the end of the needle tip 21 contacting the extension 22.
As shown in fig. 4 to 7, preferably, the projection of the first top surface 211 of the needle tip 21 on the back patch 1 may be a circumferential symmetrical outer convex shape, an axial symmetrical double outer convex shape, a single side outer convex shape, an axial symmetrical double inner concave shape, an outer convex-concave combined shape, or an outer convex-concave combined shape. The circumferential symmetry refers to the fact that the circle center of a circumscribing circle of the graph is taken as a midpoint, and the shape of the target graph can be obtained by rotating the circumscribing circle by a certain angle. The circles can rotate at any angle, the regular triangle rotates three times continuously by 120 degrees, the square rotates four times continuously by 90 degrees, the regular pentagon rotates five times continuously by 72 degrees, and the regular hexagon rotates six times continuously by 60 degrees. In summary, circumferentially symmetric means that a single pattern can be rotated repeatedly through a certain angle along the origin to obtain the final target pattern. The circumferentially symmetrical convex shape comprises a circle, a regular triangle, a regular polygon and the like. As shown in fig. 13, the concavity and convexity refer to the concavity and convexity of the upper and lower surfaces of the figure, wherein the upper and lower surfaces refer to the upper and lower surfaces of the figure, and the axisymmetric double-convexity refers to the figure which is axisymmetric and which both upper and lower are convex outward, such as a rectangle (upper right figure in fig. 13), an ellipse (upper left figure in fig. 13), and a rhombus (lower right figure in fig. 13) shown in fig. 13. The single-sided outward convexity refers to an upward convexity, such as a short flat isosceles triangle (lower left figure in fig. 13) as shown in fig. 13. Axisymmetric double concave shape means that both upper and lower are concave patterns, such as a bone shape (upper left pattern in fig. 14) and a bone optimized shape (upper right pattern in fig. 14) shown in fig. 14. The convex-concave combination shape refers to a pattern having a convex side and a concave side on the upper and lower sides, such as a crescent shape (a lower left pattern in fig. 14) and a crescent optimized shape (a lower right pattern in fig. 14) shown in fig. 14.
For the projection of the first top surface 211 with a circular symmetrical outer convex shape, including a circle, a regular triangle, a regular polygon, etc., the stress in all directions is uniform when penetrating into the barrier, the micro needle 2 is not easy to break, and if the external force is large, the needle tip 21 breaks, and the breaking direction is consistent with the acting direction of the external force. Since the triangle is a stable structure, the design of the first top surface 211 projected by the regular triangle is difficult to crack and break when the first top surface is subjected to external force on each side surface, and the structure is more tough. In addition, the triangular structure formed by regular triangle projection presents three evenly distributed acute angles of 60 degrees, and the needle tip 21 can quickly penetrate into the physical barrier, so that the effect of penetrating the physical barrier is better. For regular polygons with a circle and a number of sides equal to or greater than 4, the angle of the edges is equal to or greater than 90 degrees, and the barrier penetration effect is not as sharp as that of the regular triangle projection design. The principle is similar to that of a three-edged army thorn, the structure is stable in the actual combat process, the breaking is difficult, and the effect of penetrating human tissues is good.
For the projection of the first top surface 211 to be axisymmetric double-outer convex, the projection comprises rectangle, ellipse and diamond, and the axisymmetric outer convex surface is stressed symmetrically in the process of penetrating the barrier, so that the barrier can be penetrated smoothly. At the same time, there is a difference in the dimensions of the major and minor axes. Since a large amount of material exists in the major axis direction, when the external force direction is aligned with the major axis direction, the deformation of the tip portion 21 is less likely to occur, and cracks and breaks are less likely to occur, and when the external force direction is aligned with the minor axis direction, the deformation of the tip portion 21 is less likely to occur. Therefore, in the use description of the hierarchical microneedle patch, the recommended application of the external force direction can be increased, the external force direction is consistent with the short axis direction, the needle tip 21 is ensured to be more easily broken in the stress direction and remain in the body, the target model drug is released, and when the external force is applied in the non-recommended direction, the external force direction is inconsistent with the short axis direction, the breakage of the needle tip 21 is not easily caused, and the structural integrity is ensured. The diamond structure has sharp edges less than 90 degrees at two ends, and the needle tip 21 can quickly penetrate through the physical barrier when in use, so that the effect of piercing the physical barrier is better. Whereas for oval and rectangular shapes, either there are no ribs or the angle of the ribs is equal to 90 °, not sharp enough to penetrate the barrier, not as effective as a diamond projection design. The principle is similar to a sword, the section of the sword is diamond-shaped, and the effect of penetrating human tissues in the actual combat process is good. For a projection of the first top surface 211 with a single-sided convex shape, such as a low isosceles triangle, the needle tip 21 can smoothly penetrate the physical barrier. There is a difference in the dimensions of the major and minor axes. Since a large amount of material exists in the major axis direction, when the external force direction is aligned with the major axis direction, the deformation of the tip portion 21 is less likely to occur, and cracks and breaks are less likely to occur, and when the external force direction is aligned with the minor axis direction, the deformation of the tip portion 21 is less likely to occur. When an external force acts on the middle of the bottom edge of the short isosceles triangle, the vertex of the opposite side triangle at the acting position plays a supporting role, so that the structure is kept stable and is difficult to break; when external force acts on the top of the isosceles triangle, the opposite side of the acting position is not supported, so that the deformation is easier to occur, and cracks and fractures are initiated. Therefore, in the use description of the hierarchical microneedle patch, the recommended application direction of the external force can be added to be the direction acting on the top of the short isosceles triangle, the external force direction is consistent with the short axis direction, no opposite side supporting point exists, the needle tip 21 is ensured to be broken more easily in the stress direction and remain in the body, the target model drug is released, the external force acts on the middle point of the bottom edge of the short isosceles triangle, the breaking difficulty is increased, and when the external force acts on the long axis direction of the two sides, the material is more, and the breaking difficulty is greater. Overall, therefore, the short isosceles triangle design has a pattern of unidirectional breaks. In addition, the two ends are provided with sharp edges smaller than 60 degrees, and the needle tip 21 can quickly penetrate through the physical barrier in use, so that the effect of piercing the physical barrier is better.
For the projection of the first top surface 211 to be axisymmetric double concave, for example, a bone shape and a bone optimized shape. The axisymmetric double concave surfaces are symmetrically stressed in the process of penetrating the barrier, and can be smoothly penetrated. At the same time, there is a difference in the dimensions of the major and minor axes. Since a large amount of material exists in the major axis direction, when the external force direction is aligned with the major axis direction, the deformation of the tip portion 21 is less likely to occur, and cracks and breaks are less likely to occur, and when the external force direction is aligned with the minor axis direction, the deformation of the tip portion 21 is less likely to occur. Therefore, in the use description of the hierarchical microneedle patch, the recommended application of the external force direction can be increased, the external force direction is consistent with the short axis direction, the needle tip 21 is ensured to be more easily broken in the stress direction and remain in the body, the target model drug is released, and when the external force is applied in the non-recommended direction, the external force direction is inconsistent with the short axis direction, the breakage of the needle tip 21 is not easily caused, and the structural integrity is ensured. In addition, the bone-shaped inner concave surface plays a role in gathering peripheral tissues in the process of penetrating the physical barrier, the peripheral tissues are extruded to the vicinity of the double-side inner concave surfaces, once the needle tip 21 is stably penetrated, the peripheral tissues also extrude the inner concave surfaces, the needle tip 21 is firmly fixed in the tissues, the problem of displacement after the micro needle 2 is inserted is avoided, and the problems of reduced drug delivery efficiency and the like caused by the displacement of the micro needle 2 are avoided. Finally, the bone optimizing shape is to add two inner ear structures at two ends, so that the effect of gathering peripheral tissues when the needle tip 21 is penetrated is further improved, and the anti-displacement performance of the microneedle 2 in the inserting process is further improved. As shown in fig. 14, the adduction ear structure is that two adduction arc structures connected with the two ends of the original bone shape are respectively arranged at the two ends of the original bone shape, and the curvature radius r2 of the adduction arc 5 is smaller than the curvature radius r1 of the main body arc 4 of the bone shape.
For the projection of the first top surface 211 to be convex-concave, e.g., crescent-shaped and crescent-optimized, the needle tip 21 can smoothly penetrate into the physical barrier. There is a difference in the dimensions of the major and minor axes. Since a large amount of material exists in the major axis direction, when the external force direction is aligned with the major axis direction, the deformation of the tip portion 21 is less likely to occur, and cracks and breaks are less likely to occur, and when the external force direction is aligned with the minor axis direction, the deformation of the tip portion 21 is less likely to occur. When an external force acts on the center of the inner concave surface, the endpoints at the two sides of the acting position can play a certain role in pulling, so that the structure is kept stable, and breakage is avoided; when external force acts on the center of the outer convex surface, the supporting effect of the two side end points is weaker relatively, deformation is easier to occur, and cracks and fractures are initiated. Therefore, in the use description of the hierarchical microneedle patch, the recommended external force direction applied can be added to be the direction acting on the center of the outer convex surface, the external force direction is consistent with the short axis direction, the supporting capability of the two end points is weaker, the needle tip 21 is ensured to be broken more easily in the stress direction and is remained in the body, the target model drug is released, when the external force acts on the direction in the center of the inner concave surface, the breaking difficulty is increased, when the external force acts on the long axis direction of the two sides, the materials are more, and the breaking difficulty is larger. So, in general, the male-female bond design has a pattern of unidirectional breaks. In addition, the crescent concave surface can play a role in gathering peripheral tissues in the process of penetrating the physical barrier, the peripheral tissues are extruded to the vicinity of the single-side concave surface, once the needle tip 21 is stably penetrated, the peripheral tissues can also extrude the concave surface, the needle tip 21 is firmly fixed in the tissues, the problem of displacement after the micro needle 2 is inserted is avoided, and the problems of reduced drug delivery efficiency and the like caused by the displacement of the micro needle 2 are avoided. Finally, the crescent optimized shape is that two inner ear structures are additionally arranged at two ends, so that the effect of gathering peripheral tissues when the needle tip 21 is penetrated in is further improved, and the anti-displacement performance of the microneedle 2 in the inserting process is further improved. As shown in fig. 14, the inner ear structure is that two inner arc structures connected with the two inner arc structures are respectively arranged at two ends of the original crescent, and the curvature radius r2 of the inner arc 5 is smaller than the curvature radius r1 of the crescent main arc 4.
Preferably, the projection of the first top surface 211 projected onto the back patch 1 is a first area, and the first area is an axisymmetric double-outer convex shape (rectangle, ellipse, diamond, etc.), a single-side outer convex shape (short isosceles triangle, etc.), an axisymmetric double-inner concave shape (bone shape, bone optimization shape, etc.), an outer convex-inner concave combination shape (crescent shape, crescent optimization shape, etc.), and the value range of the ratio of the length and the width of the minimum rectangle capable of accommodating the first area is 1.1-10. A minimum value of 1.1 ensures that there is a certain dimensional difference between length and width, which can manifest itself in terms of breaking resistance. The maximum value of 10 is to ensure the stability of the needle tip 21 during processing and clinical procedures, so that the structure is not too stable and is too easy to break during processing and use. The aspect ratio is further optimized to 2-5, and the needle tip 21 can achieve both of the controllable fracture property and the structural stability when the aspect ratio is within the above-mentioned range.
The projection of the first bottom surface of the needle tip 21 onto the back patch 1 is a second area, and the value of the ratio of the length to the width of the smallest rectangle capable of accommodating the second area is 1.1-10. The projection of the first bottom surface projected on the back patch 1 is in a shape of a circular symmetrical outer convex shape, an axial symmetrical double outer convex shape, a single-side outer convex shape, an axial symmetrical double inner concave shape or a convex inner concave combination shape, the first bottom surface is positioned at the end part of the needle tip 21 contacting the extension part 22, and the shape design of the first bottom surface is the same as the first top surface 211 of the needle tip 21.
Preferably, the second plane is perpendicular to the back patch 1, and as shown in fig. 17, the projection of the needle tip 21 on the second plane is rectangular (left one in fig. 17), isosceles trapezoid (left two in fig. 17 or fig. 16), right trapezoid (right two in fig. 17) or non-right isosceles trapezoid (right one in fig. 17), and the corresponding breakable positions 300 in various projection forms are identified in the figure. When projected as a rectangle, the widths of the front projection of the first top surface 211 and the first bottom surface of the needle tip 21 are the same, but because the minimum width dimension of the projection of the first top surface 211 of the needle tip 21 is smaller and is in the micrometer level, the value range is 1-100 micrometers, preferably 20-40 micrometers, so the needle tip 21 of the rectangular front projection has better physical barrier puncturing capability, when the horizontal external pushing force acts, the lower part of the needle tip 21 and the extension 22 are connected through transition or step, the extension 22 is more in material, the lower part of the needle tip 21 is fixed, and lack of enough space for sharing deformation under the external force, so the external force only acts on the connecting area of the lower part of the needle tip 21 in a concentrated way, thereby causing local large deformation, local large strain, local large stress and easy crack generation and fracture. When in the shape of an isosceles trapezoid, the width of the front projection of the first top surface 211 of the tip portion 21 is smaller than the width of the front projection of the first bottom surface, which encounters greater resistance when puncturing the physical barrier, and a larger wound passage area and a stronger pain sensation than a rectangular front projection structure. However, since the lower portion of the needle tip 21 is made of a relatively large amount of material and has a symmetrical structure, deformation and breakage are unlikely to occur when an external pushing force is applied in the horizontal direction. Even if breakage occurs, the breakage position easily appears at the upper portion of the needle tip 21, and the area is subjected to external force, and the minimum width of the projection section is smaller, so that the material volume is smaller, the material tissue for distributing the external force is smaller, the deformation amount carried by the material per unit volume is larger, the strain is larger, and the stress is larger. When the stress under the action of the external force exceeds the fracture limit which can be born by the material, cracks can appear, and the cracks can be quickly expanded and generated. When the shape is right trapezoid, because the two sides of the right trapezoid are asymmetric, when the needle tip 21 is inserted, the length of the long side of the right trapezoid is longer, the stress area is larger, the stress is larger, and the needle tip 21 is easier to deflect near the short side direction. Since the bending load is applied to the tip portion 21 and the tensile load is applied to the long side and the compressive load is applied to the short side, the position where the crack occurs and the position where the crack is broken in the tip portion 21 having a rectangular trapezoid cross section in front view are more likely to occur on the long side of the rectangular trapezoid, and when the peak of the stress exceeds the limit that the material can withstand, the crack occurs, and the structure is broken. When the shape is a non-right-angle isosceles trapezoid, the angle and the shape of the non-right-angle isosceles trapezoid can be adjusted according to the specific requirements of the breaking position and the breaking direction, namely, the specific shape of the needle tip 21 is adjusted, but in summary, the breaking position is easier to occur on the long side of the trapezoid, the principle is similar to that of the right-angle trapezoid, and the breaking positions are different due to different stress of the sides of two different long sections of the trapezoid, so that the longer side is easier to generate cracks under the action of external force, and the structural fracture is developed. The design of the front projection cross-sectional shape of the needle tip 21 can enable the needle tip 21 to naturally form a drawing angle, so that the needle tip 21 can be taken out by drawing a complete drawing mold.
The second top surface 221 of the extension 22 is located at the end of the extension 22 contacting the tip 21 of the pin, and the projection of the second top surface 221 on the back patch 1 is a third area, and the ratio of the length to the width of the smallest rectangle capable of accommodating the third area is in the range of 1.1-10. The projection of the second top surface 221 on the back patch 1 is in a shape of a circular symmetrical outer convex shape, an axial symmetrical double outer convex shape, a single-side outer convex shape, an axial symmetrical double inner concave shape or a convex-concave combination shape, and the shape design of the second top surface 221 is the same as that of the first top surface 211 of the needle tip 21. The second bottom surface of the extension 22 is located at the end of the extension 22 contacting the needle base 23, and the projection of the second bottom surface on the back patch 1 is a fourth area, and the ratio of the length to the width of the smallest rectangle capable of accommodating the fourth area is in the range of 1.1-10. The projection of the second bottom surface projected on the back patch 1 is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or an outer convex and inner concave combination shape, and the shape design is the same as that of the first bottom surface.
Preferably, the second plane is perpendicular to the backing 1, and the projection shape of the extension 22 projected on the second plane is the same as the needle tip 21, and is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid, and the dimension is not specifically defined.
The projection of the second top surface 221 of the extension 22 onto the back patch 1 is located outside or completely coincides with the projection range of the first bottom surface of the needle tip 21 onto the back patch 1, so that in terms of three-dimensional structure, a smooth transition or a stepped structure is formed between the outer contour of the first bottom surface of the needle tip 21 and the outer contour of the second top surface 221 of the extension 22. As shown in fig. 18, when the stepped structure is provided, the sectional shapes of the tip portion 21 and the extension portion 22 are drastically changed, and the easy-to-break position 300 is located at the stepped structure, and stress concentration is easily generated under the action of external force, and the stress applied thereto is larger, so that the easy-to-break position can be more effectively controlled, and the needle tip portion 21 can remain in the body. As shown in fig. 19, when the outer contour of the first bottom surface of the tip 21 and the outer contour of the second top surface 221 of the extension 22 are smoothly transited, the smooth transition position is the easy-to-break position 300 still because the inclination angle of the tip 21 and the extension 22 is changed, so that the breaking position can be effectively controlled, and the residual of the tip 21 in the body is ensured. The smooth transition between the tip portion 21 and the extension portion 22 or the stepped configuration facilitates removal of the pattern.
The third top surface 231 of the needle base 23 is located at the end of the needle base 23 contacting the extension 22, and the projection of the third top surface 231 onto the backing 1 is the fifth area, and the ratio of the length to the width of the smallest rectangle capable of accommodating the fifth area is in the range of 1.1-10. The projection of the third top surface 231 on the back patch 1 is in a shape of a circular symmetrical outer convex shape, an axial symmetrical double outer convex shape, a single-side outer convex shape, an axial symmetrical double inner concave shape or a convex inner concave combination shape, and the shape design of the third top surface 231 is the same as that of the second top surface 221. The third bottom surface of the needle base 23 is located at the end of the needle base 23 contacting the back patch 1, and the projection of the third bottom surface on the back patch 1 is a sixth area, and the value of the ratio of the length to the width of the smallest rectangle capable of accommodating the sixth area is in the range of 1.1-10. The projection of the third bottom surface projected on the back patch 1 is in a shape of a circular symmetrical outer convex, an axisymmetrical double outer convex, a single-side outer convex, an axisymmetrical double inner concave or an outer convex inner concave combination, and the shape design of the third bottom surface is the same as that of the second bottom surface.
Preferably, the second plane is perpendicular to the backing 1, and the projection of the needle base 23 on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid, and the shape design of the needle base 23 is the same as the extension 22, and the dimension is not specifically defined.
The projection of the third top surface 231 of the needle base 23 onto the backing 1 is located outside or completely coincides with the projection range of the second bottom surface of the extension 22 onto the backing 1, so that the outer contour of the second bottom surface of the extension 22 and the outer contour of the third top surface 231 of the needle base 23 smoothly transition or have a stepped structure in terms of three-dimensional structure, see fig. 12 and 15, as the design between the extension 22 and the needle base 21.
As shown in fig. 4, when the junction between the needle tip 21 and the extension 22 has the first step surface 2211, the projected cross section of the two-part structure is changed severely, the stress concentration is easy to occur at the junction of the two-part structure, and the junction is easy to deform and break when the external force is applied, so that the break remains in the body after the needle tip 21 pierces the physical barrier, the delivery of the medicine at the needle tip 21 can be effectively realized, the local medicine dosage at the target position is ensured to be accurate, the medicine delivery efficiency is higher, and the operation is convenient.
As shown in fig. 3, the connection part between the extension part 22 and the needle base 23 is provided with a second step surface 2311, and similarly, when the external force is applied, the connection part is easy to deform and break, namely, after the needle tip 21 and the extension part 22 are penetrated into the physical barrier, the break remains in the body, so that the delivery of the medicine at the needle tip 21 and the extension part 22 can be effectively realized, the local medicine amount at the target position is ensured to be accurate, the medicine delivery efficiency is higher, and the operation is convenient.
Preferably, in the present embodiment, a plurality of extension portions 22 are provided on one needle base 23, and the end of each extension portion 22 remote from the needle base 23 is provided with a needle tip 21, and in order to facilitate drawing out, the projection profile of the lower portion of the plurality of extension portions 22 is located inside the projection profile of the third top surface 231 of the needle base 23. Preferably, a plurality of extensions 22 on one needle base 23 are uniformly spaced to ensure uniformity of the amount of drug delivered.
As shown in fig. 8, in order to further improve the controllability of the fracture, it is preferable to provide a gap 201 on the side wall of the needle tip 21, the extension 22 or the needle base 23, or a gap 201 at the connection between the needle tip 21 and the extension 22, or a gap 201 at the connection between the extension 22 and the needle base 23. It can be known that the gap 201 is a sharp transition, and is a stress concentration area, the stress peak value of the material is higher when the external force acts, and the material is easier to break when exceeding the breaking limit of the material, and a gap 201 can be arranged, so that the microneedle 2 above the gap 201 is broken in the body, and the accuracy of the breaking is ensured; a plurality of openings 201 can also be arranged, and the microneedle 2 carrying the medicine can be broken into a plurality of sections under the action of external force so as to correspond to different dosing amounts, and the openings 201 can be vertically arranged, oppositely arranged or arranged at a certain angle when seen in the plane direction parallel to the back patch 1, so that the breakage of which opening 201 is controlled. For example, as shown in fig. 20, two slits 201 perpendicular to each other are provided in the X-axis and Y-axis directions, respectively, when viewed in a plane direction parallel to the back patch 1, and the two slits 201 are located at the needle tip-extension portion transition and the extension portion-needle base portion transition, respectively, as a first slit 2011 and a second slit 2012. When the microneedle 2 receives external force in the positive direction of the X axis at the first notch 2011, stress concentration can occur at the first notch 2011, and the needle tip 21 can break along the first notch 2011; when the microneedle 2 receives an external force in the positive Y-axis direction at the opening of the second notch 2012, stress concentration occurs at the second notch 2012 of the base of the extending portion-needle, and the extending portion 22 with the needle tip 21 breaks along the second notch 2012. That is, with different positions of the notch 201, the micro needle 2 may break at different positions under the action of different external forces, so that the micro needle 2 at different portions remains in the body, thereby realizing accurate release of the medicines and also realizing release of multiple medicines.
Preferably, the side wall of the needle tip 21, the extension 22 or the needle base 23 is provided with a breaking groove 202 in a ring, which is also effective in controlling the breaking position. For example, if an external force is parallel to the plane of the back patch 1, when the breaking grooves 202 are provided, high structural stress occurs at the positions of the breaking grooves 202 where the external force acts, regardless of the change in the direction of the external force, causing crack generation and occurrence of breakage.
In general, for the opening 201, only if the external force direction is consistent with the opening direction of the opening 201, the opening 201 is easy to break, so that the external force for breaking the opening 201 has direction selectivity; in the case of the fracture groove 202, since the groove 202 is uniformly distributed in the circumferential direction, if the external force is applied beyond the fracture limit of the material, the fracture of the structure may be induced, and the external force for inducing the fracture has no direction selectivity. Of course, in other embodiments, one or more notches 201 and one or more breaking grooves 202 may be provided at the same time.
As shown in fig. 9, preferably, in the present embodiment, the third top surface 231 of the needle base 23 is provided with a plurality of extending portions 22 at intervals, one at the center, and the remaining circumferentially uniformly spaced portions are shaped like sea anemones. As shown in fig. 12, the needle base 23 may also be provided as a rectangular parallelepiped, on which one or more rows of parallel or staggered extensions 22 and needle tips 21 are provided. Of course, in other embodiments, the arrangement of the plurality of extensions 22 on one needle base 23 may be different from the arrangement described above, but adjusted as desired.
The advantage of having multiple extensions 22 and tips 21 on the third top surface 231 of the needle base 23 is that, with the same needle base 23, the single extension-tip design is the same as the bilateral slope of the isosceles triangle of the front projection of the multiple extension-tip design, but the single extension-tip design is higher, the depth of penetration into the physical barrier of the patient is deeper, the patient is more painful, the volume of the extension-tip is greater, the total amount of drug implanted into the patient is higher, and the risk of drug toxicity is greater under the same process, as shown in fig. 2 and 9.
When the multi-extension-tip design is adopted, a gap exists between each extension-tip, so the sum of the projected areas of the second bottom surfaces of the plurality of extensions 22 projected on the back patch 1 is smaller than the projected area of the second bottom surfaces of the extensions 22 of the single-extension-tip design projected on the back patch 1, namely, the sum of the projected areas of the physical wound channels generated when the multi-extension-tip design penetrates into the physical barrier of the human body is smaller than that of the single-extension-tip design, the wound degree is smaller, and the pain of the patient is smaller. In addition, with the same bilateral slope of the isosceles triangle in front view, the sum of the projected areas of the physical wound passageways is smaller, so that the sum of the resistances encountered from the physical barrier of the patient during penetration is minimal, i.e., the multi-extension-tip design is easier to fully penetrate the physical barrier of the patient, and the operation of the microneedle 2 penetration is smoother.
In addition, when the sea anemone-shaped multi-extension-needle tip design is adopted, an obvious step transition mode is adopted between the extension part 22 and the needle base 23, the projection cross section in the plane direction parallel to the back patch 1 is changed drastically, obvious stress concentration can occur at the connection position of the extension part and the needle base under the action of external force, when the stress peak value of the area exceeds the breaking limit of a material, cracks can occur at the connection area of the extension part and the needle base, structural breakage is initiated, the plurality of extension parts 22 can be controlled to be broken in a collective way, the integral breakage remains in the body, the regulation and control of the breaking mode of the micro needle 2 are realized, the local medicine quantity of a target position is ensured, and the medicine delivery efficiency is improved. The sea anemone-shaped multi-extension-needle tip design can also realize demolding well. Under the condition that the bilateral slopes of the isosceles triangle of the front projection are the same, the design height of the sea anemone-shaped multi-extension-needle tip part is shorter, the total outer surface area of the needle tip part 21 and the extension part 22 is smaller, the contact adhesion force between the mold and the mold is smaller during demolding, the microneedle 2 is easier to take out, the probability of breakage of the microneedle 2 caused by the larger adhesion force during taking out is greatly reduced, and the integrity of the microneedle 2 taken out during demolding is improved.
As shown in fig. 9 and 10, when the heights of the needle tip portion 21 and the extension portion 22 are correspondingly the same, the double-sided slope of the isosceles triangle of the front projection of the needle tip portion 21 and the extension portion 22 is more gentle, the penetration ability of the physical barrier is weakened, the sharpness is insufficient, the resistance is excessive, and it is difficult to achieve effective administration, as compared with the multiple extension portion-needle tip portion design. In addition, the projected area of the second bottom surface of the extension 22 of the single extension-needle tip design onto the backing 1 is larger, and even though the needle tip 21 and the extension 22 can effectively penetrate into the physical barrier completely, the projected area of the physical wound channel generated during penetration is larger, the degree of trauma is larger, and the pain of the patient is stronger (similar to a blunt knife cutting meat).
When the sea anemone-shaped multi-extension-needle tip design is adopted, the puncture penetration capacity of the physical barrier is enhanced, the resistance is smaller, and the medicine can be more effectively administered; the wound channel formed after the physical barrier is punctured is smaller, so that the pain of a patient can be relieved. As shown in fig. 9 and 11, when the heights and shapes of the needle tip 21 and the extension 22 are identical, the single extension-needle tip design has too small a volume of the needle tip 21 and the extension 22 compared to the multiple extension-needle tip design, and the total drug load under the same process is small. Meanwhile, only one needle tip 21 means that the physical barrier has only one piercing point, the barrier piercing efficiency is low, and once the structure breaks and is lost in the processing process, the region is completely free from drug delivery in clinical use, and the clinical treatment effect is affected. When the sea anemone-shaped multi-extension-needle tip design is adopted, the number of physical barrier puncture points can be increased, and when some needle tips 21 or extension parts 22 are broken and lost in the processing process, higher puncture efficiency can still be kept overall, meanwhile, higher total drug delivery amount is ensured, and the curative effect of patients is improved.
The embodiment also provides a processing method for processing the grading microneedle patch, which comprises the following steps:
s1, adopting 3D to print the positive mould of preparation microneedle 2 array, the material that 3D printed is photosensitive resin, and the positive mould includes basement and a plurality of microneedle portion, and mould recess has been seted up to the basement, has seted up the annular groove on the tank bottom of mould recess, and a plurality of microneedle portions all set up at the tank bottom, and are located the region that the annular groove encloses and establish.
S2, adding PDMS into the molding groove, and curing at a preset temperature T1 for a preset time period T1. The cross-linking between the chains is realized, a PDMS female die is obtained, and the PDMS female die is provided with an annular edge due to the annular groove arranged on the male die.
Preferably, the preset temperature T1 is 30-60 ℃, and the preset time T1 is 10-600 min. Preferably, in order to facilitate the removal of the cavity, the PDMS cavity having the pits may be removed from the molding groove of the photosensitive resin using a round-head wire to secure the integrity of the appearance of the PDMS cavity.
S3, pouring the matrix material solution into a groove surrounded by the annular edge, or directly placing the PDMS female die into a container filled with the matrix material solution, and continuously presetting the temperature T2 for a preset time period T2 so as to reduce the fluidity of the solution. The low temperature state can increase the viscosity of the matrix solution, and avoid the matrix material liquid in the female mold from flowing out of the female mold groove during movement, thereby affecting the final molding of the microneedle 2.
Preferably, the preset temperature T2 is 4 ℃, and the value range of the preset time period T2 is 10min-600min.
S4, placing the PDMS female die filled with the matrix material solution into a vacuum dryer, and vacuumizing at room temperature for a preset time period t3. Preferably, the preset time period t3 is greater than 1h, more preferably greater than 12h, and when greater than 12h, the matrix material solution can be completely filled into the female mold grooves, so as to ensure the structural integrity of the finally formed microneedles 2. Or placing the PDMS female mold into a centrifuge tube filled with matrix material solution, and continuously presetting the rotating speed r1 for a period of time t4 so that the solution enters a needle-shaped groove of the PDMS female mold.
Preferably, the rotation speed r1 is in the range of 100rpm-15000rpm, further optimized in the range of 8000rpm-12000rpm, and the preset time period t4 is in the range of 1min-100min, further optimized in the range of 5min-30min. The high rotational speed and the long centrifugation time are beneficial to the strong extrusion of the matrix material solution into the female die groove.
Preferably, the temperature is set to 0 ℃ to 40 ℃, preferably 0 ℃ to 10 ℃ during the centrifugal rotation. The relatively low temperature state can ensure that the viscosity of the matrix material solution is higher, and the matrix material solution entering the female mold groove can not flow out of the female mold groove when the machine is stopped under the long-time high-speed centrifugal state, and once the liquid flows out, the tip of the female mold groove enters bubbles, so that the integrity of the finally formed microneedle 2 is affected.
S5, placing the PDMS female die at a preset temperature T3 for curing and forming to realize crosslinking between chains of PVA or HA, wherein the recommended temperature is 0-100 ℃, the further optimal temperature is 20-50 ℃, the treatment time is 10-72 h, and the further optimal time is 60-180 min, and the stable curing and forming of the grading microneedle patch can be ensured in the state.
Although the embodiments of the present invention have been described above with reference to the accompanying drawings, the present invention is not limited to the above embodiments, but may be manufactured in various forms, and it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without changing the technical spirit or essential features of the present invention. Accordingly, it should be understood that the above-described embodiments are illustrative in all respects and not restrictive.
Claims (10)
1. Hierarchical microneedle patch, its characterized in that includes:
a back patch (1);
microneedle (2), microneedle (2) protrusion sets up in the one side of back subsides (1), microneedle (2) are including tip portion (21), extension (22) and the needle base (23) that connect gradually, the outer wall of tip portion (21) with the outer wall of extension (22) is encircled and is equipped with first parting line or first parting plane between the outer wall of extension (22) with encircle and be equipped with second parting line or second parting plane between the outer wall of needle base (23), needle base (23) connect in back subsides (1), microneedle (2) are parallel to arbitrary first cross-section and the second cross-section of back subsides (1) all satisfy, first cross-section is than the second cross-section is closer to back subsides (1), the second cross-section throw in first cross-section plane the projection of place on the plane with first cross-section coincidence or in first cross-section, tip portion (21), extension (22) and needle base (23) are in the second cross-section plane on the second plane and two equal two perpendicular conicity (1) do not equal.
2. The hierarchical microneedle patch according to claim 1, characterized in that the projection of the first top surface (211) of the needle tip (21) onto the back patch (1) is a circumferentially symmetrical outer convex, an axisymmetrical double outer convex, a single-sided outer convex, an axisymmetrical double inner concave or a convex-concave combination, the first top surface (211) being located at the end of the needle tip (21) remote from the extension (22);
and/or the projection of the first bottom surface of the needle tip part (21) on the back paste (1) is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex inner concave shape, and the first bottom surface is positioned at the end part of the needle tip part (21) contacting the extension part (22);
and/or, the projection of the second top surface (221) of the extension part (22) on the back patch (1) is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex-concave combination shape, and the second top surface (221) is positioned at the end part of the extension part (22) contacting the needle point part (21);
and/or the projection of the second bottom surface of the extension part (22) on the back patch (1) is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex inner concave shape, and the second bottom surface is positioned at the end part of the extension part (22) contacting the needle base part (23);
And/or, the projection of the third top surface (231) of the needle base (23) on the back patch (1) is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex-concave combination shape, and the third top surface (231) is positioned at the end of the needle base (23) contacting the extension part (22);
and/or the projection of the third bottom surface of the needle base (23) on the back patch (1) is in a shape of a circular symmetrical outer convex shape, an axisymmetrical double outer convex shape, a single-side outer convex shape, an axisymmetrical double inner concave shape or a convex inner concave shape, and the third bottom surface is positioned at the end part of the needle base (23) contacting the back patch (1).
3. The hierarchical microneedle patch according to claim 2, characterized in that the projection of the first top surface (211) onto the back patch (1) is a first area, the ratio of the length and width of the smallest rectangle that can accommodate the first area being in the range of 1.1-10;
and/or the projection of the first bottom surface projected on the back patch (1) is a second area, and the value range of the ratio of the length to the width of the smallest rectangle capable of accommodating the second area is 1.1-10;
and/or the projection of the second top surface (221) projected on the back patch (1) is a third area, and the value range of the ratio of the length to the width of the smallest rectangle capable of accommodating the third area is 1.1-10;
And/or the projection of the second bottom surface projected on the back patch (1) is a fourth area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the fourth area is 1.1-10;
and/or, the projection of the third top surface (231) projected on the back patch (1) is a fifth area, and the value range of the ratio of the length to the width of the smallest rectangle capable of accommodating the fifth area is 1.1-10;
and/or the projection of the third bottom surface projected on the back patch (1) is a sixth area, and the value range of the ratio of the length to the width of the minimum rectangle capable of accommodating the sixth area is 1.1-10.
4. The hierarchical microneedle patch according to claim 1, characterized in that the projection of the needle tip (21) onto the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid;
and/or the projection of the extension part (22) on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid;
and/or the projection of the needle base (23) on the second plane is rectangular, isosceles trapezoid, right trapezoid or non-right isosceles trapezoid.
5. A hierarchical micro needle patch according to claim 1, characterized in that one of the needle bases (23) is provided with a plurality of the extensions (22), and that the end of each extension (22) remote from the needle base (23) is provided with the needle tip (21).
6. Hierarchical microneedle patch according to claim 5, characterized in that a plurality of said extensions (22) on one of said needle bases (23) are arranged at regular intervals.
7. The hierarchical microneedle patch according to claim 1, characterized in that the junction of the needle tip (21) and the extension (22) has a first step surface (2211);
and/or the connection of the extension (22) and the needle base (23) has a second step surface (2311).
8. The hierarchical microneedle patch according to claim 1, characterized in that a gap (201) is provided on a side wall of the needle tip (21), the extension (22) or the needle base (23), or a gap (201) is provided at a junction of the needle tip (21) and the extension (22), or a gap (201) is provided at a junction of the extension (22) and the needle base (23).
9. Hierarchical micro needle patch according to claim 1, characterized in that the tip portion (21), the extension portion (22) or the side wall of the needle base portion (23) is provided with a breaking groove (202) in a ring.
10. A method of processing the hierarchical microneedle patch of any one of claims 1-9, comprising the steps of:
s1, preparing a male die of a microneedle (2) array by adopting 3D printing, wherein the 3D printing material is photosensitive resin, the male die comprises a substrate and a plurality of microneedle parts, a molding groove is formed in the substrate, an annular groove is formed in the bottom of the molding groove, and the microneedle parts are arranged at the bottom of the groove and are positioned in an area surrounded by the annular groove;
S2, adding PDMS into the molding groove, curing at a preset temperature T1 for a preset time period T1, and realizing crosslinking between chains to obtain a PDMS female mold, wherein the PDMS female mold is provided with an annular edge;
s3, pouring the matrix material solution into a groove surrounded by the annular edge, or directly placing the PDMS female die into a container filled with the matrix material solution, and continuously preserving for a preset time period T2 at a preset temperature T2 so as to reduce the fluidity of the solution;
s4, placing the PDMS female die filled with the matrix material solution into a vacuum dryer, vacuumizing at room temperature for a preset time period t3, or placing the PDMS female die into a centrifuge tube filled with the matrix material solution, and continuously placing the PDMS female die into a needle-shaped groove of the PDMS female die at a rotating speed r1 for a preset time period t 4;
s5, placing the PDMS female die at a preset temperature T3 for curing and forming.
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