A preparation mold and preparation method of drug delivery microneedle

Abstract

The invention discloses a preparation mold and preparation method of drug delivery microneedles, the preparation mold comprises an upper plate, a stripping plate, a template and an isolation layer which are arranged in sequence from top to bottom, the isolation layer is made of an air-permeable and liquid-impermeable material, a microporous area corresponding to the needle-shaped object of the microneedle is provided on the template, a plurality of micropores are provided in a microporous area, a stopper surface is provided in the substrate hole, the micropore is a through hole provided on the template, a substrate hole corresponding to the microneedle substrate is provided at a position corresponding to the microporous area on the upper plate, an annular boss having a thickness greater than that of the stripping plate is provided at the periphery of the substrate hole on the bottom surface of the upper plate, a boss hole for the annular boss to pass through is provided at a position corresponding to the annular boss on the stripping plate, a stripping hole is provided on the upper plate around the annular boss, the substrate hole and the stripping hole are both through holes, and when stripping, a stripping rod is placed in the stripping hole, the bottom end of the stripping rod pushes the stripping plate downward, and the microneedle substrate is stopped and matched with the stopper surface in the substrate hole. The invention is easy to use and has a simple stripping process.

Description

Technical Field

[0001] The invention relates to a preparation mold and a preparation method for a drug delivery microneedle, belonging to the technical field of medical equipment. Background Art

[0002] As a new transdermal drug delivery method, microneedle transdermal drug delivery combines the advantages of subcutaneous injection and transdermal patch drug delivery. It is not only painless and minimally invasive, but also has high drug absorption efficiency. In addition, patients can administer drugs by themselves during microneedle drug delivery, which is convenient and safe. Therefore, microneedle transdermal drug delivery technology has received widespread attention since its emergence. The basic structural form of drug delivery microneedles is: a group of micro needles of varying numbers are erected on a plate-like substrate (such as but not limited to a flat plate, an arc plate, etc.) of suitable thickness and suitable shape (such as but not limited to round, square, etc.). The basic use process and principle of microneedles are: under the action of appropriate pressure, microneedles are used to open the skin channel to help drugs and other bioactive substances pass through the skin, so as to achieve the distribution of bioactive substances such as drugs in the whole body or local skin, and achieve therapeutic or other beneficial effects, which has a very positive significance.

[0003] The microneedles in the prior art include solid metal microneedles, hollow metal microneedles, solid microneedles made of non-metallic materials (such as inorganic silicon materials), microneedles made of organic macromolecular materials (such as polyvinylpyrrolidone), etc. However, these existing microneedle products and their production methods have difficulties in mass production and preparation, resulting in no cases of industrial mass production of such technologies and products so far. In addition, due to the limitations of their mass production capabilities, the production costs are also relatively high.

[0004] The production of metal microneedles involves a complex process of precision machining or precision electroplating film formation, which makes it difficult to mass-produce at a low cost. In addition, due to the rigidity of the metal material and the presence of processing burrs, the skin feels very foreign to the microneedles.

[0005] The melting temperature of inorganic silicon materials is too high, and it is difficult to find suitable high-temperature resistant molds for the production of microneedles using the hot injection process. Inorganic silicon materials in a cooled state are hard and brittle, and the processing efficiency of cutting, grinding or photolithography is low.

[0006] The concentrated solution of polyvidone (PVP) is poured into microneedles through a mold. After drying and forming, the PVP microneedles are difficult to demold due to their insufficient strength. The mold used in the preparation of polyvidone microneedles is a template with micropores. Since the micropores are in the form of countersunk holes and the pore size is very small, in order to prevent the polyvidone solution from being blocked by the air in the micropores and unable to sink to the bottom of the micropores during pouring, the entire equipment needs to be placed in a closed container during the microneedle production process, and the closed container needs to be evacuated, which makes the production process very troublesome and increases the production cost. In addition, the microneedles produced by this mold are attached to the template, making it difficult to demold. Summary of the invention

[0007] The purpose of the present invention is to provide a preparation mold and preparation method for drug delivery microneedles, so as to solve the technical problems of the prior art that the microneedle production process is complicated, the cost is high and the demoulding is difficult.

[0008] The preparation mold of the drug delivery microneedle of the present invention adopts the following technical scheme: a preparation mold of the drug delivery microneedle, comprising an upper plate, a stripping plate, a template and an isolation layer arranged in sequence from top to bottom, the upper plate, the stripping plate, the stripping plate and the isolation layer are all made of heat-resistant materials, the isolation layer is made of air-permeable and liquid-impermeable material, the template is provided with a microporous area corresponding to the needle-shaped object of the microneedle, a microporous area has a plurality of micropores, the micropores are through holes opened on the template, a substrate hole corresponding to the microneedle substrate is opened at a position corresponding to the microporous area on the upper plate, an annular boss with a thickness greater than that of the stripping plate is provided on the bottom surface of the upper plate at the periphery of the substrate hole, a boss hole for the annular boss to pass through is opened at a position corresponding to the annular boss on the stripping plate, a stripping hole is opened on the upper plate around the annular boss, the substrate hole and the stripping hole are both through holes, a stop surface is provided in the substrate hole, during demolding, a stripping rod is placed in the stripping hole, the bottom end of the stripping rod pushes the stripping plate downward, and the microneedle substrate is stopped and matched with the stop surface in the substrate hole.

[0009] The substrate hole is a stepped hole that is larger at the top and smaller at the bottom. The shape and size of the small section at the bottom of the stepped hole are the same as those of the microneedle substrate. The annular boss is arranged on the periphery of the small section at the bottom of the stepped hole, and the demoulding hole is opened on the stepped surface of the stepped hole.

[0010] An annular retaining ring is provided inside the small section at the lower part of the stepped hole, and the upper surface of the annular retaining ring constitutes the stop surface.

[0011] The inner side of the small section at the lower part of the stepped hole is provided with a tapered section which gradually contracts downwards, and the tapered surface of the tapered section constitutes the stop surface.

[0012] The number of the demoulding holes is greater than two, and the demoulding holes are evenly distributed around the annular boss.

[0013] The demoulding hole is a threaded hole, and the demoulding rod is a screw that matches the thread of the demoulding hole.

[0014] The stripping plate is a metal plate.

[0015] The upper plate, the stripping plate, the template and the isolation layer are connected together by positioning bolts.

[0016] The number of microporous areas on the template is at least two, and the number of substrate holes and annular bosses on the upper plate is equal to the number of microporous areas.

[0017] The first technical solution of the method for preparing drug delivery microneedles of the present invention is: a method for preparing drug delivery microneedles, comprising the following steps: (1) heating and deforming a thermoplastic raw material for preparing microneedles to a fluid state; (2) placing the isolation layer, template, stripping plate and upper plate in claim 1 in order from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the micropore area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping plate; (3) placing the raw material heated in step (1) into the substrate hole of the upper plate; (4) pressurizing the raw material in the substrate hole, The raw material flows downward into the micropores of the micropore area of ​​the template, and part of the raw material enters the micropore area to form the needle-like object of the microneedle, while the other part remains in the substrate hole to form the microneedle substrate; (5) The liquid in the substrate hole and the micropore area is cooled to make the liquid raw material in the substrate hole and the micropore area become solid; (6) A demolding rod is placed in the demolding hole, and the demolding rod is pressed downward to make the demolding rod push the demolding plate downward, so that the template and the demolding plate are separated from the upper plate, and the upper plate with microneedles is obtained, and then the microneedles are pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0018] The second technical solution of the method for preparing drug-delivery microneedles of the present invention is: A method for preparing drug-delivery microneedles, comprising the following steps: (1) processing the thermoplastic raw material for preparing microneedles into a powder raw material, and weighing the powder raw material equal to the weight of a single microneedle; (2) placing the isolation layer, template, stripping template and upper plate in claim 1 in sequence from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the micropore area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping template; (3) placing the powder raw material weighed in step (1) into the substrate hole of the upper plate; (4) heating the powder raw material in step (3) until the powder raw material becomes a flowing state; (5) (6) The raw material in the substrate hole and the microporous area is cooled to make the flowing raw material in the substrate hole and the microporous area become solid; (7) A demolding rod is placed in the demolding hole, and the demolding rod is pressed downward to make the demolding rod push the demolding plate downward, thereby separating the template and the demolding plate from the upper plate, obtaining an upper plate with microneedles, and then pushing the microneedles upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0019] The third technical scheme of the method for preparing drug delivery microneedles of the present invention is: a method for preparing drug delivery microneedles, comprising the following steps: (1) processing a thermoplastic raw material for preparing microneedles into a solid raw material having a weight equal to that of a single microneedle; (2) placing the isolation layer, template, stripping template and upper plate in claim 1 in order from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the micropore area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping template; (3) placing the solid raw material obtained in step (1) into the substrate hole of the upper plate; (4) heating the solid raw material in step (3) until the solid raw material becomes a fluid state; (5 ) Pressurize the raw material in the substrate hole, and the raw material in the flowing state flows downward into the micropores of the template micropore area. Part of the raw material enters the micropore area to form the needle-like object of the microneedle, and the other part remains in the substrate hole to form the microneedle substrate; (6) Cool the raw material in the substrate hole and the micropore area to make the raw material in the substrate hole and the micropore area become solid; (7) Place a demolding rod in the demolding hole, press the demolding rod downward, so that the demolding rod pushes the demolding plate downward, so that the template and the demolding plate are separated from the upper plate, and the upper plate with microneedles is obtained, and then the microneedles are pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0020] The thermoplastic raw material for preparing the microneedle is one or a blend or copolymer or block copolymer of two or more of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl acetate succinate, polyethylene vinyl acetate, polyvinyl acetate, and ethylene copolymers.

[0021] The beneficial effects of the present invention are as follows: the microneedle preparation process of the present invention is to soften or melt or dissolve the raw materials for preparing the microneedles at a certain temperature to become a soft or fluid state with a certain deformability, and the fluid raw materials enter the micropores of the template, and then are formed by pressurization, cooling, and demolding. The micropores on the template of the present invention are through holes, and do not need to be operated in a vacuum environment. The thermoplastic raw materials with fluidity will be injected into the micropores, and the air in the micropores will be squeezed out by pressurizing the raw materials. The isolation layer of air-permeable and liquid-impermeable material is easy to pass through, while the thermoplastic raw materials will not pass through. The annular boss can be in close contact with the isolation layer to prevent the thermoplastic raw materials from being squeezed out from the gap between the annular boss of the upper plate and the isolation layer. After the raw material is cooled and becomes a microneedle, a demoulding rod is placed in the demoulding hole, and a force is applied to the demoulding rod so that the demoulding rod pushes the demoulding template downward, thereby separating the template from the upper plate, and the stop surface on the substrate hole cooperates with the microneedle substrate stop to prevent the microneedle needle-like object from being unable to come out of the template hole. Finally, the microneedle is pushed upward from the bottom of the upper plate substrate hole to separate the microneedle from the upper plate, thereby completing the demoulding. The microneedle preparation mold of the present invention is easy to use, the operation process is simple, the demoulding process is also very simple, and the thermoplastic raw materials are easy to obtain, which is more conducive to large-scale production, thereby reducing the production cost of microneedles. The microneedles of the thermoplastic material of the present invention have the following advantages: First, it is safe and does not cause skin allergies; second, it has a suitable hardness, and the microneedle needle-like object is sufficient to open the skin and has little or no foreign body sensation; third, it is insoluble in water, so as to prevent the microneedle needle-like object inserted into the skin from partially dissolving in the body, causing the skin pores to close quickly, affecting the subsequent drug entry; fourth, the hot melt or hot melting temperature is moderate, and the formed microneedle needle-like object has toughness and is easy to demould. However, the materials of the microneedles in the prior art cannot have these advantages at the same time. The drug delivery microneedles prepared by the mold and method of the present invention are actually blank microneedles. After the blank microneedles are made, suitable drugs or other bioactive substances are loaded on the microneedles, especially on the needle tip, by appropriate methods to make drug-loaded or bioactive substance-loaded microneedles for medical treatment or other beneficial purposes.

[0022] Preferably, the substrate hole is a stepped hole. When making the microneedle, the raw material fills the small section of the stepped hole. When the raw material is pressurized, pressure is applied only to the upper section of the stepped hole.

[0023] Preferably, the demoulding hole is a threaded hole, and the demoulding rod is a screw. During demoulding, the screw only needs to be tightened, and the screw can lift up the demoulding plate.

[0024] Preferably, the stripping plate is made of metal, which has the advantages of strong compression resistance, low cost and long service life.

[0025] Preferably, the thermoplastic material can be flexibly selected according to actual needs, and the differences in hardness, brittleness and surface properties of different materials can be utilized to achieve the most suitable purpose by mixing one, two or more materials.

[0026] The first technical solution of the method for preparing the drug delivery microneedle of the present invention only requires one heating and cooling, and has the advantages of few processing steps and easy operation. The second and third technical solutions of the method for preparing the drug delivery microneedle of the present invention require first processing the raw material into a powder or solid raw material with the same weight as the microneedle. Although the processing steps are more than the first solution, this can better ensure that the weight of the raw material entering each micropore area is equal, thereby ensuring that the weight of the produced microneedles is equal, which is conducive to improving product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 1 is a schematic structural diagram of Example 1 of a mold for preparing drug delivery microneedles of the present invention;

[0028] Figure 2 yes Figure 1 Top view of the middle and upper plate;

[0029] Figure 3 yes Figure 1 Bottom view of the middle upper plate;

[0030] Figure 4 yes Figure 1 The structural diagram of the template in the figure;

[0031] Figure 5 Schematic diagram of the structure of Example 2 of the preparation mold for drug delivery microneedles of the present invention;

[0032] Figure 6 1 is a schematic structural diagram of Example 3 of a mold for preparing a drug delivery microneedle according to the present invention;

[0033] Figure 7 is a flow chart of Example 1 of the method for preparing a drug delivery microneedle of the present invention;

[0034] Figure 8 is a flow chart of Example 2 of the method for preparing a drug delivery microneedle of the present invention;

[0035] Fig. 9 Flow chart of Example 3 of the method for preparing drug delivery microneedles of the present invention.

[0036] In the figure, 1-upper plate, 11-base plate hole, 12-annular boss, 13-demolding hole, 14-demolding rod, 15-stop surface, 16-retaining ring, 17-conical section, 2-demolding plate, 3-template, 31-microporous area, 4-isolating layer, 5-positioning bolt. DETAILED DESCRIPTION

[0037] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0038] The structure of the preparation mold of the drug delivery microneedle embodiment 1 of the present invention is as follows Figures 1 to 4 As shown, the preparation mold for the drug delivery microneedle of this embodiment includes an upper plate 1, a stripping plate 2, a template 3 and an isolation layer 4 arranged in sequence from top to bottom, the upper plate 1, the stripping plate 2, the stripping plate 3 and the isolation layer 4 are all made of heat-resistant materials, the isolation layer 4 is made of an air-permeable and liquid-impermeable material, the stripping plate 2 is a metal plate, and the upper plate 1, the stripping plate 2, the template 3 and the isolation layer 4 are connected together by positioning bolts 5. The template 3 is provided with a microporous area 31 corresponding to the needle-like object of the microneedle, and a microporous area 31 has a plurality of micropores, and the micropores are through holes opened on the template 3. A substrate hole 11 corresponding to the microneedle substrate is opened at a position corresponding to the microporous area 31 on the upper plate 1, and an annular boss 12 with a thickness greater than that of the stripping plate 2 is provided on the bottom surface of the upper plate 1 at the periphery of the substrate hole 11, and a boss hole for the annular boss 12 to pass through is opened at a position corresponding to the annular boss 12 on the stripping plate 2, and a demolding hole 13 is opened on the upper plate around the annular boss 12, and the substrate hole 11 and the demolding hole 13 are both through holes, and a stop surface 15 is provided in the substrate hole. When demolding, a demolding rod 14 is placed in the demolding hole 13, and the bottom end of the demolding rod 14 pushes the stripping plate 2 downward, and the microneedle substrate is stopped and matched with the stop surface 15 in the substrate hole.

[0039] In this embodiment, the substrate hole 11 is a stepped hole that is larger at the top and smaller at the bottom. The shape and size of the small section at the bottom of the stepped hole are the same as those of the microneedle substrate. The annular boss 12 is arranged at the periphery of the small section at the bottom of the stepped hole 11, and the demoulding hole 13 is opened on the stepped surface of the stepped hole. In this embodiment, the number of demoulding holes 13 is three, and the demoulding holes 13 are evenly distributed around the annular boss 12. The demoulding hole 13 in this embodiment is a threaded hole, and the demoulding rod 14 is a screw that matches the thread of the demoulding hole.

[0040] The microneedle preparation process is to soften or melt or melt the raw materials for preparing the microneedles at a certain temperature to become a soft or fluid state with a certain deformability. After the fluid raw materials enter the micropores of the template, they are then pressed, cooled, and demolded to be made. The micropores on the template of the present invention are through holes, and do not need to be operated in a vacuum environment. The fluid thermoplastic raw materials will be injected into the micropores. Pressurizing the raw materials will squeeze out the air in the micropores. The isolation layer of air-permeable and liquid-impermeable material is easy to pass through, while the thermoplastic raw materials will not pass through. The annular boss can be in close contact with the isolation layer to prevent the thermoplastic raw materials from being squeezed out from the gap between the annular boss of the upper plate and the isolation layer. After the raw material is cooled and becomes a microneedle, a demoulding rod, i.e., a screw, is placed in the demoulding hole, and then the screw is tightened. The screw pushes the demoulding template downward, thereby separating the template from the upper plate, and the stop surface on the substrate hole cooperates with the microneedle substrate stop to prevent the microneedle needle-like object from being unable to come out of the template hole. Finally, the microneedle is pushed upward from the bottom of the upper plate substrate hole to separate the microneedle from the upper plate, thereby completing the demoulding. The microneedle preparation mold of the present invention is easy to use, the operation process is simple, the demoulding process is also very simple, and the thermoplastic raw materials are easy to obtain, which is more conducive to large-scale production, thereby reducing the production cost of microneedles. The microneedles of the thermoplastic material of the present invention have the following advantages: First, it is safe and does not cause skin allergies; second, it has a suitable hardness, and the microneedle needle-like object is sufficient to open the skin and has little or no foreign body sensation; third, it is insoluble in water, so as to prevent the microneedle needle-like object inserted into the skin from partially dissolving in the body, causing the skin pores to close quickly, affecting the subsequent drug entry; fourth, the hot melt or hot melting temperature is moderate, and the formed microneedle needle-like object has toughness and is easy to demould. However, the materials of the microneedles in the prior art cannot have these advantages at the same time. The drug delivery microneedles prepared by the mold and method of the present invention are actually blank microneedles. After the blank microneedles are made, suitable drugs or other bioactive substances are loaded on the microneedles, especially on the needle tip, by appropriate methods to make drug-loaded or bioactive substance-loaded microneedles for medical treatment or other beneficial purposes.

[0041] The structure of the preparation mold embodiment 2 of the drug delivery microneedle of the present invention is as follows Figure 5 As shown, different from Example 1 of the mold for preparing drug delivery microneedles of the present invention, the inner side of the small section at the lower part of the stepped hole has a tapered section 17 that gradually contracts downward, and the tapered surface of the tapered section 17 constitutes the stop surface.

[0042] The structure of the mold for preparing the drug delivery microneedle of Example 3 of the present invention is as follows Figure 6 As shown, different from Example 1 of the preparation mold for drug delivery microneedles of the present invention, the substrate hole of the upper plate of the present invention is a straight through hole, the demoulding hole is arranged around the straight through hole, and the annular retaining ring 16 is arranged on the inner side of the lower part of the substrate hole.

[0043] In other embodiments of the microneedle preparation mold of the present invention, the stop surface in the substrate hole can be a conical surface, a flat surface, or a curved surface, as long as the stop surface can prevent the microneedle substrate from escaping when the demolding rod applies downward force.

[0044] In other embodiments of the microneedle preparation mold of the present invention, the number of microporous areas on the template can be any value of more than two, and the number of substrate holes and annular bosses on the upper plate is equal to the number of microporous areas.

[0045] In other embodiments of the microneedle preparation mold of the present invention, the release plate can also be made of hard plastic or other hard materials.

[0046] In other embodiments of the microneedle preparation mold of the present invention, the demolding hole can also be a plain hole without threads, and the corresponding demolding rod also has no threads. When demolding, the demolding rod is placed in the demolding hole and downward force is applied to the demolding rod.

[0047] The flowchart of Example 1 of the method for preparing the drug delivery microneedle of the present invention is as follows Figure 7 As shown, the preparation method of the drug delivery microneedle of this embodiment comprises the following steps:

[0048] (1) heating and deforming the thermoplastic raw material for preparing the microneedles to a fluid state;

[0049] (2) The isolation layer, template, stripping plate and upper plate in claim 1 are placed in order from bottom to top, and the substrate holes of the upper plate are arranged correspondingly above the microporous area on the template, and the annular boss at the bottom of the upper plate passes through the boss hole of the stripping plate;

[0050] (3) placing the raw material heated in step (1) into the substrate hole of the upper plate;

[0051] (4) Pressurizing the raw material in the substrate hole, the raw material moves downward into the micropores of the template micropore area, a portion of the raw material enters the micropore area to form the needle-like object of the microneedle, and the other portion remains in the substrate hole to form the microneedle substrate;

[0052] (5) Cooling the liquid in the substrate pores and micropores to convert the liquid raw material in the substrate pores and micropores into solid;

[0053] (6) A demolding rod is placed in the demolding hole and downward pressure is applied to the demolding rod so that the demolding rod pushes the demolding plate downward, thereby separating the template and the demolding plate from the upper plate to obtain an upper plate with microneedles. The microneedles are then pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0054] The thermoplastic raw material for preparing the microneedle is one or more blends or copolymers or block copolymers of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl acetate, polyethylene vinyl acetate, polyvinyl acetate, and ethylene copolymers. Thermoplastic materials can be flexibly selected according to actual needs, and the differences in hardness, brittleness and surface properties of different materials are utilized to achieve the most suitable purpose by mixing one, two or more materials.

[0055] The microneedle preparation mold of the present invention is easy to use and has a simple operation process, which can enable the microneedle to achieve industrial mass production. Moreover, the thermoplastic raw materials are easily available, which is more conducive to large-scale production, thereby reducing the production cost of the microneedle. The microneedle of the thermoplastic material of the present invention has the following advantages: first, it is safe and does not cause skin allergies; second, it has a suitable hardness, and the microneedle needle-like object is sufficient to stretch the skin and has less or no foreign body sensation; third, it is insoluble in water, so that the microneedle needle-like object inserted into the skin does not partially dissolve in the body, so that the skin pores are quickly closed, affecting the subsequent drug entry; fourth, the hot melt or hot melting temperature is moderate, and the formed microneedle needle-like object has toughness and is easy to demold. However, the material of the microneedle in the prior art cannot have these advantages at the same time. The drug delivery microneedle prepared by the mold and method of the present invention is actually a blank microneedle. After the blank microneedle is made, a suitable drug or other bioactive substance is loaded on the microneedle, especially on the needle tip, by a suitable method to make a drug-loaded or bioactive substance-loaded microneedle for medical treatment or other beneficial purposes. The preparation method of this embodiment only requires one heating and cooling, and has the advantages of few processing steps and easy operation.

[0056] The flowchart of Example 2 of the method for preparing the drug delivery microneedle of the present invention is as follows Figure 8 As shown, the preparation method of the drug delivery microneedle of this embodiment comprises the following steps:

[0057] (1) heating and deforming the thermoplastic raw material for preparing the microneedles to a fluid state;

[0058] (2) The isolation layer, template, stripping plate and upper plate in claim 1 are placed in order from bottom to top, and the substrate holes of the upper plate are arranged correspondingly above the microporous area on the template, and the annular boss at the bottom of the upper plate passes through the boss hole of the stripping plate;

[0059] (3) placing the raw material heated in step (1) into the substrate hole of the upper plate;

[0060] (4) Pressurizing the raw material in the substrate hole, the raw material moves downward into the micropores of the template micropore area, a portion of the raw material enters the micropore area to form the needle-like object of the microneedle, and the other portion remains in the substrate hole to form the microneedle substrate;

[0061] (5) Cooling the liquid in the substrate pores and micropores to convert the liquid raw material in the substrate pores and micropores into solid;

[0062] (6) A demolding rod is placed in the demolding hole and downward pressure is applied to the demolding rod so that the demolding rod pushes the demolding plate downward, thereby separating the template and the demolding plate from the upper plate to obtain an upper plate with microneedles. The microneedles are then pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0063] The thermoplastic raw material for preparing the microneedle is one or more blends or copolymers or block copolymers of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl acetate, polyethylene vinyl acetate, polyvinyl acetate, and ethylene copolymers. Thermoplastic materials can be flexibly selected according to actual needs, and the differences in hardness, brittleness and surface properties of different materials are utilized to achieve the most suitable purpose by mixing one, two or more materials.

[0064] The flowchart of Example 3 of the method for preparing the drug delivery microneedle of the present invention is as follows Fig. 9 As shown, the preparation method of the drug delivery microneedle of this embodiment comprises the following steps:

[0065] (1) Processing the thermoplastic raw material for preparing microneedles into a solid raw material with the same weight as a single microneedle;

[0066] (2) The isolation layer, template, stripping plate and upper plate in claim 1 are placed in order from bottom to top, and the substrate holes of the upper plate are arranged correspondingly above the microporous area on the template, and the annular boss at the bottom of the upper plate passes through the boss hole of the stripping plate;

[0067] (3) placing the solid raw material obtained in step (1) into the hole of the upper substrate;

[0068] (4) heating the solid raw material in step (3) until the solid raw material becomes fluid;

[0069] (5) Pressurizing the raw material in the substrate pores, the raw material in a flowing state flows downward into the micropores in the micropore area of ​​the template, a portion of the raw material enters the micropore area to form the needle-like objects of the microneedles, and the other portion remains in the substrate pores to form the microneedle substrate;

[0070] (6) Cooling the raw material in the substrate pores and micropores to make the raw material in the substrate pores and micropores become solid;

[0071] (7) A demolding rod is placed in the demolding hole and downward pressure is applied to the demolding rod so that the demolding rod pushes the demolding plate downward, thereby separating the template and the demolding plate from the upper plate, thereby obtaining an upper plate with microneedles, and then the microneedles are pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

[0072] The thermoplastic raw material for preparing the microneedle is one or more blends or copolymers or block copolymers of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl acetate, polyethylene vinyl acetate, polyvinyl acetate, and ethylene copolymers. Thermoplastic materials can be flexibly selected according to actual needs, and the differences in hardness, brittleness and surface properties of different materials are utilized to achieve the most suitable purpose by mixing one, two or more materials.

[0073] Embodiments 2 and 3 of the microneedle preparation method of the present invention need to first process the raw materials into powder or solid raw materials equal to the weight of the microneedles, so that the weight of the raw materials entering each micropore area can be relatively well guaranteed to be equal, thereby ensuring that the weight of the produced microneedles is equal, which is beneficial to improving product quality. The operation process of the present invention is simple, and microneedles can be industrially mass-produced. Moreover, thermoplastic raw materials are easily available, which is more conducive to large-scale production, thereby reducing the production cost of microneedles. The microneedles of thermoplastic materials of the present invention have the following advantages: first, they are safe and do not cause skin allergies; second, they have suitable hardness, and the microneedle needles are sufficient to open the skin and have little or no foreign body sensation; third, they are insoluble in water, so that the microneedle needles inserted into the skin are not partially dissolved in the body, so that the skin pores are quickly closed, affecting the subsequent drug entry; fourth, the hot melt or hot melting temperature is moderate, and the formed microneedle needles have toughness and are easy to demold. However, the materials of microneedles in the prior art cannot have these advantages at the same time. The drug delivery microneedles prepared using the mold and method of the present invention are actually blank microneedles. After the blank microneedles are made, suitable drugs or other bioactive substances are loaded on the microneedles, especially on the needle tips, by appropriate methods to make drug-loaded or bioactive substance-loaded microneedles for medical treatment or other beneficial purposes.

[0074] In other embodiments of the present invention, the pressing mechanism may also be a driving device such as a hydraulic cylinder, a pneumatic cylinder or a motor, as long as it can drive the pressing head to move downward to press the microneedle raw material. The number of microporous areas can be flexibly selected according to actual needs.

[0075] Although the embodiments of the present invention have been described in detail in the above examples, the present invention is not limited to the above embodiments, and the scope of the present invention defined by the appended claims includes all equivalent substitutes and changes.

Claims

1. A preparation mold for drug delivery microneedles, characterized in that: The invention comprises an upper plate (1), a stripping plate (2), a template (3) and an isolation layer (4) which are arranged in sequence from top to bottom. The upper plate (1), the stripping plate (2), the template (3) and the isolation layer (4) are all made of heat-resistant materials. The isolation layer (4) is made of an air-permeable and liquid-impermeable material. The template (3) is provided with a microporous area (31) corresponding to the needle-shaped object of the microneedle. A microporous area (31) has a plurality of micropores, and the micropores are through holes opened on the template (3). A substrate hole (11) corresponding to the microneedle substrate is opened at a position corresponding to the microporous area (31) on the upper plate (1). The substrate hole (11) is located on the bottom surface of the upper plate (1). An annular boss (12) having a thickness greater than that of the stripping plate (2) is provided on the periphery of (11); a boss hole for the annular boss (12) to pass through is provided at a position corresponding to the annular boss (12) on the stripping plate (2); a stripping hole (13) is provided on the upper plate around the annular boss (12); both the substrate hole (11) and the stripping hole (13) are through holes; a stop surface (15) is provided in the substrate hole; during stripping, a stripping rod (14) is placed in the stripping hole (13); the bottom end of the stripping rod (14) pushes the stripping plate (2) downward, and the microneedle substrate is stopped and matched with the stop surface (15) in the substrate hole.

2. The mold for preparing drug delivery microneedles according to claim 1, characterized in that: The substrate hole (11) is a stepped hole that is larger at the top and smaller at the bottom. The shape and size of the small section at the bottom of the stepped hole are the same as those of the microneedle substrate. The annular boss (12) is arranged on the periphery of the small section at the bottom of the stepped hole (11). The demoulding hole (13) is opened on the stepped surface of the stepped hole. The stop surface is arranged on the inner side surface of the small section at the bottom of the stepped hole.

3. The mold for preparing drug delivery microneedles according to claim 2, characterized in that: An annular retaining ring (16) is provided on the inner side of the small section at the lower part of the stepped hole, and the upper surface of the annular retaining ring constitutes the stop surface.

4. The mold for preparing drug delivery microneedles according to claim 2, characterized in that: The inner side of the small section at the lower part of the stepped hole is provided with a tapered section (17) which gradually contracts downwards, and the tapered surface of the tapered section constitutes the stop surface.

5. The mold for preparing drug delivery microneedles according to any one of claims 1 to 4, characterized in that: The number of the demoulding holes (13) is greater than two, and the demoulding holes (13) are evenly distributed on the periphery of the annular boss (12).

6. The mold for preparing drug delivery microneedles according to any one of claims 1 to 4, characterized in that: The demoulding hole (13) is a threaded hole, and the demoulding rod (14) is a screw that matches the thread of the demoulding hole.

7. The mold for preparing drug delivery microneedles according to any one of claims 1 to 4, characterized in that: The stripping plate (2) is a metal plate.

8. The mold for preparing drug delivery microneedles according to any one of claims 1 to 4, characterized in that: The upper plate (1), the stripping plate (2), the template (3) and the isolation layer (4) are connected together via positioning bolts (5).

9. The mold for preparing drug delivery microneedles according to any one of claims 1 to 4, characterized in that: The number of microporous areas (31) on the template (3) is more than one, and the number of substrate holes (11) and annular bosses (12) on the upper plate is equal to the number of microporous areas (31).

10. A method for preparing a drug delivery microneedle, characterized in that: It includes the following steps: (1) heating and deforming the thermoplastic raw material for preparing microneedles to a fluid state; (2) placing the isolation layer, template, stripping plate and upper plate in claim 1 in order from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the microporous area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping plate; (3) placing the raw material heated in step (1) into the substrate hole of the upper plate; (4) pressurizing the raw material in the substrate hole so that the raw material moves downward into the micropores in the microporous area of ​​the template, and a portion of the raw material The first step is to place a mold release rod in the mold release hole, press the mold release rod downward, and push the mold release plate downward, so that the mold release plate and the mold release plate are separated from the upper plate, and the upper plate with microneedles is obtained. Then, the microneedles are pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

11. A method for preparing a drug delivery microneedle, characterized in that: It includes the following steps: (1) Processing a thermoplastic raw material for preparing microneedles into a powder raw material, and weighing a powder raw material equal to the weight of a single microneedle; (2) Placing the isolation layer, template, stripping plate and upper plate in claim 1 in order from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the micropore area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping plate; (3) Placing the powder raw material weighed in step (1) into the substrate hole of the upper plate; (4) Heating the powder raw material in step (3) until the powder raw material becomes a flowing state; (5) Pressurizing the raw material in the substrate hole to flow The raw material in a dynamic state flows downward into the micropores in the micropore area of ​​the template, with a portion of the raw material entering the micropore area to form the needle-like object of the microneedle, and the other portion remaining in the substrate hole to form the microneedle substrate; (6) the raw material in the substrate hole and the micropore area is cooled to make the flowing raw material in the substrate hole and the micropore area become solid; (7) a demolding rod is placed in the demolding hole, and the demolding rod is pressed downward to make the demolding rod push the demolding plate downward, thereby separating the template and the demolding plate from the upper plate, obtaining an upper plate with microneedles, and then pushing the microneedles upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

12. A method for preparing a drug delivery microneedle, characterized in that: It includes the following steps: (1) Processing the thermoplastic raw material for preparing microneedles into a solid raw material with the same weight as a single microneedle; (2) Placing the isolation layer, template, stripping plate and upper plate in claim 1 in order from bottom to top, and making the substrate hole of the upper plate correspondingly arranged above the micropore area on the template, and the annular boss at the bottom of the upper plate passing through the boss hole of the stripping plate; (3) Placing the solid raw material obtained in step (1) into the substrate hole of the upper plate; (4) Heating the solid raw material in step (3) until the solid raw material becomes a fluid state; (5) Pressurizing the raw material in the substrate hole to make the fluid raw material The raw material enters the micropores of the micropore area of ​​the template downward, and a part of the raw material enters the micropore area to form the needle-shaped object of the microneedle, and the other part remains in the substrate hole to form the microneedle substrate; (6) The raw material in the flowing state in the substrate hole and the micropore area is cooled to make the flowing raw material in the substrate hole and the micropore area become solid; (7) A demolding rod is placed in the demolding hole, and the demolding rod is pressed downward to make the demolding rod push the demolding plate downward, so that the template and the demolding plate are separated from the upper plate, and the upper plate with microneedles is obtained, and then the microneedles are pushed upward from the bottom of the upper plate substrate hole to separate the microneedles from the upper plate, thereby completing the demolding.

13. The method for preparing a drug delivery microneedle according to claim 10, 11 or 12, characterized in that: The thermoplastic raw material for preparing the microneedle is one or a blend of two or more of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, polyethylene vinyl acetate, and polyvinyl acetate.

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