Drug delivery microneedle and special production template for drug delivery microneedle

Abstract

The invention discloses a drug delivery microneedle and a special production template for the drug delivery microneedle. The drug delivery microneedle includes a substrate and a needle-shaped object fixed at the bottom of the substrate. The substrate and the needle-shaped object are integrally cast together. The substrate and the needle-shaped object are made of thermoplastic material, and the needle-shaped object is a structure that is larger at the top and smaller at the bottom. The special production template for the drug delivery microneedle includes a needle-shaped object template corresponding to the needle-shaped object and the substrate of the microneedle respectively and a substrate template located above the needle-shaped object template. A microporous area is provided on the needle-shaped object template, and a plurality of micropores are provided in a microporous area. The micropores are through holes with bottom openings. The shape and size of the micropores are the same as the shape and size of the microneedle needle to be produced. A substrate hole is provided on the substrate template at a position above the corresponding microporous area. The shape and size of the substrate hole are the same as the shape and size of the microneedle substrate to be produced. The needle-shaped object template and the substrate template are integrally connected or separately provided.

Description

Technical Field

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

[0002] Oral administration of protein and peptide drugs will be degraded and ineffective after passing through the stomach and intestines, so they can only be administered by injection. Injection administration is actually a way for drugs to pass through the skin, a biological barrier, with the help of a needle. However, it only adds pain, especially long-term and frequent injections. Non-injection administration of such drugs has been a long-standing wish. For example, research on non-injection administration of insulin has been conducted since 1921 to avoid long-term and frequent injections. There have been many non-injection administration methods, of which the two most famous cases are: the first is Pfizer's inhaler, which took 14 years and cost 2.8 billion US dollars. Two years after it was launched, it was withdrawn from the market due to extremely inaccurate doses entering the body; the second is Glaxo's long-term and expensive oral insulin, which was also terminated. Therefore, the task of how to get hydrophilic protein and peptide drugs through the biological membrane barrier and into the body is very arduous.

[0003] 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. Microneedle transdermal drug delivery is to decompose a large needle into a group of short and fine microneedles to deliver drugs to the superficial layer of the subcutaneous layer without touching the deep nerves and blood vessels. It is one of the research fields of non-injection drug delivery. With the rapid growth of the types and dosages of protein peptide drugs, microneedle transdermal drug delivery research has gradually become a focus of protein peptide drug delivery. In addition, patients can self-administer drugs during microneedle administration, which is convenient and safe. Therefore, microneedle transdermal drug delivery technology has received widespread attention since its inception. The basic structural form of drug delivery microneedles is: 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.), a group of microneedles of varying numbers are erected. The basic use process and principle of microneedles are: under the action of appropriate pressure, microneedles are used to open skin channels, help drugs and other bioactive substances pass through the skin, achieve systemic or local skin distribution of drugs and other bioactive substances, achieve therapeutic or other beneficial effects, and have very positive significance.

[0004] If microneedle transdermal drug delivery can achieve the same pharmacodynamics as injection drug delivery, the demand for microneedles will be enormous. For the 13 million patients with type 1 diabetes in China alone, the daily production of insulin microneedle tablets must reach 40 million tablets, or 41,700 tablets per minute. Although research on transdermal microneedle drug delivery has made some progress, it is still far from being possible to market the product. The key points of transdermal microneedle research and development are: (1) the selection of microneedle substrates and the ultra-fine precision manufacturing technology based on the substrates; (2) the compatibility between the substrate, human skin, and the drug; and (3) the possibility of large-scale industrial production and the feasibility of low cost.

[0005] The existing microneedles include solid metal microneedles, hollow metal microneedles, solid non-metallic microneedles (such as inorganic silicon materials), organic macromolecular microneedles (such as polyvinylpyrrolidone), etc. However, these existing microneedle products and their production methods have difficulties in mass production, resulting in no industrial mass production of such technologies and products so far. In addition, due to the limitation of mass production capacity, the production cost is also high. The following is a comparison of the selection of several microneedle materials and the ultra-fine precision production technology based on the substrate:

[0006] The production of metal microneedles involves a complex process of precision machining or precision electroplating, which is difficult to mass produce at low cost. 2 There are 200 ultra-fine microneedles with a height of 1mm and a minimum diameter of 0.15mm standing on an area of ​​​​slightly larger than a 5-cent coin. The production of metal hollow microneedles requires electroplating metal layer by layer on the model and then demolding. Such production involves a complex process of ultra-fine precision machining or electroplating film formation, and the metal microneedles have a very obvious foreign body sensation on the skin due to their rigidity and processing burrs.

[0007] The melting temperature of inorganic silicon materials is too high, and it is difficult to find a suitable high-temperature resistant mold for hot injection microneedle production; the inorganic silicon materials in the cooled state are hard and brittle, and the processing efficiency of cutting, grinding or photolithography is low. Microneedles made of inorganic silicon materials also have a distinct foreign body sensation due to their rigidity, and are particularly brittle, resulting in a high probability that the needle tip will break in the superficial layer of the skin, causing other inconveniences.

[0008] 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 of the micropores is very small, in order to prevent the polyvidone solution from being blocked by the air in the micropores when pouring and unable to sink to the bottom of the micropores, during the microneedle production process, the entire device needs to be placed in a closed container and the closed container needs to be evacuated, which makes the production process very troublesome and increases the production cost. The characteristic of polyvidone microneedles is that polyvidone is very easy to absorb moisture, soften or dissolve. If it absorbs moisture outside the body, the needle will soften and be difficult to insert into the skin. For this reason, povidone microneedles must be made dry, packaged to prevent moisture, and applied quickly after opening the package, all of which increase the difficulty of promoting povidone microneedles. What is even more inconvenient is that after the microneedle is inserted into the skin, povidone immediately absorbs body fluids to dissolve the drug, and finally, the inserted part will dissolve in the skin. Since povidone degrades relatively slowly in the body, the patient will have residual discomfort for about three days.

[0009] It has been reported in the literature that the drug loading capacity of metal and silicon microneedles is extremely limited. However, the idea of ​​increasing the size and number of microneedles to increase the drug loading capacity is difficult to achieve due to many factors. At the same time, the stability test results of metal materials, silicon materials and polyvidone in long-term contact with drugs have not been reported.

[0010] Assuming that the process conditions for loading drugs on microneedles do not vary much and are less time-consuming, the key aspect affecting the microneedle yield is the time-consuming preparation of the microneedle body.

[0011] There are two ways to make solid metal microneedles. One is to make sheet-like microneedles. The production method is to punch out a triangle on a stainless steel sheet with the bottom edge still connected to the sheet and the other two sides separated from the sheet. When the stamping is completed, the triangle is erected at 90 degrees to form a microneedle array. This structure of microneedles is as follows Figure 1 As shown, this type of microneedle is relatively simple to make, but the density of the microneedles is too sparse, and the drug loading is too limited; second, the production of columnar microneedles, the minimum diameter of the conical columnar needle body is only about 0.15mm, and it must be cut with an extremely small feed amount to maintain such a small column from being impacted and disintegrated. Therefore, the production of each piece takes minutes to tens of minutes. Metal hollow microneedles need to be made by layered electroplating on the mold, which is very time-consuming. The production method and process of silicon material microneedles are similar to those of solid metal microneedles. Povidone microneedles are difficult to demold due to insufficient needle body strength, and are currently still manually operated by feel and force.

[0012] The raw material cost of solid metal microneedles, hollow metal microneedles, and silicon material microneedles is only a few cents. The most important component of the cost is the labor and energy consumption generated by the time-consuming production process and the amortization of the huge investment in mechanical cutting capabilities. This part of the cost should be above the level of "more than ten yuan to several dozen yuan per piece." Summary of the invention

[0013] The purpose of the present invention is to provide a drug delivery microneedle and a special production template for the drug delivery microneedle, so as to solve the technical problems of the prior art that the microneedle production process is complicated and the production cost is high.

[0014] The drug delivery microneedle of the present invention adopts the following technical scheme: a drug delivery microneedle, which includes a substrate and a needle-shaped object fixed at the bottom of the substrate, the substrate and the needle-shaped object are integrally cast together, the substrate and the needle-shaped object are made of thermoplastic material, and the needle-shaped object has a structure that is larger at the top and smaller at the bottom.

[0015] The needle-shaped object is a cone, ellipsoid or spherical structure.

[0016] The needle-shaped object has a two-section structure, the largest diameter of the lower section is not greater than the smallest diameter of the upper section, the upper section is cylindrical, or a cone with a larger top and a smaller bottom, or an ellipsoidal or spherical structure, and the lower section is cylindrical, or a cone with a larger top and a smaller bottom, or an ellipsoidal or spherical structure.

[0017] A step surface is provided between the upper and lower sections of the needle-shaped object.

[0018] The thermoplastic material 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.

[0019] The special production template of the drug-delivery microneedle of the present invention adopts the following technical scheme: a special production template of the drug-delivery microneedle, which includes a needle-shaped object template corresponding to the needle-shaped object and the substrate of the microneedle respectively and a substrate template located above the needle-shaped object template, the needle-shaped object template is provided with a microporous area, a microporous area has a plurality of micropores, the micropores are through holes with bottom openings, the shape and size of the micropores are the same as the shape and size of the microneedle needle to be produced, the substrate template is provided with a substrate hole located above the corresponding microporous area, the shape and size of the substrate hole are the same as the shape and size of the microneedle substrate to be produced, the needle-shaped object template and the substrate template are integrally connected or separately arranged; when the needle-shaped object template and the substrate template are separately arranged, when the microneedle is produced, the bottom surface of the substrate template and the upper surface of the needle-shaped object template are pressed and sealed under the action of external force.

[0020] The substrate hole is a cylindrical hole with a boss inside or a truncated cone-shaped hole that is larger at the top and smaller at the bottom.

[0021] The micropores are conical holes or semi-ellipsoid holes or hemispherical holes with an opening at the bottom and a larger top and a smaller bottom.

[0022] The micropore is a two-section structure, the largest diameter of the lower section is not greater than the smallest diameter of the upper section, the upper section is a cylindrical hole, or a tapered hole that is larger at the top and smaller at the bottom, or a hole with an arc-shaped vertical section, and the lower section is a cylindrical hole, or a tapered hole that is larger at the top and smaller at the bottom, or a hole with an arc-shaped vertical section.

[0023] A step surface is provided between the upper and lower sections of the microhole.

[0024] The needle-shaped object template and / or the substrate template are made of polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, aluminum, copper or stainless steel.

[0025] The beneficial effects of the present invention are as follows: 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, the processing precision of the template micropore is very high, the microneedle obtained has almost no burrs, and the microneedle needle-shaped object after cooling and forming has suitable hardness and flexibility, which is sufficient to stretch the skin and has little or no foreign body sensation. In addition, the thermoplastic material has a certain water-liquid swelling property, and the flexibility after swelling is increased, so after being inserted into the skin and contacting body fluids, the skin feels better; third, it is insoluble or has very low water solubility or can still maintain sufficient adhesion after contacting water, and can be easily pulled out after the drug administration is completed, rather than being dissolved in the skin. When the present invention is used, the thermoplastic raw material with fluidity after heating is injected into the substrate hole of the substrate template, and the raw material enters the micropore on the needle-shaped object template downward. Since the micropore is a through hole, it does not need to be operated under a vacuum environment, and the fluid microneedle raw material will be injected into the micropore. The fluid microneedle raw material can be pressurized with a pressure mechanism, which can better squeeze out the air in the micropore, so that the fluid microneedle raw material can be quickly injected into the micropore. The raw material of the microneedle of the present invention is a thermoplastic material, which has good fluidity or flexibility after heating, and can be easily cooled and solidified into a specific geometric shape under the restriction of the template. At this point, the ultra-fine and precise size requirements that the microneedle must have are converted into ultra-fine and precise size requirements for the template, and the requirements for smoothness and burr-free are converted into the same requirements for the template.

[0026] The thermoplastic material microneedles described in the present invention are blank microneedles that have not been loaded with drugs or other bioactive substances. When used, relevant drugs or bioactive substances can be loaded on the needle tips of the microneedles. These drugs and / or bioactive substances include proteins, peptides, water-soluble or fat-soluble small molecules, thereby forming individual drug-loaded microneedles.

[0027] Preferably, the substrate hole has a boss or a truncated cone hole. When the substrate template and the needle template are separately provided, after the raw material is formed, when the substrate template and the needle template are separated, the substrate of the microneedle remains in the substrate hole, and the needle of the microneedle is removed from the needle template, thereby making it easier to demold the microneedle.

[0028] Preferably, the micropores are of a structure that is larger at the top and smaller at the bottom, and the prepared microneedles are also of a structure that is larger at the top and smaller at the bottom, which facilitates the insertion of the microneedles into the skin and is beneficial for transdermal drug delivery.

[0029] Preferably, the micropore is a two-stage structure, and the prepared microneedle is also a two-stage structure, and drugs can be loaded on the lower section of the microneedle during use.

[0030] Preferably, there is a step surface between the upper and lower sections of the micropore, and there is also a step surface between the upper and lower ends of the prepared microneedle, and the step surface makes it easier for the microneedle to load drugs.

[0031] Preferably, the substrate template and / or needle-shaped object template can be made of organic materials such as polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, and metal materials such as aluminum, copper, and stainless steel. The templates made of these materials have a low affinity with the cold solid surface of thermoplastic materials and can be easily demoulded. Moreover, these materials can withstand temperatures above 200 degrees Celsius, so the template of the present invention can be used repeatedly.

[0032] 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the structure of a metal microneedle in the prior art.

[0034] Figure 2 is a schematic structural diagram of Example 1 of the drug delivery microneedle of the present invention;

[0035] Figure 3 is a schematic structural diagram of Example 2 of the drug delivery microneedle of the present invention;

[0036] Figure 4 A schematic diagram of the structure of Example 1 of the microneedle-specific production template of the present invention;

[0037] Figure 5 yes Figure 4 A cross-sectional view of

[0038] Figure 6 is a schematic diagram of a first type of micropore on a template of the present invention;

[0039] Figure 7is a schematic diagram of a second type of micropore on the template of the present invention;

[0040] Figure 8 is a schematic diagram of a third type of micropore on the template of the present invention;

[0041] Fig. 9 is a schematic diagram of a fourth type of micropore on the template of the present invention;

[0042] Fig.10 is a schematic diagram of the fifth type of micropores on the template of the present invention;

[0043] Fig.11 is a schematic diagram of a sixth type of micropore on the template of the present invention;

[0044] Fig.12 is a schematic diagram of the seventh type of micropores on the template of the present invention;

[0045] Fig.13 is a schematic diagram of an eighth type of micropore on the template of the present invention;

[0046] Fig.14 is a schematic diagram of a ninth type of microwell on the template of the present invention;

[0047] Fig.15 is a schematic structural diagram of Example 2 of a microneedle production template of the present invention;

[0048] Fig.16 is a schematic structural diagram of Example 3 of the microneedle production template of the present invention;

[0049] Fig.17 This is the blood sugar experimental data of the type I diabetes model pigs given insulin microneedles on an empty stomach and without medication on an empty stomach (blank control);

[0050] Fig.18 These are the blood glucose experimental data of type II diabetes model pigs given exenatide microneedles after eating, exenatide injection after eating (positive control), and no medication after eating (blank control).

[0051] In the figure: 1-needle template, 11-micropore area, 2-substrate template, 21-substrate hole, 22-boss, 3-microneedle, 31-substrate, 32-needle. DETAILED DESCRIPTION

[0052] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0053] The structure of Example 1 of the drug delivery microneedle of the present invention is as follows Figure 2As shown, the drug delivery microneedle of this embodiment includes a substrate 31 and a needle 32 fixed to the bottom of the substrate, the substrate 31 and the needle 32 are integrally cast together, the substrate 31 and the needle 32 are made of thermoplastic material, and the needle 32 is a structure that is larger at the top and smaller at the bottom. The thermoplastic material is one of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copolyvidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl acetate, polyethylene vinyl acetate, polyvinyl acetate, ethylene copolymers, or a blend or copolymer or block copolymer of two or more thereof. In this embodiment, as Figure 2 As shown, the microneedle needle adopts a conical structure.

[0054] The structure of Example 2 of the drug delivery microneedle of the present invention is as follows Figure 3 As shown, different from the drug delivery microneedle embodiment 1, the microneedle needle 32 in this embodiment adopts a two-section structure, the upper section is a cone with a larger upper portion and a smaller lower portion, and the lower section is a cylindrical structure, with a step surface between the upper and lower sections.

[0055] In other embodiments of the drug delivery microneedle of the present invention, the needle of the microneedle can be a conical or ellipsoidal or spherical structure; the needle of the microneedle can also be a two-section structure, the diameter of the largest part of the lower section is not greater than the diameter of the smallest part of the upper section, the upper section is cylindrical or a conical or ellipsoidal or spherical structure with a larger upper part and a smaller lower part, and the lower section is cylindrical or a conical hole with a larger upper part and a smaller lower part or an ellipsoidal or spherical structure. When the diameter of the largest part of the lower section is smaller than the diameter of the smallest part of the upper section, there is a step surface between the upper and lower sections of the needle. Other shapes and structures of the microneedle needle can be the same as the shape of the micropores in the microneedle production template of the present invention, so the drawings are omitted.

[0056] The material of the microneedle of the present invention is a thermoplastic material. The thermoplastic material has the characteristic of fluidity after heating, and is poured into the template. At the same time, the thermoplastic material can be pressure-injected. After the thermoplastic material is cooled, solidified and demolded, the microneedle is obtained. The thermoplastic material has good fluidity or flexibility after heating, and can be conveniently solidified into a specific geometric shape under the restriction of the template. Therefore, the ultra-fine and precise size requirements that the microneedle must have are converted into ultra-fine and precise size requirements for the needle-shaped object template, and the requirements for smoothness and burr-free are converted into the same requirements for the needle-shaped object template.

[0057] The thermoplastic microneedles of the present invention have the following advantages: First, they are safe and do not cause skin allergies. Thermoplastic materials belong to two different categories in terms of biosafety classification. One category is polyethylene, polyvinyl chloride, polystyrene and polypropylene approved as drug and food packaging materials and containers, and polyoxymethylene as disposable syringes. The other category is approved pharmaceutical excipients for oral and injectable drugs and fluid adsorption and purification materials in hemodialysis; second, the microneedle needles after cooling and forming have suitable hardness and flexibility, which is enough to stretch the skin and have little or no foreign body sensation. In addition, the thermoplastic materials have a certain degree of water swelling, and the flexibility after swelling increases, so after being inserted into the skin and contacting body fluids, the skin feels better; third, they are insoluble or have very low water solubility or can still maintain sufficient adhesion after contacting water, and can be easily pulled out after the drug administration is completed, instead of being dissolved in the skin. However, the materials of microneedles in the prior art cannot have these advantages at the same time.

[0058] In specific production, thermoplastic materials can be flexibly selected according to actual needs, and the differences in hardness, brittleness and surface properties of different materials can be used to achieve the most suitable purpose by mixing one, two or more materials. The density of microneedles can be flexibly selected and produced according to actual needs, and the preferred density can be 1-600 / cm 2 .

[0059] The entire process of making the microneedle of the present invention is designed and arranged according to the "optical-mechanical-electrical integration" and debugged and verified on a laboratory scale. The most time-consuming process module is hot pressing, which can complete a hot pressing process of a template containing 250 clusters of microporous areas (250 pieces) every 3 minutes, and each piece takes only "seconds". As long as it is matched with the already mature heating and cooling process space, the microneedle hot pressing process unit can be easily and simply increased, and then the scale expansion can be achieved.

[0060] The raw material cost of the drug delivery microneedle described in the present invention is only about 2 cents, and the labor and energy consumption caused by the time-consuming production of each piece is only a few cents. The most important cost component is the cost of the template. The material and self-production costs of each template containing 250 clusters of microporous areas (250 pieces) are 240 yuan to 800 yuan, and the template can be reused more than 200 times without damage. The cost amortized on each drug delivery microneedle is negligible.

[0061] Fig.17 This is the blood sugar experimental data of the type I diabetes model pigs who were given insulin microneedles on an empty stomach and those who were not given insulin on an empty stomach (blank control). Figure 3 Drug delivery microneedles are shown.

[0062] Fig.18The data are blood glucose experimental data of type II diabetes model pigs given exenatide microneedles after eating, exenatide injection after eating (positive control), and no medication after eating (blank control). Figure 3 Drug delivery microneedles are shown.

[0063] pass Fig.17 and Fig.18 It can be observed that the drug delivery microneedles can make blood sugar drop more steadily, proving that the drug effect of the drug delivery microneedles is gradually released through the skin and has the effect of sustained-release drugs.

[0064] In addition, the 30-day data from the accelerated drug stability test of the porcine insulin microneedles and exenatide microneedles produced in the preliminary test showed that no abnormalities were observed in the loaded drugs.

[0065] The structure of Example 1 of the special production template of the drug delivery microneedle of the present invention is as follows Figures 4 to 5 As shown, the special production template of the drug-delivering microneedle of this embodiment includes a needle-shaped object template 1 corresponding to the needle-shaped object and the substrate of the microneedle respectively, and a substrate template 2 located above the needle-shaped object template, the needle-shaped object template 1 is provided with a microporous area 11, and a plurality of micropores are arranged in one microporous area 11. The micropores are through holes with bottom openings, and the shape and size of the micropores are the same as the shape and size of the microneedle needle to be produced. The substrate template 2 is provided with substrate holes 21 at positions above the corresponding microporous areas 11, and the number of the substrate holes 21 is equal to the number of the microporous areas 11, and the shape and size of the substrate holes 21 are the same as the shape and size of the microneedle substrate to be produced. The needle-shaped object template 1 and the substrate template 2 of this embodiment are integrally connected.

[0066] When in use, the thermoplastic microneedle raw material with fluidity is injected into the substrate hole 21, a part of the raw material is injected into the micropores of the micropore area 11 to form a microneedle needle-like object, and the other part is located in the substrate hole 21 to form a microneedle substrate, thereby quickly and conveniently preparing an integrally formed microneedle. Since the micropores on the needle-like object template of this embodiment are through holes, it is not necessary to operate in a vacuum environment, and the fluid microneedle raw material will naturally be injected into the micropores. When in use, the fluid microneedle raw material can be pressurized with a pressure mechanism, which can better squeeze out the air in the micropores and allow the fluid microneedle raw material to be quickly injected into the micropores.

[0067] The micropores on the needle template can be made by Figure 6 The tapered hole shown is larger at the top and smaller at the bottom, the angle of the tapered surface of the tapered hole is 0° to 90°, the smallest diameter of the bottom of the tapered hole is less than 1 mm, and the thickness of the needle-shaped object template is less than 20 mm.

[0068] The micropores on the needle-shaped template can also be formed by Figure 7The semi-ellipsoidal hole shown is larger at the top and smaller at the bottom. The vertical section of the semi-ellipsoidal hole is an elliptical arc. The bottom of the semi-ellipsoidal hole has an opening with a diameter less than 1 mm. The thickness of the needle-shaped object template is less than 20 mm.

[0069] The micropores on the needle-shaped template can also be formed by Figure 8 The hemispherical hole shown is larger at the top and smaller at the bottom. The vertical section of the hemispherical hole is arc-shaped. The bottom of the hemispherical hole has an opening with a diameter less than 1 mm. The thickness of the needle-shaped object template is less than 20 mm.

[0070] The microhole can also adopt an upper and lower two-stage structure, the largest diameter of the lower stage is not greater than the smallest diameter of the upper stage, the upper stage is a cylindrical hole or a tapered hole with a larger top and a smaller bottom, or a hole with an arc-shaped vertical section, and the lower stage is a cylindrical hole or a tapered hole with a larger top and a smaller bottom, or a hole with an arc-shaped vertical section. For example, Fig. 9 As shown in FIG, both the upper and lower sections of the microhole are conical holes, and there is a step surface between the upper and lower sections; Fig.10 As shown in the figure, the upper part of the micropore is a cylindrical hole, and the lower part is a semi-ellipsoidal hole that is larger at the top and smaller at the bottom; Fig.11 As shown in FIG. 1 , the upper section of the micropore is a cylindrical hole, and the lower section is a conical hole that is larger at the top and smaller at the bottom. Fig.12 As shown in FIG. 1 , the upper section of the micropore is a tapered hole that is larger at the top and smaller at the bottom, and the lower section is a cylindrical hole; Fig.13 As shown in FIG. 1 , the upper section of the micropore is a conical hole with a larger top and a smaller bottom, and the lower section is a semi-ellipsoidal hole with a larger top and a smaller bottom. Fig.14 As shown, the upper section of the micropore is a semi-ellipsoidal hole that is larger at the top and smaller at the bottom, and the lower section is a conical hole that is larger at the top and smaller at the bottom. The maximum diameter of the lower section is smaller than the minimum diameter of the upper section.

[0071] The micropores are of a structure that is larger at the top and smaller at the bottom, and the prepared microneedles are also of a structure that is larger at the top and smaller at the bottom, which facilitates the insertion of the microneedles into the skin and is beneficial for transdermal drug delivery. Of course, the micropores can also adopt other structures.

[0072] The materials of the needle-shaped object template and the substrate template in the present invention can be the same or different. The materials of the needle-shaped object template and the substrate template can be organic materials such as polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, etc., and can also be metal materials such as aluminum, copper, or stainless steel. The templates of these materials have a low affinity with the cold solid surface of the thermoplastic material described in the present invention and can be easily demoulded. These materials can withstand temperatures above 200 degrees Celsius, so the templates can be reused repeatedly. The needle-shaped object templates made of these materials have uniformly distributed micropores, a smooth surface, and no burrs, and the smallest pore size of the micropores can reach 0.1mm.

[0073] The structure of Example 2 of the special production template of the drug delivery microneedle of the present invention is as follows Fig.15As shown, unlike Example 1, the substrate template and the needle template in this embodiment are separately provided. When the microneedle is produced, the bottom surface of the substrate template 2 and the upper surface of the needle template 2 are pressed and sealed under the action of external force. In this embodiment, the substrate hole 21 is a cylindrical hole. In order to facilitate demolding, a boss 22 is provided inside the substrate hole 21. After the microneedle raw material in the template is formed, when the substrate template 2 and the needle template 1 are separated, the substrate of the microneedle remains in the substrate hole, and the needle of the microneedle is removed from the needle template, so that the demolding of the microneedle is more convenient.

[0074] The structure of Example 3 of the special production template of the drug delivery microneedle of the present invention is as follows Fig.16 As shown, different from Example 2, the substrate hole 21 on the substrate template 2 in this embodiment is a truncated cone-shaped hole that is larger at the top and smaller at the bottom. The truncated cone hole can also allow the substrate of the microneedle to remain in the substrate hole and the needle of the microneedle to escape from the needle template when the substrate template 2 and the needle template 1 are separated.

[0075] The micropore shape structure in Examples 2 and 3 of the production template for drug delivery microneedles is the same as that in Example 1 and will not be described again here.

[0076] In the present invention, the key technology in the production of the needle-shaped template and / or the substrate template is the production of high-density, precision-sized micro-holes, and the shape of the produced micro-holes is a relatively complex geometric form. The production of micro-hole plates with such technical indicators has not been reported in the literature, and micro-hole plates with such technical indicators have not been commercially available.

[0077] 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.

[0078] The above embodiments and descriptions are only for the purpose of illustrating the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention may be subject to various changes and modifications, which are all within the scope of the present invention to be protected. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A special production template for drug delivery microneedles, characterized in that: It comprises a needle-shaped object template (1) corresponding to the needle-shaped object and the substrate of the microneedle respectively, and a substrate template (2) located above the needle-shaped object template, wherein the needle-shaped object template (1) is provided with a microporous area (11), wherein a plurality of micropores are provided in one microporous area (11), wherein the micropores are through holes with bottom openings, and wherein the shape and size of the micropores are the same as the shape and size of the microneedle-shaped object to be produced, and wherein a substrate hole (21) is provided at a position above the corresponding microporous area (11), and wherein the shape and size of the substrate hole (21) are the same as the shape and size of the microneedle substrate to be produced, and wherein the needle-shaped object template (1) and the substrate template (2) are separately provided; When the needle-shaped object template (1) and the substrate template (2) are separately provided, when producing microneedles, the bottom surface of the substrate template (2) and the upper surface of the needle-shaped object template (1) are pressed and sealed together under the action of an external force; the substrate hole (21) is a cylindrical hole with a boss (22) inside or a truncated cone-shaped hole that is larger at the top and smaller at the bottom; the micropore is an upper and lower two-section structure, the diameter of the largest part of the lower section is not greater than the diameter of the smallest part of the upper section, the upper section is a cylindrical hole or a conical hole that is larger at the top and smaller at the bottom or a hole with an arc-shaped vertical section, and the lower section is a cylindrical hole or a conical hole that is larger at the top and smaller at the bottom or a hole with an arc-shaped vertical section; there is a step surface between the upper and lower sections of the micropore; Alternatively, the micropore is a conical hole or a semi-ellipsoidal hole or a hemispherical hole with an opening at the bottom and a larger top and a smaller bottom; The needle-shaped object template (1) and / or the substrate template (2) are made of polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, aluminum, copper, or stainless steel.

2. A drug delivery microneedle prepared by the dedicated production template for drug delivery microneedles according to claim 1, comprising a substrate (31) and a needle-shaped object (32) fixed at the bottom of the substrate (31), characterized in that: The substrate (31) and the needle-shaped object (32) are integrally cast together; the substrate (31) and the needle-shaped object (32) are made of thermoplastic material; the needle-shaped object (32) is of a structure that is larger at the top and smaller at the bottom; a step surface is provided between the upper and lower sections of the needle-shaped object (32); the thermoplastic material is one or a blend or copolymer or block copolymer of two or more of polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copolyvidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl succinate acetate, polyethylene vinyl acetate, polyvinyl acetate, and ethylene copolymers.

3. The drug delivery microneedle according to claim 2, characterized in that: The needle-shaped object (32) is a conical, ellipsoidal or spherical structure.

4. The drug delivery microneedle according to claim 2, characterized in that: The needle-shaped object (32) is a two-section structure, the diameter of the largest part of the lower section is not greater than the diameter of the smallest part of the upper section, the upper section is cylindrical or a cone with a larger top and a smaller bottom, or an ellipsoid or a spherical structure, and the lower section is cylindrical or a cone with a larger top and a smaller bottom, or an ellipsoid or a spherical structure.

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