WO2020119352A1 - 一种给药微针及给药微针的专用生产模板 - Google Patents

一种给药微针及给药微针的专用生产模板 Download PDF

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WO2020119352A1
WO2020119352A1 PCT/CN2019/116963 CN2019116963W WO2020119352A1 WO 2020119352 A1 WO2020119352 A1 WO 2020119352A1 CN 2019116963 W CN2019116963 W CN 2019116963W WO 2020119352 A1 WO2020119352 A1 WO 2020119352A1
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Prior art keywords
template
needle
substrate
microneedles
microneedle
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PCT/CN2019/116963
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English (en)
French (fr)
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尹忠
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尹忠
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the invention relates to a drug delivery microneedle and a special production template for drug delivery microneedle, belonging to the technical field of medical equipment.
  • Protein and peptide drugs will be degraded and ineffective through the gastrointestinal tract, so they can only be injected. Injectable drug delivery is actually a way for the drug to pass through the biological barrier of the skin with the help of a needle. However, the pain is increased, especially for long-term frequent injections.
  • the non-injection administration of this kind of medicine is a long-cherished long-cherished wish.
  • the non-injection administration of insulin has been studied since 1921 to avoid long-term frequent injections.
  • There have been many non-injectable drug delivery methods of which the two most famous cases are two. The first is Pfizer's inhalant, which took 14 years and cost 2.8 billion US dollars. Two years after listing, it was due to the extremely inaccurate dose into the body. Delisting; The second is that Glaxo's long-term and expensive oral insulin has also been terminated. Therefore, the task of how proteins and peptides hydrophilic drugs enter the body through the biofilm barrier is very difficult.
  • microneedle transdermal drug delivery As a new type of transdermal drug delivery, microneedle transdermal drug delivery combines the advantages of subcutaneous injection drug delivery 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 the decomposition of a large needle into a set of short and tiny microneedles to deliver the drug to the superficial layer of the skin without touching the deep neurovascular, without bleeding or pain. It is a non-injectable drug research field. One. With the rapid growth of the types and dosages of protein peptide drugs, microneedle transdermal drug delivery research has gradually become the focus of protein peptide drug delivery.
  • microneedle transdermal drug delivery technology has gained wide attention since its inception.
  • the basic structural form of the microneedle for drug delivery is: on a plate-shaped substrate (such as but not limited to a flat plate, curved plate, etc.) of suitable thickness and appropriate shape (such as but not limited to a circle, square, etc.), a group is erected Various numbers of micro needles.
  • microneedles under the effect of appropriate pressure, use microneedles to open the skin channel, help drugs and other biologically active substances to pass through the skin, and achieve the distribution of biologically active substances such as drugs throughout the body or local skin to achieve treatment or Other beneficial effects have very positive significance.
  • microneedle transdermal administration can achieve pharmacodynamics equivalent to injection administration, the demand for microneedles will be huge. For the 13 million patients with type I diabetes in China alone, the daily output of insulin microneedle tablets needs to reach 40 million tablets and 41,700 tablets per minute. Although the research on transdermal microneedle administration has progressed, the product is still in the market.
  • the key points of R&D of transdermal microneedles are: (1) selection of microneedle base material, ultra-fine precision manufacturing technology based on the base material; (2) compatibility between the base material, human skin and contained drugs ; (3) The possibility of mass industrial production and the feasibility of low cost.
  • microneedles include metal solid microneedles, metal hollow microneedles, nonmetallic solid microneedles (such as inorganic silicon materials), organic macromolecular material microneedles (such as povidone), etc.
  • metal solid microneedles metal hollow microneedles
  • nonmetallic solid microneedles such as inorganic silicon materials
  • organic macromolecular material microneedles such as povidone
  • the existing ones Micro-needle products and their manufacturing methods have difficulties in mass production and preparation, so that such technologies and products have not seen the case of industrial mass production scale, and due to the limitations of their mass production capacity, the production cost is also high .
  • the following is a comparison between the selection of several microneedle materials and the ultra-fine precision manufacturing technology based on this substrate:
  • metal microneedles involves a complicated process of precision machining or precision electroplating film formation, which is difficult to mass-produce at low cost.
  • the metal block For the production of solid metal microneedles, the metal block needs to be processed into 200 microneedles with a height of 1 mm and a minimum diameter of 0.15 mm erected on an area of 3-4 cm 2 (slightly larger than 5 dimes).
  • the metal For the production of metal hollow microneedles, the metal needs to be plated on the model layer by layer and then demolded.
  • Such production involves a complicated process of ultra-fine precision machining or electroplating film formation, and due to the rigidity of metal micro-needles and the presence of processing burrs, the foreign body sensation of the metal micro-needles is quite obvious.
  • the melting temperature of the inorganic silicon material is too high, it is difficult to find a suitable high-temperature resistant mold, and the micro-needle is produced by the hot injection process; the inorganic silicon material in the cooled state has high hardness and brittleness, and the machining process of cutting, grinding or lithography is more efficient low.
  • Inorganic silicon material micro-needles also have obvious foreign body sensation due to their rigidity, especially they are very brittle, resulting in a high probability of the tip of the needle breaking into the superficial layer of the skin, resulting in other inconveniences.
  • the concentrated solution of povidone (PVP) is poured into microneedles through the mold, and the microneedles made of PVP material after drying and molding are difficult to demold because of insufficient strength.
  • the mold used in the preparation of povidone microneedles is a template with micropores. Because the micropores are in the form of countersinks, and because the pore diameter of the micropores is very small, in order to prevent the povidone solution from pouring, The obstruction of the air in the micropores cannot sink to the bottom of the micropores.
  • the entire device needs to be placed in a closed container, and the closed container is evacuated, which results in a very troublesome manufacturing process and increased manufacturing costs. Big.
  • povidone microneedles The characteristic of povidone microneedles is that povidone is very easy to absorb moisture and soften or dissolve. If it absorbs moisture in vitro, the needle softens and it is difficult to insert into the skin. For this, it is required to make the povidone microneedles dry, to seal the package moisture, and to apply it quickly after opening the package. This all promotes the use of povidone microneedles. Increased difficulty; more inconveniently, after the microneedle is inserted into the skin, povidone immediately absorbs the body fluid to dissolve the drug. Finally, the inserted part will be dissolved in the skin. Because the degradation rate of povidone in the body is relatively slow, the patient will There is residual discomfort for about three days.
  • microneedles There are two ways to make solid metal microneedles. One is to make microneedles with sheet needles. The way to make them is to punch out a triangle on the bottom of the stainless steel sheet that is still connected to the sheet and the other two sides are separated from the thin plate. At the same time when it is completed, the triangle is raised at 90 degrees to form a microneedle array.
  • the microneedles of this structure are shown in Figure 1. The production of such microneedles is relatively simple, but the density of the microneedles is too sparse, and the drug load is also Too limited; the second is the production of cylindrical needle microneedles. The minimum diameter of the tapered cylindrical needle is only about 0.15mm.
  • the production time of each piece is from minutes to tens of minutes.
  • the metal hollow microneedles need to be produced by layered electroplating on the mold, which is very time-consuming.
  • the production method of silicon material micro-needles is similar to the production process of metal solid micro-needles. Povidone microneedles are difficult to demold due to insufficient strength of the needle body. At present, they are still manually operated by hand.
  • 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 cumbersome manufacturing process and high manufacturing cost of the prior art microneedle.
  • the drug delivery microneedle of the present invention adopts the following technical solution: a drug delivery microneedle, which includes a base plate and a needle fixed on the bottom of the base plate, the base plate and the needle are integrally molded together, and the base plate and the needle
  • the needle-shaped object is made of a thermoplastic material, and the needle-shaped object has a structure of large size and small size.
  • the needle-shaped object has a conical or ellipsoidal or spherical structure.
  • the needle-like structure is a two-stage structure with the upper and lower sections, the diameter of the largest section of the lower section is not greater than the diameter of the smallest section of the upper section, the upper section is cylindrical or conical or ellipsoidal or spherical, and the lower section is cylindrical Either a cone with an upper size and a smaller size, or an ellipsoidal or spherical structure.
  • the needle has a stepped surface between the upper and lower sections.
  • thermoplastic material is polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl succinate acetate , Polyethylene vinyl acetate, polyvinyl acetate, ethylene copolymers of one or more than two blends or copolymers or block copolymers.
  • the special production template for the administration of microneedles of the present invention adopts the following technical scheme: a special production template for administration of microneedles, which includes needle templates corresponding to the needles and substrates of the microneedles and located in the needles
  • the substrate template above the template, the needle template is provided with a micro-porous area, and there are several micro-holes in a micro-porous area.
  • the micro-holes are through holes that are open at the bottom.
  • the shape and size of the micro-holes are the same as the micro
  • the needle needles have the same shape and size
  • the substrate template is provided with a substrate hole at a position above the corresponding micropore 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 object template and the substrate template are integrally connected or separately set; when the needle template and the substrate template are separately provided, when the microneedles are produced, the bottom surface of the substrate template and the upper surface of the needle template are pressed and sealed together under external force.
  • the substrate hole is a cylindrical hole provided with a boss in the inside or a circular truncated hole with a large upper and lower small.
  • the micro-holes are conical holes or semi-ellipsoid holes or semi-spherical holes that are open at the bottom and are large, large, and small.
  • the micro-hole is a two-stage structure with upper and lower sections.
  • the diameter of the largest part of the lower section is not greater than the diameter of the smallest section of the upper section.
  • the upper section is a cylindrical hole or a tapered hole with a large upper and lower small or a hole with a vertical cross section.
  • the lower section It is a cylindrical hole or a tapered hole with a large upper and lower or a hole with a vertical cross-section.
  • the material of the needle template and/or substrate template is polytetrafluoroethylene or polyoxymethylene or polyether polyketone or polyimide or aluminum or copper or stainless steel.
  • the microneedle of the thermoplastic material of the present invention has the following advantages: First, it is safe and does not cause skin irritation. Second, the processing precision of the template micropores is very high, and the prepared microneedles have almost no burrs. The microneedle needles after cooling and forming have suitable hardness and flexibility, which are enough to open the skin and have few or no foreign objects. sense.
  • thermoplastic materials all have a certain degree of water swelling, and the flexibility after swelling has increased, so the skin feels better after being inserted into the skin to contact body fluids; third, it is insoluble or the water solubility is very small or encounters After water can still maintain sufficient adhesion, after the administration can be easily pulled out, rather than dissolving in the skin.
  • thermoplastic raw material with fluidity after heating is injected into the substrate hole of the substrate template, and the raw material enters the micro hole on the needle template downward.
  • the microneedle raw material with fluidity will be injected into the micropores, and the pressure mechanism can be used to pressurize the microneedle raw material with fluidity, which can better squeeze the air out of the micropores and make the microneedle raw material with fluidity. Quickly inject into the micropore.
  • the raw material of the microneedle of the invention is a thermoplastic material.
  • the thermoplastic material has good fluidity or flexibility after heating, and can be conveniently cooled and solidified into a specific geometry under the restriction of the template. At this point, the ultra-fine and precise size requirements that the microneedles must have are converted to the ultra-fine and precise size requirements for the template, and the requirements for smoothness and no burrs are converted to the same requirements for the template.
  • thermoplastic material microneedles according to the present invention are blank microneedles that have not been loaded with drugs or other biologically active substances. When used, the microneedles can be loaded with related drugs or biologically active substances on the needle site. These drugs and/or biologically active substances Including proteins, peptides, water-soluble or fat-soluble small molecule substances, and then form various drug-loading microneedles.
  • the substrate hole has a boss or a round table hole.
  • the substrate template and the needle template are provided separately, after the raw material is formed, when the substrate template and the needle template are separated, the microneedle substrate Left in the hole of the substrate, the needles of the microneedles are released from the needle template, thereby making it easier to demold the microneedles.
  • the micropores have an upper size and a smaller size
  • the prepared microneedles are also a structure with a larger size and a lower size, which facilitates the insertion of the microneedles into the skin and facilitates transdermal administration.
  • the micropores have a two-stage structure
  • the prepared microneedles are also a two-stage structure.
  • medicine can be loaded on the lower stage of the microneedles.
  • the prepared microneedle also has a stepped surface between the upper and lower ends.
  • the stepped surface makes it easier for the microneedle to carry medicine.
  • the material of the substrate template and/or needle template may be organic materials such as polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, and metal materials such as aluminum, copper, stainless steel, etc.
  • the cold solid surface of the material has a low affinity and can be easily demolded. Moreover, these materials can withstand temperatures above 200 degrees Celsius, so the template of the present invention can be used repeatedly.
  • the thermoplastic material can be flexibly selected according to actual needs.
  • a mixture of one, two or more materials can be used to achieve the most suitable purpose.
  • FIG. 1 is a schematic structural diagram of a metal microneedle in the prior art.
  • Embodiment 1 of the microneedle for administration of the present invention is a schematic structural view of Embodiment 1 of the microneedle for administration of the present invention
  • Example 3 is a schematic structural view of Example 2 of the present invention for administering microneedles
  • Embodiment 4 is a schematic structural view of Embodiment 1 of a microneedle special production template of the present invention.
  • FIG. 5 is a cross-sectional view of FIG. 4;
  • FIG. 6 is a schematic diagram of the first micropore on the template of the present invention.
  • FIG. 7 is a schematic diagram of a second type of micropores on the template of the present invention.
  • FIG. 8 is a schematic diagram of the third micropore on the template of the present invention.
  • FIG. 9 is a schematic diagram of the fourth micropore on the template of the present invention.
  • FIG. 10 is a schematic diagram of the fifth micropore on the template of the present invention.
  • FIG. 11 is a schematic diagram of the sixth micropore on the template of the present invention.
  • FIG. 12 is a schematic diagram of the seventh micropore on the template of the present invention.
  • FIG. 13 is a schematic diagram of the eighth micropore on the template of the present invention.
  • FIG. 14 is a schematic diagram of the ninth micropore on the template of the present invention.
  • Embodiment 15 is a schematic structural view of Embodiment 2 of the microneedle production template of the present invention.
  • Embodiment 3 of the microneedle production template of the present invention is a schematic structural view of Embodiment 3 of the microneedle production template of the present invention.
  • 17 is a type I diabetes model pig fasting insulin microneedle and fasting without drug administration (blank control) blood glucose experimental data;
  • Fig. 18 is blood glucose experiment data of type II diabetes model pigs given exenatide microneedles after eating, given exenatide injection after eating (positive control) and not given after eating (blank control).
  • the structure of the first embodiment of the administration microneedle of the present invention is shown in FIG. 2.
  • the administration microneedle of this embodiment includes a substrate 31 and a needle 32 fixed on the bottom of the substrate.
  • the substrate 31 and the needle 32 are integrated Casted together, the base plate 31 and the needles 32 are made of thermoplastic material, and the needles 32 have a structure of large size and small size.
  • thermoplastic material is polyethylene, polyvinyl chloride, polystyrene, polypropylene, polymethyl methacrylate, copovidone, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl succinate acetate , Polyethylene vinyl acetate, polyvinyl acetate, ethylene copolymers of one or more than two blends or copolymers or block copolymers.
  • the microneedle needles adopt a tapered structure.
  • FIG. 3 The structure of the embodiment 2 of the administration microneedle of the present invention is shown in FIG. 3, which is different from the embodiment 1 of the administration microneedle.
  • the microneedle needle 32 adopts an upper and lower two-stage structure, and the upper stage is the upper
  • the large and small tapered, lower section is a cylindrical structure, with a stepped surface between the upper and lower sections.
  • the needles of the microneedles may be tapered or ellipsoidal or spherical; the needles of the microneedles may also be a two-stage structure with a maximum diameter at the lower section No more than the diameter of the smallest part of the upper section, the upper section is cylindrical or conical or ellipsoidal or spherical structure with large upper and lower small, the lower section is cylindrical or conical hole with small upper and lower or ellipsoidal or spherical structure .
  • the diameter at the maximum of the lower section is smaller than the diameter at the minimum of the upper section, there is a stepped surface between the upper and lower sections of the needle.
  • the other shapes and structures of the microneedle needles can be the same as the micropore shapes in the microneedle production template of the present invention, so the drawings are omitted.
  • the material of the microneedle of the invention is a thermoplastic material, which has the characteristics of fluidity when heated by the thermoplastic material, is poured into the template, and the thermoplastic material can be injected at the same time, and the microneedle is obtained after the thermoplastic material is cooled, solidified and demolded.
  • Thermoplastic material has good fluidity or flexibility after heating, and can be easily solidified into a specific geometry under the constraints of the template. Therefore, the ultra-fine and precise size requirements that the microneedles must have are converted to the ultra-fine and precise size requirements for the needle template, and the requirements for smoothness and no burrs are converted to the same requirements for the needle template.
  • the microneedle of thermoplastic material of the present invention has the following advantages: First, it is safe and does not cause skin irritation.
  • Thermoplastic materials belong to two different categories in terms of biosafety classification.
  • the first category is polyethylene, polyvinyl chloride, polystyrene and polypropylene approved as medicine and food packaging materials and containers and used as disposable injection syringes.
  • Polyoxymethylene, the other type are approved oral drugs, medicinal accessories for injections, and body fluid adsorption and purification materials in hemodialysis;
  • the second is that the microneedle needles after cooling and forming have suitable hardness and flexibility, both Enough to stretch the skin and have little or no foreign body sensation.
  • thermoplastic materials all have a certain degree of water swelling, and the flexibility after swelling has increased, so the skin feels better after being inserted into the skin to contact body fluids; third, it is insoluble or the water solubility is very small or encounters After water can still maintain sufficient adhesion, after the administration can be easily pulled out, rather than dissolving in the skin.
  • the material of the prior art microneedles cannot have these advantages at the same time.
  • thermoplastic materials can be flexibly selected according to actual needs. By using the difference between hardness and brittleness of different materials and surface properties, the most suitable purpose can be achieved through the mixed use of one, two or more materials.
  • the density of the microneedle needles can be flexibly selected and manufactured according to actual needs, and preferably 1 to 600 roots/cm 2 .
  • the whole process of making the microneedle of the present invention is in accordance with the design arrangement of "Opto-Mechatronics" and is debugged and verified on the scale of the laboratory.
  • the most time-consuming process module is hot-press injection, which can complete a hot-press injection process containing 250 clusters of microporous area (250 pieces) templates every 3 minutes, and each piece of time is only measured in "seconds". As long as it is matched with the already mature heating and cooling process space, the microneedle hot press injection process unit can be easily and simply increased, and thus the volume can be expanded.
  • the raw material cost of the administration microneedle of the present invention is only about 2 cents, and the labor and energy consumption formed by the time-consuming production of each tablet is only a few cents.
  • the main cost component is the cost of the template.
  • Each piece of material containing 250 clusters of microporous area (250 pieces) template and self-made cost is 240 yuan to 800 yuan, and the template can be reused more than 200 times, no damage is seen, and the cost of each microneedle is shared It can be ignored.
  • Fig. 17 is blood glucose experiment data of fasting insulin microneedles and fasting without emptying (blank control) in pigs of type I diabetes model.
  • the administration microneedles shown in FIG. 3 are used.
  • Fig. 18 is blood glucose experiment data of type II diabetes model pigs given exenatide microneedles after eating, given exenatide injection after eating (positive control) and not given after eating (blank control).
  • exenatide microneedle the administration microneedle shown in FIG. 3 was used.
  • Embodiment 1 of the special production template for administration of microneedles of the present invention includes needles corresponding to the needles of the microneedles and the substrate, respectively A needle template 1 and a substrate template 2 located above the needle template.
  • the needle template 1 is provided with a micropore area 11, and a micropore area 11 has a plurality of micropores.
  • the micropores are open at the bottom.
  • the shape and size of the holes and microholes are the same as the shape and size of the microneedles to be produced.
  • the substrate template 2 is provided with a substrate hole 21 at a position above the corresponding micropore area 11.
  • the number of the micropore regions 11 is equal, 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 the needle template 1 and the substrate template 2 of this embodiment are integrally connected.
  • the thermoplastic microneedle raw material with fluidity is injected into the substrate hole 21, part of the raw material is injected into the micropores of the micropore area 11 to form microneedle needles, and the other part is located in the substrate hole 21 to form the microneedle substrate, which is fast and convenient
  • the preparation of integrated microneedles Since the micropores on the needle template in this embodiment are through holes, there is no need to operate in a vacuum environment, and the microneedle raw materials with fluidity will naturally be injected into the micropores.
  • the needle material is pressurized, which can better squeeze the air out of the micropore, so that the fluid microneedle material is quickly injected into the micropore.
  • the micro-holes on the needle template can adopt the tapered holes with the largest size and the small size as shown in Figure 6.
  • the angle of the tapered surface of the tapered hole is 0° to 90°, and the diameter at the bottom of the tapered hole is less than 1mm.
  • the thickness of the needle template is less than 20mm.
  • the micro-holes on the needle template can also adopt a semi-ellipsoidal hole as shown in FIG. 7, with the vertical section of the semi-ellipsoidal hole being an elliptical arc, and the bottom of the semi-ellipsoidal hole has a diameter less than 1 mm Open, the thickness of the needle template is less than 20mm.
  • the micro-holes in the needle template can also adopt the upper and lower hemispherical holes as shown in FIG. 8.
  • the vertical cross-section of the hemispherical hole is arc-shaped, and the bottom of the hemispherical hole has an opening with a diameter of less than 1 mm.
  • the thickness of the template is less than 20mm.
  • the micro hole can also adopt a two-stage structure.
  • the diameter of the largest part of the lower part is not greater than the diameter of the smallest part of the upper part.
  • the upper part is a cylindrical hole or a tapered hole with a large upper and lower small or a hole with a vertical cross section.
  • the lower part It is a cylindrical hole or a tapered hole with a large upper and lower or a hole with a vertical cross-section.
  • the upper and lower sections of the microhole are tapered, and there is a stepped surface between the upper and lower sections; as shown in Figure 10, the upper section of the microhole is a cylindrical hole, and the lower section is the upper half and the lower half Ellipsoidal hole; as shown in Figure 11, the upper part of the microhole is a cylindrical hole, and the lower part is a tapered hole with a large upper and lower small; as shown in Figure 12, the upper part of the microhole is a tapered hole with a large upper and lower small, and the lower part is Cylindrical hole; as shown in Figure 13, the upper part of the microhole is a tapered hole with a larger upper and lower small, and the lower part is a semi-ellipsoidal hole with an upper large and lower small; as shown in Figure 14, the upper part of the microhole is upper large and small
  • the semi-ellipsoidal hole, the lower section is a tapered hole with a large top and a small bottom.
  • micropores have a structure that is large in size and small in size, and the prepared microneedles are also in a structure of large size and small size, which facilitates the insertion of the microneedles into the skin and facilitates transdermal administration.
  • the micropores can also adopt other structures.
  • the material of the needle template and the substrate template may be the same or different.
  • the material of the needle template and the substrate template can be organic materials such as polytetrafluoroethylene, polyoxymethylene, polyether polyketone, polyimide, or metal materials such as aluminum or copper or stainless steel.
  • the templates of these materials have a low affinity with the cold solid surface of the thermoplastic material of the present invention, and can be easily demolded. These materials can withstand temperatures above 200 degrees Celsius, so the template can be used repeatedly.
  • the needle template made of these materials has a uniform distribution of micropores, a smooth surface, and no burrs. The smallest pore size of the micropores can reach 0.1mm.
  • Example 2 of the special production template for administering microneedles of the present invention is shown in FIG. 15.
  • the substrate template and the needle template in this example are separately provided.
  • the substrate hole 21 is a cylindrical hole.
  • a boss 22 is provided inside the substrate hole 21.
  • FIG. 16 The structure of the embodiment 3 of the special production template for the administration of microneedles of the present invention is shown in FIG. 16, which is different from the embodiment 2 in that the substrate hole 21 on the substrate template 2 in this embodiment has a circular truncated cone shape with an upper size and a smaller size.
  • the hole and the round table hole can also be used when the substrate template 2 and the needle template 1 are separated, the substrate of the microneedle is left in the substrate hole, and the needle of the microneedle is released from the needle template.
  • micropore shape structure in Examples 2 and 3 of the production template for administration of microneedles is the same as in Example 1, and is not repeated here.
  • the key technology in the production of the needle template and/or substrate template is the production of high-density, precise-size micro-shaped holes, and the shape of the micro-shaped holes obtained is a relatively complex geometric shape.
  • the production of such micro-orifice plates of technical indicators has not been reported in the literature, nor has the micro-orifice plates of such technical indicators been commercially available.
  • 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 down to press the raw material of the microneedle.
  • 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 down to press the raw material of the microneedle.
  • the number of microporous areas is flexibly selected according to actual needs.

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Abstract

一种给药微针（3）及给药微针（3）的专用生产模板，给药微针（3）包括基板（31）和固定在基板（31）底部的针状物（32），基板（31）和针状物（32）一体浇注成形在一起，基板（31）和针状物（32）由热塑性材料制成，针状物（32）为上大下小的结构。给药微针（3）的专用生产模板包括分别与微针（3）的针状物（32）和基板（31）对应的针状物模板（1）和位于针状物模板（1）上方的基板模板（2），针状物模板（1）上设有微孔区（11），一个微孔区（11）内有若干个微孔，微孔为底部开口的通孔，微孔的形状和尺寸与待生产的微针（3）的针状物（32）的形状和尺寸相同，基板模板（2）上位于对应微孔区（11）上方的位置开设有基板孔（21），基板孔（21）的形状和尺寸与待生产的微针（3）的基板（31）的形状尺寸相同，针状物模板（1）和基板模板（2）一体连接设置或单独分开设置。

Description

一种给药微针及给药微针的专用生产模板 技术领域
本发明涉及一种给药微针及给药微针的专用生产模板，属于医疗设备技术领域。
背景技术
蛋白、多肽类药物口服会经过肠胃而被降解失效，故只能注射给药。注射给药其实就是在针头的帮助下，药物通过皮肤这一生物屏障的方式，然而徒增了痛苦，长期频繁注射尤甚。该类药物的非注射给药是由来已久的夙愿，例如从1921年就开始研究胰岛素非注射给药以避免长期的频繁注射。曾出现过很多非注射给药方式，其中最著名案例有二，第一是辉瑞公司的吸入剂，耗时14年，耗资28亿美金，上市两年后，因进入体内剂量的极度不准确而退市；第二是葛兰素公司耗长时耗巨资的口服胰岛素也宣告终止。因此，蛋白、多肽类亲水性药物如何通过生物膜屏障而输入体内的任务十分艰巨。
微针透皮给药作为一种新型透皮给药方式，其集皮下注射给药方式和透皮贴给药的优点于一体，不仅无痛微创，而且药物吸收效率高。微针透皮给药是将一根大针分解成一组短且细小的微型针头将药物递送到皮下浅层，而不触及深层的神经血管，不出血不痛苦，是非注射给药的研究领域之一。随着蛋白多肽药物种类和用量的快速增长，微针透皮给药研究逐渐成为递送蛋白多肽药物的关注点。此外，微针给药时患者可自行给药，方便安全。因此，微针透皮给药技术从开始出现就获得了广泛的关注。给药微针的基本结构形态是：在合适厚度、合适形状(比如但不限于圆形、方形等)的板状基材上(比如但不限于平板、弧形板等)，竖立着一组数量不等的微型针状物。微针的基本使用过程和原理为：在合适压力的作用下，利用微针撑开皮肤通道，帮助药物等生物活性物质穿过皮肤，实现全身或皮肤局部药物等生物活性物质分布，达到治疗或其他有益的效果，具有十分积极的意义。
微针透皮给药如能在药效学上达成与注射给药等效，则微针的需求量将十分巨大。单就中国I型糖尿病的1300万患者而言，胰岛素微针片的每天的产量需达4000万片，每分钟需达4.17万片。透皮微针给药研究虽已有所进展，但产品上市仍未可期。透皮微针研发的关键点在于：(1)微针基材选择、基于该基材的超微细精密制作技术；(2)基材、人体皮肤和所载药物三者之间的相容性；(3)巨量工业化生产的可能性和成本低廉的可行性。
现有技术的微针有金属实心微针、金属空心微针、非金属材料实心微针(如无机硅材料)、有机大分子材料微针(如聚维酮)等，但是，现有的这些微针制品及其制作方法，都存有量产制备方面的困难，致使此类技术与制品至今未见工业量产规模的案例出现，且因其量产能力的局限，导致制作成本也较高。下面是几种微针材质的选择和基于该基材的 超微细精密制作技术的比较：
金属微针的制作涉及精密机械加工或精密电镀成膜的复杂工艺过程，难以低成本规模化量产。金属实心微针的制作，需要将金属块加工成在3-4CM 2(略大于5角硬币)的面积上竖立着200根高1mm、最小值经0.15mm的超微细针状物的微针。金属空心微针的制作，需要在模型上逐层电镀上金属，然后脱模。这样的制作涉及超细微精密机械加工或电镀成膜的复杂工艺过程，且金属材质的微针因其刚性和加工毛刺的存在，皮肤对金属微针的异物感相当明显。
无机硅材料的熔融温度太高，难以找到合适的耐高温模具，进行热注工艺的微针制作；冷却状态下的无机硅材料硬度高、脆性大，切削、打磨或光刻的加工过程效率较低。无机硅材料微针因其刚性亦有明显异物感，特别是极易脆碎，导致较大概率的出现针尖部分断碎在皮肤浅层内，衍生出其它的不便。
聚维酮(PVP)浓溶液经模具浇注成微针，干燥成型后的PVP材质的微针，因为强度不足，其脱模过程较为困难。聚维酮微针制备过程中使用的模具是带有微孔的模板，由于微孔是沉孔的形式，且由于微孔孔径很小，为了防止浇注聚维酮溶液时，聚维酮溶液受微孔中空气的阻碍无法沉入到微孔底部，在微针制作过程，需要将整个设备放置在密闭容器中，将密闭容器抽真空，这样就导致制作过程就十分麻烦，制作成本就会加大。聚维酮微针的特点是，聚维酮极易吸湿软化或溶解。如在体外吸湿，则针状物软化难以插入皮内，为此，这就要求聚维酮微针制作干燥、包装隔湿、开包后要快速施用，这都给聚维酮微针的推广增加了难度；更为不便的是，微针插入皮内后，聚维酮立即吸取体液溶解释药，最后，插入部分会溶断在皮内，由于聚维酮体内降解速度相对较慢，患者会有三天左右的残留不适。
已有文献报道，金属材料微针和硅材料微针的药物的担载量极其有限的，然而加大微针尺寸与微针数量借以增加载药量的思路则受到许多因素的限制而难以实现。同时，金属材料、硅材料和聚维酮与药物长期接触的稳定性试验结果未见报道。
假设在微针上担载药物的工艺条件变异不大且耗时较少，则影响微针产量的关键方面就是微针本体的制作耗时。
金属实心微针有两种制作方式，一是片状针体微针的制作，其制作方式是，在不锈钢薄片上冲压出底边仍与薄片连接而其它两边与薄板脱离的三角形，并在冲压完成的同时，将三角形呈90度立起，形成微针列阵，这种结构的微针如图1所示，这种微针制作相对简单，但微针密度过于稀疏，载药量也就过于有限；二是柱状针体微针的制作，锥形柱状针体的最小直径处仅为0.15mm左右，必须以极其微小的进刀量进行切削，才能维持如此 细小的柱体不被冲击崩离。因此，每片的制作耗时以分钟至几十分钟计。而金属空心微针需要在模具上进行分层电镀的方法进行制作，非常耗时。硅材料微针的制作方式与制作过程类似于金属实心微针的制作相类似。聚维酮微针，因针体强度不足，脱模较为困难，目前仍是凭手感用力的手工操作。
金属实心微针、金属空心微针、硅材料微针的原料成本仅为几分钱，其成本的最主要构成部分是制作工艺耗时而产生的劳务与能源消耗以及巨大的机械切削能力的投资摊消，该部分费用构成应在“十几元至几十元/片”的水平之上。
发明内容
本发明的目的在于提供一种给药微针和该给药微针的专用生产模板，以解决现有技术的微针制作过程麻烦、制作成本高的技术问题。
本发明的给药微针采用如下技术方案：一种给药微针，其包括基板和固定在基板底部的针状物，所述基板和针状物一体浇注成形在一起，所述基板和针状物由热塑性材料制成，所述针状物为上大下小的结构。
所述针状物为锥形或椭球形或球形结构。
所述针状物为上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆柱形或者是上大下小的锥形或者是椭球形或球形结构，下段是圆柱形或者是上大下小的锥形或者是椭球形或球形结构。
所述针状物的上下两段之间具有台阶面。
所述热塑性材料为聚乙烯、聚氯乙烯、聚苯乙烯、聚丙烯、聚甲基丙烯酸甲酯、共聚维酮、乙基纤维素、羟丙基纤维素、醋酸羟丙基甲基琥珀酸酯、聚乙烯醋酸乙烯酯、聚乙酸乙烯酯、乙烯共聚物中的一种或两种以上的共混物或共聚物或嵌段共聚物。
本发明的给药微针的专用生产模板采用如下技术方案：一种给药微针的专用生产模板，其包括分别与微针的针状物和基板对应的针状物模板和位于针状物模板上方的基板模板，所述针状物模板上设有微孔区，一个微孔区内有若干个微孔，微孔为底部开口的通孔，微孔的形状和尺寸与待生产的微针针状物的形状和尺寸相同，所述基板模板上位于对应微孔区上方的位置开设有基板孔，基板孔的形状和尺寸与待生产的微针基板的形状尺寸相同，所述针状物模板和基板模板一体连接设置或单独分开设置；针状物模板和基板模板单独设置时，生产微针时，基板模板底面与针状物模板上表面在外力作用下压紧密封配合。
所述基板孔为内部设有凸台的圆柱形孔或者上大下小的圆台形孔。
所述微孔为底部开口的上大下小的锥形孔或半椭球孔或半球形孔。
所述微孔为上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆 柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔，下段是圆柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔。
所述微孔的上下两段之间具有台阶面。
所述针状物模板和/或基板模板的材质为聚四氟乙烯或聚甲醛或聚醚聚酮或聚亚酰胺或铝或铜或不锈钢。
本发明的有益效果是：本发明热塑性材质的微针具有以下优点：一是安全、不引起皮肤过敏。二是模板微孔的加工精度很高，所制得的微针几乎没有毛刺，冷却成形后的微针针状物具有合适的硬度和柔韧度，既足以撑开皮肤又较少有或没有异物感。另外，所述的热塑性材料均有一定的水液溶胀性，且溶胀后的柔韧度有所增加，故插入皮内接触体液后，皮感较好；三是不溶于或水溶度很小或遇水后仍能保持足够的粘接性，给药结束后可以方便地拉出，而不是溶断在皮内。本发明在使用时，将加热后具有流动性的热塑性原料注入基板模板的基板孔内，原料向下进入针状物模板上的微孔中，由于微孔为通孔，不需要在真空环境下操作，具有流动性的微针原料就会注入微孔内部，可以配合压力机构对流动性微针原料进行加压，能更好的把微孔中的空气挤走，使流动性的微针原料快速的注入微孔内部。本发明微针原材料为热塑性材料，热塑性材料在加热后具有很好的流动性或柔韧性，在模板的限制下可方便的冷却凝固成型为特定的几何体。至此，微针所必须具备的超细微精密尺寸要求就转换为对模板的超微细精密尺寸要求，对光洁和没有毛刺的要求就转换为对模板的同样要求。
本发明所述的热塑材料微针为尚未载入药物或其它生物活性物质的空白微针，使用时可在微针针头部位装载上相关药物或生物活性物质，这些药物和/或生物活性物质包括蛋白质、肽类、水溶性或脂溶性小分子物质，进而形成各个载药微针。
优选的，基板孔内具有凸台或者为圆台孔，在基板模板和针状物模板是分体单独设置的情况下，原料成型后，将基板模板和针状物模板分离时，微针的基板留在基板孔中，微针的针状物从针状物模板中脱出，从而使微针的脱模更加方便。
优选的，微孔为上大下小的结构，制备出的微针也是上大下小的结构，便于微针插入到皮肤内，有利于透皮给药。
优选的，微孔为两段式结构，制备出的微针也是两段式结构，使用时可以在微针下段上载药。
优选的，微孔的上下两段之间具有台阶面，制备出的微针上下两端之间也具有台阶面，台阶面使微针载药更加容易。
优选的，基板模板和/或针状物模板材质可以是聚四氟乙烯、聚甲醛、聚醚聚酮、聚亚 酰胺等有机材料以及铝、铜、不锈钢等金属材料，这些材质的模板与热塑性材料的冷固态表面亲和力较小，可以方便地脱模。而且这些材料可耐受摄氏200度以上的温度，故本发明的模板可反复多次使用。
优选的，热塑性材料可以根据实际需要灵活选用，利用不同材料硬度脆度上和表面性质上的区别，通过一种、两种或两种以上材料的混合使用，达成最合适的目的用途。
附图说明
图1是现有技术的一种金属微针的结构示意图。
图2是本发明给药微针的实施例1的结构示意图；
图3是本发明给药微针的实施例2的结构示意图；
图4本发明微针专用生产模板的实施例1的结构示意图；
图5是图4的剖视图；
图6是本发明模板上第一种微孔的示意图；
图7是本发明模板上第二种微孔的示意图；
图8是本发明模板上第三种微孔的示意图；
图9是本发明模板上第四种微孔的示意图；
图10是本发明模板上第五种微孔的示意图；
图11是本发明模板上第六种微孔的示意图；
图12是本发明模板上第七种微孔的示意图；
图13是本发明模板上第八种微孔的示意图；
图14是本发明模板上第九种微孔的示意图；
图15是本发明微针生产模板的实施例2的结构示意图；
图16是本发明微针生产模板的实施例3的结构示意图；
图17是I型糖尿病模型猪空腹给胰岛素微针和空腹不给药(空白对照)的血糖实验数据；
图18是II型糖尿病模型猪进食后给艾塞纳肽微针、进食后给艾塞纳肽注射液(阳性对照)和进食后不给药(空白对照)的血糖实验数据。
图中：1-针状物模板，11-微孔区，2-基板模板，21-基板孔，22-凸台，3-微针，31-基板，32-针状物。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。
本发明给药微针的实施例1的结构如图2所示，本实施例的给药微针包括基板31和 固定在基板底部的针状物32，所述基板31和针状物32一体浇注成形在一起，所述基板31和针状物32由热塑性材料制成，所述针状物32为上大下小的结构。所述热塑性材料是聚乙烯、聚氯乙烯、聚苯乙烯、聚丙烯、聚甲基丙烯酸甲酯、共聚维酮、乙基纤维素、羟丙基纤维素、醋酸羟丙基甲基琥珀酸酯、聚乙烯醋酸乙烯酯、聚乙酸乙烯酯、乙烯共聚物中的一种或两种以上的共混物或共聚物或嵌段共聚物。本实施例中，如图2所示，微针针状物采用锥形结构。
本发明给药微针的实施例2的结构如图3所示，与给药微针实施例1不同的是，本实施例中微针针状物32采用上下两段式结构，上段是上大下小的锥形、下段是圆柱形结构，上下两段之间具有台阶面。
在本发明给药微针其它的实施例中，微针的针状物可以是锥形或椭球形或球形结构；微针的针状物还可以是上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆柱形或者是上大下小的锥形或者是椭球形或球形结构，下段是圆柱形或者是上大下小的锥形孔或者是椭球形或球形结构。当下段最大处的直径小于上段最小处的直径，针状物的上下两段之间具有台阶面。微针针状物的其它形状结构可以与本发明微针生产模板中的微孔形状相同，故省略附图。
本发明微针的材质为热塑性材料，利用热塑性材料加热后具有流动性的特点，向模板内浇注，同时可以对热塑性材料进行压注，热塑性材料冷却固化脱模后，得到微针。热塑性材料在加热后具有很好的流动性或柔韧性，在模板的限制下可方便的凝固成型为特定的几何体。因此，微针所必须具备的超细微精密尺寸要求就转换为对针状物模板的超微细精密尺寸要求，对光洁和没有毛刺的要求就转换为对针状物模板的同样要求。
本发明热塑性材质的微针具有以下优点：一是安全、不引起皮肤过敏。热塑性材料在生物安全性分类上属于不同的两类，一类是获批可作为药物和食物包材和容器的聚乙烯、聚氯乙烯、聚苯乙烯和聚丙烯以及作为一次性注射针筒的聚甲醛，另一类都是获批的口服药、注射药的药用辅料和血液透析中的体液吸附净化材料；二是冷却成形后的微针针状物具有合适的硬度和柔韧度，既足以撑开皮肤又较少有或没有异物感。另外，所述的热塑性材料均有一定的水液溶胀性，且溶胀后的柔韧度有所增加，故插入皮内接触体液后，皮感较好；三是不溶于或水溶度很小或遇水后仍能保持足够的粘接性，给药结束后可以方便地拉出，而不是溶断在皮内。然而，现有技术的微针的材质则不能同时具备这些优点。
具体生产时，热塑性材料可以根据实际需要灵活选用，利用不同材料硬度脆度上和表面性质上的区别，通过一种、两种或两种以上材料的混合使用，达成最合适的目的用途。微针针状物的密度可以根据实际需要，灵活选用和制作，优选的可以是1～600根/cm 2。
本发明微针的制作全过程均按“光机电一体化”的设计安排并在试验室规模上加以调试验证。最为耗时的工艺模块是热压注，每3分钟可完成一块包含250簇微孔区(250片)模板的热压注工艺，每片耗时仅以“秒”计。只要与已经十分成熟的加热和冷却的工艺空间相配套，微针热压注工艺单元可方便地实现简单增加，进而可以实现放量扩产。
本发明所述给药微针的原料成本仅为2分钱左右，每片的制作耗时所形成的劳务与能源耗费也仅为几分钱，其最主要的成本构成部分为模板的费用，每块包含250簇微孔区(250片)模板的材料与自行制作费用为240元至800元，且模板可重复使用200次以上，未见损伤，均摊在每片给药微针上的费用可忽略不计。
图17是I型糖尿病模型猪空腹给胰岛素微针和空腹不给药(空白对照)的血糖实验数据。胰岛素微针采用图3所示的给药微针。
图18是II型糖尿病模型猪进食后给艾塞纳肽微针、进食后给艾塞纳肽注射液(阳性对照)和进食后不给药(空白对照)的血糖实验数据。艾塞纳肽微针采用图3所示的给药微针。
通过图17和图18，可以观察到给药微针使血糖下降比较稳定，证明给药微针的药力是透皮逐渐释放的，具有缓释药物的作用。
另外，初步试验制作的猪胰岛素微针和艾塞纳肽微针的药物加速稳定性实验的30天数据表明，未见所担载药物的异常。
本发明给药微针的专用生产模板的实施例1的结构如图4至图5所示，本实施例给药微针的专用生产模板包括分别与微针的针状物和基板对应的针状物模板1和位于针状物模板上方的基板模板2，所述针状物模板1上设有微孔区11，一个微孔区11内有若干个微孔，微孔为底部开口的通孔，微孔的形状和尺寸与待生产的微针针状物的形状和尺寸相同，所述基板模板2上位于对应微孔区11上方的位置开设有基板孔21，基板孔21的数量与微孔区11的数量相等，基板孔21的形状和尺寸与待生产的微针基板的形状尺寸相同，本实施例的针状物模板1和基板模板2是一体连接设置的。
使用时将具有流动性的热塑性微针原料注入基板孔21内，原料一部分注入微孔区11的微孔内部形成微针针状物，另一部分位于基板孔21内形成微针基板，从而快速方便的制备出一体成型的微针。由于本实施例针状物模板上的微孔为通孔，不需要在真空环境下操作，具有流动性的微针原料就会自然注入微孔内部，具体使用时可以配合压力机构对流动性微针原料进行加压，能更好的把微孔中的空气挤走，使流动性的微针原料快速的注入微孔内部。
针状物模板上的微孔可以采用如图6所示的上大下小的锥形孔，锥形孔锥面的角度为 0°到90°，锥形孔底部最小处的直径小于1mm，针状物模板的厚度小于20mm。
针状物模板上的微孔还可以采用如图7所示的上大下小的半椭球形孔，该半椭球形孔的竖截面为椭圆弧形，半椭球形孔底部具有直径小于1mm的开口，针状物模板的厚度小于20mm。
针状物模板上的微孔还可以采用如图8所示的上大下小的半球形孔，该半球形孔的竖截面为圆弧形，半球形孔底部具有直径小于1mm的开口，针状物模板的厚度小于20mm。
微孔还可以采用上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔，下段是圆柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔。例如，如图9所示，微孔上下两段均为锥形孔，且上下段之间具有台阶面；如图10所示，微孔上段为圆柱形孔，下段为上大下小的半椭球形孔；如图11所示，微孔上段为圆柱形孔，下段为上大下小的锥形孔；如图12所示，微孔上段为上大下小的锥形孔，下段为圆柱形孔；如图13所示，微孔上段为上大下小的锥形孔，下段为上大下小的半椭球形孔；如图14所示，微孔上段为上大下小的半椭球形孔，下段为上大下小的锥形孔。当下段最大处的直径小于上段最小处的直径。
微孔为上大下小的结构，制备出的微针也是上大下小的结构，便于微针插入到皮肤内，有利于透皮给药。当然，微孔还可以采用其它的结构。
本发明中针状物模板和基板模板的材质可以相同也可以不同。针状物模板和基板模板的材质可以是聚四氟乙烯、聚甲醛、聚醚聚酮、聚亚酰胺等有机材料，还可以是铝或铜或不锈钢等金属材料。这些材质的模板与本发明所述热塑性材料的冷固态表面亲和力较小，可以方便地脱模。这些材料可耐受摄氏200度以上的温度，故模板可反复使用。这些材料制成的针状物模板，微孔分布均匀、表面光滑、没有毛刺，微孔最小的孔径可达0.1mm。
本发明给药微针的专用生产模板的实施例2的结构如图15所示，与实施例1不同的是，本实施例中的基板模板和针状物模板是单独分开设置的，在微针生产时，基板模板2底面与针状物模板2上表面在外力作用下压紧密封配合。本实施例中基板孔21为圆柱形孔，为了便于脱模，在基板孔21内部设置凸台22。当模板中的微针原料成型后，将基板模板2和针状物模板1分离时，微针的基板留在基板孔中，微针的针状物从针状物模板中脱出，从而使微针的脱模更加方便。
本发明给药微针的专用生产模板的实施例3的结构如图16所示，与实施例2不同的是，本实施例中基板模板2上的基板孔21为上大下小的圆台形孔，圆台孔也能在基板模板2和针状物模板1分离时，微针的基板留在基板孔中，微针的针状物从针状物模板中脱出。
给药微针的生产模板的实施例2和3中的微孔形状结构和实施例1中相同，此处不再赘述。
本发明中，针状物模板和/或基板模板的制作中的关键技术为高密度、精密尺寸微形孔的制孔，且所制得的微形孔的形状为较为复杂几何形态。这样技术指标的微形孔板的制作未见文献报道，这样技术指标的微形孔板也未见商品市售。
在本发明的其它实施例中，压紧机构还可以液压缸、气压缸或电机等驱动装置，只要是能带动压紧头向下移动压紧微针原料即可。微孔区的数量是根据实际需要灵活选择的。
上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (11)

  1. 一种给药微针，其包括基板(31)和固定在基板(31)底部的针状物(32)，其特征在于：所述基板(31)和针状物(32)一体浇注成形在一起，所述基板(31)和针状物(32)由热塑性材料制成，所述针状物(32)为上大下小的结构。
  2. 根据权利要求1所述的给药微针，其特征在于：所述针状物(32)为锥形或椭球形或球形结构。
  3. 根据权利要求1所述的给药微针，其特征在于：所述针状物(32)为上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆柱形或者是上大下小的锥形或者是椭球形或球形结构，下段是圆柱形或者是上大下小的锥形或者是椭球形或球形结构。
  4. 根据权利要求3所述的给药微针，其特征在于：所述针状物(32)的上下两段之间具有台阶面。
  5. 根据权利要求1至4任意一项所述的给药微针，其特征在于：所述热塑性材料为聚乙烯、聚氯乙烯、聚苯乙烯、聚丙烯、聚甲基丙烯酸甲酯、共聚维酮、乙基纤维素、羟丙基纤维素、醋酸羟丙基甲基琥珀酸酯、聚乙烯醋酸乙烯酯、聚乙酸乙烯酯、乙烯共聚物中的一种或两种及两种以上的共混物或共聚物或嵌段共聚物。
  6. 一种给药微针的专用生产模板，其特征在于：其包括分别与微针的针状物和基板对应的针状物模板(1)和位于针状物模板上方的基板模板(2)，所述针状物模板(1)上设有微孔区(11)，一个微孔区(11)内有若干个微孔，微孔为底部开口的通孔，微孔的形状和尺寸与待生产的微针针状物的形状和尺寸相同，所述基板模板(2)上位于对应微孔区(11)上方的位置开设有基板孔(21)，基板孔(21)的形状和尺寸与待生产的微针基板的形状尺寸相同，所述针状物模板(1)和基板模板(2)一体连接设置或单独分开设置；针状物模板(1)和基板模板(2)单独设置时，生产微针时，基板模板(2)底面与针状物模板(1)上表面在外力作用下压紧密封配合。
  7. 根据权利要求6所述的给药微针的专用生产模板，其特征在于：所述基板孔(21)为内部设有凸台(22)的圆柱形孔或者上大下小的圆台形孔。
  8. 根据权利要求6或7所述的给药微针的专用生产模板，其特征在于：所述微孔为底部开口的上大下小的锥形孔或半椭球孔或半球形孔。
  9. 根据权利要求6或7所述的给药微针的专用生产模板，其特征在于：所述微孔为上下两段式结构，下段最大处的直径不大于上段最小处的直径，上段是圆柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔，下段是圆柱形孔或者是上大下小的锥形孔或者是竖截面为弧形的孔。
  10. 根据权利要求9所述的给药微针的专用生产模板，其特征在于：所述微孔的上下两段之间具有台阶面。
  11. 根据权利要求6或7所述的给药微针的专用生产模板，其特征在于：所述针状物模板(1)和/或基板模板(2)的材质为聚四氟乙烯或聚甲醛或聚醚聚酮或聚亚酰胺或铝或铜或不锈钢。
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CN209500524U (zh) * 2018-12-11 2019-10-18 尹忠 一种给药微针及给药微针的专用生产模板

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