Preparation device and preparation method of drug delivery microneedle
By using the fluidity of thermoplastic raw materials and pumping and pressurization forming technology in the microneedle preparation device, the existing microneedle production problems are solved, and the industrial mass production of microneedle and safe and durable preparation is achieved.
Patent Information
- Application Number
- CN201811508775.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2018-12-11
- Publication Date
- 2024-12-17
- Estimated Expiration
- 2038-12-11
AI Technical Summary
The existing microneedle production process is complex, high cost and difficult to achieve industrial mass production, the metal microneedle processing is complex, the inorganic silicone materials are difficult to prepare at low cost, and the povidone microneedle release process is difficult.
The preparation device consisting of an upper plate, a template, an isolation layer and a pumping plate is adopted to make it flow by heating the thermoplastic raw materials, and the air in the template is used to extract the air in the template, so that the raw materials enter the through-hole template, and pressurize through the compression head. After forming, cool and release.
It realizes the simple and convenient preparation of microneedles and reduces production costs. Microneedles made of thermoplastic materials have safety, appropriate hardness, water insoluble and tough, and are easy to produce in industrial mass.
Smart Images
Figure CN111300708B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a device and a method for preparing 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 the drug 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: on a substrate (such as but not limited to a flat plate, curved plate, etc.) of suitable thickness and suitable shape (such as but not limited to round, square, etc.), a group of micro needles 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 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 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. Summary of the invention
[0007] The purpose of the present invention is to provide a device and method for preparing drug delivery microneedles, so as to solve the technical problems of the prior art that the microneedle production process is complicated, costly, and cannot be mass-produced.
[0008] The preparation device of the drug delivery microneedle of the present invention adopts the following technical scheme: the preparation device of the drug delivery microneedle comprises an upper plate, a template, an isolation layer and an exhaust plate which are arranged in sequence from top to bottom, the upper plate, the template, the isolation layer and the exhaust plate 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 stepped hole which is larger at the top and smaller at the bottom is opened at a position corresponding to the microporous area on the upper plate, the shape and size of the small section at the lower part of the stepped hole is the same as that of the microneedle substrate, a cavity is provided in the exhaust plate, an exhaust hole connected to the cavity is opened at a position corresponding to the microporous area on the exhaust plate, an exhaust pipe connected to the cavity is provided outside the exhaust plate, a clamping mechanism is provided above the upper plate, the clamping mechanism comprises a clamping head for inserting into the large section at the upper part of the stepped hole, the size of the clamping head is larger than the size of the small section at the lower part of the stepped hole.
[0009] The clamping mechanism comprises a clamping rod fixedly connected above a clamping head, the clamping head and the clamping rod are integrally connected, a spring is sleeved on the clamping rod, and a spring compression mechanism for compressing the spring is provided above the spring.
[0010] The spring compression mechanism includes a clamping plate, a through hole is provided on the clamping plate for the clamping rod to pass through, the spring is sleeved on the clamping rod at a position between the clamping plate and the clamping head, a clamping stud is installed in the clamping plate, and a clamping nut or a handwheel is spirally assembled on the clamping stud at a position above the clamping plate.
[0011] A positioning plate is also provided between the upper plate and the clamping plate. A positioning hole is provided on the positioning plate corresponding to the position of each stepped hole. The diameter of the positioning hole is equal to the diameter of the clamping head. The clamping head passes through the positioning hole and is inserted into the large section at the upper part of the stepped hole.
[0012] The spring compression mechanism includes a sleeve and a clamping cover threadedly connected to the upper end of the sleeve. An internal thread matching the thread of the lower end of the sleeve is provided in the large section at the upper part of the stepped hole. The lower end of the sleeve is threadedly connected to the large section at the upper part of the stepped hole. The clamping rod and the spring are used to be installed inside the sleeve. The clamping cover includes an annular wall and a top cover connected to the upper part of the annular wall. A hole for the clamping rod to pass through is provided on the top cover. The annular wall is spirally assembled on the upper end of the sleeve, and the top cover compresses the spring.
[0013] A soft heat-resistant gasket is also provided between the large section at the upper part of the stepped hole and the pressing head.
[0014] Positioning bolts are arranged between the upper plate and the air extraction plate.
[0015] The number of microporous areas on the template is at least two, and the number of stepped holes on the upper plate is equal to the number of microporous areas.
[0016] The first technical scheme of the preparation method of the drug delivery microneedle of the present invention is: the preparation method of the drug delivery microneedle comprises the following steps: (1) heating the thermoplastic raw material for preparing the microneedle to a fluid state; (2) placing the exhaust plate, the isolation layer, the template and the upper plate in order from bottom to top, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) placing the raw material heated in step (1) into the stepped holes of the upper plate; (4) The vacuum pipe evacuates the cavity of the vacuum plate, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template; (5) The raw material in the step hole is pressurized by a clamping head, so that the raw material is pressed downward in the step hole and enters the micropores in the microporous area of the template; (6) The fluid raw material in the step hole is cooled and cooled. After the raw material in the step hole and the micropores is cooled and cooled and becomes solid, the clamping head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing the demolding.
[0017] The second technical scheme of the preparation method of the drug delivery microneedle of the present invention is: the preparation method of the drug delivery microneedle comprises the following steps: (1) processing the thermoplastic raw material for preparing the microneedle into a powder raw material, and weighing the powder raw material equal to the weight of a single microneedle; (2) placing the exhaust plate, the isolation layer, the template and the upper plate in order from bottom to top, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) placing the powder raw material weighed in step (1) into the small section below the stepped holes of the upper plate; (4) ) until the powder raw material becomes a fluid state; (5) the cavity of the exhaust plate is evacuated through the exhaust pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template; (6) the raw material in the step hole is pressurized by a clamping head, so that the raw material is pressed downward in the step hole and enters the micropores in the microporous area of the template; (7) the fluid raw material in the step hole and the microporous area is cooled and cooled. After the raw material is cooled and cooled and becomes solid, the clamping head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing the demolding.
[0018] The third technical scheme of the preparation method of the drug delivery microneedle of the present invention is: the preparation method of the drug delivery microneedle comprises the following steps: (1) processing the thermoplastic raw material for preparing the microneedle into a solid raw material with the same weight as that of a single microneedle; (2) placing the exhaust plate, the isolation layer, the template and the upper plate in order from bottom to top, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) placing the solid raw material obtained in step (1) into the small section below the stepped holes of the upper plate; (4) The solid raw material is heated until it becomes a fluid state; (5) the cavity of the exhaust plate is evacuated through the exhaust pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template; (6) the raw material in the step hole is pressurized by a clamping head, so that the raw material is pressed downward in the step hole and enters the micropores in the microporous area of the template; (7) the fluid raw material in the step hole and the microporous area is cooled and cooled. After the raw material is cooled and becomes solid, the clamping head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing the demolding.
[0019] The steps of evacuating the cavity of the evacuation plate and pressurizing the raw material in the stepped hole are performed simultaneously.
[0020] Before the pressing head presses the raw material in the stepped hole, a gasket is placed on the raw material, and the pressing head presses the raw material through the gasket.
[0021] 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.
[0022] The beneficial effects of the present invention are as follows: the microneedle preparation process of the present invention 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, and to evacuate the cavity of the evacuation plate through the evacuation pipe, so that the air in the microporous area of the template is evacuated through the isolation layer, and the raw materials gradually enter the microporous area of the template, and are made through pressurization, cooling, and demolding. The micropores on the template of the present invention are through holes, and the fluid raw materials can enter the micropores of the template, and the cavities of the evacuation plate are evacuated so that the fluid thermoplastic raw materials fill the micropores. The pressing head pressurizes the thermoplastic raw materials and squeezes out the air in the micropores. The isolation layer of the air-permeable and liquid-impermeable material facilitates the extraction of the air in the micropores of the template, and the thermoplastic raw materials will not be lost through the isolation layer. The microneedle preparation device of the present invention is easy to use and has a simple operation process, which can realize industrial mass production of microneedles, 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 made of thermoplastic material 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 stretch the skin while having little or no foreign body sensation; third, they are insoluble in water, so as to prevent the microneedle needles inserted into the skin from partially dissolving in the body, causing the skin pores to close quickly and affecting the subsequent entry of drugs; fourth, the hot melting or hot melting temperature is moderate, and the formed microneedle needles are tough and 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 by the device 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 a suitable method to make drug-loaded or bioactive substance-loaded microneedles for medical treatment or other beneficial purposes.
[0023] Preferably, a spring is sleeved on the pressing rod, and the spring is compressed by a spring compression mechanism, thereby applying force to the pressing head, thereby pressing the thermoplastic raw material.
[0024] Preferably, a compression spring is compressed using a clamping plate and a clamping stud. When in use, the clamping nut or handwheel is rotated to move the clamping plate downward, thereby compressing the spring to pressurize the thermoplastic raw material. The clamping plate moves downward as a whole, the thermoplastic material is evenly stressed, and the specifications of the manufactured microneedles are consistent, which is beneficial to improving production quality.
[0025] Preferably, the sleeve and the compression cover are used to compress the spring. When in use, the compression cover is rotated to compress the spring, thereby pressurizing the thermoplastic raw material. This has the advantages of simple structure and convenient operation, which is conducive to experimental personnel to process and manufacture it by themselves in the laboratory.
[0026] Preferably, the pressing head applies pressure to the thermoplastic raw material through the heat-resistant gasket to prevent the pressing head from adhering to the thermoplastic raw material, and the thermoplastic raw material is subjected to uniform force, thereby improving product quality.
[0027] The first technical solution of the method for preparing drug delivery microneedles 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 drug delivery microneedles of the present invention require first processing the raw materials into powders or solids with equal weights of microneedles. Although the processing steps are more than the first solution, this can better ensure that the weight of the raw materials 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
[0028] Figure 1 1 is a schematic structural diagram of Example 1 of a device for preparing drug delivery microneedles of the present invention;
[0029] Figure 2 yes Figure 1 Schematic diagram of the structure of the middle and upper plate;
[0030] Figure 3 yes Figure 1 The structural diagram of the template in the figure;
[0031] Figure 4 1 is a schematic structural diagram of Example 2 of a device for preparing drug delivery microneedles of the present invention;
[0032] Figure 5 is a flow chart of Example 1 of the method for preparing a drug delivery microneedle of the present invention;
[0033] Figure 6 is a flow chart of Example 2 of the method for preparing a drug delivery microneedle of the present invention;
[0034] Figure 7 Flow chart of Example 3 of the method for preparing drug delivery microneedles of the present invention.
[0035] In the figure, 1-upper plate, 2-template, 21-microporous area, 3-isolation layer, 4-exhaust plate, 41-cavity, 42-exhaust hole, 5-exhaust pipe, 6-pressing mechanism, 61-pressing head, 62-pressing rod, 63-spring, 64-pressing plate, 65-pressing stud, 66-pressing nut, 67-positioning plate, 68-pressing cover, 681-annular wall, 682-top cover, 69-sleeve. DETAILED DESCRIPTION
[0036] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.
[0037] The structure of the preparation device of the drug delivery microneedle embodiment 1 of the present invention is as follows Figures 1 to 3As shown, the preparation device of the drug delivery microneedle of this embodiment includes an upper plate 1, a template 2, an isolation layer 3 and an air extraction plate 4 arranged in sequence from top to bottom, wherein the upper plate 1, the template 2, the isolation layer 3 and the air extraction plate 4 are all made of heat-resistant materials, the isolation layer 3 is made of a gas-permeable and liquid-impermeable material, the template 2 is provided with a microporous area 21 corresponding to the needle-shaped object of the microneedle, a microporous area 21 has a plurality of micropores, and the micropores are through holes opened on the template 2, and the upper plate 1 is provided with a large upper and a small lower portion at a position corresponding to the microporous area 21 The stepped hole 11 has the same shape and size as the microneedle substrate in the small section at the bottom of the stepped hole 11. A cavity 41 is provided in the air pumping plate 4. An air pumping hole 42 connected to the cavity 41 is opened at a position corresponding to the micropore area 21 on the air pumping plate 4. An air pumping pipe 5 connected to the cavity is provided outside the air pumping plate 4. A clamping mechanism 6 is provided above the upper plate. The clamping mechanism 6 includes a clamping head 61 for inserting into the large section at the top of the stepped hole 11. The size of the clamping head 61 is larger than the size of the small section at the bottom of the stepped hole 11.
[0038] In this embodiment, the clamping mechanism includes a clamping rod 62 fixedly connected to the top of the clamping head 61, the clamping head 61 is integrally connected with the clamping rod 62, a spring 63 is sleeved on the clamping rod, and a spring compression mechanism for compressing the spring is arranged above the spring 63. The spring compression mechanism includes a clamping plate 64, the clamping plate 64 is provided with a through hole for the clamping rod 62 to pass through, the spring 63 is sleeved on the clamping rod 62 at a position between the clamping plate 64 and the clamping head 61, a clamping stud 65 is installed in the clamping plate 64, and a clamping nut 66 is spirally assembled on the clamping stud 65 at a position above the clamping plate, and in other embodiments, the clamping nut can be replaced by a hand wheel. A positioning plate 67 is also provided between the upper plate and the clamping plate, and a positioning hole is provided on the positioning plate 67 corresponding to the position of each stepped hole 11, and the diameter of the positioning hole is equal to the diameter of the clamping head, and the clamping head 61 passes through the positioning hole and is inserted into the large section at the top of the stepped hole 11. A soft heat-resistant gasket 7 is provided between the large section at the upper part of the stepped hole 11 and the pressing head, and a positioning bolt 8 is provided between the upper plate 1 and the air extraction plate 4.
[0039] The number of microporous areas 21 on the template is at least two, and the number of stepped holes on the upper plate is equal to the number of microporous areas. Figure 3 As shown, the number of microporous areas 21 on the template of this example is 8, and the 8 microporous areas are distributed on the template. The clamping studs apply pressure to the springs on the clamping rods corresponding to the 8 microporous areas through the clamping plate, which is conducive to uniform force on the raw materials in each microporous area. Of course, this embodiment is only a schematic diagram. In other embodiments, the number of microporous areas should be flexibly selected according to actual needs.
[0040] The microneedle preparation process of this embodiment 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. The process of heating the raw materials can be carried out outside the device of the present invention or inside the device of the present invention. The cavity of the vacuum plate is evacuated through the vacuum pipe, and the air in the microporous area of the template is evacuated through the isolation layer. The fluid raw material gradually enters the microporous area of the template and is made through pressurization, cooling, and demolding. The micropores on the template of the present invention are through holes, and the fluid raw material can enter the micropores of the template. The cavity of the vacuum plate is evacuated so that the fluid thermoplastic raw material fills the micropores. The pressing head pressurizes the thermoplastic raw material and squeezes out the air in the micropores. The isolation layer of the air-permeable and liquid-impermeable material facilitates the extraction of air in the micropores of the template, and the thermoplastic raw material will not be lost through the isolation layer.
[0041] This embodiment utilizes a clamping plate and a clamping stud to compress the spring. When in use, the clamping nut is rotated to move the clamping plate downward, thereby compressing the spring to pressurize the thermoplastic raw material. The clamping plate moves downward as a whole, the thermoplastic material is evenly stressed, and the manufactured microneedles have consistent specifications, which is beneficial to improving production quality.
[0042] The structure of the preparation device of the drug delivery microneedle embodiment 2 of the present invention is as follows Figure 4 As shown, the preparation device of the drug delivery microneedle of this embodiment includes an upper plate 1, a template 2, an isolation layer 3 and an exhaust plate 4 arranged in sequence from top to bottom, wherein the upper plate 1, the template 2, the isolation layer 3 and the exhaust plate 4 are all made of heat-resistant materials, the isolation layer 3 is made of a gas-permeable and liquid-impermeable material, the template 2 is provided with a microporous area 21 corresponding to the needle-like object of the microneedle, a microporous area 21 has a plurality of micropores, and the micropores are through holes opened on the template 2, and the upper plate 1 is provided with an upper large and lower The small stepped hole 11, the shape and size of the small section at the bottom of the stepped hole 11 are the same as those of the microneedle substrate, the air pumping plate 4 is provided with a cavity 41, and the position corresponding to the microporous area 21 on the air pumping plate 4 is provided with an air pumping hole 42 connected to the cavity 41, and the air pumping plate 4 is provided with an air pumping pipe 5 connected to the cavity, and the upper plate is provided with a clamping mechanism 6, which includes a clamping head 61 for inserting into the large section at the top of the stepped hole 11, and the size of the clamping head 61 is larger than the size of the small section at the bottom of the stepped hole 11. A soft heat-resistant gasket 7 is also provided between the large section at the top of the stepped hole 11 and the clamping head, and a positioning bolt 8 is provided between the upper plate 1 and the air pumping plate 4.
[0043] In this embodiment, the clamping mechanism includes a clamping rod 62 fixedly connected to the top of the clamping head 61, the clamping head 61 is integrally connected to the clamping rod 62, a spring 63 is sleeved on the clamping rod, and a spring compression mechanism for compressing the spring is provided above the spring 63. The spring compression mechanism includes a sleeve 69 and a clamping cover 68 threadedly connected to the upper end of the sleeve 69, the large section at the upper part of the stepped hole 11 is provided with an internal thread matched with the thread at the lower end of the sleeve 69, the lower end of the sleeve 69 is threadedly connected to the large section at the upper part of the stepped hole 11, the clamping rod 62 and the spring 63 are used to be installed inside the sleeve 69, the clamping cover 68 includes an annular wall 681 and a top cover 682 connected to the upper part of the annular wall 681, the top cover 682 is provided with a hole for the clamping rod to pass through, the annular wall 681 is screwed on the upper end of the sleeve 69, and the top cover compresses the spring.
[0044] The microneedle preparation process of this embodiment 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. The process of heating the raw materials can be carried out outside the device of the present invention or inside the device of the present invention. The cavity of the vacuum plate is evacuated through the vacuum pipe, and the air in the microporous area of the template is evacuated through the isolation layer. The fluid raw material gradually enters the microporous area of the template and is made through pressurization, cooling, and demolding. The micropores on the template of the present invention are through holes, and the fluid raw material can enter the micropores of the template. The cavity of the vacuum plate is evacuated so that the fluid thermoplastic raw material fills the micropores. The pressing head pressurizes the thermoplastic raw material and squeezes out the air in the micropores. The isolation layer of the air-permeable and liquid-impermeable material facilitates the extraction of air in the micropores of the template, and the thermoplastic raw material will not be lost through the isolation layer. The use process of the clamping mechanism of this embodiment is as follows: screw the lower part of the sleeve into the large section of the stepped hole of the upper plate, put the heat-resistant gasket into the sleeve, then put the clamping rod into the sleeve, then screw the clamping cover onto the upper part of the sleeve, and let the clamping rod pass through the threaded hole on the clamping cover, rotate the clamping cover to compress the spring, so that the clamping head presses the gasket and the raw material. This embodiment uses the sleeve and the clamping rod with a spring to pressurize the thermoplastic material, which has the advantages of simple structure and convenient operation, and is conducive to the experimenters to process and manufacture by themselves in the laboratory.
[0045] The flowchart of Example 1 of the method for preparing the drug delivery microneedle of the present invention is as follows Figure 5 As shown, the preparation method of the drug delivery microneedle of this embodiment comprises the following steps:
[0046] (1) heating the thermoplastic raw material for preparing the microneedles to a fluid state;
[0047] (2) Place the exhaust plate, isolation layer, template and upper plate in order from bottom to top, and arrange the stepped holes of the upper plate above the microporous area on the template, and the exhaust holes of the exhaust plate below the microporous area on the template;
[0048] (3) placing the raw material heated in step (1) into the stepped hole of the upper plate;
[0049] (4) The air in the microporous area of the template is evacuated through the exhaust pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template;
[0050] (5) Use a pressing head to pressurize the raw material in the step hole so that the raw material is pressed downward in the step hole into the micropores in the micropore area of the template;
[0051] (6) The fluid raw material in the step hole is cooled down. After the raw material in the step hole and the micropore is cooled down and becomes solid, the pressing head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing demolding.
[0052] In the above steps, the steps of evacuating the cavity of the exhaust plate and pressurizing the raw material in the stepped hole are performed simultaneously.
[0053] Before the pressing head presses the raw material in the stepped hole, a gasket is placed on the raw material, and the pressing head presses the raw material through the gasket.
[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 device of the present invention is easy to use and has a simple operation process, which can enable the microneedles 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 microneedles. The microneedles made 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 needle-like objects are sufficient to stretch the skin and have less or no foreign body sensation; third, they are insoluble in water, so that the microneedle needle-like objects inserted into the skin are not partially dissolved in the body, so that the skin pores are quickly closed, affecting the subsequent entry of drugs; fourth, the hot melt or hot melting temperature is moderate, and the formed microneedle needle-like objects have toughness and are easy to demold. 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 device 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 a suitable method to make drug-loaded or bioactive substance-loaded microneedles 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 6 As shown, the preparation method of the drug delivery microneedle of this embodiment comprises the following steps:
[0057] (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;
[0058] (2) Place the exhaust plate, isolation layer, template and upper plate in order from bottom to top, and arrange the stepped holes of the upper plate above the microporous area on the template, and the exhaust holes of the exhaust plate below the microporous area on the template;
[0059] (3) placing the powdered raw material weighed in step (1) into the small section below the stepped hole of the upper plate;
[0060] (4) heating the powder material in step (3) until the powder material becomes fluid;
[0061] (5) The cavity of the exhaust plate is evacuated through the exhaust pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template;
[0062] (6) Use a pressing head to pressurize the raw material in the step hole so that the raw material is pressed downward in the step hole into the micropores in the micropore area of the template;
[0063] (7) The fluid raw material in the step hole and micropore area is cooled. After the raw material is cooled and becomes solid, the pressing head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing demolding.
[0064] In the above steps, the steps of evacuating the cavity of the exhaust plate and pressurizing the raw material in the stepped hole are performed simultaneously.
[0065] Before the pressing head presses the raw material in the stepped hole, a gasket is placed on the raw material, and the pressing head presses the raw material through the gasket.
[0066] 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.
[0067] The flowchart of Example 3 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:
[0068] (1) Processing the thermoplastic raw material for preparing microneedles into a solid raw material with the same weight as a single microneedle;
[0069] (2) Place the exhaust plate, isolation layer, template and upper plate in order from bottom to top, and arrange the stepped holes of the upper plate above the microporous area on the template, and the exhaust holes of the exhaust plate below the microporous area on the template;
[0070] (3) placing the solid raw material obtained in step (1) into the small section below the stepped hole of the upper plate;
[0071] (4) heating the solid raw material in step (3) until the solid raw material becomes fluid;
[0072] (5) The cavity of the exhaust plate is evacuated through the exhaust pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template;
[0073] (6) Use a pressing head to pressurize the raw material in the step hole so that the raw material is pressed downward in the step hole into the micropores in the micropore area of the template;
[0074] (7) The fluid raw material in the step hole and micropore area is cooled. After the raw material is cooled and becomes solid, the pressing head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing demolding.
[0075] In the above steps, the steps of evacuating the cavity of the exhaust plate and pressurizing the raw material in the stepped hole are performed simultaneously.
[0076] Before the pressing head presses the raw material in the stepped hole, a gasket is placed on the raw material, and the pressing head presses the raw material through the gasket.
[0077] 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.
[0078] Embodiments 2 and 3 of the microneedle preparation method of the present invention need to first process the raw materials into solids or powders with equal weight of microneedles, so that the weight of the raw materials of the microneedles 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 as to prevent the microneedle needles 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 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 by the device 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.
[0079] The above embodiment is a preferred embodiment of the present invention. In other embodiments of the present invention, the pressing mechanism can 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 also be flexibly selected according to actual needs.
[0080] 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 device for preparing drug delivery microneedles, characterized in that: The invention comprises an upper plate (1), a template (2), an isolation layer (3) and an air extraction plate (4) which are arranged in sequence from top to bottom. The upper plate (1), the template (2), the isolation layer (3) and the air extraction plate (4) are all made of heat-resistant materials. The isolation layer (3) is made of a gas-permeable but liquid-impermeable material. The template (2) is provided with a microporous area (21) corresponding to the needle-shaped object of the microneedle. A microporous area (21) has a plurality of micropores, and the micropores are through holes opened on the template (2). A stepped hole (11) with a larger top and a smaller bottom is opened at a position on the upper plate (1) corresponding to the microporous area (21). The shape and size of the small section at the bottom of the stepped hole (11) are the same as those of the microneedle substrate, a cavity (41) is provided inside the air extraction plate (4), an air extraction hole (42) connected to the cavity (41) is opened at a position corresponding to the micropore area (21) on the air extraction plate (4), an air extraction pipe (5) connected to the cavity is provided outside the air extraction plate (4), and a clamping mechanism (6) is provided above the upper plate, the clamping mechanism (6) includes a clamping head (61) for inserting into the large section at the top of the stepped hole (11), and the size of the clamping head (61) is larger than the size of the small section at the bottom of the stepped hole (11).
2. The device for preparing drug delivery microneedles according to claim 1, characterized in that: The clamping mechanism comprises a clamping rod (62) fixedly connected to the top of a clamping head (61); the clamping head (61) and the clamping rod (62) are integrally connected; a spring (63) is sleeved on the clamping rod; and a spring compression mechanism for compressing the spring is provided above the spring (63).
3. The device for preparing drug delivery microneedles according to claim 2, characterized in that: The spring compression mechanism comprises a clamping plate (64), the clamping plate (64) is provided with a through hole for a clamping rod (62) to pass through, the spring (63) is sleeved on the clamping rod (62) at a position between the clamping plate (64) and the clamping head (61), a clamping stud (65) is inserted into the clamping plate (64), and a clamping nut (66) or a hand wheel is screwedly mounted on the clamping stud (65) at a position above the clamping plate.
4. The device for preparing drug delivery microneedles according to claim 3, characterized in that: A positioning plate (67) is further provided between the upper plate (1) and the clamping plate (64). A positioning hole is provided on the positioning plate (67) at a position corresponding to each stepped hole (11). The diameter of the positioning hole is equal to the diameter of the clamping head. The clamping head (61) passes through the positioning hole and is inserted into the large section at the upper portion of the stepped hole (11).
5. The device for preparing drug delivery microneedles according to claim 2, characterized in that: The spring compression mechanism comprises a sleeve (69) and a compression cover (68) threadedly connected to the upper end of the sleeve (69); an internal thread matched with the thread of the lower end of the sleeve (69) is provided in a large section at the upper part of the stepped hole (11); the lower end of the sleeve (69) is threadedly connected to the large section at the upper part of the stepped hole (11); the compression rod (62) and the spring (63) are used to be installed inside the sleeve (69); the compression cover (68) comprises an annular wall surface (681) and a top cover (682) connected to the upper part of the annular wall surface (681); the top cover (682) is provided with a hole for the compression rod to pass through; the annular wall surface (681) is threadedly assembled on the upper end of the sleeve (69); and the top cover compresses the spring.
6. The device for preparing drug delivery microneedles according to any one of claims 1 to 5, characterized in that: A soft heat-resistant gasket (7) is also provided between the large section at the upper part of the stepped hole (11) and the pressing head.
7. The device for preparing drug delivery microneedles according to any one of claims 1 to 5, characterized in that: Positioning bolts (8) are provided between the upper plate (1) and the air extraction plate (4).
8. The device for preparing drug delivery microneedles according to any one of claims 1 to 5, characterized in that: The number of microporous areas (21) on the template (2) is at least two, and the number of stepped holes (11) on the upper plate is equal to the number of microporous areas (21).
9. A method for preparing a drug delivery microneedle, characterized in that: It includes the following steps: (1) heating the thermoplastic raw material for preparing microneedles to a fluid state; (2) placing the exhaust plate, isolation layer, template and upper plate in claim 1 in order from bottom to top, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) placing the raw material heated in step (1) into the stepped holes of the upper plate; (4) exhausting the cavity of the exhaust plate through an exhaust pipe, the air in the microporous area of the template is exhausted through the isolation layer, and the raw material gradually enters the microporous area of the template; (5) using the pressing head in claim 1 to pressurize the raw material in the stepped holes, so that the raw material is pressed downward in the stepped holes and enters the micropores in the microporous area of the template; (6) cooling the fluid raw material in the stepped holes, and after the raw material in the stepped holes and the micropores is cooled and becomes solid, removing the pressing head and the upper plate, separating the solid from the template, and obtaining the microneedles, thereby completing demolding.
10. 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 powder raw material, and weighing the powder raw material equal to the weight of a single microneedle; (2) Placing the exhaust plate, isolation layer, template and upper plate in claim 1 from bottom to top in sequence, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) Placing the powder raw material weighed in step (1) into the small section below the stepped holes of the upper plate; (4) Heating the powder raw material in step (3) until the powder raw material becomes fluid dynamic state; (5) evacuating the cavity of the exhaust plate through the exhaust pipe, the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template; (6) using the clamping head in claim 1 to pressurize the raw material in the step hole, so that the raw material is pressed downward in the step hole and enters the micropores in the microporous area of the template; (7) cooling the fluid raw material in the step hole and the microporous area, after the raw material is cooled and becomes solid, remove the clamping head and the upper plate, separate the solid from the template, obtain the microneedle, and complete 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 solid raw material having a weight equal to that of a single microneedle; (2) Placing the exhaust plate, isolation layer, template and upper plate in claim 1 in order from bottom to top, and making the stepped holes of the upper plate correspondingly arranged above the microporous area on the template, and the exhaust holes of the exhaust plate correspondingly arranged below the microporous area on the template; (3) Placing the solid raw material obtained in step (1) into the small section below the stepped holes of the upper plate; (4) Heating the solid raw material in step (3) until the solid raw material becomes a fluid state; (5) The air in the microporous area of the template is evacuated through the vacuum pipe, and the air in the microporous area of the template is evacuated through the isolation layer, and the raw material gradually enters the microporous area of the template; (6) The raw material in the step hole is pressurized using the clamping head in claim 1, so that the raw material is pressed downward in the step hole and enters the micropores in the microporous area of the template; (7) The fluid raw material in the step hole and the microporous area is cooled and cooled. After the raw material is cooled and becomes solid, the clamping head and the upper plate are removed, and the solid is separated from the template to obtain the microneedle, thereby completing the demolding.
12. The method for preparing a drug delivery microneedle according to claim 9, 10 or 11, characterized in that: The steps of evacuating the cavity of the evacuation plate and pressurizing the raw material in the stepped hole are performed simultaneously.
13. The method for preparing a drug delivery microneedle according to claim 9, 10 or 11, characterized in that: Before the pressing head presses the raw material in the stepped hole, a gasket is placed on the raw material, and the pressing head presses the raw material through the gasket.
14. The method for preparing a drug delivery microneedle according to claim 9, 10 or 11, 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.