CN117261048A - Layered microneedle molding method and layered microneedle molding device - Google Patents
Layered microneedle molding method and layered microneedle molding device Download PDFInfo
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- CN117261048A CN117261048A CN202210674759.2A CN202210674759A CN117261048A CN 117261048 A CN117261048 A CN 117261048A CN 202210674759 A CN202210674759 A CN 202210674759A CN 117261048 A CN117261048 A CN 117261048A
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
- B29C33/0022—Multi-cavity moulds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C33/00—Moulds or cores; Details thereof or accessories therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/26—Moulds or cores
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C39/00—Shaping by casting, i.e. introducing the moulding material into a mould or between confining surfaces without significant moulding pressure; Apparatus therefor
- B29C39/22—Component parts, details or accessories; Auxiliary operations
- B29C39/42—Casting under special conditions, e.g. vacuum
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
- B29C41/34—Component parts, details or accessories; Auxiliary operations
- B29C41/38—Moulds, cores or other substrates
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C45/00—Injection moulding, i.e. forcing the required volume of moulding material through a nozzle into a closed mould; Apparatus therefor
- B29C45/17—Component parts, details or accessories; Auxiliary operations
- B29C45/26—Moulds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C69/00—Combinations of shaping techniques not provided for in a single one of main groups B29C39/00 - B29C67/00, e.g. associations of moulding and joining techniques; Apparatus therefore
- B29C69/02—Combinations of shaping techniques not provided for in a single one of main groups B29C39/00 - B29C67/00, e.g. associations of moulding and joining techniques; Apparatus therefore of moulding techniques only
-
- 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
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Dermatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Manufacturing & Machinery (AREA)
- Media Introduction/Drainage Providing Device (AREA)
Abstract
In order to solve the problems of high viscosity requirement and influence on microneedle molding and raw material selection in the conventional doctor-blading process of microneedle molding, the invention provides a layered microneedle molding method, which comprises the following operation steps: the method comprises the steps of arranging a semi-closed cavity to cover a molding surface, filling microneedle molding liquid in the semi-closed cavity, immersing the molding surface by the microneedle molding liquid, and carrying out vacuum suction on an air suction surface of a microneedle molding die to lead the microneedle molding liquid into the microneedle cavity; separating the microneedle mould from the semi-closed cavity, and removing the microneedle forming liquid outside the microneedle cavity. Meanwhile, the invention also discloses a layered microneedle molding device. The layered microneedle molding method provided by the invention can effectively solve the problem of non-infiltration shrinkage of the microneedle molding liquid on the surface of the microneedle molding area, and expands the viscosity application range of the microneedle molding liquid.
Description
Technical Field
The invention belongs to the technical field of microneedle preparation, and relates to a layered microneedle molding method and a layered microneedle molding device.
Background
In the traditional layered microneedle preparation process, the forming liquid is introduced into the microneedle cavity of the forming die in an atomization spraying mode, the introduction efficiency of the mode is low, the problems that the forming liquid is wasted and more bubbles are contained in the forming microneedle are solved, the forming liquid is extruded in a scraping mode to be introduced into the microneedle cavity on the surface of the forming die in order to solve the problems, however, the viscosity of the forming liquid needs to be limited in the existing scraping process, when the viscosity of the forming liquid is too low, the flowability of the forming liquid on the surface of the forming die is too strong, the forming liquid is spread everywhere to be difficult to meet the scraping condition, and the wettability of materials such as silicone resin and the forming liquid is not high, so that the forming liquid is not infiltrated and contracted on the surface of the forming die easily, namely the forming liquid is agglomerated on the surface of the forming die, the forming liquid is not introduced into the top of part of the microneedle cavity, the problem that the introduction amount of the forming liquid in different microneedle cavities is inconsistent is caused, and the microneedle carrying amount is insufficient, and good drug effect cannot be exerted. Some existing forming dies, as shown in patent CN113491675a, are provided with a slot for forming a substrate on the top surface of the microneedle cavity, through which the mobility of the microneedle forming liquid can be limited to a certain extent, but the vacuum suction process can cause part of the microneedle forming liquid to enter the microneedle cavity to further reduce the microneedle forming liquid in the slot, so that the microneedle forming liquid cannot infiltrate and shrink on the bottom surface of the slot, and the drug loading of the microneedle cavity at different positions is affected.
On the other hand, because the size of the microneedle cavity is in the micron level, air is easy to leave, vacuum conditions are required to be set for suction after blade coating so as to lead the forming liquid into the microneedle cavity, when the viscosity of the forming liquid is too high, the efficiency of the forming liquid in the forming cavity can be influenced, the forming liquid with high viscosity is unfavorable for leading out bubbles in the subsequent microneedle cavity, the bubbles are easy to remain, meanwhile, the requirement of the existing blade coating process on the viscosity of the forming liquid also greatly limits the types of optional raw materials for preparing the microneedle, a large amount of auxiliary materials are required to be added in the forming liquid so as to improve the viscosity of the forming liquid, and the actual drug loading of the microneedle is influenced.
Disclosure of Invention
Aiming at the problems of high viscosity requirement and influence on microneedle molding and raw material selection in the conventional knife coating process of microneedle molding, the invention provides a layered microneedle molding method and a layered microneedle molding device.
The technical scheme adopted by the invention for solving the technical problems is as follows:
in one aspect, the invention provides a layered microneedle molding method comprising the following steps:
microneedle molding: the microneedle molding die comprises a molding surface and an air extraction surface, a microneedle molding area for molding microneedles is arranged on the microneedle molding die, the microneedle molding area is made of breathable materials, a plurality of microneedle cavities are arranged on the surface of the microneedle molding area, semi-closed cavities are arranged and can be covered on the molding surface in a separable manner, microneedle molding liquid is filled in the semi-closed cavities, the microneedle molding liquid submerges the molding surface, and vacuum suction is carried out on the air extraction surface of the microneedle molding die to lead the microneedle molding liquid into the microneedle cavities; separating the microneedle mould from the semi-closed cavity, and removing microneedle forming liquid outside the microneedle cavity;
and (3) forming a substrate: and applying the substrate forming liquid to the forming surface of the microneedle forming die, curing, forming and demolding to obtain the layered microneedle comprising the microneedle and the substrate.
Alternatively, the viscosity of the microneedle molding liquid is 1.680-50000 cps at 25 ℃.
Optionally, the semi-closed cavity is a groove-shaped structure with an opening at the top, and the forming surface detachably closes the opening at the top of the semi-closed cavity.
Optionally, the minimum distance between the liquid level of the microneedle molding liquid and the molding surface is greater than 0.1mm.
Optionally, in the "microneedle molding" operation, a molding surface of the microneedle molding mold is set downward, so that the molding surface covers and seals the top opening of the semi-closed cavity, the microneedle molding mold and the semi-closed cavity are inverted, so that the semi-closed cavity is located above the microneedle molding mold, the microneedle molding liquid is immersed in the molding surface, and vacuum suction is performed on an air suction surface of the microneedle molding mold, so that the microneedle molding liquid is led into the microneedle cavity;
vacuum suction is maintained, the microneedle molding die and the semi-closed cavity are inverted again, the microneedle molding die and the semi-closed cavity are separated, film scraping operation is carried out on the molding surface, and microneedle molding liquid outside the microneedle cavity is scraped into the semi-closed cavity.
Optionally, a sealing ring is arranged at the inner edge of the top opening of the semi-closed cavity, and the molding surface of the microneedle molding die abuts against the sealing ring to close the semi-closed cavity.
Optionally, a step groove for positioning the microneedle molding mold is formed in the inner edge of the top opening of the semi-closed cavity, and the sealing ring is located in the step groove.
Optionally, the microneedle molding die comprises a support plate and a plurality of microneedle molding areas, the shape of the microneedle molding areas is consistent with the shape of the substrate of the layered microneedle to be prepared, the microneedle molding areas are embedded in the support plate at intervals, the support plate is made of a rigid material, and the microneedle molding areas are made of a flexible breathable material.
Optionally, the surface air pressure of the molding surface is greater than the surface air pressure of the air extraction surface.
Optionally, the "microneedle molding" operation further includes a curing operation for the microneedle molding liquid in the microneedle cavity.
Optionally, in the operation of "forming a substrate", a coating mold is used to cover a forming surface of the microneedle forming mold, a plurality of substrate forming through holes are formed in positions of the coating mold corresponding to the microneedle forming areas, a substrate forming liquid is applied to a surface of the coating mold, the substrate forming liquid is scraped into and fills the substrate forming through holes by a scraper, curing operation is performed on the substrate forming liquid, the coating mold and the microneedle forming mold are separated, and the layered microneedle comprising the microneedle and the substrate is obtained by demolding.
On the other hand, the invention provides a layered microneedle molding device, which comprises a semi-closed cavity, a microneedle molding die and a vacuum suction device, wherein the semi-closed cavity is provided with a top opening, the microneedle molding die comprises a molding surface and a suction surface, a microneedle molding area for molding microneedles is arranged on the microneedle molding die, the microneedle molding area is made of breathable materials, the microneedle molding area extends to the molding surface and the suction surface, a plurality of microneedle cavities are arranged on the surface of the molding surface, the microneedle molding die is detachably closed at the top opening position of the semi-closed cavity, the molding surface faces towards the semi-closed cavity, and the vacuum suction device is used for performing vacuum suction on the surface of the microneedle molding die, which is away from the semi-closed cavity.
According to the layered microneedle molding method provided by the invention, the semi-closed cavity is adopted for accommodating the microneedle molding liquid, and the semi-closed cavity is arranged on the molding surface of the microneedle molding die, so that the microneedle molding liquid is immersed in the molding surface of the microneedle molding die, the operation mode can effectively ensure the coverage of the microneedle molding liquid on the microneedle cavity, the problem that the introduction amount of each microneedle cavity is inconsistent due to the flowability of the microneedle molding liquid is avoided, meanwhile, the distance between the liquid level of the microneedle molding liquid and the molding surface is controlled, the problem that the microneedle molding liquid cannot infiltrate and shrink on the surface of a microneedle molding area is solved, the vacuum suction operation is matched, the microneedle molding liquid can be introduced into the microneedle cavity, the microneedle molding liquid is separated from the semi-closed cavity after being introduced into the microneedle cavity, and the microneedle molding liquid outside the microneedle cavity is scraped, so that the consistency of the microneedle molding liquid in different microneedle cavities is ensured due to the fact that the microneedle molding liquid is already introduced into the microneedle cavity, the viscosity in the microneedle cavity is low, the viscosity in the microneedle molding liquid can be successfully increased, the range can be increased for developing the active ingredient, and the filling amount of the microneedle can be effectively improved, and the filling material is required to be used for the microneedle molding material is increased, and the active ingredient can be used for developing.
Drawings
FIG. 1 is a schematic diagram of a semi-enclosed cavity and microneedle mould according to the present invention;
FIG. 2 is a schematic view of another view angle structure of the semi-enclosed cavity and the microneedle mould provided by the invention;
FIG. 3 is a schematic cross-sectional view of a microneedle mould provided by the invention;
FIG. 4 is a schematic structural view of a coating die and a microneedle mould provided by the invention;
FIG. 5 is an electron micrograph of a layered microneedle provided in example 1 of the present invention;
fig. 6 is an electron micrograph of a layered microneedle provided in comparative example 1 of the present invention.
Reference numerals in the drawings of the specification are as follows:
1. microneedle molding dies; 11. an air extraction surface; 12. molding surface; 13. a microneedle molding zone; 131. a microneedle cavity; 2. a semi-enclosed cavity; 21. a stepped groove; 22. a seal ring; 3. coating a die; 31. and forming the through holes.
Detailed Description
In order to make the technical problems, technical schemes and beneficial effects solved by the invention more clear, the invention is further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention.
Referring to fig. 1 to 4, an embodiment of the present invention provides a layered microneedle molding method, comprising the following steps:
microneedle molding: the microneedle molding die 1 comprises a molding surface 12 and an air suction surface 11, a microneedle molding area 13 for molding microneedles is arranged on the microneedle molding die 1, the microneedle molding area 13 is made of a breathable material, a plurality of microneedle cavities 131 are arranged on the surface of the microneedle molding area 13, a semi-closed cavity 2 is arranged to cover the molding surface 12 in a separable manner, microneedle molding liquid is filled in the semi-closed cavity 2, the molding surface 12 is immersed by the microneedle molding liquid, and vacuum suction is carried out on the air suction surface 11 of the microneedle molding die 1 to lead the microneedle molding liquid into the microneedle cavities 131; separating the microneedle mould 1 from the semi-closed cavity 2, and removing the microneedle mould liquid outside the microneedle cavity 131;
and (3) forming a substrate: the substrate molding liquid is applied to the molding surface 12 of the microneedle molding die 1, cured and molded, and demolded to obtain layered microneedles including microneedles and a substrate.
Through adopting semi-closed cavity 2 to carry out the holding of microneedle molding liquid, set up semi-closed cavity 2 on the molding surface 12 of microneedle molding die 1 simultaneously, make microneedle molding liquid submergence microneedle molding die 1's molding surface 12, this kind of mode of operation can effectively guarantee the coverage of microneedle molding liquid to microneedle cavity 131, avoid microneedle molding liquid because its mobility leads to appearing the inconsistent problem of each microneedle cavity 131 introduction amount, simultaneously, control the liquid level of microneedle molding liquid with distance between the molding surface 12, in order to overcome the not infiltration shrinkage problem of microneedle molding liquid at microneedle molding zone 13 surface, cooperation vacuum pumping operation, can lead into microneedle molding liquid in microneedle cavity 131, break away from again after leading into microneedle cavity 131 the molding surface 12 of microneedle molding liquid, carry out the scraping operation to microneedle cavity 131 outside microneedle molding liquid because microneedle molding liquid has led into in microneedle cavity 131 this moment, the scraping operation has guaranteed the consistent viscosity in the microneedle cavity 131 even if the liquid is wide enough to the wide to the microneedle molding liquid has adopted the viscosity of the wide consistency in the microneedle cavity 131, can also be the wide to the applied material expansion volume of the applied to the microneedle molding liquid, and has improved the active ingredient can be used for the preparation method, and the required the high-efficient material concentration of the needle is filled with the needle.
In the description of the present invention, the term "layered microneedle" refers to a microneedle array structure in which microneedles and a substrate are manufactured using different materials, and in general, a molding material of the microneedles may be selected as a soluble material including, but not limited to, acrylonitrile-butadiene-styrene copolymer (ABS), ethylene-vinyl acetate copolymer, polyvinylidene chloride, polyfluorene, polyperfluoroene, polyacrylonitrile, polyvinyl ketone, dextran, cellulose, heparin, hyaluronic acid (hyaluronic acid), alginate, etc., and a molding material of the substrate may be selected as a soluble material or a poorly soluble material. Depending on the requirements, it is possible to add only or both pharmaceutically or cosmetically active ingredients to the microneedles, which may be trace amounts of active substances, DNA, RNA, pharmaceutical preparations and vaccines.
In the preparation of layered microneedles, it is necessary to perform the microneedles and the substrate through different steps.
In some embodiments, the microneedle molding fluid has a viscosity of 1.680 to 50000cps at 25 ℃.
By adopting the layered microneedle molding method provided by the invention, the viscosity requirement on the microneedle molding liquid can be effectively reduced, the application range of the microneedle molding liquid is improved, and when the viscosity of the microneedle molding liquid at 25 ℃ is in the range, the layered microneedle molding method provided by the invention is suitable for preparation. In particular, the layered microneedle molding method provided by the invention is particularly suitable for low-viscosity microneedle molding liquid which is difficult to operate in a conventional microneedle molding process, wherein the low-viscosity microneedle molding liquid is 1.680-1000 cps in viscosity at 25 ℃, and when the layered microneedle molding method provided by the invention adopts the low-viscosity microneedle molding liquid, the filling of the tip of the microneedle cavity 131 is facilitated, and a complete microneedle structure is obtained.
In different embodiments, the semi-enclosed cavity 2 may be configured in different structures, specifically, the enclosed cavity may be a groove-shaped structure, a cylindrical structure, or an amorphous structure with an opening.
In some embodiments, the weight ratio of excipient to active ingredient in the microneedle molding liquid is (1-120): 1.
As shown in fig. 1 and 2, in an embodiment, the semi-enclosed cavity 2 is a groove structure with an open top, and the molding surface 12 detachably closes the open top of the semi-enclosed cavity 2.
In some embodiments, in the "microneedle molding" operation, the molding surface 12 of the microneedle molding mold 1 is disposed downward, so that the molding surface 12 covers and seals the top opening of the semi-closed cavity 2, the microneedle molding mold 1 and the semi-closed cavity 2 are inverted, the semi-closed cavity 2 is located above the microneedle molding mold 1, the microneedle molding liquid is immersed in the molding surface 12, and the suction surface 11 of the microneedle molding mold 1 is subjected to vacuum suction, so that the microneedle molding liquid is introduced into the microneedle cavity 131;
the vacuum suction is maintained, the microneedle mould 1 and the semi-closed cavity 2 are inverted again, the microneedle mould 1 and the semi-closed cavity 2 are separated, the film scraping operation is carried out on the moulding surface 12, and the microneedle moulding liquid outside the microneedle cavity 131 is scraped into the semi-closed cavity 2.
Through the operation of scraping the film on the molding surface 12 after the molding die 1 is inverted, the residual microneedle molding liquid on the surface of the die can be better scraped into the semi-closed cavity 2 by utilizing the downward gravity of the microneedle molding liquid, so that the recycling of the microneedle molding liquid is realized, and meanwhile, the pollution caused by the residual microneedle molding liquid on the surface of the die when the die is repeatedly used is effectively avoided, and the production process and the final product cannot meet the related requirements of GMP (good manufacturing practice) regulations.
By inverting the semi-closed cavity 2, the microneedle molding liquid can flow downwards under the action of gravity and cover the molding surface 12 of the microneedle molding die 1, and it should be noted that, in other embodiments, the semi-closed cavity 2 may not be inverted, and specifically, the semi-closed cavity 2 may be obliquely arranged so that the microneedle molding liquid can cover the molding surface 12; or the semi-closed cavity 2 is directly covered on the molding surface 12 without inversion or tilting operation, and the microneedle molding liquid is injected into the semi-closed cavity 2 in a pipeline mode.
In some embodiments, in the "microneedle molding" operation, the microneedle molding mold 1 and the semi-closed cavity 2 may be disposed vertically, so that the microneedle molding liquid may be ensured to be able to submerge the molding surface 12. Specifically, when the "film scraping operation" is performed, the microneedle molding mold 1 may be disposed vertically, and the semi-closed cavity 2 may be disposed below the microneedle molding mold 1, so as to scrape the excessive microneedle molding liquid into the semi-closed cavity 2.
In some embodiments, a sealing ring 22 is arranged at the inner edge of the top opening of the semi-closed cavity 2, and the molding surface 12 of the microneedle molding die 1 abuts against the sealing ring 22 to close the semi-closed cavity 2.
In some embodiments, the inner edge of the top opening of the semi-closed cavity 2 is provided with a step groove 21 for positioning the microneedle mould 1, and the sealing ring 22 is located in the step groove 21.
The step groove 21 is used for limiting the position of the microneedle molding die 1, ensuring that the molding surface 12 completely covers the top opening of the semi-closed cavity 2, and the sealing ring 22 is used for ensuring the fit between the top opening of the semi-closed cavity 2 and the edge of the molding surface 12, so that the leakage of microneedle molding liquid is avoided.
The seal 22 may be selected from elastomeric rubber seals.
When the microneedle molding area 13 is made of rigid materials, the rigid materials are difficult to deform, and the tips of the microneedles are easy to break due to stress during demolding, so that the microneedles do not have good penetrating performance, and meanwhile, the broken microneedles influence the preparation of the next batch of microneedle patches; in the preferred embodiment, the microneedle mould section 13 is a flexible material having deformable properties relative to a rigid material, which advantageously provides an extremely gentle demoulding process that reduces the compressive stress of the microneedle cavities 131 during the microneedle mould release process, but due to the deformability of the flexible material, shrinks during the curing of the microneedles and the substrate to deform the microneedle mould section 13, which is also detrimental to the microneedle mould effect and mould release.
In a preferred embodiment, the microneedle mould 1 comprises a support plate and a plurality of microneedle mould areas 13, the shape of the microneedle mould areas 13 is consistent with the shape of the substrate of the layered microneedle to be prepared, the microneedle mould areas 13 are embedded on the support plate at intervals, the support plate is made of a rigid material, and the microneedle mould areas 13 are made of a flexible breathable material.
Compared with the prior art that the whole Zhang Chengxing mold is sucked, and then the size and shape corresponding to the microneedle patch are obtained through subsequent cutting, in the embodiment, the microneedle molding areas 13 with the shapes and the sizes consistent with the shapes of the bases of the layered microneedles are arranged on the supporting plate, and the microneedle molding liquid in the semi-closed cavity 2 is pumped into the range of the microneedle molding areas 13 through the sucking action of the vacuum sucking device on the microneedle molding areas 13, so that the increase of subsequent cutting steps and the waste of the microneedle molding liquid are avoided.
In some embodiments, the rigid material is selected from monocrystalline silicon, stainless steel, aluminum plates, titanium plates, silicate glass, quartz glass, ceramics, polytetrafluoroethylene, polyetheretherketone (PEEK), pyridinium propane sulfonate, and the like, and the flexible material is selected from silicone.
In the embodiment, the microneedle molding die 1 is prepared by combining a flexible material and a rigid material, and the microneedle molding area 13 of the flexible material is fixed on the supporting plate of the rigid material, so that the supporting plate has supporting and fixing functions on the microneedle molding area 13 and is used for keeping the stability of the shape of the microneedle molding area 13; the microneedle cavity 131 arranged on the microneedle molding area 13 is used for curing and molding the microneedles, the flexible material is used for reducing the stress applied in the process of releasing the microneedles, the integrity of the microneedles after releasing is improved, and meanwhile, the shape of the microneedle molding area 13 is fixed through the support plate made of the rigid material, so that the shape change of the microneedle molding area 13 in the process of curing and shrinking the microneedle molding liquid can be avoided, and the molding effect and the release integrity of the microneedles are further effectively improved.
In some embodiments, the plurality of microneedle mould areas 13 are arranged in a matrix or randomly dispersed.
In a preferred embodiment, a plurality of the microneedle mould areas 13 are arranged in a matrix.
In some embodiments, the microneedle cavity 131 is a tapered cavity with a tip facing the interior of the microneedle molding zone 13, such as a rounded tip, an elliptical tip, a regular polygonal tip, an irregular polygonal tip, or the like.
In some embodiments, the microneedle cavities 131 have a depth of 1 μm to 1000 μm and a maximum diameter (i.e., base diameter) of 5 μm to 3000 μm. Meanwhile, in order to ensure that the microneedle array has a certain density, the distance between the microneedle cavities 131 is 4 μm to 1000 μm.
In some embodiments, the air pressure on the surface of the molding surface 12 is greater than the air pressure on the surface of the suction surface 11, and the air pressure on the surface of the suction surface 11 is less than or equal to 0.5Mpa, and in preferred embodiments, the air pressure on the surface of the suction surface 11 is less than 0.1Mpa.
Under the vacuum condition, the efficiency and depth of the microneedle molding liquid entering the microneedle cavities 131 are improved.
In some embodiments, the time of vacuum pumping is between 0.5 and 10 minutes.
In some embodiments, the minimum distance of the liquid level of the microneedle molding liquid from the molding surface is greater than 0.1mm.
In the description of the present invention, the term "minimum distance of the liquid surface of the microneedle molding liquid from the molding surface 12" means: one point is selected on the liquid surface of the microneedle mould liquid, the other point is selected on the moulding surface 12, and when the connecting line between the two selected points is the shortest, the minimum distance between the liquid surface of the microneedle mould liquid and the moulding surface 12 is defined.
Under the condition that the minimum distance between the liquid surface of the microneedle molding liquid and the molding surface is greater than 0.1mm, the non-infiltration shrinkage of the microneedle molding liquid on the surface of the microneedle molding zone 13 can be effectively inhibited, the whole coverage of the microneedle molding liquid on the molding surface 12 is ensured, and the consistency of the microneedle molding liquid amount filled in each microneedle cavity 131 is improved.
In particular embodiments, the minimum distance of the liquid level of the microneedle molding liquid from the molding surface may be 0.1mm, 0.5mm, 0.9mm, 1mm, 2mm, 3mm, 5mm, or 8mm.
In some embodiments, the "microneedle molding" operation further comprises a curing operation of the microneedle molding fluid in the microneedle cavity 131.
In some embodiments, the curing and molding mode of the microneedle molding liquid can be one or more of heat curing, heat convection drying, heat conduction drying and/or heat radiation drying, normal-temperature convection drying, normal-temperature standing drying, low-temperature convection drying, low-temperature standing drying, reduced-pressure drying, normal-pressure drying, microwave drying, chemical crosslinking and UV curing.
In one embodiment, the microneedle molding liquid is cured and molded by air-drying at 20-25deg.C for 0.5-4 hr to avoid decomposition of active components in the molding liquid. Meanwhile, the air speed is controlled within the range of 0.2-6m/s, so that the forming liquid is not blown out of the microneedle cavity 131, and the curing rate is not reduced due to the too low air speed, and the production efficiency is not affected.
As shown in fig. 4, in some embodiments, in the "substrate molding" operation, a coating mold 3 is used to cover the molding surface 12 of the microneedle molding mold 1, a plurality of substrate molding through holes 31 are formed in the coating mold 3 corresponding to the positions of the microneedle molding areas 13, a substrate molding liquid is applied to the surface of the coating mold 3, the substrate molding liquid is scraped into and filled into the plurality of substrate molding through holes 31 by a doctor blade, the substrate molding liquid is cured, the coating mold 3 and the microneedle molding mold 1 are separated, and the layered microneedle including the microneedle and the substrate is obtained by demolding.
Another embodiment of the present invention provides a layered microneedle molding device, which includes a semi-closed cavity 2, a microneedle molding mold 1, and a vacuum suction device, where the semi-closed cavity 2 is provided with a top opening, the microneedle molding mold 1 includes a molding surface 12 and a suction surface 11, a microneedle molding area 13 for molding microneedles is provided on the microneedle molding, the microneedle molding area 13 is made of a breathable material, the microneedle molding area 13 extends to the molding surface 12 and the suction surface 11, a plurality of microneedle cavities 131 are provided on a surface of the microneedle molding area 13 on the molding surface 12, the microneedle molding mold 1 detachably closes a top opening position of the semi-closed cavity 2, the molding surface 12 faces the semi-closed cavity 2, and the vacuum suction device is used for vacuum sucking a surface of the microneedle molding mold 1 facing away from the semi-closed cavity 2.
In some embodiments, the layered microneedle device further comprises a coating mold 3, the coating mold 3 is detachably covered on the molding surface 12 of the microneedle device 1, and a plurality of substrate molding through holes 31 are formed in the coating mold 3 corresponding to the positions of the microneedle device forming areas 13.
The invention is further illustrated by the following specific examples:
example 1
The embodiment is used for explaining the layering microneedle molding method provided by the invention, and comprises the following operation steps:
microneedle molding: the microneedle molding die comprises a molding surface and an air extraction surface, a microneedle molding area for molding microneedles is arranged on the microneedle molding die, the microneedle molding area is made of breathable materials, the microneedle molding area extends to the molding surface and the air extraction surface, a plurality of microneedle cavities are arranged on the surface of the microneedle molding area, semi-closed cavities are arranged to cover the molding surface, microneedle molding liquid is filled in the semi-closed cavities, the semi-closed cavities are of groove-shaped structures with open tops, the molding surface of the microneedle molding die is downwards arranged, the molding surface covers and seals the open tops of the semi-closed cavities, the microneedle molding die and the semi-closed cavities are inverted, the semi-closed cavities are arranged above the microneedle molding die, the viscosity of the microneedle molding liquid at 25 ℃ is 1.680, the minimum distance between the liquid surfaces of the microneedle molding liquid and the molding surface is 3mm, and the air extraction surface is subjected to vacuum molding of the microneedles, and the microneedle molding liquid is led into the cavity;
separating the microneedle molding die from the semi-closed cavity, removing microneedle molding liquid outside the microneedle cavity, and performing air drying and curing on the microneedle molding liquid in the microneedle cavity;
and (3) forming a substrate: the method comprises the steps of covering a forming surface of a microneedle forming mold by a coating mold, providing a plurality of substrate forming through holes at positions of the coating mold corresponding to a plurality of microneedle forming areas, applying substrate forming liquid to the surface of the coating mold, scraping the substrate forming liquid into and filling the substrate forming through holes by a scraper, solidifying the substrate forming liquid, separating the coating mold from the microneedle forming mold, and demolding to obtain the layered microneedle comprising the microneedle and the substrate.
The obtained layered micro-needle is observed by an electron microscope, and the obtained electron microscope photograph is shown in fig. 5, so that the layered micro-needle obtained by the layered micro-needle molding method provided by the invention has higher drug loading capacity and excellent needle morphology.
Comparative example 1
This comparative example is used for comparative illustration of the layered microneedle molding method provided by the present invention, comprising the following steps of:
microneedle molding: the microneedle molding die comprises a molding surface and an air extraction surface, a microneedle molding area for molding the microneedle is arranged on the microneedle molding die, the microneedle molding area is made of breathable materials, the microneedle molding area extends to the molding surface and the air extraction surface, a plurality of microneedle cavities are arranged on the surface of the microneedle molding area, a metal net is covered on the molding surface, the microneedle molding liquid is coated on the molding surface through the metal net, the viscosity of the microneedle molding liquid at 25 ℃ is 1.680cps, a scraping knife is used for scraping the metal net, the microneedle molding liquid is extruded into the microneedle cavities, and the air extraction surface of the microneedle molding die is vacuumized, so that the microneedle molding liquid is led into the microneedle cavities;
air-drying and solidifying the microneedle molding liquid in the microneedle cavity;
and (3) forming a substrate: the method comprises the steps of covering a forming surface of a microneedle forming mold by a coating mold, providing a plurality of substrate forming through holes at positions of the coating mold corresponding to a plurality of microneedle forming areas, applying substrate forming liquid to the surface of the coating mold, scraping the substrate forming liquid into and filling the substrate forming through holes by a scraper, solidifying the substrate forming liquid, separating the coating mold from the microneedle forming mold, and demolding to obtain the layered microneedle comprising the microneedle and the substrate.
The obtained layered micro-needles are observed by an electron microscope, and the obtained electron microscope photograph is shown in fig. 6, so that the layered micro-needles obtained by the conventional film scraping operation have lower drug loading rate, and meanwhile, the drug loading rates of different micro-needles are obviously uneven.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, and alternatives falling within the spirit and principles of the invention.
Claims (12)
1. A layered microneedle molding method, comprising the following steps:
microneedle molding: the microneedle molding die comprises a molding surface and an air extraction surface, a microneedle molding area for molding microneedles is arranged on the microneedle molding die, the microneedle molding area is made of breathable materials, a plurality of microneedle cavities are arranged on the surface of the microneedle molding area, semi-closed cavities are arranged and can be covered on the molding surface in a separable manner, microneedle molding liquid is filled in the semi-closed cavities, the microneedle molding liquid submerges the molding surface, and vacuum suction is carried out on the air extraction surface of the microneedle molding die to lead the microneedle molding liquid into the microneedle cavities; separating the microneedle mould from the semi-closed cavity, and removing microneedle forming liquid outside the microneedle cavity;
and (3) forming a substrate: and applying the substrate forming liquid to the forming surface of the microneedle forming die, curing, forming and demolding to obtain the layered microneedle comprising the microneedle and the substrate.
2. The layered microneedle molding process of claim 1, wherein the microneedle molding fluid has a viscosity of 1.680 to 50000cps at 25 ℃.
3. The layered microneedle molding method of claim 1, wherein the semi-closed cavity is a groove-like structure with a top opening, and the molding surface detachably closes the top opening of the semi-closed cavity.
4. The layered microneedle molding method of claim 1, wherein the minimum distance of the liquid surface of the microneedle molding liquid from the molding surface is greater than 0.1mm.
5. The layered microneedle molding method according to claim 3, wherein in the microneedle molding operation, a molding surface of a microneedle molding die is set downward, the molding surface is made to cover and close a top opening of the semi-closed cavity, the microneedle molding die and the semi-closed cavity are inverted, the semi-closed cavity is located above the microneedle molding die, the microneedle molding liquid is immersed in the molding surface, and vacuum suction is performed on a suction surface of the microneedle molding die to introduce the microneedle molding liquid into the microneedle cavity;
vacuum suction is maintained, the microneedle molding die and the semi-closed cavity are inverted again, the microneedle molding die and the semi-closed cavity are separated, film scraping operation is carried out on the molding surface, and microneedle molding liquid outside the microneedle cavity is scraped into the semi-closed cavity.
6. The layered microneedle molding method of claim 3, wherein a sealing ring is provided at an inner edge of the top opening of the semi-closed cavity, and the molding surface of the microneedle molding die abuts against the sealing ring to close the semi-closed cavity.
7. The layered microneedle molding method of claim 6, wherein the top opening inner edge of the semi-closed cavity is provided with a stepped groove for positioning the microneedle molding die, and the seal ring is positioned in the stepped groove.
8. The layered microneedle molding method of claim 3, wherein the microneedle molding die comprises a support plate and a plurality of microneedle molding zones, the shape of the microneedle molding zones is consistent with the shape of the substrate of the layered microneedle to be prepared, the plurality of microneedle molding zones are embedded on the support plate at intervals, the support plate is made of a rigid material, and the microneedle molding zones are made of a flexible breathable material.
9. The layered microneedle molding method of claim 1, wherein the surface air pressure of the molding face is greater than the surface air pressure of the suction face.
10. The layered microneedle molding method of claim 1, wherein the step of "microneedle molding" further comprises curing the microneedle molding fluid in the microneedle cavity.
11. The layered microneedle molding method according to claim 1, wherein in the "substrate molding" operation, a coating mold is used to cover the molding surface of the microneedle molding mold, a plurality of substrate molding through holes are formed in the coating mold at positions corresponding to the plurality of microneedle molding areas, a substrate molding liquid is applied to the surface of the coating mold, the substrate molding liquid is scraped into and fills the plurality of substrate molding through holes by a doctor blade, the curing operation is performed on the substrate molding liquid, the coating mold and the microneedle molding mold are separated, and the layered microneedle comprising the microneedle and the substrate is obtained by demolding.
12. The utility model provides a layering microneedle forming device, its characterized in that, includes semi-closed cavity, microneedle forming die and vacuum pumping device, open-top has been seted up to semi-closed cavity, microneedle forming die includes shaping face and pumping face, be provided with the microneedle shaping district that is used for shaping the microneedle on the microneedle shaping, the microneedle shaping district is ventilative material, just the microneedle shaping district extends to shaping face with pumping face, the microneedle shaping district is located the surface of shaping face is provided with a plurality of microneedle cavities, microneedle forming die detachably seals the open-top position of semi-closed cavity, just shaping face orientation semi-closed cavity, vacuum pumping device is used for right the microneedle forming die deviates from semi-closed cavity's surface carries out vacuum pumping.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202210674759.2A CN117261048A (en) | 2022-06-15 | 2022-06-15 | Layered microneedle molding method and layered microneedle molding device |
| PCT/CN2023/089167 WO2023241213A1 (en) | 2022-06-15 | 2023-04-19 | Layered microneedle molding method and layered microneedle molding device |
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| CN202210674759.2A CN117261048A (en) | 2022-06-15 | 2022-06-15 | Layered microneedle molding method and layered microneedle molding device |
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| JP2011012050A (en) * | 2009-06-03 | 2011-01-20 | Bioserentack Co Ltd | Microneedle array using porous substrate and method for producing the same |
| CN105643839B (en) * | 2015-12-24 | 2018-01-12 | 广州新济药业科技有限公司 | Mould for preparing micropin chip and preparation method thereof |
| CN105498082B (en) * | 2015-12-24 | 2017-10-27 | 广州新济药业科技有限公司 | Micropin chip and preparation method thereof |
| CN107050635A (en) * | 2016-12-30 | 2017-08-18 | 向卓林 | A kind of soluble micropin of segmented, microneedle array and preparation method thereof |
| CN109420245A (en) * | 2017-08-30 | 2019-03-05 | 优微（珠海）生物科技有限公司 | The manufacturing method of soluble micropin |
| WO2019058329A1 (en) * | 2017-09-22 | 2019-03-28 | Sabic Global Technologies B.V. | Methods and systems of producing microneedle arrays |
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