CN113908425A - Method for rapidly preparing microneedle patch - Google Patents
Method for rapidly preparing microneedle patch Download PDFInfo
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- CN113908425A CN113908425A CN202111305236.2A CN202111305236A CN113908425A CN 113908425 A CN113908425 A CN 113908425A CN 202111305236 A CN202111305236 A CN 202111305236A CN 113908425 A CN113908425 A CN 113908425A
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- microneedle
- methacryloylated
- rapidly preparing
- basal layer
- patch according
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 20
- 235000010413 sodium alginate Nutrition 0.000 claims description 20
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- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims description 7
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- OOIBFPKQHULHSQ-UHFFFAOYSA-N (3-hydroxy-1-adamantyl) 2-methylprop-2-enoate Chemical compound C1C(C2)CC3CC2(O)CC1(OC(=O)C(=C)C)C3 OOIBFPKQHULHSQ-UHFFFAOYSA-N 0.000 claims description 2
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- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 2
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Images
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/0204—Specific forms not provided for by any of groups A61K8/0208 - A61K8/14
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/733—Alginic acid; Salts thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
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- 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
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- A—HUMAN NECESSITIES
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- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0046—Solid microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Health & Medical Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
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- Hematology (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
The application provides a method for rapidly preparing a microneedle patch, which adopts a two-step method to prepare microneedles, and simultaneously, the microneedle body and the basal layer are made of different materials, so that the strength of the microneedle body is improved, better puncture skin and drug loading are facilitated, different materials are selected by the basal layer, the cost is low, the flexibility is good, and better use experience is obtained for users. The invention prepares the substrate layer by utilizing a photo-crosslinking curing mode, can be cured and molded only a few minutes at most, can greatly save equipment cost and production time, save energy consumption, reduce cost and improve production efficiency. And the two-step method for manufacturing the microneedle also greatly reduces the manufacturing cost of the microneedle and improves the manufacturing efficiency.
Description
Technical Field
The invention relates to the field of microneedle patch preparation, in particular to a method for quickly and efficiently preparing a microneedle patch.
Background
Most of the traditional preparation methods of the soluble microneedles are drying method molding, drying equipment with high temperature control requirements is required, and the equipment cost is high; in the heating and drying process, the active ingredients carried in the microneedles are easy to inactivate, and the microneedles are long in drying time, low in efficiency and high in cost.
Disclosure of Invention
The invention aims to provide a method for quickly preparing a microneedle patch, which aims to solve the technical defects in the prior art and adopts the technical scheme that:
the method comprises the following two steps: manufacturing a needle body part, and a second step: and (5) manufacturing a microneedle substrate layer.
Preferably, the material of the needle body part is sodium alginate with high G (alpha-L-guluronic acid) (G: M is more than 1.2: 1) content, and sodium hyaluronate with low molecular weight is mixed. Wherein the sodium alginate with high G content can enhance the hardness and strength of the needle body by drying and solidifying, thereby improving the pricking rate of the needle body and increasing the transdermal administration efficiency. In addition, sodium hyaluronate has low molecular weight and high hardness after drying, and can also play the role. Therefore, Sodium Alginate (SA) with high G content and sodium Hyaluronate (HA) with low molecular weight are selected. In addition, the research finds that the strength of the needle body can be further improved by mixing the two components, so that the scheme of mixing the two components is selected when the needle body is manufactured.
Preferably, the material of the basal layer is a methacrylated photosensitive biomaterial, including but not limited to one or more of methacryloylated polyvinyl alcohol (PVAMA), methacryloylated gelatin (GelMA), methacryloylated hyaluronic acid (HAMA), methacryloylated Chondroitin Sulfate (CSMA), methacryloylated sodium alginate (ALMA), methacryloylated carboxymethyl chitosan (CMCSMA), methacryloylated silk fibroin (FibMA), methacryloylated type I collagen (CollMA), methacryloylated elastin (ElaMA), methacryloylated chondroitin sulfate (ChSMA), methacryloylated Chitosan (CSMA), methacryloylated dextran (DexMA), and methacryloylated Polycaprolactone (PCLMMA).
Preferably, when the solution for preparing the microneedle needle body is prepared, the high-G sodium alginate is selected to have the viscosity of 10-200 cps; the low molecular weight sodium hyaluronate is selected from the specification of molecular weight of 1000-50000 Da. The content of sodium alginate is 3-20%, and the content of low molecular weight sodium hyaluronate is 5-16%. Related medicaments such as insulin, analgesic components, cosmetic components, vaccines and the like can be compounded according to the requirement of microneedle medicament loading.
When the solution for preparing the microneedle substrate layer is prepared, one or more of the methacryloylated photosensitive biomaterials are selected. The preparation concentration is 2-30% according to different types and molecular weights. Adding 0.3-6% w/w of photoinitiator. Photoinitiators include, but are not limited to, ionic photoinitiators, free radical photoinitiators. Such as benzoin and derivatives thereof, acetophenone derivatives, aromatic ketones. Such as TPO photoinitiators, TPO-L photoinitiators, 907 photoinitiators, ITX photoinitiators, EDB photoinitiators, 184 photoinitiators, 1173 photoinitiators, BDK photoinitiators, OMBB photoinitiators, CBP photoinitiators, etc.
Preferably, the microneedle body preparation solution is injected into a self-made unique microneedle mould, the redundant solution on the surface layer is removed, and the microneedle array without the basal layer is obtained after drying.
Preferably, the preparation of the microneedle body substrate layer is to pour the solution for preparing the substrate layer into a mould containing the solidified microneedle array, wherein the thickness of the solution is 0.5 mm-5 mm. And after centrifugation or vacuum pumping, respectively curing the substrate layer for several seconds to several minutes under the irradiation of ultraviolet light of 250 nm-420 nm according to different types of photoinitiators to form a film. Then drying for about 3-30 min, and demoulding to obtain the microneedle product with high needle body strength, which is used for cosmetic or painless transdermal administration.
Compared with the traditional preparation method, the traditional method mainly depends on drying, forming and film forming, the method needs drying equipment with high price and high temperature control requirement, the drying time is long-more than hours, the efficiency is low, and the cost is high. The microneedle manufactured by the two-step method has the advantages that the manufacturing cost of the microneedle is greatly reduced, the manufacturing efficiency is improved, the strength of the microneedle body is better, the microneedle can conveniently puncture skin and carry medicine, different materials are selected for the basal layer, the cost is low, the flexibility is good, and a user can obtain better use experience.
Drawings
Fig. 1 is a photograph of a microneedle patch prepared.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope and implementation of the present invention are not limited thereto. The present invention may be embodied in many different forms and is not limited to the embodiments described herein.
Example 1
Preparation of microneedles containing common SA Using two-step Process
The first step is as follows: and (3) manufacturing a needle body part, injecting a common SA (viscosity of 10-200 cps) solution into a microneedle mould, removing the redundant solution on the surface layer, and drying to obtain the microneedle array without the basal layer.
The second step is that: manufacturing a microneedle substrate layer, namely pouring a solution for preparation (containing 2-30% of methylacryloylated gelatin (GelMA) and 0.3-6% of w/w photoinitiator) into a mold for preparing the microneedle array without the substrate layer in the first step, wherein the thickness of the solution is 5mm, centrifuging or vacuumizing, respectively irradiating for several seconds to several minutes under 250-420 nm ultraviolet light according to different types of the photoinitiator, rapidly curing the substrate layer to form a film, and then drying for about 3-30 min to obtain the microneedle product with high needle body strength by demolding.
Example 2
Using a two-step process, microneedles containing high G content sodium alginate (G: M >1.2: 1) were prepared
The first step is as follows: and (3) manufacturing a needle body part, injecting a high-G-content sodium alginate (the viscosity is 10-200 cps) solution into a microneedle mould, removing the redundant solution on the surface layer, and drying to obtain the microneedle array without the basal layer.
The second step is that: and (2) manufacturing a microneedle substrate layer, namely pouring a solution for preparation (containing 2-30% of methylacryloylated gelatin (GelMA) and 0.3-6% of w/w photoinitiator) into a mold for preparing the microneedle array without the substrate layer in the step one, wherein the thickness of the solution is 0.5mm, centrifuging or vacuumizing, respectively irradiating for several seconds to several minutes under 250-420 nm ultraviolet light according to different types of the photoinitiator, rapidly curing the substrate layer to form a film, and then drying for about 3-30 min to obtain the microneedle product with high needle body strength by demolding.
Example 3
Using a two-step procedure, microneedles containing high G content sodium alginate (G: M >1.2: 1) and low molecular weight HA were prepared
The first step is as follows: manufacturing a needle body part, mixing 3-20% of high-G sodium alginate (G: M is more than 1.2: 1) with the viscosity of 10-200 cps and 5-16% of low-molecular-weight HA, injecting the mixed solution into a microneedle mould, removing the redundant solution on the surface layer, and drying to obtain the microneedle array without a basal layer.
The second step is that: manufacturing a microneedle substrate layer, namely pouring a solution for preparation (containing 2-30% of methylacryloylated gelatin (GelMA) and 0.3-6% of w/w photoinitiator) into a mold for preparing the microneedle array without the substrate layer in the first step, wherein the thickness of the solution is 5mm, centrifuging or vacuumizing, respectively irradiating for several seconds to several minutes under 250-420 nm ultraviolet light according to different types of the photoinitiator, rapidly curing the substrate layer to form a film, and then drying for about 3-30 min to obtain the microneedle product with high needle body strength by demolding.
The strength of the microneedle bodies prepared in examples 1 to 3 was measured, and the data were as follows:
as can be seen from the above, the needle body of the invention adopts SA with high G content (G: M is more than 1.2: 1) as the raw material, so that the prepared microneedle has high strength, high puncture rate and high administration effect. The mechanical strength (breaking stress) of the microneedle prepared by the common SA is 0.03-0.09N, the mechanical strength of the microneedle prepared by the SA with high G content can reach 0.22-0.31N, and the mechanical strength of the microneedle compounded with the SA with low molecular weight can reach more than 0.4N, so that the microneedle can meet daily use.
Compared with the traditional preparation method, the two-step method for preparing the microneedle has the advantages of short preparation time, low cost, high efficiency (see the table below), less labor, higher working efficiency, lower production cost, higher strength of the needle body and standard compliance of the basal layer.
Claims (10)
1. A method for rapidly preparing a microneedle patch is characterized by comprising the following steps: the method comprises the following two steps: manufacturing a needle body part, and a second step: and (5) manufacturing a microneedle substrate layer.
2. The method for rapidly preparing a microneedle patch according to claim 1, wherein: the needle body part is prepared by injecting a microneedle body preparation solution into a microneedle mould, removing excess solution on the surface layer and drying to obtain the microneedle array without the basal layer.
3. The method for rapidly preparing a microneedle patch according to claim 1, wherein: and the basal layer is formed by pouring the solution for preparing the basal layer into the mould for preparing the microneedle array without the basal layer in the first step, centrifuging or vacuumizing, and then solidifying.
4. The method for rapidly preparing the microneedle patch according to claim 2, wherein: the preparation liquid of the microneedle body comprises sodium alginate with high G content (G: M is more than 1.2: 1) and sodium hyaluronate with low molecular weight.
5. The method for rapidly preparing the microneedle patch according to claim 4, wherein: the content of sodium alginate in the microneedle body preparation liquid is 3-20%, the viscosity is 10-200 cps, the content of low-molecular-weight sodium hyaluronate is 5-16%, and the molecular weight is 1000-50000 Da.
6. The method for rapidly preparing the microneedle patch according to claim 4, wherein: the microneedle body preparation solution can be compounded with medicines.
7. The method for rapidly preparing the microneedle patch according to claim 6, wherein: the compound medicine comprises any one or more of insulin, an analgesic component, a cosmetic component and a vaccine.
8. The method for rapidly preparing a microneedle patch according to claim 1, wherein: the main component of the micro-needle basal layer is a methacryloylated photosensitive biomaterial, and the micro-needle basal layer comprises one or more of methacryloylated polyvinyl alcohol (PVAMA), methacryloylated gelatin (GelMA), methacryloylated hyaluronic acid (HAMA), methacryloylated Chondroitin Sulfate (CSMA), methacryloylated sodium alginate (ALMA), methacryloylated carboxymethyl chitosan (CMCSMA), methacryloylated fibroin (FibMA), methacryloylated type I collagen (Col1MA), methacryloylated elastin (ElaMA), methacryloylated chondroitin sulfate (ChSMA), methacryloylated Chitosan (CSMA), methacryloylated dextran (DexMA) and methacryloylated Polycaprolactone (PCLMMA).
9. The method for rapidly preparing a microneedle patch according to claim 1, wherein: when the microneedle substrate layer solution is prepared, a methacryloylated photosensitive biological material is selected firstly, then the concentration of the prepared solution is 2% -30% according to the difference of types and molecular weights, 0.3% -6% w/w of a photoinitiator is added, and the photoinitiator comprises but is not limited to an ionic photoinitiator and a free radical photoinitiator.
10. The method for rapidly preparing a microneedle patch according to claim 3, wherein: the thickness of the microneedle basal layer liquid is 0.5 mm-5 mm.
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