CN112516452A - Frozen microneedle array and preparation method and application thereof - Google Patents
Frozen microneedle array and preparation method and application thereof Download PDFInfo
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- CN112516452A CN112516452A CN202011505621.7A CN202011505621A CN112516452A CN 112516452 A CN112516452 A CN 112516452A CN 202011505621 A CN202011505621 A CN 202011505621A CN 112516452 A CN112516452 A CN 112516452A
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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
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
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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
Abstract
The invention discloses a frozen microneedle array and a preparation method and application thereof, based on the principle that water-containing substances can be hardened from soft by freezing, the frozen microneedle array is prepared by introducing a freezing process in the template replication process, is simple to operate, convenient to popularize and capable of being produced in large scale, the prepared frozen microneedle array can be prepared from various solutions or hydrogel, the limitation of microneedles on material selection is eliminated, and in addition, the freezing process hardly damages the activity of bioactive substances, so that the frozen microneedle array has the capability of carrying various bioactive substances, has universality and is expected to be used in various biological and medical fields.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a frozen microneedle array and a preparation method and application thereof.
Background
The micro-needle array mainly comprises a substrate and a micro-scale needle point, and can penetrate through an epidermal layer while not contacting with a capillary and a nerve ending, so that the permeability and the drug absorption rate of the skin can be remarkably enhanced, and a minimally invasive and painless transdermal drug delivery mode is provided. In recent years, the field of microneedles has rapidly developed, however, some challenges are still faced. First, the materials that comprise microneedle arrays need to have mechanical strength to puncture the epidermis, which greatly limits the range of material choices, e.g., some materials with higher water content cannot be used. In addition, microneedles can be used to carry and deliver some bioactive substances, but these bioactive substances tend to be easily inactivated, and have high and different requirements on the environment and the preparation process. Therefore, development of a general-purpose microneedle capable of carrying a plurality of bioactive substances has been desired.
After freezing, water can form hard ice, and the icing process in nature is a typical example of softening to rigidity. Inspired by the above, after the micro-needle array is frozen, the hardness of the water-containing material forming the micro-needle array is obviously increased, which is enough to puncture the epidermis, and the limitation of the material to the micro-needles is broken. In addition, many bioactive substances are stored in a freezing environment and can recover activity after being recovered at normal temperature, so that the frozen microneedles cannot damage the bioactive substances and are expected to become a universal delivery platform for different bioactive substances.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a frozen microneedle array and a preparation method and application thereof aiming at the defects of the prior art, the frozen microneedle array is prepared by introducing a freezing process in template replication, and the prepared microneedles get rid of the limitation of materials and have good universality.
In order to achieve the technical purpose, the technical scheme adopted by the invention is as follows: a method for preparing a frozen microneedle array, comprising the steps of:
s1, dripping the microneedle raw material liquid on the surface of the polydimethylsiloxane template with the hole array, fully filling the microneedle raw material liquid in the holes of the polydimethylsiloxane template, removing the redundant microneedle raw material liquid outside the holes, and then curing the microneedle raw material liquid in the hole array;
s2, further covering a layer of wet gauze on the hole array of the polydimethylsiloxane template to serve as a microneedle substrate;
s3, placing the polydimethylsiloxane template, the microneedle raw material liquid and the microneedle substrate integrally at a low temperature for freezing treatment, and then peeling the frozen material from the polydimethylsiloxane template to obtain the frozen microneedle array.
Further, the holes of the hole array are in an inverted cone shape or an inverted square pyramid shape.
Further, when the holes are reverse conical holes, the hole pitch is 800 μm, the hole depth is 850 μm, and the hole diameter is 150-600 μm; when the holes are reverse regular quadrangular pyramid holes, the pitch of the holes is 200-800 μm, the depth of the holes is 300-850 μm, and the bottom side length of the holes is 150-600 μm.
Further, in step S1, the microneedle material liquid is selected from one or more than two of methacrylate gelatin, methylated hyaluronic acid, methylated alginic acid and methylated silk fibroin, and the microneedle material liquid is cured by mixing a photoinitiator with a volume fraction of 1% and ultraviolet irradiation for 20S to 1min, wherein the photoinitiator is 2-hydroxy-2-methyl propiophenone.
Further, in step S1, the microneedle material solution is made of sodium alginate, and is solidified by mixing an excess calcium chloride solution with a volume fraction of 10% and absorbing an upper calcium chloride solution after sufficient reaction.
Further, in step S1, the microneedle material liquid is selected from matrigel, and the microneedle material liquid is cured by standing at 37 ℃ for a certain period of time.
Further, in step S1, the method for filling the holes with the microneedle material solution is centrifugation at 1000rpm for 3min or vacuum treatment for 5 min.
Further, in step S3, the freezing treatment is performed under conditions of-20 ℃ or lower for freezing for 12 hours or more, and the storage temperature of the frozen microneedle array is 0 ℃ or lower.
The invention also provides a frozen microneedle array, which is prepared by adopting the preparation method of the frozen microneedle array.
The invention also provides an application of the frozen microneedle array in preparation of a drug-loaded frozen microneedle, wherein the drug-loaded frozen microneedle is loaded in a microneedle of the frozen microneedle array as a bioactive substance, and the bioactive substance comprises micromolecules, proteins and probiotics.
Compared with the prior art, the invention has the beneficial effects that:
1) the invention provides a frozen microneedle array which can be made of hydrogel and other various water-containing materials, and simultaneously maintains a certain mechanical strength, so that the limitation of the materials on the traditional microneedles is broken;
2) the frozen microneedle array provided by the invention can be used for carrying various bioactive substances including small molecules, proteins and probiotics, ensures the activity of the bioactive substances, and can be used in various biomedical fields.
3) The invention provides a method for preparing a frozen microneedle array by adding a freezing process in a template copying process based on the principle that water-containing substances can be hardened from soft by freezing, the method is simple and convenient, easy to operate and low in technical requirement, the freezing process hardly damages the activity of bioactive substances, and the method has universality and is beneficial to popularization and industrial preparation.
Drawings
FIG. 1 is a flow chart illustrating the preparation of a frozen microneedle array according to the present invention;
FIG. 2 is a structural diagram of a frozen methacrylate gelatin microneedle carrying rhodamine B in example 1 of the present invention;
FIG. 3 is a diagram of a frozen calcium alginate microneedle carrying green fluorescent-labeled insulin according to example 2 of the present invention;
FIG. 4 is a fluorescent image of a rat skin punctured by a frozen calcium alginate microneedle carrying green fluorescent-labeled insulin according to example 2 of the present invention;
fig. 5 is a top fluorescent view of a frozen microneedle array of the present invention: wherein, A is the frozen methacrylate gelatin microneedle carrying the rhodamine B of the embodiment 1; b is the frozen calcium alginate microneedle carrying the green fluorescent labeled insulin of example 2, and C is the frozen matrigel microneedle carrying the Bacillus subtilis of example 3.
Wherein the reference numerals are: microneedle raw material liquid 1, a polydimethylsiloxane template 2 and gauze 3.
Detailed Description
In order to make those skilled in the art better understand the technical solution of the present invention, the following detailed description of the embodiments of the present invention is provided with reference to the accompanying drawings.
The experimental procedures used in the examples below are, unless otherwise specified, conventional procedures and the reagents, methods and equipment used are, unless otherwise specified, conventional in the art.
The present invention provides a frozen microneedle array, referring to fig. 1, the preparation of which comprises the following steps:
s1, dripping the microneedle raw material liquid 1 on the surface of a polydimethylsiloxane template 2 with a hole array, fully filling the microneedle raw material liquid in the holes of the polydimethylsiloxane template 2, removing the excess microneedle raw material liquid 1 outside the holes, and then curing the microneedle raw material liquid 1 in the hole array;
wherein, the holes of the hole array are in an inverted cone shape or an inverted square pyramid shape; when the holes are reverse conical holes, the hole pitch is 800 μm, the hole depth is 850 μm, and the hole diameter is 150-600 μm; when the holes are reverse regular quadrangular pyramid holes, the pitch of the holes is 200-800 μm, the depth of the holes is 300-850 μm, and the bottom side length of the holes is 150-600 μm.
Further, the method for fully filling the microneedle raw material liquid 1 in the holes is centrifugation at 1000rpm for 3min or vacuum treatment for 5 min;
s2, further covering a layer of wet gauze 3 on the hole array of the polydimethylsiloxane template 2 to serve as a microneedle substrate;
s3, freezing the polydimethylsiloxane template 2, the microneedle raw material liquid 1 and the microneedle substrate at a low temperature for more than 12h under the condition of freezing below-20 ℃, then stripping the frozen material from the polydimethylsiloxane template 2 to obtain a frozen microneedle array, and storing the frozen microneedle array at a temperature below 0 ℃.
In step S1, microneedle material solution 1 is selected from one or more of methacrylate gelatin, methylated hyaluronic acid, methylated alginic acid, methylated silk fibroin, sodium alginate, and matrigel;
when the microneedle raw material liquid 1 is selected from one or more than two materials of methacrylate gelatin, methylated hyaluronic acid, methylated alginic acid and methylated silk fibroin, the microneedle raw material liquid 1 is cured by mixing a photoinitiator with the volume fraction of 1% and carrying out ultraviolet irradiation for 20 s-1 min, wherein the photoinitiator is 2-hydroxy-2-methyl propiophenone; when the microneedle raw material liquid 1 is made of a sodium alginate material, the microneedle raw material liquid 1 is solidified by mixing an excessive calcium chloride solution with the volume fraction of 10 percent, and absorbing an upper calcium chloride solution after full reaction; when the microneedle material fluid 1 is selected from matrigel, the microneedle material fluid 1 is cured by standing at 37 ℃ for a certain period of time.
The invention also provides application of the frozen microneedle array in preparation of the drug-carrying frozen microneedle, wherein the drug-carrying frozen microneedle is loaded inside a microneedle of the frozen microneedle array as a bioactive substance, and is specifically mixed in a microneedle raw material liquid, and the bioactive substance comprises small molecules, proteins and probiotics.
Example 1
A frozen methacrylate gelatin microneedle carrying rhodamine B is prepared by the following steps:
s1, preparing a drug-loaded microneedle stock solution A: preparing an aqueous solution containing 15% by mass of methacrylate gelatin and 1% by volume of 2-hydroxy-2-methyl propiophenone, and mixing 1mg/mL of rhodamine B into the aqueous solution;
s2 preparation of drug-loaded frozen microneedle array
S21, dropwise adding 100 mu l of drug-loaded microneedle raw material liquid A on the surface of a polydimethylsiloxane template 2 with an inverted cone-shaped hole array (the hole distance is 200 mu m, the hole depth is 300 mu m, and the hole diameter is 150 mu m) by using a pipette, carrying out vacuum treatment for 5min to fully fill the inverted cone-shaped holes, sucking the excess microneedle raw material liquid 1 outside the inverted cone-shaped holes by using the pipette, carrying out ultraviolet irradiation for 20S to solidify the drug-loaded microneedle raw material liquid A in the inverted cone-shaped holes to obtain a drug-loaded tip A;
s22, covering a layer of wet gauze 3 on the hole array of the polydimethylsiloxane template 2 to be used as a microneedle substrate;
s23, placing the polydimethylsiloxane template 2, the drug-loaded tip A and the microneedle substrate integrally at-80 ℃ for freezing for 12h, then peeling the frozen material from the polydimethylsiloxane template 2 to obtain the frozen methacrylate gelatin microneedle carrying the rhodamine B shown in figure 2, and storing the frozen methacrylate gelatin microneedle below 0 ℃ for later use.
Example 2
A frozen calcium alginate microneedle carrying green fluorescence labeled insulin is prepared by the following steps:
s1, preparing a drug-loaded microneedle stock solution B: preparing a very low-viscosity sodium alginate solution with the mass fraction of 4%, and mixing green fluorescence labeled insulin (the final content is 0.5 mg/mL) into the solution;
s2 preparation of drug-loaded frozen microneedle array
S21, dropwise adding 400 mu l of drug-loaded microneedle raw material liquid B onto the surface of a polydimethylsiloxane template 2 with an inverted cone-shaped hole array (the hole pitch is 700 mu m, the hole depth is 850 mu m, and the hole diameter is 600 mu m) by using a pipette, centrifuging for 3min at 1000rpm to fully fill the drug-loaded microneedle raw material liquid B into the inverted cone-shaped holes, sucking the excessive drug-loaded microneedle raw material liquid B outside the inverted cone-shaped holes by using the pipette, dropwise adding 400 mu l of calcium chloride solution with the mass fraction of 10% onto the hole surfaces, after fully reacting for 15min, sucking the calcium chloride solution, and curing and molding the drug-loaded microneedle raw material liquid B to obtain a drug-loaded tip B;
s22, covering a layer of wet gauze 3 on the hole array of the polydimethylsiloxane template 2 to be used as a microneedle substrate;
s23, placing the polydimethylsiloxane template 2, the drug-loaded tip B and the microneedle substrate integrally at-20 ℃ for freezing for 48h, then peeling the frozen material from the polydimethylsiloxane template 2 to obtain the frozen calcium alginate microneedle carrying the green fluorescence labeled insulin shown in figure 3, and storing at the temperature below 0 ℃ for later use.
Example 3
A frozen matrigel microneedle carrying bacillus subtilis is prepared by the following steps:
s1, preparation of microneedle material liquid C carrying living microorganisms: bacillus subtilis (from North Nabiont Co., Ltd.) was mixed with a matrigel (U.S.A.)Corning corporation) wherein the final content of Bacillus subtilis is 108/mL；
S2 preparation of drug-loaded frozen microneedle array
S21, dropwise adding 300 mu l of drug-loaded microneedle raw material liquid C on the surface of a polydimethylsiloxane template 2 with an inverted square pyramid-shaped hole array (the hole pitch is 400 mu m, the hole depth is 800 mu m, and the hole diameter is 600 mu m) by using a pipette, centrifuging for 3min at 1000rpm to fully fill the drug-loaded microneedle raw material liquid C in the inverted square pyramid-shaped holes, sucking the excessive drug-loaded microneedle raw material liquid C outside the inverted cone-shaped holes by using the pipette, placing the drug-loaded microneedle raw material liquid C at 37 ℃ for 20min, and curing the drug-loaded microneedle raw material liquid C into gel to obtain a drug-loaded tip C;
s22, covering a layer of wet gauze 3 on the hole array of the polydimethylsiloxane template 2 to be used as a microneedle substrate;
s23, placing the polydimethylsiloxane template 2, the drug-loaded tip C and the microneedle substrate integrally at-80 ℃ for freezing for 24h, then peeling the frozen material from the polydimethylsiloxane template 2 to obtain the frozen matrigel microneedle loaded with the bacillus subtilis, and storing the frozen matrigel microneedle at the temperature below 0 ℃ for later use.
Example 4: mechanical strength verification of frozen microneedle arrays prepared according to the invention
In order to verify that the frozen microneedle array prepared by the invention has enough mechanical strength and can pierce skin, the back of a white mouse is prepared, and the frozen calcium alginate microneedle loaded with green fluorescent marker insulin prepared in example 2 is reversely buckled on the back skin of the white mouse wiped by alcohol; immediately thereafter, the microneedle substrate was removed after the ice had melted by pressing with a force of 10N for 2 min.
As can be seen from the fluorescence photograph of rat skin shown in FIG. 4, the tip of the frozen microneedle array has a certain mechanical strength, and can pierce the rat skin and release the drug therein, thereby getting rid of the limitation of microneedle on material selection.
Example 5: drug-loading verification of frozen microneedle arrays prepared in the invention
In order to verify that the frozen microneedle array prepared by the invention can effectively carry bioactive substances, the frozen methacrylate gelatin microneedles carrying rhodamine B in example 1 and the frozen calcium alginate microneedles carrying green fluorescence labeled insulin in example 2 are observed under a fluorescence microscope, and the results are shown in fig. 5A and fig. 5B.
As can be seen from fig. 5A and 5B, both of the frozen microneedles showed strong fluorescence, indicating that the frozen microneedle array of the present application can successfully load the drug and preserve the fluorescence properties thereof.
Further, the Bacillus subtilis-carrying frozen matrigel microneedles of example 3 were rewound on a polydimethylsiloxane template 2, returned to room temperature, immersed in a phosphate buffer containing a viable bacterial stain SYTO (0.1% by volume) for 30min, and then observed under a fluorescence confocal microscope, with the results shown in FIG. 5C.
As can be seen in fig. 5C, bacillus subtilis was heavily stained, demonstrating its successful loading and activity retention in frozen microneedles.
The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-mentioned embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may be made by those skilled in the art without departing from the principle of the invention.
Claims (10)
1. A method for preparing a frozen microneedle array, comprising the steps of:
s1, dripping the microneedle raw material liquid (1) on the surface of a polydimethylsiloxane template (2) with a hole array, fully filling the microneedle raw material liquid into the holes of the polydimethylsiloxane template (2), removing the excess microneedle raw material liquid (1) outside the holes, and then curing the microneedle raw material liquid (1) in the hole array;
s2, further covering a layer of wet gauze (3) on the hole array of the polydimethylsiloxane template (2) to be used as a microneedle substrate;
s3, the polydimethylsiloxane template (2), the microneedle raw material liquid (1) and the microneedle substrate are integrally frozen at low temperature, and then the frozen material is peeled from the polydimethylsiloxane template (2) to obtain the frozen microneedle array.
2. The method for preparing a frozen microneedle array according to claim 1, wherein: the holes of the hole array are in an inverted cone shape or an inverted square pyramid shape.
3. The method for preparing a frozen microneedle array according to claim 2, wherein: when the holes are reverse conical holes, the hole pitch is 800 μm, the hole depth is 850 μm, and the hole diameter is 150-600 μm; when the holes are reverse regular quadrangular pyramid holes, the pitch of the holes is 200-800 μm, the depth of the holes is 300-850 μm, and the bottom side length of the holes is 150-600 μm.
4. The method for preparing a frozen microneedle array according to claim 1, wherein: in step S1, the microneedle material liquid (1) is selected from one or more of methacrylate gelatin, methylated hyaluronic acid, methylated alginic acid, and methylated silk fibroin, the microneedle material liquid (1) is cured by mixing a photoinitiator with a volume fraction of 1% and ultraviolet irradiation for 20S to 1min, and the photoinitiator is 2-hydroxy-2-methyl propiophenone.
5. The method for preparing a frozen microneedle array according to claim 1, wherein: in step S1, the microneedle material liquid (1) is made of sodium alginate, and the microneedle material liquid (1) is solidified by mixing an excess calcium chloride solution with a volume fraction of 10% and absorbing an upper calcium chloride solution after sufficient reaction.
6. The method for preparing a frozen microneedle array according to claim 1, wherein: in step S1, the microneedle material liquid (1) is selected from matrigel, and the microneedle material liquid (1) is cured by standing at 37 ℃ for a certain period of time.
7. The method for preparing a frozen microneedle array according to claim 1, wherein: in step S1, the method for filling the microneedle material liquid (1) in the holes is centrifugation at 1000rpm for 3min or vacuum treatment for 5 min.
8. The method for preparing a frozen microneedle array according to claim 1, wherein: in step S3, the freezing condition is below-20 deg.C for more than 12h, and the storage temperature of the frozen microneedle array is below 0 deg.C.
9. A frozen microneedle array prepared by the method for preparing a frozen microneedle array according to any one of claims 1 to 8.
10. The use of the frozen microneedle array of claim 9 for the preparation of a drug-loaded frozen microneedle, wherein the drug-loaded frozen microneedle is loaded with a bioactive substance comprising small molecules, proteins, probiotics inside the microneedle of the frozen microneedle array.
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| CN202011505621.7A CN112516452A (en) | 2020-12-18 | 2020-12-18 | Frozen microneedle array and preparation method and application thereof |
| PCT/CN2021/136345 WO2022127662A1 (en) | 2020-12-18 | 2021-12-08 | Frozen microneedle array, preparation method therefor and application thereof |
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| CN113521523A (en) * | 2021-07-14 | 2021-10-22 | 温州医科大学慈溪生物医药研究院 | Microneedle drug delivery system for treating wound surface and application thereof |
| CN114558116A (en) * | 2022-03-09 | 2022-05-31 | 西安交通大学 | Microneedle with accurate controllable pulse type drug release function and preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022127662A1 (en) * | 2020-12-18 | 2022-06-23 | 南京鼓楼医院 | Frozen microneedle array, preparation method therefor and application thereof |
| CN113521523A (en) * | 2021-07-14 | 2021-10-22 | 温州医科大学慈溪生物医药研究院 | Microneedle drug delivery system for treating wound surface and application thereof |
| CN114558116A (en) * | 2022-03-09 | 2022-05-31 | 西安交通大学 | Microneedle with accurate controllable pulse type drug release function and preparation method |
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| WO2022127662A1 (en) | 2022-06-23 |
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