CN114272374B - Photosensitive controlled-release microneedle and preparation method thereof - Google Patents
Photosensitive controlled-release microneedle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a photosensitive controlled release microneedle and a preparation method thereof, wherein the microneedle comprises a shell and a cavity, and the cavity is prepared by a laser pore-forming mode; the needle body is formed by crosslinking a poly (methyl vinyl ether/maleic acid) copolymer and an acrylate copolymer; the cavity is used for loading the up-conversion nano powder and the active medicine; the micro-needle can be excited by near infrared light, the up-conversion nano powder in the micro-needle is converted into ultraviolet light, and the polymer is de-crosslinked under the stimulation of the ultraviolet light, so that the controlled release effect is achieved. The preparation method can prepare standardized products, and the release rate of the medicine is adjusted according to illumination, so that the use is convenient.
Description
Technical Field
The invention belongs to the technical field of transdermal drug delivery, and particularly relates to a photosensitive controlled-release microneedle and a preparation method thereof.
Background
The sustained-release microneedle is a novel transdermal drug delivery preparation which can realize continuous and gentle delivery of drugs after being applied to the skin, is suitable for long-term drug delivery and narrow-window drug use, has the advantages of reducing drug administration times, improving the drug administration safety and convenience of patients and the like, greatly improves the drug administration compliance of the patients, and plays an important role in the research of novel microneedle drug delivery preparations. However, in the prior art, the sustained release microneedles mostly adopt a strategy that the microneedles absorb body fluid and swell to release the drugs, such as patents CN112472659 and CN102202720, etc., and such sustained release microneedles belong to the preset setting of drug sustained release rate, and cannot be uniformly applied to different drugs or different disease degrees, that is, cannot achieve controlled release. Hardy et al disclose a light-operated slow release microneedle, physically wrap up the conjugate of benzoin and adriamycin by polyacrylic acid cross-linked polymer, when receiving the light, the conjugate chain of benzoin and adriamycin is broken, release medicament adriamycin; under the strategy, on one hand, the chemical structure of the drug is limited; on the other hand, the photosensitive group can be broken to release the drug under the ultraviolet illumination, and the microneedle can not release the drug without the illumination; on the other hand, the skin is damaged due to the failure of precise control during irradiation with ultraviolet light, and the damage to human body is very large (Hardy JG, Larraneta E, Donnelly R F, et al. hydrogel-forming microorganisle array systems from light-reactive materials for on-demand transdermal drug delivery [ J ]. molecular pharmaceuticals, 2016,13 (3)).
Disclosure of Invention
In order to solve the technical problems, the invention provides a photosensitive controlled release microneedle which comprises a polymer shell crosslinked by photosensitive groups and a cavity capable of loading a medicament and up-conversion nano powder. The upconversion nanometer powder can convert 980nm near infrared light into 350-360 nm ultraviolet light, and the crosslinking density of the polymer shell is reduced after the polymer shell is stimulated, so that the slow release rate can be regulated and controlled according to the illumination time. The 980nm near-infrared light hardly has damage to human bodies and has strong penetrability, and the polymer shell wraps the up-conversion nano powder, so that the radiation of ultraviolet rays to other tissues in the human body can be reduced, and the safety is high.
The invention is realized by the following technical scheme:
a photosensitive controlled release microneedle comprises a shell and a cavity, wherein the shell comprises a needle body and a substrate.
The needle body is formed by crosslinking a poly (methyl vinyl ether/maleic acid) copolymer and an acrylate copolymer; the acrylate copolymer is formed by copolymerizing an acrylate compound and a monomer A, wherein the monomer A has the following molecular structure:
further, the acrylate compound is selected from one or a combination of methyl methacrylate, ethyl acrylate and methyl acrylate.
Further, the poly (methyl vinyl ether/maleic acid) copolymer is in a liquid state, and the intrinsic viscosity (1% aqueous solution) thereof is 2.5 to 10 dL/g.
In the microneedle forming process, carboxyl in the poly (methyl vinyl ether/maleic acid) copolymer and hydroxyl in the acrylate copolymer are subjected to condensation esterification reaction to form a bond. When exposed to ultraviolet light, the ester bonds are cleaved, thereby decrosslinking.
The invention provides a preparation method of a monomer A, which comprises the following steps: dissolving 4' -hydroxy benzoin and 2-bromoethyl methacrylate in acetone, adding potassium carbonate, heating to 60 ℃, performing reflux reaction for 8 hours, and purifying to obtain a monomer A which is white solid powder.
The invention provides a preparation method of an acrylate copolymer, which comprises the following steps: mixing an acrylate monomer and a monomer A according to a feeding ratio, adding an initiator, and heating to 80-100 ℃ for reaction.
The invention provides a preparation method of the microneedle, which comprises the following steps:
(1) preparation of an acylchlorinated poly (methyl vinyl ether/maleic acid) copolymer: mixing poly (methyl vinyl ether/maleic acid) copolymer and thionyl chloride in chloroform, heating to 60 ℃, stirring for 6h, evaporating to volatilize the solvent, drying the obtained product in an oven at 80 ℃ for 24h to obtain acyl chlorinated poly (methyl vinyl ether/maleic acid) copolymer, and placing the copolymer in a dry environment for later use.
(2) Preparing a casting solution: in polyethylene glycol, acyl chloride poly (methyl vinyl ether/maleic acid) copolymer and acrylate copolymer are mixed, heated to 60 ℃, stirred uniformly and ultrasonically treated to remove bubbles.
(3) And (3) injecting the casting liquid obtained in the step (2) into a PDMS mold, performing ultrasonic treatment, leveling until no liquid residue is left on the upper surface of the mold, and curing and crosslinking in an oven at 80 ℃ for 24 hours.
(4) And (3) carrying out pore-forming on the maximum cross section of the needle body by utilizing laser pore-forming, wherein the pore size is 1/3-1/5 of the volume of the needle body.
(5) And injecting the liquid sol carrying the upconversion nanometer powder and the active drug into the hole, and continuously putting the hole into an oven for drying and curing.
(6) And (5) pouring a layer of film-forming polymer on the mould in the step (5), pressing the film-forming polymer after being strickled, putting the film-forming polymer into an oven for continuous drying and film forming, and demoulding to obtain the microneedle array for the controlled release medicament.
The upconversion nanometer powder adopted by the invention is NaYF 4 :Bi,Yb。
The up-conversion nano powder and the active drug are dispersed in a solution containing sol, the sol is in a solid state after being dried, and different sols can be independently selected according to the property of the drug.
The polyethylene glycol is preferably PEG-200-400, is used as a plasticizer and is also used as a solvent, and can reduce the generation of bubbles due to solvent volatilization in the needle body curing process.
The polymer shell has high strength when being dried, can pierce the stratum corneum and the epidermis, and swells and softens after absorbing body fluid, thereby providing a passage for the slow release of the drug in the cavity, namely the micro-needle has certain slow release under the condition of not receiving illumination; after receiving irradiation, the crosslinking density of the microneedle is reduced, the slow release is further accelerated, and the slow release rate of the microneedle can be adjusted according to the illumination time.
The invention has the following advantages and beneficial effects:
the preparation method can prepare standardized products, and the release rate of the medicine is adjusted according to illumination, so that the use is convenient. The patch containing the microneedle array only swells and does not dissolve after absorbing water in body fluid in the skin, can be pasted on the surface of the skin for a long time to absorb the body fluid to form a micro-channel in a needle body to achieve the administration effect of slow release and controlled release, can be taken out integrally after administration is finished, and has excellent mechanical property and obvious controlled release effect.
Drawings
Fig. 1 is a schematic structural view of a microneedle patch for controlled release of a drug.
Fig. 2 is a schematic view of a microneedle.
FIG. 3 is a graph of the emission spectrum of the upconversion nanopowder under excitation by 980nm light.
Fig. 4 is a graph of pressure versus displacement for the sample.
FIG. 5 is a graph of swelling rate of samples in PBS solution at different illumination times as a function of time.
FIG. 6 is a graph showing the time-dependent drug release rate of samples under different illumination time.
Detailed Description
The present invention will be described in further detail with reference to specific examples, which are not intended to limit the present invention in any manner. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Referring to the attached drawing 1, the microneedle patch comprises a shell and a cavity, wherein the shell comprises a needle body and a substrate, and the cavity is formed by laser pore-forming.
The length of the needle body is 300-600 mu m, and the diameter of the maximum cross-sectional area (namely the upper surface) is 150-200 mu m. The thickness of the substrate is 0.5-1 mm. The volume of the cavity is 1/3-1/5 of the volume of the needle body.
A schematic representation of a photosensitive controlled release microneedle is shown in figure 2.
The needle body is formed by crosslinking a poly (methyl vinyl ether/maleic acid) copolymer and an acrylate copolymer.
The cavity is used for loading the drug containing the upconversion nanopowder and the active drug.
1. Method for preparing acrylic ester copolymer
The acrylic ester copolymer is a copolymer of a monomer A and an acrylic ester monomer, and the acrylic ester monomer can be one or a combination of methyl methacrylate, ethyl acrylate and methyl acrylate.
(1) Preparation of monomer A: adding 4' -hydroxy benzoin and 2-bromoethyl methacrylate into acetone, adding potassium carbonate, heating to 60 ℃, refluxing and reacting for 8h, filtering after the reaction is finished, performing silica gel column chromatography after spin-drying, and drying by using DCM as an eluent to obtain white solid powder. The feeding molar ratio of the 4 '-hydroxy benzoin to the 2-bromoethyl methacrylate is 1:1.2, the adding amount of potassium carbonate is 2% of the mass of the 4' -hydroxy benzoin, and the yield is 65-78%.
Of monomers A 1 H-NMR，δ(CDCl 3 )：2.11(C＝C-CH3,s,3)，4.37～4.58(O-CH2-CH2-O,t,4)，5.18(O-H,s,1)6.42～6.44(Ar-CH-CO,d,1)，6.57(C＝CH2,s,2)，6.77～6.80(Ar 1 -H,d,2)，7.26～6.29(Ar 1 -H,d,2)，7.55～7.61(Ar 2 -H,t,2)，7.65～7.67(Ar 2 -H,t,1)，8.02～8.04(Ar 2 -H,d,2)。
(2) Preparing an acrylate copolymer, weighing an acrylate monomer and a monomer A, dissolving the acrylate monomer and the monomer A in toluene, adding BPO, heating to 90 ℃, polymerizing for 3 hours, carrying out reduced pressure rotary evaporation on the obtained reaction liquid at 120-150 ℃ to obtain a crude product, dissolving the crude product with DCM again, adding an isovolumetric sodium thiosulfate aqueous solution for washing until the starch potassium iodide test paper does not turn blue, washing with deionized water, and carrying out rotary drying on an organic phase to obtain the acrylate copolymer; the molar ratio of the acrylate monomer to the monomer A is 3-5: 1, and the addition amount of the BPO is 1% of the total mass of the monomers.
2. Method for preparing sol solution containing up-conversion nanopowder and active drug
(1) Upconversion nanopowder NaYF 4 Preparation of Yb and Bi: oxide Bi of lanthanoid series 2 O 3 、Yb 2 O 3 、Y 2 O 3 And NaOH, and dissolved in 50% strength trifluoroacetic acid at 95 ℃, the mixed solution was placed in a three-necked flask and evaporated to dryness under argon purge. Oleic acid and oleylamine were then added to a three-necked flask and heated to 120 ℃ and magnetically stirred for 30min to remove water and oxygen. The solution was heated to 275 ℃ at a rate of about 12 ℃/min under argon and stirred vigorously at this temperature for 0.5 h. Cooling the mixture to room temperature, pouring the mixture into acetone, carrying out ultrasonic precipitation in an ultrasonic cleaner, then centrifuging the mixture for 10min at 11000rpm, and washing the precipitate for multiple times by using ethanol to obtain NaYF 4 Yb, Bi nanocrystals.
(2) Preparation of sol solutions containing upconverting nanopowders and active drug
The active drug which can be loaded by the microneedle can be chemical drugs and skin care components, protein and polypeptide drugs are not recommended to be loaded, and the active drug is easy to deteriorate and inactivate under ultraviolet radiation.
The liquid sol is a mixed solution of polysaccharide and metal salt.
Further, the polysaccharide can be selected from at least one soluble substance of biological origin selected from gelatin, hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin (sulfuric acid), dextran (sulfuric acid), polylysine (polylysine), and pullulan; the metal salt can be selected from one of ferric chloride, calcium chloride and copper chloride.
The method specifically comprises the step of uniformly mixing up-conversion nano powder, an active drug, polysaccharide and metal salt in a solution to obtain a sol solution containing the up-conversion nano powder and the active drug.
The solvent of the hydrosol is selected according to the solubility of the active drug, and preferably ethanol (fat-soluble drug) and water (water-soluble drug).
The mass mixing ratio of the up-conversion nano powder to the polysaccharide to the metal salt to the solvent is 2-10: 40-60: 1-10: 100.
3. microneedle preparation method
(1) Preparation of an acylchlorinated poly (methyl vinyl ether/maleic acid) copolymer: mixing poly (methyl vinyl ether/maleic acid) copolymer and thionyl chloride in chloroform, heating to 60 ℃, stirring for 6h, performing rotary evaporation to volatilize the solvent, drying the obtained product in an oven at 80 ℃ for 24h to obtain acyl chlorinated poly (methyl vinyl ether/maleic acid) copolymer, and placing the copolymer in a drying environment for later use; the poly (methyl vinyl ether/maleic acid) copolymer has an intrinsic viscosity of 2.5 to 10 (1% aqueous solution); the feeding mass ratio of the poly (methyl vinyl ether/maleic acid) copolymer to thionyl chloride is 10: 5.
(2) Preparing a casting solution: in polyethylene glycol, mixing acyl chloride poly (methyl vinyl ether/maleic acid) copolymer and acrylate copolymer, heating to 60 ℃, stirring uniformly, and removing bubbles by ultrasonic; the polyethylene glycol is PEG-200-400; the mixing mass ratio of the acyl chloride poly (methyl vinyl ether/maleic acid) copolymer to the acrylate copolymer is 2: 2-3.
(3) And (3) injecting the casting liquid obtained in the step (2) into a PDMS mold, centrifuging, leveling until no liquid residue is left on the upper surface of the mold, and placing the mold into an oven with the temperature of 80 ℃ for curing and crosslinking for 24 hours.
(4) And (3) carrying out pore-forming on the maximum cross section of the needle body by utilizing laser pore-forming, wherein the pore size is 1/3-1/5 of the volume of the needle body.
(5) And injecting the liquid sol loaded with the up-conversion nano powder and the active drug into the hole, and continuously putting the hole into an oven for drying and curing.
(6) And (5) pouring a layer of film-forming polymer on the mould in the step (5), pressing the film-forming polymer after being strickled, putting the film-forming polymer into an oven for continuous drying and film forming, and demoulding to obtain the microneedle array for the controlled release medicament.
The film-forming polymer may be the casting liquid of step (3), and may also be independently selected from: polyurethane and its derivatives, silica gel and its derivatives, polyacrylic acid and its derivatives.
Further, between the step (5) and the step (6), a layer of adhesive can be coated on the upper surface of the PDMS mold, so that the PDMS mold can be adhered to the skin surface.
EXAMPLE 1 preparation of acrylate copolymer
Weighing an acrylate monomer and a monomer A, dissolving the acrylate monomer and the monomer A in toluene, adding BPO, heating to 90 ℃, polymerizing for 3h, carrying out reduced pressure rotary evaporation on the obtained reaction solution at 120-150 ℃ to obtain a crude product, dissolving the crude product with DCM again, adding an isovolumetric sodium thiosulfate aqueous solution for washing until the starch potassium iodide test paper is not blue, washing with deionized water, and carrying out rotary drying on an organic phase to obtain an acrylate copolymer; the molar ratio of the acrylate monomer to the monomer A is 3-5: 1, and the addition amount of the BPO is 1% of the total mass of the monomers.
TABLE 1
Mn was measured by GPC, and the solvent was tetrahydrofuran.
For content of photosensitive groups 1 The solvent was CDCl as determined by H-NMR 3 。
Example 2 preparation of upconversion nanopowders
Up-conversion nanopowder NaY 0.978 F 4 Preparation of 2% Yb and 0.2% Bi: 0.002mmol Bi of lanthanide oxide 2 O 3 、0.02mmol Yb 2 O 3 、0.978mmol Y 2 O 3 And 2mmol of NaOH were mixed and dissolved in 50% strength trifluoroacetic acid at 95 ℃ and the mixed solution was placed in a 100mL three-necked flask and evaporated to dryness under a purge of argon. Then 16mL of oleic acid and 8mL of oleylamine were added to a three-necked flask, heated to 120 ℃ and magnetically stirred for 30min to remove water and oxygen. The solution was heated to 275 ℃ at a rate of about 12 ℃/min under argon and stirred vigorously at this temperature for 0.5 h. Cooling the mixture to room temperature, pouring into acetone, performing ultrasonic precipitation in an ultrasonic cleaner, centrifuging at 11000rpm for 10min, and washing the precipitate with ethanol for multiple times to obtain NaY 0.978 F 4 2% of Yb and 0.2% of Bi nano powder.
The emission spectrum of the nano powder under the excitation of 980nm light is shown in the attached figure 3.
EXAMPLE 3 preparation of a Liquidgel containing an Up-converting nanopowder and an active drug
In this example, a liquid gel was prepared using doxorubicin as a model drug.
The preparation method comprises the following steps: sequentially adding polysaccharide, up-conversion nano powder and adriamycin into a solvent according to a feeding ratio, uniformly stirring, ultrasonically dispersing the up-conversion nano powder into the solution, and slowly dropwise adding a metal salt solution (with the concentration of 5g/L) while stirring to obtain the hydrogel loaded with the nano powder and the active drug.
TABLE 2
Example 4 preparation of microneedle arrays
Preparing a casting solution, mixing an acyl chloride poly (methyl vinyl ether/maleic acid) copolymer (PVM/MA) and an acrylate copolymer in polyethylene glycol, heating to 60 ℃, uniformly stirring, and removing bubbles by ultrasonic; the polyethylene glycol is PEG-200-400; the mixing mass ratio of the acyl chloride poly (methyl vinyl ether/maleic acid) copolymer to the acrylate copolymer is 2: 2-3.
The casting liquid comprises the following components:
TABLE 3
The pouring liquid adopts PEG-200, the PEG-200 is added to control the viscosity of the pouring liquid, and the viscosity is tested at 30 ℃.
Injecting the obtained casting liquid into a PDMS mold, centrifuging at 3000rpm, leveling until no liquid residue is left on the upper surface of the mold, and placing the mold into an oven with the temperature of 80 ℃ for curing and crosslinking for 24 hours. And after the solidification, standing and cooling, performing pore-forming on the maximum cross section of the needle body by utilizing laser pore-forming, and injecting the hydrosol (sample Y2) carrying the up-conversion nano powder and the active drug into a fine needle injection hole with the diameter of a pinhole of 80 mu m, wherein the injection amount is 0.5-0.8 nL.
And centrifuging again, and then putting the mixture into an oven for drying and curing, wherein the curing temperature is 80-100 ℃, and the curing time is 24 hours.
And after cooling, pouring a layer of pouring liquid on the surface of the mold, controlling the thickness to be 0.5-1 mm, pressing after strickling, putting into an oven for continuous drying and film forming, and demolding to obtain the photosensitive controlled release microneedle array.
The film-forming polymer of the substrate is not limited in the present invention, and the casting liquid may be selected, and may be independently selected from: polyurethane and its derivatives, silica gel and its derivatives, polyacrylic acid and its derivatives.
Test one microneedle mechanical Strength test
The mechanical strength of the microneedles was characterized with a pressure-tensile tester. The specific method comprises the following steps: the microneedle is pasted on the upper surface of a cuboid copper table by using a double-sided adhesive tape, and is placed in the center of a horizontal objective table of a pressure-tension tester, the testing range is 0.05N-60N, the compression rate is 0.5mm/min, and the change curve of the pressure along with the displacement is obtained.
The pressure at a compressive displacement of 0.45mm for each sample is shown in Table 4, where the pressure-displacement curves for samples A1-A5 are shown in FIG. 4.
TABLE 4
| Sample (I) | Pressure, N | Sample (I) | Pressure, N |
| A1 | 52 | A6 | 28 |
| A2 | 64 | A7 | 37 |
| A3 | 48 | A8 | 47 |
| A4 | 53 | A9 | 55 |
| A5 | 42 | |
45 |
As can be seen from the results of table 4 and fig. 4, the higher the relative content of PVM/MA in the sample, the higher the viscosity, the higher the mechanical strength of the microneedle; in addition, the mechanical strength of the microneedles is higher with more photosensitive groups of the acrylate copolymer at the same PVM/MA content and viscosity; all of the above results are due to the increased crosslink density of the microneedles.
Test two swelling Property test
The swelling performance of the microneedles was tested by gravimetric method. The specific method comprises the following steps: putting the microneedle patch into a buffer solution containing PBS (7.4), irradiating the microneedle with 980nm light for 0min, 5min, 10min, 20min and 30min, respectively, taking out the microneedle patch at different times, absorbing excessive water on the surface with absorbent paper, weighing, and recording the change of the swelling degree of the microneedle patch with time.
The swelling ratio of sample A4 as a function of time at different illumination times is shown in FIG. 5.
As can be seen from the figure, as the light exposure time increased, the swelling equilibrium time of the microneedles decreased, and the swelling ratio also significantly increased. After the micro-needle is in swelling equilibrium, the liquid in the micro-needle can be freely exchanged with the outside, so that the release speed of the drug is slower before the micro-needle is in swelling equilibrium. Therefore, the swelling degree and the swelling balance time of the microneedle can be regulated and controlled by regulating and controlling the illumination time.
Test three in vitro sustained release Performance tests
And testing the slow release performance of the microneedle by measuring the absorbance of the adriamycin in the solution by adopting an ultraviolet spectrophotometry. The specific method comprises the following steps: drawing a relation curve of absorbance and concentration; putting the microneedle patch into 5mL of buffer solution containing PBS (7.4), randomly and respectively irradiating the microneedle with 980nm light for 0min, 5min, 10min, 20min and 30min, then placing at 37 ℃, taking out the solution in the beaker at regular intervals, measuring the absorbance of the solution at 490nm by using an ultraviolet spectrophotometer, pouring the liquid back into the beaker in time after the test is finished, and recording the change of the slow release rate along with the time.
Sample a4 shows drug release over time at different illumination times with reference to figure 6.
As can be seen from the figure, the release amount of the prodrug is small in 10h, which is consistent with the result of the second test, i.e., the release efficiency of the prodrug is low when the microneedle swells and balances, and the drug is released rapidly when the microneedle swells and balances; in addition, the microneedle drug release is stable in about 100 hours and the illumination time is 10-30 min, and the release rate reaches 95%.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. The photosensitive controlled-release microneedle is characterized by comprising a shell and a cavity, wherein the shell comprises a needle body and a substrate, and the cavity is prepared in a laser pore-forming manner; the needle body is formed by crosslinking a poly (methyl vinyl ether/maleic acid) copolymer and an acrylate copolymer; the cavity is loaded with gel containing up-conversion nano powder, active medicine, polysaccharide and metal salt;
the acrylic ester copolymer is synthesized by copolymerizing an acrylic ester compound and a compound with a structural formula I,
the acrylate compound is selected from one or a combination of methyl methacrylate, ethyl acrylate and methyl acrylate;
the up-conversion nano powder is NaYF 4 Bi and Yb capable of emitting light of 350-360 nm under the excitation of 980nm light.
2. The photosensitive controlled-release microneedle according to claim 1, wherein the length of the microneedle body is 300-600%
m, the diameter of the largest cross-sectional area is 150-200
m, the thickness of the substrate is 0.5-1 mm; the volume of the cavity is 1/3-1/5 of the volume of the needle body.
3. The photosensitive controlled-release microneedle according to claim 1, wherein the up-conversion nanopowder is NaYF 4 Bi and Yb are prepared by the following steps: oxide Bi of lanthanoid series 2 O 3 、Yb 2 O 3 、Y 2 O 3 Mixing with NaOH and dissolving in 50% trifluoroacetic acid at 95 deg.C, placing the mixed solution in a three-neck flask, and evaporating to dryness under argon purge; then adding oleic acid and oleylamine into a three-neck flask, heating to 120 ℃, and magnetically stirring for 30min to remove water and oxygen; under the protection of argon, heating the solution to 275 ℃ at the speed of 12 ℃/min, and stirring vigorously at the temperature for 0.5 h; cooling the mixture to room temperature, pouring the mixture into acetone, carrying out ultrasonic precipitation in an ultrasonic cleaner, then centrifuging the mixture for 10min at 11000rpm, and washing the precipitate for multiple times by using ethanol to obtain NaYF 4 Yb and Bi nano powder.
4. The photosensitive controlled-release microneedle according to claim 1, wherein the number average molecular weight of the acrylate-based copolymer is 10000-15000 g/mol; the feeding molar ratio of the acrylate compound to the compound of the structural formula I is 3-5: 1.
5. The method for preparing a photosensitive controlled-release microneedle according to any one of claims 1 to 4, comprising the steps of:
(1) preparation of an acylchlorinated poly (methyl vinyl ether/maleic acid) copolymer: mixing the poly (methyl vinyl ether/maleic acid) copolymer with thionyl chloride, heating for reaction, and spin-drying to obtain an acyl-chlorinated poly (methyl vinyl ether/maleic acid) copolymer;
(2) preparing a casting solution: in polyethylene glycol, mixing acyl chloride poly (methyl vinyl ether/maleic acid) copolymer and acrylate copolymer, heating and stirring uniformly, and removing bubbles by ultrasonic; controlling the viscosity of the casting solution to be 1-1.5 multiplied by 10 4 mPa·s；
(3) Injecting the casting liquid obtained in the step (2) into a PDMS mold, performing ultrasonic treatment, and placing the PDMS mold into an oven at 80 ℃ for curing and crosslinking for 24 hours;
(4) performing pore forming on the maximum cross section of the needle body by using laser pore forming, wherein the pore size is 1/3-1/5 of the volume of the needle body;
(5) uniformly mixing the up-conversion nano powder, the active drug, the polysaccharide and the metal salt in a solvent to form a liquid gel, injecting the liquid gel into a hole, and continuously putting the hole into an oven for drying and curing;
(6) and (5) pouring a layer of film-forming polymer on the mould in the step (5), pressing the film-forming polymer after being strickled, putting the film-forming polymer into an oven for continuous drying and film forming, and demoulding to obtain the microneedle array for the controlled release medicament.
6. The method according to claim 5, wherein the active drug of step (5) is a chemical drug or a skin care ingredient; the polysaccharide is at least one selected from gelatin, hyaluronic acid, alginic acid, pectin, carrageenan, chondroitin sulfate, dextran sulfate, polylysine and pullulan; the metal salt is selected from one of ferric chloride, calcium chloride and copper chloride.
7. The method according to claim 5, wherein the solvent of step (5) is selected according to the solubility of the active drug, and is selected from ethanol or water.
8. The preparation method according to claim 5, wherein the mass mixing ratio of the upconversion nanopowder, the polysaccharide, the metal salt and the solvent in the step (5) is 2-10: 40-60: 1-10: 100.
9. the method according to claim 5, wherein the film-forming polymer in step (6) is selected from one of the casting liquid in step (3), polyurethane, silica gel, and polyacrylic acid.
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