CN114533649A - Separable microneedle array capable of drug delivery and in-situ labeling and preparation method thereof - Google Patents

Separable microneedle array capable of drug delivery and in-situ labeling and preparation method thereof Download PDF

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CN114533649A
CN114533649A CN202210003636.6A CN202210003636A CN114533649A CN 114533649 A CN114533649 A CN 114533649A CN 202210003636 A CN202210003636 A CN 202210003636A CN 114533649 A CN114533649 A CN 114533649A
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microneedle array
vivo
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王琳
王征
陈伟
范慧玲
许仁珪
李琪琳
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Tongji Medical College of Huazhong University of Science and Technology
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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
    • A61K9/0012—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
    • 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
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • 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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Abstract

The invention discloses a separable microneedle array capable of delivering a drug and in-situ labeling in vivo and a preparation method thereof, belonging to the field of preparation of in-situ labeled microneedles in vivo. The separable microneedle array for drug delivery, which has the in-vivo in-situ labeling function, provided by the invention has the advantages of effective transdermal drug delivery capability, information labeling and storage functions and good biocompatibility; any number and pattern can be obtained by arranging and combining the microneedle arrays, and the skin of a treated subject is marked with visual information, so that paperless recording is realized; meanwhile, in the application of treatment or prevention administration, the micro-needle has the advantages of small wound on human skin, low pain degree, high acceptance of a subject on the micro-needle administration mode and high clinical transformation potential.

Description

Separable microneedle array capable of drug delivery and in-situ labeling and preparation method thereof
Technical Field
The invention relates to the technical field of microneedle preparation capable of being marked in situ in vivo, in particular to a separable microneedle array capable of being subjected to drug delivery and being marked in situ in vivo and a preparation method thereof.
Background
The common modes of administration currently include oral administration, where first pass elimination of the liver greatly reduces the bioavailability of the drug, and injection, which is invasive and associated with pain, and children and some patients may panic or even be sick of the needle.
For patients who need multi-dose administration (repeated administration) or people who need vaccination, clinical medical staff need to record the administration times, and information among different medical units is not intercommunicated, and internet information records and paper-based records in poor areas cannot be conveniently stored and easily lost.
Based on the reasons, the common injection administration mode can not meet the requirements of painless, real-time and simple recording of people needing multi-dose injection administration.
Disclosure of Invention
The present invention aims to provide a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a method for preparing the same, so as to solve the problems of the background art.
In order to achieve the purpose, the invention provides the following technical scheme:
the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end.
As a further scheme of the invention: the method comprises the following steps:
s1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane;
s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven;
s3: preparing a solution from a medicament with a therapeutic dose or a required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment;
s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing;
s5: and (3) constructing a base layer, namely adding a methyl cellulose (CMC) solution into the PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature.
As a still further scheme of the invention: the height of the microneedles in the microneedle model design in the S1 is 300-2000 microns, the microneedles are integrally in a shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100.
As a still further scheme of the invention: the dye used in S2 includes, but is not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet.
As a still further scheme of the invention: the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes.
As a still further scheme of the invention: the drying temperature in the S2 and the S4 is 0-100 ℃, and the drying time is 0-96 hours.
As a still further scheme of the invention: the pressure of the vacuum in the S3 is 0-10 kilopascal, the vacuum time is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like.
As a still further scheme of the invention: the polymer used in S4 includes, but is not limited to, carboxymethyl cellulose (CMC) and sodium Alginate (ALG), the concentration of sodium Alginate (ALG) is 0-10%, the concentration of Polycaprolactone (PCL) is 0-100%, the solvent includes, but is not limited to, dichloromethane, and the standing time in S4 is 0-60 min.
As a still further scheme of the invention: the methylcellulose (CMC) concentration used in S4 and S5 was 0-10%.
As a still further scheme of the invention: the low-temperature preservation temperature in the S5 is-80 to 4 ℃.
Compared with the prior art, the invention has the beneficial effects that:
the separable microneedle array for drug delivery, which has the in-vivo in-situ labeling function, provided by the invention has the advantages of effective transdermal drug delivery capability, information labeling and storage functions and good biocompatibility; any number and pattern can be obtained by arranging and combining the microneedle arrays, and the skin of a treated subject is marked with visual information, so that paperless recording is realized; meanwhile, in the application of treatment or prevention administration, the micro-needle has the advantages of small wound on human skin, low pain degree, high acceptance of a subject on the micro-needle administration mode and high clinical transformation potential.
Drawings
FIG. 1 is a diagram of a mushroom-shaped microneedle array model according to the present invention;
fig. 2 is a drawing of a microneedle preparation mold according to the present invention;
FIG. 3 is a pictorial representation of a microneedle array of the present invention;
FIG. 4 is a scanning electron microscope image of a single microneedle structure of the present invention;
FIG. 5 is a drawing of a microneedle array penetrating a pig skin in accordance with the present invention;
FIG. 6 is a view showing the arrangement of microneedle arrays of the present invention combined with the actual illustrations of the numbers "1" and "2";
FIG. 7 is a fluorescent display diagram showing the arrangement and combination of the microneedle arrays of the present invention with the numbers "1" and "2";
FIG. 8 is a view showing the actual state and fluorescence of the microneedle array of the present invention labeled "1" on the pigskin;
FIG. 9 is a view showing the actual state and fluorescence of the microneedle array of the present invention labeled "2" on pigskin;
FIG. 10 is a view showing the actual display of the microneedle array of the present invention after marking "1" and "2" on the skin of SD rat;
FIG. 11 is a graph showing fluorescence after marking "1" and "2" on the skin of SD rats with the microneedle array according to the present invention;
fig. 12 is a graph showing HE staining of an important tissue of a mouse treated with a microneedle array according to the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a preparation method thereof, the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end, S1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane; the height of the microneedles in the microneedle model design in S1 is 300-2000 microns, the microneedles are integrally in the shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100; s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and then placing into an oven for drying; dyes used in S2 include, but are not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet; the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes; the drying temperature in S2 and S4 is 0-100 ℃, and the drying time is 0-96 hours; s3: preparing a solution from a medicament with a therapeutic dose or a preventive required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment; the pressure of the vacuum in S3 is 0-10 kilopascal, and the time of the vacuum is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like; s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing; the polymer used in S4 includes, but is not limited to, polymers such as carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and the sodium Alginate (ALG) is used at a concentration of 0-10%, and Polycaprolactone (PCL) is used at a concentration of 0-100%, and the solvent includes, but is not limited to, dichloromethane; standing for 0-60 minutes in S4; the methylcellulose (CMC) concentration used in S4 and S5 is 0-10%; s5: constructing a substrate layer, namely adding a methyl cellulose (CMC) solution into a PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature; the temperature of the low-temperature preservation in S5 is-80 to 4 ℃.
As shown in fig. 1 and 2, a primitive mushroom-shaped microneedle array model was designed using SOLIDWORKS 2020 software, a mold was printed out using orange resin using an X1903D printer, a mold for preparing microneedles was constructed using polydimethylsiloxane, 100 μ L of 9% crystal violet or 0.1mg/ml Fluorescein Isothiocyanate (FITC) dye solution was added, and centrifuged for 10 minutes using a horizontal rotor centrifuge, and the centrifuge was 2000 rpm.
Example 2: a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a preparation method thereof, the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end, S1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane; the height of the microneedles in the microneedle model design in S1 is 300-2000 microns, the microneedles are integrally in the shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100; s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven; dyes used in S2 include, but are not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet; the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes; the drying temperature in S2 and S4 is 0-100 ℃, and the drying time is 0-96 hours; s3: preparing a solution from a medicament with a therapeutic dose or a preventive required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment; the pressure of the vacuum in S3 is 0-10 kilopascal, and the time of the vacuum is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like; s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing; the polymer used in S4 includes, but is not limited to, polymers such as carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and the sodium Alginate (ALG) is used at a concentration of 0-10%, and Polycaprolactone (PCL) is used at a concentration of 0-100%, and the solvent includes, but is not limited to, dichloromethane; standing for 0-60 minutes in S4; the methylcellulose (CMC) concentration used in S4 and S5 is 0-10%; s5: constructing a substrate layer, namely adding a methyl cellulose (CMC) solution into a PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature; the temperature of the low-temperature preservation in S5 is-80 to 4 ℃.
As shown in fig. 3 and fig. 4, 1mL of 1.5% sodium Alginate (ALG) and 1mL of 1.5% carboxymethylcellulose (CMC) are mixed and added into a mold, the mold is placed in an oven at 37 ℃ for a night, then 20 μ L of 10% Polycaprolactone (PCL) (solvent is dichloromethane) is placed for 15 minutes, after dichloromethane is completely volatilized, 1mL of 3% carboxymethylcellulose (CMC) is continuously added, a basal layer is formed after the carboxymethylcellulose (CMC) is dried to play a supporting role, and finally the microneedle patch is taken out of the mold by using tweezers.
Example 3: a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a preparation method thereof, the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end, S1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane; the height of the microneedles in the microneedle model design in S1 is 300-2000 microns, the microneedles are integrally in the shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100; s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven; dyes used in S2 include, but are not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet; the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes; the drying temperature in S2 and S4 is 0-100 ℃, and the drying time is 0-96 hours; s3: preparing a solution from a medicament with a therapeutic dose or a preventive required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment; the pressure of the vacuum in S3 is 0-10 kilopascal, and the time of the vacuum is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like; s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing; the polymer used in S4 includes, but is not limited to, polymers such as carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and the sodium Alginate (ALG) is used at a concentration of 0-10%, and Polycaprolactone (PCL) is used at a concentration of 0-100%, and the solvent includes, but is not limited to, dichloromethane; standing for 0-60 minutes in S4; the methylcellulose (CMC) concentration used in S4 and S5 is 0-10%; s5: constructing a substrate layer, namely adding a methyl cellulose (CMC) solution into a PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature; the temperature of the low-temperature preservation in S5 is-80 to 4 ℃.
As shown In fig. 8 and 9, the microneedle arrays carrying the crystal violet dye are arranged and combined into numbers 1 'and 2', after the microneedle array 1 'and 2' are inserted into the pigskin, 200 μ L of deionized water is used for infiltration treatment and the basal layer is peeled off, the needle tip is kept In the pigskin, an In Vivo imaging system (BRUKER In-Vivo FX PRO) is used for setting the excitation wavelength to be 620nm, the emission wavelength to be 700nm, the exposure time range to be 1-3 seconds and the aperture to be 0.95, and the pigskin is imaged and photographed.
Example 4: a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a preparation method thereof, the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end, S1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane; the height of the microneedles in the microneedle model design in S1 is 300-2000 microns, the microneedles are integrally in the shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100; s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven; dyes used in S2 include, but are not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet; the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes; the drying temperature in S2 and S4 is 0-100 ℃, and the drying time is 0-96 hours; s3: preparing a solution from a medicament with a therapeutic dose or a preventive required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment; the pressure of the vacuum in S3 is 0-10 kilopascal, and the time of the vacuum is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like; s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing; the polymer used in S4 includes, but is not limited to, polymers such as carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and the sodium Alginate (ALG) is used at a concentration of 0-10%, and Polycaprolactone (PCL) is used at a concentration of 0-100%, and the solvent includes, but is not limited to, dichloromethane; standing for 0-60 minutes in S4; the methylcellulose (CMC) concentration used in S4 and S5 is 0-10%; s5: constructing a substrate layer, namely adding a methyl cellulose (CMC) solution into a PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature; the temperature of the low-temperature preservation in S5 is-80 to 4 ℃.
As shown In fig. 10 and 11, the microneedle arrays carrying Fluorescein Isothiocyanate (FITC) are arranged and combined into numbers "1" and "2", after the microneedle arrays "1" and "2" are inserted into SD rats, the backs of the rats are covered with a 2 cm-by-6 cm patch for protection, an In Vivo imaging system (BRUKER In-Vivo FX PRO) is used, the exposure time range is set to be 1-2 seconds, the aperture is 0.95, the excitation light wavelength is 490nm, the emission wavelength is 530nm, and the SD rats are monitored by imaging and photographing, and the dot matrix of the patterns of the numbers "1" and "2" can be clearly seen without obvious attenuation or photobleaching phenomena, thus proving that the patent microneedle arrays have excellent light stability.
Example 5: a separable microneedle array capable of drug delivery and in-situ labeling in vivo and a preparation method thereof, the separable microneedle array is loaded with a drug and a fluorescent dye, and is prepared based on an aqueous solution of carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and has a thick tip end and a thin bottom end, S1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane; the height of the microneedles in the microneedle model design in S1 is 300-2000 microns, the microneedles are integrally in the shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100; s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven; dyes used in S2 include, but are not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet; the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes; the drying temperature in S2 and S4 is 0-100 ℃, and the drying time is 0-96 hours; s3: preparing a solution from a medicament with a therapeutic dose or a preventive required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment; the pressure of the vacuum in S3 is 0-10 kilopascal, and the time of the vacuum is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like; s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing; the polymer used in S4 includes, but is not limited to, polymers such as carboxymethyl cellulose (CMC) and sodium Alginate (ALG), and the sodium Alginate (ALG) is used at a concentration of 0-10%, and Polycaprolactone (PCL) is used at a concentration of 0-100%, and the solvent includes, but is not limited to, dichloromethane; standing for 0-60 minutes in S4; the methylcellulose (CMC) concentration used in S4 and S5 is 0-10%; s5: constructing a substrate layer, namely adding a methyl cellulose (CMC) solution into a PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature; the temperature of the low-temperature preservation in S5 is-80 to 4 ℃.
As shown in fig. 12, after 8 weeks of using the patent microneedle array to stick into the BALB/c mouse, the mouse was euthanized, and the heart, liver, spleen, lung, and kidney tissues were subjected to HE staining to judge the biosafety of the patent microneedle array.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims (10)

1. A separable microneedle array capable of being used for drug delivery and in-situ labeling in vivo and a preparation method thereof are characterized in that: the microneedle array is loaded with drugs and fluorescent dyes and is prepared based on carboxymethyl cellulose (CMC) and sodium Alginate (ALG) aqueous solution, and has a thick tip end and a thin bottom end.
2. The separable microneedle array capable of being delivered and labeled in situ in vivo and the preparation method thereof according to claim 1, wherein: the method comprises the following steps:
s1: designing a microneedle model with a thicker original tip and a thinner bottom end by using SOLIDWORKS 2020 software, and constructing a mold for preparing microneedles by using polydimethylsiloxane;
s2: preparing a dye solution, adding the dye solution into a PDMS mold, centrifuging, and drying in an oven;
s3: preparing a solution from a medicament with a therapeutic dose or a required dose, adding the prepared medicament solution into a PDMS (polydimethylsiloxane) mold, and performing vacuum pumping and centrifugal treatment;
s4: constructing a microneedle array, namely mixing a sodium Alginate (ALG) solution and a carboxymethyl cellulose (CMC) solution, adding the mixture into a PDMS negative mould, putting the PDMS negative mould into an oven, drying, adding a PCL solution, and standing;
s5: and (3) constructing a base layer, namely adding a methyl cellulose (CMC) solution into the PDMS negative mould, drying, taking out the microneedle patch from the mould, and storing at low temperature.
3. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the height of the microneedles in the microneedle model design in the S1 is 300-2000 microns, the microneedles are integrally in a shape with thicker tips and thinner bottoms, and the number of the microneedles in each array is 1-100.
4. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the dye used in S2 includes, but is not limited to, Fluorescein Isothiocyanate (FITC) or crystal violet.
5. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the centrifugation speed in S2 and S3 is 0-4000 rpm, and the centrifugation time is 0-60 minutes.
6. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the drying temperature in the S2 and the S4 is 0-100 ℃, and the drying time is 0-96 hours.
7. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the pressure of the vacuum in the S3 is 0-10 kilopascal, the vacuum time is 0-60 minutes, and the medicine includes but is not limited to therapeutic medicine, preventive medicine, vaccine and the like.
8. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the polymer used in S4 includes, but is not limited to, carboxymethyl cellulose (CMC) and sodium Alginate (ALG), the concentration of sodium Alginate (ALG) is 0-10%, the concentration of Polycaprolactone (PCL) is 0-100%, the solvent includes, but is not limited to, dichloromethane, and the standing time in S4 is 0-60 min.
9. The separable microneedle array capable of drug delivery and in-situ labeling according to claim 2 and its preparation method, wherein: the methylcellulose (CMC) concentration used in S4 and S5 was 0-10%.
10. The separable microneedle array capable of being delivered and labeled in situ in vivo and the method for preparing the same according to claim 2, wherein: the low-temperature preservation temperature in the S5 is-80 to 4 ℃.
CN202210003636.6A 2022-01-05 2022-01-05 Separable microneedle array capable of drug delivery and in-situ labeling and preparation method thereof Pending CN114533649A (en)

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CN111544573A (en) * 2019-03-26 2020-08-18 华中科技大学同济医学院附属协和医院 Soluble microneedle for promoting hair growth and preparation method thereof
CN113577042A (en) * 2021-07-16 2021-11-02 华中科技大学 Soluble microneedle patch for targeted diagnosis and treatment of skin diseases and preparation thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104706626A (en) * 2015-03-25 2015-06-17 北京化工大学 Microneedle patch convenient for administrating animal vaccine and preparation method of microneedle patch
CN111544758A (en) * 2019-03-26 2020-08-18 华中科技大学同济医学院附属协和医院 Photosensitizer-loaded soluble microneedle, microneedle array and preparation method
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