CN112472662A - Drug-loaded microsphere-microneedle array with controllable drug delivery, preparation method and application - Google Patents
Drug-loaded microsphere-microneedle array with controllable drug delivery, preparation method and application Download PDFInfo
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Abstract
The invention provides a drug-loaded microsphere-microneedle array with controllable drug delivery, a preparation method and application. The drug-loaded microspheres in the microsphere-microneedle array prepared by the invention have good sphericity and drug release rate, are uniformly filled in each needle point, and are penetrated into the skin by the microneedles to assist the microspheres to be uniformly distributed under the skin, so that the purpose of controllable transdermal drug delivery is achieved. The controllable drug delivery polymer drug-loaded microsphere-microneedle array has the advantages of good drug controllability, low preparation cost, simplicity and easiness in operation and the like, is high in practicability and is suitable for popularization.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to a drug-loaded microsphere-microneedle array with controllable drug delivery, a preparation method and application.
Background
Microsphere administration is an efficient administration means. The microspheres can carry a sufficient amount of drug and are slowly released in a controlled manner to maintain an effective drug concentration in the blood. The hydrogel microspheres have the characteristics of softness, large specific surface area and good biocompatibility, so the drug-loaded microspheres are widely applied to the field of drug delivery.
The traditional ways of applying the drug-loaded microspheres to the lesion site include subcutaneous injection, oral administration, etc. The most common, highly effective way of doing this is by subcutaneous injection. However, the application of the drug-loaded microspheres is limited due to the defects that pain is caused by the aid of an injector, the compliance of a patient is poor, wound infection is easily caused, the microspheres are unevenly distributed under the skin, and the like.
To solve this problem, we propose to use microneedles instead of syringes to penetrate the skin, assisting the distribution of the microspheres under the skin. The micro-needle is composed of a substrate and a series of regularly arranged needle points, and the needle points with the length of hundreds of micrometers can penetrate through the stratum corneum of the skin to form a micrometer-sized channel. The micro-needle is filled with the drug-loaded microspheres, the micro-needle can assist the microspheres to be uniformly distributed under the skin, and the microspheres can controllably release drugs at focus positions. The preparation method of the drug-loaded microsphere-microneedle is simple, the drug release rate is high, and the drug delivery method is painless, efficient and convenient.
Therefore, in the invention, a polymer microsphere-microneedle array for controlled drug delivery is designed and invented with the assistance of microneedles, and can be used in the field of transdermal drug delivery.
Disclosure of Invention
The invention aims to provide a drug-loaded microsphere-microneedle array with controllable drug delivery, a preparation method and application aiming at the defects of the prior art.
The invention adopts the following technical scheme:
a preparation method of a drug-loaded microsphere-microneedle array with controllable drug delivery comprises the following steps:
s1 preparation of drug-loaded microspheres
Mixing a drug and hydrogel to prepare hydrogel and a drug mixed solution as an internal phase, wherein the hydrogel is prepared by mixing Black Phosphorus (BP), N-isopropylacrylamide (NIPAM) and acrylamide (AAM) according to a certain proportion; the outer phase is an oil phase which is not mutually soluble with the inner phase, the outer phase and the inner phase are injected into a microfluidic device, monodisperse single emulsion droplets are formed by utilizing the shearing force between two phase solutions, the droplets are solidified and collected, and the droplets are rinsed for a plurality of times by using alcohol and deionized water to obtain polymer drug-loaded microspheres with uniform particle sizes;
s2 preparation of drug-loaded microsphere-microneedle array
Preparing a hydrogel solution, pouring the hydrogel solution into the microneedle template, and vacuumizing to enable the hydrogel solution to fill the gaps of the microneedle template; and filling the drug-loaded microspheres obtained in the step S1 in the needle point part of the microneedle template, then performing crosslinking curing, and finally stripping from the microneedle template to obtain the drug-loaded microsphere-microneedle array.
Further, in S1, the hydrogel of the drug-loaded microsphere is formed by mixing Black Phosphorus (BP), N-isopropylacrylamide (NIPAM), acrylamide (AAM) and water.
Further, in S1, in the hydrogel of the drug-loaded microsphere, the mass volume ratio of the Black Phosphorus (BP) to the water is 0.2-1%; the mass volume ratio of N-isopropylacrylamide (NIPAM) to water is 10-20%; the mass volume ratio of acrylamide (AAM) to water is 0.6-1.5%.
Further, in S1, the droplet size may be changed by adjusting the flow rates of the microfluidic inner and outer phases.
Further, in S1, the diameter of the prepared drug-loaded microsphere is between 200 and 500 μm.
Further, in S2, the side length of the bottom of the microneedle is 500-700 μm, the length of the microneedle is 500-1000 μm, and the distance between adjacent needle points is 500-1000 μm.
Further, in S2, the hydrogel is formed by mixing ethoxylated trimethylolpropane triacrylate (ETPTA), polyethylene glycol (PEG), and water.
Further, in S2, in the hydrogel solution, the volume ratio of the ethoxylated trimethylolpropane triacrylate (ETPTA) to water is 50-80%, and the volume ratio of the polyethylene glycol (PEG) to water is 20-40%.
Further, in S2, in the drug-loaded microsphere-microneedle array, the needle tip of each microneedle is filled with one or more drug-loaded microspheres, and the drug-loaded microspheres are uniformly distributed in the microneedle.
The invention also provides a drug-loaded microsphere-microneedle array with controllable drug delivery, which is prepared according to the preparation method.
The invention also provides application of the drug-loaded microsphere-microneedle array in the field of transdermal drug delivery.
The invention has the beneficial effects that:
(1) the hydrogel drug-loaded microspheres are prepared in a microfluidic manner, the method is simple, the cost is low, the recycling rate is high, and the size of the drug-loaded microspheres is easy to control;
(2) the micro-needle array can be firmly attached to the skin, so that the effect of uniform administration is realized, the defects that the micro-needle is unevenly distributed at a wound part and is easy to fall off are overcome, and the painless portable administration is realized;
(3) the hydrogel microsphere comprises Black Phosphorus (BP), the Black Phosphorus (BP) is a photo-thermal responsive material, has near-infrared photo-responsiveness, can convert light into heat and promote the melting of hydrogel, thereby promoting the release of the drugs in the hydrogel and realizing the controlled release of the drugs, and has strong practical value.
Drawings
FIG. 1 is a schematic view of a microfluidic system for preparing single emulsion microspheres according to the present invention;
FIG. 2 is a diagram of an infrared responsive light mirror for preparing single emulsion microspheres according to the present invention;
FIG. 3 is a flow chart of the preparation of drug-loaded microspheres-microneedles according to the present invention;
FIG. 4 is a photograph of a drug loaded microsphere-microneedle phototube of the present invention;
fig. 5 is a fluorescent picture of controllable drug delivery of the drug-loaded microsphere-microneedle of the invention.
The specific implementation mode is as follows:
in order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention. The conditions not specified in the examples are generally those in routine experiments.
A preparation method of a drug-loaded microsphere-microneedle array with controllable drug delivery comprises the following steps:
s1 preparation of drug-loaded microspheres
Mixing a drug and hydrogel to prepare hydrogel and a drug mixed solution as an internal phase, wherein the hydrogel is prepared by mixing Black Phosphorus (BP), N-isopropylacrylamide (NIPAM) and acrylamide (AAM) according to a certain proportion; the outer phase is an oil phase which is not mutually soluble with the inner phase, the outer phase and the inner phase are injected into the microfluidic device, a monodisperse single emulsion droplet is formed by utilizing the shearing force between two phases of solution, and the size of the droplet can be changed by adjusting the flow velocity of the inner phase and the outer phase of the microfluidic device; solidifying and collecting, rinsing for several times by using alcohol and deionized water to obtain polymer drug-loaded microspheres (the diameter is between 200 and 500 mu m) with uniform particle sizes; the hydrogel of the drug-loaded microsphere is formed by mixing 0.2-1% of Black Phosphorus (BP), 10-20% of N-isopropylacrylamide (NIPAM) and 0.6-1.5% of acrylamide (AAM).
S2 preparation of drug-loaded microsphere-microneedle array
Preparing a hydrogel solution, pouring the hydrogel solution into the microneedle template, and vacuumizing to enable the hydrogel solution to fill the gaps of the microneedle template; filling the drug-loaded microspheres obtained in the step S1 in the needle point part of the microneedle template, and stripping the cured drug-loaded microspheres from the microneedle template to obtain a drug-loaded microsphere-microneedle array; the side length of the bottom of the microneedle is 500-700 mu m, the length of the microneedle is 500-1000 mu m, and the distance between adjacent needle points is 500-1000 mu m; the hydrogel is prepared by mixing 50-80% of ethoxylated trimethylolpropane triacrylate (ETPTA) and 20-40% of polyethylene glycol (PEG); in the drug-carrying microsphere-microneedle array, one or more drug-carrying microspheres are filled in the needle point of each microneedle, and the drug-carrying microspheres are uniformly distributed in the microneedles.
Example 1 preparation of drug-loaded microsphere-microneedle arrays for controlled drug delivery
S1 preparation of drug-loaded microspheres
Preparing a micro-fluidic device by a capillary tube with the outer diameter of 1 mm and the inner diameter of 500 mu m, drawing and grinding an inner phase tube into a required caliber by a machine, performing hydrophobic treatment on an outer phase tube by octadecyl trimethoxy silane, and coaxially assembling the inner phase tube and the outer phase tube; the inner phase tube is communicated with 15 percent of NIPAM, 0.2 percent of BP, 0.9 percent of AAM solution, 0.2 IU of insulin and 1 percent of photoinitiator mixed solution, the outer phase tube is communicated with sunflower seed oil, and the flow rate of the inner phase and the flow rate of the outer phase are controlled by a peristaltic pump to control the size of liquid drops; and vertically irradiating the generated single emulsion liquid drop by using an ultraviolet lamp for 30s, collecting the single emulsion liquid drop, and washing the single emulsion liquid drop by using absolute ethyl alcohol and ultrapure water for 3 times respectively for 1 minute each time to obtain the drug-loaded microsphere with the particle size of 200 mu m.
S2 preparation of drug-loaded microsphere-microneedle array
Preparing a mixed solution of 70% ETPTA, 30% PEG and 1% photoinitiator, dropwise adding the prepared solution into a microneedle template (the length of a needle is 860 mu m, the bottom side length of the needle is 360 x 360 mu m, the distance between the needle point and the microneedle is 700 mu m, and the number array is 10 x 10), vacuumizing for 5 minutes, and fully filling the mixed solution into the needle point of the microneedle template; and (4) filling the drug-loaded microspheres obtained in the step S1 in the needle point positions of the microneedle template one by one, then curing by ultraviolet vertical irradiation for 10S, and finally, carefully stripping from the template to obtain the drug-loaded microsphere-microneedle array.
Example 2 preparation of drug-loaded microsphere-microneedle arrays for controlled drug delivery
S1 preparation of drug-loaded microspheres
Preparing a micro-fluidic device by a capillary tube with the outer diameter of 1 mm and the inner diameter of 500 mu m, drawing and grinding an inner phase tube into a required caliber by a machine, performing hydrophobic treatment on an outer phase tube by octadecyl trimethoxy silane, and coaxially assembling the inner phase tube and the outer phase tube; the inner phase pipe is communicated with 10 percent of NIPAM, 0.5 percent of BP, 1.2 percent of AAM solution, 0.2 IU of insulin and 1 percent of photoinitiator mixed solution, the outer phase pipe is communicated with sunflower seed oil, and the flow rate of the inner phase and the flow rate of the outer phase are controlled by a peristaltic pump to control the size of liquid drops; and vertically irradiating the generated single emulsion liquid drop for 30s by using an ultraviolet lamp, and washing the single emulsion liquid drop by using absolute ethyl alcohol and ultrapure water respectively for 3 times, wherein each time is 1 minute, so as to obtain the drug-loaded microsphere with the particle size of 300 mu m.
S2 preparation of drug-loaded microsphere-microneedle array
Preparing a mixed solution of 70% ETPTA, 30% PEG and 1% photoinitiator, dropwise adding the prepared solution into a microneedle template (the length of a needle is 1000 microns, the bottom side length of the needle is 400 x 400 microns, the distance of the needle tip is 1000 microns, and the number of arrays is 10 x 10), vacuumizing for 5 minutes, and fully filling the mixed solution into the needle tip of the microneedle template; and (4) filling the drug-loaded microspheres obtained in the step S1 in the needle point positions of the microneedle template one by one, then curing by ultraviolet vertical irradiation for 10S, and finally, carefully stripping from the template to obtain the drug-loaded microsphere-microneedle array.
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 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, for those skilled in the art, several modifications and decorations without departing from the principle of the present invention should be regarded as the protection scope of the present invention.
Claims (10)
1. A preparation method of a drug-loaded microsphere-microneedle array with controllable drug delivery is characterized by comprising the following steps:
s1 preparation of drug-loaded microspheres
Mixing a drug and hydrogel to prepare hydrogel and a drug mixed solution as an internal phase, wherein the hydrogel is prepared by mixing black phosphorus, N-isopropyl acrylamide and acrylamide according to a certain proportion; the outer phase is an oil phase which is not mutually soluble with the inner phase, the outer phase and the inner phase are injected into a microfluidic device, monodisperse single emulsion droplets are formed by utilizing the shearing force between two phase solutions, the droplets are solidified and collected, and the droplets are rinsed for a plurality of times by using alcohol and deionized water to obtain polymer drug-loaded microspheres with uniform particle sizes;
s2 preparation of drug-loaded microsphere-microneedle array
Preparing a hydrogel solution, pouring the hydrogel solution into the microneedle template, and vacuumizing to enable the hydrogel solution to fill the gaps of the microneedle template; and filling the drug-loaded microspheres obtained in the step S1 in the needle point part of the microneedle template, and stripping the cured drug-loaded microspheres from the microneedle template to obtain the drug-loaded microsphere-microneedle array.
2. The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S1, the hydrogel of the drug-loaded microsphere is formed by mixing 0.2-1% of black phosphorus, 10-20% of N-isopropylacrylamide and 0.6-1.5% of acrylamide.
3. The method for preparing a drug-loaded microsphere-microneedle array according to claim 1, wherein in S1, the droplet size can be changed by adjusting the flow rate of the microfluidic inner phase and the microfluidic outer phase.
4. The method for preparing a drug-loaded microsphere-microneedle array for controlled drug delivery according to claim 1, wherein in S1, the diameter of the prepared drug-loaded microsphere is 200-500 μm.
5. The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S2, the side length of the bottom of the microneedle is 500-700 μm, the needle length is 500-1000 μm, and the distance between adjacent needle points is 500-1000 μm.
6. The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S2, the hydrogel solution is prepared by mixing ethoxylated trimethylolpropane triacrylate and polyethylene glycol.
7. The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S2, the hydrogel solution is prepared by mixing 50-80% of ethoxylated trimethylolpropane triacrylate and 20-40% of polyethylene glycol.
8. The method for preparing a drug-loaded microsphere-microneedle array according to claim 1, wherein in S2, each microneedle tip of the drug-loaded microsphere-microneedle array is filled with one or more drug-loaded microspheres, and the drug-loaded microspheres are uniformly distributed in the microneedle.
9. A drug-loaded microsphere-microneedle array for controlled drug delivery, which is prepared by the preparation method according to any one of claims 1 to 8.
10. The application of the drug-loaded microsphere-microneedle array of any one of claims 1-8 in the field of transdermal drug delivery.
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| PCT/CN2021/137087 WO2022143101A1 (en) | 2020-12-28 | 2021-12-10 | Drug-carrying microsphere-microneedle array for controllable drug administration, preparation method therefor, and application thereof |
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| CN113797439A (en) * | 2021-09-27 | 2021-12-17 | 山东大学 | Near-infrared response hydrogel microneedle patch and preparation method thereof |
| WO2022143101A1 (en) * | 2020-12-28 | 2022-07-07 | 南京鼓楼医院 | Drug-carrying microsphere-microneedle array for controllable drug administration, preparation method therefor, and application thereof |
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| CN102000020B (en) * | 2010-11-17 | 2012-10-10 | 河南羚锐制药股份有限公司北京药物研究院 | Novel micro-needle patch containing degradable polymer and preparation method thereof |
| BR112020013872A2 (en) * | 2018-01-07 | 2020-12-01 | Avraham Amir | high-load microneedles and skin augmentation compositions |
| CN111568854B (en) * | 2020-06-09 | 2022-09-09 | 重庆医药高等专科学校 | Preparation method of triptolide transdermal microneedle patch product for external use |
| CN112472662A (en) * | 2020-12-28 | 2021-03-12 | 南京鼓楼医院 | Drug-loaded microsphere-microneedle array with controllable drug delivery, preparation method and application |
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| WO2022143101A1 (en) * | 2020-12-28 | 2022-07-07 | 南京鼓楼医院 | Drug-carrying microsphere-microneedle array for controllable drug administration, preparation method therefor, and application thereof |
| CN113797439A (en) * | 2021-09-27 | 2021-12-17 | 山东大学 | Near-infrared response hydrogel microneedle patch and preparation method thereof |
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