WO2022143101A1

WO2022143101A1 - Drug-carrying microsphere-microneedle array for controllable drug administration, preparation method therefor, and application thereof

Info

Publication number: WO2022143101A1
Application number: PCT/CN2021/137087
Authority: WO
Inventors: 赵远锦; 樊璐; 王月桐; 张大淦; 商珞然
Original assignee: 南京鼓楼医院
Priority date: 2020-12-28
Filing date: 2021-12-10
Publication date: 2022-07-07
Also published as: CN112472662A

Abstract

A drug-carrying microsphere-microneedle array for controllable drug administration, a preparation method therefor, and application thereof. The method comprises: preparing drug-carrying microspheres with a uniform particle size on the basis of a microfluidic technique, placing the drug-carrying microspheres into a pyramid microneedle template filled with a microneedle hydrogel solution, curing same, and then removing the microneedle template to obtain a drug-carrying microsphere-microneedle array. In the prepared drug-carrying microsphere-microneedle array, the drug-carrying microspheres have good sphericity, a good drug release rate and uniformly fill each needle tip, and a microneedle punctures into the skin to assist in the uniform subcutaneous distribution of the drug-carrying microspheres, thereby achieving the aim of controllable transdermal drug administration. The drug-carrying microsphere-microneedle array for controllable drug administration has the advantages of good drug controllability, a low preparation cost, easy operation, etc., has high practicability, and is suitable for popularization.

Description

A drug-loaded microsphere-microneedle array with controllable drug delivery, preparation method and application

technical field

The invention belongs to the technical field of biological materials, and in particular relates to a drug-carrying microsphere-microneedle array with controllable administration, a preparation method and an application.

Background technique

Microsphere drug delivery is an efficient drug delivery method. The microspheres can carry a sufficient amount of drug and release it slowly and controllably to maintain effective drug concentration in the blood. Due to the softness, large specific surface area and good biocompatibility of hydrogel microspheres, drug-loaded microspheres are widely used in the field of drug delivery.

The traditional ways of applying drug-loaded microspheres to the lesions include subcutaneous injection, spraying, oral administration, etc., of which the most common and efficient way is subcutaneous injection. However, due to the need to use a syringe to cause pain, poor patient compliance, and easy to cause wound infection, uneven distribution of microspheres under the skin and other shortcomings, limiting the application of drug-loaded microspheres.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a drug-loaded microsphere-microneedle array with controllable drug delivery, preparation method and application, aiming at the deficiencies of the prior art. Microneedles are composed of a base and a series of neatly arranged needle tips, which are hundreds of microns long and can penetrate the stratum corneum of the skin to form micron-sized channels. The drug-loaded microspheres are filled in the microneedles, and the microneedles can assist the microspheres to be evenly distributed under the skin, and the microspheres can controllably release the drug at the lesion site. The preparation method of the drug-loaded microsphere-microneedle is simple, the drug release rate is high, and it is a painless, efficient and convenient means of administration, and can be used in the field of transdermal administration.

The present invention adopts following technical scheme:

A preparation method of drug-loaded microsphere-microneedle array with controllable administration, comprising the following steps:

S1. Preparation of drug-loaded microspheres: the drug and the microsphere hydrogel solution are mixed to prepare a mixed solution of the microsphere hydrogel solution and the drug as the internal phase, and the microsphere hydrogel solution is composed of black phosphorus (BP) , N-isopropylacrylamide (NIPAM), and acrylamide (AAM) are mixed with water in a certain proportion; the outer phase is an oil phase that is immiscible with the inner phase, and the outer and inner phases are injected into the microfluidic device, using The shear force between the two-phase solutions forms monodisperse single emulsion droplets, which are solidified and collected, rinsed several times with alcohol and deionized water to obtain polymer drug-loaded microspheres with uniform particle size;

S2. Preparation of drug-loaded microsphere-microneedle array: prepare a microneedle hydrogel solution, pour the microneedle hydrogel solution into the microneedle template, and fill the microneedles with the microneedle hydrogel solution by vacuuming The voids of the template; the drug-loaded microspheres obtained from S1 are filled in the tip of the microneedle template, then cross-linked and cured, and finally peeled off from the microneedle template to obtain a drug-loaded microsphere-microneedle array.

Further, in S1, in the microsphere hydrogel solution, the mass volume ratio of black phosphorus (BP) to 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 of the single emulsion droplets can be changed by adjusting the flow rates of the inner and outer phases of the microfluidic control.

Further, the diameter of the drug-loaded microspheres prepared by S1 is between 200-500 μm.

Further, in S2, the microneedle bottom edge length of the prepared microneedle array is 500-700 μm, the needle length is 500-1000 μm, and the distance between adjacent needle tips is 500-1000 μm.

Further, in S2, the microneedle hydrogel solution is formed by mixing ethoxylated trimethylolpropane triacrylate (ETPTA) and polyethylene glycol (PEG) with water.

Further, in S2, in the microneedle hydrogel solution, the volume ratio of ethoxylated trimethylolpropane triacrylate (ETPTA) to water is 50-80%, and polyethylene glycol (PEG) and The volume ratio of water is 20-40%.

Further, in S2, in the drug-loaded microsphere-microneedle array, each microneedle tip is filled with one or more drug-loaded microspheres, and the drug-loaded microspheres are uniformly distributed in the microneedles.

The present invention also provides a drug-loading microsphere-microneedle array with controllable administration, which is prepared according to the above-mentioned preparation method.

The present invention also provides the application of the above-mentioned drug-loaded microsphere-microneedle array in the preparation of transdermal medicaments.

Beneficial effects of the present invention:

1. The present invention prepares the hydrogel drug-loaded microspheres in a microfluidic manner, the method is simple, the cost is low, the reusability is high, and the size of the drug-loaded microspheres is easy to control;

2. In the present invention, microneedles are used instead of syringes, and drug-loaded microspheres are filled into microneedle arrays, and the obtained microspheres-microneedle arrays can be firmly attached to the skin, realizing the effect of uniform administration and overcoming the problems of microspheres. The disadvantage of uneven distribution at the wound site and easy to fall off, to achieve painless portable drug delivery;

3. The microsphere hydrogel in the drug-loaded microspheres of the present invention contains black phosphorus (BP), which is a photothermal responsive material, has near-infrared photoresponsivity, and can convert light into heat, It has a strong practical value to promote the melting of the hydrogel, thereby promoting the release of the drug in the hydrogel and realizing the controlled release of the drug.

Description of drawings

Fig. 1 is the schematic diagram of preparing single emulsion microspheres by microfluidic control of the present invention;

Fig. 2 is the infrared response photomicrograph of the single emulsion microsphere prepared by the present invention;

FIG. 3 is a flow chart of the preparation of the drug-loaded microsphere-microneedle array of the present invention;

Fig. 4 is the light microscope picture of the drug-loaded microsphere-microneedle array of the present invention;

Fig. 5 is a fluorescent picture of the controllable drug delivery of the drug-loaded microsphere-microneedle array of the present invention.

Detailed ways:

In order to make the purposes, 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 in conjunction with the embodiments of the present invention. Obviously, the described embodiments are the present invention. some examples, but not all examples. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present invention. The implementation conditions not specified in the examples are usually the conditions in routine experiments.

S1. Preparation of drug-loaded microspheres:

The drug is mixed with the microsphere hydrogel solution to prepare a mixed solution of the microsphere hydrogel solution and the drug as the internal phase, and the microsphere hydrogel solution is composed of black phosphorus (BP), N-isopropylacrylamide ( NIPAM) and acrylamide (AAM) are mixed with water in a certain proportion; the outer phase is an oil phase that is immiscible with the inner phase. Monodisperse single emulsion droplets, the size of the droplets can be changed by adjusting the flow rates of the inner and outer phases of the microfluidic control; solidify and collect, rinse with alcohol and deionized water for several times to obtain polymer drug-loaded microspheres with uniform particle size (diameter between 200-500μm); microsphere hydrogel solution consists of 0.2-1w/v% black phosphorus (BP), 10-20w/v% N-isopropylacrylamide (NIPAM), 0.6-1.5w /v% Acrylamide (AAM) mixed with water.

S2. Preparation of drug-loaded microsphere-microneedle array:

Prepare a microneedle hydrogel solution, pour the microneedle hydrogel solution into the microneedle template, and fill the gap of the microneedle template with the microneedle hydrogel solution by vacuuming; fill the drug-loaded microspheres obtained in S1 At the tip of the microneedle template, peel off the microneedle template after curing to obtain a drug-loaded microsphere-microneedle array; the bottom side length of the microneedle is 500-700 μm, the needle length is 500-1000 μm, and the distance between adjacent needle tips is 500-1000 μm; the microneedle hydrogel solution is prepared by mixing 50-80v/v% ethoxylated trimethylolpropane triacrylate (ETPTA) and 20-40v/v% polyethylene glycol (PEG) with water. In the drug-loaded microsphere-microneedle array, the tip of each microneedle is filled with one or more drug-loaded microspheres, and the drug-loaded microspheres are evenly distributed in the microneedles.

Example 1 Preparation of drug-loaded microsphere-microneedle array for controllable drug delivery

S1. Preparation of drug-loaded microspheres:

As shown in Figure 1, the microfluidic device was prepared by a capillary tube with an outer diameter of 1 mm and an inner diameter of 500 μm. The inner phase tube was machined and ground to the required diameter. The tubes were coaxially assembled; the inner phase tube was connected to 15w/v% NIPAM, 0.2w/v% BP, 0.9w/v% AAM solution, 0.2IU insulin and 1v/v% photoinitiator mixed solution, and the outer phase tube was connected to sunflower oil , use a peristaltic pump to control the flow rate of the internal and external phases to control the size of the droplets; vertically irradiate the single emulsion droplets generated by an ultraviolet lamp for 30 s and collect them, and then wash them with absolute ethanol and deionized water for 3 times each for 1 minute each time, to obtain particles. Drug-loaded microspheres with a diameter of 200 μm.

S2. Preparation of drug-loaded microsphere-microneedle array:

As shown in Figure 3, a mixed solution of 70v/v% ETPTA, 30v/v% PEG and 1v/v% photoinitiator was prepared, and the prepared mixed solution was added dropwise to the microneedle template (needle length 860 μm, needle bottom side length 360*360μm, needle tip distance 700μm, number array 10*10), vacuumize for 5 minutes, so that the mixed solution is fully filled in the needle tip of the microneedle template; the drug-loaded microspheres obtained in S1 are filled one by one in the needle tip of the microneedle template Then, it was cured by vertical ultraviolet irradiation for 10s, and finally it was carefully peeled off from the microneedle template to obtain a drug-loaded microsphere-microneedle array, as shown in Figure 4.

Example 2 Preparation of drug-loaded microsphere-microneedle array for controllable drug delivery

S1. Preparation of drug-loaded microspheres:

The microfluidic device was prepared by a capillary tube with an outer diameter of 1 mm and an inner diameter of 500 μm. The inner phase tube was machined and ground to the required diameter. The outer phase tube was hydrophobicized by octadecyltrimethoxysilane, and the inner and outer phase tubes were coaxially assembled; The phase tube is connected to 10w/v% NIPAM, 0.5w/v% BP, 1.2w/v% AAM solution, 0.2IU insulin and 1v/v% photoinitiator mixed solution, the external phase tube is connected to sunflower oil, and the peristaltic pump is used to control the internal and external The phase flow rate was used to control the droplet size; the single emulsion droplets were irradiated vertically with an ultraviolet lamp for 30 s, and then washed with absolute ethanol and deionized water for 3 times each for 1 minute to obtain drug-loaded microspheres with a particle size of 300 μm .

S2. Preparation of drug-loaded microsphere-microneedle array:

Prepare a mixed solution of 70v/v% ETPTA, 30v/v% PEG and 1v/v% photoinitiator, and add the prepared mixed solution dropwise to the microneedle template (needle length 1000μm, needle bottom edge length 400*400μm, needle tip distance 1000μm, the number of arrays is 10*10), vacuumed for 5 minutes, so that the mixed solution was fully filled in the tip of the microneedle template; the drug-loaded microspheres obtained in S1 were filled one by one on the tip of the microneedle template, and then vertical Irradiated for 10s to cure, and finally peeled off carefully from the microneedle template to obtain a drug-loaded microsphere-microneedle array.

The above are only the preferred embodiments of the present invention, and the protection scope of the present invention is not limited to the above-mentioned embodiments. All technical solutions under the idea of the present invention belong to the protection scope of the present invention. For personnel, several improvements and modifications without departing from the principles of the present invention should be regarded as the protection scope of the present invention.

Claims

A preparation method of drug-loaded microsphere-microneedle array with controllable administration, characterized in that it comprises the following steps:

S1. Preparation of drug-loaded microspheres: the drug and the microsphere hydrogel solution are mixed to prepare a mixed solution of the microsphere hydrogel solution and the drug as the internal phase, and the microsphere hydrogel solution is composed of black phosphorus, N- Isopropylacrylamide, acrylamide and water are mixed; the outer phase is an oil phase that is immiscible with the inner phase, the outer phase and the inner phase are injected into the microfluidic device, and the shear force between the two-phase solutions is used to form a monodisperse Single emulsion droplets are solidified and collected to obtain drug-loaded microspheres with uniform particle size;

S2. Preparation of drug-loaded microsphere-microneedle array: prepare a microneedle hydrogel solution, pour the microneedle hydrogel solution into the microneedle template, and fill the microneedles with the microneedle hydrogel solution by vacuuming The space of the template; the drug-loaded microspheres obtained in S1 are filled in the tip of the microneedle template, and after curing, they are peeled off from the microneedle template to obtain a drug-loaded microsphere-microneedle array.
The method for preparing a drug-loaded microsphere-microneedle array with controllable administration according to claim 1, wherein in S1, in the microsphere hydrogel solution, the concentration of black phosphorus is 0.2-1w/ v%, the concentration of N-isopropylacrylamide is 10-20w/v%, and the concentration of acrylamide is 0.6-1.5w/v%.
The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S1, the liquid of the single emulsion droplet can be changed by adjusting the flow rates of the microfluidic inner phase and the outer phase drop size.
The method for preparing a drug-loaded microsphere-microneedle array with controllable administration according to claim 1, wherein the diameter of the drug-loaded microsphere prepared by S1 is between 200-500 μm.
The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S2, the microneedle bottom side length of the prepared microneedle array is 500-700 μm, and the needle length is 500-700 μm. It is 500 to 1000 μm, and the distance between adjacent needle tips is 500 to 1000 μm.
The method for preparing a drug-loaded microsphere-microneedle array with controllable administration according to claim 1, wherein in S2, the microneedle hydrogel solution is made of ethoxylated trimethylolpropane trimethylolide Acrylate and polyethylene glycol mixed with water.
The method for preparing a drug-loaded microsphere-microneedle array with controllable administration according to claim 6, wherein in S2, in the microneedle hydrogel solution, ethoxylated trimethylolpropane The concentration of triacrylate is 50-80 v/v%, and the concentration of polyethylene glycol is 20-40 v/v%.
The method for preparing a drug-loaded microsphere-microneedle array with controllable drug delivery according to claim 1, wherein in S2, in the drug-loaded microsphere-microneedle array, each microneedle tip is One or more drug-loaded microspheres are filled, and the drug-loaded microspheres are evenly distributed in the microneedles.
A drug-loaded microsphere-microneedle array with controllable administration, characterized in that it is prepared according to the preparation method described in any one of claims 1 to 8.
Application of the drug-loaded microsphere-microneedle array according to claim 9 in the preparation of transdermal medicaments.