CN110201296A - A kind of conducting polymer microneedle patch and preparation method thereof for controlled drug release - Google Patents

Abstract

The invention relates to a conductive polymer microneedle patch for controlled drug release and a preparation method thereof. The microneedle patch includes a working electrode, a counter electrode and a reference electrode; the working electrode is one or more of a single microneedle, a microneedle array or a microneedle series combination pattern; the microneedle is conductive The polymer microneedle is composed of a polymer solid microneedle, an inert metal layer and a drug-loaded conductive polymer film layer; the controlled release of drugs is realized through electrical stimulation. The invention is an integrated product combining a microneedle and a conductive polymer drug delivery system. The microneedle is used to pierce the skin, and the subcutaneous release of the drug carried by the microneedle is regulated by electrical stimulation. The preparation process of the drug-loaded conductive polymer microneedle of the present invention is simple, low in cost, good in biocompatibility, does not cause pain during use, and can be used for short-term or long-term controlled drug release.

Description

A conductive polymer microneedle patch for controlled drug release and its preparation method

technical field

The invention belongs to the technical field of transdermal drug delivery, in particular to a conductive polymer microneedle patch for controlled drug release and a preparation method thereof.

Background technique

Microneedle drug delivery is an emerging transdermal drug delivery method, which mainly has two delivery methods. One is that the needle body contains a drug structure. After the microneedle is inserted into the skin, the drug can be absorbed by the skin within a certain period of time and enter the human body's circulatory system; Treatment destroys the stratum corneum of the skin, thereby greatly improving the absorption efficiency of the skin to the drug compared with the traditional transdermal delivery method. Microneedle administration has the characteristics of convenience, painlessness, and high efficiency, which can improve patient compliance. However, it is difficult to achieve controlled drug release with microneedle administration at this stage.

In recent decades, intelligent drug sustained-release systems with electrical stimulation response characteristics have aroused great interest of researchers. Among them, conductive polymers are widely used as matrix materials in the study of drug sustained release systems. Conductive polymers have the advantages of light weight, high strength, and easy processing, and can be driven by a lower voltage (≤1V) to change their oxidation-reduction state. Most conductive polymers also have good biocompatibility. These advantages are It has laid a good foundation for its application in the field of drug delivery.

Drug loading can be easily realized by using the doping characteristics of conductive polymers, and drugs can also be loaded by physical embedding. The oxidation-reduction state of conductive polymers can be changed by applying external electrical stimulation, thereby causing changes in the charge, doping level, conductivity and volume of the polymer, thereby realizing the regulation of nerve growth factors, anti-inflammatory drugs, hormones and genes. controlled release of substances.

Patents such as CN 105832651 A and CN 107313092 A disclose methods for controlling drug release in response to electrical stimulation of conductive polymer polypyrrole. For the electrical stimulation of conductive polymers to control drug release, the method of implanting drug-loaded conductive polymer membranes into the body is mostly used, which is complicated and painful.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art. The present invention provides a conductive polymer microneedle patch for controlled drug release and its preparation by introducing microneedles into a drug release system based on conductive polymers. method.

The technical solution is as follows:

The conductive polymer microneedle patch for controlled drug release according to the present invention includes a working electrode, a counter electrode and a reference electrode; the working electrode is a single microneedle, a microneedle array or a combination pattern of microneedles in series One or more of them; the microneedle is a conductive polymer microneedle, which is composed of a polymer solid microneedle, an inert metal layer and a drug-loaded conductive polymer film layer; the controlled release of the drug is realized through electrical stimulation.

Further, the needle body and the base of the polymer solid microneedle are integrally formed by biodegradable polymer materials, and the biodegradable polymer materials are polylactic acid, L-lactic acid, polyglycolic acid One or more; the length of the needle body is between 200-1000 microns, and the diameter of the bottom is between 10-800 microns; the material of the inert metal layer is gold, silver, platinum, palladium, iridium and indium tin oxide one or more of .

Further, the counter electrode and the reference electrode are composed of polymer solid microneedles and an inert metal layer, wherein: the material of the inert metal layer of the counter electrode is one or more of gold, silver and platinum; the reference electrode is One or more of silver, silver/silver chloride ink, gold and platinum, and the thickness of the inert metal layer is between 1-1000 nanometers.

Further, the inert metal layer is coated on the polymer solid microneedles by one or more methods of sputtering, spraying, dipping and deposition, and at the same time, a conductive circuit pattern is obtained to connect the microneedles in series, and Forms contacts for external circuits.

Further, the material of the conductive polymer film layer is made of one or more of polyphenylethylene, polyaniline, polypyrrole, polythiophene and its derivatives, and the thickness is between 0.01-100 microns, so The conductive polymer film layer is obtained by one-step or two-step electrochemical polymerization, and the electrochemical polymerization method is one or more of cyclic voltammetry, constant potential, constant current, dynamic potential scanning method, and pulse method.

Further, the loaded drug is one or more of cationic drugs, anionic drugs and neutral drugs, and is loaded on the conductive high in the molecular film.

Further, the method for realizing the controlled release of drugs through electrical stimulation is one or more of cyclic voltammetry, constant potential method, and constant current method.

Further, the drug loading is achieved by changing one or more of the length of the microneedle, the size of the microneedle array, the composition and concentration of the electrolyte, and the thickness of the drug-loaded conductive polymer film.

Further, the electronically regulated release mode of the drug is one or more of on-demand release, continuous release, and pulse release.

The preparation method of the above-mentioned conductive polymer microneedle patch for controlled drug release is as follows:

(1) Prepare polymer solid microneedles, solid microneedle arrays or solid microneedle patterns with a base by template method;

(2) A mask with a three-electrode circuit pattern is covered on the microneedle base, and an inert metal layer is covered on the solid microneedle body and its base by sputtering, spraying, dipping or deposition methods, and its thickness is between 1- Between 1000 nm, then remove the mask;

(3) Prepare a solution containing a conductive polymer monomer and a drug, and drop the uniformly mixed solution on the microneedle, so that the needle body is completely immersed in the solution;

(4) Connect the electrodes in the microneedle to the corresponding electrodes of the electrochemical workstation, the microneedle is the working electrode, and the reference electrode is one of saturated calomel electrode, silver/silver chloride electrode and mercury/mercuric oxide electrode or more, adopt cyclic voltammetry, constant potential method, constant current method, dynamic potential scanning method or pulse method to carry out electrochemical polymerization, remove excess solution in the microneedle, rinse, and dry to obtain a drug-loaded high-conductivity Molecular microneedles.

The specific application method of the above-mentioned conductive polymer microneedle patch for controllable drug release is: connect the electrodes in the microneedle to the corresponding electrodes in the power supply, and use cyclic voltammetry, constant voltage method, pulse method or constant The current method applies a certain electrical signal to the microneedle, thereby stimulating the release of the drug in the needle body.

The conductive polymer microneedle patch with electrical stimulation responsiveness described in the present invention is an integrated product combining a drug-loaded conductive polymer film and a microneedle. After the microneedle is inserted into the skin, the drug can be controlled by electrical stimulation. The release can reduce the damage to the skin and reduce the pain of the patient, and the preparation method is simple and easy.

Description of drawings

1 is a schematic diagram of a top view of a microneedle array template;

Fig. 2 is a schematic diagram along line A-A in Fig. 1;

3 is a schematic diagram of a top view of a mask;

4 is a schematic diagram of a top view of a conductive polymer microneedle patch;

Fig. 5 is a schematic diagram of a longitudinal section of a single microneedle.

Fig. 6 is a schematic diagram of cooperation between the microneedle and the patch.

Reference signs:

1-microneedle template, 2-pair electrode contact, 3-working electrode contact, 4-reference electrode contact, 5-conductive trace, 6-microneedle, 7-microneedle body, 8-carrying The conductive polymer film of medicine, 9-inert metal layer, 10-microneedle base.

Detailed ways

In order for those skilled in the art to better understand the technical solution of the present invention, a conductive polymer microneedle patch for controlled drug release provided by the present invention and its preparation method will be described in detail below with reference to the accompanying drawings. The following examples are only used to illustrate the present invention but not to limit the scope of the present invention.

【Example 1】

(1) Mix the liquid polydimethylsiloxane prepolymer and the curing agent in a mass ratio of 10:1, stir evenly, and then vacuumize to remove the air bubbles, then pour it into a horizontally placed container. Put the container in an oven at 60°C to cure for 2-6 hours to obtain a polydimethylsiloxane sheet with uniform thickness; then take the sheet out of the container and put it into the working chamber of the laser engraving machine. Morphological adjustment of laser parameters, micro-nano processing of polydimethylsiloxane flakes to prepare microneedle templates, and a microneedle array template with an array density of 3×3 and a height of 600 μm (as shown in Figure 1 and Figure 2) ;

(2) Place an appropriate amount of polylactic acid solid particles on the microneedle template, and then heat it at 200°C for 20 minutes to fully melt the polylactic acid, then take out the template, mold it when the polylactic acid is in a molten state, and wait for it to cool to room temperature After demoulding, a solid polymer microneedle patch with a base can be obtained;

(3) Cover the solid microneedle base with a mask engraved with a certain circuit pattern (as shown in Figure 3), and then use a small ion sputtering instrument to spray gold on the surface of the solid microneedle to coat the surface with a layer of gold film, and then remove the mask to obtain a gold-plated solid polymer microneedle patch;

(4) Using sodium fluorescein as a model drug, prepare a solution containing pyrrole monomer and sodium fluorescein, wherein the concentration of pyrrole monomer is 0.2mol/L, and the concentration of sodium fluorescein is 0.02mol/L;

(5) Immerse the microneedle prepared in (3) into the solution prepared in (4) to ensure that the solution completely covers the microneedle area, and then connect the three electrodes of the microneedle patch to the corresponding three electrodes of the electrochemical workstation , the electrochemical polymerization was carried out by constant voltage method, wherein the polymerization voltage was 0.8V, and the polymerization charge was 1mC. After the polymerization is completed, take out the microneedle, rinse the obtained microneedle with ultrapure water for 3-5 times, and air-dry naturally to obtain a conductive polymer microneedle patch loaded with the model drug (as shown in Figure 4 and Figure 5), in which the conductive polymer microneedle patch is obtained. The thickness of the polymer film is about 1 μm.

[Example 2]

(1) Mix the liquid polydimethylsiloxane prepolymer and the curing agent in a mass ratio of 10:1, stir evenly, and then vacuumize to remove the air bubbles, then pour it into a horizontally placed container. Put the container in an oven at 60°C to cure for 2-6 hours to obtain a polydimethylsiloxane sheet with uniform thickness; then take the sheet out of the container and put it into the working chamber of the laser engraving machine. Morphological adjustment of laser parameters, micro-nano processing of polydimethylsiloxane flakes to prepare micro-needle templates, and a micro-needle array template with an array density of 3×3 and a height of 600 μm;

(2) Place an appropriate amount of polylactic acid solid particles on the microneedle template, and then heat it at 200°C for 20 minutes to fully melt the polylactic acid, then take out the template, mold it when the polylactic acid is in a molten state, and wait for it to cool to room temperature After demoulding, a solid polymer microneedle patch with a base can be obtained;

(3) Cover the microneedle base with a mask with a three-electrode circuit pattern, use a small ion sputtering instrument to spray gold on the surface of the solid microneedle, and obtain a solid polymer microneedle patch coated with a layer of gold film on the surface, Then remove the mask and set aside;

(4) Using sodium fluorescein as a model drug, prepare a solution containing pyrrole monomer and sodium fluorescein, wherein the concentration of pyrrole monomer is 0.2mol/L, and the concentration of sodium fluorescein is 0.02mol/L;

(5) Drop the solution prepared in (4) on the microneedle patch prepared in (3), so that the solution completely covers the microneedle area, and then connect the three electrodes of the microneedle patch to the corresponding three electrodes of the electrochemical workstation. The electrodes are connected, the microneedle is the working electrode, the counter electrode is the platinum electrode, and the reference electrode is the saturated calomel electrode. Electrochemical polymerization is carried out by constant voltage method, wherein the polymerization voltage is 0.8V, and the polymerization charge is 1mC. After the polymerization is completed, remove the excess solution on the surface of the microneedle patch, and remove the mask attached in (3), then rinse the obtained microneedle with ultrapure water for 3-5 times, and let it dry naturally to obtain the model drug. A conductive polymer microneedle patch, in which the thickness of the conductive polymer film is about 1 μm.

The application method of the above-mentioned conductive polymer microneedle patch for controlled drug release is as follows: the electrodes in the microneedles are respectively connected to the corresponding electrodes in the power supply, and the polymer solid microneedles and inert metal microneedles obtained in step (2) layer constitutes the microneedle as the counter electrode and the reference electrode, and the drug-loaded microneedle obtained in step (5) is used as the working electrode, and the electric signal is applied to the microneedle by cyclic voltammetry, constant voltage method, pulse method or constant current method, thereby Stimulate the release of the drug in the needle.

The invention is an integrated product combining a microneedle and a conductive polymer drug delivery system. The microneedle is used to pierce the skin, and the subcutaneous release of the drug carried by the microneedle is regulated by electrical stimulation. The preparation process of the drug-loaded conductive polymer microneedle of the present invention is simple, low in cost, good in biocompatibility, does not cause pain during use, and can be used for short-term or long-term controlled drug release.

The examples of the present invention have been described in detail above in conjunction with the accompanying drawings, but the present invention is not limited to the above-mentioned examples. Within the scope of knowledge possessed by those of ordinary skill in the art, various modifications can also be made without departing from the gist of the present invention. Changes should also be regarded as the protection scope of the present invention.

Claims (10)

1. A conductive polymer microneedle patch for controlled drug release, characterized in that it includes a working electrode, a counter electrode and a reference electrode; the working electrode is a single microneedle, a microneedle array or a series combination of microneedles One or more of the patterns; the microneedle is a conductive polymer microneedle, which is composed of a polymer solid microneedle, an inert metal layer and a drug-loaded conductive polymer film layer; the controlled release of the drug is realized through electrical stimulation. 2. The conductive polymer microneedle patch for controlled drug release according to claim 1, wherein the needle body and the base of the polymer solid microneedle are integrally formed by biodegradable polymer materials Prepared, the biodegradable polymer material is one or more of polylactic acid, L-lactic acid, and polyglycolic acid; the length of the needle body is between 200-1000 microns, and the diameter of the bottom is between 10-800 microns ; The material of the inert metal layer is one or more of gold, silver, platinum, palladium, iridium and indium tin oxide. 3. The conductive polymer microneedle patch for controlled drug release according to claim 2, wherein the counter electrode and the reference electrode are made of polymer solid microneedles and an inert metal layer, wherein: The material of the electrode inert metal layer is one or more of gold, silver and platinum; the reference electrode is one or more of silver, silver/silver chloride ink, gold and platinum, and the thickness of the inert metal layer is 1 -1000nm. 4. The conductive polymer microneedle patch for controlled drug release according to claim 3, wherein the inert metal layer is formed by one or more of sputtering, spraying, dipping and deposition The method is coated on the polymer solid microneedle, and at the same time obtains a conductive circuit pattern, connects each microneedle in series, and forms a contact for an external circuit. 5. the conductive polymer microneedle patch for controllable drug release according to claim 4, is characterized in that, the material of described conductive polymer film layer is made of polyphenylethylene, polyaniline, polypyrrole, polythiophene It is made of one or more of its derivatives, and the thickness is between 0.01-100 microns. The conductive polymer film layer is obtained by one-step or two-step electrochemical polymerization, and the electrochemical polymerization method is cyclic voltammetry One or more of the method, constant potential, constant current, dynamic potential scanning method, and pulse method. 6. The conductive polymer microneedle patch for controlled drug release according to claim 5, wherein the medicine carried is one or more of cationic medicine, anionic medicine and neutral medicine, through One or more methods of doping, physical embedding, and covalent bonding are loaded into the conductive polymer film. 7. The conductive polymer microneedle patch for controlled drug release according to claim 6, wherein the method for realizing the controlled release of medicine by electrical stimulation is cyclic voltammetry, potentiostatic method, and constant current method one or more of. 8. The conductive polymer microneedle patch for controlled drug release according to claim 7, wherein the drug loading is achieved by changing the length of the microneedle, the size of the microneedle array, the composition and concentration of the electrolyte, and the It is realized by one or more of the thicknesses of the drug-conducting polymer film. 9. The conductive polymer microneedle patch for controllable drug release according to claim 8, characterized in that the electrically regulated release mode of the drug is one or more of release on demand, continuous, and pulsed . 10. A method for preparing a conductive polymer microneedle patch for controlled drug release, comprising the following steps: (1) Prepare polymer solid microneedles, solid microneedle arrays or solid microneedle patterns with a base by template method; (2) A mask with a three-electrode circuit pattern is covered on the microneedle base, and an inert metal layer is covered on the solid microneedle body and its base by sputtering, spraying, dipping or deposition methods, and its thickness is between 1- Between 1000 nm, then remove the mask; (3) Prepare a solution containing a conductive polymer monomer and a drug, and drop the uniformly mixed solution on the microneedle, so that the needle body is completely immersed in the solution; (4) Connect the electrodes in the microneedle to the corresponding electrodes of the electrochemical workstation, the microneedle is the working electrode, the counter electrode is a platinum electrode, and the reference electrode is a saturated calomel electrode, a silver/silver chloride electrode and a mercury/oxidation electrode. One or more of the mercury electrodes are electrochemically polymerized by cyclic voltammetry, constant potential method, constant current method, dynamic potential scanning method or pulse method, and then the excess solution in the microneedle is removed, rinsed, and dried to obtain The drug-loaded conductive polymer microneedle according to any one of claims 1-9.