CN107007927A - A kind of microneedle array drug paste and preparation method being administered based on electric field driven - Google Patents

Abstract

The invention discloses a microneedle array drug patch based on electric field-driven drug delivery. The patch structure includes: a microneedle array base; a microneedle array located on the upper surface of the microneedle array base, the microneedle array is wrapped in an elastic drug-loaded layer, and the elastic drug-loaded layer is an elastic biocompatible material , and the material is mixed with medicine; an absorption gasket set with the base of the microneedle array; and an electrode sheet attached to the lower surface of both the base of the microneedle array and the absorption gasket. The invention improves the drug loading capacity, administration efficiency, integration degree, ease of use and anti-infection safety, and is more conducive to production and popularization and application. The invention also discloses a preparation method of the microneedle array patch.

Description

A microneedle array patch based on electric field-driven drug delivery and its preparation method

technical field

The invention relates to a medicinal patch and a preparation method thereof, in particular to a microneedle array medicinal patch based on electric field-driven drug delivery and a preparation method thereof.

Background technique

With the development of biotechnology, there are more and more biological agents based on macromolecules such as polypeptides, oligonucleotides, and proteins. The route of administration is a common problem encountered in clinical practice of biological agents. Although oral administration is safe, simple, convenient and low-cost, biological agents are easily degraded in the liver and gastrointestinal tract when taken orally, reducing the effective utilization of biological agents, and some drugs will cause certain damage to the digestive tract Although injection administration has avoided the shortcoming of the curative effect of oral medicine, it is difficult to keep the stable blood drug concentration in the body, frequent injection also easily causes great misery and inconvenience to the patient. Traditional drug delivery methods include sublingual drug delivery, rectal drug delivery, and spray inhalation. However, these drug delivery methods can only be used for a few drugs, which cannot meet the needs of today's drug delivery. In addition, the above-mentioned traditional administration method also has the problem that the drug cannot be completely diluted.

At present, emerging drug delivery methods mainly include transdermal drug delivery and microneedle drug delivery. Transdermal administration is to paste the drug on the skin surface in the form of a coating agent, and use the penetration of the skin to carry out the drug delivery. However, due to the hindrance of the skin, the delivery efficiency of the drug is low and the speed is slow; the microneedle delivery is relatively efficient and has both It has four advantages of high efficiency, low damage, slow release and fast speed.

The microneedle transdermal drug delivery system has the dual advantages of injection and transdermal drug delivery, which can improve drug transdermal rate and absorption. The current main methods of microneedle drug delivery are: puncture after coating, coating after puncture, hollow microneedle and so on. However, the puncture operation after coating is more complicated and the drug loading is limited; the coating operation after puncture is relatively simple but the anti-infection ability is low; although the hollow microneedles avoid the shortcomings of the former two, the concentrated difficulty is reflected in the production of microneedles. Difficulty and material selection.

Contents of the invention

The present invention provides a microneedle array drug patch based on electric field-driven drug delivery, which integrates the three processes of coating, puncture, and transmission, effectively simplifying the steps of microneedle drug delivery. In order to achieve the above-mentioned purpose, the present invention The technical solutions adopted are:

A microneedle array drug patch based on electric field-driven drug delivery, comprising: a microneedle array base; a microneedle array located on the upper surface of the microneedle array base, the microneedle array is wrapped in an elastic drug-loaded layer, and the elastic load The drug layer is an elastic biocompatible material, and the material is mixed with drugs; an absorption gasket set with the microneedle array base; and an electrode sheet attached to the lower surfaces of both the microneedle array base and the absorption gasket.

When using the microneedle array patch of the present invention, the microneedle array patch (the electrode piece on the patch is used as the positive electrode) is directly pasted on the skin, and an electrode piece is pasted on the corresponding symmetrical part on the opposite side of the skin as the negative pole. Connect the two electrodes to the positive and negative poles of the electrotherapy machine. After checking that the electrotherapy machine is in the correct state, turn on the electrotherapy machine to achieve a suitable strength so that the two electrodes can work normally. Then press the outer surface of the electrode sheet on the patch to compress the elastic drug-loaded layer, so that the tip of the microneedle array in the elastic drug-loaded layer penetrates the elastic drug-loaded layer and penetrates the skin, forming micropores in the skin for drug delivery channels, since the elastic drug-loaded layer contains drugs, the elastic drug-loaded layer continues to administer drugs through the microporous drug delivery channels, and the potential difference generated by the two electrode sheets forms an electric field to accelerate drug penetration and absorption. At the end of pressing, the elastic drug-loaded layer returns to its original shape, and the microneedle array exits the skin and returns to the elastic drug-loaded layer. When in use, the outer surface of the electrode sheet can be pressed multiple times to prevent the microporous drug delivery channel from repairing and closing. As the administration time goes by, the drug in the elastic drug-loaded film will become less and less. At this time, the electric current of the electrotherapy machine can be appropriately increased to prevent drug accumulation and continue to release at a certain rate. Therefore, the microneedle array patch of the present invention can be integrated into a controllable and intelligent circuit by cleverly setting the electrode sheet so that the drug penetration solution can be driven by an electric field, which is conducive to the realization of the most cutting-edge biomedical engineering solution—— The integrated minimally invasive treatment method of "acquisition of pathological signals-intelligent diagnosis-intelligent controlled release of drugs" integrates the three processes of coating, puncture and transmission into one, which effectively simplifies the steps of microneedle drug delivery.

As a preferred embodiment of the microneedle array patch of the present invention, the electrode sheet is connected to a direct current electrotherapy machine through a wire, and the current intensity is 0.03-0.1mA/cm2 continuously adjustable.

The elastic drug-loaded layer is an elastic biocompatible material. The elastic drug-loaded layer in the present invention is used as a drug-controlled release interlayer, and its elastic material is used to store different types of macromolecular drugs, vaccines, etc., and at the same time protect micro-organisms. The needle array prevents breakage and prevents bacterial infection through the microhole array administration channel. The elastic drug-loaded layer can sustain sustained drug release through the skin, and its effective sustained-release time and speed are mainly regulated by changing the drug content in the elastic drug-loaded layer. The elastic material of the elastic drug-loading layer is preferably but not limited to hydrogel (such as hyaluronic acid hydrogel), elastic porous material (such as sponge) and the like.

In the microneedle array patch of the present invention, the drug in the elastic drug-loaded layer is generally a macromolecular drug such as influenza vaccine or insulin, and the drug is evenly distributed in the elastic material.

The electrode sheet is attached to the lower surface of both the microneedle array substrate and the absorbent gasket. As a preferred embodiment of the microneedle array patch of the present invention, the area of the electrode sheet is larger than that of the microneedle array substrate and the lower surface of the absorbent gasket. The total area of the surface. When the area of the electrode sheet is greater than the total area of the lower surface of both the micropore array base and the absorbing gasket, since the periphery of the electrode sheet is coated with a viscous material pressure-sensitive adhesive, the electrode sheet exceeds the micropore array base The part with the absorbing gasket is sticky, and this part can be directly pasted on the skin surface during use, so that the micropore array base, the micropore array, the elastic drug-loaded layer and the absorbing gasket are wrapped between the electrode sheet and the skin. Specifically, the electrode sheet may be a silicone electrode sheet or a non-woven electrode sheet.

As a preferred embodiment of the microneedle array patch of the present invention, when in use, the microneedle array needs to pierce the skin to form a microhole array drug delivery channel, but in order to prevent the tip discharge from causing electroporation and causing pain to the patient, Therefore, the microneedle array is preferably rigid biocompatible insulating material, specifically, it can be prepared from PMMA material, epoxy resin, composite insulating material with biocompatible coating or plating. Further, the microneedle array is in the form of an array, and the height of the microneedles in the microneedle array is no more than 1500 microns.

As a preferred embodiment of the microneedle array patch of the present invention, since the pressure-sensitive adhesive is used for pasting the skin and the electrode sheet, it is directly pasted on the surface of the skin, and it is firm after being pressed, so the hyposensitive adhesive is required to have Good skin biocompatibility and non-toxicity, specifically, the pressure-sensitive adhesive adopts medical pressure-sensitive adhesive, and the thickness of the pressure-sensitive adhesive should not exceed the thickness of the water-absorbing gasket.

The absorbent gasket is used to absorb the liquid produced during the medication process. As a preferred embodiment of the microneedle array patch of the present invention, the absorbent gasket should be made of soft materials with water absorption properties. Specifically, medical absorbent pads can be used. Its thickness does not exceed the height of the base of the microneedle array. The hollow part in the middle needs to be cut out for the absorption gasket, which is just inserted into the base of the microneedle array, so as to achieve a good effect of absorbing liquid.

As a preferred embodiment of the microneedle array patch of the present invention, the microneedle array substrate needs to have a certain hardness, and at the same time, it can enhance electroosmotic drug delivery. Specifically, the base material of the microneedle array is selected to be a biocompatible metal material or a polymer material coated with a conductive film.

In addition, the present invention provides a method for preparing the above-mentioned microneedle array patch that is easy to operate and easy to implement. To achieve this purpose, the following steps are included:

Step 1: making a microneedle array base, then making a microneedle array on the upper surface of the microneedle array base, and cleaning and disinfecting the surface of the made microneedle array with a biocompatibility modifier;

Step 2: Mix the diffusible drug into the elastic biocompatible material to obtain the elastic drug-loaded layer;

Step 3: adding the elastic drug-loaded layer prepared in step 2 to the microneedle array and solidifying the elastic drug-loaded layer;

Step 4: Put the microneedle array base into the absorbent gasket;

Step 5: Coat the outer periphery of the electrode with pressure-sensitive adhesive and stick it on the lower surface of both the microneedle array base and the absorbent gasket made in step 4. The microneedle array patch of the present invention is obtained.

The invention improves the drug loading capacity, administration efficiency, integration degree, ease of use and anti-infection safety, and is more conducive to production and popularization and application.

Description of drawings

Figure 1 is a schematic structural view of the microneedle array patch in the embodiment of the present invention;

Fig. 2 is a schematic diagram of sticking the microneedle array patch on the skin in the embodiment of the present invention;

Figure 3 is a schematic diagram of the electric field generated by the electrode sheet of the microneedle array patch in the embodiment of the present invention when it works normally;

Fig. 4 is a schematic diagram of the pressing and puncturing process of the microneedle array patch under the electric field in the embodiment of the present invention;

Fig. 5 is a schematic diagram of the sustained release of the microneedle array patch under the action of an electric field in the embodiment of the present invention.

detailed description

In order to better illustrate the purpose, technical solutions and advantages of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and specific embodiments.

An embodiment of the microneedle array patch of the present invention, as shown in FIG. 4. Elastic drug-loaded layer 5, electrode sheet 6, absorption gasket 7. The microneedle array 1 is located on the upper surface of the microneedle array base 2, the microneedle array 1 is wrapped in the elastic drug-loaded layer 5, and the elastic drug-loaded layer 5 is mixed with diffusible drugs 4; the absorbent gasket 7 is set with the microneedle array base 2 ; The electrode sheet 6 is attached to the lower surface of both the microneedle array substrate 2 and the absorption gasket 7 .

The microneedle array 1 is made of PMMA material, epoxy resin, and composite insulating material with biocompatible coating, the material of the microneedle array substrate 2 is stainless steel, and the pressure-sensitive adhesive 3 is medical pressure-sensitive Glue, the diffusible drug 4 is a macromolecular drug such as influenza vaccine or insulin, the material of the elastic drug-loaded layer 5 is sponge, the electrode sheet 6 is a silicone electrode sheet, and the absorbent gasket 7 is a medical absorbent pad.

In this example, the volume of the diffusible drug 4 contained in the elastic drug-loaded layer 5 is 100 μL. And the diffusible drug 4 is uniformly distributed in the elastic drug-loaded layer 5 .

The area of the electrode sheet 6 is greater than the total area of the lower surfaces of the microneedle array base 2 and the absorbing gasket 7, and there is a certain thickness of medical pressure-sensitive adhesive 3 on the periphery of the electrode sheet 6. When in use, this part can be pasted directly on the surface of the skin, so that the micropore array 1, the elastic drug-loading layer 5 and the diffusible drug 4 contained therein are coated between the electrode sheet 6 and the skin.

As shown in Figure 2, when in use, the microneedle array patch (the electrode on the patch is used as the positive electrode) described in the embodiment of the present invention is directly pasted on the skin, and an electrode is pasted on the corresponding symmetrical part on the opposite side of the skin as the negative pole. Connect the two electrode sheets to the positive and negative electrodes of the electrotherapy machine. There are two electrode sheets, one is the electrode sheet on the microneedle array patch, which acts as the positive electrode, and the other electrode acts on the symmetrical position of the contralateral skin as the negative electrode. (not shown in the figure), and connect the electrotherapy machine (not shown in the figure) with wires, connect the two electrode sheets with the positive and negative poles of the electric therapy machine correctly through the wires, and fix the electrodes properly. The current of electrotherapy machine adopts direct current, the intensity is 0.03-0.1mA/cm2.

The microneedle array patch described in this example is prepared by the following method:

Step 1: Fabricate a microneedle array substrate, then fabricate a microneedle array on the upper surface of the microneedle array substrate, and clean and disinfect the surface of the prepared microneedle array with a biocompatibility modifier;

Step 2: Mix the diffusible drug into the elastic biocompatible material to obtain the elastic drug-loaded layer;

Step 3: adding the elastic drug-loaded layer prepared in step 2 to the microneedle array by spin coating and solidifying the elastic drug-loaded layer;

Step 4: Put the microneedle array base into the absorbent gasket;

Step 5: Coat the outer periphery of the electrode sheet with pressure-sensitive adhesive and stick it on the lower surface of both the microneedle array base and the absorbing gasket prepared in step 4 to obtain the microneedle array patch of the present invention.

The use process of the microneedle array patch of the present invention is as follows: First, as shown in Figure 2, the whole microneedle array patch described in Figure 1 is directly pasted on the skin 8, at this time, the electrodes on the microneedle array patch The sheet is the positive electrode; and an electrode sheet is attached to the corresponding symmetrical part on the opposite side of the skin as the negative electrode (not shown in the figure).

Secondly, as shown in Figure 3, gently press the two electrode sheets to ensure that they are firmly pasted, and after checking that the electrotherapy machine is in the correct state, turn on the electrotherapy machine to achieve a suitable strength to make the two electrode sheets work normally and generate an electric field. The arrow group 9 in the figure represents the schematic diagram of electric field lines, which is just for the convenience of understanding, not intuitive.

Again, as shown in Figure 4, the outer surface of the electrode sheet on the microneedle array patch is pressed to compress the elastic drug-loaded layer in contact with the skin, so that the tip of the microneedle array in the elastic drug-loaded layer penetrates the elastic carrier. The upper surface of the drug layer pierces the skin to form microporous drug delivery channels in the skin.

Finally, as shown in Figure 5, when the pressing ends, the elastic drug-loaded layer returns to its original shape, and the microneedle array exits the skin and returns to the elastic drug-loaded layer. The drug-loaded layer is continuously administered through the microporous drug delivery channel. The potential difference generated by the two electrodes will accelerate drug penetration and absorption. When in use, the outer surface of the adhesive layer can be pressed several times to prevent the microporous drug delivery channel from being repaired and closed, and the potentiometer of the electrotherapy machine can be adjusted to control the current to adjust the drug delivery speed. When the drug in the elastic drug-loaded film decreases, the current of the electrotherapy machine can be appropriately increased to prevent drug accumulation and continue to release at a certain rate.

The following is the effect test of the microneedle array patch described in the embodiment of the present invention.

1. Construction of animal models of diabetes

Select 30 pure-line, clean-grade, female Kunming rats, weighing about 30g. Alloxan was dissolved in 0.9% normal saline at a concentration of 2%. Each mouse was injected intraperitoneally on an empty stomach at a dose of 6 mg alloxan, fed in a single cage, and rationed water and food. After fasting for 12 hours, take blood from the tail, and use a blood glucose meter to detect the blood sugar level. When the blood sugar level is ≥ 10.0mmol/L, it is enough.

2. Experimental grouping The mice in the constructed animal model of diabetes were randomly divided into three groups, 10 in each group, as control group 1, control group 2 and test group respectively.

3. Test method

Experimental group mice

Using the microneedle array drug patch described in the embodiment of the present invention, wherein the elastic material in the elastic drug-loaded layer is a 1mm thick sponge, the drug is insulin injection, and the drug content of the elastic drug-loaded layer is 100 μL; use an 8×8 square array for the microneedle array. The electrode sheet is made of silicone electrode sheet, and a long enough wire is used to connect the electric current of the electrotherapy machine to prevent the mouse from running and loosening the electrode sheet.

The microneedle array patch described in the embodiment of the present invention was pasted on the abdominal skin of the mice in the test group after hair removal. Turn on the electrotherapy machine, use direct current with an intensity of 0.05A/cm2, and apply a pressure of about 10N/cm2 to the outer surface of the electrode pad for 2 seconds, then release it for 8 seconds, and repeat this 3 times to complete the insulin transdermal transfer.

Control group 1 mice

Paste the microneedle array patch described in the above-mentioned embodiment of the present invention on the abdominal skin of the experimental group mice after hair removal, without turning on the electrotherapy machine, only apply a pressure of about 10 N/cm2 to the outer surface of the electrode sheet and press for 2 seconds , and then release for 8 seconds, so repeat 3 times.

Control group 2 mice

Only apply a pressure of about 10N/cm2 to the upper surface of the abdominal skin of the mouse after hair removal for 2 seconds, and then release it for 8 seconds, repeating this 3 times. After administration for 30min, 60min, 120min, and 180min, the blood glucose concentrations of the mice in the control group and the test group were tested respectively, and the average value was taken for each group. The test results are shown in Table 1.

Table 1 Results of blood glucose concentration in control group and experimental group after administration

time after administration Control group 1 mean blood glucose concentration (mmol/L) Control group 1 mean blood glucose concentration (mmol/L) Average blood glucose concentration of experimental group (mmol/L) initial average blood glucose concentration 20 20 20 30min after administration twenty three 20 19 60min after administration twenty two 18 17 120min after administration 20 17 15.5 180min after administration 19 16.5 14

From the results in Table 1, it can be seen that the blood glucose concentration of the rats increased after eating, but at the same time in the experimental group, the blood glucose concentration was lower than that of the two control groups. In particular, although the mice in the control group 2 can also reduce the average blood glucose concentration, the blood glucose concentration of the experimental group at the same time is lower than that of the control group 2, indicating that the introduction of the electric field can accelerate the release and penetration of drugs. Thus, the existence of efficacy of the microneedle array patch of the embodiment of the present invention can be confirmed.

Apparently, the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, rather than limiting the implementation of the present invention. For those of ordinary skill in the art, other changes or changes in different forms can be made on the basis of the above description. It is not necessary and impossible to exhaustively list all the implementation manners here. All modifications, equivalent replacements and improvements made within the spirit and principles of the present invention shall be included within the protection scope of the claims of the present invention.

Claims (10)

1. a kind of microneedle array drug paste being administered based on electric field driven, it is characterised in that including：Microneedle array substrate；Positioned at micro- The microneedle array of pin array substrate upper surface, the microneedle array is rolled in elastic drug-loaded layer, and the elastic drug-loaded layer is elasticity Biocompatible materials, and be mixed with medicine in the material；The absorption packing ring being set with microneedle array substrate；Attach In the electrode slice of both microneedle array substrate and absorption packing ring lower surface.

2. the microneedle array drug paste according to claim 1, it is characterised in that the periphery of the electrode slice scribbles pressure-sensitive Glue, and the gross area of the area more than both microneedle array substrate and absorption packing ring lower surface of the electrode slice.

3. the microneedle array drug paste according to claim 1, it is characterised in that the elastic biocompatible materials Can be hyaluronic acid gel or sponge；The electrode slice can be silica gel electrode slice or non-woven fabrics electrode slice.

4. according to any described microneedle array drug paste of claim 1 to 3, it is characterised in that the electrode slice is by leading Line connects direct current therapy unit, and current strength is 0.03-0.1mA/cm2 continuously adjustabes.

5. the microneedle array drug paste according to claim 4, it is characterised in that the material of the microneedle array can be firm The bio-compatible insulating materials of property.

6. the microneedle array drug paste according to claim 5, it is characterised in that the microneedle array by PMMA materials, Epoxy resin, the composite insulating material with biocompatible coating or coating are prepared from.

7. the microneedle array drug paste according to claim 6, it is characterised in that the microneedle array goes out in the form of an array It is existing, and the micropin in the microneedle array is high no more than 1500 microns.

8. the microneedle array drug paste according to claim 7, it is characterised in that the absorption packing ring is by with water imbibition The flexible material of energy is made, and thickness is no more than microneedle array substrate level；The pressure sensitive adhesive is medical pressure sensitive adhesive, and pressure-sensitive Thickness of the thickness of glue no more than water suction packing ring.

9. the microneedle array drug paste according to claim 8, it is characterised in that the material of the microneedle array substrate is Metal material with biocompatibility or the high polymer material for being coated with conducting film.

10. the preparation method of microneedle array drug paste as described in claim any one of 1-9, it is characterised in that including：

Step 1:Microneedle array substrate is made, microneedle array is then made in the upper surface of microneedle array substrate, and to making Good microneedle array surface carries out biocompatibility modifying agent cleaning and sterilizing；

Step 2：Diffusible medicine is mixed into the biocompatible materials of elasticity, elastic drug-loaded layer is obtained；

Step 3:The elastic drug-loaded layer that step 2 is prepared is added on microneedle array and makes the elastic drug-loaded layer Solidification；

Step 4：Microneedle array substrate is inserted in absorption packing ring；Step 5：Electrode slice periphery is coated into pressure sensitive adhesive to be attached to The lower surface of both microneedle array substrate and absorption packing ring that step 4 is made.