A band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery and its preparation method

Abstract

The present invention belongs to the field of medical materials, and provides a band-aid type microneedle patch for glucose monitoring and photothermal-responsive drug delivery and a preparation method thereof, including: monitoring microneedles, drug delivery microneedles, medical tape, and grooves; a plurality of grooves are arranged at intervals on the medical tape, and the monitoring microneedle array and the drug delivery microneedle array are respectively arranged in different grooves; the structures of the monitoring microneedles and the drug delivery microneedles are both needles loaded on a substrate; the substrate material of the monitoring microneedles is a zwitterionic polycarboxybetaine hydrogel loaded with glucose oxidase, catalase, and a chromogenic agent, and the needle body material of the monitoring microneedles is a polyethylene glycol hydrogel; the substrate material of the drug delivery microneedles is a polyethylene glycol hydrogel, and the needle body material of the drug delivery microneedles is a polyethylene glycol hydrogel loaded with a photothermal agent graphene and a drug insulin. By applying this patch to the finger, glucose monitoring and timely drug delivery can be achieved simultaneously, facilitating the daily life of diabetic patients.

Description

Technical Field

[0001] The present invention belongs to the field of medical materials, and particularly relates to a band-aid type microneedle patch for glucose monitoring and photothermal-responsive drug delivery and a preparation method thereof. Background Art

[0002] Disclosing the information of this background art section is only intended to increase the understanding of the overall background of the present invention, and is not necessarily regarded as an admission or an implication in any form that this information constitutes the prior art already known to those of ordinary skill in the art.

[0003] Diabetes is a chronic disease mainly marked by hyperglycemia. In daily life, patients need to constantly monitor their blood glucose concentration and take or inject drugs in a timely manner to control blood glucose levels. Blood glucose meters are a type of instrument commonly used for blood glucose measurement. According to their working principles, traditional commercial blood glucose meters can be divided into optoelectronic type and electrode type. Each type of blood glucose meter has its own advantages and disadvantages. However, they have a common problem, that is, patients usually need to perform frequent blood sampling. This not only increases the complexity of daily operations, but also sharply increases the infection risk of patients. In addition, diabetic patients often need to take oral medications or inject insulin to control blood glucose, but taking medications is often accompanied by side effects such as gastrointestinal reactions, abdominal discomfort or allergic reactions, and frequent drug injections will bring serious physical harm and psychological burden, bringing great pain to patients.

[0004] Microneedles are a type of micro-needle structure, which have the characteristics of small size and high precision, and can simultaneously realize the functions of substance detection and drug delivery. On the one hand, by detecting the concentration of substances in the interstitial fluid of the skin, microneedles can effectively avoid complex, exposed, and repetitive blood sampling tests; on the other hand, microneedle drug delivery can reduce the possible side effects of drugs in the digestive tract during oral administration. Compared with subcutaneous injection, microneedle arrays can use multiple needles to administer drugs over a large area, and the drugs can be released into the interstitial fluid only by penetrating the stratum corneum, greatly reducing the pain caused by injection reaching the dermis layer and truly realizing painless and non-invasive drug delivery. Therefore, microneedles are expected to play a huge role in the blood glucose monitoring and drug delivery treatment of diabetic patients.

[0005] The paper "Study on a bilayer microneedle patch for synchronous blood glucose detection and automatic regulation of insulin release" discloses a bilayer microneedle patch (MNDF) prepared by cross-linking sodium alginate and chondroitin sulfate modified with 3-aminophenylboronic acid, which has sufficient mechanical strength to pierce the stratum corneum. MNDF can provide self-regulated insulin delivery according to blood glucose levels and can display blood glucose levels in the form of color changes.

[0006] There is also research and development of an insulin "smart patch", which designs artificial vesicles to store insulin and glucose-sensing enzymes and controls the release according to blood glucose levels.

[0007] However, there is currently no band-aid type microneedle patch that integrates diagnosis and treatment and controls blood sugar by triggering drug delivery through photothermal response. Summary of the Invention

[0008] In order to solve the problems of frequent operations of traditional blood glucose meters and insulin injections and poor patient compliance, the present invention provides a band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery. By applying this patch to the finger, glucose monitoring and timely drug delivery can be achieved simultaneously, facilitating the daily life of diabetic patients.

[0009] Compared with existing microneedle patches, when the drug delivery microneedles of the present invention are irradiated under near-infrared light, due to the photothermal effect of graphene in the needle tips, the temperature of the microneedles can rise within a short time. After reaching the melting point of the polyethylene glycol hydrogel, the needle tips start to melt, thereby releasing insulin to achieve drug delivery. As a non-contact heating method for the human body, the photothermal effect has a fast heating speed and the generated heat has no side effects on the human body. The increase in the temperature of the microneedles can also accelerate the diffusion of insulin to achieve rapid drug delivery.

[0010] In order to achieve the above object, the present invention adopts the following technical solutions:

[0011] In a first aspect of the present invention, there is provided a band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery, comprising: monitoring microneedles, drug delivery microneedles, medical tape, and grooves; a plurality of grooves are spacedly arranged on the medical tape, and a monitoring microneedle array and a drug delivery microneedle array are respectively arranged in different grooves; the structures of the monitoring microneedles and the drug delivery microneedles are both a needle body loaded on a substrate.

[0012] The substrate material of the monitoring microneedles is a zwitterionic polycarboxybetaine hydrogel loaded with glucose oxidase, catalase, and a chromogenic agent, and the needle body material of the monitoring microneedles is a polyethylene glycol hydrogel;

[0013] The substrate material of the drug delivery microneedles is a polyethylene glycol hydrogel, and the needle body material of the drug delivery microneedles is a polyethylene glycol hydrogel loaded with a photothermal agent graphene and a drug insulin.

[0014] In some embodiments, the shape of the needle body is conical, the needle length is between 600 - 800 um, the needle tip is 10 - 15 um, and the bottom diameter of the microneedle is 300 um.

[0015] In some embodiments, the thickness of the substrate is 1.2 - 1.8 mm or 1.5 mm, and the substrate size is between 8.8×8.8 mm - 9.0×9.0 mm or 8.9×8.9 mm.

[0016] In some embodiments, the microneedle array is arranged in a 10×10 pattern, and the distance between the needles is between 650 - 800 um.

[0017] In some embodiments, the medical tape is a medical transparent waterproof elastic tape, with a length of 7 - 11 cm, a width of 2 - 3 cm, the monitoring microneedles and the drug - delivering microneedles are spaced 2 - 3 cm apart, and the microneedles are 2 - 3 cm away from both ends of the tape.

[0018] In some embodiments, the depth of the groove is 1.2 - 1.6 mm or 1.5 mm.

[0019] The second aspect of the present invention provides a method for preparing a band - aid - type microneedle patch for glucose monitoring and photothermal - response drug delivery, comprising:

[0020] Mix the zwitterionic monomer, cross - linker, initiator, sodium chloride and water evenly, and then add glucose oxidase, catalase and chromogenic agent, and mix evenly to form a prepolymer solution for the monitoring microneedle base.

[0021] Add PEG and cross - linker into physiological saline to dissolve them, forming a prepolymer solution for the monitoring microneedle body or a prepolymer solution for the drug - delivering microneedle base.

[0022] Take out a part of the prepolymer solution for the drug - delivering microneedle base, add graphene and insulin, and mix evenly to form a prepolymer solution for the drug - delivering microneedle body.

[0023] Perform hydrophilic treatment on the PDMS negative mold of the microneedle.

[0024] Add the prepolymer solution for the monitoring microneedle body and the prepolymer solution for the monitoring microneedle base into the PDMS mold successively, initiate polymerization, and demold to obtain the monitoring microneedles.

[0025] Add the prepolymer solution for the drug - delivering microneedle body and the prepolymer solution for the drug - delivering microneedle base into the PDMS mold drop - by - drop successively, initiate polymerization, and demold to obtain the drug - delivering microneedles.

[0026] Paste the two kinds of microneedles on the cut medical tape respectively, and then a band - aid - type microneedle patch for glucose monitoring and photothermal - response drug delivery is formed.

[0027] In some embodiments, in the prepolymer solution for the monitoring microneedle base, the cross - linker is N - methylene bisacrylamide, the initiator is ammonium persulfate, and the chromogenic agent is copper sulfate.

[0028] In some embodiments, in the prepolymer solution for the monitoring microneedle body or the prepolymer solution for the drug - delivering microneedle base, the cross - linker is N - hydroxypropionamide or 1 - acetyl - 2 - sulfanylacetate.

[0029] The present invention provides the above - mentioned application of the band - aid - type microneedle patch for glucose monitoring and photothermal - response drug delivery in the medical field.

[0030] Advantages of the present invention

[0031] (1) The band-aid type microneedle patch of the present invention can achieve real-time glucose monitoring, and the detection results are displayed with an intuitive color change.

[0032] (2) The band-aid type microneedle patch of the present invention can release drugs under the excitation of near-infrared light, and the drug release amount can be controlled by adjusting the illumination time according to the detection results.

[0033] (3) The band-aid type microneedle patch of the present invention is small in volume, convenient to carry and move.

[0034] (4) The raw materials of the band-aid type microneedle patch of the present invention are easy to obtain, and it is mainly made by steps such as micro-molding and bonding. The manufacturing process is simple and the operation is convenient.

[0035] (5) The band-aid type microneedle patch of the present invention is mainly assembled by two microneedles and a medical transparent waterproof elastic tape, which is convenient for repeatable manufacturing and easy for industrialization.

[0036] (6) The preparation method of the present invention is simple, highly practical and easy to popularize. Description of the Drawings

[0037] The attached drawings forming a part of this specification are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention.

[0038] Figure 1 Schematic structural diagram of the microneedle patch, in which, 01 monitoring microneedle, 02 drug delivery microneedle, 03 medical transparent waterproof elastic tape, 04 groove;

[0039] Figure 2 Schematic diagram of the single needle material of the monitoring microneedle, in which, 05 monitoring microneedle substrate, 06 monitoring microneedle body;

[0040] Figure 3 Schematic diagram of the single needle material of the drug delivery microneedle, in which, 07 drug delivery microneedle substrate, 08 drug delivery microneedle body;

[0041] Figure 4 Schematic diagram of the microneedle array;

[0042] Figure 5 Flow chart of the preparation of the microneedle patch. Detailed Description of the Invention

[0043] It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0044] Explanation of terms:

[0045] "Needle tip distance" refers to the distance between the center lines of adjacent conical needle bodies.

[0046] The following combines specific embodiments to further elaborate on the present invention. It should be noted that the specific embodiments are explanations rather than limitations of the present invention.

[0047] As Figure 1 shown, the present invention provides a band-aid type microneedle patch applicable to glucose monitoring and photothermal-responsive drug delivery. Its main structure includes: monitoring microneedles 01, drug delivery microneedles 02, a medical transparent waterproof elastic tape 03, and a groove 04. Among them, the schematic diagram of the single-needle material of the monitoring microneedle 01 is as Figure 2 shown. The monitoring microneedle base 05 is a zwitterionic polycarboxybetaine (PCB) hydrogel, carrying glucose oxidase (GOD), catalase (CAT), and the color developer copper sulfate (CuSO4). The monitoring microneedle body 06 is a polyethylene glycol (PEG) hydrogel; the schematic diagram of the single-needle material of the drug delivery microneedle 02 is as Figure 3 shown. Both the drug delivery microneedle base 07 and the drug delivery microneedle body 08 are polyethylene glycol (PEG) hydrogels, and the drug delivery microneedle body 08 carries the photothermal agent graphene and the drug insulin.

[0048] The structural designs of the two types of microneedles are as follows: The needle body shape is conical, the needle length is between 600 - 800 um, the needle tip is 10 - 15 um, the bottom diameter of the microneedle is 300 um, the distance between needles is between 650 - 800 um, the number array is arranged in a 10×10 layout, and the microneedle bases 05 and 07 are about 1.5 mm thick, forming a base size of about 8.9×8.9 mm.

[0049] In the above band-aid type microneedle patch, the medical transparent waterproof elastic tape 03 should be long enough, generally 7 - 11 cm in length and 2 - 3 cm in width. Among them, the distance between the two types of microneedles is 2 - 3 cm, and the microneedles are 2 - 3 cm away from both ends of the tape, so that the tape can fully wrap around and be fixed on the finger. And a 1.5 mm deep groove 04 is provided in the microneedle part, as Figure 1 shown, so that the microneedles can be fixed on the tape 03.

[0050] Furthermore, the present invention provides a preparation method for a band-aid type microneedle patch for glucose monitoring and photothermal-responsive drug delivery, including the following steps:

[0051] Step 1, Preparation of microneedle slurry: Add carboxybetaine zwitterionic monomer and crosslinking agent N-methylenebisacrylamide (MBAA) into 2 mL of sodium chloride solution with a concentration of 1 mol / L according to the amounts of 40% and 1% mass concentration respectively. After ultrasonic treatment and sufficient mixing, add 2 mg of initiator ammonium persulfate (APS), 1 mL of glucose oxidase solution with a concentration of 1×10 -9 mol / L and 1 mL of catalase solution with a concentration of 1×10 -9 mol / L. Finally, add 1 mL of copper sulfate solution with a concentration of 0.015 mol / L and gently shake until the solution color is uniform to form a prepolymer solution for monitoring microneedle substrate 05. Dissolve 0.2 mmol of polyethylene glycol propionate and 1.6 mmol of N-hydroxysuccinamide (NHS) in 15 mL of physiological saline and dissolve them with a magnetic stirrer at room temperature to form prepolymer solutions for monitoring microneedle body 06 and drug delivery microneedle substrate 07. Take out about one-eighth of the solution, add 0.2 mg of graphene and 75 U of insulin, and then mix evenly to form a prepolymer solution for drug delivery microneedle body 08.

[0052] Step 2, Mold treatment: Treat the PDMS female mold of the microneedle with plasma machine to make it hydrophilic.

[0053] Step 3, Microneedle forming: Drop the prepolymer solutions of monitoring microneedle body 06 and monitoring microneedle substrate 05 into the PDMS mold successively. Select a suitable crosslinking method according to the added crosslinking agent. For example, when using MBAA, the microneedles need to be placed in an environment of 37°C for photopolymerization reaction to obtain monitoring microneedles 01; Drop the prepolymer solutions of drug delivery microneedle body 08 and drug delivery microneedle substrate 07 into the PDMS mold successively. Select a suitable crosslinking method according to the added crosslinking agent to obtain drug delivery microneedles 02.

[0054] Step 4, Microneedle demolding: Peel the two types of microneedles from the mold.

[0055] Step 5, Production of microneedle patch: Set two grooves on the medical transparent waterproof elastic adhesive tape, and paste the two types of microneedles into the grooves on the cut medical transparent waterproof elastic adhesive tape respectively, that is, a band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery is formed.

[0056] Working process:

[0057] The band-aid type microneedle patch can be used for glucose monitoring and drug administration in diabetic patients. It contains two microneedles located at both ends of the patch. The monitoring microneedle 01 is used for glucose monitoring. After the PEG hydrogel microneedle body 06 absorbs interstitial fluid, glucose in the interstitial fluid is converted into gluconic acid and hydrogen peroxide by glucose oxidase located at the monitoring microneedle base 05. Then, the hydrogen peroxide generated is decomposed by catalase to produce water and oxygen atoms. Different concentrations of oxygen atoms produced cause different colors when copper sulfate is oxidized. When the blood glucose concentration increases, the glucose concentration in the interstitial fluid also rises. Therefore, the oxygen atoms produced by enzymatic decomposition increase, and the microneedle base will gradually show light blue, green, yellow, light brown, brown, dark brown (close to black). The glucose concentration is monitored by the change in the color of the microneedle base. The drug delivery microneedle 02 is used for transdermal delivery of insulin. When the patient observes the color change of the monitoring microneedle base 05, the drug delivery microneedle 02 can be placed under near-infrared light for irradiation. Graphene in the drug delivery microneedle body 08 converts light energy into heat energy, causing the temperature of the microneedle body to rise. When the temperature rises to the melting point of the PEG hydrogel (50 °C), the drug delivery microneedle body 08 dissolves to release insulin, achieving control of blood glucose concentration.

[0058] Usage method: The patient pinches the microneedle patch with one hand and wraps and pastes the patch on any finger of the other hand. For convenient observation and near-infrared light irradiation, one end of the monitoring microneedle 01 can be attached to the back of the hand side, and one end of the drug delivery microneedle 02 can be attached to the palm side. The patient should closely observe the color change of the monitoring microneedle 01 within one to two hours after eating. When the color gradually deepens, the palm should be spread out as soon as possible to expose the drug delivery microneedle 02 to near-infrared light irradiation, increase the temperature and release the drug to control blood glucose.

[0059] The above are only the preferred embodiments of the present invention and are not used to limit the present invention. For those skilled in the art, the present invention can have various changes and modifications. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery, characterized in that, Including: Monitoring microneedles, drug delivery microneedles, medical tape, and grooves; the monitoring microneedles and drug delivery microneedles are located at both ends of the patch; two grooves are arranged at intervals on the medical tape, and the monitoring microneedle array and the drug delivery microneedle array are respectively arranged in different grooves; the structures of the monitoring microneedles and the drug delivery microneedles are both needles loaded on the substrate. The substrate material of the monitoring microneedles is zwitterionic polycarboxybetaine hydrogel loaded with glucose oxidase, catalase, and chromogenic agent, and the needle body material of the monitoring microneedles is polyethylene glycol hydrogel. The substrate material of the drug delivery microneedles is polyethylene glycol hydrogel, and the needle body material of the drug delivery microneedles is polyethylene glycol hydrogel loaded with photothermal agent graphene and drug insulin.

2. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, characterized in that, The shape of the needle body is conical, the needle length is between 600 - 800 um, the tip of the needle is 10 - 15 um, and the bottom diameter of the microneedle is 300 um.

3. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, wherein The thickness of the substrate is 1.2 - 1.8 mm, and the substrate size is between 8.8×8.8 mm - 9.0×9.0 mm.

4. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, characterized in that, The thickness of the substrate is 1.5 mm.

5. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, characterized in that, The substrate size is 8.9×8.9 mm.

6. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, characterized in that, The microneedle array is arranged in a 10×10 pattern, and the distance between needles is between 650 - 800 um.

7. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, wherein The medical tape is a medical transparent waterproof elastic tape, with a length of 7 - 11 cm and a width of 2 - 3 cm. The monitoring microneedles and the drug delivery microneedles are separated by 2 - 3 cm, and the microneedles are 2 - 3 cm away from both ends of the tape.

8. The plaster-type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, characterized in that, The depth of the groove is 1.2 - 1.6 mm.

9. The band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 1, wherein The depth of the groove is 1.5 mm.

10. A preparation method of a band - aid - type microneedle patch for glucose monitoring and photothermal - response drug delivery as claimed in claim 1, including: Mix zwitterionic monomer, cross - linker, initiator, sodium chloride, and water evenly, and then add glucose oxidase, catalase, and chromogenic agent, and mix evenly to form a prepolymer solution for the monitoring microneedle substrate. Add PEG and cross - linker to physiological saline to dissolve them, forming a prepolymer solution for the monitoring microneedle body or a prepolymer solution for the drug delivery microneedle substrate. Take out a part of the prepolymer solution for the drug delivery microneedle substrate, add graphene and insulin, and mix evenly to form a prepolymer solution for the drug delivery microneedle body. Perform hydrophilic treatment on the PDMS negative mold of the microneedles. Add the prepolymer solution for the monitoring microneedle body and the prepolymer solution for the monitoring microneedle substrate into the PDMS mold successively, initiate polymerization, and demold to obtain the monitoring microneedles. Drop the prepolymer solution for the drug delivery microneedle body and the prepolymer solution for the drug delivery microneedle substrate into the PDMS mold successively, initiate polymerization, and demold to obtain the drug delivery microneedles. Paste the two kinds of microneedles on the cut medical tape respectively, namely forming a band - aid - type microneedle patch for glucose monitoring and photothermal - response drug delivery.

11. The preparation method of the band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 10, characterized in that, In the prepolymer solution for the monitoring microneedle substrate, the cross - linker is N - methylene bisacrylamide, the initiator is ammonium persulfate, and the chromogenic agent is copper sulfate.

12. The preparation method of the band-aid type microneedle patch for glucose monitoring and photothermal response drug delivery according to claim 10, characterized in that, In the prepolymer solution for the monitoring microneedle body or the prepolymer solution for the drug delivery microneedle substrate, the cross - linker is N - hydroxypropane amide, or 1 - acetyl - 2 - sulfonyl acetate.

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