Microwave controlled-release corrosion type microneedle emplastrum

Abstract

The microwave controlled-release corrosion type microneedle emplastrum comprises corrosion type microneedles, emplastrum, a microwave device, a power supply device, a regulation and control device and a fixing device, medicine is carried in the emplastrum, the corrosion type microneedles are arranged in a matrix mode and embedded in an emplastrum body layer, the emplastrum does not contain percutaneous absorption enhancer, and the microwave device is connected with the microwave device. The arrangement sequence of the corrosion type microneedle, the emplastrum and the microwave device is as follows: the corrosion type microneedle, the emplastrum and the microwave device. The microwave controlled-release corrosion type microneedle emplastrum is applied to the skin surface and organically combines a microwave mediation technology, an emplastrum, a corrosion type microneedle technology and an intelligent controlled-release technology to form a synergistic complementary effect; the problems that a traditional skin preparation is difficult to penetrate through a skin barrier, the drug release rate cannot be accurately controlled, and the dosage cannot be adjusted in time are solved, and transdermal drug absorption is facilitated to achieve the treatment effect to achieve safe and intelligent treatment.

Description

Technical Field

[0001] The invention relates to a transdermal drug delivery system, in particular to a microwave controlled-release dissolution type microneedle patch suitable for delivering drugs of various molecular weights. Background Art

[0002] Adhesive plasters are a type of plaster, which refers to a type of sheet-shaped external preparation made of drug extracts and / or chemical drugs with suitable matrices and base materials for skin application, which can produce local or systemic effects. Patches are divided into two categories: gel plasters and rubber-plasters. They are applied to the skin and can produce systemic or local effects. The advantages of patches are strong adhesion, large drug loading, easy use, painless and non-invasive, and good patient compliance.

[0003] Plasters have a large drug loading capacity and a long duration, and have made significant progress in drug delivery and treatment (especially the delivery and treatment of traditional Chinese medicine), but there are still the following bottlenecks:

[0004] (1) Skin barrier penetration problem: The stratum corneum is the main obstacle to transdermal drug absorption. For large molecule drugs, such as proteins and peptides, penetrating the skin barrier remains a challenge.

[0005] (2) Unable to precisely control the drug release rate: Although some researchers have prepared controlled-release patches to achieve precise drug release, in actual applications, precisely controlling the drug release rate remains a technical challenge.

[0006] (3) The dosage of drug treatment cannot be adjusted in time: The skin type, thickness and pathological condition of patients vary greatly, which affects the transdermal absorption efficiency of the drug, resulting in different treatment effects for different people. The dosage needs to be adjusted in time according to the patient and the condition. The current patches cannot achieve timely adjustment of the dosage.

[0007] (4) Contains a large amount of transdermal absorption enhancers: Patches contain a large amount of transdermal absorption enhancers, which are not only prone to cause adverse reactions such as skin allergies, but also have potential safety risks after being absorbed into the blood, such as causing hemolysis.

[0008] To overcome these bottlenecks, researchers and developers are exploring new drug delivery technologies, improving controlled-release mechanisms, optimizing manufacturing processes, and seeking more effective clinical trial designs.

[0009] Microneedles are also preparations applied to the skin. They are usually made of metal materials and non-degradable polymers, such as silicon and titanium dioxide. They can be drug-loaded or not. Their advantage is that they puncture the epidermis and form microchannels required for drug penetration. Microneedles are usually used for skin pretreatment before active drug ingredients, that is, to open instant microchannels on the skin and increase the permeability of drug ingredients. Although microneedle technology can penetrate the biological barrier of the skin to form microchannels required for drug penetration, the transport pathway cannot be kept unobstructed for a long time after microneedle pretreatment, so the subsequent continuous drug delivery cannot be guaranteed. In recent years, researchers have prepared various types of microneedles, but the microneedles themselves have limited drug loading and cannot maintain long-term effects.

[0010] Therefore, the development of safe and intelligent skin preparations that are applicable to a wide range of drugs (especially heat-labile or easily inactivated biomacromolecule drugs), can timely adjust the dosage, and achieve rapid release and continuous drug delivery is of great significance for the therapeutic effect of drugs. At present, there is no safe and intelligent skin preparation that can deliver drugs of various molecular weights, timely adjust the dosage, and achieve rapid release and continuous drug delivery. Summary of the invention

[0011] The purpose of the present invention is to overcome the shortcomings of the prior art, namely: the lack of a safe and intelligent skin preparation that can deliver drugs of various molecular weights, timely adjust the dosage, and achieve rapid release and continuous drug delivery, and to provide a microwave controlled release dissolution type microneedle patch to achieve the goal of safe, effective, convenient, and personalized skin drug delivery treatment.

[0012] The inventors have found that microwaves can penetrate the skin. When microwaves are applied to the human body, they can produce thermal and non-thermal effects, causing tissue temperature to rise and the distribution and arrangement of charged particles such as human milk fat and red blood cells to change, thus promoting the absorption of drugs. Therefore, if "microwave-mediated technology, plaster, dissolving microneedle and intelligent controlled release" are organically combined to produce a microwave-controlled release dissolving microneedle plaster, the advantages of various technologies can be complemented to make up for the shortcomings of single technology application.

[0013] After a large number of experiments, the microwave controlled release dissolving microneedle patch of the present invention is obtained, which comprises a dissolving microneedle, a patch, a microwave device, a power supply device, a regulating device and a fixing device, and the patch carries a drug;

[0014] The above-mentioned erosion-type microneedle matrix is ​​arranged and embedded in the paste layer of the above-mentioned patch, the length of the microneedle is 50 to 2000 μm, the base diameter is 50 to 300 μm, the tip diameter is 0.5 to 30 μm, and the cross-section of the needle body is circular or equidistant polygonal;

[0015] The above-mentioned plaster is a plaster or a plaster, which does not contain a percutaneous absorption enhancer;

[0016] The arrangement order of the above-mentioned dissolving microneedles, plaster and microwave device is dissolving microneedles - plaster - microwave device;

[0017] The microwave device has an operating frequency of 2450 MHz and an output power of 1 to 90 W.

[0018] The power supply device is electrically connected to the control device and the microwave device, and is used to provide the electric energy required for the control device and the microwave device to work;

[0019] The above-mentioned control device is used to control various parameters of the above-mentioned microwave device;

[0020] The fixing device is used to fix the microwave controlled release dissolving type microneedle patch on the skin surface;

[0021] The above-mentioned erosion-type microneedle is a solid microneedle with a length of 250 to 750 μm, a base diameter of 120 to 220 μm, a tip diameter of 2 to 10 μm, and a circular or equidistant polygonal cross section of the needle body;

[0022] The above-mentioned erosion-type microneedle is a hollow microneedle with a length of 250 to 750 μm, a base diameter of 150 to 250 μm, a tip diameter of 3 to 15 μm, and a circular or equidistant polygonal cross section of the needle body;

[0023] The above-mentioned dissolving microneedles carry drugs;

[0024] The microwave device has an output power of 5 to 35 W.

[0025] The microwave device has an output power of 10 to 25 W.

[0026] The above-mentioned plaster is a gel plaster;

[0027] The above-mentioned plaster is a rubber plaster;

[0028] The above-mentioned control device is connected to external electronic equipment or software via wireless Bluetooth, and the parameter control mode includes human active control and intelligent automatic control;

[0029] The above-mentioned fixing device fixes the microwave controlled-release dissolving microneedle patch on the skin surface of the limbs or trunk by means of a strap or an ergonomic bracket;

[0030] The above-mentioned straps are fixed by buckles, adhesives or elastic bands;

[0031] The above-mentioned ergonomic bracket conforms to the morphological characteristics of the limbs or the trunk, ensuring that the microwave controlled release dissolving microneedle patch fits closely with the skin;

[0032] The microwave controlled release dissolution type microneedle patch of the present invention has the following advantages:

[0033] (1) Penetrate the biological barrier of the skin and form microchannels required for drug penetration.

[0034] (2) Increase the drug loading capacity of the preparation to ensure the drug continues to take effect.

[0035] (3) Reduce the risk of blockage. Microwave-mediated technology can keep the microchannels of the skin unobstructed after microneedle erosion, reducing the risk of blockage and improving the reliability of drug delivery.

[0036] (4) Good stability. Since the microwave-controlled release dissolving microneedle patch is a solid preparation, it has good stability, strong environmental adaptability and long shelf life for heat-sensitive or easily inactivated biomacromolecule drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 A schematic diagram of the structure of a microwave-controlled-release dissolving microneedle patch (10: dissolving microneedle; 20: patch; 30: microwave device; 40: power supply device; 50: regulating device; 60: fixing device).

[0038] Figure 2 Schematic diagram of the erosion-type microneedle (1: tip; 2: cross section of the needle body; 3: base). DETAILED DESCRIPTION

[0039] The specific embodiments of the present invention will be described in detail below. It should be noted that the technical features or combinations of technical features described in the following embodiments should not be considered isolated, and they can be combined with each other to achieve better technical effects.

[0040] like Figure 1 As shown, the microwave controlled release dissolving microneedle patch of the present invention comprises: dissolving microneedles 10, a patch 20, a microwave device 30, a power supply device 40, a control device 50, and a fixing device 60. The dissolving microneedles 10 are arranged in a matrix and embedded in the paste layer of the patch 20. The length of the microneedles is 50 to 2000 μm, the base diameter is 50 to 300 μm, the tip diameter is 0.5 to 30 μm, and the cross section of the needle body is circular or equidistant polygonal; the area of ​​the patch is 12 cm 2, does not contain a percutaneous absorption promoter; the arrangement order of the erosion-type microneedle 10, the plaster 20 and the microwave device 30 is: the erosion-type microneedle 10 - the plaster 20 - the microwave device 30; the working frequency of the microwave device 30 is 2450MHz, and the output power is 1-90W of microwaves; the power supply device 40 is electrically connected to the control device 50 and the microwave device 30, and is used to provide the electric energy required for the control device 50 and the microwave device 30 to work; the control device 50 is used to control the various parameters of the microwave device 30; the fixing device 60 is used to fix the microwave controlled-release erosion-type microneedle plaster on the skin surface.

[0041] Example 1 Animal Experiment of Microwave Controlled Release Dissolution Type Microneedle Patch

[0042] Each experimental group is configured according to the components and proportions within the protection scope of the claims of this application, while each control group lacks a certain technical feature or the technical feature exceeds the protection scope of the claims of this application.

[0043] (1) Microneedle materials:

[0044] A: Insoluble materials, specifically silicon dioxide (SiO2)

[0045] B: Soluble materials, divided into B1: polylactic acid (PLA); B2: polylactic acid-glycolic acid copolymer (PLGA); B3: hyaluronic acid (HA)-povidone (PVP); B4: polyvinyl alcohol (PVA).

[0046] (2) Microneedle types: solid and hollow.

[0047] (3) Simulated drugs: FITC-PEG5000-COOH (fluorescein isothiocyanate-carboxyl-modified polyethylene glycol) of different molecular weights. Simulated drugs of different molecular weights are labeled as follows: Y1: 1000Da; Y2: 5000Da; Y3: 10000Da; Y4: 20000Da.

[0048] (4) Drug delivery method: I: only the plaster is loaded with drugs; II: both the microneedles and the plaster are loaded with drugs.

[0049] (5) Patch type: T1: gel patch; T2: rubber patch.

[0050] (6) Experimental subjects: healthy adult guinea pigs.

[0051] (7) Experimental methods: Healthy adult guinea pigs were divided into an experimental group and a control group according to the design in Table 1, with 6 in each group. After the guinea pigs were anesthetized, the backs were shaved. Each group applied the microneedle patch to the same part of the guinea pig's back for 120 min, and the control device was used to stop the microwave for 10 min at 20 min to evaluate the control ability of the control device, and then the microwave device was turned on until the end.

[0052] Table 1 Design of experimental and control groups

[0053]

[0054]

[0055] Note: “ / ” indicates that the device is missing; “√” indicates that the device exists; “Microneedle pretreatment”: pre-treat the skin with microneedles of specified specifications, and remove the microneedles after destroying the stratum corneum; “*” indicates that the parameter exceeds the indicator range of the claim item of the patent of this invention;.

[0056] Example 2 Application effect of microwave controlled release dissolution type microneedle patch

[0057] The second embodiment of the present invention is a summary of the application effect of Example 1. Blood was collected from each group of animals in Example 1 at 0, 5, 15, 30, 60, and 120 minutes, and the concentration of simulated drugs in the blood was analyzed by fluorescence measurement. The double-blind method was used to evaluate the speed at which the drug penetrates the skin into the blood circulation, the microwave regulation response capability, the area under the blood drug concentration curve, and the stability of the blood drug concentration curve. Each index was divided into 0-10 levels from low to high, and the higher the index rating, the better. At the same time, the restlessness of the animals (after waking up) was observed. The application effect summary is shown in Table 2.

[0058] Table 2 Application effects of experimental group and control group

[0059]

[0060]

[0061] The experimental results of the experimental group and the control group are shown in Table 2. As can be seen from the results, the efficiency of the experimental group of the microwave controlled release dissolving microneedle patch of the present invention is significantly higher than that of most control groups, and the effects of groups 3, 4 and 6 are the best among the experimental groups, but the animals in group 6 are frequently agitated.

[0062] Compared with the experimental group, the microwave controlled-release dissolving microneedle patch in the control group had poor transdermal efficiency or serious problems, especially in control groups 1, 4, 5, 9 and 11. Although some indicators of control groups 2, 3, 6 to 8 were high, there were many problems and potential safety hazards.

[0063] The experimental results in Table 2 prove that any device and its parameters in the technical protection scheme of the present invention are mutually coordinated and indispensable. The lack of any device and its parameters in the technical protection scheme of the present invention will have a significant impact on the transdermal absorption efficiency of the drug. The microwave controlled release dissolving microneedle patch of the present invention organically combines "microwave mediated technology, patch, dissolving microneedle and intelligent controlled release" to play a synergistic and complementary role, is suitable for long-term application, has the characteristics of safety, high efficiency, controlled release and long-term effect, and has good application prospects.

[0064] The above detailed description is a specific description of a feasible embodiment of the invention, and the embodiment is not intended to limit the scope of the invention. Any equivalent implementation or change that does not deviate from the invention should be included in the scope of the invention. In addition, those skilled in the art can also make various modifications, additions and substitutions in other forms and details within the scope and spirit disclosed in the claims of the invention. Of course, these various modifications, additions and substitutions made according to the spirit of the invention should be included in the scope of the invention.

Claims

1. A microwave controlled release dissolution type microneedle patch, characterized in that: The microwave controlled release dissolving microneedle patch comprises dissolving microneedles, a patch, a microwave device, a power supply device, a regulating device and a fixing device, wherein the patch carries drugs; the dissolving microneedles are arranged in a matrix and embedded in the paste layer of the patch, the length of the microneedles is 50 to 2000 μm, the base diameter is 50 to 300 μm, the tip diameter is 0.5 to 30 μm, and the cross section of the needle body is circular or equidistant polygonal; the patch is a gel plaster or a rubber plaster and does not contain a percutaneous absorption promoter; the arrangement order of the dissolving microneedles, the patch and the microwave device is: dissolving microneedles - patch - microwave device; the microwave device has an operating frequency of 2450 MHz and an output power of 1 to 90 W of microwaves; the power supply device is electrically connected to the regulating device and the microwave device, and is used to provide the electric energy required for the operation of the regulating device and the microwave device; the regulating device is used to regulate various parameters of the microwave device; the fixing device is used to fix the microwave controlled release dissolving microneedle patch on the skin surface.

2. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The erosion-type microneedle is a solid microneedle with a length of 250 to 750 μm, a base diameter of 120 to 220 μm, a tip diameter of 2 to 10 μm, and a circular or equidistant polygonal cross section.

3. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The erosion-type microneedle is a hollow microneedle with a length of 250 to 750 μm, a base diameter of 150 to 250 μm, a tip diameter of 3 to 15 μm, and a needle body cross section of a circle or an equidistant polygon.

4. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The erosion-type microneedles carry drugs.

5. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The output power of the microwave device is 1-30W microwave.

6. The microwave controlled release dissolution type microneedle patch according to claim 5, characterized in that: The output power of the microwave device is 5-20W microwaves.

7. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The plaster is a gel plaster.

8. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The plaster is a rubber plaster.

9. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The control device is connected to external electronic equipment or software via wireless Bluetooth, and the parameter control modes include human active control and intelligent automatic control.

10. The microwave controlled release dissolution type microneedle patch according to claim 1, characterized in that: The fixing device uses a strap or an ergonomic bracket to fix the microwave controlled-release dissolving microneedle patch on the skin surface of the limbs or trunk. The strap is fixed by buckles, adhesives or elastic bands. The ergonomic bracket conforms to the morphological characteristics of the limbs or trunk to ensure that the microwave controlled-release dissolving microneedle patch fits tightly to the skin.

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