Ultrasonic controlled-release corrosion type microneedle patch

Abstract

The ultrasonic controlled-release corrosion type microneedle patch comprises corrosion type microneedles, a patch body, an ultrasonic device, a power supply device, a regulation and control device and a fixing device, medicine is carried in the patch body, the corrosion type microneedles are arranged in a matrix mode and embedded in an adhesive layer of the patch body, the patch body does not contain a controlled-release film, and the ultrasonic device is arranged on the patch body. The arrangement sequence of the corrosion type microneedle, the patch and the ultrasonic device is as follows: the corrosion type microneedle, the patch and the ultrasonic device. The ultrasonic controlled-release corrosion type microneedle patch is applied to the skin surface and organically combines an ultrasonic mediation technology, a patch, 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 loading capacity is limited, the drug release rate cannot be accurately controlled, and the dosage cannot be adjusted in time are solved, and the transdermal drug absorption effect can be achieved to achieve intelligent and efficient treatment.

Description

Technical Field

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

[0002] Patches are thin, flexible preparations made of raw materials and suitable materials for application on the skin to produce systemic or local effects. Patches can be used on intact skin surfaces or diseased or incomplete skin surfaces. The advantages of patches are strong adhesion, ease of use, painlessness, and good patient compliance.

[0003] Patches have made significant progress in the field of drug delivery, 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) Limited drug loading capacity: The drug loading capacity of the patch is limited, especially for the larger doses of drugs required for long-term treatment, and the sustained effect cannot be guaranteed.

[0006] (3) 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.

[0007] (4) 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.

[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 intelligent and efficient skin preparations that are applicable to a wide range of drugs (especially heat-labile or easily inactivated biomacromolecule drugs), can adjust the dosage in time, and achieve rapid release and continuous drug delivery is of great significance for the therapeutic effect of drugs. At present, there is no intelligent and efficient skin preparation that can deliver drugs of various molecular weights, adjust the dosage in time, 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 intelligent and efficient skin preparations that can deliver drugs of various molecular weights, timely adjust the dosage, and achieve rapid release and continuous drug delivery, and to provide an ultrasonic 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 the advantages of various technologies can be complemented to make up for the shortcomings of a single technology application by organically combining "ultrasound-mediated technology, patches, dissolving microneedles and intelligent controlled release" to produce ultrasonic controlled-release dissolving microneedle patches.

[0013] After a large number of experiments, the ultrasonic controlled release dissolving microneedle patch of the present invention is obtained, which comprises a dissolving microneedle, a patch, an ultrasonic 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 adhesive layer of the above-mentioned patch, the length of the microneedle is 50-2000 μm, the base diameter is 50-300 μm, the tip diameter is 0.5-30 μm, and the cross-section of the needle body is circular or equidistant polygonal;

[0015] The patch is one of the adhesive dispersion type, peripheral adhesive type, and reservoir type, and does not contain a controlled release membrane;

[0016] The arrangement order of the above-mentioned dissolving microneedle, patch and ultrasonic device is dissolving microneedle - patch - ultrasonic device;

[0017] The above-mentioned ultrasonic device has a transmitting frequency of 0.1 to 20 MHz and an intensity of 0.1 to 5 W / m 2 Ultrasound;

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

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

[0020] The above-mentioned fixing device is used to fix the ultrasonic 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 above-mentioned ultrasonic device has a transmitting frequency of 0.5-5 MHz and an intensity of 0.5-3 W / m 2 Ultrasound;

[0025] The above-mentioned ultrasonic device has a transmitting frequency of 2-3 MHz and an intensity of 0.6-1 W / m 2 Ultrasound;

[0026] The patches described above are of the reservoir type;

[0027] 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;

[0028] The above-mentioned fixing device fixes the ultrasonic controlled release dissolving microneedle patch on the skin surface of the limbs or trunk by means of a strap or an ergonomic bracket;

[0029] The above-mentioned straps are fixed by buckles, adhesives or elastic bands;

[0030] The above-mentioned ergonomic stent conforms to the morphological characteristics of the limbs or trunk, ensuring that the ultrasonic controlled release dissolving microneedle patch fits tightly with the skin;

[0031] The above-mentioned patches include patches and plasters.

[0032] The ultrasonic controlled release dissolving 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 clogging. Ultrasound-mediated technology can keep the microchannels of the skin unobstructed after microneedle erosion, reducing the risk of clogging and improving the reliability of drug delivery.

[0036] (4) Good stability. Since the ultrasonic 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 an ultrasonic controlled-release dissolving microneedle patch (10: dissolving microneedle; 20: patch; 30: ultrasonic 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 ultrasonic controlled release dissolving microneedle patch of the present invention comprises: dissolving microneedles 10, a patch 20, an ultrasonic device 30, a power supply device 40, a regulating device 50, and a fixing device 60. The dissolving microneedles 10 are arranged in a matrix and embedded in the adhesive 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 patch area is 5 cm 2 , without controlled release membrane; the arrangement order of the erosion-type microneedle 10, patch 20 and ultrasonic device 30 is: erosion-type microneedle 10 - patch 20 - ultrasonic device 30; the ultrasonic device 30 has an emission frequency of 0.5-30 MHz and an intensity of 0.1-0.3 W / m 2The power supply device 40 is electrically connected to the control device 50 and the ultrasonic device 30, and is used to provide the electric energy required for the control device 50 and the ultrasonic device 30 to work; the control device 50 is used to control various parameters of the ultrasonic device 30; the fixing device 60 is used to fix the ultrasonic controlled release dissolving microneedle patch on the skin surface.

[0041] Example 1 Animal Experiment of Ultrasonic Controlled Release Dissolution 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 loading method: I: only the patch is loaded with drugs; II: both the microneedles and the patch are loaded with drugs.

[0049] (5) Patch type: T1: dispersed adhesive type; T2: peripheral adhesive type; T3: reservoir type.

[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, their backs were shaved. Each group applied a microneedle patch to the same part of the guinea pig's back for 120 min. At 20 min, the control device was used to terminate ultrasound for 10 min to evaluate the control ability of the control device, and then the ultrasound 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 ultrasonic controlled release dissolving 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 the simulated drug 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 ultrasonic regulation response ability, 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 agitation 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 ultrasonic controlled release dissolving microneedle patch of the present invention is significantly higher than that of most of the control groups. Among the experimental groups, the effects of groups 3, 4 and 6 are the best, but the animals in group 6 are frequently agitated.

[0062] Compared with the experimental group, the transdermal efficiency of the ultrasonic controlled-release dissolving microneedle patch in the control group was poor or had serious problems, especially in control groups 1, 4, 5, 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 ultrasonic controlled release dissolving microneedle patch of the present invention organically combines "ultrasound-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. Ultrasonic controlled release dissolution type microneedle patch, characterized in that: The ultrasonic controlled release dissolving microneedle patch comprises dissolving microneedles, a patch, an ultrasonic device, a power supply device, a regulating device and a fixing device, and the patch carries drugs; the dissolving microneedles are arranged in a matrix and embedded in the adhesive 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 one of the viscose dispersion type, peripheral viscose type, and reservoir type, and does not contain a controlled release membrane; the arrangement order of the dissolving microneedles, the patch and the ultrasonic device is: dissolving microneedles-patch-ultrasonic device; the transmission frequency of the ultrasonic device is 0.1 to 20 MHz, and the intensity is 0.1 to 5 W / m 2 The power supply device is electrically connected to the regulating device and the ultrasonic device, and is used to provide the electric energy required for the regulating device and the ultrasonic device to work; the regulating device is used to regulate various parameters of the ultrasonic device; the fixing device is used to fix the ultrasonic controlled release dissolving microneedle patch on the skin surface.

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

5. The ultrasonic controlled release dissolution type microneedle patch according to claim 1, characterized in that: The ultrasonic device has a transmitting frequency of 0.5 to 5 MHz and an intensity of 0.5 to 3 W / m 2 Ultrasound.

6. The ultrasonic controlled release dissolution type microneedle patch according to claim 5, characterized in that: The ultrasonic device has a transmitting frequency of 2 to 3 MHz and an intensity of 0.6 to 1 W / m 2 Ultrasound.

7. The ultrasonic controlled release dissolution type microneedle patch according to claim 1, characterized in that: The patch is of reservoir type.

8. The ultrasonic 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.

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

10. The ultrasonic controlled release dissolution type microneedle patch according to claim 1, characterized in that: The patch includes a patch and a plaster.

Images