Flexible conformal ultrasound patch for transdermal treatment of gout patients and control method

Abstract

This invention discloses a flexible conformal ultrasonic patch and its control method for transdermal treatment of gout patients. The flexible conformal ultrasonic patch includes a flexible ultrasonic transducer array layer, a thermosensitive nanocomposite gel layer, and a limiting perimeter layer. The thermosensitive nanocomposite gel layer simultaneously serves as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, a coupling medium for ultrasonic propagation, and a drug reservoir. When the flexible ultrasonic transducer array layer is operational, the generated ultrasonic thermal effect triggers a phase transition in the thermosensitive hydrogel, thereby accelerating the release of drugs from the drug-containing nanocarrier. This invention's flexible conformal ultrasonic patch achieves the technical effects of integrated structure, controllable drug release, and excellent thermal safety, meeting the clinical needs for transdermal ultrasonic drug delivery to joints in gout patients.

Description

Technical Field

[0001] This invention relates to the field of medical device technology, and in particular to a flexible conformal ultrasonic patch and control method for transdermal treatment of gout patients, which is especially suitable for transdermal drug delivery to irregular joints such as the knee, ankle, and finger joints. Background Technology

[0002] This section provides only background information relevant to this disclosure and is not necessarily prior art.

[0003] Gout is a crystal-related arthropathy caused by the deposition of monosodium urate crystals and is directly related to hyperuricemia. Its clinical features include hyperuricemia and recurrent acute gouty arthritis attacks, tophi deposition, joint destruction, and deformities. Currently, gout treatment mainly relies on oral medications (such as nonsteroidal anti-inflammatory drugs, colchicine, and uric acid-lowering drugs) to control symptoms and lower uric acid levels. However, long-term medication use has significant side effects (such as gastrointestinal reactions and liver and kidney damage), difficulty in ensuring patient compliance, and high treatment costs.

[0004] Ultrasound-guided transdermal drug delivery, a non-invasive physical permeation technique, has garnered significant attention in recent years. Its basic principle involves utilizing the cavitation, radiation pressure, and thermal effects of ultrasound waves to temporarily disrupt the barrier structure of the stratum corneum, creating microscopic channels for drug entry and thus promoting transdermal absorption. Compared to oral administration, ultrasound-guided transdermal delivery allows for targeted local drug delivery, reduces systemic toxicity, and increases drug concentration at the lesion site. This technique offers advantages such as targeted local delivery, avoidance of the first-pass effect in the liver, and reduced systemic toxicity, leading to its widespread clinical application.

[0005] Ultrasonic coupling patches are important consumables used in conjunction with ultrasonic therapy devices. Their main functions include: serving as a coupling medium for ultrasonic propagation, filling the space between the ultrasonic probe and the skin, eliminating air gaps, and ensuring effective transmission of ultrasonic energy.

[0006] Several design schemes for ultrasound coupling patches have been disclosed in the prior art. For example, Chinese utility model patent CN214181160U discloses a hydrophilic gel skeleton coupling patch, which consists of a skeleton gel sheet, an aluminum sheet, and a medical plaster from top to bottom. The skeleton gel sheet uses hydroxypropyl methylcellulose (HPMC) hydrophilic gel material as a drug carrier, which can increase the drug loading capacity and achieve uniform release. However, the aluminum sheet used in this design is a rigid support structure, which is prone to heat accumulation under ultrasound, posing a risk of burns; at the same time, the rigid structure limits the adaptability of the patch to joint areas.

[0007] For example, Chinese utility model patent CN211410674U discloses a coupling patch specifically for transdermal drug delivery to the knee joint. It features an optimized design tailored to the unique anatomical structure of the knee joint, using a rectangular medical fabric that wraps around the joint with Velcro fasteners at both ends for enhanced fixation. Traditional aluminum sheets are replaced with a metal mesh with diamond-shaped grooves, improving the patch's flexibility and reducing the attenuation of ultrasound waves. However, while the metal mesh improves flexibility, the metal material still poses a potential risk of heating under ultrasound. Furthermore, the drug carrier still uses a non-woven cotton patch, resulting in a relatively simple drug release method that makes it difficult to achieve long-lasting sustained release and on-demand drug delivery.

[0008] For example, Chinese utility model patent CN218739862U discloses an ultrasonic coupling patch, including an mounting layer and a coating structure. The coating structure employs a first conductive gel, a second conductive gel, and a microgroove design, allowing the drug to be evenly distributed within the microgroove during application, resulting in a tighter fit with the skin. However, this design still relies on a rigid ultrasonic probe, lacking overall flexibility and making it difficult to fully adapt to skin deformation during joint movement.

[0009] As can be seen from the above existing technologies, current ultrasound coupling patches still face the following technical bottlenecks when applied to joint areas:

[0010] 1. Structural rigidity limits fit performance. Existing patches generally use aluminum sheets or metal mesh as the support structure. Although this can improve ultrasound transmission, the presence of metal components increases the overall rigidity of the patch, making it difficult to fully adapt to the curvature and dynamic deformation of the joint area. During joint movement, the patch is prone to localized lifting or slippage, leading to ultrasound coupling failure and affecting the treatment effect.

[0011] 2. Limited drug release mechanism. Current patches primarily use non-woven cotton sheets or hydrophilic gels as drug carriers, releasing drugs via free diffusion, making precise control of the release rate difficult. While hydrophilic gels can achieve uniform release, they cannot dynamically adjust the release rate according to treatment needs (such as acute versus chronic phases), nor can they provide long-term sustained release of drugs, necessitating frequent patch replacements and impacting patient compliance.

[0012] 3. Multi-material interfaces lead to acoustic energy loss. Existing patches are usually composed of multiple layers of different materials, including support layers, coupling layers, and drug layers. The acoustic impedance mismatch between different materials can cause ultrasound energy to be reflected and attenuated at the interface, reducing energy transmission efficiency and affecting the treatment effect.

[0013] 4. Metal components pose thermal safety risks. Under continuous ultrasound, metal sheets or mesh may generate heat accumulation, especially during high-intensity or prolonged treatments. The local temperature rise may exceed the safety threshold, posing a risk of burns to the skin or deep tissues.

[0014] To address the aforementioned technical challenges, it is necessary to develop a novel, fully flexible, transdermal ultrasound patch that achieves integrated structure, controllable drug release, and excellent thermal safety to meet the clinical needs of transdermal drug delivery to joint sites. Summary of the Invention

[0015] In view of the technical problems existing in the prior art, such as the structural rigidity limiting the fit performance, the single drug release mode, the sound energy loss caused by multiple material interfaces, and the thermal safety risks of metal components, the present invention aims to provide a flexible conformal ultrasonic patch for transdermal treatment of gout patients and a control method thereon.

[0016] To overcome the shortcomings of existing technologies, one of the objectives of this invention is to provide a flexible conformal ultrasound patch for transdermal treatment of gout patients, comprising an integrated layered structure, which, from top to bottom, consists of:

[0017] A flexible ultrasonic transducer array layer includes a flexible substrate and multiple piezoelectric transducer units integrated on the flexible substrate, wherein the multiple piezoelectric transducer units constitute a phased array transducer array.

[0018] A thermosensitive nanocomposite gel layer is attached to the lower surface of the flexible ultrasonic transducer array layer. The thermosensitive hydrogel material serves as the framework matrix, and drug-containing nanocarriers are uniformly dispersed within the framework matrix. The drug-containing nanocarriers encapsulate the active ingredients of therapeutic drugs.

[0019] The limiting edge layer is a ring-shaped foam edge, which is disposed on the lower surface of the flexible ultrasonic transducer array layer and on the periphery of the temperature-sensitive nanocomposite gel layer to accommodate the temperature-sensitive nanocomposite gel layer.

[0020] The thermosensitive nanocomposite gel layer serves simultaneously as an encapsulation buffer layer of the flexible ultrasonic transducer array layer, a coupling medium for ultrasonic propagation, and a drug reservoir. When the flexible ultrasonic transducer array layer is in operation, the generated ultrasonic thermal effect triggers a phase transition in the thermosensitive hydrogel, thereby accelerating the release of drugs from the drug-containing nanocarrier.

[0021] Furthermore, the thermosensitive hydrogel material is selected from one or more of hydroxypropyl methylcellulose (HPMC), hyaluronic acid (HA), or poly(N-isopropylacrylamide) (PNIPAM), and has the property of undergoing reversible volume phase change or swelling degree change in the temperature range of 32-40℃.

[0022] Furthermore, the thermosensitive nanocomposite gel layer uses a composite thermosensitive hydrogel as a matrix. The preparation process of the composite thermosensitive hydrogel is as follows: Hydroxypropyl methylcellulose is selected as the first thermosensitive hydrogel skeleton material, and N-isopropylacrylamide is selected as the second thermosensitive hydrogel skeleton material. They are crosslinked with N,N'-methylenebisacrylamide for 2.5-3.5 hours under the action of ammonium persulfate initiator. The molar ratio of the first thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (2-6):1, and the molar ratio of the second thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (0.5-3):1. The amount of initiator is 3-5% of the total amount of the above materials. After the two crosslinking materials are mixed, a drug penetration-enhancing hydrogel matrix suitable for ultrasound delivery is obtained.

[0023] Furthermore, the drug-containing nanocarrier is one or more of PLGA microspheres, liposomes, nanovesicles or polymer micelles loaded with active ingredients of therapeutic drugs, with a particle size of 100nm-10μm, uniformly dispersed in a thermosensitive hydrogel matrix, and a mass fraction of 5%-30%.

[0024] Furthermore, the flexible substrate material of the flexible ultrasonic transducer array layer is selected from one or more of polyimide (PI), polydimethylsiloxane (PDMS), or liquid crystal polymer (LCP); the piezoelectric transducer unit is one or more of PZT piezoelectric ceramic micropillars, PMN-PT single crystals, or PVDF piezoelectric films.

[0025] Furthermore, the flexible conformal ultrasonic patch also includes a release film coated on the lower surface of the limiting perimeter layer and the temperature-sensitive nanocomposite gel layer.

[0026] Furthermore, the flexible conformal ultrasound patch also includes a fixing band, which is connected to the upper surface or edge of the flexible ultrasound transducer array layer to fix the patch to the joint.

[0027] Furthermore, the fixing strap is an elastic strap with hook and loop fasteners at both ends.

[0028] Furthermore, the flexible conformal ultrasound patch also includes a temperature sensor and a microcontroller. The temperature sensor is disposed within the temperature-sensitive nanocomposite gel layer or on the surface of the skin contact layer for real-time monitoring of local temperature. The microcontroller is electrically connected to the temperature sensor and the flexible ultrasound transducer array layer for dynamically adjusting ultrasound output parameters based on the temperature feedback signal.

[0029] The second objective of this invention is achieved by the following technical solution: a drug release control method based on the above-described fully flexible temperature-sensitive sustained-release ultrasonic transdermal patch, characterized by comprising the following steps:

[0030] Step S1: Apply the patch to the patient's joint area, ensuring that the skin contact layer adheres tightly to the skin;

[0031] Step S2: Select either the chronic maintenance mode or the acute rapid drug delivery mode according to the treatment needs;

[0032] Step S3: Activate the flexible ultrasonic transducer array layer to generate ultrasonic waves, and control the local temperature rise by adjusting the ultrasonic output parameters;

[0033] Step S4: Local temperature rise triggers a phase transition in the thermosensitive hydrogel, changing the gel's network structure and permeability;

[0034] Step S5: The phase change effect causes a change in the drug release rate of the drug-containing nanocarrier, enabling on-demand drug delivery;

[0035] Step S6: The temperature sensor monitors the local temperature in real time, and the microcontroller dynamically adjusts the ultrasound output based on the temperature feedback to ensure treatment safety.

[0036] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0037] The fully flexible ultrasonic transdermal patch of the present invention achieves the technical effects of integrated structure, controllable drug release, and excellent thermal safety performance, so as to meet the clinical needs of ultrasonic transdermal drug delivery to joints in gout.

[0038] 1. Optimized Fit to Adapt to Joint Dynamics: The fit is optimized through the synergistic effect of a flexible layered structure, achieving structural integration. The flexible transducer array layer provides overall patch flexibility, while the improved temperature-sensitive nanocomposite gel layer and the limiting edge layer act as buffer layers to adaptively fill uneven skin surfaces. Furthermore, the improved temperature-sensitive nanocomposite gel layer also serves the following functions: acting as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, providing mechanical support and flexible conformability; acting as a coupling medium for ultrasonic propagation, achieving acoustic impedance matching and reducing acoustic energy loss; and acting as a drug reservoir, enabling long-term sustained drug release through drug-containing nanocarriers.

[0039] 2. Long-lasting and effectively controlled drug release: This invention utilizes PLGA microspheres, liposomes, and other nanocarriers to encapsulate drugs, uniformly dispersing them within a hydrogel framework to form a dual sustained-release system. The nanocarriers themselves can control the drug release rate, prolong the release cycle, reduce patch replacement frequency, and improve patient compliance, making it particularly suitable for personalized home treatment needs. Simultaneously, the nanocarriers protect drug activity and improve stability. Furthermore, temperature-sensitive controlled release enables on-demand drug delivery. This invention utilizes the thermal effect of ultrasound operation as a trigger signal, regulating the drug release rate of the drug-containing nanocarriers through the phase transition of the temperature-sensitive hydrogel. When rapid drug delivery is needed (e.g., during an acute gout attack), the ultrasound output intensity is increased, and the local temperature rise triggers the gel phase transition, accelerating drug release from the nanocarriers. When maintenance therapy is needed (e.g., during chronic remission), the ultrasound output is reduced, the gel returns to its initial state, and the drug is continuously released at a sustained-release rate. This physical controlled-release mechanism requires no additional heating elements or valve structures, making it simple and reliable. This invention employs a phased-array transducer array, using electronic control to focus and deflect the ultrasound beam, precisely delivering ultrasound energy to the target joint region. The thermal effect of ultrasound is concentrated at the lesion site, triggering local drug release and achieving spatial targeted delivery of drugs, thereby improving efficacy and reducing drug waste.

[0040] 3. Single material interface and low acoustic energy loss: This invention integrates the ultrasonic coupling medium and the drug reservoir into a single temperature-sensitive nanocomposite gel layer, eliminating the interfaces between multiple layers of different materials in existing technologies. This avoids ultrasonic energy reflection and attenuation caused by acoustic impedance mismatch, thus improving energy transmission efficiency. The temperature-sensitive nanocomposite gel layer is directly bonded to the flexible transducer array, achieving optimized matching of acoustic characteristics.

[0041] 4. Elimination of the risk of metal burns: This invention eliminates the use of metal aluminum sheets or meshes in existing technologies, employing a fully flexible layered structure. This eliminates the risk of burns from heated metal components under ultrasonic treatment, significantly improving treatment safety. The combination of the flexible ultrasonic transducer array layer and the temperature-sensitive nanocomposite gel layer gives the entire patch excellent flexibility, allowing it to bend and deform freely with joint movement. Furthermore, the integrated temperature sensor and microcontroller in this invention monitor the temperature of the treatment area in real time, automatically reducing the ultrasonic output when the temperature approaches a safe threshold to prevent overheating damage. This closed-loop feedback control mechanism ensures that the treatment process remains within a safe range. Attached Figure Description

[0042] Figure 1 This is a schematic diagram of the structure of a flexible conformal ultrasonic patch for transdermal treatment of gout patients according to a preferred embodiment of the present invention;

[0043] Figure 2 This is an exploded view of a flexible conformal ultrasonic patch for transdermal treatment of gout patients according to a preferred embodiment of the present invention.

[0044] Figure 3 This is a schematic diagram of the microstructure of the temperature-sensitive nanocomposite gel layer in this invention;

[0045] Figure 4 This is a top view of the flexible ultrasonic transducer array layer in this invention.

[0046] Figure 5 This is a schematic diagram illustrating the application of a flexible conformal ultrasonic patch for transdermal treatment of gout patients, according to a preferred embodiment of the present invention.

[0047] In the image: 100, Flexible conformal ultrasonic patch;

[0048] 1. Flexible ultrasonic transducer array layer; 11. Flexible substrate; 12. Piezoelectric transducer unit; 2. Thermosensitive nanocomposite gel layer; 21. Drug-containing nanocarrier; 3. Limiting perimeter layer; 4. Release layer; 41. First release film; 42. Second release film; 5. Fixing tape;

[0049] 200. Independent loss material layer;

[0050] A. Skin. Detailed Implementation

[0051] The present invention will now be further described in conjunction with the accompanying drawings and specific embodiments. It should be noted that, without conflict, the various embodiments or technical features described below can be arbitrarily combined to form new embodiments.

[0052] In this invention, unless otherwise specified, all parts and percentages are by weight, and the equipment and raw materials used are commercially available or commonly used in the art. Unless otherwise specified, the methods in the following embodiments are conventional methods in the art.

[0053] like Figure 1-5 As shown, a flexible conformal ultrasound patch 100 for transdermal treatment of gout patients includes an integrated layered structure, which, from top to bottom, consists of:

[0054] The flexible ultrasonic transducer array layer 1 includes a flexible substrate 11 and a plurality of piezoelectric transducer units 12 integrated on the flexible substrate, wherein the plurality of piezoelectric transducer units constitute a phased array transducer array; used to generate focused or deflected ultrasonic beams.

[0055] Thermosensitive nanocomposite gel layer 2 is attached to the lower surface of the flexible ultrasonic transducer array layer. It is made of thermosensitive hydrogel material as the skeleton matrix. Drug-containing nanocarriers 21 are uniformly dispersed in the skeleton matrix. The drug-containing nanocarriers encapsulate the active ingredients of therapeutic drugs.

[0056] The limiting edge layer 3 is an annular foam edge layer, which is disposed on the lower surface of the flexible ultrasonic transducer array layer and on the periphery of the temperature-sensitive nanocomposite gel layer to accommodate the temperature-sensitive nanocomposite gel layer.

[0057] The temperature-sensitive nanocomposite gel layer also serves as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, a coupling medium for ultrasonic propagation, and a drug reservoir.

[0058] The thermosensitive nanocomposite gel layer also has the following functions: serving as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, providing mechanical support and flexible conformability; serving as a coupling medium for ultrasonic propagation, achieving acoustic impedance matching and reducing acoustic energy loss; serving as a drug reservoir, enabling long-term sustained release of drugs through drug-containing nanocarriers; when the flexible ultrasonic transducer array layer is working, the generated ultrasonic waves produce a thermal effect in the tissue, which raises the local temperature of the thermosensitive nanocomposite gel layer, triggering a phase transition in the thermosensitive hydrogel, thereby accelerating the release of drugs from the drug-containing nanocarriers and realizing ultrasound-triggered on-demand drug delivery.

[0059] As a further preferred embodiment, the thermosensitive hydrogel material is selected from one or more of hydroxypropyl methylcellulose (HPMC), hyaluronic acid (HA), or poly(N-isopropylacrylamide) (PNIPAM), and has the property of undergoing reversible volume phase change or swelling degree change in the temperature range of 32-40℃.

[0060] As a further preferred embodiment, the thermosensitive nanocomposite gel layer uses a composite thermosensitive hydrogel as a matrix. The preparation process of the composite thermosensitive hydrogel is as follows: Hydroxypropyl methylcellulose is selected as the first thermosensitive hydrogel skeleton material, and N-isopropylacrylamide is selected as the second thermosensitive hydrogel skeleton material. They are crosslinked with N,N'-methylenebisacrylamide for 2.5-3.5 hours under the action of ammonium persulfate initiator. The molar ratio of the first thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (2-6):1, and the molar ratio of the second thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (0.5-3):1. The amount of initiator is 3-5% of the total amount of the above materials. After the two crosslinking materials are mixed, a drug penetration-enhancing hydrogel matrix suitable for ultrasound delivery is obtained.

[0061] As a further preferred embodiment, the drug-containing nanocarrier is one or more of PLGA microspheres, liposomes, nanovesicles or polymer micelles loaded with active ingredients of therapeutic drugs, with a particle size of 100nm-10μm, uniformly dispersed in a thermosensitive hydrogel matrix, and a mass fraction of 5%-30%.

[0062] As a further preferred option, the active ingredient of the therapeutic drug is a traditional Chinese medicine extract or a Western medicine preparation for treating gout.

[0063] As a further preferred embodiment, the flexible substrate material of the flexible ultrasonic transducer array layer is selected from one or more of polyimide (PI), polydimethylsiloxane (PDMS), or liquid crystal polymer (LCP); the piezoelectric transducer unit is one or more of PZT piezoelectric ceramic micropillars, PMN-PT single crystals, or PVDF piezoelectric films.

[0064] In this invention, the temperature-sensitive nanocomposite gel layer can be used as a consumable material and processed into an independent component. When used by the patient, the release layer is directly torn off, and the side with the temperature-sensitive nanocomposite gel material is attached to the flexible ultrasound transducer array layer for direct transdermal ultrasound treatment.

[0065] Specifically, such as Figure 2 As shown, the independent loss material layer 200 includes a limiting edge layer 3, a temperature-sensitive nanocomposite gel layer 2 housed in the limiting edge layer, a first release film 41 covering the lower surface of the limiting edge layer and the temperature-sensitive nanocomposite gel layer, and a second release film 42 covering the upper surface of the limiting edge layer and the temperature-sensitive nanocomposite gel layer. The first release film 41 and the second release film 42 together constitute the release layer 4.

[0066] The limiting edge layer is a foam edge layer, which is arranged in a ring around the periphery of the temperature-sensitive nanocomposite gel layer to limit the position of the gel layer and prevent drug leakage; the first release film is covered by a low-sensitivity medical pressure-sensitive adhesive on the lower surface of the limiting edge layer and the temperature-sensitive nanocomposite gel layer for protection before use; the second release film is covered by a low-sensitivity medical pressure-sensitive adhesive on the upper surface of the limiting edge layer and the temperature-sensitive nanocomposite gel layer for protection before use.

[0067] As a further preferred embodiment, the flexible conformal ultrasound patch also includes a fixing band 5, which is connected to the upper surface or edge of the flexible ultrasound transducer array layer and is used to fix the patch to the joint.

[0068] As a further preferred embodiment, the fixing strap is an elastic strap with hook and loop fasteners at both ends.

[0069] As a further preferred embodiment, the flexible conformal ultrasound patch also includes a temperature sensor and a microcontroller. The temperature sensor is disposed within the temperature-sensitive nanocomposite gel layer or on the surface of the skin contact layer for real-time monitoring of local temperature. The microcontroller is electrically connected to the temperature sensor and the flexible ultrasound transducer array layer for dynamically adjusting ultrasound output parameters based on the temperature feedback signal.

[0070] Furthermore, the present invention also provides a control method based on the above-mentioned flexible conformal ultrasonic patch for transdermal treatment of gout patients, comprising the following steps:

[0071] Step S1: Apply the patch to the patient's joint area, ensuring that the skin contact layer adheres tightly to the skin;

[0072] Step S2: Select either the chronic maintenance mode or the acute rapid drug delivery mode according to the treatment needs;

[0073] Step S3: Activate the flexible ultrasonic transducer array layer to generate ultrasonic waves, and control the local temperature rise by adjusting the ultrasonic output parameters;

[0074] Step S4: Local temperature rise triggers a phase transition in the thermosensitive hydrogel, changing the gel's network structure and permeability;

[0075] Step S5: The phase change effect causes a change in the drug release rate of the drug-containing nanocarrier, enabling on-demand drug delivery;

[0076] Step S6: The temperature sensor monitors the local temperature in real time, and the microcontroller dynamically adjusts the ultrasound output based on the temperature feedback to ensure treatment safety.

[0077] Example 1: Flexible conformal ultrasonic patch

[0078] A flexible conformal ultrasound patch 100 for transdermal therapy of gout patients includes an integrated layered structure, comprising, from top to bottom:

[0079] The flexible ultrasonic transducer array layer 1 includes a flexible substrate 11 and a plurality of piezoelectric transducer units 12 integrated on the flexible substrate, wherein the plurality of piezoelectric transducer units constitute a phased array transducer array; used to generate focused or deflected ultrasonic beams.

[0080] Thermosensitive nanocomposite gel layer 2 is attached to the lower surface of the flexible ultrasonic transducer array layer. It is made of thermosensitive hydrogel material as the skeleton matrix. Drug-containing nanocarriers are uniformly dispersed in the skeleton matrix. The drug-containing nanocarriers encapsulate the active ingredients of therapeutic drugs.

[0081] The limiting edge layer 3 is an annular foam edge layer, which is disposed on the lower surface of the flexible ultrasonic transducer array layer and on the periphery of the temperature-sensitive nanocomposite gel layer to accommodate the temperature-sensitive nanocomposite gel layer.

[0082] The temperature-sensitive nanocomposite gel layer also serves as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, a coupling medium for ultrasonic propagation, and a drug reservoir.

[0083] The thermosensitive nanocomposite gel layer also has the following functions: serving as an encapsulation buffer layer for the flexible ultrasonic transducer array layer, providing mechanical support and flexible conformability; serving as a coupling medium for ultrasonic propagation, achieving acoustic impedance matching and reducing acoustic energy loss; serving as a drug reservoir, enabling long-term sustained release of drugs through drug-containing nanocarriers; when the flexible ultrasonic transducer array layer is working, the generated ultrasonic waves produce a thermal effect in the tissue, which raises the local temperature of the thermosensitive nanocomposite gel layer, triggering a phase transition in the thermosensitive hydrogel, thereby accelerating the release of drugs from the drug-containing nanocarriers and realizing ultrasound-triggered on-demand drug delivery.

[0084] This invention addresses the size specifications for different joint parts.

[0085] This invention can be designed with a series of size specifications according to different joint parts, as shown in the table below:

[0086]

[0087] This example demonstrates the fabrication of a flexible, conformal ultrasonic patch for transdermal treatment of gout patients, using a patch for the knee.

[0088] (1) The thermosensitive nanocomposite gel layer for the knee is prepared by the following method: (11) Preparation of thermosensitive hydrogel matrix

[0089] Hydroxypropyl methylcellulose was selected as the first thermosensitive hydrogel framework material, and N-isopropylacrylamide was selected as the second thermosensitive hydrogel framework material. They were crosslinked with N,N'-methylenebisacrylamide for 3 hours under the action of ammonium persulfate initiator. The molar ratio of the first thermosensitive hydrogel framework material to N,N'-methylenebisacrylamide was 4:1, and the molar ratio of the second thermosensitive hydrogel framework material to N,N'-methylenebisacrylamide was 1:1. The amount of initiator was 4% of the total amount of the above materials. After the two crosslinking materials were mixed, a drug penetration-enhancing hydrogel dressing suitable for ultrasound delivery was obtained. The molecular structure of this excipient has multiple spaces, which can store drug molecules and water molecules. It has a large storage capacity and can continuously and orderly release. The gelation temperature of the two materials is about 37-40℃. A stable gel is formed under body temperature. It softens further after ultrasonic heating. The crosslinking materials can resist external temperature changes well without causing damage to the gel matrix layer due to temperature or ultrasound. (12) Preparation of drug-containing PLGA microspheres

[0090] Preparation method of PLGA microspheres: PLGA microspheres loaded with triptolide were prepared by dissolving the above-mentioned triptolide and PLGA (polylactic acid-glycolic acid copolymer) in a 1:9 mass ratio in a mixed solvent of dichloromethane and anhydrous ethanol (5:1), and then sonicating. The solution was then slowly added dropwise to a 1.5% polyvinyl alcohol (PVA) aqueous phase under stirring to form an O / W emulsion. Stirring was continued for 3 hours until the organic solvent completely evaporated, and microspheres were formed. The microspheres were collected by ultracentrifugation (12000 rpm, 4℃) and freeze-dried. The resulting microspheres had a particle size of 2-5 μm and a drug loading of approximately 8%.

[0091] (13) Preparation of foam edging

[0092] Medical foam material is selected and cut into a ring structure with an outer rectangle (50mm×50mm) and an inner square (42mm×42mm). The foam thickness is 2.5mm and the rim width is 4mm, thus obtaining the limiting rim layer.

[0093] (14) Preparation of temperature-sensitive nanocomposite gel layer

[0094] The thermosensitive hydrogel matrix was dissolved in pure water at a mass fraction of 10% and allowed to fully swell and dissolve. The prepared drug-containing PLGA microspheres were added to the thermosensitive hydrogel matrix at a mass fraction of 15% and stirred thoroughly to ensure uniform dispersion of the microspheres. Vacuum degassing was performed to eliminate air bubbles. The microspheres were then injected into the foam perimeter to form a thermosensitive nanocomposite gel layer with a thickness controlled at 2.5 mm.

[0095] (14) Composite release layer

[0096] Medical pressure-sensitive adhesive with a thickness of 0.1 mm is coated on the surfaces of two layers of release paper, and then respectively laminated on the lower and upper surfaces of the limiting edge layer and the temperature-sensitive nanocomposite gel layer to protect the temperature-sensitive nanocomposite gel material, thus obtaining the first release film 41 and the second release film 42.

[0097] (2) Adhesive flexible ultrasonic transducer array layer

[0098] In this invention, the flexible ultrasonic transducer array layer can be prepared by the following method: A polyimide (PI) flexible circuit board with a thickness of 0.1 mm is used as the flexible substrate, exhibiting good flexibility and temperature resistance. A serpentine copper electrode is fabricated on the PI substrate using photolithography. PZT piezoelectric ceramic micropillars (2 mm × 2 mm × 1 mm) are bonded to the electrodes using conductive adhesive to form an 8 × 8 phased array transducer array with a total area of ​​40 mm × 40 mm, a transducer unit spacing of 2.5 mm, and an operating frequency of 1 MHz. The transducer array is then protected by PDMS encapsulation with a thickness of 0.2 mm. Alternatively, commercially available curved surface mount devices can also be used.

[0099] During treatment, the second release film 42 on the thermosensitive nanocomposite gel layer in step (1) is torn off, and the thermosensitive nanocomposite gel layer is attached to the lower surface of the flexible ultrasonic transducer array layer. The other side of the thermosensitive nanocomposite gel layer is attached to the surface of the joint skin A.

[0100] During the treatment phase, depending on the patient's needs, either a chronic maintenance mode or an acute rapid drug delivery mode can be selected. In the chronic maintenance mode, the ultrasound output parameters can be set as follows: frequency 1MHz, sound intensity 0.5W / cm². 2 In pulse mode (20% duty cycle), ultrasound output is administered for 30 minutes, once daily. During this mode, the ultrasonic thermal effect is mild, with a local temperature rise of approximately 2-3°C. The HPMC gel remains stable, and the PLGA microspheres release the drug at a sustained-release rate of approximately 0.2 mg / h. A single treatment can maintain an effective drug concentration for 24 hours. When patients are in the acute phase of gout and require rapid drug administration, an acute-phase rapid drug administration mode can be selected: Adjust the ultrasound output parameters: frequency 1MHz, sound intensity 2.0W / cm², continuous wave mode, ultrasound output for 30 minutes, twice daily. This mode enhances the ultrasonic thermal effect, with a local temperature rise of approximately 5-7°C. The mixed gel matrix temperature reaches 39-41°C. Upon temperature increase, the mixed gel matrix softens, molecular chain movement is enhanced, and porosity increases. Simultaneously, ultrasonic vibration promotes drug diffusion within the gel, and the PLGA microspheres degrade more rapidly under elevated temperature conditions, significantly increasing the drug release rate. The release rate can reach 2-3 mg / h, 10-15 times the basal rate, rapidly relieving acute pain and inflammatory symptoms.

[0101] Example 2

[0102] This embodiment is an ankle patch. The difference from Example 1 is the choice of thermosensitive hydrogel and nanocarrier. For the rest of the preparation method, please refer to Example 1.

[0103] a. Hydroxypropyl methylcellulose was selected as the first thermosensitive hydrogel framework material, and N-isopropylacrylamide was selected as the second thermosensitive hydrogel framework material. Both were crosslinked with N,N'-methylenebisacrylamide for 2.5 h under the action of ammonium persulfate initiator. The molar ratio of the first thermosensitive hydrogel framework material to the N,N'-methylenebisacrylamide was 2:1, and the molar ratio of the second thermosensitive hydrogel framework material to the N,N'-methylenebisacrylamide was 3:1. The amount of initiator was 3% of the total amount of the above materials. After the two crosslinking materials were mixed, a drug penetration-enhancing hydrogel matrix suitable for ultrasound delivery was obtained.

[0104] b. Preparation of drug-containing liposomes

[0105] Liposomes loaded with traditional Chinese medicine extracts were prepared using a thin-film dispersion method. The mass ratio of phospholipids to cholesterol was 4:1, and the mass ratio of drug to phospholipids was 1:10. The liposome particle size was controlled within the range of 100-200 nm. The liposomes promoted transdermal absorption and, in synergy with ultrasonic cavitation, enhanced drug penetration.

[0106] b. Preparation of temperature-sensitive nanocomposite gel

[0107] The thermosensitive hydrogel matrix was dissolved in pure water at a mass fraction of 8% and allowed to swell and dissolve completely. The prepared drug-containing PLGA microspheres were added to the thermosensitive hydrogel matrix at a mass fraction of 20% and stirred thoroughly to ensure uniform dispersion of the microspheres. Vacuum degassing was performed to eliminate air bubbles. The microspheres were then injected into the foam perimeter to form a thermosensitive nanocomposite gel layer with a thickness controlled at 2 mm.

[0108] Example 3: Patch Panel with Integrated Temperature Feedback Control

[0109] Based on Example 1 or 2, this embodiment adds an intelligent feedback control module to achieve closed-loop temperature control. Specifically, a temperature sensor is integrated into the temperature-sensitive nanocomposite gel layer and connected to an external microcontroller via a flexible wire.

[0110] In this example, the microcontroller has a preset target temperature range of 38-40℃ and a safe temperature threshold of 42℃. The PID control algorithm dynamically adjusts the ultrasound output power to keep the temperature of the treatment area stable within the target range.

[0111] Its working process is as follows: In the initial stage, the microcontroller outputs ultrasound according to the preset treatment plan; in the temperature rising stage, when the temperature approaches the upper limit of the target range, the microcontroller reduces the output power; in the temperature maintenance stage, the PID algorithm finely adjusts the temperature to stabilize it within the target range; when the temperature exceeds 42℃, the ultrasound output is immediately stopped, an alarm is triggered, and temperature over-limit protection is achieved.

[0112] In this example, the temperature control accuracy is ±0.5℃, the drug release rate fluctuation is <10%, the treatment safety is significantly improved, and there is no risk of burns.

[0113] Comparative Example 1: Flexible Conformal Ultrasonic Patch

[0114] The difference from Example 1 is that in the knee-use thermosensitive nanocomposite gel layer, the thermosensitive hydrogel matrix is ​​made of hydroxypropyl methylcellulose as the single thermosensitive hydrogel skeleton material, while the other conditions and parameters are the same as in Example 1.

[0115] The preparation of the thermosensitive hydrogel matrix in step (11) is as follows:

[0116] Hydroxypropyl methylcellulose was selected as the thermosensitive hydrogel skeleton material and crosslinked with N,N'-methylenebisacrylamide for 3 hours under the action of ammonium persulfate initiator. The molar ratio of thermosensitive hydrogel skeleton material to N,N'-methylenebisacrylamide was 4:1, and the amount of initiator was 4% of the total amount of the above materials, thus obtaining a drug penetration-enhancing hydrogel dressing suitable for ultrasound delivery.

[0117] Comparative Example 2: Flexible Conformal Ultrasonic Patch

[0118] The difference from Example 1 is that in the knee-use thermosensitive nanocomposite gel layer, the thermosensitive hydrogel matrix is ​​made of hydroxypropyl methylcellulose as the single thermosensitive hydrogel skeleton material, while the other conditions and parameters are the same as in Example 1.

[0119] The preparation of the thermosensitive hydrogel matrix in step (11) is as follows:

[0120] N-Isopropylacrylamide was selected as the thermosensitive hydrogel framework material and crosslinked with N,N'-methylenebisacrylamide for 3 hours under the action of ammonium persulfate initiator. The molar ratio of the thermosensitive hydrogel framework material to N,N'-methylenebisacrylamide was 1:1, and the amount of initiator was 4% of the total amount of the above materials, thus obtaining a drug penetration-enhancing hydrogel dressing suitable for ultrasound delivery.

[0121] To further verify the therapeutic effect of the present invention's conformal ultrasonic patch in the ultrasonic delivery therapy, triptolide saline mixture (triptolide concentration 0.01 g / ml), the flexible conformal ultrasonic patch from Example 1, and the flexible conformal ultrasonic patches from Comparative Examples 1-2 were respectively connected to an ultrasonic delivery device. The acute phase rapid drug delivery mode was selected, and the ultrasonic output parameters were adjusted as follows: frequency 1 MHz, sound intensity 2.0 W / cm², continuous wave mode, ultrasonic output for 30 min, enhanced ultrasonic thermal effect, local temperature rise of approximately 5-7℃, and the temperature of the mixed gel matrix reaching 39-41℃. 1 ml samples were taken at 5 min, 10 min, 20 min, 25 min, and 30 min. After dissolution, the drug solution was analyzed by high-performance liquid chromatography (HPLC) at a column temperature of 30℃ and a mobile phase of methanol:water = 95:5 (triptolide solubility). The drug penetration data are shown in the table below.

[0122]

[0123] As can be seen from the table, the flexible conformal ultrasonic patch of this invention has a good permeation-enhancing effect, and its transdermal effect is higher than that of the control mixture. Furthermore, the composite thermosensitive nanocomposite gel has a better drug delivery effect than the single thermosensitive nanocomposite gel.

[0124] The above embodiments are merely preferred embodiments of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-substantial changes and substitutions made by those skilled in the art based on the present invention shall fall within the scope of protection claimed by the present invention.

Claims

1. A flexible conformal ultrasonic patch for transdermal treatment of gout patients, characterized in that, Including an integrated layered structure, from top to bottom as follows: A flexible ultrasonic transducer array layer includes a flexible substrate and multiple piezoelectric transducer units integrated on the flexible substrate, wherein the multiple piezoelectric transducer units constitute a phased array transducer array. A thermosensitive nanocomposite gel layer is attached to the lower surface of the flexible ultrasonic transducer array layer. The thermosensitive hydrogel material serves as the framework matrix, and drug-containing nanocarriers are uniformly dispersed within the framework matrix. The drug-containing nanocarriers encapsulate the active ingredients of therapeutic drugs. The limiting edge layer is a ring-shaped foam edge, which is disposed on the lower surface of the flexible ultrasonic transducer array layer and on the periphery of the temperature-sensitive nanocomposite gel layer to accommodate the temperature-sensitive nanocomposite gel layer. The thermosensitive nanocomposite gel layer serves simultaneously as an encapsulation buffer layer of the flexible ultrasonic transducer array layer, a coupling medium for ultrasonic propagation, and a drug reservoir. When the flexible ultrasonic transducer array layer is in operation, the generated ultrasonic thermal effect triggers a phase transition in the thermosensitive hydrogel, thereby accelerating the release of drugs from the drug-containing nanocarrier.

2. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 1, characterized in that, The thermosensitive hydrogel material is selected from one or a mixture of two or more of hydroxypropyl methylcellulose, hyaluronic acid, or poly(N-isopropylacrylamide).

3. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 1, characterized in that, The thermosensitive nanocomposite gel layer uses a composite thermosensitive hydrogel as a matrix. The preparation process of the composite thermosensitive hydrogel is as follows: Hydroxypropyl methylcellulose is selected as the first thermosensitive hydrogel skeleton material, and N-isopropylacrylamide is selected as the second thermosensitive hydrogel skeleton material. They are crosslinked with N,N'-methylenebisacrylamide for 2.5-3.5 hours under the action of ammonium persulfate initiator. The molar ratio of the first thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (2-6):1, and the molar ratio of the second thermosensitive hydrogel skeleton material to the N,N'-methylenebisacrylamide is (0.5-3):

1. The amount of initiator is 3-5% of the total amount of the above materials. After the two crosslinking materials are mixed, a drug penetration-enhancing hydrogel matrix suitable for ultrasound delivery is obtained.

4. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 1, characterized in that, The drug-containing nanocarrier is one or more of PLGA microspheres, liposomes, nanovesicles or polymer micelles loaded with active ingredients of therapeutic drugs, with a particle size of 100nm-10μm, uniformly dispersed in a thermosensitive hydrogel matrix, and a mass fraction of 5%-30%.

5. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 1, characterized in that, The flexible substrate material of the flexible ultrasonic transducer array layer is selected from one or more of polyimide, polydimethylsiloxane, or liquid crystal polymer; the piezoelectric transducer unit is one or more of PZT piezoelectric ceramic micropillars, PMN-PT single crystals, or PVDF piezoelectric films.

6. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 1, characterized in that, The flexible conformal ultrasonic patch also includes a release film coated on the lower surface of the limiting perimeter layer and the temperature-sensitive nanocomposite gel layer.

7. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in any one of claims 1-6, characterized in that, The flexible conformal ultrasonic patch also includes a fixing band, which is connected to the upper surface or edge of the flexible ultrasonic transducer array layer to fix the patch to the joint.

8. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in claim 7, characterized in that, The fixing strap is an elastic strap with hook and loop fasteners at both ends.

9. The flexible conformal ultrasonic patch for transdermal treatment of gout patients as described in any one of claims 1-6, characterized in that, The flexible conformal ultrasound patch also includes a temperature sensor and a microcontroller. The temperature sensor is disposed within the temperature-sensitive nanocomposite gel layer or on the surface of the skin contact layer for real-time monitoring of local temperature. The microcontroller is electrically connected to the temperature sensor and the flexible ultrasound transducer array layer for dynamically adjusting ultrasound output parameters based on the temperature feedback signal.

10. A control method based on the fully flexible temperature-sensitive sustained-release ultrasonic transdermal patch according to any one of claims 1-9, characterized in that, Includes the following steps: Step S1: Apply the patch to the patient's joint area, ensuring that the skin contact layer adheres tightly to the skin; Step S2: Select either the chronic maintenance mode or the acute rapid drug delivery mode according to the treatment needs; Step S3: Activate the flexible ultrasonic transducer array layer to generate ultrasonic waves, and control the local temperature rise by adjusting the ultrasonic output parameters; Step S4: Local temperature rise triggers a phase transition in the thermosensitive hydrogel, changing the gel's network structure and permeability; Step S5: The phase change effect causes a change in the drug release rate of the drug-containing nanocarrier, enabling on-demand drug delivery; Step S6: The temperature sensor monitors the local temperature in real time, and the microcontroller dynamically adjusts the ultrasound output based on the temperature feedback to ensure treatment safety.

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