Anesthesia gel patch for radial artery puncture and application

Abstract

The application provides a radial artery puncture anesthetic gel patch and application, and relates to the technical field of clinical medicine. The anesthetic gel patch comprises, from top to bottom, a backing layer, a storage and indication layer and a skin contact layer; wherein the storage and indication layer contains a local anesthetic compound, a storage library and temperature-sensitive color-changing microcapsules; the skin contact layer is a soluble drug-loaded microneedle array, and the soluble drug-loaded microneedle array is loaded with lidocaine hydrochloride. The anesthetic gel patch realizes the integration of the dual functions of anesthesia and artery positioning, solves the clinical pain points of slow onset and long-time coverage of traditional surface anesthetic creams; at the same time, the radial artery position is visually and accurately indicated, helping the operator to accurately determine the puncture point, reducing the dependence on palpation experience, and being especially suitable for special patient groups with weakened arterial pulsation.

Description

Technical Field

[0001] This invention relates to the field of clinical medical technology, and in particular to an anesthetic gel patch for radial artery puncture and its application. Background Technology

[0002] Radial artery puncture is a common clinical diagnostic and therapeutic procedure, widely used in arterial blood gas analysis, invasive blood pressure monitoring, and interventional treatments. Because the radial artery is superficial and richly supplied with nerve endings, patients often experience significant pain during the puncture, sometimes even leading to limb movement due to pain, increasing the risk of puncture failure and, in severe cases, causing complications such as vasospasm and hematoma. Therefore, adequate local anesthesia before puncture is crucial for improving the success rate and patient comfort.

[0003] Currently, the commonly used anesthesia methods for radial artery puncture in clinical practice mainly include topical anesthesia and injection anesthesia. Topical anesthesia often uses lidocaine cream or patches, which achieve an anesthetic effect through skin absorption. However, its onset time is relatively long, usually requiring more than 60 minutes of application to achieve the ideal depth of anesthesia. Furthermore, the drug's penetration efficiency across the stratum corneum barrier is limited, making it difficult to meet the needs of emergency or rapid diagnostic and treatment scenarios. Injection anesthesia, while having a rapid onset, is itself an invasive procedure, increasing patient discomfort and psychological burden. Additionally, the injection process may cause local tissue swelling, which can interfere with artery palpation and localization.

[0004] Besides the effectiveness of anesthesia, accurate localization of the radial artery is also crucial for successful puncture. Currently, clinical practice mainly relies on the operator's finger palpation of the radial artery pulsation to determine the puncture point. This method is highly dependent on the operator's experience, and in cases of shock, edema, or obesity, the arterial pulsation weakens, significantly increasing the difficulty of localization. Although some auxiliary localization devices have emerged, such as ultrasound guidance or Doppler flow detectors, these devices are expensive and cumbersome to operate, making them difficult to widely apply as routine puncture aids. In summary, existing anesthetic products for radial artery puncture have technical drawbacks such as slow onset of action, inability to accurately locate the puncture site, and inconvenience of use. There is an urgent need to develop a new product that combines rapid anesthesia with arterial visualization to meet the dual demands of efficiency and accuracy in clinical procedures.

[0005] Therefore, this invention is proposed. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides an anesthetic gel patch for radial artery puncture and its application. This anesthetic patch integrates anesthesia and positioning functions, is easy and quick to operate, reduces patients' anxiety and psychological burden, and improves the efficiency and success rate of clinical procedures.

[0007] In order to achieve the objective of this invention, the following technical solution is adopted: This invention provides an anesthetic gel patch for radial artery puncture, comprising, from top to bottom, a backing layer, a storage and indicator layer, and a skin contact layer; The storage and indicator layer contains a local anesthetic complex, a storage tank, and thermosensitive color-changing microcapsules; The skin contact layer is a soluble drug-loaded microneedle array, which is loaded with lidocaine hydrochloride.

[0008] Furthermore, the local anesthetic complex, by weight percentage, comprises the following raw materials: Lidocaine hydrochloride 40%–60%; Tetracaine free base 20%–40%; Laurozone 5%–15%; Vitamin E succinate 0.5%–2%.

[0009] Furthermore, the local anesthetic complex, by weight percentage, comprises the following raw materials: Lidocaine hydrochloride 49.5%, tetracaine free base 39.5%, lauryl acetonide 10%, vitamin E succinate 1%.

[0010] Furthermore, the thermosensitive color-changing microcapsule is composed of a core material and a wall material in a mass ratio of (2:1) to (1:2).

[0011] Furthermore, the thermosensitive color-changing microcapsule is composed of a core material and a wall material in a mass ratio of 1:1.

[0012] Furthermore, the core material, by weight percentage, is composed of the following raw materials: Cholesterol nonanoate 60%–70%; Cholesterol oleyl carbonate 30%–40%; The wall material, by weight percentage, is composed of the following raw materials: A 3% (w / w) aqueous solution of gelatin; A 3% (w / w) aqueous solution of gum arabic.

[0013] Furthermore, the core material, by weight percentage, is composed of the following raw materials: Cholesterol nonanoate 65%, cholesterol oleyl carbonate 35%; Furthermore, the gelatin aqueous solution and the gum arabic aqueous solution in the wall material are mixed at a volume ratio of 1:1.

[0014] Furthermore, the storage facility is composed of the following raw materials, by weight percentage: Sodium polyacrylate 1%–3%; Polyvinylpyrrolidone K90 2%–5%; Glycerin 10%–20%; Deionized water 60%–87%.

[0015] Furthermore, the storage facility is composed of the following raw materials, by weight percentage: Sodium polyacrylate 2%, polyvinylpyrrolidone K90 3%, glycerin 15%, deionized water 65%.

[0016] Furthermore, based on the percentage by weight of the skin contact layer, it is composed of the following raw materials: Sodium hyaluronate 10%–20%; Polyvinylpyrrolidone K30 10%~20%; Lidocaine hydrochloride 5%–15%; Trehalose 2%–5%; Deionized water 40%–73%.

[0017] Furthermore, based on the percentage by weight of the skin contact layer, it is composed of the following raw materials: Sodium hyaluronate 15%, polyvinylpyrrolidone K30 15%, lidocaine hydrochloride 10%, trehalose 3%, deionized water 57%.

[0018] Furthermore, the particle size of the thermosensitive color-changing microcapsules is 10μm to 30μm.

[0019] Furthermore, the particle size of the thermosensitive color-changing microcapsules is 20 μm.

[0020] Furthermore, the molecular weight of the sodium hyaluronate is 10kDa to 50kDa.

[0021] Furthermore, the molecular weight of the sodium hyaluronate is 10 kDa.

[0022] The present invention also provides the application of the above-mentioned anesthetic gel patch for radial artery puncture in medical anesthesia products.

[0023] The present invention also provides a method for preparing the above-mentioned anesthetic gel patch for radial artery puncture, comprising the following steps: S1. Add lidocaine hydrochloride and tetracaine free base to anhydrous ethanol and stir until clear. Then add laurocapram and vitamin E succinate, stir thoroughly, then evaporate under reduced pressure to remove ethanol, dry, grind, and obtain local anesthetic complex powder. S2. Prepare a 3% gelatin aqueous solution and dissolve it in a 60°C water bath. Prepare a 3% gum arabic aqueous solution and dissolve it in a 60°C water bath. Mix the gelatin aqueous solution and gum arabic aqueous solution at a volume ratio of 1:1, adjust the pH, and keep warm. Take the core material according to the formula, mix the core material and wall material under the stirring of a high-speed shear emulsifier, emulsify for 5 to 10 minutes, stir, slowly add 10% acetic acid solution, adjust the pH value of the system to 4.0 to 4.2, stir until uniform, add 2 to 3 times the volume of deionized water at a temperature of 5℃ to 10℃ to lower the temperature of the system to below 10℃; Subsequently, a 25% glutaraldehyde solution was added to the system, with the amount added being 0.5% to 1% of the gelatin mass. The mixture was stirred for 1 to 2 hours, then allowed to stand. The supernatant was discarded, and the microcapsules were repeatedly washed with cold water, filtered, and frozen to obtain thermosensitive color-changing microcapsule powder. S3. Dissolve trehalose in water, add sodium hyaluronate to swell overnight, and finally add lidocaine hydrochloride and polyvinylpyrrolidone K30 to dissolve, stir evenly, centrifuge to remove bubbles, and then place in a needle tip mold to solidify and shape. S4. Mix glycerol and purified water and heat to 50°C. While stirring, add sodium polyacrylate and polyvinylpyrrolidone K90 to form a uniform and transparent gel matrix, and then cool to 30°C. S5. Add the local anesthetic complex powder to the transparent gel matrix, then add the thermosensitive color-changing microcapsule powder, stir at a low speed of 200 rpm to degas, and obtain the composite gel. S6. Pour the composite gel into the mold formed in step S3, then cover the surface of the composite gel with a backing film, ensure it adheres tightly, remove air bubbles, dry, peel it off from the mold, and cut it to the required size.

[0024] The present invention has the following technical effects: The anesthetic gel patch for radial artery puncture provided by this invention achieves integrated anesthesia and arterial localization through innovative structural design and material combination. The patch uses a soluble drug-loaded microneedle array as the skin contact layer, with lidocaine hydrochloride loaded at the microneedle tips. This allows for rapid puncture of the stratum corneum, precisely delivering the anesthetic drug to the dermis, significantly shortening the onset time of anesthesia. Ideal epidermal anesthesia can be achieved within 1-3 minutes after application, effectively relieving puncture pain and addressing the clinical pain points of traditional topical anesthetics, such as slow onset and the need for prolonged application.

[0025] Meanwhile, thermosensitive color-changing microcapsules are introduced into the storage and indicator layer. These microcapsules use cholesterol ester liquid crystal materials as the core material and can undergo phase transitions within a narrow temperature range close to human body temperature to show color changes. When the patch is attached to the wrist, the blood flow temperature in the radial artery is slightly higher than that of the surrounding tissue, which causes the skin temperature in the artery's course area to rise. This allows for intuitive and accurate visualization of the radial artery's location, helping operators to accurately determine the puncture point and reducing reliance on palpation experience. This is especially suitable for special patient groups with weakened arterial pulsation.

[0026] In addition, this patch integrates anesthesia and positioning functions into a single patch. It can simultaneously perform anesthesia and arterial identification with a single application, making it simple and quick to use. This reduces patients' anxiety and psychological burden, and improves the efficiency and success rate of clinical procedures. Detailed Implementation

[0027] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0028] In a first aspect, the present invention provides an anesthetic gel patch for radial artery puncture, comprising a backing layer, a storage and indicator layer and a skin contact layer arranged sequentially from top to bottom; The storage and indicator layer contains a local anesthetic complex, a storage tank, and thermosensitive color-changing microcapsules; The skin contact layer is a soluble drug-loaded microneedle array, which is loaded with lidocaine hydrochloride.

[0029] In some embodiments, the local anesthetic complex is composed of the following ingredients, by weight percentage: Lidocaine hydrochloride 40%–60%; Tetracaine free base 20%–40%; Laurozone 5%–15%; Vitamin E succinate 0.5%–2%.

[0030] In some embodiments, the local anesthetic complex is composed of the following ingredients, by weight percentage: Lidocaine hydrochloride 49.5%, tetracaine free base 39.5%, lauryl acetonide 10%, vitamin E succinate 1%.

[0031] The local anesthetic complex comprises three key components: lidocaine hydrochloride, a water-soluble salt that rapidly dissociates in water, providing an initial, rapid anesthetic effect; tetracaine, a highly lipid-soluble base that easily penetrates biological membranes but has poor water solubility and slow release, providing long-lasting anesthesia; and lauryl azeladenone, whose long alkyl chain and polar head group in its molecular structure act as "molecular bridges," forming complex structures with lidocaine hydrochloride and tetracaine. Vitamin E succinate is used to prevent tetracaine oxidation and improve formulation stability.

[0032] The lidocaine hydrochloride component in the complex is highly polar. When the complex comes into contact with skin tissue fluid, lidocaine molecules competitively bind hydrogen bonds with water molecules, dissociating and dissolving first from the complex's hydrogen bond network. This ensures that within 1-3 minutes of application, a sufficient amount of anesthetic enters the subcutaneous tissue through the microneedle channel, rapidly blocking sodium ion channels in the nerves and achieving immediate, painless puncture. The tetracaine in the complex has high lipid solubility and binds more tightly to laurocapram. It slowly dissociates from the complex after lidocaine release. Due to the high protein binding rate of tetracaine, it can form a "reservoir effect" in local tissues, continuously releasing and maintaining the anesthetic effect for 2-4 hours, meeting the needs of radial artery catheterization and prolonged surgeries.

[0033] Lauryl acetone in the complex is not simply an added excipient, but rather uniformly dispersed in the complex at the molecular level. When the drug in the complex begins to dissociate, the lauryl acetone molecules are released. Its long-chain alkyl structure can insert into the lipid bilayer between the cells of the stratum corneum, increasing lipid fluidity and opening hydrophilic channels. Because lauryl acetone forms hydrogen bonds with lidocaine and tetracaine during the complex preparation stage, the drug molecules are in a "pre-bound" state when they reach the skin surface. This state lowers the energy barrier for drug molecules to enter the stratum corneum, resulting in a higher transdermal rate.

[0034] By forming a hydrogen bond network, the complex locks the two drugs in a thermodynamically unstable amorphous state (high-energy state). The solubility of the drug in this state is much greater than that of the crystalline drug.

[0035] The microneedle tip is enriched with a high concentration of "rapid-acting anesthetic," while the gel layer disperses this "ternary complex." Due to the presence of the complex, the drug in the gel layer is released slowly in a bound state, preventing it from rushing into the microneedle channel and causing a burst release, nor from damaging the microneedle structure due to an excessive concentration gradient.

[0036] In some embodiments, the thermosensitive color-changing microcapsule is composed of a core material and a wall material in a mass ratio of (2:1) to (1:2).

[0037] In some embodiments, the thermosensitive color-changing microcapsule is composed of a core material and a wall material in a 1:1 mass ratio.

[0038] The core material is a thermosensitive color-changing functional component (cholesterol ester liquid crystal), and the wall material is the encapsulation wall material (gelatin-gum arabic complex) that surrounds the core material. The core-to-wall ratio directly affects the encapsulation efficiency, mechanical strength, thermal response sensitivity, and release characteristics of the microcapsules. A ratio that is too high (>2:1) may result in an excessively thin wall material, making the microcapsules prone to rupture; a ratio that is too low (<1:2) results in insufficient core material content and a weak color-changing signal. A ratio between 2:1 and 1:2 ensures the preparation of stable microcapsules under different process conditions.

[0039] By controlling the core-to-wall ratio, the microcapsules possess both excellent thermal conductivity (thin wall material allows for rapid heat transfer to the core) and sufficient mechanical strength (thick enough wall material prevents breakage during preparation and use). Within this ratio range, the microcapsules can undergo rapid, reversible phase transition color change within a narrow temperature range close to human body temperature (approximately 33°C to 37°C), with a response time within seconds, meeting the clinical need for real-time indication of arterial pulsation.

[0040] In some embodiments, the core material is composed of the following raw materials, by weight percentage: Cholesterol nonanoate 60%–70%; Cholesterol oleyl carbonate 30%–40%; The wall material, by weight percentage, is composed of the following raw materials: A 3% (w / w) aqueous solution of gelatin; A 3% (w / w) aqueous solution of gum arabic.

[0041] In some embodiments, the core material is composed of the following raw materials, by weight percentage: Cholesterol nonanoate 65%, cholesterol oleyl carbonate 35%; Furthermore, the gelatin aqueous solution and the gum arabic aqueous solution in the wall material are mixed at a volume ratio of 1:1.

[0042] Thermosensitive color-changing microcapsules are composed of a cholesterol-type liquid crystal mixture, with cholesterol nonanoate as the main component and cholesterol oleyl carbonate as the excipient, used to increase color saturation. Through precise formulation, the microcapsules undergo continuous changes in molecular helical pitch within a narrow temperature range of 34°C to 35°C, resulting in a reversible color transition from colorless to bright red. The most pronounced bright red color is observed in the range of 34.3°C to 34.7°C (the typical range of skin surface temperature rise caused by radial artery pulsation).

[0043] The advantage of this design lies in the fact that the surface temperature of the non-arterial area of ​​the forearm at rest is typically 32-34°C, lower than the discoloration initiation temperature (34°C), thus the patch remains colorless and transparent. However, the radial artery pulsation continuously delivers warmer blood (approximately 36.5-37°C) from deeper layers to the epidermis, creating a localized, continuous, and relatively stable 0.5-1.5°C "hot zone" directly above the artery. This zone can reach or exceed 34°C, triggering the microcapsule's discoloration. Simultaneously, the microcapsules exhibit rapid response to the rapid temperature fluctuations of approximately 0.1-0.3°C per second caused by the pulse, producing subtle color flashes synchronized with the heartbeat, further enhancing the specificity of arterial localization.

[0044] A gelatin-gum arabic composite coagulation system is developed using a composite coagulation method. The liquid crystal core material is emulsified and dispersed in a gelatin solution, and the pH is adjusted to 4.0–4.5. This allows the positively charged gelatin and negatively charged gum arabic to interact electrostatically, depositing on the surface of the core material droplets to form a dense capsule wall. The capsule wall exhibits good water permeability (allowing for heat conduction) and mechanical strength (preventing breakage during preparation), and also demonstrates good biocompatibility and no toxicity risk.

[0045] In some embodiments, the storage tank is composed of the following raw materials, by weight percentage: Sodium polyacrylate 1%–3%; Polyvinylpyrrolidone K90 2%–5%; Glycerin 10%–20%; Deionized water 60%–87%.

[0046] In some embodiments, the storage tank is composed of the following raw materials, by weight percentage: Sodium polyacrylate 2%, polyvinylpyrrolidone K90 3%, glycerin 15%, deionized water 65%.

[0047] The storage container serves as the gel matrix carrying the local anesthetic complex and the thermosensitive color-changing microcapsules. Sodium polyacrylate is a superabsorbent polymer that provides the gel framework and adhesion; polyvinylpyrrolidone K90 is a superfilm-forming polymer that increases the gel's cohesion and film-forming properties; glycerin is a plasticizer and humectant that prevents the gel from drying and cracking, while also providing flexibility; and deionized water is the solvent and swelling medium.

[0048] This formulation forms a uniform, transparent gel matrix with excellent spreadability, adhesion, and biocompatibility. The synergistic effect of sodium polyacrylate and polyvinylpyrrolidone K90 gives the gel moderate viscosity and cohesive strength, enabling it to firmly support microcapsules and drug complexes while allowing for complete demolding during patch removal. The moisturizing effect of glycerin ensures the gel remains soft during storage and use, preventing hardening and failure due to moisture evaporation. This gel matrix has no mechanical damaging effect on thermosensitive color-changing microcapsules and does not affect their color-changing properties.

[0049] In some embodiments, the skin contact layer is composed of the following raw materials as a percentage by weight: Sodium hyaluronate 10%–20%; Polyvinylpyrrolidone K30 10%~20%; Lidocaine hydrochloride 5%–15%; Trehalose 2%–5%; Deionized water 40%–73%.

[0050] In some embodiments, the skin contact layer is composed of the following raw materials as a percentage by weight: Sodium hyaluronate 15%, polyvinylpyrrolidone K30 15%, lidocaine hydrochloride 10%, trehalose 3%, deionized water 57%.

[0051] The skin contact layer serves as the matrix material for the soluble drug-loaded microneedle array. Sodium hyaluronate, a natural polysaccharide with excellent water solubility and biocompatibility, is the main framework material for the microneedles. Polyvinylpyrrolidone K30, a synthetic polymer, regulates the mechanical strength and dissolution rate of the microneedles. Lidocaine hydrochloride is an anesthetic drug. Trehalose, a disaccharide, acts as a stabilizer and protectant during the microneedle formation process, preventing drug inactivation during drying.

[0052] The microneedles prepared by this formulation possess sufficient mechanical strength to penetrate the stratum corneum (approximately 20–50 μm thick) while rapidly dissolving (within 1–3 minutes) upon contact with tissue fluid, releasing lidocaine hydrochloride. The molecular weight of sodium hyaluronate affects the dissolution rate and mechanical properties of the microneedles—lower molecular weights (10 kDa) dissolve quickly but have lower strength, while higher molecular weights (50 kDa) have higher strength but dissolve slowly; a balance of performance is achieved in the 10–50 kDa range. The addition of trehalose protects the activity of the protein / polysaccharide materials during microneedle formation, ensuring the stability of the microneedles during storage.

[0053] In some embodiments, the particle size of the thermosensitive color-changing microcapsules is 10 μm to 30 μm.

[0054] In some embodiments, the particle size of the thermosensitive color-changing microcapsules is 20 μm.

[0055] Microcapsule particle size affects its color-changing response speed, dispersion uniformity, and visual recognizability. If the particle size is too small (<10 μm), the color-changing signal of a single microcapsule is weak and difficult to detect with the naked eye; if the particle size is too large (>30 μm), it is prone to sedimentation in the gel, resulting in uneven dispersion and potentially affecting the patch's flexibility and skin adhesion. A particle size range of 10–30 μm is the optimal choice after comprehensively considering the above factors.

[0056] Within this particle size range, the microcapsules can be uniformly dispersed in the storage gel, resulting in a consistent overall appearance of the patch. Each microcapsule exhibits a sufficiently strong color-changing signal; the overlapping color-changing areas of multiple microcapsules form a clearly visible colored pattern, precisely outlining the course of the radial artery. Simultaneously, the microcapsules of this size do not significantly affect the patch's flexibility or skin fit, ensuring patient comfort.

[0057] In some embodiments, the molecular weight of the sodium hyaluronate is 10 kDa to 50 kDa.

[0058] In some embodiments, the molecular weight of the sodium hyaluronate is 10 kDa.

[0059] The molecular weight of sodium hyaluronate directly affects its water solubility, film-forming properties, mechanical strength, and biodegradation rate. Low molecular weight sodium hyaluronate (<10 kDa) dissolves rapidly but lacks sufficient mechanical strength, making it difficult to form sufficiently rigid microneedles; high molecular weight sodium hyaluronate (>50 kDa) has good film-forming properties and high strength, but dissolves slowly, potentially delaying drug release. The 10–50 kDa range achieves a balance between "sufficient strength for skin penetration" and "rapid dissolution for drug release."

[0060] The microneedles prepared using sodium hyaluronate within this molecular weight range have sharp tips and sufficient compressive strength, enabling them to reliably penetrate the stratum corneum without breaking. After insertion into the skin, the microneedles rapidly absorb water, swell, and dissolve in the tissue fluid, completing drug release within 1–3 minutes, perfectly matching the clinical operation time window. Simultaneously, sodium hyaluronate itself possesses excellent biocompatibility and moisturizing properties, leaving no residue and causing no irritation after the microneedles dissolve.

[0061] Secondly, the present invention also provides the application of the above-mentioned anesthetic gel patch for radial artery puncture in medical anesthesia products.

[0062] Thirdly, the present invention also provides a method for preparing the above-mentioned anesthetic gel patch for radial artery puncture, comprising the following steps: S1. Add lidocaine hydrochloride and tetracaine free base to anhydrous ethanol and stir until clear. Then add laurocapram and vitamin E succinate, stir thoroughly, then evaporate under reduced pressure to remove ethanol, dry, grind, and obtain local anesthetic complex powder. S2. Prepare a 3% gelatin aqueous solution and dissolve it in a 60°C water bath. Prepare a 3% gum arabic aqueous solution and dissolve it in a 60°C water bath. Mix the gelatin aqueous solution and gum arabic aqueous solution at a volume ratio of 1:1, adjust the pH, and keep warm. Take the core material according to the formula, mix the core material and wall material under the stirring of a high-speed shear emulsifier, emulsify for 5 to 10 minutes, stir, slowly add 10% acetic acid solution, adjust the pH value of the system to 4.0 to 4.2, stir until uniform, add 2 to 3 times the volume of deionized water at a temperature of 5℃ to 10℃ to lower the temperature of the system to below 10℃; Subsequently, a 25% glutaraldehyde solution was added to the system, with the amount added being 0.5% to 1% of the gelatin mass. The mixture was stirred for 1 to 2 hours, then allowed to stand. The supernatant was discarded, and the microcapsules were repeatedly washed with cold water, filtered, and frozen to obtain thermosensitive color-changing microcapsule powder. S3. Dissolve trehalose in water, add sodium hyaluronate to swell overnight, and finally add lidocaine hydrochloride and polyvinylpyrrolidone K30 to dissolve, stir evenly, centrifuge to remove bubbles, and then place in a needle tip mold to solidify and shape. S4. Mix glycerol and purified water and heat to 50°C. While stirring, add sodium polyacrylate and polyvinylpyrrolidone K90 to form a uniform and transparent gel matrix, and then cool to 30°C. S5. Add the local anesthetic complex powder to the transparent gel matrix, then add the thermosensitive color-changing microcapsule powder, stir at a low speed of 200 rpm to degas, and obtain the composite gel. S6. Pour the composite gel into the mold formed in step S3, then cover the surface of the composite gel with a backing film, ensure it adheres tightly, remove air bubbles, dry, peel it off from the mold, and cut it to the required size.

[0063] The following is a detailed explanation using specific embodiments: Example 1: Preparation of anesthetic gel patch 1.1 Preparation of local anesthetic complex Weigh 49.5g lidocaine hydrochloride, 39.5g tetracaine free base, 1g vitamin E succinate, 10g laurocapram, and 500mL anhydrous ethanol.

[0064] Add lidocaine hydrochloride and tetracaine free base to anhydrous ethanol, place on a magnetic stirrer, and stir at 500 rpm until completely dissolved to form a clear solution.

[0065] While stirring, lauryl acetone and vitamin E succinate were slowly added dropwise, and stirring was continued for 15 minutes to ensure thorough mixing at the molecular level. The mixture was then transferred to a rotary evaporator. The water bath temperature was set to 45°C and the vacuum degree to 0.08 MPa, and ethanol was removed by vacuum evaporation.

[0066] After the solvent is mostly removed, a viscous paste is obtained. This paste is then transferred to a vacuum drying oven and dried at 30°C for 24 hours to completely remove any residual solvent. The dried solid is then removed and gently ground in a mortar and pestle under dry conditions (humidity <20%) to obtain a local anesthetic compound powder, which is then sealed and stored for later use.

[0067] 1.2 Preparation of thermosensitive color-changing microcapsules Prepare a 3% gelatin aqueous solution and dissolve it in a water bath at 60°C. Prepare a 3% gum arabic aqueous solution and dissolve it in a water bath at 60°C. Mix the gelatin aqueous solution and gum arabic aqueous solution at a volume ratio of 1:1 until homogeneous, adjust the pH to 8, and keep the temperature at 50°C for later use.

[0068] Take 6.5g of cholesterol nonanoate and 3.5g of cholesterol oleyl carbonate, and slowly add the core material to 200mL of the above wall material mixture while stirring in a high-speed shear emulsifier (10000rpm). Emulsify for 10 minutes to form an O / W type emulsion with uniform particle size.

[0069] Transfer the emulsion to a reaction vessel and keep stirring (500 rpm). Slowly add 10% acetic acid solution to adjust the pH of the system to 4.2. Observe the system change from milky white to slightly turbid. Continue stirring and add 2 to 3 times the volume (specifically, 2 to 3 times the volume of the system) of deionized water at a temperature of 5°C to 10°C to lower the temperature of the system to below 10°C. Subsequently, a 25% glutaraldehyde solution was added to the system at a concentration of 1% of the gelatin mass. The mixture was stirred for 2 hours to further cross-link the capsule walls, thereby improving mechanical strength and impermeability. After standing, the supernatant was discarded, and the microcapsules were repeatedly washed with cold water, filtered, and frozen to obtain thermosensitive color-changing microcapsule powder.

[0070] 1.3 Preparation of microneedle tips Weigh 15g of 10kDa sodium hyaluronate, 10g of lidocaine hydrochloride, 15g of polyvinylpyrrolidone K30, 3g of trehalose, and 57g of deionized water.

[0071] Trehalose was dissolved in water, sodium hyaluronate was added to swell overnight, and finally lidocaine hydrochloride and polyvinylpyrrolidone K30 were added to dissolve and stir well. After centrifugation to remove bubbles, a needle tip spotting solution was obtained. This liquid has low viscosity, which is convenient for filling micron-sized pores.

[0072] Place the PDMS microneedle negative mold (200 μm orifice diameter, 300 μm depth) in a vacuum chamber or centrifuge adapter, drop the spotting solution onto the mold surface, and place the mold in a centrifuge. Centrifuge at 4000 rpm for 10–15 minutes. The centrifugal force forces the spotting solution to completely fill the depression at the microneedle tip.

[0073] Remove the mold and gently scrape off any excess liquid from the surface of the mold with a scraper. Place the mold in a desiccator and dry at room temperature for 1-2 hours to allow the needle tip to initially solidify. Centrifuge again at 3000 rpm for 5 minutes to ensure that the base material is tightly bonded to the solidified needle tip without any air bubbles. Place the mold in an oven and dry at 40°C for 24 hours until completely dry.

[0074] 1.4 Preparation of Gel Matrix Weigh 15g of glycerin, 65g of deionized water, 2g of sodium polyacrylate, and 3g of polyvinylpyrrolidone K90.

[0075] Mix glycerin and deionized water, heat to 50°C, and while stirring, add sodium polyacrylate and polyvinylpyrrolidone K90 and continue stirring until completely dissolved to form a uniform and transparent gel matrix. Cool down to 30°C.

[0076] 10g of local anesthetic complex powder was added to a transparent gel matrix, followed by 5g of thermosensitive color-changing microcapsule powder. The mixture was stirred at a low speed of 200rpm to remove bubbles and obtain a composite gel.

[0077] 1.5 Assembly Remove the composite gel from the mold containing the cured microneedle tip prepared in step 1.3, and cover the mold surface with a limiting frame or baffle to control the thickness of the base layer. Pour the composite gel into the limiting frame to evenly cover the tip base, centrifuge or let it stand again to allow the gel to level, then cover with a backing layer, ensure tight adhesion, remove air bubbles, dry, peel it off from the mold, and cut it to the required size.

[0078] Experiment Example 1: Experiment to Verify the Effect of Anesthesia Grouping: Experimental group: using the anesthetic gel patch of this invention; Control group: treated with conventional lidocaine cream; Blank group: No anesthetic products were used.

[0079] Experimental subjects: Healthy volunteers (age 18–60 years, BMI 18.5–24.9 kg / m²) 2 (No history of cardiovascular disease) Experimental methods: Each group was applied to the radial artery area of ​​the forearm.

[0080] The needle prick pain test (VAS score) was performed at 1, 3, 5, 10, 15 and 30 minutes, and the time to achieve effective anesthesia was recorded for each group.

[0081] Record the time required for each group to achieve effective anesthesia (VAS score ≤3).

[0082] Using a standard pain testing needle (Von Frey fiber) or a 20G sterile injection needle, insert the needle vertically into the center of the skin in the patch coverage area with constant force (bending the needle at a 30-degree angle). Perform the test three times consecutively and take the average VAS score.

[0083] The sample size for each group is n=20. The VAS score ranges from 0 to 10, where 0 represents no pain and 10 represents severe pain.

[0084] The experimental results are shown in Tables 1 and 2.

[0085] Table 1: Comparison of VAS scores at different time points for each group ( )

[0086] Note: Compared with the control group, p<0.01 (independent samples t test).

[0087] Table 2: Time (min) required to achieve effective anesthesia (VAS≤3) in each group

[0088] Note: Compared with the control group, p<0.01 (independent samples t test).

[0089] Experiment Example 2: Verification Experiment of Artery Visualization and Localization Function Experimental subjects: Healthy volunteers (15 normal, 15 obese, and 15 with low blood pressure; among them, the obese group had a BMI ≥ 28 kg / m²). 2 Low blood pressure group: systolic blood pressure <90 mmHg and / or diastolic blood pressure <60 mmHg) Experimental methods: Anesthesia gel patches were applied to the radial artery area of ​​the volunteer's wrist. The color change along the artery was observed within 30 seconds. Simultaneously, Doppler ultrasound was used to locate the radial artery, and the consistency between the discolored area and the ultrasound localization was compared. Multiple operators independently determined the puncture point, and the success rate of localization was recorded. The experimental results are shown in Tables 3 and 4.

[0090] Table 3: Comparison of the color-changing positioning effect of patches in volunteers with different physical conditions ( )

[0091] Note: Compared with the normal group, p<0.05 (independent samples t-test or chi-square test).

[0092] Table 4: Consistency Analysis of Discoloration Area and Ultrasonic Localization

[0093] Overlap rate = (overlapping area between the discolored area and the actual course of the artery / total actual course area of ​​the artery) × 100%.

[0094] Experiment Example 3: Microneedle Puncture Performance and Drug Release Experiment Experimental subject: isolated pig skin Experimental Groups: Microneedle assembly: Anesthesia gel patch (containing a soluble drug-loaded microneedle array) prepared in Example 1. Needle-free gel group: This group used a composite gel with the same formulation as in Example 1 (containing a local anesthetic complex and thermosensitive color-changing microcapsules), but without a soluble drug-loaded microneedle array. The gel layer was applied directly to the skin without microneedle insertion. This group was used to compare and verify the effect of microneedle physical penetration enhancement on the drug release rate. Control group: A commercially available traditional lidocaine cream (5% lidocaine content, w / w) was applied to the skin surface according to the product instructions, with a thickness of approximately 1 mm. This group was used to compare the drug release efficiency difference between the patch of the present invention and traditional topical anesthetic preparations.

[0095] Experimental methods: Apply the patch to the skin model and apply the same pressure (5N, for 10 seconds).

[0096] Tissue sectioning techniques were used to observe the depth of microneedle insertion and whether it broke.

[0097] The drug release rate of microneedles at 1, 3, 5, and 10 minutes was measured (lidocaine content was detected by HPLC), and the drug penetration of each group was compared. The experimental results are shown in Tables 5 and 6.

[0098] Table 5: Microneedle Puncture Performance Parameters

[0099] Table 6: Comparison of cumulative drug release rates of different groups at different time points (%) )

[0100] Note: Compared with the microneedle group. p<0.01 (independent samples t-test). The cumulative release rates of the needle-free gel group and the control group at each time point were significantly lower than those of the microneedle group, confirming that the physical permeation-enhancing effect of the microneedle array is the key to achieving rapid drug release.

[0101] The above results confirm that the microneedle array of the present invention has good mechanical properties and excellent drug delivery efficiency, and can complete the rapid release of anesthetic drugs within 1-3 minutes, meeting the needs of rapid clinical puncture.

[0102] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the technical solutions of the embodiments of the present invention.

Claims

1. An anesthetic gel patch for radial artery puncture, characterized in that, It includes, from top to bottom, a backing layer, a storage and indicator layer, and a skin contact layer; The storage and indicator layer contains a local anesthetic complex, a storage tank, and thermosensitive color-changing microcapsules; The skin contact layer is a soluble drug-loaded microneedle array, which is loaded with lidocaine hydrochloride.

2. The anesthetic gel patch for radial artery puncture according to claim 1, characterized in that, The local anesthetic complex is composed of the following raw materials, based on a mass percentage of the local anesthetic complex: Lidocaine hydrochloride 40%–60%; Tetracaine free base 20%–40%; Laurozone 5%–15%; Vitamin E succinate 0.5%–2%.

3. The anesthetic gel patch for radial artery puncture according to claim 1, characterized in that, The thermosensitive color-changing microcapsule is composed of a core material and a wall material in a mass ratio of (2:1) to (1:2).

4. The anesthetic gel patch for radial artery puncture according to claim 3, characterized in that, The core material, by weight percentage, is composed of the following raw materials: Cholesterol nonanoate 60%–70%; Cholesterol oleyl carbonate 30%–40%; The wall material is composed of gelatin and gum arabic, wherein the mass fraction of the gelatin aqueous solution is 3% and the mass fraction of the gum arabic aqueous solution is 3%, and the gelatin aqueous solution and the gum arabic aqueous solution are mixed at a volume ratio of 1:

1.

5. The anesthetic gel patch for radial artery puncture according to claim 1, characterized in that, The storage tank is composed of the following raw materials, by weight percentage: Sodium polyacrylate 1%–3%; Polyvinylpyrrolidone K90 2%–5%; Glycerin 10%–20%; Deionized water 60%–87%.

6. The anesthetic gel patch for radial artery puncture according to claim 1, characterized in that, The skin contact layer is composed of the following raw materials, by weight percentage: Sodium hyaluronate 10%–20%; Polyvinylpyrrolidone K30 10%~20%; Lidocaine hydrochloride 5%–15%; Trehalose 2%–5%; Deionized water 40%–73%.

7. The anesthetic gel patch for radial artery puncture according to claim 1, characterized in that, The temperature-sensitive color-changing microcapsules have a particle size of 10μm to 30μm.

8. The anesthetic gel patch for radial artery puncture according to claim 6, characterized in that, The molecular weight of the sodium hyaluronate is 10kDa to 50kDa.

9. The use of an anesthetic gel patch for radial artery puncture as described in any one of claims 1 to 8 in medical anesthetic products.

Images