Controlled-release long-acting fever cooling patch and preparation method thereof

Abstract

The invention relates to the field of medical patches, and discloses a controlled-release long-acting fever cooling patch which comprises a temperature response type material layer located on the outermost side of the fever cooling patch and used for triggering rapid release of medicine when the body temperature rises; the medicine composite layer is located on the inner side of the temperature response type material layer and used for compounding the antipyretic medicine and the traditional Chinese medicine ingredients together through a carrier, providing stable release of the medicine and enhancing the medicine effect; the invention also discloses a preparation method of the controlled-release long-acting fever cooling patch, which comprises the following steps: preparing the temperature response type material layer, dissolving the poly (N-isopropylacrylamide) or the copolymer thereof in a proper amount of solvent, coating the surface of the patch substrate with the solution, and drying to obtain the temperature response type material layer. The multi-layer composite structure is combined with the temperature and humidity response type material, so that the sustained release and long-acting antipyretic effect of the medicine are realized, the medicine release rate is automatically adjusted, the lasting and stable antipyretic effect is ensured, the medicine waste is reduced, and the convenience and comfort are improved.

Description

Technical Field

[0001] The invention relates to the field of medical patches, in particular to a controlled-release long-acting antipyretic patch and a preparation method thereof. Background Art

[0002] A fever-reducing patch is a common topical drug patch, usually used to relieve high temperature symptoms caused by fever. The principle is usually to help lower body temperature and relieve discomfort caused by high fever through a combination of physical cooling and drug release. The main function of a fever-reducing patch is to relieve high fever by regulating the surface temperature of the skin and promoting heat dissipation. However, traditional fever-reducing patches have some limitations, such as unstable drug release, short duration of antipyretic effect, inability to automatically adjust the drug release rate according to changes in body temperature, and inability to relieve other fever-related symptoms (such as headache, fatigue, etc.).

[0003] There are two main types of fever patches on the market: one is a fever patch that mainly uses physical cooling, which uses heat-absorbing materials to transfer body heat to the outside world to cool down; the other is a drug-controlled release fever patch that relies on the slow release of drugs to achieve a fever-reducing effect. These two types of fever patches each have certain advantages, but also face some shortcomings:

[0004] 1. Unstable drug release: Most of the existing controlled-release antipyretic patches use simple drug embedding technology, and the drug release rate is often not accurately adjusted, and cannot effectively respond to changes in body temperature. For example, under high temperature conditions, the drug may be released too quickly, resulting in drug waste; and when the body temperature returns to normal, the drug release rate cannot be slowed down in time, thus affecting the sustainability of the drug effect.

[0005] 2. Single drug effect: Most antipyretic patches only contain antipyretic drugs such as acetaminophen, and cannot relieve other symptoms caused by fever, such as headaches, muscle aches, etc. Moreover, traditional antipyretic drugs may develop drug resistance or side effects when used for a long time, causing the effect to gradually weaken.

[0006] 3. Limitations of patch design: Existing antipyretic patches mostly adopt a single-layer structure, and only achieve cooling effects through drug release, lacking an intelligent mechanism to adjust drug release according to changes in skin temperature and humidity. In addition, most antipyretic patches are made of non-degradable materials, which burden the environment after use.

[0007] In order to solve the above problems, the present invention provides a controlled-release long-acting antipyretic patch and a preparation method thereof. Summary of the invention

[0008] In view of the deficiencies in the prior art, the present invention provides a controlled-release long-acting cooling patch and a preparation method thereof, which solve the problems of unstable drug release, inability to automatically adjust the release rate according to changes in body temperature and humidity, and lack of multifunctional synergistic effects in the existing cooling patches.

[0009] To achieve the above objectives, the present invention is implemented through the following technical solutions: a controlled-release long-acting antipyretic patch, comprising:

[0010] The temperature-responsive material layer is located on the outermost side of the antipyretic patch and is used to trigger the rapid release of the drug when the body temperature rises;

[0011] The drug compound layer is located inside the temperature-responsive material layer and is used to compound the antipyretic drug and the Chinese medicine ingredients through a carrier to provide stable release of the drug and enhance the efficacy;

[0012] A humidity responsive material layer, which is located inside the drug composite layer and is used to sense changes in humidity on the skin surface and adjust the drug release rate according to the changes in humidity;

[0013] The biodegradable material layer is located inside the moisture responsive material layer and is used to provide a slowly degradable drug release function.

[0014] Preferably, the temperature responsive material is poly (N-isopropylacrylamide) or its copolymer, which accounts for 5%-15% of the total mass, and the drug composite layer includes acetaminophen and at least one traditional Chinese medicine ingredient, the traditional Chinese medicine ingredient includes but is not limited to honeysuckle, bupleurum and mint, which accounts for 35%-50% of the total mass.

[0015] Preferably, the humidity responsive material layer is composed of polyvinyl alcohol or sodium carboxymethyl cellulose, which accounts for 10%-20% of the total mass, and the biodegradable material layer is polylactic acid-glycolic acid copolymer, which accounts for 20%-30% of the total mass.

[0016] A method for preparing a controlled-release long-acting cooling patch is prepared using the above-mentioned controlled-release long-acting cooling patch components, comprising the following steps:

[0017] Prepare a temperature-responsive material layer, dissolve poly (N-isopropylacrylamide) or its copolymer in a suitable amount of solvent, apply it on the surface of the patch substrate, and obtain the temperature-responsive material layer after drying;

[0018] Prepare a drug composite layer, mix acetaminophen and Chinese medicinal ingredients honeysuckle, bupleurum, and mint with a drug carrier in proportion, evenly coat the mixture on the inner side of the temperature-responsive material layer, and dry it to form a film;

[0019] Prepare a humidity responsive material layer, dissolve polyvinyl alcohol or sodium carboxymethyl cellulose in water, apply it on the inner side of the drug composite layer, and dry it to form a humidity responsive material layer;

[0020] The biodegradable material layer is prepared by dissolving or melting the polylactic acid-glycolic acid copolymer and coating it on the inner side of the humidity responsive material layer, and drying to obtain the biodegradable material layer;

[0021] The layers are stacked in the above order, and subjected to hot pressing or cold pressing treatment to finally obtain a controlled-release long-acting fever-reducing patch.

[0022] Preferably, the specific steps of preparing the temperature responsive material layer are as follows:

[0023] Dissolve poly (N-isopropylacrylamide) or its copolymer, select a solvent that dissolves poly (N-isopropylacrylamide), such as water, methanol or ethanol, with a solution concentration of 5%-10% w / v, heat to 50°C-60°C to promote dissolution, stir at a speed of 300-500 rpm, and continue stirring for 30-60 minutes.

[0024] Coating the temperature-responsive material layer: Use spin coating or scraping to evenly coat the solution on the surface of the patch substrate. The thickness of the temperature-responsive material layer after coating is 10-20 μm.

[0025] Drying treatment: Place the coated substrate in an oven for drying until the temperature-responsive material layer is completely dry. During the drying process, the relative humidity is controlled at 30%-50% RH to make the film layer uniform and free of bubbles.

[0026] Preferably, the specific steps of preparing the drug composite layer are as follows:

[0027] Preparation of drug complex: the concentration of acetaminophen is 20%-40% w / w in the composite layer, the total concentration of Chinese herbal ingredients is 5%-20% w / w with the antipyretic drug, liposomes or microemulsions are selected, and if a microemulsion carrier is used, a water-oil-surfactant system is used for preparation;

[0028] Mixing and uniform dispersion: Paracetamol and Chinese medicine ingredients are uniformly mixed with liposomes or microemulsions through ultrasonic treatment, with a power of 300W-500W, a time of 5-10min, and a frequency of 20-40kHz;

[0029] Coating the drug composite layer: Use spin coating or blade coating to evenly coat the mixture on the inner side of the temperature-responsive material layer, and the thickness of the drug composite layer is 20-50 μm;

[0030] Drying treatment: Place the coated drug composite layer in an oven for drying.

[0031] Preferably, the liposome carrier is composed of phospholipids, cholesterol or their derivatives, and the ratio of the liposome carrier is 10%-15% w / w. The microemulsion carrier is a water-oil type microemulsion, comprising water, an oil phase and an emulsifier, and the ratio of the microemulsion carrier is 15%-20% w / w.

[0032] Preferably, the specific steps of preparing the humidity responsive material layer are as follows:

[0033] Dissolve polyvinyl alcohol or sodium carboxymethyl cellulose, use water as solvent, dissolve concentration is 3%-5% w / v, heat the solution to 60℃-80℃, and continue stirring for 30-60min;

[0034] Coating the humidity responsive material layer: Use spin coating or blade coating to evenly coat the polyvinyl alcohol or sodium carboxymethyl cellulose solution on the inner side of the drug composite layer, and the thickness of the humidity responsive material layer is controlled to be 10-20 μm;

[0035] Drying treatment: Drying the coated humidity responsive material layer.

[0036] Preferably, the specific steps of preparing the biodegradable material layer are as follows:

[0037] Dissolving or melting polylactic acid-glycolic acid copolymer: using dichloromethane or chloroform as a solvent, or directly heating polylactic acid-glycolic acid copolymer by hot melt method, the dissolving concentration is 5%-15% w / v, and the melting temperature is 150°C-180°C;

[0038] Coating the biodegradable material layer: using a spin coating method or a blade coating method, the polylactic acid-glycolic acid copolymer solution or melt is evenly coated on the inner side of the humidity responsive material layer, and the thickness of the biodegradable material layer is 20-50 μm;

[0039] Drying treatment: The coated biodegradable material layer is placed in an oven for drying.

[0040] Preferably, in the coating step, the spin coating speed can be controlled at 500-1000 rpm, the scraper speed of the scraper coating method is 5-10 cm / s, and in the drying step, the drying temperature is 50° C.-60° C. and the drying time is 30-60 min.

[0041] The present invention provides a controlled-release long-acting antipyretic patch and a preparation method thereof, which has the following beneficial effects:

[0042] 1. The present invention realizes the sustained release of drugs and long-lasting antipyretic effect by combining temperature-responsive materials, humidity-responsive materials and biodegradable materials through multi-layer composite structure design. In particular, the addition of the humidity-responsive material layer can adjust the release rate of the drug according to the change of skin surface humidity while maintaining the sustained release of the drug, thereby prolonging the antipyretic effect time. Compared with traditional antipyretic patches, the present invention can continuously maintain body temperature at a lower level, achieve a longer antipyretic effect, reduce the need for users to frequently change patches, and improve the convenience and comfort of use.

[0043] 2. The present invention introduces temperature-responsive materials and humidity-responsive materials so that drug release can be automatically adjusted according to changes in body temperature and skin surface humidity. The temperature-responsive material triggers rapid drug release when body temperature rises, while the humidity-responsive material adjusts the drug release rate according to changes in skin surface humidity. The advantage of this design is that drug release not only meets physiological needs but can also be precisely regulated according to actual conditions, thus avoiding the situation of excessive or insufficient drug in traditional fever-reducing patches and ensuring the stability of drug efficacy.

[0044] 3. The controlled-release antipyretic patch of the present invention combines a dual response mechanism of temperature and humidity, and can be adjusted according to different environmental conditions while optimizing drug release. The temperature-responsive material layer quickly releases the drug when the body temperature is too high, ensuring that the drug can take effect quickly at high temperatures; the humidity-responsive material adjusts the release rate according to changes in skin humidity, further extending the effective release time of the drug, ensuring that the drug can continue to and stably play an antipyretic role during long-term use. This multiple response mechanism not only improves the utilization rate of the drug, but also reduces drug waste, ensuring a more lasting antipyretic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The present invention is a flow chart of the preparation method. DETAILED DESCRIPTION

[0046] The following will be combined with the drawings in the specification of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0047] Please see attached Figure 1 The embodiment of the present invention provides a controlled-release long-acting antipyretic patch, comprising:

[0048] The temperature-responsive material layer is located on the outermost side of the antipyretic patch and is used to trigger the rapid release of the drug when the body temperature rises;

[0049] The drug compound layer is located inside the temperature-responsive material layer and is used to compound the antipyretic drug and the Chinese medicine ingredients through a carrier to provide stable release of the drug and enhance the efficacy;

[0050] A humidity responsive material layer, which is located inside the drug composite layer and is used to sense changes in humidity on the skin surface and adjust the drug release rate according to the changes in humidity;

[0051] The biodegradable material layer is located inside the moisture responsive material layer and is used to provide a slowly degradable drug release function.

[0052] The temperature responsive material is poly (N-isopropylacrylamide) or its copolymer, which accounts for 5%-15% of the total mass. The drug composite layer includes acetaminophen and at least one Chinese medicinal ingredient, which includes but is not limited to honeysuckle, bupleurum and mint, which accounts for 35%-50% of the total mass.

[0053] The humidity responsive material layer is composed of polyvinyl alcohol or sodium carboxymethyl cellulose, which accounts for 10%-20% of the total mass, and the biodegradable material layer is polylactic acid-glycolic acid copolymer, which accounts for 20%-30% of the total mass.

[0054] Specifically, the temperature-responsive material layer is an important component of the controlled-release long-acting antipyretic patch of the present invention. This layer uses poly N-isopropylacrylamide or its copolymer as the main component, which plays a temperature-responsive function. Poly N-isopropylacrylamide will undergo a phase transition when the body temperature rises, causing the hydrophilicity of the material to change, thereby triggering the rapid release of the drug. This feature enables the antipyretic drug to be quickly released in the case of high fever (for example, body temperature exceeding 38.5°C), thereby achieving a timely response to the antipyretic effect.

[0055] Ratio range: The composition of the temperature-responsive material layer accounts for 5%-15% of the total mass of the controlled-release patch, wherein the concentration of poly (N-isopropylacrylamide) can be adjusted as needed to ensure that the drug release achieves maximum efficacy within the desired body temperature range.

[0056] Advantages: It can ensure that the drug can be released in time when the body temperature is too high, and as the body temperature recovers, the drug release rate is slowed down to avoid drug overdose. At the same time, it avoids the trouble of frequent replacement of traditional antipyretic patches and improves patient compliance.

[0057] The drug composite layer is one of the key layers of the present invention. It ensures that the drug is evenly distributed and stably released in the controlled-release antipyretic patch through reasonable drug combination and carrier design. The drug composite layer not only contains the commonly used antipyretic drug, acetaminophen, but also can add Chinese herbal medicine ingredients such as honeysuckle, bupleurum, mint and other Chinese herbal medicines according to demand. Through the combination of these Chinese herbal medicine ingredients, not only can the antipyretic effect be enhanced, but also the discomfort caused by high body temperature, such as headache, cough, sore throat and other symptoms can be relieved.

[0058] Ratio range: The drug components in the drug composite layer account for 35%-50% of the total mass, of which the concentration of acetaminophen is 20%-40% and the concentration of Chinese medicine components is 5%-20%. The specific ratio can be adjusted according to the needs of the patient.

[0059] Advantages: Combining modern chemical drugs with traditional Chinese medicine ingredients, enhancing drug stability and bioavailability through drug carriers (such as liposomes or microemulsions), and ensuring continuous and uniform release of drugs on the patch. The design of the drug composite layer not only improves the antipyretic effect, but also can play a synergistic role through Chinese medicine ingredients to improve other discomfort symptoms that may occur during the antipyretic process, such as analgesia and anti-inflammation.

[0060] The humidity-responsive material layer is designed to respond to changes in humidity on the skin surface. It can adjust the drug release rate according to changes in skin humidity. This layer of material regulates the rate of drug release through hydration. When the humidity on the patch surface increases, the hydrophilicity of the humidity-responsive material layer increases, thereby promoting the release of the drug; when the humidity decreases, the release rate slows down.

[0061] Ratio range: The humidity responsive material layer accounts for 10%-20% of the total mass of the controlled release antipyretic patch. Commonly used humidity responsive materials include polyvinyl alcohol and sodium carboxymethyl cellulose. These materials can effectively regulate the effect of humidity on drug release and ensure the stability of drugs in different environments.

[0062] Advantages: The humidity response mechanism further optimizes the drug release system, enabling it to adapt to changes in different skin conditions, prevent excessive or uneven release, and ensure a smooth and continuous antipyretic effect. At the same time, it can prevent excessive penetration of the drug into the skin and reduce drug waste.

[0063] The biodegradable material layer provides the controlled release antipyretic patch of the present invention with a slow degradation function. The layer is mainly composed of polylactic acid-glycolic acid copolymer, has good biodegradability, and can be slowly decomposed on the skin surface, thereby extending the sustained release time of the drug. The degradation rate of polylactic acid-glycolic acid copolymer can be controlled by adjusting its molecular weight and copolymerization ratio to ensure that the drug release matches the skin metabolism and avoid drug overdose or underdose.

[0064] Proportion range: The biodegradable material layer accounts for 20%-30% of the total mass of the controlled-release antipyretic patch. The concentration of PLGA can be adjusted as needed to ensure that the sustained release of the drug is compatible with the metabolic process of the skin.

[0065] Advantages: As a biodegradable material, polylactic acid-co-glycolic acid copolymer can not only ensure the continuous release of drugs, but also avoid environmental pollution through natural degradation after use. This layer not only increases the use cycle of the fever patch, but also reduces the adverse reactions that may be caused by excessive use.

[0066] A method for preparing a controlled-release long-acting cooling patch, characterized in that it is prepared using a controlled-release long-acting cooling patch component according to any one of claims 1 to 3, comprising the following steps:

[0067] Prepare a temperature-responsive material layer, dissolve poly (N-isopropylacrylamide) or its copolymer in a suitable amount of solvent, apply it on the surface of the patch substrate, and obtain the temperature-responsive material layer after drying;

[0068] Prepare a drug composite layer, mix acetaminophen and Chinese medicinal ingredients honeysuckle, bupleurum, and mint with a drug carrier in proportion, evenly coat the mixture on the inner side of the temperature-responsive material layer, and dry it to form a film;

[0069] Prepare a humidity responsive material layer, dissolve polyvinyl alcohol or sodium carboxymethyl cellulose in water, apply it on the inner side of the drug composite layer, and dry it to form a humidity responsive material layer;

[0070] The biodegradable material layer is prepared by dissolving or melting the polylactic acid-glycolic acid copolymer and coating it on the inner side of the humidity responsive material layer, and drying to obtain the biodegradable material layer;

[0071] The layers are stacked in the above order, and subjected to hot pressing or cold pressing treatment to finally obtain a controlled-release long-acting fever-reducing patch.

[0072] The specific steps of preparing the temperature responsive material layer are as follows:

[0073] Dissolve poly (N-isopropylacrylamide) or its copolymer, select a solvent that dissolves poly (N-isopropylacrylamide), such as water, methanol or ethanol, with a solution concentration of 5%-10% w / v, heat to 50°C-60°C to promote dissolution, stir at a speed of 300-500 rpm, and continue stirring for 30-60 minutes.

[0074] Coating the temperature-responsive material layer: Use spin coating or scraping to evenly coat the solution on the surface of the patch substrate. The thickness of the temperature-responsive material layer after coating is 10-20 μm.

[0075] Drying treatment: Place the coated substrate in an oven for drying until the temperature-responsive material layer is completely dry. During the drying process, the relative humidity is controlled at 30%-50% RH to make the film layer uniform and free of bubbles.

[0076] The specific steps for preparing the drug composite layer are as follows:

[0077] Preparation of drug complex: the concentration of acetaminophen is 20%-40% w / w in the composite layer, the total concentration of Chinese herbal ingredients is 5%-20% w / w with the antipyretic drug, liposomes or microemulsions are selected, and if a microemulsion carrier is used, a water-oil-surfactant system is used for preparation;

[0078] Mixing and uniform dispersion: Paracetamol and Chinese medicine ingredients are uniformly mixed with liposomes or microemulsions through ultrasonic treatment, with a power of 300W-500W, a time of 5-10min, and a frequency of 20-40kHz;

[0079] Coating the drug composite layer: Use spin coating or blade coating to evenly coat the mixture on the inner side of the temperature-responsive material layer, and the thickness of the drug composite layer is 20-50 μm;

[0080] Drying treatment: Place the coated drug composite layer in an oven for drying.

[0081] The liposome carrier is composed of phospholipids, cholesterol or their derivatives, and the ratio of the liposome carrier is 10%-15% w / w. The microemulsion carrier is a water-oil type microemulsion, including water, oil phase and emulsifier, and the ratio of the microemulsion carrier is 15%-20% w / w.

[0082] The specific steps for preparing the humidity responsive material layer are as follows:

[0083] Dissolve polyvinyl alcohol or sodium carboxymethyl cellulose, use water as solvent, dissolve concentration is 3%-5% w / v, heat the solution to 60℃-80℃, and continue stirring for 30-60min;

[0084] Coating the humidity responsive material layer: Use spin coating or blade coating to evenly coat the polyvinyl alcohol or sodium carboxymethyl cellulose solution on the inner side of the drug composite layer, and the thickness of the humidity responsive material layer is controlled to be 10-20 μm;

[0085] Drying treatment: Drying the coated humidity responsive material layer.

[0086] The specific steps of preparing the biodegradable material layer are as follows:

[0087] Dissolving or melting polylactic acid-glycolic acid copolymer: using dichloromethane or chloroform as a solvent, or directly heating polylactic acid-glycolic acid copolymer by hot melt method, the dissolving concentration is 5%-15% w / v, and the melting temperature is 150°C-180°C;

[0088] Coating the biodegradable material layer: using a spin coating method or a blade coating method, the polylactic acid-glycolic acid copolymer solution or melt is evenly coated on the inner side of the humidity responsive material layer, and the thickness of the biodegradable material layer is 20-50 μm;

[0089] Drying treatment: The coated biodegradable material layer is placed in an oven for drying.

[0090] In the coating step, the spin coating speed can be controlled at 500-1000 rpm, the scraper speed of the scraper coating method is 5-10 cm / s, and the drying temperature in the drying step is 50° C.-60° C., and the drying time is 30-60 min.

[0091] Embodiment 1:

[0092] Steps for preparing controlled-release long-acting antipyretic patch:

[0093] Temperature responsive material layer:

[0094] Poly (N-isopropylacrylamide) was dissolved in methanol at a concentration of 8% w / v at a dissolution temperature of 55° C. and stirred for 30 min to ensure uniform dissolution.

[0095] The temperature responsive material layer is coated on the surface of the patch substrate by spin coating, and the thickness of the temperature responsive material layer after coating is 15 μm.

[0096] Drying treatment: The drying temperature is set at 50°C, the humidity is controlled at 40% RH, and the drying time is 45 minutes to ensure that the film layer is uniform and free of bubbles.

[0097] Drug compound layer:

[0098] The concentration of acetaminophen in the drug composite layer is 30% w / w, and the concentration of the Chinese medicinal ingredients honeysuckle, bupleurum and mint is 15% w / w.

[0099] The drug carrier adopts a microemulsion (water-oil-surfactant system) with a microemulsion ratio of 18% w / w.

[0100] Ultrasonic treatment was performed at a power of 350 W, a frequency of 30 kHz, and a time of 7 min to ensure uniform mixing of the drug and the carrier.

[0101] The drug composite layer was coated on the inner side of the temperature-responsive material layer by a doctor blade coating method, and the thickness of the drug composite layer was 40 μm.

[0102] Humidity responsive material layer:

[0103] Polyvinyl alcohol (PVA) was dissolved in water, the solution concentration was 4% w / v, the dissolution temperature was 70° C., and the stirring time was 45 min.

[0104] The solution was coated on the inner side of the drug composite layer by spin coating, and the thickness of the humidity responsive material layer was 15 μm.

[0105] Drying treatment: drying temperature is 60°C, humidity control is 50% RH, and drying time is 50 minutes.

[0106] Biodegradable material layer:

[0107] Poly(lactic-co-glycolic acid) (PLGA) was dissolved in dichloromethane, and the solution concentration was 10% w / v.

[0108] The solution was coated on the inner side of the humidity responsive material layer by spin coating, and the thickness of the biodegradable material layer was 30 μm.

[0109] Drying treatment: drying temperature is 55℃ and drying time is 40min.

[0110] Summary: In Example 1, a controlled-release long-acting antipyretic patch was prepared according to the basic technical scheme, involving four main structural layers: temperature-responsive material, drug composite layer, humidity-responsive material layer, and biodegradable material layer. The material concentration, coating thickness, and process conditions of each layer were designed according to conventional methods to ensure that the functionality of each layer was achieved.

[0111] The temperature-responsive material layer uses poly (N-isopropylacrylamide), selects methanol as the solvent and is coated by spin coating. The thickness is set to 15 μm, which meets the controlled release requirements.

[0112] The ratio of the antipyretic drug acetaminophen to the traditional Chinese medicine ingredients honeysuckle, bupleurum and mint in the drug composite layer is reasonable, and the drug carrier adopts microemulsion to ensure the stability and controllable release of the drug.

[0113] The humidity responsive material layer uses polyvinyl alcohol to ensure responsiveness to humidity changes, and has a thickness of 15μm.

[0114] The biodegradable material layer is coated with polylactic acid-glycolic acid copolymer on the inner side of the humidity responsive layer with a thickness of 30 μm, which helps to achieve long-term drug release.

[0115] In summary, Example 1 provides a basic controlled-release antipyretic patch solution. This solution ensures the function and stability of different material layers by rationally selecting materials and coating processes, and has a certain drug release control capability. However, the overall effect is still biased towards traditional controlled-release patches, and there is still room for further optimization.

[0116] Embodiment 2:

[0117] On the basis of Example 1, the following aspects were adjusted to improve the controlled release effect and the performance of the material layer.

[0118] Temperature responsive material layer:

[0119] Poly (N-isopropylacrylamide) was continued to be used, but the dissolving solvent was changed from methanol to ethanol, the solution concentration was increased to 10% w / v, the dissolving temperature was increased to 60°C, and the stirring time was adjusted to 45 min to speed up the dissolution rate.

[0120] The thickness of the temperature-responsive material layer was increased to 18 μm, and the coating was carried out by a scraper coating method with a scraper speed of 6 cm / s to ensure uniform coating.

[0121] Drug compound layer:

[0122] The concentration of acetaminophen was increased to 35% w / w, and the proportion of the Chinese medicinal ingredients honeysuckle, bupleurum, and mint was adjusted to 20% w / w, thereby enhancing the concentration of the Chinese medicinal ingredients.

[0123] Microemulsion was used as the drug carrier, and the carrier ratio was increased to 20% w / w to improve the stability of the drug and its permeability on the skin.

[0124] During the ultrasonic treatment, the power was increased to 400 W, the frequency was 35 kHz, and the time was extended to 8 min to further improve the uniformity of drug dispersion.

[0125] Humidity responsive material layer:

[0126] The humidity responsive material layer is changed from polyvinyl alcohol to sodium carboxymethyl cellulose, which increases the sensitivity to humidity changes.

[0127] The concentration of sodium carboxymethyl cellulose solution was 4% w / v, the dissolution temperature was 80°C, and the stirring was performed for 45 minutes.

[0128] Using the spin coating method, the thickness of the humidity responsive material layer was increased to 18 μm, and the rotation speed during coating was 1000 rpm to ensure more uniform coating.

[0129] Biodegradable material layer:

[0130] The poly(lactic acid-co-glycolic acid) was dissolved in chloroform solvent, the solution concentration was 12% w / v, and the melting temperature was 170°C.

[0131] The coating thickness was increased to 35 μm and applied by knife coating with a knife speed of 8 cm / s.

[0132] Summary: In Example 2, multiple optimizations were made to Example 1 to further improve the controlled release effect and drug stability. The main improvements were reflected in the dissolution method of the temperature-responsive material layer, the drug concentration and carrier selection of the drug composite layer, the modification of the humidity-responsive material layer, and the coating thickness of the biodegradable material layer.

[0133] Temperature-responsive material layer: The dissolving solvent was changed from methanol to ethanol, and the dissolving concentration and thickness of the temperature-responsive material layer (18 μm) were increased, optimizing the triggering speed and release efficiency of the material. The coating was done by blade coating to ensure the uniformity of the film layer.

[0134] Drug composite layer: The concentration of acetaminophen was increased (35% w / w), and the concentration of traditional Chinese medicine ingredients was increased to 20% w / w, which enhanced the drug efficacy and comprehensive therapeutic effect. The carrier was increased from microemulsion to a higher ratio (20% w / w), further increasing the permeability of the drug on the skin.

[0135] Humidity responsive material layer: By using sodium carboxymethyl cellulose (CMC) instead of the original polyvinyl alcohol, the humidity responsive material layer is made more sensitive to changes in skin humidity, further optimizing the drug release control.

[0136] Biodegradable material layer: The coating thickness (35 μm) was increased to enhance the sustainability of drug release, and the coating process was optimized to ensure the stability and uniformity of the coating film layer.

[0137] Example 2 By increasing the drug concentration of the drug composite layer, increasing the thickness of the temperature-responsive material layer, and optimizing the composition of the humidity-responsive material (using CMC), the drug release rate and efficiency of the controlled-release antipyretic patch have been significantly improved. In particular, significant progress has been made in the permeability and long-term release of the drug. This improved solution provides more efficient drug utilization and more sophisticated control, and is particularly suitable for drugs that need to maintain stable release under different temperature and humidity conditions.

[0138] Embodiment 3:

[0139] On the basis of Example 2, the drug release efficiency is further improved by introducing a new coating process and optimizing the formulation of the drug composite layer.

[0140] Temperature responsive material layer:

[0141] Continue to use poly (N-isopropylacrylamide) and acrylic acid copolymer, select water-ethanol mixed solvent as dissolving solvent, concentration is 9% w / v, dissolving temperature is set at 62° C., stirring time is 50 min.

[0142] The spin coating method was adopted with a rotation speed of 1200 rpm, and the thickness of the temperature responsive material layer after coating was 20 μm.

[0143] Drying conditions: drying temperature is 65℃, humidity is controlled at 45%RH, drying time is 60min, ensuring the film layer is smooth and uniform.

[0144] Drug compound layer:

[0145] The concentration of acetaminophen is adjusted to 40% w / w, and the concentration of the Chinese medicinal ingredients honeysuckle, bupleurum, and mint is adjusted to 25% w / w to enhance the efficacy of the drug.

[0146] The use of a two-phase microemulsion carrier, a water-oil-water system, and a microemulsion ratio of 25% w / w further improved the drug release rate and skin permeability.

[0147] The thickness of the drug composite layer was further increased to 50 μm and ultrasonic treatment was performed with a power of 500 W, a frequency of 40 kHz, and a time of 10 min to ensure uniform dispersion of the drug.

[0148] Humidity responsive material layer:

[0149] Sodium carboxymethyl cellulose was dissolved in water at a concentration of 4% w / v, a dissolution temperature of 85°C, and a stirring time of 50 min.

[0150] Using the spin coating method, the thickness of the humidity responsive material layer was increased to 20 μm, the rotation speed during coating was 1200 rpm, the drying temperature was 70° C., the humidity was controlled at 50% RH, and the drying time was 60 min.

[0151] Biodegradable material layer:

[0152] The polylactic acid-glycolic acid copolymer was dissolved in a mixed solvent of dichloromethane and chloroform, the solution concentration was 15% w / v, and the melting temperature was 180°C.

[0153] The coating was carried out by blade coating, with a coating thickness of 45 μm, a blade speed of 10 cm / s, a drying temperature of 70° C., and a drying time of 70 min.

[0154] Summary: Example 3 further optimized the technology on the basis of Example 2, mainly focusing on further optimization of the drug complex layer, humidity responsive material layer and biodegradable material layer. By adjusting the carrier system, improving the dispersibility of the drug complex, increasing the sensitivity of the humidity responsive material layer, etc., the controlled release effect and duration of the drug effect of the antipyretic patch were further improved.

[0155] Temperature-responsive material layer: Poly (N-isopropylacrylamide) (PNIPAM) was used again and compounded with acrylic copolymer, the dissolving solvent (water-ethanol mixed solvent) was optimized, and the dissolving concentration and coating thickness were further increased to 20μm. The coating process accelerated the uniform coating of the material by increasing the rotation speed (1200rpm).

[0156] Drug compound layer: The concentration of acetaminophen is increased to 40% w / w, and the concentration of Chinese medicine ingredients is increased to 25% w / w, thereby enhancing the compounding effect of the drugs. The use of a two-phase microemulsion carrier (water-oil-water) greatly enhances the permeability and stability of the drugs.

[0157] Humidity responsive material layer: Sodium carboxymethyl cellulose (CMC) was continued to be used, and the dissolution concentration and coating process were further optimized. The thickness of the humidity responsive material layer after coating was 20 μm, and a higher rotation speed (1200 rpm) was used for coating, which improved the consistency and functionality of the layers.

[0158] Biodegradable material layer: An improved PLGA formula is used, and the coating thickness is increased to 45μm. Precise coating by blade coating ensures the uniformity and stability of the film layer and improves the sustained release of drugs.

[0159] Example 3, based on the previous two examples, further improves the controlled release performance and drug penetration effect of the antipyretic patch by using a two-phase microemulsion carrier, optimizing the concentration of the drug composite layer and the sensitivity of the humidity response layer. In particular, the performance under high temperature and high humidity conditions is more superior, the drug release is more stable, and it can adapt to different environmental conditions. Through these optimizations, the controlled release effect and duration of the drug have been significantly improved, further enhancing the practicality and efficacy of the product.

[0160] Summary:

[0161] Example 1: A basic controlled-release antipyretic patch solution is provided to ensure that the drug can be released on demand and has certain temperature and humidity response performance. Although it has a basic drug release effect, there is still room for further improvement, especially in terms of drug concentration and drug efficacy persistence.

[0162] Example 2: By increasing the drug concentration of the drug composite layer, improving the humidity-responsive material layer (changing polyvinyl alcohol to sodium carboxymethyl cellulose) and other technical measures, the controlled release effect and drug stability are further optimized, and the persistence of drug efficacy and long-acting release ability are enhanced.

[0163] Example 3: Based on Example 2, by using a two-phase microemulsion carrier and further optimizing the thickness and composition of each layer, the controlled release efficiency and drug permeability of the cooling patch are significantly improved, so that the cooling effect can be maintained for a long time in various environments, especially under high temperature and high humidity conditions.

[0164] Experiment 1: Drug release rate and permeability experiment

[0165] Purpose:

[0166] The advantages of the controlled-release long-acting antipyretic patch of the present invention in terms of drug release rate and permeability are verified to ensure that it can continuously and stably release drugs over a long period of time and that the drugs can effectively penetrate into the deep layers of the skin.

[0167] Experimental group settings:

[0168] Control group 1: traditional antipyretic patch (rapid drug release);

[0169] Control group 2: Existing controlled-release antipyretic patch on the market (single controlled-release mechanism);

[0170] Experimental group: the controlled-release long-acting antipyretic patch of the present invention (multi-layer controlled-release mechanism, combined with temperature and humidity responsive layers).

[0171] Experimental steps:

[0172] Preparation of artificial skin model:

[0173] Pig skin or synthetic skin (such as collagen basement membrane) is used to simulate human skin.

[0174] The artificial skin was moistened with saline and spread flat on the laboratory bench.

[0175] Patch adhesion and heating:

[0176] Three types of cooling patches (a traditional cooling patch, an existing controlled-release cooling patch, and a controlled-release long-acting cooling patch of the present invention) were pasted on the surface of the artificial skin.

[0177] A constant temperature water bath was used to maintain the skin surface temperature at 37°C to simulate the normal body temperature of the human body and keep the skin moist.

[0178] Drug release experiment:

[0179] Using the dialysis bag method: place the artificial skin with the antipyretic patch into the dialysis bag, seal the bag mouth and immerse it in PBS buffer to simulate the body fluid environment.

[0180] At different time points (1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours), the drug concentration in the solution was determined using HPLC.

[0181] The drug release amounts at different time points were recorded to draw the drug release curve.

[0182] Drug Permeation Analysis:

[0183] After the experiment, the skin was removed and the skin samples were cut using the frozen section technique to observe the penetration depth of the drug in the skin in layers.

[0184] HPLC was used to measure drug concentrations at different layers of the skin (epidermis, dermis) to determine whether the drug had penetrated deep into the skin.

[0185] Table 1:

[0186]

[0187] Summary and analysis of experimental results:

[0188] Traditional antipyretic patch: The drug is released rapidly in a short period of time, with the highest drug concentration within 1 hour, and then the release rate drops sharply, causing the drug to become ineffective and unable to maintain a lasting antipyretic effect.

[0189] Existing controlled-release antipyretic patches: drug release is relatively stable, but the drug concentration still tends to be saturated after 24 hours, and it cannot continuously provide an effective amount of drug, lacking a longer-term release effect.

[0190] The controlled-release antipyretic patch of the present invention has a stable drug release rate and can still maintain a certain drug concentration after 24 hours. The drug penetration depth can effectively penetrate the skin surface and distribute in the dermis, proving that it has a strong sustained release ability and a longer period of drug efficacy maintenance.

[0191] Experiment 2: Experiment on the persistence of antipyretic effect

[0192] Purpose:

[0193] By testing the effects of different cooling patches in a simulated high fever environment, the significant advantages of the controlled-release long-acting cooling patch of the present invention in terms of sustained cooling effect were verified.

[0194] Experimental group settings:

[0195] Control group 1: traditional antipyretic patch (rapid release of drugs, short-term antipyretic effect);

[0196] Control group 2: Existing controlled-release antipyretic patches on the market (relatively simple release mechanism, relatively stable effect, but not long-lasting);

[0197] Experimental group 1: the controlled-release long-acting antipyretic patch of the present invention (combining the dual response mechanism of temperature and humidity to continuously release the drug);

[0198] Experimental Group 2: The controlled-release long-acting cooling patch of the present invention, with the humidity-responsive material layer removed (only having the temperature-responsive controlled-release function).

[0199] Experimental steps:

[0200] Animal experiment preparation:

[0201] Healthy adult rabbits were used and 6 rabbits were selected per group to ensure that the animals were balanced in size and health status.

[0202] The rabbits were heated to 39.5°C in a hot water bath to maintain a constant hyperthermic state.

[0203] Cooling patch paste:

[0204] For each group of rabbits, different antipyretic patches were applied at the same time point (control group 1, control group 2, experimental group 1, experimental group 2).

[0205] Monitor each rabbit's body temperature.

[0206] Temperature monitoring:

[0207] The core body temperature of the animals was measured every 1 hour using either an implantable temperature sensor (implanted under the rabbit's skin) or an infrared thermal imaging camera.

[0208] Record body temperature changes every 12 hours and monitor body temperature stability.

[0209] Evaluation of the persistence of antipyretic effect:

[0210] The time from when the rabbit's body temperature reached 39.5°C to when it began to cool down, and the time required for its body temperature to drop from 39.5°C to 37.5°C were recorded.

[0211] Observe and record the body temperature recovery of the animals at different time points (24 hours, 48 ​​hours, and 72 hours).

[0212] Observations during the experiment:

[0213] Observe whether the rabbits in the experimental and control groups have abnormal reactions such as decreased appetite and mental depression to ensure the safety of the experiment.

[0214] Table 2:

[0215]

[0216]

[0217] Summary and analysis of experimental results:

[0218] Traditional cooling patch: Although the cooling effect is more obvious in the early stage, the body temperature returns to normal levels after 24 hours, and the cooling effect cannot be maintained continuously.

[0219] Controlled-release cooling patches on the market: They have a longer duration of action than traditional cooling patches, but the cooling effect still weakens after 48 hours, and the body temperature gradually rises to near normal temperature.

[0220] The controlled-release antipyretic patch of the present invention has an obvious and sustained antipyretic effect, and the body temperature is stably maintained below 37.5°C. The body temperature remains stable within 72 hours, showing an excellent long-term antipyretic effect.

[0221] The antipyretic patch of the present invention without the humidity responsive material layer: after removing the humidity responsive material layer, the antipyretic effect is still strong, but compared with the complete multi-layer controlled release structure, the antipyretic duration is slightly shorter.

[0222] Summary and analysis: Through the 48-hour to 72-hour antipyretic continuity test, the controlled-release antipyretic patch of the present invention shows obvious advantages in long-lasting antipyretic effect, especially the addition of the humidity-responsive material layer can further prolong the drug release effect and provide a more lasting antipyretic effect.

[0223] Experiment 3: Skin irritation and biocompatibility test

[0224] Purpose:

[0225] The skin irritation and biocompatibility of the controlled-release long-acting antipyretic patch of the present invention were further verified to ensure that its long-term use has no adverse effects on the skin and meets biosafety standards.

[0226] Experimental group settings:

[0227] Control group 1: traditional antipyretic patch (containing strong chemical ingredients and adhesives);

[0228] Control group 2: Existing controlled-release antipyretic patch on the market (traditional controlled-release mechanism, poor drug stability);

[0229] Experimental group 1: the controlled-release long-acting antipyretic patch of the present invention (combining the dual response mechanism of temperature and humidity, with strong biocompatibility);

[0230] Experimental group 2: The controlled-release long-acting cooling patch of the present invention (the humidity-responsive material layer is removed, and the patch still has the temperature-responsive controlled-release effect).

[0231] Experimental steps:

[0232] Animal model preparation:

[0233] Healthy adult rabbits or guinea pigs (select 6 for each group) were used and divided into four groups, with different antipyretic patches applied to each group.

[0234] The cooling patch is pasted on the animal's back skin through the skin test method (i.e. patch method). At the beginning of the experiment, the skin should be free of damage.

[0235] Skin irritation assessment:

[0236] Every 12 hours after the start of the experiment, check the skin surface for redness, edema, inflammation, peeling, skin ulcers, etc.

[0237] Use an optical microscope (or electron microscope) to analyze the skin layer and observe changes on the skin surface.

[0238] Skin changes were recorded every 24 hours and continued to be observed for up to 72 hours.

[0239] Biocompatibility testing:

[0240] Skin histological analysis was performed on animals in different groups. After removing the antipyretic patch, HE staining was used to observe the structural integrity of the skin, whether there was foreign body reaction, inflammatory reaction, etc.

[0241] Observe the health status of skin cells 72 hours after using the cooling patch.

[0242] Data collection and analysis:

[0243] The skin reactions of each group of experiments were scored using a skin irritation scoring system (0-3 points: 0 for no irritation and 3 for severe irritation).

[0244] Histological section analysis is used to evaluate the repair of skin cells and the integrity of tissue structure.

[0245] Table 3:

[0246]

[0247] Summary and analysis of experimental results:

[0248] Traditional antipyretic patch: After 72 hours of experiment, the skin showed redness and edema, the allergic reaction was obvious, and histological sections showed slight ulcers and epidermal damage.

[0249] Controlled-release antipyretic patches on the market: slight skin redness and edema, fewer allergic reactions, but slight epidermal damage was observed under a microscope.

[0250] The controlled-release antipyretic patch of the present invention: after 72 hours of use, there is no redness or swelling on the skin, no allergic reaction, and histological sections show that the skin cells are healthy and undamaged, indicating that the patch has good biocompatibility.

[0251] The antipyretic patch of the present invention without the humidity responsive material layer has the same antipyretic effect as the complete controlled-release patch, but has the same biocompatibility and irritation to the skin without any adverse reactions.

[0252] Summary and analysis: By comparing the skin irritation and biocompatibility of the experimental group and the control group, the controlled-release antipyretic patch of the present invention performed outstandingly in terms of biosafety and skin compatibility, significantly reduced skin irritation, and no abnormal reactions were observed after long-term use.

[0253] Comprehensive experimental summary:

[0254] Through experimental verification in multiple dimensions, the controlled-release long-acting antipyretic patch of the present invention has shown obvious advantages in terms of drug release, antipyretic effect, skin irritation and biocompatibility:

[0255] Drug release: The present invention can provide continuous and stable drug release, and the drug can effectively penetrate into the deep layer of the skin, ensuring a long-term antipyretic effect.

[0256] Antipyretic effect: The antipyretic effect of the product of the present invention can last for 48 hours, which is significantly better than traditional antipyretic patches and controlled-release antipyretic patches on the market.

[0257] Skin irritation: The controlled-release cooling patch of the present invention has low irritation to the skin, completely avoiding the allergy and damage problems that may be caused by traditional cooling patches, and showing excellent biocompatibility.

[0258] Through the above experimental data and analysis, the present invention significantly improves the comprehensive performance of the cooling patch on the basis of the existing technology, solves the problems of traditional cooling patches and existing controlled-release cooling patches in terms of sustainability, skin irritation and safety, and has obvious technical progress and advantages.

[0259] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A controlled-release long-acting antipyretic patch, characterized in that: include: The temperature-responsive material layer is located on the outermost side of the antipyretic patch and is used to trigger the rapid release of the drug when the body temperature rises; The drug compound layer is located inside the temperature-responsive material layer and is used to compound the antipyretic drug and the Chinese medicine ingredients through a carrier to provide stable release of the drug and enhance the efficacy; A humidity responsive material layer, which is located inside the drug composite layer and is used to sense changes in humidity on the skin surface and adjust the drug release rate according to the changes in humidity; The biodegradable material layer is located inside the moisture responsive material layer and is used to provide a slowly degradable drug release function.

2. A controlled-release long-acting cooling patch according to claim 1, characterized in that: The temperature responsive material is poly (N-isopropylacrylamide) or its copolymer, which accounts for 5%-15% of the total mass. The drug composite layer includes acetaminophen and at least one Chinese medicinal ingredient, which includes but is not limited to honeysuckle, bupleurum and mint, which accounts for 35%-50% of the total mass.

3. The controlled-release long-acting cooling patch according to claim 1, characterized in that: The humidity responsive material layer is composed of polyvinyl alcohol or sodium carboxymethyl cellulose, which accounts for 10%-20% of the total mass, and the biodegradable material layer is polylactic acid-glycolic acid copolymer, which accounts for 20%-30% of the total mass.

4. A method for preparing a controlled-release long-acting antipyretic patch, characterized in that: The preparation method is prepared by using the controlled-release long-acting cooling patch component according to any one of claims 1 to 3, comprising the following steps: Prepare a temperature-responsive material layer, dissolve poly (N-isopropylacrylamide) or its copolymer in a suitable amount of solvent, apply it on the surface of the patch substrate, and obtain the temperature-responsive material layer after drying; Prepare a drug composite layer, mix acetaminophen and Chinese medicinal ingredients honeysuckle, bupleurum, and mint with a drug carrier in proportion, evenly coat the mixture on the inner side of the temperature-responsive material layer, and dry it to form a film; Prepare a humidity responsive material layer, dissolve polyvinyl alcohol or sodium carboxymethyl cellulose in water, apply it on the inner side of the drug composite layer, and dry it to form a humidity responsive material layer; The biodegradable material layer is prepared by dissolving or melting the polylactic acid-glycolic acid copolymer and coating it on the inner side of the humidity responsive material layer, and drying it to obtain the biodegradable material layer; The layers are stacked in the above order, and subjected to hot pressing or cold pressing treatment to finally obtain a controlled-release long-acting fever-reducing patch.

5. The method for preparing a controlled-release long-acting cooling patch according to claim 4, characterized in that: The specific steps of preparing the temperature responsive material layer are as follows: Dissolve poly (N-isopropylacrylamide) or its copolymer, select a solvent that dissolves poly (N-isopropylacrylamide), such as water, methanol or ethanol, with a solution concentration of 5%-10% w / v, heat to 50°C-60°C to promote dissolution, stir at a speed of 300-500 rpm, and continue stirring for 30-60 minutes. Coating the temperature-responsive material layer: Use spin coating or scraping coating to evenly coat the dissolved liquid on the surface of the patch substrate. The thickness of the temperature-responsive material layer after coating is 10-20 μm. Drying treatment: Place the coated substrate in an oven for drying until the temperature-responsive material layer is completely dry. During the drying process, the relative humidity is controlled at 30%-50% RH to make the film layer uniform and free of bubbles.

6. The method for preparing a controlled-release long-acting cooling patch according to claim 4, characterized in that: The specific steps of preparing the drug composite layer are as follows: Preparation of drug complex: the concentration of acetaminophen is 20%-40% w / w in the composite layer, the total concentration of Chinese herbal ingredients is 5%-20% w / w with the antipyretic drug, liposomes or microemulsions are selected, and if a microemulsion carrier is used, a water-oil-surfactant system is used for preparation; Mixing and uniform dispersion: Paracetamol and Chinese medicine ingredients are uniformly mixed with liposomes or microemulsions through ultrasonic treatment, with a power of 300W-500W, a time of 5-10min, and a frequency of 20-40kHz; Coating the drug composite layer: Use spin coating or blade coating to evenly coat the mixture on the inner side of the temperature-responsive material layer, and the thickness of the drug composite layer is 20-50 μm; Drying treatment: Place the coated drug composite layer in an oven for drying.

7. The method for preparing a controlled-release long-acting cooling patch according to claim 6, characterized in that: The liposome carrier is composed of phospholipids, cholesterol or their derivatives, and the ratio of the liposome carrier is 10%-15% w / w. The microemulsion carrier is a water-oil type microemulsion, comprising water, oil phase and emulsifier, and the ratio of the microemulsion carrier is 15%-20% w / w.

8. The method for preparing a controlled-release long-acting cooling patch according to claim 4, characterized in that: The specific steps of preparing the humidity responsive material layer are as follows: Dissolve polyvinyl alcohol or sodium carboxymethyl cellulose, use water as solvent, dissolve concentration is 3%-5% w / v, heat the solution to 60℃-80℃, and continue stirring for 30-60min; Coating the humidity responsive material layer: Use spin coating or blade coating to evenly coat the polyvinyl alcohol or sodium carboxymethyl cellulose solution on the inner side of the drug composite layer, and the thickness of the humidity responsive material layer is controlled to be 10-20 μm; Drying treatment: Drying the coated humidity responsive material layer.

9. The method for preparing a controlled-release long-acting cooling patch according to claim 4, characterized in that: The specific steps of preparing the biodegradable material layer are as follows: Dissolving or melting polylactic acid-glycolic acid copolymer: using dichloromethane or chloroform as a solvent, or directly heating polylactic acid-glycolic acid copolymer by hot melt method, the dissolving concentration is 5%-15% w / v, and the melting temperature is 150°C-180°C; Coating the biodegradable material layer: using a spin coating method or a blade coating method, the polylactic acid-glycolic acid copolymer solution or melt is evenly coated on the inner side of the humidity responsive material layer, and the thickness of the biodegradable material layer is 20-50 μm; Drying treatment: The coated biodegradable material layer is placed in an oven for drying.

10. The method for preparing a controlled-release long-acting cooling patch according to claim 4, characterized in that: In the coating step, the spin coating speed can be controlled at 500-1000 rpm, the scraper speed of the scraper coating method is 5-10 cm / s, and the drying temperature in the drying step is 50° C.-60° C., and the drying time is 30-60 min.

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