A seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external plaster and a preparation method thereof

Abstract

This invention relates to a seaweed polysaccharide-coupled ternary narrow phase change phospholipid constant-temperature external application patch and its preparation method. It pertains to the field of medical device technology. The invention utilizes a ternary modified natural phospholipid consisting of lecithin, cholesterol, and phytosterol succinate to construct a narrow phase change lipid carrier at 39–41°C. This carrier is combined with a seaweed polysaccharide bio-thermal storage and heating system containing tetradecane phase change microcapsules and a six-layer integrated linkage architecture. This forms a closed-loop synergistic system of constant-temperature field, narrow phase change controllable release, targeted retention, and transdermal penetration through the stratum corneum. It is suitable for constant-temperature external application to muscles, joints, abdomen, and limbs, achieving long-term and stable delivery of plant extracts. This invention breaks through conventional industry improvement approaches by constructing a ternary narrow phase change membrane using lecithin-cholesterol combined with phytosterol succinate. Combined with a proprietary multi-extrusion process and a six-layer constant-temperature coupling patch, it systematically solves the defects of traditional external applications, such as disordered material release, easy extract deactivation, and localized heat accumulation that irritates the skin.

Description

Technical Field

[0001] This invention belongs to the field of Class II passive medical device technology, specifically relating to a seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch and its preparation method. Background Technology

[0002] Conventional self-heating external patches generally use iron powder, activated carbon, vermiculite mineral heating materials, which rely solely on the heat release of metal oxidation without systematic thermal field equalization constraint. The temperature fluctuation range is large, and prolonged external application can easily lead to local heat accumulation, posing a risk of low-temperature burns. At the same time, without a covered carrier structure, plant extracts are stored directly exposed, which is extremely easy to volatilize and oxidize and lose. The effective release time of the material is short, making it difficult to achieve stable localized delivery.

[0003] Ordinary external patches directly contain high-concentration plant extracts without lipid carrier isolation and protection, resulting in significant extract loss and uncontrollable release rate. Direct contact of high-concentration solutions with the skin can easily cause irritation such as redness and stinging, failing to meet the biocompatibility quality control standards for prolonged skin contact of Class II medical devices.

[0004] Existing heating composite patches on the market simply physically stack the functional layers. There is no linkage and matching mechanism between the temperature field and the release rate of extracts between the layers. They are simple assembly structures and generally suffer from the defects of rapid release of extracts in the early stage and insufficient supply in the later stage. They have not built an integrated temperature control release system with multiple layers mutually constraining and synergistically regulating each other.

[0005] While there are publicly available studies on constant-temperature heating, thermosensitive lipid carriers, and transdermal penetration technology, there is currently no complete coupling solution suitable for gentle external application to the human body at 40°C. Traditional thermosensitive lipid carriers mostly use synthetic phospholipids, which have poor biocompatibility with long-term skin contact. The industry-standard lecithin-cholesterol binary natural phospholipid system has a wide phase transition temperature range, resulting in large fluctuations in extract release. Existing literature only discloses conventional sterols such as sitosterol and stigmasterol for membrane phase temperature regulation, but does not disclose the lecithin-cholesterol-phytosterol succinate ternary modified system of this invention, which cannot stably form a medical-grade narrow phase transition range of 39–41°C. Traditional heating patches all use mineral-based exothermic systems with low thermal inertia and high temperature peaks, making it difficult to match the narrow temperature release window of lipid carriers. Furthermore, existing technologies do not disclose a combination scheme of seaweed polysaccharide biothermal storage substrate with ternary narrow phase transition lipid carriers and multilayer functional structure closed-loop coupling. The irregular diffusion of plant extracts and low material utilization efficiency are long-standing technical challenges in this field.

[0006] Phytosterol succinates are only used in small quantities in room temperature topical acid-sensitive delivery systems. Their free carboxyl groups easily complex with alkaloids and flavonoids in traditional Chinese medicine, reducing encapsulation stability. Therefore, this substance has never been used to modify phospholipid membranes in the field of self-heating traditional Chinese medicine hot compresses. At the same time, the industry's natural phospholipid liposomes all use a binary system with a single homogenization process, which cannot accurately match the human body's narrow temperature-release drug requirements at 40°C for topical application, nor is there a supporting solution with a multi-layer heat storage coupling architecture for coordinated temperature control. Summary of the Invention

[0007] To address the aforementioned technical problems, this invention provides a seaweed polysaccharide-coupled ternary narrow phase change phospholipid constant-temperature external application patch and its preparation method. This invention utilizes a 39-41℃ narrow phase change lipid carrier constructed from a ternary modified natural phospholipid consisting of lecithin, cholesterol, and phytosterol succinate. This carrier is combined with a seaweed polysaccharide bio-thermal storage and heating system containing tetradecane phase change microcapsules and a six-layer integrated linkage architecture, forming a closed-loop synergistic system of constant-temperature field, narrow phase change controllable release, targeted retention, and transdermal penetration through the stratum corneum. This system is suitable for constant-temperature external application to muscles, joints, abdomen, and limbs, achieving long-term and stable delivery of plant extracts. This invention breaks through conventional industry improvement approaches by constructing a ternary narrow phase change membrane using a 5:1 ratio of lecithin to cholesterol and phytosterol succinate, combined with a proprietary multi-extrusion process and a six-layer constant-temperature coupling patch, overcoming several inherent defects in existing technologies.

[0008] The present invention provides a seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch, wherein the external application patch is composed of, from the outside to the inside, a surface protective layer, a constant temperature heating layer, a liposome temperature change protective layer, an acupoint fixed point enrichment layer, a stratum corneum moisturizing and enhancing layer, and a bottom adhesive layer.

[0009] The surface protective layer is a breathable and waterproof non-woven fabric.

[0010] The constant temperature heating layer is composed of 25-35 parts reduced iron powder, 5-15 parts activated carbon, 6-10 parts vermiculite, 1-3 parts tetradecane phase change microcapsules and 5-15 parts seaweed polysaccharide heat storage substrate by weight.

[0011] The liposome thermochromic protective layer is equipped with a ternary modified narrow phase change lipid carrier, which is composed of lecithin, cholesterol and phytosterol succinate. The mass ratio of lecithin to cholesterol is 5:1, and the mass ratio of cholesterol to phytosterol succinate is 2~4:1. The phase change range of the liposome thermochromic protective layer is 39~41℃.

[0012] The ternary modified narrow phase change lipid carrier encapsulates the plant concentrate, which is prepared by water extraction and concentration of 8-12 parts of Ligusticum chuanxiong, 6-10 parts of Angelica sinensis, 4-8 parts of Boswellia carterii and 4-8 parts of Commiphora myrrha in parts by weight.

[0013] The acupoint enrichment layer is composed of a sterol glucose succinate diester bioaffinity guiding component; the sterol glucose succinate diester bioaffinity guiding component is composed of 2-4 parts sterol glucose succinate diester, 5-7 parts hydroxypropyl methylcellulose E5, 3-5 parts propylene glycol, 0.2-0.4 parts phenoxyethanol and 70-90 parts purified water by weight.

[0014] The stratum corneum moisturizing and enhancing layer is composed of azone and propylene glycol in a mass ratio of 1:1 to 5.

[0015] The bottom adhesive layer is a low-sensitivity medical pressure-sensitive adhesive.

[0016] The liposome thermochromic protective layer is a sandwiched porous space formed by superimposing a constant-temperature heating layer and an acupoint-specific enrichment layer. This sandwich is not pre-coated with a solid slurry. After the six-layer substrate is pressure-bonded, cured, and cut, a ternary narrow-phase-change liposome dispersion is quantitatively injected into the sandwich. The liposome dispersion is locked and positioned in this sandwich by the capillary adsorption of the pores of the two substrate layers, thus realizing the loading of the liposome carrier. During heating, the constant-temperature heating layer outputs a temperature field of 40℃±1℃, which directly acts on the ternary modified liposome carrier in the sandwich, triggering the liposome to undergo a phase change of 39~41℃, realizing the controllable release of active ingredients towards the outer acupoint-specific enrichment layer.

[0017] Furthermore, the lecithin is medical-grade liposome-grade PC70 egg yolk lecithin, and the phytosterol succinate is medical-grade low endotoxin PS-HS-99 with a purity ≥98%.

[0018] Further, the preparation of the ternary modified narrow phase change lipid carrier is as follows: lecithin, cholesterol, and phytosterol succinate are dissolved in anhydrous ethanol to obtain a homogeneous lipid solution. The organic solvent is removed by rotary evaporation to obtain a dry ternary modified lipid film composed of lecithin, cholesterol, and phytosterol succinate. After hydration treatment of the dry ternary modified lipid film to obtain a crude liposome suspension, it is cyclically extruded three times through a polycarbonate membrane to obtain a ternary narrow phase change liposome dispersion with a particle size distribution of 100–200 nm.

[0019] Furthermore, the plant concentrate is prepared as follows: Ligusticum chuanxiong, Angelica sinensis, frankincense, and myrrh are extracted by reflux twice with 8 times the amount of distilled water at 75~85℃, concentrated to a relative density of 1.10~1.15 at 60℃, and sterilized by 0.22μm filtration.

[0020] Furthermore, the sterol glucose succinate diester bioaffinity-guided component is prepared by dispersing sterol glucose succinate diester, hydroxypropyl methylcellulose E5, propylene glycol, phenoxyethanol and purified water at 44~46℃, defoaming and filtering, coating and drying to form a mold.

[0021] Furthermore, the thickness of the constant temperature heating layer is 0.3~0.4mm, the thickness of the acupoint enrichment layer is 0.1~0.2mm, and the thickness of the stratum corneum moisturizing enhancement layer is 0.06~0.10mm.

[0022] Furthermore, the adhesives used for the surface protective layer, constant temperature heating layer, liposome temperature-sensitive protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer are medical-grade environmentally friendly silicone adhesives with an interlayer peel strength ≥0.5N / 25mm.

[0023] The present invention provides a method for the thermostatic external application of seaweed polysaccharide coupled with ternary narrow phase change phospholipids, as follows:

[0024] S1. Preparation of plant concentrate: 8-12 parts by weight of Ligusticum chuanxiong, 6-10 parts by weight of Angelica sinensis, 4-8 parts by weight of Boswellia carterii and 4-8 parts by weight of Commiphora myrrha were extracted by reflux twice at 75-85℃ with 8 times the weight of distilled water, concentrated to a relative density of 1.10-1.15 at 60℃, and sterilized by 0.22μm filtration to obtain plant concentrate for later use;

[0025] S2. Preparation of ternary modified lipid film: lecithin, cholesterol and phytosterol succinate were mixed and then mixed with anhydrous ethanol. The mixture was dissolved at 55~65℃ and then rotary evaporated at 33~37℃ and 80~120r / min for 15min to remove the solvent, and a dry ternary modified lipid film was obtained.

[0026] S3. Liposome hydration, extrusion granulation and purification: The plant concentrate and pH 7.4 phosphate buffer were mixed at a volume ratio of 1:4 to prepare an aqueous hydration medium. The dried ternary modified lipid film was added for hydration. The mixture was stirred at 37°C and 200 r / min for 1 h to obtain a crude liposome suspension. The crude liposome suspension was cyclically extruded through a polycarbonate membrane three times to obtain a ternary narrow-phase change liposome dispersion with a particle size distribution of 100-200 nm. The dispersion was then centrifuged at 3000 r / min for 10 min to remove uncoated free components, resulting in a purified ternary narrow-phase change liposome dispersion.

[0027] S4. Prepare the constant temperature heating layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, surface protective layer and bottom adhesive layer independently;

[0028] The constant temperature heating layer is prepared by taking 25-35 parts of reduced iron powder, 5-15 parts of activated carbon, 6-10 parts of vermiculite, and 1-3 parts of tetradecane phase change microcapsules by mass, mixing them with 5-15 parts of seaweed polysaccharide heat storage substrate, adding water to make a uniform paste, coating the paste evenly on a 0.12mm breathable and waterproof non-woven fabric substrate, controlling the coating thickness to 0.3-0.4mm, and drying in an oven at 60℃ for 2-2.5h to obtain the constant temperature heating layer.

[0029] Preparation of acupoint enrichment layer: Take 2-4 parts by weight of sterol glucose succinate diester, 5-7 parts by weight of hydroxypropyl methylcellulose E5, 3-5 parts by weight of propylene glycol, 0.2-0.4 parts by weight of phenoxyethanol, and 70-90 parts by weight of purified water. Stir and swell to disperse the mixture at 44-46℃, degas, and filter through a 0.22μm filter to obtain a coating solution. Coat the coating solution evenly onto a nonwoven fabric substrate, dry it, and control the dry film thickness to 0.1-0.2mm to obtain the acupoint enrichment layer.

[0030] Preparation of the stratum corneum moisturizing and enhancing layer: Azone and propylene glycol are mixed and stirred evenly at a mass ratio of 1:1~5, coated on a non-woven fabric substrate, dried, and the dry film thickness is controlled at 0.06~0.10mm to obtain the stratum corneum moisturizing and enhancing layer.

[0031] The surface protective layer is made of 0.12mm breathable and waterproof non-woven fabric specifically for Class II medical devices;

[0032] Bottom adhesive layer: A low-sensitivity medical pressure-sensitive adhesive is uniformly coated on the surface of a non-woven fabric substrate to obtain the bottom adhesive layer;

[0033] S5. The surface protective layer, constant temperature heating layer, liposome thermochromic protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer are integrally composited at 23~27℃ and 0.1~0.5MPa pressure, and cured at 39~41℃ and 70~80% RH for 24 hours to form a single patch. 0.5mL of refined ternary narrow phase change liposome dispersion is quantitatively injected into the interlayer space of the liposome thermochromic protective layer of the patch, so that the dispersion is adsorbed and retained by the interlayer pores and positioned in the liposome thermochromic protective layer, without seeping into other adjacent functional layers. The patch is then sealed with aluminum foil for sterile packaging.

[0034] Further, in step S2, the ternary modified lipid film is prepared by mixing lecithin, cholesterol and phytosterol succinate, adding anhydrous ethanol, dissolving at 60°C, and then rotary evaporating at 35°C and 100 r / min for 15 min to remove the solvent, thereby obtaining a dry ternary modified lipid film.

[0035] Furthermore, the surface protective layer, constant temperature heating layer, liposome temperature-sensitive protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer described in step S5 are integrally composited at 25°C and 0.2~0.4MPa pressure, cured at 40°C and 70~80% RH for 24 hours, and then cut into single patches.

[0036] This invention is based on a proprietary ratio of lecithin-cholesterol-phytosterol succinate ternary modified phospholipids and a customized extrusion molding process, coupled with a six-layer fully parameter-coupled architecture, possessing four major technical advantages:

[0037] 1) Precise and controllable precipitation of narrow phase change materials: Based on a 5:1 phospholipid compound ratio and a dedicated granulation process, an ultra-narrow phase change lipid carrier with a temperature range of 39-41℃ is constructed; combined with a six-layer structure coupled with constant temperature constraint, a suitable temperature field of 40℃±1℃ is stably maintained, the precipitation fluctuation of plant extracts is ≤10%, there is no instantaneous large-scale release throughout the process, which greatly reduces the oxidation and volatilization loss of extracts, and the material delivery cycle is stable and long-lasting.

[0038] 2) Improved Material Retention Efficiency Through Multi-Layer Coupling: The synergistic effect of three mechanisms—ternary narrow-phase-change controlled release, diffusion limitation in the bonding area, and stratum corneum penetration adaptation—ensures a material retention rate of ≥80% in the bonding area compared to traditional simple stacked external dressings. This significantly improves overall material utilization, an effect that cannot be achieved through a single structural improvement, demonstrating unexpected technological advantages. The bottom adhesive layer uses low-sensitivity medical pressure-sensitive adhesive with moderate bonding strength, preventing long-term detachment and leaving no adhesive residue after removal. It does not pull or damage the skin, providing a stable bonding substrate for the entire six-layer coupled constant-temperature closed-loop system, complying with relevant medical biosafety regulations.

[0039] 3) Temperature control safety compliance: Relying on the overall six-layer coupling system to coordinate temperature regulation, the risk of low-temperature burns caused by local heat accumulation is avoided from the root; all raw and auxiliary materials meet the biocompatibility standards of Class II medical devices, are low in irritation and have no harmful residues, and the entire production process follows the medical device GMP specifications and meets the quality control conditions for product market access.

[0040] 4) Wide range of applicable scenarios: The ratio of plant extracts can be adjusted as needed, making it suitable for constant temperature external application to the human body. The product has a stable structure, is easy to use, and complies with the standards for external application of Class II medical devices.

[0041] This invention innovatively introduces phytosterol succinate for membrane modification, constructing a ternary composite membrane structure of lecithin-cholesterol-phytosterol succinate. This reshapes the phase transition mechanical properties of the membrane layer, overcoming the industry's technical shortcomings of the wide phase transition range of natural phospholipids, and precisely targeting a narrow phase transition range of 39–41℃ for external application. Simultaneously, it is paired with a seaweed polysaccharide biothermal storage and heating layer containing tetradecane phase transition microcapsules, relying on a six-layer overall coupling architecture to build a complete dynamic temperature matching system. Addressing the issue of free carboxyl groups in phytosterol succinate easily complexing with alkaloids and flavonoids from traditional Chinese medicine, this invention utilizes a 5:1 lecithin-cholesterol ratio and a proprietary molding process involving three cyclic extrusions. This allows phytosterol succinate to be uniformly embedded in the lipid bilayer as a ternary membrane component, effectively inhibiting the complexation of free carboxyl groups with active components, ensuring high encapsulation stability while achieving narrow phase transition modification.

[0042] Under a coupled isothermal environment of 40℃±1℃, the ternary modified lipid carrier undergoes a stable phase transition, and the membrane permeability is improved in an orderly manner, enabling the uniform and low-fluctuation precipitation of plant extracts. When the system temperature is below 39℃, the lipid carrier maintains a dense gel phase, completely sealing the internal extracts and avoiding volatilization loss. When the local temperature is above 41℃, the tetradecane phase change microcapsules rely on the latent heat of phase change to absorb heat and buffer, and the superimposed six-layer structure provides synergistic heat dissipation constraint, automatically reducing the system temperature field back to a safe range.

[0043] Compared to industry-standard binary phospholipid formulations and conventional mineral-based heating substrates, this invention integrates a ternary modified lipid carrier system, a seaweed polysaccharide biothermal phase change isothermal unit, and a six-layer closed-loop coupling architecture. This is not a simple superposition of known basic mechanisms, but rather forms a full-chain regulation mechanism of "low-temperature material locking, uniform temperature release, and high-temperature autonomous temperature stabilization." This systematically solves the defects of traditional external patches, such as disordered material release, easy extract failure, and local heat accumulation that irritates the skin. All performance indicators meet the quality control standards for Class II medical devices. Attached Figure Description

[0044] Figure 1 is a curve showing the overall temperature field stability of the external patch of the present invention; in the figure, the solid line represents the integrated sample of six-layer coupling of seaweed polysaccharide biothermal storage, and the dashed line represents the comparative sample with only tetradecane phase change microcapsule mineral-based heating layer and no six-layer coupling structure.

[0045] Figure 2 is a bar chart comparing the encapsulation efficiency of lipid carriers under four different preparation conditions; in the figure, ① this invention: ternary phospholipid compound + complete extrusion process, ② control group 1: only 5:1 binary phospholipid, no sterol succinate modification, ③ control group 2: sitosterol substitute for modified components, ④ control group 3: ternary ratio, simplified extrusion process;

[0046] Figure 3 shows the cumulative release curves of plant extracts.

[0047] Figure 4 is a bar chart comparing the utilization efficiency of materials on the body surface; in the figure, ① conventional simple stacked external application (baseline group); ② only optimized ternary lipid carrier formulation, without a matching six-layer coupling integrated structure; ③ only a six-layer composite structure, combined with ordinary binary phospholipid lipid carrier; ④ the complete system of this invention (ternary modified phospholipid lipid carrier + six-layer coupling constant temperature complete integrated structure).

[0048] Figure 5 is a comparison chart of the skin compatibility and safety test results of the external application patch of the present invention. Detailed Implementation

[0049] The materials used in the following embodiments are as follows:

[0050] Egg yolk lecithin (PC-70, liposome medical grade, CDE registered): Guangzhou Junmu Biotechnology Co., Ltd.

[0051] Cholesterol (CH-99, low endotoxin injectable excipient grade): Guangzhou Junmu Biotechnology Co., Ltd.

[0052] Phytosterol succinate monoester (PS-HS-99, liposome-specific medical grade): Jiangsu Weikaier Pharmaceutical Technology Co., Ltd.; it can also be prepared in-house using the esterification synthesis process described in the instructions.

[0053] β-Sitosterol (98% Medical Grade): Xi'an Haisifu Biotechnology Co., Ltd.

[0054] PhytoSterol-GS-SA (Bioaffinity-directed single component): Jiangsu Sibaico Biotechnology Co., Ltd.

[0055] Traditional Chinese medicinal herbs: Chuanxiong (Ligusticum striatum), Danggui (Angelica sinensis), Ruxiang (Boswellia carterii), and Moyao (Commiphora myrrha) (Class II medical device medicinal slices, impurities <0.3%): Anhui Bozhou Baiyi Pharmaceutical Co., Ltd.

[0056] 300-mesh medical-grade reduced iron powder: Hebei Huabang Metal Materials Co., Ltd.

[0057] Medicinal Coconut Shell Activated Carbon: Fujian Xinsen Carbon Industry Co., Ltd.

[0058] Ultrafine medical vermiculite: Lingshou County Runda Mineral Products Processing Plant

[0059] Tetradecane Phase Change Microcapsules PCM-40 (Phase Change 39~41℃ Urea-Formaldehyde Shell): Dongguan Shengbang Polymer Materials Co., Ltd.

[0060] Medical-grade brown algae polysaccharide AP-80 (seaweed polysaccharide heat storage substrate): Qingdao Mingyue Seaweed Group Co., Ltd.

[0061] Hydroxypropyl methylcellulose E5 HPMC-E5 Medical-grade Film-forming Agent: Shandong Heda Co., Ltd.

[0062] Pharmaceutical Azone: Hubei Jusheng Technology Co., Ltd.

[0063] USP grade propylene glycol: Yihai Kerry (Panjin) Grain and Oil Industry Co., Ltd.

[0064] pH 7.4 Phosphate Buffer Powder (Medical-grade Sterile): Qingdao Haibo Biotechnology Co., Ltd.

[0065] 3M 1533L Hypoallergenic Medical-Grade Acrylic Pressure-Sensitive Adhesive: 3M China Co., Ltd.

[0066] 0.12mm Medical-grade Breathable and Waterproof Non-woven Fabric: Shandong Chenxing Medical Technology Co., Ltd.

[0067] Medical environmentally friendly adhesive KL-6638AB (room temperature curing medical silicone gel pressure-sensitive adhesive): Shenzhen Kanglibang Technology Co., Ltd.

[0068] USP Anhydrous Ethanol: Shandong Yucheng Xinhao Chemical Co., Ltd.

[0069] All other reagents were domestically produced analytical grade.

[0070] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the spirit of the contents disclosed in the present invention will be described in detail below. After understanding the embodiments of the present invention, any person skilled in the art can make changes and modifications based on the technology taught in the present invention without departing from the spirit and scope of the present invention.

[0071] The illustrative embodiments and descriptions of the present invention are used to explain the present invention, but are not intended to limit the present invention.

[0072] Currently, the industry commonly uses artificially synthesized phospholipids such as DPPC to prepare thermosensitive lipid carriers with a phase transition temperature of approximately 41°C. This invention uses only medical raw materials that meet the standards for Class II medical device excipients to construct a ternary composite membrane system of lecithin-cholesterol-phytosterol succinate. It is equipped with an integrated proprietary preparation process that combines film dispersion with multiple extrusion granulation, which improves the shortcomings of traditional natural phospholipid carriers, such as wide phase transition range, poor structural stability, and low material encapsulation rate. It can stably produce lipid carriers with an ultra-narrow phase transition range of 39–41°C, high batch reproducibility, and structural stability. This narrow phase transition property cannot be obtained by simply adjusting conventional formulations and processes in this field.

[0073] The main raw and auxiliary materials formulations in the following embodiments are as follows:

[0074] Plant-based soothing ingredients: 10g of Ligusticum chuanxiong, 8g of Angelica sinensis, 6g of Boswellia carterii, and 6g of Commiphora myrrha. All of these are medical device-grade Chinese medicinal materials with impurity content meeting the standards and satisfying the quality control standards for Class II medical device raw materials.

[0075] Raw materials for liposome preparation: 50g lecithin, 10g cholesterol, 3g phytosterol succinate, 100mL anhydrous ethanol, 500mL pH7.4 phosphate buffer; a ternary modified phospholipid membrane was constructed by compounding phytosterol succinate with lecithin and cholesterol in a mass ratio of 5:1.

[0076] The patch's six-layer coupling structure consists of the following raw materials: 0.12mm medical breathable and waterproof non-woven fabric, 30g iron powder, 10g activated carbon, 8g vermiculite, 2g tetradecane phase change microcapsules, 10g seaweed polysaccharide heat-retaining substrate, 3g bio-affinity guiding component (sterol glucose succinate diester), 6g hydroxypropyl methylcellulose E5, 0.3g phenoxyethanol, 5g azone, 15g propylene glycol (5g for acupoint layer + 10g for stratum corneum), 80mL purified water, 20g hypoallergenic medical pressure-sensitive adhesive, and 10mL medical environmentally friendly adhesive KL-6638AB.

[0077] All raw and auxiliary materials have undergone sterility, toxicology, and skin biocompatibility testing, and can only be used in preparation after all indicators have passed.

[0078] The plant concentrate is prepared by: taking 10g of Ligusticum chuanxiong, 8g of Angelica sinensis, 6g of Boswellia carterii, and 6g of Commiphora myrrha, adding 8 times their weight of distilled water, and refluxing twice at 80℃ for 2 hours each time; combining the extracts and concentrating to a relative density of 1.10~1.15 at 60℃, and sterilizing with a 0.22μm filter membrane to obtain the final medicinal solution.

[0079] Example 1

[0080] In this embodiment, the mass ratio of lecithin to cholesterol is limited to 5:1, and phytosterol succinate is added as a dedicated membrane-modifying component. These three components form a unique ternary ratio system. Removing this modifying component prevents the product from achieving the target narrow phase transition range. The phase transition control precision of this ternary system is comparable to that of synthetic phospholipids, while retaining the excellent skin biocompatibility of natural phospholipids, meeting the requirements for long-term external application in Class II medical devices. The specific preparation process steps are as follows:

[0081] Step 1: Extraction and purification of plant-based soothing components

[0082] The Chinese medicinal materials of the above-mentioned plant-based soothing ingredients were pulverized, and 8 times the weight of distilled water was added. The mixture was extracted twice by reflux in an 80°C water bath, with each extraction lasting 2 hours. The two extracts were combined and concentrated until the relative density of the liquid was 1.10–1.15 at 60°C. The solution was then filtered through a 0.22 μm filter membrane for sterilization and set aside for later use.

[0083] Step 2: Preparation of ternary modified lipid films

[0084] Weigh lecithin and cholesterol in a 5:1 mass ratio, add phytosterol succinate (commercially available medical grade, model PS-HS-99, purchased from Jiangsu Weikaier Pharmaceutical Technology Co., Ltd.), pour in anhydrous ethanol, and dissolve thoroughly in a 60℃ water bath to obtain a homogeneous lipid solution; rotary evaporate at 35℃ and 100r / min for 15min to completely remove the organic solvent, forming a uniform and dense ternary modified lipid film on the inner wall of the container; this ternary compound combination is a necessary technical condition for achieving a narrow phase transition of 39-41℃.

[0085] Step 3: Active component coating and particle size adjustment

[0086] The plant concentrate obtained after sterilization of the filter membrane in step 1 was mixed with pH 7.4 phosphate buffer at a volume ratio of 1:4, and then added to a ternary modified lipid membrane for hydration. The mixture was stirred at 37℃ and 200r / min for 1h to obtain a crude liposome suspension. The suspension was cyclically extruded three times through a 100nm polycarbonate membrane to precisely control the liposome particle size distribution within the 100-200nm monodisperse range, improve membrane regularity, and ensure narrow phase transition response and uniform release.

[0087] Step 4: Liposome Refining and Shaping

[0088] The extruded liposome suspension was centrifuged at 3000 rpm for 10 min to remove unencapsulated free plant components and impurities, yielding a refined ternary narrow-phase-change liposome dispersion. The liposome particle size variation coefficient was found to be 12%, and the active component encapsulation rate was 88%. It stably maintained narrow-phase-change characteristics at 39–41℃, and its sterility and endotoxin levels met the standards for Class II medical devices. Adjusting the ternary compound ratio, replacing the modified sterol, or omitting the three extrusion granulation steps would prevent the liposome encapsulation rate and phase-change range from meeting the aforementioned medical standards.

[0089] Example 2

[0090] The overall manufacturing process of the six-layer coupled constant temperature physiotherapy heat therapy patch

[0091] Step 1: Preparation of the constant temperature heating layer: Take 30g of reduced iron powder, 10g of activated carbon, 8g of vermiculite, and 2g of tetradecane phase change microcapsules, mix them thoroughly with 10g of seaweed polysaccharide heat storage substrate, add an appropriate amount of distilled water to make a paste, and evenly coat it onto the surface protective layer non-woven fabric substrate (i.e., the inner side of 0.12mm medical breathable and waterproof non-woven fabric), control the coating thickness to 0.3~0.4mm, and dry it in a 60℃ oven for 2~2.5h to obtain the physical phase change constant temperature heating layer. This heating layer only provides basic oxidation exothermic and phase change temperature regulation capabilities and cannot achieve precise temperature control on its own. It needs to work in conjunction with the heat dissipation constraints and temperature field matching of the six-layer coupled architecture to stably construct a medical-compatible temperature field of 40℃±1℃. Under standard operating conditions (25℃), the highest temperature of the system does not exceed 40.2℃, and under multiple environmental operating conditions (25~45℃), the upper limit of the highest temperature of the system is ≤42℃. The system's highest temperature is ≤42℃, and the effective constant temperature operation can reach more than 8 hours, providing an adapted phase change reaction environment for ternary narrow phase change liposomes.

[0092] Step 2: Preparation of the remaining functional layers: Prepare the bio-affinity-guided coating solution: Take 3g sterol glucosuccinate diester, 6g hydroxypropyl methylcellulose E5, 5g propylene glycol, 0.3g phenoxyethanol, and 80mL purified water; disperse hydroxypropyl methylcellulose E5 in purified water at 44-46℃ until completely swollen and transparent, then add propylene glycol and sterol glucosuccinate diester sequentially, stir at 300r / min for 30min to disperse evenly, cool to room temperature, add phenoxyethanol, degas, and filter through a 0.22μm filter membrane to obtain a homogeneous coating solution; evenly coat the coating solution onto nonwoven fabric, dry to form a 0.1-0.2mm thick acupoint enrichment layer; mix 5g azone and 10g propylene glycol (mass ratio 1:2) and coat to form a 0.06-0.10mm thick stratum corneum moisturizing and enhancing layer; directly select a 0.12mm thick surface protective layer. Class II medical device special breathable and waterproof non-woven fabric; bottom adhesive layer: a low-sensitivity medical pressure-sensitive adhesive is uniformly coated on the surface of the non-woven fabric substrate to obtain the bottom adhesive layer.

[0093] Step 3: Six-layer coupled structure composite molding

[0094] The outer protective layer, constant temperature heating layer, liposome temperature-sensitive protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer are sequentially stacked from the outside to the inside. Medical-grade environmentally friendly silicone adhesive is used for integrated lamination at 25℃ and 0.3MPa pressure. After lamination, it is placed in an environment of 40℃ and 75% relative humidity for 24 hours for curing. Relying on the mutual constraint of the parameters of each layer and the stress adaptation, the interlayer peel strength is ≥0.5N / 25mm (actually measured according to GB / T 2792--2014, 180° peel after curing at 40℃ / 75% RH for 24 hours). There is no delamination or degumming during long-term storage, and the structure has excellent stability.

[0095] Step 4: Cutting and Aseptic Sealing

[0096] The composite six-layer integrated substrate is cut into standard 10cm×12cm patches. 0.5mL of refined ternary narrow-phase-change liposome dispersion is quantitatively injected into the interlayer space of the liposome thermochromic protective layer of the patch. Relying on the capillary adsorption effect of the adjacent two substrate layers, the liposome dispersion is locked and positioned within the interlayer of the liposome thermochromic protective layer, inhibiting the dispersion from migrating to the constant-temperature heating layer and the acupoint enrichment layer. The patches are individually sealed in aluminum foil bags and, after passing sterility and endotoxin tests, the finished product of this invention, a coupled constant-temperature physiotherapy hot compress, is obtained.

[0097] Step 5: Comprehensive performance testing of the finished product

[0098] The finished product utilizes a ternary modified phospholipid narrow phase change liposome integrated with a six-layer coupled isothermal structure, resulting in a surface soothing and therapeutic effect that is more than three times better than traditional simple assembly heat therapy patches. Under a coupled isothermal condition of 40℃, it can sustain stable release for 6.5 hours, with component analysis showing fluctuations of only 8%, and the enrichment rate of active components at acupoints reaching 81%. Long-term application of the product does not cause skin irritation such as erythema or edema. The endotoxin detection value is 0.3 EU / mL, and all indicators meet the quality and safety control standards for Class II medical devices.

[0099] To verify the comprehensive technical advantages brought about by the synergistic effect of the ternary phospholipid-specific formula, customized preparation process, and six-layer integrated coupling structure of this invention, multiple sets of prior art control experiments were set up. Conventional simple stacked external application patches, binary phospholipid lipid carrier external application patches, and ordinary sterol modified lipid carrier products were used as comparative examples. The results showed that the comprehensive performance of this invention is significantly better than that of existing solutions, and all indicators meet the quality control standards for Class II medical devices. The specific control experiment data are shown below.

[0100] Multiple control experiments systematically verified the unique technical advantages of the integrated coupling architecture of this invention from five dimensions: temperature field stability, liposome physical properties, material release characteristics, material utilization efficiency, and mass production stability.

[0101] 1. Comparative analysis of temperature field stability

[0102] This comparative example uses only tetradecane microcapsule heating material to prepare the heat patch.

[0103] Preparation process for this comparative example:

[0104] Heating layer materials: 30g iron powder, 10g activated carbon, 8g vermiculite, 2g tetradecane phase change microcapsules; no seaweed polysaccharide heat storage substrate added; water is added to make a slurry, which is then coated onto non-woven fabric and dried at 60℃ to obtain a 0.35mm heating layer. There is no independent acupoint enrichment layer or stratum corneum moisturizing and enhancing layer; the six-layer pressure lamination and 40℃ / 75% RH curing process is not performed; the binary phospholipid liposome dispersion is directly mixed into the low-sensitivity pressure-sensitive adhesive and uniformly coated onto the bottom layer fabric; only the surface non-woven fabric + drug-loaded adhesive layer are manually and simply bonded together, cut into 10cm×12cm patches, each patch containing 0.5mL of binary liposome dispersion, and sealed with aluminum foil.

[0105] Testing standards:

[0106] The standard implemented was GB / T 34402-2017 "Heat Patches"; the ambient temperature was 25℃ and the relative humidity was 60%; a multi-point temperature recorder with an accuracy of ±0.1℃ was used, with a sampling interval of 30 minutes; medical silicone simulated human skin, with the sensor closely attached to the acupoint area in the center of the patch, and the outside was covered with breathable cotton cloth to simulate everyday clothing; three parallel samples were used in each group, and data were collected continuously for 8 hours; the peak temperature, the lowest temperature, and the cumulative time of stabilization in the range of 40℃±1℃ were recorded throughout the process, and the temperature field curve was plotted in Figure 1. Figure 1 shows the overall temperature stability curve of the product of this invention. In the figure, the solid line represents the integrated six-layer coupled seaweed polysaccharide biothermal storage sample, and the dashed line represents the comparative sample with only a tetradecane phase change microcapsule mineral-based heating layer and no six-layer coupling structure. As can be seen from the figure, the narrow stable temperature field of 40℃±1℃ is achieved by the synergistic effect of the seaweed polysaccharide biothermal storage heating system, the ternary modified narrow phase change lipid carrier, and the six-layer integrated coupling architecture. As can be seen from the curve, relying on the overall heat dissipation constraint of the six-layer composite structure, combined with the seaweed polysaccharide heat storage heating system doped with tetradecane phase change microcapsules, the product can maintain a stable standard working range of 40℃±1℃ for a long time within an 8-hour working cycle. The highest temperature of the system does not exceed 40.2℃, the temperature change is gradual throughout the process, and the constant temperature battery life can reach more than 8 hours.

[0107] Comparing the dotted-line comparative curves reveals that when using the same tetradecane phase-change microcapsule heating material, but without a complete six-layer coupled heat dissipation structure and without temperature field matching design with the ternary lipid carrier, the system's peak temperature significantly exceeds the limit, and the overall fluctuation is drastic, making it impossible to achieve high-precision narrow-range constant temperature control. Using only tetradecane microcapsule heating material without six-layer coupled heat dissipation constraints results in drastic temperature field fluctuations, making it highly susceptible to overheating and unable to stably maintain the 40℃±1℃ medical-grade temperature range.

[0108] The solid curve maintains a stable temperature range of 39.2–40.2℃ throughout, with minimal temperature fluctuations, precisely matching the 39–41℃ exclusive phase transition response window of the ternary modified phospholipid lipid carrier. In contrast, the comparative example showed a system temperature exceeding 42℃ and peaking at 43.2℃ over 2–4 hours, with a temperature fluctuation of 4.4℃ (38.8–43.2℃). After 8 hours, the temperature dropped to 38.8℃, below the lower limit of the compatible phase transition temperature range, significantly exceeding the 39–41℃ compatible phase transition temperature range for the lipid carrier, which could lead to uncontrolled material precipitation. Utilizing a six-layer integrated coupling architecture for coordinated temperature control, the system can maintain a stable output of 40℃±1℃ under various environmental conditions (25℃, 35℃, 45℃), with a maximum temperature not exceeding 42℃, and an effective constant temperature duration of over 8 hours. After accelerated aging testing, the system temperature fluctuation was only 0.5℃. This high-precision and high-stability constant temperature characteristic is achieved through the coordinated efforts of the entire coupling system, and is not a performance that a single heating material can achieve on its own.

[0109] The comparative results directly confirm that precise temperature control cannot be achieved by relying solely on tetradecane phase change microcapsules as a single heating material. It must be integrated and coordinated with seaweed polysaccharide biothermal storage matrix, six-layer coupled heat dissipation architecture, and ternary narrow phase change lipid carrier to construct a stable temperature field suitable for the smooth precipitation of materials. This precise temperature control effect is a unique technical advantage generated by the synergistic effect of the entire coupling system.

[0110] 2. Comparative analysis of lipid carrier encapsulation efficiency

[0111] Four groups were set up, with all four groups using the same standard: the plant concentrate, hydration, centrifugation, and solvent conditions were completely identical, with only a single variable being changed. The encapsulation efficiency was detected using the HPLC differential method.

[0112] The four groups are as follows:

[0113] ① Experimental group

[0114] Ingredients: 50g lecithin, 10g cholesterol, 3g phytosterol succinate;

[0115] Process: Same as in Example 1.

[0116] Three control groups were set up:

[0117] ② Control group 1 (only 5:1 diphospholipids, no sterol succinates)

[0118] Ingredients: 50g lecithin, 10g cholesterol, no added phytosterol succinate;

[0119] Process: Except for the absence of phytosterol succinate, the process is the same as in Example 1; encapsulation rate is 72%.

[0120] ③ Control group 2 (β-sitosterol replaced the modified component in equal amounts)

[0121] Ingredients: 50g lecithin, 10g cholesterol, 3g β-sitosterol;

[0122] Process: Except for replacing phytosterol succinate with β-sitosterol in equal amounts, the process is the same as in Example 1; encapsulation rate is 75%.

[0123] ④ Control group 3 (ternary raw materials, simplified extrusion process)

[0124] Ingredients: 50g lecithin, 10g cholesterol, 3g phytosterol succinate;

[0125] Process: Unlike Example 1, except that it is only subjected to a single extrusion of a 100nm polycarbonate film once, the rest is the same as Example 1; the encapsulation rate is 78%.

[0126] Figure 2 The bar charts comparing the encapsulation efficiency of lipid carriers under the four different preparation conditions above serve to demonstrate the irreplaceable nature of the lecithin-cholesterol-phytosterol succinate ternary modified phospholipid system and the complete extrusion molding process of this invention. The four experimental sample groups were set up as follows: ① Experimental group (ternary phospholipid compound system + complete multi-stage extrusion molding process); ② Control group 1, only a 5:1 binary phospholipid system, without the addition of phytosterol succinate modification component; ③ Control group 2, using sitosterol to replace the phytosterol succinate modification component of this invention; ④ Control group 3, retaining the ternary phospholipid ratio, omitting the three-stage extrusion molding process. The encapsulation efficiencies of the four groups were 88%, 72%, 75%, and 78%, respectively.

[0127] As shown in the bar chart, the sample of this invention, using a 5:1 phospholipid ratio combined with a tertiary compound of phytosterol succinate and a complete extrusion molding process, achieved an encapsulation rate of 88% for plant extracts, and multiple batches of samples exhibited uniform and stable physical properties. Removing the tertiary modified component, replacing it with conventional sterol raw materials, or simplifying the extrusion granulation process all resulted in a significant decrease in the encapsulation rate of the lipid carrier, deterioration of membrane structure regularity, and an inability to consistently achieve a narrow phase transition range of 39–41°C. These comparative results fully demonstrate that only when the tertiary phospholipid compound system is combined with a complete set of proprietary molding processes can excellent material encapsulation and temperature-controlled phase transition performance be obtained. This comprehensive performance cannot be achieved through binary phospholipid formulations, conventional sterol modification, or simplified preparation processes; it represents an unexpected synergistic effect. All performance indicators of the carrier meet the quality control standards for Class II medical devices.

[0128] Existing binary phospholipid systems, as well as conventionally modified liposomes using phytosterol and stigmasterol, all exhibit phase transition temperature ranges greater than 5°C, resulting in large fluctuations and poor controllability in material release. This invention, however, employs a 5:1 phospholipid ratio + phytosterol succinate ternary compound system, coupled with a complete set of proprietary extrusion molding processes, to stably prepare lipid carriers with particle sizes of 100–200 nm and well-defined structures, precisely achieving an ultra-narrow phase transition range of 39–41°C. Replacing the sterol type, eliminating the ternary compound system, adjusting the phospholipid ratio, or simplifying the molding process all fail to achieve the same narrow phase transition performance, resulting in unexpected technical effects that cannot be replicated by conventional sterol modification techniques.

[0129] 3. Comparative Study on Long-Lasting and Uniform Release Effect

[0130] This comparative example is a conventional carrier-free external dressing.

[0131] Comparative raw materials:

[0132] Lipid ingredients: 50g lecithin, 10g cholesterol (diphospholipids, phytosterol succinate-free);

[0133] Heating layer: 30g iron powder, 10g activated carbon, 8g vermiculite, does not contain tetradecane phase change microcapsules or seaweed polysaccharides;

[0134] Preparation process:

[0135] Diphospholipid film preparation, hydration, three-stage extrusion, centrifugation, and preparation of binary liposome dispersion;

[0136] The exothermic powder is slurried, coated, and dried; it is a non-heat-storage phase change material.

[0137] No separate preparation of acupoint enrichment layer or keratin-enhancing layer; binary liposomes, azone, and propylene glycol are all mixed into low-sensitivity pressure-sensitive adhesive and coated in one go; only two layers are manually bonded together, without pressure bonding or constant temperature curing process;

[0138] Cut 10cm×12cm patches, load each patch with 0.5mL of binary liposome dispersion and seal.

[0139] Release rate uniform test conditions:

[0140] The environment was 25℃ and RH 60%, and medical silicone was used to simulate human skin. The patch was applied immediately after unpacking and covered with breathable cotton cloth. Sampling time points: 1h, 2h, 3h, 4h, 6h, and 8h. The active ingredient was quantitatively detected by HPLC, and the cumulative release rate was calculated. The average value of 3 parallel patches in each group was taken, and the release curve was plotted in Figure 3.

[0141] Figure 3 shows the cumulative release curves of plant extracts. The curves are divided into two groups: the solid line represents the cumulative release rate (%) of the extract of the sample of this invention (ternary modified lipid carrier + six-layer coupled constant temperature integrated system); the dashed line represents the cumulative release rate (%) of the extract of the comparative sample (simple stacked external application + binary phospholipid lipid carrier).

[0142] The comparative sample exhibited the drawbacks of initial bursts of release, rapid saturation, and near-stagnation of release in the later stages. The sample of this invention showed a consistently stable release rate throughout, without any sudden bursts or subsequent depletion of release material. This invention utilizes a six-layer coupled isothermal structure synergistically adapted with a ternary modified narrow phase change lipid carrier to achieve uniform and gradual release of plant extracts within a stable temperature field of 40℃±1℃. The cumulative release rate is ≥75% after 6 hours and ≥90% after 8 hours, without any issues of initial bursts or insufficient release in the later stages. In contrast, the comparative sample, composed of a conventional simple stacked external patch and a binary broad phase change lipid carrier, showed a steep rise and fall in the release curve, indicating poor uniformity of release.

[0143] The curve variation clearly demonstrates that only by using a ternary modified phospholipid carrier in conjunction with a six-layer coupled isothermal system can a continuous and stable material release effect be achieved. This steady-state controlled release performance cannot be achieved using existing conventional binary phospholipid formulations and simple composite structures, representing an unexpected synergistic effect. Looking at the segmented curve data, the material release rate in the comparative example (1-3 hours) was too rapid, with a large amount of material released instantaneously in a short period, resulting in a severe shortage of subsequent supply. In contrast, the curve of this invention shows a gentle and uniform upward trend, with a long-term stable release rate, meeting the requirements for stable material delivery over long periods.

[0144] 4. Material utilization efficiency comparison ratio

[0145] Four comparative examples were based on a unified standard: patch size 10cm×12cm, each patch loaded with 0.5mL of the corresponding liposome dispersion; test environment 25℃, RH60%, silicone simulated skin application for 8h; HPLC detection of the active substances retained in the application area, and the relative efficacy multiple was calculated based on group ①.

[0146] ① Standard simple stacked external dressing (baseline group)

[0147] Diphospholipid liposomes (using only diphospholipids, including 50g lecithin and 10g cholesterol, without sterol succinate); the heating layer formulation removes tetradecane microcapsules and seaweed polysaccharide heat storage substrate; the difference from the preparation method in Example 2 is that: the six independent functional layers of the present invention are not set, only the heating layer and the drug-loaded pressure-sensitive adhesive backing layer mixed with diphospholipid liposomes are prepared; the diphospholipid liposome dispersion is directly mixed into the low-sensitivity medical pressure-sensitive adhesive and coated to obtain the drug-loaded pressure-sensitive adhesive backing layer, and the liposomes are not injected after interlayering; the heating layer and the drug-loaded pressure-sensitive adhesive backing layer are manually and simply stacked and bonded, without pressure integration and curing process; other operations not mentioned are performed according to the corresponding conditions in Example 2, and after cutting, the sample is sealed with aluminum foil to obtain the reference group sample.

[0148] Preparation of Comparative Example ①:

[0149] Diphospholipid liposome dispersion was directly mixed with hypoallergenic medical pressure-sensitive adhesive and coated onto a non-woven fabric backing to obtain a drug-loaded pressure-sensitive adhesive backing layer. A heating layer without tetradecane phase change microcapsules and seaweed polysaccharide heat storage substrate was prepared according to the formula. The heating layer and the drug-loaded pressure-sensitive adhesive backing layer were simply bonded and stacked by hand without pressure bonding or curing. The pieces were cut into 10cm×12cm patches and sealed with aluminum foil.

[0150] ② Only the ternary lipid carrier is optimized, without the six-layer coupling structure.

[0151] The ternary complete phospholipid formula (50g lecithin, 10g cholesterol, 3g phytosterol succinate) was prepared according to Example 1 to obtain ternary liposomes; the heating layer formula removed tetradecane phase change microcapsules and seaweed polysaccharide heat storage substrate. The preparation method differed from Example 2 in that: the six-layered functional layer was not set; only the heating layer and the drug-loaded pressure-sensitive adhesive backing layer mixed with ternary liposomes were prepared; the ternary liposome dispersion was directly mixed into the low-sensitivity medical pressure-sensitive adhesive and coated to obtain the drug-loaded pressure-sensitive adhesive backing layer; the liposomes were not injected after interlayering; the heating layer and the drug-loaded pressure-sensitive adhesive backing layer were manually and simply stacked and bonded without pressure integration or curing; other operations not mentioned were performed according to the corresponding conditions in Example 2; after cutting, the samples were sealed with aluminum foil to obtain the samples in this group.

[0152] ③ A six-layer composite structure, combined with a binary phospholipid lipid carrier

[0153] Lipid raw materials: 50g lecithin, 10g cholesterol, phytosterol succinate-free, to prepare binary liposomes;

[0154] Heating layer: Contains a complete set of heat storage phase change raw materials (iron powder, activated carbon, vermiculite, tetradecane microcapsules, seaweed polysaccharide);

[0155] The six-layer patch was prepared according to the complete process of Example 2, with the independent preparation of the six layers, pressure-integrated composite, and curing processes all retained; after cutting, 0.5 mL of binary liposome dispersion was loaded into the liposome thermochromic protective layer interlayer and sealed with aluminum foil.

[0156] ④ This invention is a complete system

[0157] The ternary phospholipid raw material is extruded three times to produce ternary liposomes; containing a heat storage phase change heating layer; the complete process of Example 2 is followed: six-layer coating, pressure bonding, curing, interlayer loading of liposome dispersion, and sealing to obtain the finished product.

[0158] This comparative example is a conventional simple stacked external application; and an optimized lipid carrier without a six-layer coupling structure.

[0159] Figure 4 shows a bar chart comparing the utilization efficiency of materials on the body surface. Four groups of samples were set up in the experiment: ① conventional simple stacked external application; ② optimized ternary lipid carrier formulation only, without the accompanying six-layer coupling integrated structure; ③ using only a six-layer composite structure, combined with a common binary phospholipid lipid carrier; ④ the complete system of this invention (ternary modified phospholipid lipid carrier + six-layer coupled isothermal integrated structure). The two groups of samples that only improved the lipid carrier formulation or only optimized the six-layer composite structure showed limited improvement in material retention in the application area; while the complete coupling system of this invention significantly improved the overall material utilization efficiency, with an overall optimization effect far superior to single-structure or single-raw material improvement schemes. This performance improvement is generated by the synergistic effect of the ternary narrow phase change lipid carrier and the six-layer coupled isothermal system, and is not a performance that can be achieved by a single raw material or single-layer structure alone. This invention integrates a ternary modified narrow phase change lipid carrier for precise controlled release, a diffusion-limiting layer for material retention in the bonding region, a stratum corneum penetration-enhancing layer, and a six-layer coupled isothermal architecture to create a complete material regulation and linkage system. Compared with conventional simple stacked external patches, the material retention and utilization performance are significantly optimized. This level of material regulation and optimization cannot be achieved by simply adjusting a single lipid formulation, improving a single layer structure, or simply stacking existing technologies. This is an unexpected technical effect produced by the integrated and synergistic combination of the ternary modified phospholipid system and the six-layer coupled architecture.

[0160] Traditional simple, overlapping topical patches lack multi-layered containment, controlled release, and penetration-adaptation coupling mechanisms, resulting in severe disordered diffusion of plant extracts and low effective utilization. This invention, through a full-chain coupling and linkage of ternary precise controlled release, diffusion containment in the adhesion area, stratum corneum penetration adaptation, and six-layer constant temperature stable field, significantly improves the material retention and utilization efficiency in the adhesion area, achieving an effective component enrichment rate of ≥80%. This overall material regulation effect cannot be achieved through single-formula or single-layer structural improvement, representing an unexpected synergistic effect that conventional technological improvements cannot predict.

[0161] 5. Mass production batch stability

[0162] Test Plan

[0163] Experimental animals: Healthy New Zealand white rabbits, half male and half female, weighing 2.0~2.5kg; hair was removed from both sides of the spine on the back 24 hours before the experiment, and the experimental area was 3cm×3cm with intact skin without any damage;

[0164] Test groups: Batch 1, Batch 2, and Batch 3 of the present invention were prepared using the preparation method of Example 2, and three batches of simulated mass-produced products were prepared in parallel and repeatedly to obtain three batches (the relative standard deviation of the core performance indicators of the three batches of mass-produced products was ≤5%, the batch consistency was excellent, and the quality control requirements for large-scale and standardized production of Class II medical devices were met); negative control group (blank non-woven fabric + low-sensitivity pressure-sensitive adhesive, without fever, lipids, or traditional Chinese medicine components); positive control group (non-woven fabric impregnated with 0.5% sodium dodecyl sulfate SDS solution).

[0165] Operating procedures: Five independent test areas were divided on the back of a single white rabbit, with a 2cm interval between groups; each group of patches was applied for 72 hours; the patches were removed at 24 hours, 48 ​​hours, and 72 hours, the skin was wiped with warm water, and left to stand for 30 minutes. The erythema and edema were scored according to national standards, and the average score of comprehensive stimulation for each group was calculated.

[0166] Judgment criteria: - No erythema and edema (0 points), ± very slight erythema, + mild irritation, ++ moderate irritation, +++ severe irritation.

[0167] Implementation Standards

[0168] GB / T 16886.1-2011 Biological evaluation of medical devices – Part 1: Evaluation and testing in the risk management process

[0169] GB / T 16886.10-2017 Biological evaluation of medical devices - Part 10: Irritation and skin sensitization tests.

[0170] Figure 5 This serves as a comparison of the product's skin compatibility and safety test results. This invention relies on a six-layer coupled isothermal structure to evenly conduct heat within the system, avoiding the risk of low-temperature burns caused by localized heat accumulation from the source. Simultaneously, it utilizes a ternary modified natural phospholipid lipid carrier with excellent biocompatibility. After conducting a 72-hour long-term external application skin irritation test, multiple batches of Sample 2 from Example 2 and the corresponding negative control group showed no irritation such as erythema or edema on the tested skin. The positive control group, however, showed a significant moderate skin irritation reaction, with clear differences in the test results among the groups. The above comparative results confirm that the entire coupling system has low skin irritation and good safety in use, fully meeting the biocompatibility access quality control standards for Class II medical devices requiring long-term skin contact.

[0171] The supporting test data is shown in the table below:

[0172]

[0173] Symbol explanation: -: No erythema / edema, no irritation ±: Very slight erythema, almost no irritation +: Mild erythema / edema, mild irritation ++: Moderate erythema / edema, moderate irritation

[0174] Figure 5 shows a comparison of the skin compatibility and safety test results of the topical patch of the present invention. The horizontal axis represents, in order, the finished product batch 1, finished product batch 2, finished product batch 3 of the present invention, the negative control group, and the positive control group; the vertical axis represents the average score of skin irritation after 72 hours of occlusion (0 points for no irritation, 1 point for mild irritation, and 2 points for moderate irritation), used to visually compare the degree of skin irritation in each group. The column height of the three batches of samples of the present invention and the negative control group was 0, indicating no skin irritation. The average score of the positive control group was approximately 1.67, indicating moderate skin irritation, and the difference between the groups was significant.

[0175] In summary, comparative experiments on three types of systems—conventional assembled topical patches, binary phospholipid lipid systems, and ordinary sterol-modified lipid systems—confirm that this invention integrates ternary modified phospholipid formulation, proprietary liposome molding process, and a six-layer coupled isothermal architecture, achieving multiple technological breakthroughs.

[0176] ① Temperature field control performance: After the same heat generation and heat storage system is separated from the six-layer coupled heat dissipation and thermal field constraint, the temperature control accuracy deteriorates significantly. The high-precision narrow-range constant temperature performance is a unique technical feature generated by the synergistic coupling of the whole system.

[0177] ② Liposome phase transition performance: Conventional binary phospholipid systems and ordinary sterol modification schemes cannot achieve an ultra-narrow phase transition range of 39-41℃. The ternary compound system of this invention breaks through the industry technical limitation of the wide phase transition range of natural phospholipids. This physical property advantage cannot be obtained through conventional simple modification.

[0178] ③ Material release stability: Relying on the ternary narrow phase change characteristics and the precise matching of the six-layer coupled constant temperature system, the material is released steadily and slowly throughout the process. The technical defects of disordered release, sudden release in the early stage and insufficient release in the later stage cannot be solved by replacing a single material or improving a single layer structure.

[0179] ④ Synergistic advantages in material utilization: The multi-layer closed-loop coupling structure significantly optimizes material retention rate and release uniformity, and the overall performance improvement exceeds the expectations of conventional structure superposition, which is a typical unexpected technical effect;

[0180] ⑤ Mass production quality control stability: The entire formulation system and preparation process parameters are completely solidified, with small batch-to-batch differences and good repeatability, fully complying with the standardized production quality control specifications for Class II medical devices.

Claims

1. A seaweed polysaccharide heat-storing coupled ternary narrow phase change phospholipid constant-temperature external application patch, characterized in that, The external patch consists of, from the outside in, a surface protective layer, a constant temperature heating layer, a lipid body temperature-sensitive protective layer, an acupoint enrichment layer, a stratum corneum moisturizing and enhancing layer, and a bottom adhesive layer. The surface protective layer is a breathable and waterproof non-woven fabric. The constant temperature heating layer is composed of 25-35 parts reduced iron powder, 5-15 parts activated carbon, 6-10 parts vermiculite, 1-3 parts tetradecane phase change microcapsules and 5-15 parts seaweed polysaccharide heat storage substrate by weight. The liposome thermochromic protective layer is equipped with a ternary modified narrow phase change lipid carrier, which is composed of lecithin, cholesterol and phytosterol succinate. The mass ratio of lecithin to cholesterol is 5:1, and the mass ratio of cholesterol to phytosterol succinate is 2~4:

1. The phase change range of the liposome thermochromic protective layer is 39~41℃. The ternary modified narrow phase change lipid carrier encapsulates the plant concentrate, which is prepared by water extraction and concentration from 8-12 parts of Ligusticum chuanxiong, 6-10 parts of Angelica sinensis, 4-8 parts of Boswellia carterii and 4-8 parts of Commiphora myrrha. The acupoint enrichment layer is composed of a sterol glucose succinate diester bioaffinity guiding component; the sterol glucose succinate diester bioaffinity guiding component is composed of 2-4 parts sterol glucose succinate diester, 5-7 parts hydroxypropyl methylcellulose E5, 3-5 parts propylene glycol, 0.2-0.4 parts phenoxyethanol and 70-90 parts purified water by weight. The stratum corneum moisturizing and enhancing layer is composed of azone and propylene glycol in a mass ratio of 1:(1~5); The bottom adhesive layer is a low-sensitivity medical pressure-sensitive adhesive.

2. The seaweed polysaccharide heat-storing coupled ternary narrow phase change phospholipid constant-temperature external application patch according to claim 1, characterized in that, The lecithin is medical-grade liposome-grade PC-70 egg yolk lecithin, and the phytosterol succinate is medical-grade low endotoxin PS-HS-99 with a purity ≥98%.

3. The seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch according to claim 1, characterized in that, The ternary modified narrow phase change lipid carrier is prepared as follows: lecithin, cholesterol, and phytosterol succinate are dissolved in anhydrous ethanol to obtain a homogeneous lipid solution. The organic solvent is removed by rotary evaporation to obtain a dry ternary modified lipid film composed of lecithin, cholesterol, and phytosterol succinate. The dry ternary modified lipid film is hydrated to obtain a crude liposome suspension, which is then cyclically extruded three times through a polycarbonate membrane to obtain a ternary narrow phase change liposome dispersion with a particle size distribution of 100–200 nm.

4. The seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch according to claim 1, characterized in that, The plant concentrate was prepared as follows: Ligusticum chuanxiong, Angelica sinensis, frankincense, and myrrh were extracted by reflux twice with 8 times the amount of distilled water at 75-85℃, concentrated to a relative density of 1.10-1.15 at 60℃, and then sterilized by 0.22μm filtration.

5. The seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch according to claim 1, characterized in that, The sterol glucose succinate diester bioaffinity-directing component is prepared by dispersing sterol glucose succinate diester, hydroxypropyl methylcellulose E5, propylene glycol, phenoxyethanol and purified water at 44-46℃, followed by degassing, filtration, coating, drying and molding.

6. The seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch according to claim 1, characterized in that, The thickness of the constant temperature heating layer is 0.3~0.4mm, the thickness of the acupoint enrichment layer is 0.1~0.2mm, and the thickness of the stratum corneum moisturizing enhancement layer is 0.06~0.10mm.

7. The seaweed polysaccharide heat storage coupled ternary narrow phase change phospholipid constant temperature external application patch according to claim 1, characterized in that, The adhesives used for the top protective layer, constant temperature heating layer, liposome temperature-sensitive protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer are medical-grade environmentally friendly silicone adhesives with an interlayer peel strength ≥0.5N / 25mm.

8. A method for preparing the seaweed polysaccharide thermally regenerative coupled ternary narrow phase change phospholipid isothermal external application according to any one of claims 1 to 7, characterized in that, The preparation method of the external dressing is as follows: S1. Preparation of plant concentrate: 8-12 parts by weight of Ligusticum chuanxiong, 6-10 parts by weight of Angelica sinensis, 4-8 parts by weight of Boswellia carterii and 4-8 parts by weight of Commiphora myrrha were extracted by reflux twice with 8 times the amount of distilled water at 75-85℃, concentrated to a relative density of 1.10-1.15 at 60℃, and sterilized by 0.22μm filtration to obtain plant concentrate for later use; S2. Preparation of ternary modified lipid film: lecithin, cholesterol and phytosterol succinate were mixed and then mixed with anhydrous ethanol. The mixture was dissolved at 55~65℃ and then rotary evaporated at 33~37℃ and 80~120r / min for 15min to remove the solvent, and a dry ternary modified lipid film was obtained. S3. Liposome hydration, extrusion granulation and purification: The plant concentrate and pH 7.4 phosphate buffer were mixed at a volume ratio of 1:4 to prepare an aqueous hydration medium. The dried ternary modified lipid film was added for hydration. The mixture was stirred at 37°C and 200 r / min for 1 h to obtain a crude liposome suspension. The crude liposome suspension was cyclically extruded through a polycarbonate membrane three times to obtain a ternary narrow-phase change liposome dispersion with a particle size distribution of 100-200 nm. The dispersion was then centrifuged at 3000 r / min for 10 min to remove uncoated free components, resulting in a purified ternary narrow-phase change liposome dispersion. S4. Prepare the constant temperature heating layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, surface protective layer, and bottom adhesive layer independently; The constant temperature heating layer is prepared by taking 25-35 parts of reduced iron powder, 5-15 parts of activated carbon, 6-10 parts of vermiculite, and 1-3 parts of tetradecane phase change microcapsules by mass, mixing them with 5-15 parts of seaweed polysaccharide heat storage substrate, adding water to make a uniform paste, and uniformly coating the paste onto a 0.12mm breathable and waterproof non-woven fabric substrate, controlling the coating thickness to be 0.3-0.4mm, and drying in an oven at 60℃ for 2-2.5h to obtain the constant temperature heating layer. Preparation of acupoint enrichment layer: Take 2-4 parts by weight of sterol glucose succinate diester, 5-7 parts by weight of hydroxypropyl methylcellulose E5, 3-5 parts by weight of propylene glycol, 0.2-0.4 parts by weight of phenoxyethanol, and 70-90 parts by weight of purified water. Stir and swell to disperse the mixture at 44-46℃, degas, and filter through a 0.22μm filter to obtain a coating solution. Coat the coating solution evenly onto a nonwoven fabric substrate, dry it, and control the dry film thickness to 0.1-0.2mm to obtain the acupoint enrichment layer. Preparation of the stratum corneum moisturizing and enhancing layer: Azone and propylene glycol are mixed and stirred evenly at a mass ratio of 1:(1~5), coated onto a non-woven fabric substrate, dried, and the dry film thickness is controlled at 0.06~0.10mm to obtain the stratum corneum moisturizing and enhancing layer. The surface protective layer is made of 0.12mm breathable and waterproof non-woven fabric specifically for Class II medical devices; Bottom adhesive layer: A low-sensitivity medical pressure-sensitive adhesive is uniformly coated on the surface of a non-woven fabric substrate to obtain the bottom adhesive layer; S5. The surface protective layer, constant temperature heating layer, liposome thermochromic protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer, and bottom adhesive layer are integrally composited at 23~27℃ and 0.1~0.5MPa pressure, cured at 39~41℃ and 70~80% RH for 24 hours, and cut into single patches. 0.5mL of refined ternary narrow phase change liposome dispersion is quantitatively injected into the interlayer space of the liposome thermochromic protective layer of the patch, so that the dispersion is adsorbed and retained by the interlayer pores and positioned in the liposome thermochromic protective layer, without seeping into other adjacent functional layers. The patch is then sealed with aluminum foil for sterile packaging.

9. The method for preparing a seaweed polysaccharide thermally regenerative coupled ternary narrow phase change phospholipid isothermal external application patch according to claim 8, characterized in that, In step S2, the ternary modified lipid film was prepared by mixing lecithin, cholesterol and phytosterol succinate, adding anhydrous ethanol, dissolving at 60°C, and then rotary evaporating at 35°C and 100 r / min for 15 min to remove the solvent, thus obtaining a dry ternary modified lipid film.

10. The method for preparing a seaweed polysaccharide thermally coupled ternary narrow phase change phospholipid isothermal external application according to claim 8, characterized in that, The surface protective layer, constant temperature heating layer, liposome temperature-sensitive protective layer, acupoint enrichment layer, stratum corneum moisturizing and enhancing layer and bottom adhesive layer described in step S5 are integrally composited at 25℃ and 0.2~0.4MPa pressure, cured at 40℃ and 70~80%RH for 24 hours to form a single patch.

Images