Formula of Chinese herbal medicine patch for activating blood and dredging meridians and collaterals

Abstract

The invention discloses a formula of a Chinese herbal medicine patch for activating blood and dredging meridians and collaterals. According to the invention, a distinct-level efficacy system is formed through a monarch, minister, assistant and guide compatibility theory of traditional Chinese medicines and a modern preparation technology. The monarch drug group is used for promoting blood circulation to remove blood stasis as a core and is matched with the channel-clearing and collateral-activating components of the ministerial drug group, so that local qi-blood circulation can be effectively promoted, and the meridian blocking state is improved. The traditional transdermal limitation is broken through by an intelligent permeation enhancing technology adopted by the adjuvant drug group, so that the drug components rapidly permeate into deep tissues and are continuously released, the advantage of overall regulation of traditional Chinese medicines is reserved, and the problem of low bioavailability of an external preparation is solved. The precise design of each component in spatial distribution and time release realizes quick-acting and long-acting dynamic balance, is particularly suitable for the requirements of different pathological stages such as chronic strain or acute sprain, forms multi-target intervention in the aspects of improving microcirculation, relieving pain, eliminating swelling and the like, and has a wide application prospect. And compared with the traditional plaster, the plaster better meets the requirement of modern clinic on precise treatment.

Description

Technical Field

[0001] The present invention belongs to the technical field of Chinese herbal medicine patches, and specifically relates to a formula for a Chinese herbal medicine patch for promoting blood circulation and dredging meridians. Background Art

[0002] Chinese herbal medicine patches for promoting blood circulation and dredging meridians are external patches made from extracts of various Chinese herbal medicines with the effects of promoting blood circulation to remove blood stasis and dredging meridians. These patches are usually guided by traditional Chinese medicine theory, and Chinese medicinal materials with the effects of promoting blood circulation to disperse stasis and promoting qi movement to relieve pain, such as safflower, angelica, chuanxiong, salvia miltiorrhiza, and peach kernel, are selected and processed through modern technology. By applying them to specific acupoints or affected areas of the human body, the active ingredients of the medicine are absorbed through the skin and reach the lesion directly, playing the role of promoting local blood circulation, relieving muscle and bone pain, and dredging meridian blockages. Such patches are commonly used to treat traumatic injuries, neck, shoulder, waist and leg pain, rheumatic joint pain, etc. caused by qi stagnation and blood stasis, and have the characteristics of convenient use, quick effect, and less side effects. They are an important application form in the external treatment methods of traditional Chinese medicine and are deeply favored by patients.

[0003] However, the traditional preparation process is difficult to balance the requirements of quick effect and long effect, and the single physical mixing method leads to uneven distribution of active ingredients, which is likely to cause local irritation or waste of active ingredients. In addition, the conventional matrix has insufficient temperature sensitivity and cannot achieve dynamic regulation of drug release, while the simple inclusion technology is difficult to break through the limitation of the skin barrier on lipophilic components, resulting in insufficient drug concentration in deep tissues and affecting the overall efficacy. Summary of the Invention

[0004] The purpose of the present invention is to provide a formula for a Chinese herbal medicine patch for promoting blood circulation and dredging meridians in order to solve the above-mentioned problems.

[0005] The technical solution adopted by the present invention is as follows: A formula for a Chinese herbal medicine patch for promoting blood circulation and dredging meridians, the formula includes:

[0006] King drug group (core for promoting blood circulation and dredging meridians):

[0007] Safflower ultrafine powder (breaking blood stasis and removing stasis) 20 - 25 parts by weight;

[0008] Chuanxiong nano-liposome (guiding the drug to move upward) 15 - 25 parts by weight;

[0009] Salidroside extract (improving microcirculation) 10 - 20 parts by weight;

[0010] Minister drug group (synergistic effect):

[0011] Total saponins of notoginseng microemulsion (two-way regulation) 12 - 20 parts by weight;

[0012] Rhizoma Corydalis alkaloid sustained-release granules (targeted analgesia) 8 - 10 parts by weight;

[0013] Caulis Spatholobi iridoid complex (activating meridians and collaterals) 10 - 20 parts by weight;

[0014] Assistant drug group (transdermal penetration enhancement):

[0015] Menthol-β-cyclodextrin inclusion complex (intelligent penetration enhancement) 6 - 15 parts by weight;

[0016] Ionic liquid-loaded curcumin (deep penetration) 5 parts by weight;

[0017] Nanometer zinc oxide-loaded capsaicin (controlled release) 3 - 5 parts by weight;

[0018] Matrix system

[0019] Thermosensitive hydrogel matrix (phase transition temperature 32°C) 100 - 125 parts by weight;

[0020] Sodium alginate sustained-release matrix 15 - 20 parts by weight;

[0021] Medical-grade silicone pressure-sensitive adhesive 20 - 25 parts by weight.

[0022] In a preferred embodiment, the method for preparing the Chinese herbal medicine patch using the formula includes the following steps:

[0023] S1: Obtain the fat-soluble components from the safflower raw material by supercritical CO2 extraction, prepare the safflower ultrafine powder using molecular sieve fractionation technology. At the same time, compound the ligusticum wallichii extract with phospholipids and prepare the ligusticum wallichii nano-liposomes using the thin-film dispersion method;

[0024] S2: Mix the total saponins of notoginseng with the emulsifier and prepare the microemulsion system through a high-pressure homogenizer. The alkaloids of Corydalis yanhusuo and the sustained-release excipients are formed into sustained-release granules through fluidized bed coating. The Caulis Spatholobi extract is included with cyclodextrin to obtain the iridoid complex;

[0025] S3: Use microfluidic chip technology to mix the salidroside extract, the notoginseng total saponin microemulsion, and the Corydalis yanhusuo sustained-release granules in proportion to construct a multi-layer drug-loaded microsphere with a core-shell structure;

[0026] S4: Form an inclusion complex of menthol and β-cyclodextrin by the saturated aqueous solution method, dissolve curcumin in a specific ionic liquid to make a drug-loaded system, and complete the loading of capsaicin and nanometer zinc oxide by the solvent evaporation method;

[0027] S5: Heat the thermosensitive hydrogel matrix to a molten state at 40°C, sequentially add the sodium alginate sustained-release matrix and the medical-grade silicone pressure-sensitive adhesive, and stir at a speed of 500 rpm to form a homogeneous matrix

[0028] S6: Add all the active ingredients prepared in S1 to S4 to the matrix system in three gradients. After vacuum degassing treatment, use a precision coater to form an ointment layer with a thickness of 0.3 mm on the release paper.

[0029] S7: Conduct staged curing treatment in a temperature control room. First, pre-cure for 30 minutes in an environment of 25°C, then crosslink by ultraviolet irradiation for 15 minutes, and finally cut into patches with a specification of 6×8 cm.

[0030] S8: After the finished product is sterilized by 60Co irradiation, it is packaged with an aluminum-plastic composite film, and the thermosensitive phase change characteristics detection and in vitro transdermal release verification are completed.

[0031] In a preferred embodiment, in step S1, the safflower raw material is placed in a supercritical CO2 extraction device. Set the extraction pressure to 25 MPa, control the temperature at 45°C for 2 hours, and collect the fat-soluble extract. The obtained product passes through a molecular sieve grading system and sequentially passes through 200-mesh and 500-mesh stainless steel sieves to obtain ultrafine powder with a particle size less than 10 microns. At the same time, mix the aqueous extract of Ligusticum chuanxiong and soybean phospholipids in a mass ratio of 1:3, and use the thin-film dispersion method in a 55°C water bath. After removing the organic solvent by vacuum rotary evaporation, use a high-pressure homogenizer to cycle 5 times under the condition of 15,000 psi to obtain a nano-liposome suspension with a particle size distribution of 80-120 nm.

[0032] In a preferred embodiment, in step S2, the total saponins of Panax notoginseng and polyoxyethylene castor oil are mixed in a ratio of 15%, and deionized water is added to adjust the total solid content to 8%. Treat it through a high-pressure homogenizer at a pressure of 70 MPa for 3 cycle periods to form a microemulsion system with a particle size less than 100 nm. The alkaloids of Corydalis yanhusuo and ethyl cellulose are mixed in a ratio of 2:1, and bottom spraying coating is carried out using a fluidized bed coating equipment at an inlet air temperature of 40°C, controlling the atomization pressure at 0.3 MPa, and finally obtaining sustained-release granules with a coating weight gain of 30%. The iridoid glycosides of Spatholobus suberectus and hydroxypropyl-β-cyclodextrin are stirred in an aqueous solution at 50°C for 8 hours in a molar ratio of 1:4, and white inclusion compound powder is obtained by freeze-drying.

[0033] In a preferred embodiment, in step S3, a microfluidic chip device is used. Set the inner layer phase as the salidroside ethanol solution, the middle layer phase as the Panax notoginseng microemulsion system, and the outer layer phase as the suspension of Corydalis yanhusuo sustained-release granules. Control the synchronous flow rates of the three phases to be 0.8 mL / min, 1.2 mL / min, and 2.0 mL / min respectively, and form three-layer core-shell structure microspheres with a diameter of 200±50 μm at the chip outlet. The collected microspheres are immediately transferred to a -40°C low-temperature curing box for freezing and shaping, and the water content of the final product is controlled below 3%.

[0034] In a preferred embodiment, in step S4, menthol and β-cyclodextrin are dissolved in deionized water at 45°C in a molar ratio of 1:1, magnetically stirred for 12 hours, then allowed to stand for crystallization, and the inclusion complex crystals are collected by centrifugation and treated in a vacuum drying oven at 50°C for 6 hours. Curcumin is dissolved in a choline-capric acid ionic liquid system, and the drug loading is controlled at 12%, and a homogeneous drug-loaded solution is formed by stirring at a constant temperature of 60°C for 4 hours. Capsaicin and nano-zinc oxide are dispersed in an ethanol-water mixed solvent in a mass ratio of 1:5, treated with an ultrasonic cell disruptor for 30 minutes, and then concentrated to a semi-solid state at 60°C under reduced pressure in a rotary evaporator.

[0035] In a preferred embodiment, in step S5, the thermosensitive hydrogel matrix is preheated in a melting tank at 40 ± 2°C for 30 minutes, and sodium alginate powder and silicone pressure-sensitive adhesive are added in sequence. A double planetary mixer is used to mix at a speed of 500 rpm for 45 minutes, and the pH value of the system is adjusted to 6.8 - 7.2 in three times during this period. After mixing, it is transferred to a vacuum degassing tank, and degassing treatment is continuously carried out under a negative pressure of -0.08 MPa for 20 minutes, and finally the matrix viscosity is controlled at 15000 ± 2000 mPa·s.

[0036] In a preferred embodiment, in step S6, the active ingredients are added in three stages: first, ligusticum wallichii liposomes and notoginseng microemulsions are added, and stirred at a low speed of 200 rpm for 15 minutes; second, rhodiola rosea microspheres and Corydalis yanhusuo granules are added, the temperature is raised to 38°C and stirring is maintained for 30 minutes; in the final stage, a penetration enhancer component is added, and after cooling to 30°C, continuous mixing is carried out for 1 hour. The coating process uses a servo-controlled coating head, the die lip gap is set at 0.3 mm, the running speed of the substrate is 0.8 m / min, and it immediately enters a hot air drying tunnel at 45°C for 20 minutes after coating.

[0037] In a preferred embodiment, in step S7, the pre-curing stage is carried out in an environment with a temperature of 25 ± 2°C and a relative humidity of 55%, and the material is allowed to stand for 30 minutes to complete preliminary shaping. The ultraviolet cross-linking treatment uses a UV light source with a wavelength of 365 nm, the irradiation intensity is 15 mW / cm 2 , the conveyor belt speed is 0.5 m / min, ensuring that each patch receives a cumulative light energy of 1800 mJ / cm 2 . The slitting process uses a servo die-cutting machine, the tool pressure is set at 5 kg / cm 2 , and the product after slitting is immediately transferred to an aluminum foil bag for sealed packaging.

[0038] In a preferred embodiment, in step S8, the sterilization process uses a 60Co γ-ray irradiation device, and the product loading density is controlled at 15 kg / m 3The irradiation dose was set at 25 kGy, and the transmission speed was adjusted to 0.3 m / min. After the packaged finished products were stored for 72 hours at a temperature of 25°C and a humidity of 40%, a thermosensitive phase transition test was conducted to detect whether the phase transition temperature was stable at 32 ± 0.5°C. For the in vitro transdermal experiment, a modified Franz diffusion cell was used, maintaining the temperature of the receptor fluid at 37 ± 0.5°C, and continuously monitoring the drug permeation amount for 24 hours to ensure that the cumulative release rate reached more than 85% of the standard requirements.

[0039] In summary, due to the adoption of the above technical solutions, the beneficial effects of the present invention are as follows:

[0040] 1. In the present invention, the compatibility theory of monarch, minister, assistant, and guide in traditional Chinese medicine and modern preparation technology form a well-defined efficacy system. The monarch drug group focuses on promoting blood circulation and removing blood stasis, and together with the meridians-unblocking components of the minister drug group, can effectively promote local qi and blood circulation and improve the state of meridian blockage. The intelligent penetration-enhancing technology adopted by the assistant and guide drug group breaks through the traditional transdermal limitations, enabling the drug components to quickly penetrate into the deep tissues and be continuously released. It not only retains the advantages of the overall regulation of traditional Chinese medicine but also solves the problem of low bioavailability of topical preparations. The precise design of each component in terms of spatial distribution and time release achieves a dynamic balance between rapid efficacy and long-term effect, especially meeting the needs of different pathological stages such as chronic strain or acute sprain.

[0041] 2. In the present invention, the unity of safety and effectiveness is achieved through innovative preparation processes. The combination of the thermosensitive matrix and the sustained-release structure can not only avoid skin irritation caused by the sudden release of drug concentration in traditional patches but also ensure a stable therapeutic concentration at the lesion site. The application of the ionic liquid drug delivery system and the nanodelivery technology significantly improves the skin permeability of lipophilic active ingredients while reducing the risk of damage to the skin barrier function. The design of the multi-layer drug-loaded microspheres enables drug components with different properties to target corresponding tissue layers, forming multi-target interventions in improving microcirculation, relieving pain, and eliminating swelling, etc., which better meets the modern clinical requirements for precise treatment compared with traditional plasters. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 It is a schematic diagram of the preparation process principle of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0043] In order to make the objectives, technical solutions, and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0044] Example 1:

[0045] Refer to Figure 1 ,

[0046] A formula for a traditional Chinese herbal medicine patch for activating blood circulation and dredging collaterals, the formula includes:

[0047] The monarch drug group (core for activating blood circulation and dredging collaterals):

[0048] Safflower ultrafine powder (promoting blood circulation to remove blood stasis) 20 parts by weight;

[0049] Ligusticum wallichii nano-liposome (guiding the drug to act upward) 15 parts by weight;

[0050] Salidroside extract (improving microcirculation) 10 parts by weight;

[0051] The minister drug group (synergistic effect):

[0052] Total saponins of Panax notoginseng microemulsion (two-way regulation) 12 parts by weight;

[0053] Rhizoma Corydalis alkaloid sustained-release granules (targeted analgesia) 8 parts by weight;

[0054] Compound iridoid glycosides of Spatholobus suberectus (dredging collaterals) 10 parts by weight;

[0055] The assistant and courier drug group (transdermal penetration enhancement):

[0056] Menthol-β-cyclodextrin inclusion complex (intelligent penetration enhancement) 6 parts by weight;

[0057] Ionic liquid-loaded curcumin (deep penetration) 5 parts by weight;

[0058] Nanometer zinc oxide-loaded capsaicin (controlled release) 3 parts by weight;

[0059] Matrix system

[0060] Thermosensitive hydrogel matrix (phase transition temperature 32 °C) 100 parts by weight;

[0061] Sodium alginate sustained-release matrix 15 parts by weight;

[0062] Medical-grade silicone pressure-sensitive adhesive 20 parts by weight.

[0063] The method for preparing the traditional Chinese herbal medicine patch using the formula includes the following steps:

[0064] S1: Obtain the fat-soluble components of safflower raw materials by supercritical CO2 extraction, prepare safflower ultrafine powder using molecular sieve fractionation technology, and at the same time compound the Ligusticum wallichii extract with phospholipids and prepare Ligusticum wallichii nano-liposome using the thin film dispersion method

[0065] S2: Mix the total saponins of Panax notoginseng with an emulsifier and prepare a microemulsion system through a high-pressure homogenizer. The Rhizoma Corydalis alkaloid and sustained-release excipients are formed into sustained-release granules by fluidized bed coating, and the Spatholobus suberectus extract is obtained as a compound iridoid glycoside through cyclodextrin inclusion

[0066] S3: Use microfluidic chip technology to mix salidroside extract, total saponins of Panax notoginseng microemulsion, and Corydalis yanhusuo sustained-release granules in proportion to construct multilayer drug-loaded microspheres with a core-shell structure.

[0067] S4: Form an inclusion complex of menthol and β-cyclodextrin by the saturated aqueous solution method, dissolve curcumin in a specific ionic liquid to prepare a drug-loaded system, and complete the loading of capsaicin and nano-zinc oxide by the solvent evaporation method.

[0068] S5: Heat the thermosensitive hydrogel matrix to a molten state at 40 °C, sequentially add sodium alginate sustained-release matrix and medical-grade silicone pressure-sensitive adhesive, and stir at a speed of 500 rpm to form a homogeneous matrix.

[0069] S6: Gradually add all the active ingredients prepared in S1 to S4 to the matrix system in three steps. After vacuum degassing treatment, use a precision coater to form an ointment layer with a thickness of 0.3 mm on the release paper.

[0070] S7: Conduct staged curing treatment in a temperature control room. First, pre-cure for 30 minutes in an environment at 25 °C, then crosslink by ultraviolet irradiation for 15 minutes, and finally cut into patches with a specification of 6×8 cm.

[0071] S8: After the finished product is sterilized by 60Co irradiation, it is packaged with an aluminum-plastic composite film, and the thermosensitive phase change characteristics detection and in vitro transdermal release verification are completed.

[0072] In step S1, the safflower raw material is placed in a supercritical CO2 extraction device. Set the extraction pressure to 25 MPa, control the temperature at 45 °C for 2 hours, and collect the lipophilic extract. The obtained product passes through a molecular sieve grading system and sequentially passes through 200-mesh and 500-mesh stainless steel sieves to obtain ultrafine powder with a particle size less than 10 microns. At the same time, mix the aqueous extract of Ligusticum chuanxiong and soybean phospholipids in a mass ratio of 1:3, treat them by the thin-film dispersion method in a 55 °C water bath, remove the organic solvent by vacuum rotary evaporation, and then use a high-pressure homogenizer to circulate and treat 5 times under the condition of 15000 psi to obtain a nano-liposome suspension with a particle size distribution of 80 - 120 nm.

[0073] In step S2, mix total saponins of Panax notoginseng and polyoxyethylene castor oil in a proportion of 15%, add deionized water to adjust the total solid content to 8%, and treat them by a high-pressure homogenizer at a pressure of 70 MPa for 3 cycle periods to form a microemulsion system with a particle size less than 100 nm. Mix Corydalis yanhusuo alkaloids and ethyl cellulose in a ratio of 2:1, and perform bottom spraying coating at an inlet air temperature of 40 °C using a fluidized bed coating device, control the atomization pressure at 0.3 MPa, and finally obtain sustained-release granules with a coating weight gain of 30%. Mix the iridoids of Spatholobus suberectus and hydroxypropyl-β-cyclodextrin in a molar ratio of 1:4 and stir in an aqueous solution at 50 °C for 8 hours, and obtain white inclusion complex powder by freeze-drying.

[0074] In step S3, a microfluidic chip device is used. The inner phase is set as the salidroside ethanol solution, the middle phase is the pseudo-ginseng microemulsion system, and the outer phase is the rhizoma corydalis sustained-release granule suspension. The synchronous flow rates of the three phases are controlled at 0.8 mL / min, 1.2 mL / min, and 2.0 mL / min respectively, and three-layer core-shell structure microspheres with a diameter of 200 ± 50 μm are formed at the chip outlet. The collected microspheres are immediately transferred to a low-temperature curing box at -40°C for freezing and shaping, and the moisture content of the final product is controlled below 3%.

[0075] In step S4, menthol and β-cyclodextrin are dissolved in deionized water at 45°C in a molar ratio of 1:1, magnetically stirred for 12 hours, then allowed to stand for crystallization. The inclusion complex crystals are collected by centrifugation and treated in a vacuum drying oven at 50°C for 6 hours. Curcumin is dissolved in a choline-capric acid ionic liquid system, and the drug loading is controlled at 12%. A homogeneous drug-loaded solution is formed by stirring at a constant temperature of 60°C for 4 hours. Capsaicin and nano-zinc oxide are dispersed in an ethanol-water mixed solvent in a mass ratio of 1:5, treated with an ultrasonic cell disruptor for 30 minutes, and then concentrated to a semi-solid state at 60°C under reduced pressure in a rotary evaporator.

[0076] In step S5, the temperature-sensitive hydrogel matrix is preheated in a melting tank at 40 ± 2°C for 30 minutes, and sodium alginate powder and silicone pressure-sensitive adhesive are added in sequence. A double planetary mixer is used to mix at a speed of 500 rpm for 45 minutes, and the pH value of the system is adjusted to 6.8 - 7.2 in three times during this period. After mixing, it is transferred to a vacuum degassing tank and continuously degassed at a negative pressure of -0.08 MPa for 20 minutes. The final viscosity of the matrix is controlled at 15000 ± 2000 mPa·s.

[0077] In step S6, the active ingredients are added in three stages: first, chuanxiong liposomes and pseudo-ginseng microemulsion are added and stirred at a low speed of 200 rpm for 15 minutes; second, rhodiola microspheres and rhizoma corydalis granules are added, the temperature is raised to 38°C and stirring is maintained for 30 minutes; in the final stage, the penetration enhancer component is added, and after cooling to 30°C, continuous mixing is carried out for 1 hour. The coating process uses a servo-controlled coating head, the die lip gap is set at 0.3 mm, the running speed of the substrate is 0.8 m / min, and after coating, it immediately enters a hot air drying tunnel at 45°C for 20 minutes.

[0078] In step S7, the pre-curing stage is carried out in an environment with a temperature of 25 ± 2°C and a relative humidity of 55%. The material is allowed to stand for 30 minutes to complete the preliminary shaping. The ultraviolet cross-linking treatment uses a UV light source with a wavelength of 365 nm, an irradiation intensity of 15 mW / cm 2 , the conveyor belt speed is 0.5 m / min, ensuring that each patch receives a cumulative light energy of 1800 mJ / cm 2 . The slitting process uses a servo die-cutting machine, the tool pressure is set at 5 kg / cm 2 , and the product after slitting is immediately transferred to an aluminum foil bag for sealed packaging.

[0079] In step S8, a 60Co γ-ray irradiation device is used for the sterilization process, and the product loading density is controlled at 15 kg / m 3 , the irradiation dose is set at 25 kGy, and the transmission speed is adjusted to 0.3 m / min. After the packaged finished product is stored for 72 hours in an environment with a temperature of 25°C and a humidity of 40%, a thermosensitive phase change test is carried out to detect whether the phase change temperature is stable at 32 ± 0.5°C. The in vitro transdermal experiment uses a modified Franz diffusion cell, maintains the receptor fluid temperature at 37 ± 0.5°C, continuously monitors the drug permeation amount for 24 hours, and ensures that the cumulative release degree reaches more than 85% of the standard requirements.

[0080] Example 2:

[0081] Refer to Figure 1 ,

[0082] A formula for a traditional Chinese herbal medicine patch for promoting blood circulation and dredging meridians, the formula includes:

[0083] King drug group (core for promoting blood circulation and dredging meridians):

[0084] Safflower ultrafine powder (promoting blood circulation to remove blood stasis) 25 parts by weight;

[0085] Ligusticum wallichii nano-liposome (guiding the drug upward) 25 parts by weight;

[0086] Salidoside extract (improving microcirculation) 20 parts by weight;

[0087] Minister drug group (synergistic effect):

[0088] Total saponins of Panax notoginseng microemulsion (two-way regulation) 20 parts by weight;

[0089] Sustained-release granules of Corydalis yanhusuo alkaloids (targeted analgesia) 10 parts by weight;

[0090] Compound of cycloartenol glycosides from Spatholobus suberectus (dredging meridians) 20 parts by weight;

[0091] Assistant and messenger drug group (transdermal penetration enhancement):

[0092] Menthol-β-cyclodextrin clathrate (intelligent penetration enhancement) 15 parts by weight;

[0093] Ionic liquid-loaded curcumin (deep penetration) 5 parts by weight;

[0094] Nanometer zinc oxide-loaded capsaicin (controlled release) 5 parts by weight;

[0095] Matrix system

[0096] Thermosensitive hydrogel matrix (phase change temperature 32°C) 125 parts by weight;

[0097] Sodium alginate sustained-release matrix 20 parts by weight;

[0098] 25 parts by weight of medical-grade silicone pressure-sensitive adhesive.

[0099] The method for preparing the Chinese herbal medicine patch using the formula includes the following steps:

[0100] S1: Obtain the fat-soluble components from safflower raw materials by supercritical CO2 extraction, prepare ultrafine safflower powder using molecular sieve fractionation technology. At the same time, compound the ligusticum wallichii extract with phospholipids and prepare ligusticum wallichii nano-liposomes using the thin-film dispersion method.

[0101] S2: Mix total saponins of notoginseng with an emulsifier and prepare a microemulsion system through a high-pressure homogenizer. Corydalis alkaloids and sustained-release excipients form sustained-release granules through fluidized bed coating, and the extract of millettia reticulata is included with cyclodextrin to obtain an iridoid complex.

[0102] S3: Use microfluidic chip technology to mix the salidroside extract, the notoginseng total saponin microemulsion, and the corydalis sustained-release granules in proportion to construct a multi-layer drug-loaded microsphere with a core-shell structure.

[0103] S4: Form an inclusion complex of menthol and β-cyclodextrin by the saturated aqueous solution method, dissolve curcumin in a specific ionic liquid to make a drug-loaded system, and complete the loading of capsaicin and nano-zinc oxide by the solvent evaporation method.

[0104] S5: Heat the temperature-sensitive hydrogel matrix to a molten state at 40 °C, sequentially add the sodium alginate sustained-release matrix and the medical-grade silicone pressure-sensitive adhesive, and stir at a speed of 500 rpm to form a homogeneous matrix.

[0105] S6: Gradually add all the active ingredients prepared in S1 to S4 to the matrix system in three times. After vacuum degassing treatment, form an ointment layer with a thickness of 0.3 mm on the release paper through a precision coater.

[0106] S7: Perform staged curing treatment in a temperature control room. First, pre-cure in an environment at 25 °C for 30 minutes, then crosslink by ultraviolet irradiation for 15 minutes, and finally cut into patches with a specification of 6×8 cm.

[0107] S8: After the finished product is sterilized by 60Co irradiation, it is packaged with an aluminum-plastic composite film, and the temperature-sensitive phase change characteristics detection and in vitro transdermal release verification are completed.

[0108] In step S1, the safflower raw material is placed in a supercritical CO2 extraction device. The extraction pressure is set at 25 MPa, the temperature is controlled at 45 °C for 2 hours, and the fat-soluble extract is collected. The obtained product passes through a molecular sieve classification system and sequentially passes through 200-mesh and 500-mesh stainless steel sieves to obtain an ultrafine powder with a particle size less than 10 microns. At the same time, the aqueous extract of Ligusticum chuanxiong and soybean phospholipids are mixed at a mass ratio of 1:3, treated by the thin film dispersion method in a 55 °C water bath. After removing the organic solvent by vacuum rotary evaporation, it is cyclically treated 5 times with a high-pressure homogenizer under the condition of 15000 psi to obtain a nano-liposome suspension with a particle size distribution of 80 - 120 nm.

[0109] In step S2, the total saponins of Panax notoginseng and polyoxyl castor oil are mixed at a ratio of 15%, and deionized water is added to adjust the total solid content to 8%. It is treated by a high-pressure homogenizer at a pressure of 70 MPa for 3 cycle periods to form a microemulsion system with a particle size less than 100 nm. The alkaloids of Corydalis yanhusuo and ethylcellulose are mixed at a ratio of 2:1, and bottom spraying coating is carried out by a fluidized bed coating device at an inlet air temperature of 40 °C, controlling the atomization pressure at 0.3 MPa, and finally obtaining sustained-release granules with a coating weight gain of 30%. The iridoid substances of Spatholobus suberectus and hydroxypropyl-β-cyclodextrin are stirred in an aqueous solution at 50 °C for 8 hours at a molar ratio of 1:4, and white inclusion compound powder is obtained by freeze-drying.

[0110] In step S3, a microfluidic chip device is used. The inner layer phase is set as the salidroside ethanol solution, the middle layer phase is the Panax notoginseng microemulsion system, and the outer layer phase is the suspension of Corydalis yanhusuo sustained-release granules. The synchronous flow rates of the three phases are controlled at 0.8 mL / min, 1.2 mL / min, and 2.0 mL / min respectively, and three-layer core-shell structured microspheres with a diameter of 200 ± 50 μm are formed at the chip outlet. The collected microspheres are immediately transferred to a -40 °C low-temperature curing box for freezing and shaping, and the moisture content of the final product is controlled below 3%.

[0111] In step S4, menthol and β-cyclodextrin are dissolved in deionized water at 45 °C, magnetically stirred for 12 hours and then allowed to stand for crystallization. The inclusion compound crystals are collected by centrifugation and treated in a 50 °C vacuum drying oven for 6 hours. Curcumin is dissolved in a choline-capric acid ionic liquid system, controlling the drug loading at 12%, and a homogeneous drug-loaded solution is formed by constant temperature stirring at 60 °C for 4 hours. Capsaicin and nano-zinc oxide are dispersed in an ethanol-water mixed solvent at a mass ratio of 1:5, treated by an ultrasonic cell disruptor for 30 minutes, and then concentrated to a semi-solid state at 60 °C under reduced pressure in a rotary evaporator.

[0112] In step S5, the thermosensitive hydrogel matrix is preheated in a melting tank at 40±2°C for 30 minutes, and sodium alginate powder and silicone pressure-sensitive adhesive are added in sequence. A double planetary mixer is used to mix at a speed of 500 rpm for 45 minutes, and the pH value of the system is adjusted to 6.8 - 7.2 in three times during this period. After mixing, it is transferred to a vacuum degassing tank, and degassing treatment is continuously carried out under a negative pressure of -0.08 MPa for 20 minutes. Finally, the matrix viscosity is controlled at 15000±2000 mPa·s.

[0113] In step S6, the active ingredients are added in three stages: at first, ligusticum wallichii liposomes and notoginseng microemulsions are added, and stirred at a low speed of 200 rpm for 15 minutes; secondly, rhodiola microspheres and Corydalis yanhusuo granules are added, the temperature is raised to 38°C and stirring is maintained for 30 minutes; in the last stage, the penetration enhancer component is added, and after the temperature is lowered to 30°C, continuous mixing is carried out for 1 hour. The coating process uses a servo-controlled coating head, the die lip gap is set at 0.3 mm, the running speed of the substrate is 0.8 m / min, and it immediately enters a hot air drying tunnel at 45°C for 20 minutes after coating.

[0114] In step S7, the pre-curing stage is carried out in an environment with a temperature of 25±2°C and a relative humidity of 55%, and the material is allowed to stand for 30 minutes to complete the preliminary shaping. The ultraviolet cross-linking treatment uses a UV light source with a wavelength of 365 nm, the irradiation intensity is 15 mW / cm 2 , the conveyor belt speed is 0.5 m / min, ensuring that each patch receives a cumulative light energy of 1800 mJ / cm 2 . The slitting process uses a servo die cutter, the tool pressure is set at 5 kg / cm 2 , and the product after slitting is immediately transferred to an aluminum foil bag for sealed packaging.

[0115] In step S8, the sterilization process uses a 60Co γ-ray irradiation device, the product loading density is controlled at 15 kg / m 3 , the irradiation dose is set at 25 kGy, and the transmission speed is adjusted to 0.3 m / min. After the packaged finished product is stored in an environment with a temperature of 25°C and a humidity of 40% for 72 hours, a thermosensitive phase change test is carried out to detect whether the phase change temperature is stable at 32±0.5°C. The in vitro percutaneous experiment uses a modified Franz diffusion cell, maintaining the temperature of the receptor fluid at 37±0.5°C, continuously monitoring the drug penetration amount for 24 hours, and ensuring that the cumulative release degree reaches more than 85% of the standard requirements

[0116] As can be seen from the above: In the present invention, the theory of monarch, minister, assistant, and guide compatibility of traditional Chinese medicine and modern preparation technologies form a well-defined efficacy system. The monarch drug group focuses on promoting blood circulation to remove blood stasis, and in combination with the meridians-unblocking components of the minister drug group, can effectively promote local qi and blood circulation and improve the state of meridian blockage. The intelligent penetration enhancement technology adopted by the assistant and guide drug group breaks through the traditional transdermal limitations, enabling the drug components to quickly penetrate into deep tissues and be continuously released. This not only retains the advantages of the overall regulation of traditional Chinese medicine but also solves the problem of low bioavailability of topical preparations. The precise design of the spatial distribution and time release of each component achieves a dynamic balance between rapid efficacy and long-term efficacy, which is particularly suitable for the needs of different pathological stages such as chronic strain or acute sprain.

[0117] In the present invention, the unity of safety and effectiveness is achieved through innovative preparation processes. The combination of the temperature-sensitive matrix and the sustained-release structure can not only avoid skin irritation caused by the sudden release of drug concentration in traditional patches but also ensure a stable action concentration of therapeutic components at the lesion site. The application of the ionic liquid drug delivery system and the nano-delivery technology significantly improves the skin penetration rate of lipophilic active components while reducing the risk of damage to the skin barrier function. The design of the multi-layer drug-loaded microspheres enables drug components with different properties to target corresponding tissue layers, forming multi-target interventions in improving microcirculation, relieving pain, eliminating swelling, etc., which better meets the modern clinical requirements for precise treatment compared with traditional plasters.

[0118] It should be noted that in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "including" or any other variant thereof is intended to cover non-exclusive inclusion, so that a process, method, article, or device including a series of elements not only includes those elements but also includes other elements not expressly listed, or elements inherent to such process, method, article, or device. Without further limitation, an element defined by the statement "including a..." does not exclude the existence of additional identical elements in the process, method, article, or device including the said element.

[0119] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A formula for a traditional Chinese medicine patch for activating blood circulation and dredging meridians, characterized in that: The formula includes: The monarch drug group: 20 - 25 parts by weight of safflower ultrafine powder; 15 - 25 parts by weight of chuanxiong nano-liposomes; 10 - 20 parts by weight of salidroside extract; The minister drug group: 12 - 20 parts by weight of total saponins of notoginseng microemulsion; 8 - 10 parts by weight of rhizoma corydalis alkaloid sustained-release granules; 10 - 20 parts by weight of coptidis chinensis iridoid complex; The assistant and guiding drug group: 6 - 15 parts by weight of menthol-β-cyclodextrin inclusion complex; 5 parts by weight of ionic liquid-loaded curcumin; 3 - 5 parts by weight of nano-zinc oxide-loaded capsaicin; Matrix system 100 - 125 parts by weight of thermosensitive hydrogel matrix; 15 - 20 parts by weight of sodium alginate sustained-release matrix; 20 - 25 parts by weight of medical-grade silicone pressure-sensitive adhesive.

2. The formulation of a traditional Chinese herbal medicine patch for activating blood circulation and dredging meridians according to claim 1, characterized in that: The method for preparing the Chinese herbal medicine patch using the formula includes the following steps: S1: The safflower raw material is subjected to supercritical CO2 extraction to obtain the fat-soluble components, and the safflower ultrafine powder is prepared by molecular sieve fractionation technology. At the same time, the chuanxiong extract is compounded with phospholipids, and the chuanxiong nano-liposomes are prepared by the thin film dispersion method; S2: The total saponins of notoginseng are mixed with an emulsifier, and a microemulsion system is prepared by a high-pressure homogenizer. The rhizoma corydalis alkaloid and the sustained-release excipient are coated by fluidized bed to form sustained-release granules, and the coptidis chinensis extract is included by cyclodextrin to obtain the iridoid complex; S3: Using microfluidic chip technology, the salidroside extract, the total saponins of notoginseng microemulsion and the rhizoma corydalis sustained-release granules are mixed in proportion to construct a multi-layer drug-loaded microsphere with a core-shell structure; S4: Menthol and β-cyclodextrin are formed into an inclusion complex by the saturated aqueous solution method, curcumin is dissolved in a specific ionic liquid to form a drug-loaded system, and capsaicin and nano-zinc oxide are loaded by the solvent evaporation method; S5: The thermosensitive hydrogel matrix is heated to a molten state at 40°C, and the sodium alginate sustained-release matrix and the medical-grade silicone pressure-sensitive adhesive are added in sequence, and stirred at a speed of 500 rpm to form a homogeneous matrix S6: All the active ingredients prepared in S1 to S4 are added to the matrix system in three gradients. After vacuum degassing treatment, a 0.3 mm thick ointment layer is formed on the release paper by a precision coater; S7: Carry out staged curing treatment in the temperature control room. First, pre-cure in an environment of 25°C for 30 minutes, then crosslink by ultraviolet irradiation for 15 minutes, and finally cut into patches with a specification of 6×8 cm; S8: After the finished product is sterilized by 60Co irradiation, it is packaged with an aluminum-plastic composite film, and the thermosensitive phase change characteristics detection and in vitro transdermal release verification are completed.

3. The formulation of a traditional Chinese herbal medicine patch for activating blood circulation and dredging meridians according to claim 1, characterized in that: In the step S1, the safflower raw material is placed in a supercritical CO2 extraction device, the extraction pressure is set at 25 MPa, the temperature is controlled at 45°C for 2 hours, and the fat-soluble extract is collected; the obtained product passes through a molecular sieve fractionation system and passes through 200-mesh and 500-mesh stainless steel sieves in sequence to obtain an ultrafine powder with a particle size less than 10 microns; at the same time, the chuanxiong water extract and soybean phospholipids are mixed at a mass ratio of 1:3, treated by the thin film dispersion method in a 55°C water bath, and after removing the organic solvent by vacuum rotary evaporation, it is cycled 5 times under the condition of 15000 psi using a high-pressure homogenizer to obtain a nano-liposome suspension with a particle size distribution of 80 - 120 nm.

4. The formula of a traditional Chinese medicine plaster for activating blood circulation and dredging meridians as described in claim 1, characterized in that: In step S2, total saponins of Panax notoginseng and polyoxyl castor oil are mixed at a ratio of 15%, and deionized water is added to adjust the total solid content to 8%. It is processed through a high-pressure homogenizer at a pressure of 70 MPa for 3 cycle periods to form a microemulsion system with a particle size less than 100 nm; tetrahydropalmatine and ethylcellulose are mixed at a ratio of 2:1, and bottom spraying coating is carried out by a fluidized bed coating device at an inlet air temperature of 40 °C, controlling the atomization pressure at 0.3 MPa, and finally obtaining sustained-release granules with a coating weight gain of 30%; iridoid glycosides of Spatholobus suberectus and hydroxypropyl-β-cyclodextrin are stirred in an aqueous solution at 50 °C for 8 hours at a molar ratio of 1:4, and white inclusion complex powder is obtained through freeze-drying.

5. The formula of a traditional Chinese medicine patch for activating blood circulation and dredging meridians according to claim 1, characterized in that: In step S3, a microfluidic chip device is used, setting the inner layer phase as the salidroside ethanol solution, the middle layer phase as the Panax notoginseng microemulsion system, and the outer layer phase as the suspension of Corydalis yanhusuo sustained-release granules; controlling the synchronous flow rates of the three phases to be 0.8 mL / min, 1.2 mL / min, and 2.0 mL / min respectively, and forming three-layer core-shell structured microspheres with a diameter of 200 ± 50 μm at the chip outlet; the collected microspheres are immediately transferred to a low-temperature curing box at -40 °C for freezing and shaping, and the water content of the final product is controlled below 3%.

6. The formula of a traditional Chinese medicine plaster for activating blood circulation and dredging meridians according to claim 1, characterized in that: In step S4, menthol and β-cyclodextrin are dissolved in deionized water at 45 °C, magnetically stirred for 12 hours and then left to crystallize, centrifuged to collect the inclusion complex crystals and processed in a vacuum drying oven at 50 °C for 6 hours; curcumin is dissolved in a choline-capric acid ionic liquid system, controlling the drug loading to be 12%, and a homogeneous drug-loaded solution is formed by constant temperature stirring at 60 °C for 4 hours; capsaicin and nano-zinc oxide are dispersed in an ethanol-water mixed solvent at a mass ratio of 1:5, processed by an ultrasonic cell disruptor for 30 minutes, and then concentrated to a semi-solid state at 60 °C under reduced pressure in a rotary evaporator.

7. The formulation of a traditional Chinese herbal plaster for activating blood circulation and dredging meridians according to claim 1, characterized in that: In step S5, the temperature-sensitive hydrogel matrix is preheated in a melting tank at 40 ± 2 °C for 30 minutes, and sodium alginate powder and silicone pressure-sensitive adhesive are added in sequence; a double planetary mixer is used to mix at a speed of 500 rpm for 45 minutes, and the pH value of the system is adjusted to 6.8 - 7.2 in three times during this period; after mixing, it is transferred to a vacuum degassing tank, and degassing treatment is continuously carried out under a negative pressure of -0.08 MPa for 20 minutes, and finally the matrix viscosity is controlled at 15000 ± 2000 mPa·s.

8. The formulation of a traditional Chinese medicine plaster for activating blood circulation and dredging channels as described in claim 1, characterized in that: In step S6, the active ingredients are added in three stages: firstly, ligustrazine liposomes and Panax notoginseng microemulsion are added, and stirred at a low speed of 200 rpm for 15 minutes; secondly, Rhodiola microspheres and Corydalis yanhusuo granules are added, the temperature is raised to 38 °C and stirring is maintained for 30 minutes; in the final stage, the penetration enhancer component is added, and after cooling to 30 °C, continuous mixing is carried out for 1 hour; for the coating process, a servo-controlled coating head is used, setting the die lip gap at 0.3 mm, the running speed of the substrate at 0.8 m / min, and after coating, it immediately enters a hot air drying tunnel at 45 °C for 20 minutes.

9. The formula of a traditional Chinese medicine plaster for activating blood circulation and dredging meridians according to claim 1, characterized in that: In the step S7, the pre-curing stage is carried out in an environment with a temperature of 25 ± 2 °C and a relative humidity of 55%. The material is left standing for 30 minutes to complete the preliminary shaping. The ultraviolet cross-linking treatment uses a UV light source with a wavelength of 365 nm and an irradiation intensity of 15 mW / cm 2 , the conveyor belt speed is 0.5 m / min, ensuring that each patch receives a cumulative light energy of 1800 mJ / cm 2 ; The slitting process uses a servo die-cutting machine, and the tool pressure is set at 5 kg / cm 2 . After slitting, the product is immediately transferred to an aluminum foil bag for sealed packaging.

10. The formulation of a traditional Chinese medicine plaster for activating blood circulation and dredging meridians according to claim 1, characterized in that: In the step S8, a 60Co γ-ray irradiation device is used for the sterilization process, and the product loading density is controlled at 15 kg / m 3 , the irradiation dose is set at 25 kGy, and the transmission speed is adjusted to 0.3 m / min; after the packaged finished product is stored for 72 hours in an environment with a temperature of 25°C and a humidity of 40%, a thermosensitive phase transition test is carried out to detect whether the phase transition temperature is stably at 32 ± 0.5°C; for the in vitro transdermal experiment, a modified Franz diffusion cell is used, the temperature of the receptor fluid is maintained at 37 ± 0.5°C, and the drug permeation amount is continuously monitored for 24 hours to ensure that the cumulative release degree reaches more than 85% of the standard requirements.

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