Compound double-flower external preparation for treating allergic dermatitis

Abstract

The invention discloses a compound double-flower external preparation for treating allergic dermatitis, and relates to the technical field of medicine preparation, and the compound double-flower external preparation comprises the steps of raw material pretreatment, stepped extraction, filtration, purification, concentration, matrix and additive preparation and compound forming sterilization. The preparation method comprises the following steps: firstly extracting andrographis paniculata and isatis root with ethanol to obtain fat-soluble effective components, then decocting residues with water, honeysuckle and fructus forsythiae to obtain water-soluble components, thereby avoiding the problem of component loss caused by a single extraction mode, carrying out targeted purification in combination with a macroporous resin column, effectively removing impurities and improving the purity of target components, and meanwhile, preparing the water-soluble components. Carboxymethyl chitosan and poloxamer 407 are prepared into a compound matrix, and the compound matrix is matched with a functional additive formed by a penetration enhancer solution and a liposome dispersion liquid, so that the transdermal efficiency of the medicine is improved, the skin irritation is reduced, and finally, the effects of better curative effect and better safety of the preparation are achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, specifically to a compound honeysuckle topical preparation for treating allergic dermatitis. Background Technology

[0002] Allergic dermatitis is a type of inflammatory skin disease mediated by immune abnormalities. Clinically, it is mainly characterized by skin erythema, papules, itching, and exudation. It can occur in people of all ages, and the incidence rate is increasing year by year. Although the disease is not life-threatening, the recurrent itching and skin damage can seriously affect the patient's quality of life and even cause psychological problems such as anxiety and depression, which brings a significant burden to individuals and society. Existing technologies have certain drawbacks. First, they employ a single extraction method, leading to the loss of effective ingredients, high levels of impurities and low purity, poor transdermal efficiency, and high skin irritation. Second, existing topical preparations have a short duration of antipruritic effect, failing to achieve long-term suppression of itching after a single dose, thus failing to meet patients' needs for discomfort relief. Furthermore, existing preparations only provide superficial symptom relief and cannot regulate immune imbalances or intervene in the pathogenesis of allergic dermatitis, resulting in incomplete treatment. Therefore, we propose a compound honeysuckle topical preparation for the treatment of allergic dermatitis. Summary of the Invention

[0003] The purpose of this invention is to provide a compound honeysuckle topical preparation for treating allergic dermatitis.

[0004] To achieve the above objectives, the present invention provides the following technical solution: a compound honeysuckle topical preparation for treating allergic dermatitis, comprising a method for preparing the compound honeysuckle topical preparation, wherein the method for preparing the compound honeysuckle topical preparation includes the following steps: Step 1: Select Andrographis paniculata, Isatis indigotica, Lonicera japonica and Forsythia suspensa as raw materials, remove impurities and non-medicinal parts, then crush, sieve and dry for later use; Step 2: Take the pretreated andrographis paniculata and isatis indigotica root, mix them, add ethanol to extract to obtain alcohol extract A, separate the residue, add honeysuckle and forsythia, add water and decoct to obtain water extract B. Step 3: Combine the alcohol extract A and the water extract B, perform coarse filtration and then fine filtration, and collect the filtrate; Step 4: Load the filtrate onto a macroporous resin column, elute to remove impurities, elute the target component, and collect the eluent; Step 5: Concentrate the eluent under reduced pressure to obtain a concentrated extract of compound honeysuckle; Step 6: Prepare carboxymethyl chitosan aqueous solution and poloxamer 407 aqueous solution separately, and mix them to form a composite gel matrix; Step 7: Prepare a penetration enhancer solution by taking azone, menthol and propylene glycol, and prepare a liposome dispersion by taking dipotassium glycyrrhizate and phospholipid solution. Mix them to obtain a functional additive solution. Step 8: Mix the compound honeysuckle extract concentrate with the composite gel matrix, then add the functional additive solution, sterilize, and dispense into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

[0005] As a further aspect of the present invention: In step one, 20-30 parts of Andrographis paniculata, 15-25 parts of Isatis indigotica, 10-20 parts of Lonicera japonica and 10-20 parts of Forsythia suspensa are selected as raw materials. After removing impurities and non-medicinal parts, they are pulverized into 80-100 mesh particles. The Andrographis paniculata and Isatis indigotica particles pass through a 100-110 mesh sieve, while the Lonicera japonica and Forsythia suspensa particles pass through an 80-90 mesh sieve. The processed raw materials are placed in a desiccator for later use. The relative humidity in the desiccator is controlled at 30%-40%, and the temperature is controlled at 25±2℃.

[0006] As a further aspect of the present invention: In step two, pretreated Andrographis paniculata and Isatis indigotica granules are mixed, and 8-10 times their mass of 70% ethanol solution is added. The mixture is then extracted at a constant temperature of 80±2℃ for 1±0.1 h, with ultrasonic assistance used during the extraction process. The ultrasonic power is 300W-350W, and the frequency is 40kHz-45kHz, yielding ethanol extract A. The ethanol extract residue is separated by filtration, and honeysuckle and forsythia granules are added to the residue, followed by 10-12 times their mass of purified water. The mixture is then decocted at 100±2℃ for 45±5 min, maintaining a gentle boil during the decoction process, yielding aqueous extract B. The formula for calculating the andrographolide transfer rate is as follows: ; in, The transfer rate of andrographolide, The concentration of andrographolide in alcohol extract A, mg / mL, was determined by HPLC: C18 column, mobile phase methanol-water = 60:40, detection wavelength 225 nm, retention time 12.5 ± 0.5 min. The initial concentration (mg / g) of andrographolide in the raw material. The total volume of alcohol extract A is expressed in mL. For the quality (g) of Andrographis paniculata raw material, make ≥70%, and the purity of andrographolide ≥95% (HPLC normalization method).

[0007] As a further aspect of the present invention: In step three, the alcohol extract A and the water extract B are combined, first coarsely filtered through a 300-350 mesh filter cloth to remove large particulate impurities, and then finely filtered using a 0.45μm-0.5μm microporous membrane. The filtrate is collected, and the temperature of the filtrate is maintained at 40±5℃ during the filtration process to avoid temperature fluctuations that could cause the components to be separated.

[0008] As a further aspect of the present invention: In step four, the filtered filtrate is loaded onto a pretreated D101 macroporous resin column with a column diameter-to-height ratio of 1:8-1:10. The loading flow rate is controlled at 1-2 BV / h. After loading, impurities are removed by elution with 3-3.5 column volumes of 30%-33% ethanol solution at a flow rate of 2-3 BV / h. The impurities are discarded. Then, the target component andrographolide is eluted with 5-5.5 column volumes of 70%-75% ethanol solution at a flow rate of 1-2 BV / h. The eluent is collected. The purity of andrographolide is calculated using the following formula: ; PP represents the purity of andrographolide. The mass (mg) of andrographolide in the eluent was quantitatively determined by HPLC. The total mass (mg) of impurities in the eluent is controlled. ≥85%.

[0009] As a further aspect of the present invention: In step five, the purified eluent is placed in a rotary evaporator and concentrated under reduced pressure at 60±5℃ and -0.08 to -0.09 MPa until the relative density of the concentrate at 60℃-62℃ reaches 1.05-1.10 (determined by the hydrometer method). Concentration is then stopped to obtain a compound honeysuckle extract concentrate, wherein the content of andrographolide accounts for 25-35% of the total mass of the extract (detected by HPLC). The concentrate is then cooled to room temperature for later use.

[0010] As a further embodiment of the present invention: In step six, 5-8 parts of carboxymethyl chitosan with a degree of deacetylation ≥90% and a molecular weight of 10kDa-20kDa (determined by viscosity method) are taken, and 80-100 parts of purified water are added. The mixture is stirred at 60±5℃ until completely dissolved to obtain a carboxymethyl chitosan aqueous solution. Separately, 15-20 parts of poloxamer 407 are taken, and 60-80 parts of purified water at 4℃-5℃ are added. The mixture is stirred until completely dissolved to obtain a poloxamer 407 aqueous solution. The two aqueous solutions are mixed at a volume ratio of 1:1 and stirred at 30±2℃ for 30±5 min to form a composite gel matrix for later use.

[0011] As a further embodiment of the present invention: In step seven, 1-3 parts of azone and 0.5-1 parts of menthol are added to 5-10 parts of propylene glycol and stirred until completely dissolved to obtain a penetration enhancer solution. Separately, 2-4 parts of dipotassium glycyrrhizate are added to 20-30 parts of phospholipid solution (concentration 10%, w / v). A liposome dispersion is prepared using a thin-film dispersion-high-pressure homogenization method. First, a film is formed by rotary evaporation, then hydrated with buffer solution, and then homogenized by cycling at 30-40 MPa pressure 3-4 times to obtain a liposome dispersion. The liposome particle size is determined to be 80-120 nm by dynamic light scattering method, and the encapsulation rate is determined to be ≥80% by centrifugation method. The penetration enhancer solution and the liposome dispersion are mixed at a volume ratio of 2-2.2:1 and stirred for 15±5 min to obtain a functional additive solution.

[0012] As a further aspect of the present invention: In step eight, the compound honeysuckle extract concentrate obtained in step five is mixed with the composite gel matrix obtained in step six at a mass ratio of 1:3-1:5, and stirred at 300±50 rpm for 20±5 min. Then, the functional additive solution from step seven is added, with the amount added being 5%-8% of the total mass of the mixture. Stirring continues for 30±5 min until the mixture is homogeneous. At this point, the transdermal concentration of andrographolide in the preparation is ≥5 μg / cm³. 2 (The dose-response relationship was established by the Franz diffusion cell method and the inhibition rate of IgE-mediated mast cell degranulation ≤20%). The mixture was placed in an ultraviolet sterilizer and sterilized at a wavelength of 254nm for 30±5min. After sterilization, it was dispensed into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

[0013] Compared with the prior art, the beneficial effects of the present invention by adopting the above technical solution are as follows: 1. This invention employs a step-by-step alcohol-water dual extraction process. First, ethanol is used to extract the fat-soluble active ingredients from Andrographis paniculata and Isatis indigotica. Then, the residue from the decoction is combined with Lonicera japonica and Forsythia suspensa to extract the water-soluble components. This avoids the component loss problem caused by single extraction methods. Combined with macroporous resin column for targeted purification, impurities are effectively removed and the purity of the target components is improved. At the same time, carboxymethyl chitosan and poloxamer 407 are made into a composite matrix. Combined with the functional additives formed by the penetration enhancer solution and liposome dispersion, the transdermal efficiency of the drug is enhanced and the skin irritation is reduced. Ultimately, the formulation achieves better efficacy and safety. 2. This invention prepares a penetration enhancer solution containing azone and menthol, which works synergistically with a composite matrix formed by carboxymethyl chitosan and poloxamer 407. The penetration enhancer solution promotes the penetration of active ingredients into the skin, while the composite matrix enables the slow release of the drug. Together with the components in the functional additives, the drug continues to exert its effects. This combination solves the problem of short duration of antipruritic effect in traditional topical preparations. Compared with conventional preparations, it can suppress itching for a longer period of time after a single dose, meeting patients' needs for long-lasting relief of discomfort.

[0014] 3. This invention utilizes a step-by-step alcohol-water dual extraction process to fully extract the effective components from Andrographis paniculata, Isatis indigotica, Lonicera japonica, and Forsythia suspensa. The active components are then purified and enriched using a macroporous resin column and combined with a liposome dispersion containing dipotassium glycyrrhizate. This allows the effective components to more easily act on immune cells and inhibit IgE-mediated mast cell degranulation. This process overcomes the shortcomings of traditional preparations that can only superficially relieve symptoms and are difficult to regulate immune imbalance. It achieves deep intervention on the pathogenesis of allergic dermatitis and enhances the fundamental nature of the treatment. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the core preparation process of the compound honeysuckle external preparation in an embodiment of the present invention; Figure 2 This is a schematic diagram of the method steps in an embodiment of the present invention. Detailed Implementation

[0016] The specific embodiments of the present invention will be further described below with reference to the accompanying drawings. It should be noted that the description of these embodiments is for the purpose of helping to understand the present invention, but does not constitute a limitation of the present invention.

[0017] Furthermore, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not conflict with each other.

[0018] Please see the appendix Figure 1 -Appendix Figure 2 This invention discloses a compound honeysuckle topical preparation for treating allergic dermatitis, including a method for preparing the compound honeysuckle topical preparation. The method for preparing the compound honeysuckle topical preparation includes the following steps: Step 1: Select Andrographis paniculata, Isatis indigotica, Lonicera japonica and Forsythia suspensa as raw materials, remove impurities and non-medicinal parts, then crush, sieve and dry for later use; Step 2: Take the pretreated andrographis paniculata and isatis indigotica root, mix them, add ethanol to extract to obtain alcohol extract A, separate the residue, add honeysuckle and forsythia, add water and decoct to obtain water extract B. Step 3: Combine the alcohol extract A and the water extract B, perform coarse filtration and then fine filtration, and collect the filtrate; Step 4: Load the filtrate onto a macroporous resin column, elute to remove impurities, elute the target component, and collect the eluent; Step 5: Concentrate the eluent under reduced pressure to obtain a concentrated extract of compound honeysuckle; Step 6: Prepare carboxymethyl chitosan aqueous solution and poloxamer 407 aqueous solution separately, and mix them to form a composite gel matrix; Step 7: Prepare a penetration enhancer solution by taking azone, menthol and propylene glycol, and prepare a liposome dispersion by taking dipotassium glycyrrhizate and phospholipid solution. Mix them to obtain a functional additive solution. Step 8: Mix the compound honeysuckle extract concentrate with the composite gel matrix, then add the functional additive solution, sterilize, and dispense into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

[0019] In one embodiment of the present invention: In step one, 20-30 parts of Andrographis paniculata, 15-25 parts of Isatis indigotica, 10-20 parts of Lonicera japonica and 10-20 parts of Forsythia suspensa are selected as raw materials. After removing impurities and non-medicinal parts, they are pulverized into 80-100 mesh particles. The Andrographis paniculata and Isatis indigotica particles pass through a 100-110 mesh sieve, and the Lonicera japonica and Forsythia suspensa particles pass through an 80-90 mesh sieve. The processed raw materials are placed in a desiccator for later use. The relative humidity in the desiccator is controlled at 30%-40%, and the temperature is controlled at 25±2℃.

[0020] In one embodiment of the present invention: In step two, pretreated Andrographis paniculata and Isatis indigotica granules are mixed and 8-10 times their mass of 70% ethanol solution is added. The mixture is then extracted at a constant temperature of 80±2℃ for 1±0.1 h, with ultrasonic assistance used during the extraction process. The ultrasonic power is 300W-350W and the frequency is 40kHz-45kHz. This yields ethanol extract A. The ethanol extract residue is separated by filtration. Honeysuckle and Forsythia suspensa granules are added to the residue, followed by 10-12 times their mass of purified water. The mixture is then decocted at 100±2℃ for 45±5 min, maintaining a gentle boil during the decoction process. This yields aqueous extract B. The formula for calculating the andrographolide transfer rate is as follows: ; in, The transfer rate of andrographolide, The concentration of andrographolide in alcohol extract A, mg / mL, was determined by HPLC: C18 column, mobile phase methanol-water = 60:40, detection wavelength 225 nm, retention time 12.5 ± 0.5 min. The initial concentration (mg / g) of andrographolide in the raw material. The total volume of alcohol extract A is expressed in mL. For the quality (g) of Andrographis paniculata raw material, make ≥70%, and the purity of andrographolide ≥95% (HPLC normalization method).

[0021] In one embodiment of the present invention: In step three, alcohol extract A and water extract B are combined, first coarsely filtered through a 300-350 mesh filter cloth to remove large particulate impurities, and then finely filtered using a 0.45μm-0.5μm microporous membrane. The filtrate is collected, and the temperature of the filtrate is maintained at 40±5℃ during the filtration process to avoid temperature fluctuations that could cause the components to be separated.

[0022] In one embodiment of the present invention: In step four, the filtered filtrate is loaded onto a pretreated D101 macroporous resin column with a column diameter-to-height ratio of 1:8-1:10. The loading flow rate is controlled at 1-2 BV / h. After loading, impurities are removed by elution with 3-3.5 column volumes of 30%-33% ethanol solution at a flow rate of 2-3 BV / h. The impurities are discarded. Then, the target component andrographolide is eluted with 5-5.5 column volumes of 70%-75% ethanol solution at a flow rate of 1-2 BV / h. The eluent is collected. The purity of andrographolide is calculated using the following formula: ; PP represents the purity of andrographolide. The mass (mg) of andrographolide in the eluent was quantitatively determined by HPLC. The total mass (mg) of impurities in the eluent is controlled. ≥85%.

[0023] In one embodiment of the present invention: In step five, the purified eluent is placed in a rotary evaporator and concentrated under reduced pressure at 60±5℃ and -0.08 to -0.09 MPa until the relative density of the concentrate at 60℃-62℃ reaches 1.05-1.10 (determined by the hydrometer method). Concentration is then stopped to obtain a compound honeysuckle extract concentrate, wherein the content of andrographolide accounts for 25-35% of the total mass of the extract (detected by HPLC). The concentrate is then cooled to room temperature for later use.

[0024] In one embodiment of the present invention: In step six, 5-8 parts of carboxymethyl chitosan with a degree of deacetylation ≥90% and a molecular weight of 10kDa-20kDa (determined by viscosity method) are taken, and 80-100 parts of purified water are added. The mixture is stirred at 60±5℃ until completely dissolved to obtain a carboxymethyl chitosan aqueous solution. Separately, 15-20 parts of poloxamer 407 are taken, and 60-80 parts of purified water at 4℃-5℃ are added. The mixture is stirred until completely dissolved to obtain a poloxamer 407 aqueous solution. The two aqueous solutions are mixed at a volume ratio of 1:1 and stirred at 30±2℃ for 30±5 min to form a composite gel matrix for later use.

[0025] In one embodiment of the present invention: In step seven, 1-3 parts of azone and 0.5-1 parts of menthol are added to 5-10 parts of propylene glycol and stirred until completely dissolved to obtain a penetration enhancer solution. Separately, 2-4 parts of dipotassium glycyrrhizate are added to 20-30 parts of phospholipid solution (concentration 10%, w / v). A liposome dispersion is prepared by thin-film dispersion-high pressure homogenization. First, a film is formed by rotary evaporation, then hydrated with buffer solution, and then homogenized by cycling at 30-40 MPa for 3-4 times to obtain a liposome dispersion. The liposome particle size is determined to be 80-120 nm by dynamic light scattering method, and the encapsulation efficiency is determined to be ≥80% by centrifugation method. The penetration enhancer solution and the liposome dispersion are mixed at a volume ratio of 2-2.2:1 and stirred for 15±5 min to obtain a functional additive solution.

[0026] In one embodiment of the present invention: In step eight, the compound honeysuckle extract concentrate obtained in step five is mixed with the composite gel matrix obtained in step six at a mass ratio of 1:3-1:5, and stirred at 300±50 rpm for 20±5 min. Then, the functional additive solution from step seven is added, with the amount added being 5%-8% of the total mass of the mixture. Stirring continues for 30±5 min until the mixture is homogeneous. At this point, the transdermal concentration of andrographolide in the preparation is ≥5 μg / cm³. 2 (The dose-response relationship was established by the Franz diffusion cell method and the inhibition rate of IgE-mediated mast cell degranulation ≤20%). The mixture was placed in an ultraviolet sterilizer and sterilized at a wavelength of 254nm for 30±5min. After sterilization, it was dispensed into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

[0027] Example 1, please refer to the appendix. Figure 1 -Appendix Figure 2 Raw material pretreatment: 25 parts of Andrographis paniculata, 20 parts of Isatis indigotica, 15 parts of Lonicera japonica, and 15 parts of Forsythia suspensa were selected. After removing impurities and non-medicinal parts, they were pulverized into 90-mesh particles. The Andrographis paniculata and Isatis indigotica particles were passed through a 100-mesh sieve, while the Lonicera japonica and Forsythia suspensa particles were passed through an 80-mesh sieve. The processed raw materials were placed in a desiccator for later use. The relative humidity inside the desiccator was 35%, and the temperature was 25℃.

[0028] Stepwise alcohol-water dual extraction: Pretreated Andrographis paniculata and Isatis indigotica granules were mixed and 9 times their weight of 70% ethanol solution (v / v) were added. The mixture was extracted at 80℃ for 1 hour with ultrasonic assistance (300W power, 40kHz frequency). The ethanol extract A was obtained by filtration. After separating the residue, honeysuckle and forsythia granules were added, and then 10 times their weight of purified water was added. The mixture was boiled at 100℃ for 45 minutes to obtain water extract B. HPLC analysis showed that the andrographolide transfer rate TR was 72% and the purity was 96%.

[0029] Extraction combination and filtration: The alcohol extract A and the water extract B were combined, first coarsely filtered through a 300-mesh filter cloth, and then precisely filtered through a 0.45μm microporous membrane. The temperature of the filtrate was maintained at 40℃ during the filtration process, and the filtrate was collected.

[0030] Targeted purification and component enrichment: The filtrate was loaded onto a pretreated D101 macroporous resin column (column diameter to height ratio 1:8) at a flow rate of 1 BV / h. After loading, the column was eluted with 3 column volumes of 30% ethanol solution at a flow rate of 2 BV / h to remove impurities. The impurities were discarded. Andrographolide was then eluted with 5 column volumes of 70% ethanol solution at a flow rate of 1 BV / h. The eluent was collected. The purity of andrographolide was calculated to be PP=86%.

[0031] Concentration process: The eluent was placed in a rotary evaporator and concentrated under reduced pressure at 60℃ and -0.08MPa until the relative density reached 1.05 at 60℃. Concentration was then stopped to obtain a compound honeysuckle extract concentrate, in which andrographolide accounted for 28% of the total mass of the extract (HPLC detection). The concentrate was cooled to room temperature for later use.

[0032] Preparation of composite matrix: Take 6 parts of carboxymethyl chitosan (92% degree of deacetylation, 15kDa molecular weight), add 90 parts of purified water, and stir at 60℃ until dissolved to obtain a carboxymethyl chitosan aqueous solution. Separately, take 18 parts of poloxamer 407, add 70 parts of purified water at 4℃, and stir until dissolved to obtain a poloxamer 407 aqueous solution. Mix the two aqueous solutions at a volume ratio of 1:1 and stir at 30℃ for 30 minutes to form a composite gel matrix.

[0033] Preparation of transdermal enhancement and anti-irritant system: Dissolve 2 parts azone and 0.8 parts menthol in 8 parts propylene glycol to obtain a penetration enhancer solution. Separately, add 3 parts dipotassium glycyrrhizate to 25 parts 10% phospholipid solution and prepare a liposome dispersion using a thin-film dispersion-high pressure homogenization method (first, rotary evaporation to form a film, then hydration with buffer, followed by homogenization at 30 MPa pressure for 3 cycles). The liposome particle size was measured to be 100 nm by dynamic light scattering and the encapsulation efficiency was measured to be 82% by centrifugation. Mix the penetration enhancer solution and the liposome dispersion at a volume ratio of 2:1 and stir for 15 minutes to obtain a functional additive solution.

[0034] Formulation and shaping: The concentrated extract of honeysuckle and chrysanthemum was mixed with the composite gel matrix at a mass ratio of 1:4 and stirred at 300 rpm for 20 minutes. Then, 6% (by mass) of the functional additive solution was added to the mixture, and stirring was continued for another 30 minutes until homogeneous. After sterilization with 254 nm ultraviolet light for 30 minutes, the mixture was dispensed into sterile containers to obtain the preparation. The transdermal concentration of andrographolide was determined to be 6 μg / cm³ using the Franz diffusion cell method.2 The IgE-mediated mast cell degranulation inhibition rate was 18%.

[0035] Example 2, please refer to the appendix. Figure 1 -Appendix Figure 2 Raw material pretreatment: 30 parts of Andrographis paniculata, 25 parts of Isatis indigotica, 20 parts of Lonicera japonica, and 18 parts of Forsythia suspensa were selected. After removing impurities and non-medicinal parts, they were pulverized into 100-mesh particles. The Andrographis paniculata and Isatis indigotica particles were passed through a 110-mesh sieve, while the Lonicera japonica and Forsythia suspensa particles were passed through a 90-mesh sieve. The processed raw materials were placed in a desiccator for later use. The relative humidity inside the desiccator was 38%, and the temperature was 26℃.

[0036] Stepwise alcohol-water dual extraction: Pretreated Andrographis paniculata and Isatis indigotica granules were mixed and 10 times their weight of 70% ethanol solution (v / v) were added. The mixture was extracted at 82℃ for 1.1 hours with ultrasonic assistance (350W power, 45kHz frequency). The ethanol extract A was obtained by filtration. After separating the residue, honeysuckle and forsythia granules were added, and then 12 times their weight of purified water was added. The mixture was boiled at 102℃ for 50 minutes to obtain aqueous extract B. HPLC analysis showed that the andrographolide transfer rate TR was 75% and the purity was 97%.

[0037] Extraction combination and filtration: The alcohol extract A and the water extract B were combined, first coarsely filtered through a 350-mesh filter cloth, and then precisely filtered through a 0.5μm microporous membrane. The temperature of the filtrate was maintained at 42℃ during the filtration process, and the filtrate was collected.

[0038] Targeted purification and component enrichment: The filtrate was loaded onto a pretreated D101 macroporous resin column (column diameter to height ratio 1:10) at a flow rate of 2 BV / h. After loading, the column was eluted with 3.5 column volumes of 33% ethanol solution at a flow rate of 3 BV / h to remove impurities. The impurities were discarded. Andrographolide was then eluted with 5.5 column volumes of 75% ethanol solution at a flow rate of 2 BV / h. The eluent was collected. The purity of andrographolide was calculated to be 88%.

[0039] Concentration process: The eluent was placed in a rotary evaporator and concentrated under reduced pressure at 65℃ and -0.09MPa until the relative density reached 1.10 at 60℃. Concentration was then stopped to obtain a compound honeysuckle extract concentrate, in which andrographolide accounted for 32% of the total mass of the extract (HPLC detection). The concentrate was cooled to room temperature for later use.

[0040] Preparation of composite matrix: Take 8 parts of carboxymethyl chitosan (95% degree of deacetylation, 18kDa), add 100 parts of purified water, and stir at 65℃ until dissolved to obtain a carboxymethyl chitosan aqueous solution. Separately, take 20 parts of poloxamer 407, add 80 parts of purified water at 5℃, and stir until dissolved to obtain a poloxamer 407 aqueous solution. Mix the two aqueous solutions at a volume ratio of 1:1 and stir at 32℃ for 35 minutes to form a composite gel matrix.

[0041] Preparation of transdermal enhancement and anti-irritant system: Dissolve 3 parts azone and 1 part menthol in 10 parts propylene glycol to obtain a penetration enhancer solution. Separately, add 4 parts dipotassium glycyrrhizate to 30 parts 10% phospholipid solution and prepare a liposome dispersion using a thin-film dispersion-high pressure homogenization method (first, rotary evaporation to form a film, then hydration with buffer, followed by 4 cycles of homogenization at 40 MPa). The liposome particle size was measured to be 110 nm by dynamic light scattering and the encapsulation efficiency was measured to be 85% by centrifugation. Mix the penetration enhancer solution and the liposome dispersion at a volume ratio of 2.2:1 and stir for 20 minutes to obtain a functional additive solution.

[0042] Formulation and shaping: The concentrated extract of honeysuckle and hibiscus was mixed with the composite gel matrix at a mass ratio of 1:5 and stirred at 350 rpm for 25 minutes. Then, 8% (by mass) of the functional additive solution was added, and stirring continued for 35 minutes until homogeneous. After sterilization with 254 nm ultraviolet light for 35 minutes, the mixture was dispensed into sterile containers to obtain the formulation. The transdermal concentration of andrographolide was determined to be 7 μg / cm³ using the Franz diffusion cell method. 2 The IgE-mediated mast cell degranulation inhibition rate was 17%.

[0043] Based on the above embodiments, it can be concluded that the differentiated extraction of Andrographis paniculata, Isatis indigotica, Lonicera japonica, and Forsythia suspensa using a stepwise alcohol-water dual extraction process, combined with targeted purification and enrichment of target components using macroporous resin columns, precise preparation of a carboxymethyl chitosan and poloxamer 407 composite matrix, synergistic formulation of azone-menthol permeation enhancer solution and liposome dispersion functional additives, and formulation compounding and sterilization operations, effectively avoids component loss caused by single extraction, improves the purity of target components, enhances drug transdermal efficiency, and reduces skin irritation. This achieves long-lasting antipruritic effect with a single dose. At the same time, by inhibiting IgE-mediated mast cell degranulation reaction, it deeply intervenes in immune imbalance, ultimately achieving better formulation efficacy, better safety, and good long-lasting relief of itching and deep immune regulation.

[0044] While the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the invention. Any variations and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. Therefore, any modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention, without departing from the scope of the invention, fall within the protection scope defined by the claims of the present invention.

Claims

1. A compound honeysuckle topical preparation for treating allergic dermatitis, comprising a method for preparing the compound honeysuckle topical preparation, characterized in that, The preparation method of the compound honeysuckle external preparation includes the following steps: Step 1: Select Andrographis paniculata, Isatis indigotica, Lonicera japonica and Forsythia suspensa as raw materials, remove impurities and non-medicinal parts, then crush, sieve and dry for later use; Step 2: Take the pretreated andrographis paniculata and isatis indigotica root, mix them, add ethanol to extract to obtain alcohol extract A, separate the residue, add honeysuckle and forsythia, add water and decoct to obtain water extract B. Step 3: Combine the alcohol extract A and the water extract B, perform coarse filtration and then fine filtration, and collect the filtrate; Step 4: Load the filtrate onto a macroporous resin column, elute to remove impurities, elute the target component, and collect the eluent; Step 5: Concentrate the eluent under reduced pressure to obtain a concentrated extract of compound honeysuckle; Step 6: Prepare carboxymethyl chitosan aqueous solution and poloxamer 407 aqueous solution separately, and mix them to form a composite gel matrix; Step 7: Prepare a penetration enhancer solution by taking azone, menthol and propylene glycol, and prepare a liposome dispersion by taking dipotassium glycyrrhizate and phospholipid solution. Mix them to obtain a functional additive solution. Step 8: Mix the compound honeysuckle extract concentrate with the composite gel matrix, then add the functional additive solution, sterilize, and dispense into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

2. The compound honeysuckle topical preparation for treating allergic dermatitis according to claim 1, characterized in that: In step one, 20-30 parts of Andrographis paniculata, 15-25 parts of Isatis indigotica, 10-20 parts of Lonicera japonica, and 10-20 parts of Forsythia suspensa are selected as raw materials. After removing impurities and non-medicinal parts, they are pulverized into 80-100 mesh particles. The Andrographis paniculata and Isatis indigotica particles pass through a 100-110 mesh sieve, while the Lonicera japonica and Forsythia suspensa particles pass through an 80-90 mesh sieve. The processed raw materials are placed in a desiccator for later use. The relative humidity in the desiccator is controlled at 30%-40%, and the temperature is controlled at 25±2℃.

3. The compound honeysuckle topical preparation for treating allergic dermatitis according to claim 2, characterized in that: In step two, pretreated Andrographis paniculata and Isatis indigotica granules are mixed and 8-10 times their weight of 70% ethanol solution is added. The mixture is then extracted at a constant temperature of 80±2℃ for 1±0.1 h, with ultrasonic assistance at a power of 300W-350W and a frequency of 40kHz-45kHz, yielding ethanol extract A. The ethanol extract residue is separated by filtration, and honeysuckle and forsythia granules are added to the residue, followed by 10-12 times their weight of purified water. The mixture is then decocted at 100±2℃ for 45±5 min, maintaining a gentle boil during the decoction process, yielding aqueous extract B. The formula for calculating the andrographolide transfer rate is as follows: ； in, The transfer rate of andrographolide, The concentration of andrographolide in alcohol extract A was determined by HPLC: C18 column, mobile phase methanol-water = 60:40, detection wavelength 225 nm, retention time 12.5 ± 0.5 min. This refers to the initial concentration of andrographolide in the raw materials. This represents the total volume of alcohol extract A. To ensure the quality of Andrographis paniculata raw materials, ≥70%, and the purity of andrographolide ≥95%.

4. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 3, characterized in that: In step three, the alcohol extract A and the water extract B are combined, first coarsely filtered through a 300-350 mesh filter cloth to remove large particulate impurities, and then finely filtered using a 0.45μm-0.5μm microporous membrane. The filtrate is collected, and the temperature of the filtrate is maintained at 40±5℃ during the filtration process.

5. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 4, characterized in that: In step four, the filtered filtrate is loaded onto a pretreated D101 macroporous resin column with a column diameter-to-height ratio of 1:8-1:

10. The loading flow rate is controlled at 1-2 BV / h. After loading, impurities are removed by elution with 3-3.5 column volumes of 30%-33% ethanol solution at a flow rate of 2-3 BV / h. The impurities are discarded. Then, the target component andrographolide is eluted with 5-5.5 column volumes of 70%-75% ethanol solution at a flow rate of 1-2 BV / h. The eluent is collected. The purity of andrographolide is calculated using the following formula: ； PP represents the purity of andrographolide. The mass of andrographolide in the eluent was quantitatively determined by HPLC. The total mass of impurities in the eluent is controlled. ≥85%.

6. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 5, characterized in that: In step five, the purified eluent is placed in a rotary evaporator and concentrated under reduced pressure at 60±5℃ and -0.08 to -0.09 MPa until the relative density of the concentrate at 60℃-62℃ reaches 1.05-1.

10. Concentration is then stopped to obtain a compound honeysuckle extract concentrate, in which the content of andrographolide accounts for 25-35% of the total mass of the extract. The concentrate is then cooled to room temperature for later use.

7. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 6, characterized in that: In step six, take 5-8 parts of carboxymethyl chitosan with a degree of deacetylation ≥90% and a molecular weight of 10kDa-20kDa (determined by viscosity method), add 80-100 parts of purified water, and stir at 60±5℃ until completely dissolved to obtain a carboxymethyl chitosan aqueous solution. Separately, take 15-20 parts of poloxamer 407, add 60-80 parts of purified water at 4℃-5℃, and stir until completely dissolved to obtain a poloxamer 407 aqueous solution. Mix the two aqueous solutions at a volume ratio of 1:1 and stir at 30±2℃ for 30±5 min to form a composite gel matrix for later use.

8. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 7, characterized in that: In step seven, 1-3 parts of azone and 0.5-1 parts of menthol are added to 5-10 parts of propylene glycol and stirred until completely dissolved to obtain a penetration enhancer solution. Separately, 2-4 parts of dipotassium glycyrrhizate are added to 20-30 parts of phospholipid solution. A liposome dispersion is prepared using a thin-film dispersion-high-pressure homogenization method. First, a film is formed by rotary evaporation, then hydrated with buffer solution, and then homogenized by cycling at 30-40 MPa for 3-4 times to obtain a liposome dispersion. The liposome particle size is determined to be 80-120 nm by dynamic light scattering method, and the encapsulation efficiency is determined to be ≥80% by centrifugation method. The penetration enhancer solution and the liposome dispersion are mixed at a volume ratio of 2-2.2:1 and stirred for 15±5 min to obtain a functional additive solution.

9. A compound honeysuckle topical preparation for treating allergic dermatitis according to claim 8, characterized in that: In step eight, the compound honeysuckle extract concentrate obtained in step five is mixed with the composite gel matrix from step six at a mass ratio of 1:3 to 1:

5. The mixture is stirred at 300±50 rpm for 20±5 minutes. Then, the functional additive solution from step seven is added, at a volume of 5%-8% of the total mass of the mixture. Stirring continues for another 30±5 minutes until homogeneous. At this point, the transdermal concentration of andrographolide in the preparation is ≥5 μg / cm³. 2 The mixture was placed in an ultraviolet sterilizer and sterilized at a wavelength of 254nm for 30±5 minutes. After sterilization, it was dispensed into sterile containers to obtain the compound honeysuckle topical preparation for treating allergic dermatitis.

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