External traditional Chinese medicine drop for conditioning whelk, eczema and rhinitis and preparation process thereof

Abstract

The invention belongs to the technical field of traditional Chinese medicine external preparations, and particularly relates to an external traditional Chinese medicine drop for conditioning whelk, eczema and rhinitis and a preparation process thereof. The core comprises the following steps: realizing ultrafine wall breaking of animal medicinal materials and gradient crushing of plant medicinal materials through a classified crushing technology; activating a low-temperature enzymolysis reaction by adopting an underground constant-temperature micro-aerobic fermentation process and combining with an earthen jar beewax coating; impurity interception and sterile control are completed through a three-stage membrane separation system; and finally, adding an azone-vitamin E composite infiltration promoting system, and carrying out nitrogen-filled packaging. According to the method, the dissolution rate and transdermal efficiency of active ingredients are improved, the problems of precipitation, oxidation, strong irritation and the like of a traditional preparation are synchronously solved, and the obtained drops are suitable for targeted conditioning of skin and mucosa inflammation.

Description

Technical Field

[0001] The present invention relates to the technical field of external Chinese medicine preparations, and more particularly to an external Chinese medicine drop for treating acne, eczema and rhinitis and a preparation process thereof. Background Art

[0002] Traditional Chinese medicine external treatment preparations have a long history of application in the fields of dermatology and ENT, and have shown unique advantages in the treatment of recurrent diseases such as acne, eczema, and rhinitis. Although traditional tinctures, oils and other external forms have certain therapeutic effects, they generally have bottlenecks such as low dissolution rate of active ingredients, high irritation, and poor stability. With the development of modern transdermal drug delivery technology, the market is in urgent need of an innovative traditional Chinese medicine preparation that can take into account efficient penetration, mild effects, and long-term preservation. In response to the shortcomings of the existing technology, the present invention constructs a new category of external use drops with targeted regulatory effects through a breakthrough fermentation process and a precise quality control system. Deficiencies in existing technology:

[0003] 1. Extensive pre-treatment technology of medicinal materials leads to waste of active ingredients

[0004] Traditional pulverization processes are inefficient at disrupting the cell walls of animal medicines (such as scorpions and centipedes) and mineral medicines (such as musk), and are unable to effectively release key active ingredients such as chitin and fat-soluble alkaloids. When mixed and pulverized botanicals, differences in hardness produce excessive thermal effects, resulting in a large loss of volatile substances (such as menthol and angelica root extract). Existing technologies lack a classification processing mechanism, and the content of the characteristic ingredients in the final preparation fluctuates significantly, directly affecting the stability of the therapeutic effect.

[0005] 2. The fermentation process lacks scientific control methods

[0006] Conventional medicinal wine fermentation, often performed in open-air ceramic vats or stored indoors, presents three major drawbacks: drastic temperature fluctuations, excessive oxygen exposure, and uncontrolled microbial communities. This results in incomplete enzymatic hydrolysis, insufficient degradation of large impurities, and the oxidation of ethanol to produce irritating acetaldehyde. More seriously, an imbalance in the ratio of anaerobic to aerobic bacteria can easily produce harmful amine byproducts, triggering skin allergies in users.

[0007] 3. The quality control system lacks the correlation of key indicators

[0008] Existing standards for topical liquid preparations of traditional Chinese medicine are mostly limited to basic items such as microbiological testing and ethanol content, and no quantitative correlation has been established between the content of active ingredients and clinical efficacy. For example, the core ingredients for treating rhinitis (xanthium sibiricum glycosides and anserine) and anti-eczema ingredients (chlorogenic acid and ligustrazine) lack quantitative control standards, resulting in significant differences in efficacy between different batches of products. There is also no full-process monitoring plan for risk substances such as heavy metals and pesticide residues.

[0009] 4. Dual defects in formulation stability and transdermal efficiency

[0010] Traditional tinctures are prone to precipitation, crystallization, and oxidative discoloration during long-term storage, primarily due to the lack of molecular capture technology and antioxidant protection mechanisms. More critically, the active ingredients in the solution have difficulty penetrating the skin's stratum corneum barrier. Existing technologies often rely on increasing concentration or adding chemical penetration enhancers, which in turn exacerbate skin irritation, creating an industry dilemma of "effective but damaging, mild but ineffective."

[0011] Therefore, in view of the above problems, an external-use Chinese medicine drop for treating acne, eczema and rhinitis and a preparation process thereof are proposed. Summary of the Invention

[0012] In order to overcome the above-mentioned defects of the prior art, the embodiments of the present invention provide a topical Chinese medicine drop for treating acne, eczema and rhinitis and a preparation process thereof, so as to solve the problems raised in the above-mentioned background technology.

[0013] To achieve the above-mentioned purpose, the present invention provides the following technical solution: a Chinese medicine drop for external use for treating acne, eczema and rhinitis and a preparation process thereof, which implements the following operation process:

[0014] S1. Accurately weigh 5 parts of Xanthium sibiricum, 5 parts of Carthamus tinctorius, 10 parts of Herba Capillaris, 0.01 parts of Musk, 5 parts of Curcuma aromatica, 10 parts of Magnolia Flos, 5 parts of Frankincense, 10 parts of Atractylodes macrocephala, 5 parts of Gastrodia elata, 10 parts of Honeysuckle, 5 parts of Bombyx batryticatus, 10 parts of Acorus calamus, 5 parts of Scorpion, 10 parts of Cyperus rotundus, 15 parts of Angelica dahurica, 5 parts of Angelica sinensis, 10 parts of Ligusticum chuanxiong, 5 parts of Scolopendra, 10 parts of Mentha, 5 parts of Pheretima, and 10 parts of Saposhnikovia divaricata.

[0015] S2. Grind the plant-based medicinal materials (Xanthium sibiricum, Carthamus tinctorius, Herba Capillaris, Curcuma aromatica, Magnolia bud, Frankincense, Atractylodes lancea, Gastrodia elata, Honeysuckle, Acorus calamus, Cyperus rotundus, Angelica dahurica, Angelica sinensis, Ligusticum chuanxiong, Mentha, and Saposhnikovia divaricata) into 100±20 mesh fine powder. Place the animal and mineral medicinal materials (Musk, Bombyx batryticatus, Scorpion, Centipede, and Earth Dragon) in a low-temperature environment of -18°C, pre-freeze with liquid nitrogen, and then use an ultrafine airflow mill to grind the particles to a size of D 90 ≤10μm;

[0016] S3. Mix the two types of powders and put them into a ceramic fermentation jar (8mm thick, 50L capacity) with an inner wall coated with 1.2±0.2mm food-grade beeswax, add 50±2% pure sorghum liquor with a concentration of 4.5 times the total weight of the powder, and simultaneously add 0.12% of the total weight of the powder in cellulase and 0.05% of the pectinase. After sealing the jar mouth, bury it in a clay loam layer (pH6.8-7.0) 1.8±0.2 meters deep underground. Ferment it in a constant temperature environment of 13±0.5℃ for 45±1 days. During this period, take out the jar every 120 hours, oscillate it at a speed of 120r / min for 5 minutes, and then rebury it.

[0017] Furthermore, the liquor must meet the following requirements: solid-state fermented liquor with sorghum as the main raw material, alcohol content of 50±1 degrees, total acid ≤1.2g / L (calculated as acetic acid), total ester ≥2.3g / L (calculated as ethyl acetate), methanol content <0.04g / 100mL, and does not contain artificial synthetic additives such as saccharin sodium and cyclamate.

[0018] Furthermore, the ultrafine grinding process parameters are as follows: the grinding chamber temperature is maintained at -15±3℃, the nitrogen protection flow rate is 15L / min, the grinding pressure is 0.8MPa, the classification wheel speed is 3800r / min, and the grinding cycle is monitored online by a laser particle size analyzer until D 90 The process stops automatically when the particle size is ≤10μm. The powder after crushing should be stored in an argon environment for no more than 2 hours.

[0019] Furthermore, the underground fermentation environment control includes: the soil moisture content at the burial point is 22±3%, a temperature sensor array is arranged around the urn (accuracy ±0.1°C), the data is transmitted to the ground monitoring system in real time, and the micro-geothermal regulation device is activated when the temperature deviates from 13°C; a 30cm humus layer is covered above the fermentation container to isolate it from light, and the oxygen concentration throughout the fermentation process is ≤5% vol.

[0020] Furthermore, gradient separation is performed after fermentation is completed: first, large particles of impurities are removed by initial filtration with a 200-mesh stainless steel filter, then cross-flow filtration is performed through a 0.8-μm ceramic membrane under a transmembrane pressure of 0.4 MPa, and finally terminal sterilization is performed through a 0.22-μm polyvinylidene fluoride (PVDF) filter membrane. The filtration temperature is constant at 25±1°C, and the real-time monitoring of the filtrate transmittance must be ≥96% (λ=600nm).

[0021] Furthermore, its physical and chemical indicators are: pH value 6.1±0.1, ethanol content 19±1% ​​vol, viscosity 28±2 mPa·s (25° C.), conductivity ≤50 μS / cm, and non-volatile matter content ≥15 mg / mL.

[0022] Furthermore, the active ingredient content control range is: chlorogenic acid 1.30±0.05mg / mL, ligustrazine 0.20±0.02mg / mL, angelica dahurica 0.42±0.03mg / mL, musk ketone 1.05±0.1μg / mL, matrine ≥0.18mg / mL, and arsenic salt ≤2ppm, lead ≤5ppm, and cadmium ≤0.3ppm.

[0023] Furthermore, the final preparation treatment includes: adding 0.08% of azone and 0.02% of vitamin E by total volume to the filtrate, mixing, secondary filtration through a 0.45 μm microporous membrane, filling into a brown borosilicate glass dropper bottle (with a UV blocking rate of >99%) under a nitrogen-filled (oxygen content <0.5%) environment, immediately evacuating to -0.09 MPa after filling and filling with high-purity nitrogen to seal, and storing at 15-20° C. in a dark environment.

[0024] The technical effects and advantages of the present invention are as follows:

[0025] Compared with the existing technology, the present invention improves the release efficiency of active ingredients by establishing a refined processing system for medicinal material classification, adopts a technical path that combines deep freezing and wall breaking of animal drugs with gradient crushing of plant drugs; innovatively designs an underground constant temperature micro-aerobic fermentation environment, uses ceramic jars with beeswax coating and humus covering to construct a stable anaerobic ecology, activates the low-temperature enzyme system through precise temperature and humidity control, and realizes the full degradation of large molecular impurities and the efficient conversion of target components; combines the three-stage membrane separation technology to intercept invalid components step by step and monitor the transmittance in real time to ensure the clarity and sterility of the medicinal solution; finally introduces an azone-vitamin E composite penetration-enhancing system to cooperate with the inert gas encapsulation process, greatly enhances the transdermal absorption efficiency while avoiding chemical stimulation, and simultaneously solves the common industry problems such as precipitation and oxidation of traditional preparations, low transdermal rate, and poor batch stability, forming a closed loop of Chinese medicine external-use drops preparation technology that integrates efficient extraction, targeted delivery, and long-term stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 It is the overall preparation process framework diagram of the present invention.

[0027] Figure 2 It is the ultrafine grinding control flow chart of the present invention.

[0028] Figure 3 This is a diagram of the intelligent fermentation monitoring system of the present invention. DETAILED DESCRIPTION

[0029] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0030] Implementation process 1: Standard industrialized production model

[0031] Core features: fully automated control + online quality monitoring

[0032] Applicable scenarios: GMP certified pharmaceutical factory large-scale production

[0033] Step 1: Raw material pretreatment

[0034] Weigh the medicinal materials accurately by weight and then classify them:

[0035] Plant medicinal materials (16 kinds including Xanthium sibiricum and Carthamus tinctorius) were put into a universal grinder, the speed was set at 2800 r / min, the grinding time was 15 minutes, and the powder particle size was controlled by a 100-mesh vibrating screen (80-120 mesh accounted for ≥95%).

[0036] Animal mineral medicinal materials (5 kinds including musk and silkworm) were pre-frozen in a -18℃ cold storage for 2 hours, and then transferred to an ultrafine airflow mill (nitrogen flow rate 20L / min, pressure 0.9MPa). The particle size was monitored in real time until D 90 ≤10μm(D 90 90% of the particles are smaller than this value).

[0037] Step 2: Enzymatic activation

[0038] Enzymatic activation was performed sequentially in a stainless steel mixing tank (304L, volume coefficient 0.7): First, the herbal and animal powders were precisely mixed in a 1:1 volume ratio (volume error ≤ ±3%). Then, 50-proof sorghum liquor (ethanol content 50±1% vol, total esters ≥ 2.3 g / L) was added at a volume four times the total weight of the mixed powders. Cellulase (addition rate 0.12% w / w) and pectinase (addition rate 0.05% w / w) were simultaneously added. Finally, the mixture was stirred at a constant speed of 40±2 rpm for 30±0.5 minutes (the tank temperature was maintained at 25±1°C by a jacket cooling water system, with torque fluctuation ≤8%) to achieve homogenization of the enzyme-substrate system and pre-degradation of the cell wall. This process, through a volumetric mixing strategy (to address differences in animal powder density), coordinated enzyme activity control (matching the optimal cellulase and pectinase temperatures), and dynamic viscosity monitoring (endpoint viscosity 35±3 mPa·s), provided a highly reactive substrate for subsequent fermentation.

[0039] Step 3: Intelligent underground fermentation

[0040] 1. Fermentation Vessel Preparation

[0041] The mixed liquid is transferred to a specially made beeswax jar (100L capacity, 10mm wall thickness). The inner wall of the jar is coated with a 1.2±0.2mm layer of food-grade beeswax. The jar is then sealed and placed in a pressure-resistant underground chamber to ensure physical isolation of the fermentation container.

[0042] 2. Precise control of underground environment

[0043] The cabin is buried at a depth of 1.8 meters and the soil environmental parameters are maintained through an integrated control system:

[0044] Temperature: 13.0±0.3℃ (geothermal heat pump dynamic compensation).

[0045] Humidity: 85±3% (closed-loop control of ultrasonic humidifier).

[0046] Oxygen concentration: ≤5% vol (nitrogen automatic replacement system).

[0047] Environmental stability reaches industrial-grade standards (coefficient of fluctuation CV≤0.8%).

[0048] 3. Periodic Oscillation Activation

[0049] The fermentation cycle is 45 days, and the ceramic jar is automatically lifted every 120 hours, and a six-axis robotic arm performs three-dimensional oscillation:

[0050] Oscillation speed: 120r / min (angular acceleration ≤ 3g).

[0051] Duration: 5.0±0.2 minutes.

[0052] Movement trajectory: elliptical vortex mode (amplitude 50mm).

[0053] Function: break the precipitation layer and promote the efficiency of enzyme-substrate mass transfer.

[0054] 4. Real-time biological reaction monitoring

[0055] Real-time monitoring via immersive sensor arrays:

[0056] pH value: 5.8-6.2 (online electrode, accuracy ±0.05).

[0057] Ethanol concentration: 18-22% vol (infrared spectroscopy, error ±0.3% vol).

[0058] The data is synchronized to the central control system, and the adjustment mechanism is automatically triggered when the limit is exceeded.

[0059] Step 4: Cascade membrane separation

[0060] The fermentation broth passes through a three-stage filtration system:

[0061] Coarse filtration: 200 mesh titanium alloy filter, flow rate 500L / h, remove particles >75μm.

[0062] Fine filtration: 0.8μm alumina ceramic membrane, transmembrane pressure 0.4MPa, circulation flow rate 3m / s.

[0063] Sterilization: 0.22μm PVDF pleated filter, operating temperature 25℃, real-time feedback control of light transmittance (triggering the next process when ≥96%).

[0064] Step 5: Finalize the preparation

[0065] Add 1000L of filtrate separated by three-stage membrane (transmittance ≥ 96%) to a nitrogen-protected reactor (oxygen content ≤ 50ppm), accurately add 0.8L of azone (0.08% v / v) and vitamin E The composite penetration-enhancing system was constructed by adding 0.2L (0.02% v / v); stirring was then performed at a constant speed of 30±2r / min for 45±1min (temperature controlled at 25±0.5°C, and automatically terminated when the viscosity reached 28±2mPa·s) to fully disperse the penetration enhancer; the solution was then terminally filtered through a 0.45μm polyethersulfone filter membrane at 0.15MPa (retaining undissolved particles, microbial limit ≤10CFU / 100mL); the solution was then filled into UV-blocking brown borosilicate glass bottles (UV380nm blocking rate >99%, filling accuracy ±0.5mL) in a nitrogen-filled chamber with an oxygen content of <0.5%; the solution was finally evacuated to -0.09±0.01MPa (residual oxygen <0.1%), filled with 99.999% high-purity nitrogen, sealed, labeled, and stored in the dark at 15±1°C (active ingredient decay ≤1.5% within 12 months). This process achieves synergistic optimization of formulation stability and transdermal efficiency through inert environment operation and precise parameter control (such as stirring torque fluctuation ≤5% and filter membrane pressure difference monitoring <0.3MPa).

[0066] Implementation process 2: laboratory test preparation

[0067] Core features: miniaturized equipment + low-cost alternative

[0068] Applicable scenarios: Sample trial production in R&D institutions

[0069] Step 1: Refined processing of raw materials

[0070] In order to improve the release efficiency of active ingredients in medicinal materials, this process adopts a differentiated processing strategy:

[0071] 1. Botanical Material Processing: Use a household wall crusher (1800W) to perform staged crushing. First, perform coarse crushing (30 seconds) to reduce the initial particle size to approximately 2mm to reduce mechanical heating effects. Then, add ice water (temperature ≤10°C) to cool the temperature and perform fine crushing (90 seconds). High-frequency shear force is used to reduce the powder fineness to a pass rate of >90% through a 100-mesh sieve, ensuring that the plant cell walls are fully ruptured to release heat-sensitive components such as chlorogenic acid.

[0072] 2. Processing of animal medicinal materials: For high-chitin medicinal materials such as scorpions and centipedes, first place them in a household refrigerator at -20°C for 24 hours to solidify the tissue structure; then transfer them to a mortar and grind them manually. Check the particle size distribution with a 300-mesh sieve every 10 minutes. Repeat the operation until the sieve pass rate is greater than 80%. This process cumulatively destroys the chitin skeleton, significantly increasing the specific surface area of ​​the final powder and optimizing the dissolution efficiency of active ingredients (such as scorpion venom peptides).

[0073] Step 2: Simple enzymatic fermentation

[0074] In order to achieve efficient fermentation under non-industrial conditions, this process adopts the following standardized operating procedures:

[0075] Accurately add the ingredients to a 5L glass wide-mouth bottle. First, mix 500g of the drug powder (according to the formula of claim 1), add 2000ml of 45% alcohol Erguotou liquor (wine-to-powder mass ratio of 4:1), and simultaneously add 0.6g of food-grade cellulase (enzyme addition amount 0.12% w / w). Ensure the system is homogenized by magnetic stirring (200r / min, 5 minutes). Then seal the bottle mouth and transfer it to a 1.5-meter deep courtyard pit. Lay a 10cm sand layer at the bottom of the pit (humidity buffer layer, moisture content 15-20%), and build a high-precision electronic thermometer and hygrometer (Bluetooth real-time data transmission to mobile terminal, monitoring accuracy ±0.5℃ / ±3%RH).

[0076] Periodic oscillation activation was implemented during the fermentation process: the jars were taken out every Sunday and manually shaken horizontally for 2 minutes (120 ± 5 times to break up the sediment layer and promote enzyme-substrate contact. After completion, the pit was immediately backfilled to maintain a constant temperature environment (target temperature 13 ± 2 °C).

[0077] Step 3: Traditional filtration and purification

[0078] 1. Primary filtration: Four layers of medical absorbent gauze are folded with equal tension and fixed to a glass funnel. The liquid is poured through the funnel in batches under gravity, with an initial flow rate of 15-20 mL / min. This step effectively retains plant fibers ≥100 μm and fermentation residues, reducing the filtrate turbidity to ≤50 NTU.

[0079] 2. Precision Filtration: Replace the original filter element in your household water purifier with a 0.45μm polypropylene (PP) cotton depth filter element (pore size tolerance ±0.05μm). A peristaltic pump provides 0.1-0.3MPa positive pressure to achieve deep retention of particles 1-50μm in the solution. Before use, pre-rinse the filter element with 500mL of pure water until the conductivity of the rinse water is ≤10μS / cm.

[0080] 3. Terminal Sterilization: Use a sterile 20 mL syringe to draw the finely filtered solution. Connect it to a pre-sterilized 0.22 μm syringe filter (polyethersulfone, 25 mm diameter) and collect the filtrate at a constant injection rate of ≤ 0.5 mL / s. This process is performed in a clean bench to ensure a microbial limit of ≤ 10 CFU / mL.

[0081] Step 4: Stability Enhancement

[0082] In order to improve the transdermal efficiency and long-term stability of the drug solution, a three-step strengthening treatment is implemented:

[0083] 1. Penetration Enhancement Treatment: Accurately add 0.08 mL of azone (a medical-grade transdermal enhancer) to every 100 mL of drug solution and achieve uniform dispersion using magnetic stirring (300 rpm for 10 minutes). This procedure utilizes the lipid fluidity of azone to enhance the stratum corneum penetration of active ingredients (such as chlorogenic acid and ligustrazine), resulting in a ≥35% increase in transdermal absorption compared to the untreated group (verified by Franz diffusion cell).

[0084] 2. Antioxidant Protection: Add 0.02g of vitamin E (from food-grade softgels) and emulsify using a vortex mixer (2000 rpm, 2 minutes) in the dark. Vitamin E, as a free radical scavenger, inhibits the ethanol oxidation side reaction, maintaining a peroxide value of ≤0.1 meq / kg (HPLC monitoring) in the accelerated test at 40°C.

[0085] 3. Inert Gas Packaging: Fill the liquid into a brown borosilicate glass reagent bottle (UV barrier > 90%). Then, fill the bottle with lighter-grade butane gas (purity ≥ 95%, oxygen content < 1%) above the liquid level to form a vapor phase protective layer. Immediately evacuate to -0.08MPa after packaging, seal the bottle, and store at 15-20°C in a dark environment. Ensure a precipitation rate of ≤ 0.5% and an active ingredient retention rate of > 98% within 12 months (GC-MS stability monitoring).

[0086] Implementation process three: innovative enzymatic hydrolysis-fermentation coupling process

[0087] Core features: biological enzyme directional cell wall breaking + gradient temperature fermentation

[0088] Applicable scenarios: extraction requirements for highly active ingredients

[0089] Step 1 Ultrafine Grinding Innovation

[0090] 1. Differentiation preprocessing

[0091] Classification and treatment are implemented based on the biological characteristics of different medicinal materials:

[0092] Cuticle Softening Treatment (Bombyx batryticatus / Earth Dragon): Immerse the insect in a 2% sodium bicarbonate (NaHCO3) solution at a drug-to-liquid ratio of 1:8 by mass. Constantly shake (50 rpm) at 25±2°C for 60 minutes. This alkaline environment effectively hydrolyzes the chitin-protein complex in the cuticle, creating a porous structure in the insect's cuticle (electron microscopy reveals a 62% increase in porosity).

[0093] Body surface purification (scorpions / centipedes): Use 40kHz high-frequency ultrasonic cleaning machine (power density 0.5W / cm 3) forms cavitation bubbles on the medicinal material's surface. During the treatment, a liquid-to-solid ratio of 5:1 (ultrapure water was used as the medium) was maintained for 20 minutes, with an ultrasonic energy density of 240 kJ / kg. This process can strip away surface microbial communities (reducing the total colony count by 3.8 log CFU / g) and loosen the arthropod membranes.

[0094] 2. Deep cold cycle wall breaking

[0095] Establish a three-step physical wall-breaking system:

[0096] Liquid nitrogen quick freezing stage: After pretreatment, the medicinal materials are transferred to a liquid nitrogen quick freezing chamber (-196°C) and rapidly frozen for 5 minutes (cooling rate ≥ 100°C / min) to promote the formation of micron-sized ice crystals in the water inside the cells;

[0097] Constant temperature thawing stage: immediately transfer to a constant temperature water bath at 37±0.5℃ (temperature control accuracy ±0.1℃) and thaw for 10 minutes to melt the ice crystals and generate shear stress;

[0098] Cyclic strengthening mechanism: The above freeze-thaw process was repeated three times, destroying the cell wall and chitin skeleton through repeated phase transitions (micro-CT showed that the fracture area of ​​the shell structure reached 85%).

[0099] 3. Particle size quality control verification

[0100] After the cell wall is broken, the powder undergoes three levels of quality control:

[0101] Online monitoring: Laser particle size analyzer (Malvern Mastersizer 3000) integrated in the ultrafine grinding chamber, real-time feedback 90 value;

[0102] Offline verification: Take samples from each batch and perform scanning electron microscope (SEM) observation (accelerating voltage 15kV) to confirm that 90% of the particles are ≤8μm (e.g. Figure 3 Particle size distribution spectrum);

[0103] Functional association: This particle size range ensures the effective release of active ingredients (scorpion venom peptide dissolution rate ≥92%, earthworm plasmin activity retention rate ≥95%).

[0104] Step 2: Activation of the enzyme ladder

[0105] Enzymatic hydrolysis is carried out in two stages:

[0106] Stage 1 (25°C, 24h):

[0107] 0.1% papain (specialized in decomposing animal protein) and 0.05% chitinase (decomposing insect shells) were added, and the mixture was stirred at a speed of 50 r / min.

[0108] Second stage (40℃, 12h):

[0109] 0.15% β-glucosidase (to release aglycones) and 0.08% xylanase (to decompose hemicellulose) were added, and stirring was stopped and the reaction was allowed to stand.

[0110] Step 3: Gradient temperature fermentation

[0111] Fermentation is carried out in different temperature zones:

[0112]

[0113] Step 4: Membrane separation optimization

[0114] Innovative tangential flow filtration system:

[0115] First stage: 500kDa hollow fiber membrane (removes large molecules such as tannins).

[0116] Secondary: 100 kDa ceramic membrane (protein retention).

[0117] Terminal: 10kDa spiral membrane (enrichment of target active ingredients).

[0118] Step 5: Nano-permeation technology

[0119] First, get 0.5 gram of Angelica dahurica extract and place it in a suitable container, add 10 milliliters of azone as matrix and osmotic carrier. Mixed system is placed in ultrasonic processor, under specific ultrasonic frequency 53kHz, carry out ultrasonic treatment for 30 minutes. This process purpose is to impel Angelica dahurica extract to fully disperse and evenly emulsify in the azone matrix, form the nano-scale composite emulsion that outward appearance is uniform, translucent state. After treating that above-mentioned composite nano-emulsification system forms, accurately measure this compound, join in the target medicinal liquid in the ratio of 0.1% of total medicinal liquid quality. For guaranteeing the high dispersion of compound in medicinal liquid, particle size uniformity and with the sufficient compatibility of medicinal liquid, follow-up is introduced high-pressure homogenization process with the mixed system of medicinal liquid and compound. Be set as the working condition of 15,000 pounds per square inch (psi) under homogenization pressure, the mixed material is circulated through the homogenization cavity and is handled 3 times in total. This high-pressure homogenization treatment can significantly reduce the particle size of the complex particles, improve the physical stability of the system, enhance its effectiveness as a penetration enhancer, and ultimately ensure that the complex reaches an ideal nanoscale dispersion state in the entire drug solution system, laying the foundation for subsequent formulation stability and transdermal absorption effect.

[0120] Finally, a few points should be explained: First, in the description of this application, it should be noted that, unless otherwise specified or limited, the terms "mounted," "connected," and "connected" should be understood in a broad sense, and may refer to mechanical or electrical connections, internal communication between two components, or direct connection. "Up," "down," "left," and "right" are only used to indicate relative positional relationships. When the absolute positions of the objects being described change, the relative positional relationships may also change.

[0121] Secondly: The drawings of the embodiments disclosed in the present invention only involve structures related to the embodiments disclosed in the present invention. Other structures may refer to conventional designs. The same embodiment and different embodiments of the present invention may be combined with each other without conflict.

[0122] Finally: The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A Chinese medicine drop for external use for treating acne, eczema and rhinitis and its preparation process, characterized in that Implement the following operating procedures: S1. Accurately weigh 5 parts of Xanthium sibiricum, 5 parts of Carthamus tinctorius, 10 parts of Herba Capillaris, 0.01 parts of Musk, 5 parts of Curcuma aromatica, 10 parts of Magnolia Flos, 5 parts of Frankincense, 10 parts of Atractylodes macrocephala, 5 parts of Gastrodia elata, 10 parts of Honeysuckle, 5 parts of Bombyx batryticatus, 10 parts of Acorus calamus, 5 parts of Scorpion, 10 parts of Cyperus rotundus, 15 parts of Angelica dahurica, 5 parts of Angelica sinensis, 10 parts of Ligusticum chuanxiong, 5 parts of Scolopendra, 10 parts of Mentha, 5 parts of Pheretima, and 10 parts of Saposhnikovia divaricata. S2. Grind the plant-based medicinal materials (Xanthium sibiricum, Carthamus tinctorius, Herba Capillaris, Curcuma aromatica, Magnolia bud, Frankincense, Atractylodes lancea, Gastrodia elata, Honeysuckle, Acorus calamus, Cyperus rotundus, Angelica dahurica, Angelica sinensis, Ligusticum chuanxiong, Mentha, and Saposhnikovia divaricata) into 100±20 mesh fine powder. Place the animal and mineral medicinal materials (Musk, Bombyx batryticatus, Scorpion, Centipede, and Earth Dragon) in a low-temperature environment of -18°C, pre-freeze with liquid nitrogen, and then use an ultrafine airflow mill to grind the particles to a size of D 90 ≤10μm; S3. Mix the two types of powders and put them into a ceramic fermentation jar (8mm thick, 50L capacity) with an inner wall coated with 1.2±0.2mm food-grade beeswax, add 50±2% pure sorghum liquor with a concentration of 4.5 times the total weight of the powder, and simultaneously add 0.12% of the total weight of the powder in cellulase and 0.05% of the pectinase. After sealing the jar mouth, bury it in a clay loam layer (pH6.8-7.0) 1.8±0.2 meters deep underground. Ferment it in a constant temperature environment of 13±0.5℃ for 45±1 days. During this period, take out the jar every 120 hours, oscillate it at a speed of 120r / min for 5 minutes, and then rebury it.

2. The external Chinese medicine drops for treating acne, eczema and rhinitis and its preparation process as claimed in claim 1, characterized in that The liquor must meet the following requirements: solid-state fermented liquor with sorghum as the main raw material, alcohol content of 50±1 degrees, total acid ≤1.2g / L (calculated as acetic acid), total ester ≥2.3g / L (calculated as ethyl acetate), methanol content <0.04g / 100mL, and does not contain artificial synthetic additives such as saccharin sodium and cyclamate.

3. The external Chinese medicine drops for treating acne, eczema and rhinitis and its preparation process as claimed in claim 1, characterized in that The ultrafine grinding process parameters are as follows: the temperature of the grinding chamber is maintained at -15±3℃, the nitrogen protection flow rate is 15L / min, the grinding pressure is 0.8MPa, the classification wheel speed is 3800r / min, and the grinding cycle is monitored online by a laser particle size analyzer until D 90 The process stops automatically when the particle size is ≤10μm. The powder after crushing should be stored in argon environment for no more than 2 hours.

4. The external Chinese medicine drops for treating acne, eczema and rhinitis and its preparation process as claimed in claim 1, characterized in that Underground fermentation environmental control includes: soil moisture content of 22±3% at the burial point, a temperature sensor array (accuracy of ±0.1°C) is arranged around the urn, data is transmitted to the ground monitoring system in real time, and a micro-geothermal regulation device is activated when the temperature deviates from 13°C; a 30cm layer of humus soil is covered above the fermentation container to isolate it from light, and the oxygen concentration throughout the fermentation process is ≤5% vol.

5. The external Chinese medicine drops for treating acne, eczema and rhinitis and its preparation process as claimed in claim 1, characterized in that After fermentation is completed, gradient separation is performed: first, large particles of impurities are removed by initial filtration with a 200-mesh stainless steel filter, then cross-flow filtration is performed through a 0.8-μm ceramic membrane at a transmembrane pressure of 0.4 MPa, and finally terminal sterilization is performed through a 0.22-μm polyvinylidene fluoride (PVDF) filter membrane. The filtration temperature is constant at 25±1°C, and the filtrate transmittance is monitored in real time and must be ≥96% (λ=600nm).

6. A Chinese medicine drop for external use for treating acne, eczema and rhinitis prepared by the method according to claims 1-5, characterized in that Its physical and chemical indicators are: pH value 6.1±0.1, ethanol content 19±1% ​​vol, viscosity 28±2 mPa·s (25° C.), conductivity ≤50 μS / cm, and non-volatile matter content ≥15 mg / mL.

7. The external Chinese medicine drops for treating acne, eczema and rhinitis according to claim 6, characterized in that Active ingredient content control range: chlorogenic acid 1.30±0.05mg / mL, ligustrazine 0.20±0.02mg / mL, angelica dahurica 0.42±0.03mg / mL, musk ketone 1.05±0.1μg / mL, matrine ≥0.18mg / mL, and arsenic salt ≤2ppm, lead ≤5ppm, cadmium ≤0.3ppm.

8. The external Chinese medicine drops for treating acne, eczema and rhinitis and its preparation process as claimed in claim 1, characterized in that The final preparation process includes: adding 0.08% of azone and 0.02% of vitamin E by total volume to the filtrate, mixing, secondary filtration through a 0.45 μm microporous membrane, filling into a brown borosilicate glass dropper bottle (with a UV blocking rate of >99%) under a nitrogen-filled (oxygen content <0.5%) environment, immediately evacuating to -0.09 MPa after filling, filling with high-purity nitrogen, and sealing, and storing at 15-20° C. in a dark environment.

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