Traditional Chinese medicine composition for treating skin diseases and preparation method thereof

Abstract

The invention discloses a traditional Chinese medicine composition for treating skin diseases and a preparation method of the traditional Chinese medicine composition. The traditional Chinese medicine composition is prepared from the following raw materials in parts by weight: 6-12 parts of radix notoginseng, 8-15 parts of radix salviae miltiorrhizae, 10-20 parts of rhizoma chuanxiong, 8-15 parts of rhizoma curcumae longae, 15-35 parts of radix angelicae sinensis, 3-8 parts of sandalwood, 3-8 parts of fructus aurantii immaturus, 40-60 parts of ramulus cinnamomi, 8-15 parts of rhizoma corydalis, 8-15 parts of rhizoma curcumae, 2-5 parts of flos carthami, 5-12 parts of radix puerariae, 8-15 parts of radix rehmanniae, 3-8 parts of pericarpium citri reticulatae and 8-15 parts of spica prunellae. The traditional Chinese medicine composition is prepared from 3-8 parts of radix trichosanthis, 15-35 parts of tribulus terrestris, 15-35 parts of cicada slough, 5-12 parts of stiff silkworm and 8-15 parts of rhizoma drynariae. According to a multi-target collaborative mechanism, network pharmacology proves that 12 pathological pathways such as IL-17A and the like can be regulated and controlled, and the TNF-alpha inhibition rate is 89% and the barrier repair speed is increased by 2.3 times through key component combination. According to a transdermal synergistic technology, the specific surface area of the medicine reaches 8.5 m < 2 > / g through superfine grinding, a Franz test shows that the penetration amount of tanshinone is increased by 3.7 times, and the onset time is shortened to 8.3 minutes. Dual scar regulation and control: the thickness of scars in 12 weeks is reduced by half through TGF-beta3 up-regulation and alpha-SMA inhibition, and the collagen order degree is improved by 3.2 times.

Description

Technical Field

[0001] The present invention relates to traditional Chinese medicine, and specifically refers to a traditional Chinese medicine composition for treating skin diseases and a preparation method thereof. Background Art

[0002] As a globally prevalent disease, the treatment of skin diseases faces many challenges. According to statistics of the World Health Organization, patients with chronic skin diseases such as acute / chronic urticaria, eczema, pruritus of unknown etiology, dermatitis (such as: neurodermatitis, traumatic dermatitis, etc.), traumatic tissue hyperplasia (such as: keloid), acne, herpes virus, solar dermatitis, allergic dermatitis, contact dermatitis, acne, etc. account for 15%-30% of the total population, and the recurrence rate is as high as 60%. Existing treatment methods are mainly divided into two categories: chemical drugs (such as glucocorticoids, immunosuppressants) and traditional Chinese medicine preparations, but both have significant defects:

[0003] 1. Limitations of chemical drugs:

[0004] Glucocorticoid drugs (such as halometasone): Although they can quickly relieve symptoms, long-term use can lead to skin atrophy (incidence rate 23%), telangiectasia (incidence rate 18%), and drug resistance (the effective rate drops to 42% after continuous use for 4 weeks).

[0005] Biological agents (such as IL-17A inhibitors): They have strong targeting, but are expensive (annual treatment cost ≥ 200,000 yuan), and there is an infection risk (the incidence rate of severe infection in clinical trials is 3.8%).

[0006] Antihistamines (such as loratadine): They have limited efficacy for chronic pruritus (the 24-hour antipruritic effective rate is only 58%), and cannot improve the skin barrier function.

[0007] 2. Defects of traditional Chinese medicine preparations:

[0008] Low transdermal absorption efficiency: The conventional pulverization process (80-100 mesh) results in a specific surface area of the drug of only 1.2-1.5 m 2 / g, and the skin penetration rate of liposoluble components such as tanshinone IIA is less than 10%

[0009] (Franz diffusion cell test data).

[0010] Serious loss of active ingredients: Traditional moist heat sterilization (121°C / 15 min) causes the degradation rate of thermosensitive components (such as curcumol) to reach 32%-45% (HPLC detection).

[0011] Insufficient microbial control: Workshop-style production results in the total number of aerobic bacteria in the powder generally ≥

[0012] 300 CFU / g (3 times the upper limit of the standard in the 2020 edition of the Chinese Pharmacopoeia).

[0013] Single dosage form: More than 90% of the external traditional Chinese medicine dosage forms are ointments or oils, which have problems such as strong greasiness, shallow action level (only reaching the epidermal layer), and inconvenience in children's medication.

[0014] 3. Blank areas of the existing technology:

[0015] Scar repair field: Clinically, there is a lack of compound drugs that can simultaneously inhibit hyperplasia (by regulating TGF-β1) and promote remodeling (activating TGF-β3). Existing silicone gels can only improve the appearance of scars and have no intervention effect on the pathological process.

[0016] Precision medication for children: The error rate of traditional dosing methods (such as manual sub-packaging) is ≥20%, and there is a lack of support from pharmacokinetic studies (90% of traditional Chinese medicines in the pediatric medication guidelines lack children's dosage standards).

[0017] Multi-target synergistic mechanism: Single-component drugs (such as tripterygium glycosides) can inhibit IL-6, but cannot simultaneously regulate VEGF-mediated angiogenesis and neurogenic inflammation (activation of TRPV1 channels).

[0018] Technical development bottlenecks Recent studies (such as the review in the Journal of Ethnopharmacology in 2021) have pointed out that the treatment of skin diseases with traditional Chinese medicines faces three major scientific challenges:

[0019] Vague association between components and targets: The synergistic mechanism of multiple components in the compound is unclear, resulting in a single quality control index (only detecting 1-2 markers);

[0020] Disconnection between process and efficacy: There is a lack of quantitative correlation research between key process parameters such as comminution particle size and sterilization method and drug efficacy;

[0021] Lagging behind in dosage form innovation: It fails to combine modern transdermal technologies (such as nanocrystals and microneedles) to improve bioavailability.

[0022] In response to the above problems, the present invention realizes technological upgrading through the following breakthrough designs:

[0023] Compatibility optimization guided by network pharmacology: 19 core components were screened based on the TCMSP database, and their binding energies (≤-6.5 kcal / mol) with targets such as IL-17R and JAK2 were verified through molecular docking to form a multi-pathway synergistic action network;

[0024] Innovation of cryogenic ultrafine comminution technology: Using liquid nitrogen-cooled vortex comminution (-15°C) to make the retention rate of heat-sensitive components ≥95%, while increasing the specific surface area to 8.5 m 2 / g;

[0025] Dynamic intelligent sterilization system: Integrating pulsed UV and electron beam irradiation to achieve a microbial load of ≤ 50 CFU / g without damaging the active ingredients;

[0026] Precise pediatric drug administration plan: Based on the PBPK model, a sub-dose algorithm (R 2

[0027] = 0.987) was developed to create an anti-misquantification and sub-packaging system.

[0028] This plan is the first to deeply integrate modern pharmaceutical engineering technology with traditional Chinese medicine theory, solving the industry pain points of slow onset, shallow effect, and poor safety of traditional preparations, and providing a new solution for the treatment of skin diseases. Summary of the Invention

[0029] The technical problem to be solved by the present invention is to overcome the above-mentioned technical defects and provide a traditional Chinese medicine composition for treating skin diseases and its preparation method.

[0030] To solve the above technical problems, the technical solution provided by the present invention is a traditional Chinese medicine composition for treating skin diseases and its preparation method:

[0031] A traditional Chinese medicine composition for treating skin diseases, characterized in that it is composed of the following raw materials in parts by weight: 6 - 12 parts of Panax notoginseng, 8 - 15 parts of Salvia miltiorrhiza, 10 - 20 parts of Ligusticum chuanxiong, 8 - 15 parts of Curcuma longa, 15 - 35 parts of Angelica sinensis, 3 - 8 parts of Santalum album, 3 - 8 parts of Fructus Aurantii Immaturus, 40 - 60 parts of Ramulus Cinnamomi, 8 - 15 parts of Corydalis yanhusuo, 8 - 15 parts of Rhizoma Zedoariae, 2 - 5 parts of Carthamus tinctorius, 5 - 12 parts of Pueraria lobata, 8 - 15 parts of Rehmannia glutinosa, 3 - 8 parts of Pericarpium Citri Reticulatae, 8 - 15 parts of Prunella vulgaris, 3 - 8 parts of Trichosanthes kirilowii Maxim., 15 - 35 parts of Tribulus terrestris, 15 - 35 parts of Cryptotympana pustulata Fabricius, 5 - 12 parts of Bombyx batryticatus, 8 - 15 parts of Drynaria fortunei.

[0032] As an improvement, the precise parts by weight of each raw material are: 9 parts of Panax notoginseng, 10 parts of Salvia miltiorrhiza, 15 parts of Ligusticum chuanxiong, 10 parts of Curcuma longa, 25 parts of Angelica sinensis, 5 parts of Santalum album, 5 parts of Fructus Aurantii Immaturus, 50 parts of Ramulus Cinnamomi, 10 parts of Corydalis yanhusuo, 10 parts of Rhizoma Zedoariae, 3 parts of Carthamus tinctorius, 7.5 parts of Pueraria lobata, 10 parts of Rehmannia glutinosa, 5 parts of Pericarpium Citri Reticulatae, 10 parts of Prunella vulgaris, 5 parts of Trichosanthes kirilowii Maxim., 25 parts of Tribulus terrestris, 25 parts of Cryptotympana pustulata Fabricius, 8 parts of Bombyx batryticatus, 10 parts of Drynaria fortunei.

[0033] As an improvement, it includes: (1) Raw material pretreatment: Using an X-ray foreign object separator to remove impurities with a rejection accuracy of ≤ 0.3 mm 3 ; (2) Low-temperature pulverization: Pulverizing with a vortex pulverizer in a low-temperature environment of -15°C to 0°C, controlling the material temperature ≤ 25°C; (3) Particle size control: Classifying through a 200-mesh vibrating screen and collecting powders with a passing rate ≥ 95%; (4) Dynamic sterilization: Implementing pulsed ultraviolet irradiation sterilization during the powder conveying process, with an irradiation intensity of 120 - 150 μW / cm2 .

[0034] As an improvement, in step (2): the primary crushing is performed using a shearing crusher at a speed of 800-1200 rpm to crush the particles to 80-100 mesh;

[0035] The secondary crushing uses a liquid nitrogen-cooled ball mill, the grinding medium is zirconia beads, the particle size is 0.5-1mm, and the grinding time is 30-60min.

[0036] As an improvement, in step (4): after sterilization, the powder is subjected to vacuum freeze drying, the pre-freezing temperature is maintained at -40°C for 4 hours, the pressure in the sublimation drying stage is 10-30Pa, and the desorption drying temperature is 35°C.

[0037] As an improvement, the following quality indicators are included: Notoginsenoside R1 content ≥ 0.8 mg / g

[0038] Tanshinone IIA content ≥1.2mg / g

[0039] Puerarin content ≥2.5mg / g

[0040] Microbial limits: total aerobic bacteria ≤ 100 CFU / g, total mold and yeast count ≤ 10 CFU / g.

[0041] As an improvement, the use of a Chinese medicine composition in the preparation of a medicine for treating the following diseases: the use of a Chinese medicine composition in the preparation of a medicine for treating the following diseases: acute / chronic urticaria, eczema, pruritus of unknown cause, dermatitis (such as: neurological, traumatic, etc.), traumatic tissue hyperplasia (such as: keloid), acne, herpes virus, solar dermatitis, allergic dermatitis, contact dermatitis, intractable eczema, nodular prurigo, seborrheic dermatitis, atopic dermatitis, cutaneous amyloidosis, etc.

[0042] As an improvement, it can be made into any one of the following: nanosuspension (particle size 100-300nm), transdermal microneedle patch (needle height 500-800μm), and thermosensitive gel (phase transition temperature 32-35°C).

[0043] As an improvement, the composition is composed of the composition according to any one of claims 1-2 and a transdermal enhancer, wherein the transdermal enhancer is a composite system of 1-3% azone, 0.5-1.5% menthol, and 2-5% propylene glycol, and the drug loading amount is 15-25% (w / w).

[0044] A traditional Chinese medicine oral preparation: 50-70% of the composition according to any one of claims 1-2, 20-30% of a prebiotic composition (fructooligosaccharide: inulin = 3:1), and 10-15% of an enteric coating material (hydroxypropyl methylcellulose phthalate), to form sustained-release micropellets with a gastric emptying time of ≥2h.

[0045] The advantages of the present invention compared with the prior art are as follows:

[0046] Multi-target synergistic mechanism: Network pharmacology confirms that it can regulate 12 pathological pathways such as IL-17A (the coverage range is 4.2 times larger than that of single components). The combination of key components achieves an 89% TNF-α inhibition rate and a 2.3-fold acceleration of barrier repair.

[0047] Transdermal enhancement technology: Ultrafine comminution makes the specific surface area of the drug reach 8.5 m 2 / g. The Franz test shows that the penetration amount of tanshinone is increased by 3.7 times, and the onset time is shortened to 8.3 minutes.

[0048] Dual regulation of scars: By upregulating TGF-β3 (2.7 times) and inhibiting α-SMA (61%), the scar thickness is halved in 12 weeks, and the collagen orderliness is increased by 3.2 times.

[0049] Intelligent preparation system: It contains a quick-acting component (puerarin Tmax 0.9 h) and a long-acting carrier (AUC 587.4 h·ng / mL), and the combination of UV-electron beam sterilization makes the microbial load ≤ 50 CFU / g.

[0050] Precision quality control system: Establish three-level standards of chemistry (notoginsenoside R1 ≥ 0.8 mg / g), biology (IL-6 inhibition ≥ 65%), and physics (D90 ≤ 20 μm). The dynamic production process reduces energy consumption by 42% and increases the utilization rate of medicinal materials to 98.7%. Detailed implementation manners

[0051] To facilitate the understanding of this application, the following will give a more comprehensive description of this application.

[0052] A traditional Chinese medicine composition for treating skin diseases and its preparation method:

[0053] A traditional Chinese medicine composition for treating skin diseases, characterized in that it is composed of the following raw materials in parts by weight: 6-12 parts of notoginseng, 8-15 parts of salvia miltiorrhiza, 10-20 parts of chuanxiong rhizome, 8-15 parts of turmeric, 15-35 parts of angelica sinensis, 3-8 parts of sandalwood, 3-8 parts of immature bitter orange, 40-60 parts of cassia twig, 8-15 parts of Corydalis yanhusuo, 8-15 parts of zedoary, 2-5 parts of safflower, 5-12 parts of kudzu root, 8-15 parts of rehmannia glutinosa, 3-8 parts of tangerine peel, 8-15 parts of prunella vulgaris, 3-8 parts of trichosanthes root, 15-35 parts of tribulus terrestris, 15-35 parts of cicada slough, 5-12 parts of bombyx batryticatus, 8-15 parts of drynaria rhizome.

[0054] As an improvement, the precise weight parts of each raw material are as follows: 9 parts of Panax notoginseng, 10 parts of Salvia miltiorrhiza, 15 parts of Ligusticum chuanxiong, 10 parts of Curcuma longa, 25 parts of Angelica sinensis, 5 parts of Santalum album, 5 parts of Aurantii Fructus Immaturus, 50 parts of Cinnamomum cassia, 10 parts of Corydalis yanhusuo, 10 parts of Rhizoma zedoariae, 3 parts of Carthamus tinctorius, 7.5 parts of Pueraria lobata, 10 parts of Rehmannia glutinosa, 5 parts of Citrus reticulata Blanco, 10 parts of Prunella vulgaris L., 5 parts of Trichosanthes kirilowii Maxim., 25 parts of Tribulus terrestris L., 25 parts of Cryptotympana pustulata Fabricius, 8 parts of Bombyx batryticatus, and 10 parts of Drynaria fortunei (Kunze) J. Sm..

[0055] As an improvement, it includes: (1) Raw material pretreatment: Use an X-ray foreign object separator to remove impurities, and the removal accuracy is ≤0.3 mm 3 ; (2) Low-temperature pulverization: Pulverize using a vortex pulverizer in a low-temperature environment of -15°C to 0°C, and control the material temperature ≤25°C; (3) Particle size control: Classify through a 200-mesh vibrating screen, and collect the powder with a passing rate ≥95%; (4) Dynamic sterilization: Implement pulsed ultraviolet irradiation sterilization during the powder conveying process, and the irradiation intensity is 120 - 150 μW / cm 2 .

[0056] As an improvement, in step (2): For primary pulverization, use a shearing pulverizer with a rotation speed of 800 - 1200 rpm and pulverize to 80 - 100 meshes;

[0057] For secondary pulverization, use a ball mill cooled by liquid nitrogen, with zirconia beads as the grinding medium, a particle size of 0.5 - 1 mm, and a grinding time of 30 - 60 min.

[0058] As an improvement, in step (4): After sterilization, the powder is subjected to vacuum freeze-drying treatment. The pre-freezing temperature is maintained at -40°C for 4 h, the pressure during the sublimation drying stage is 10 - 30 Pa, and the analytical drying temperature is 35°C.

[0059] As an improvement, it includes the following quality indicators: The content of notoginsenoside R1 ≥0.8 mg / g

[0060] The content of tanshinone IIA ≥1.2 mg / g

[0061] The content of puerarin ≥2.5 mg / g

[0062] Microbial limit: The total number of aerobic bacteria ≤100 CFU / g, and the total number of molds and yeasts ≤10 CFU / g.

[0063] As an improvement, the application of the traditional Chinese medicine composition in the preparation of drugs for treating the following diseases: The application of the traditional Chinese medicine composition in the preparation of drugs for treating the following diseases: acute / chronic urticaria, eczema, pruritus of unknown etiology, dermatitis (such as: neurodermatitis, traumatic, etc.), traumatic tissue hyperplasia (such as: keloid), acne, herpes virus, solar dermatitis, allergic dermatitis, contact dermatitis, intractable eczema, nodular prurigo, seborrheic dermatitis, atopic dermatitis, cutaneous amyloidosis, etc.

[0064] As an improvement, it can be made into any one of the following: nano-suspension (particle size 100 - 300 nm), transdermal microneedle patch (needle height 500 - 800 μm), thermosensitive gel (phase transition temperature 32 - 35 °C).

[0065] As an improvement, it is composed of the composition described in any one of claims 1 - 2 and a transdermal enhancer, wherein: the transdermal enhancer is a composite system of 1 - 3% azone, 0.5 - 1.5% menthol, and 2 - 5% propylene glycol, and the drug loading amount is 15 - 25% (w / w).

[0066] A traditional Chinese medicine oral preparation: 50 - 70% of the composition described in any one of claims 1 - 2, 20 - 30% of prebiotic composition (fructooligosaccharide: inulin = 3:1), 10 - 15% of enteric coating material (hydroxypropyl methylcellulose phthalate), and made into sustained-release pellets with a gastric emptying time ≥ 2 h.

[0067] Example 1: Industrial production of high-precision powder (annual output of 10 tons) - Raw material pretreatment stage:

[0068] Removal of metal foreign matters:

[0069] Use Sesotec GmbH RAYCON XR - Pro type X - ray detection system (resolution 0.2 mm 3 , detection accuracy ±0.05 mm)

[0070] Set up dual - channel detection: ferrous metals (sensitivity 0.3 mm), non - ferrous metals (sensitivity 0.5 mm), glass (density ≥ 2.5 g / cm 3 )

[0071] Verification of rejection rate: Continuously pass 200 kg of raw materials, and the impurity residue amount ≤ 3 ppm (GB / T5009.12 - 2017 standard)

[0072] Color sorting and grading of medicinal materials:

[0073] Adopt TOMRA 5B - HS type hyperspectral sorter (spectral range 400 - 1700 nm)

[0074] Establish a standard spectral library for medicinal materials:

[0075] Authentic notoginseng: Reflectivity ≥ 68% at 980 nm

[0076] Mildewed medicinal materials: Absorbance ≥ 0.75 at 1450 nm

[0077] Sorting efficiency: Process 500 kg per hour, and the rejection rate of defective products ≥ 99.8%

[0078] Ultra - fine grinding process:

[0079] Three - stage low - temperature comminution system:

[0080] Precooling treatment: The medicinal materials are left standing in a - 25°C low - temperature warehouse for 4 hours (monitored by a temperature recorder DT - 8894E)

[0081] Primary comminution:

[0082] Equipment: FitzMill M5A hammer mill (rotation speed 1500 rpm)

[0083] Control parameters: Feeding speed 50 kg / h, discharge particle size D50 = 150 μm (detected by Malvern Mastersizer 3000)

[0084] Secondary comminution:

[0085] Equipment: Alpine 100AFG fluidized - bed jet mill (pressure 0.8 MPa, classifier wheel rotation speed 6500 rpm)

[0086] Temperature control: Maintain the temperature in the comminution chamber at - 10 ± 2°C by liquid nitrogen injection

[0087] Finished product index: D90 ≤ 15 μm, specific surface area ≥ 8.5 m 2 / g (measured by BET method)

[0088] Dynamic sterilization system:

[0089] Continuous sterilization device:

[0090] First sterilization area: Pulse UV sterilization (wavelength 185 nm / 254 nm, intensity 200 μW / cm 2 , exposure time 6 s)

[0091] Second sterilization area: Electron beam irradiation (energy 10 MeV, dose 12 kGy, transmission speed 0.5 m / s)

[0092] On - line monitoring:

[0093] The microbial load is detected in real - time by the ATP bioluminescence method (LuminUltra System). The total number of aerobic bacteria after sterilization ≤ 50 CFU / g (GB15979 - 2002 standard)

[0094] Packaging process:

[0095] Use a BOSCH SVE2521 type full - automatic filling and packaging line for nitrogen - filling packaging: Oxygen residue ≤ 0.5% (ZwickRoell O2 analyzer)

[0096] Aluminum - plastic composite film parameters:

[0097] Outer layer: 12 μm PET (oxygen permeability ≤ 3 cm3 / m 2 ·24 h)

[0098] Intermediate layer: 9 μm aluminum foil (number of pinholes ≤ 2 / m 2 )

[0099] Inner layer: 50 μm CPP (heat seal strength ≥ 40 N / 15 mm)

[0100] Example 2: Development of instant nano-dispersion Nanonization treatment:

[0101] High-pressure homogenization process equipment: ATSAH-1000D nano-disperser (pressure 1500 bar, number of cycles 10) Dispersing medium: phosphate buffer solution containing 0.5% Poloxamer 188 (pH 6.8) Finished product characteristics:

[0102] Zeta potential: -35 mV (measured by Malvern Zetasizer Nano ZS90)

[0103] Particle size distribution: D50 = 220 nm, PDI ≤ 0.2

[0104] Stability enhancement treatment:

[0105] Add 0.2% trehalose as a lyoprotectant

[0106] Freeze-drying procedure:

[0107] Pre-freezing stage: Maintain at -45 °C for 4 h (cooling rate 1 °C / min)

[0108] Primary drying: Maintain at -20 °C / 50 Pa for 24 h

[0109] Secondary drying: Maintain at 25 °C / 10 Pa for 8 h

[0110] Redissolution time: After adding normal saline at 37 °C, the complete dispersion time ≤ 15 s Example 3: Multicenter clinical validation (n = 328 cases) Study design:

[0111] Randomized double-blind controlled trial (experimental group: the powder of the present invention, control group: compound flumetasone ointment)

[0112] Evaluation criteria:

[0113] For acute eczema, the EASI score is used (range 0 - 72 points)

[0114] For scar repair, the POSAS scale is used (double-blind evaluation by patients and observers)

[0115] Efficacy data:

[0116]

[0117] Molecular mechanism verification:

[0118] Western blot analysis (skin biopsy samples)

[0119] TGF-β3 expression level: increased by 2.7 times in the experimental group compared with the control group (gray value analysis)

[0120] MMP-1 activity: increased by 3.2 times (zymography)

[0121] Flow cytometry:

[0122] The positive rate of IL-4 in CD4+ T cells decreased by 58% (P<0.01)

[0123] The expression of α-SMA in fibroblasts decreased by 61% (P<0.005)

[0124] Example 4: Pharmacokinetic study - Human absorption test (n = 12 healthy volunteers):

[0125] Drug administration regimen: Single oral administration of 9 g powder (batch meeting GMP standards)

[0126] Detection method:

[0127] Determination of blood drug concentration by UPLC-MS / MS method (Agilent 6495C triple quadrupole)

[0128] Chromatographic conditions:

[0129] Chromatographic column: Waters HSS T3 (2.1×100 mm, 1.8 μm)

[0130] Mobile phase: 0.1% formic acid water - acetonitrile gradient elution

[0131] Key parameters:

[0132]

[0133] Food effect study: The bioavailability decreased by 23% (P = 0.012) when taken with cold water, and the Cmax increased by 18% (P = 0.043) when taken with high-fat diet

[0134] Example 5: Development of an intelligent drug delivery system - Thermosensitive gel patch:

[0135] Matrix formulation:

[0136] Poloxamer 407 (18% w / v)

[0137] Hydroxypropyl methylcellulose (2% w / v)

[0138] Azone (3% w / v)

[0139] Phase transition characteristics:

[0140] Sol-gel transition temperature: 33.5 ± 0.3 °C (measured by rheometer)

[0141] Viscoelastic parameters: G = 850 Pa, G = 120 Pa (frequency 1 Hz)

[0142] Transdermal characteristics:

[0143] Using Franz diffusion cell (ex vivo porcine skin):

[0144] 24-hour cumulative permeation amount: Tanshinone IIA 12.8 μg / cm 2 , Puerarin 45.6 μg / cm 2

[0145] Steady-state flux: 3.2 times higher than that of traditional ointment

[0146] Technical details description:

[0147] Synergistic mechanism of ultrafine comminution:

[0148] When the particle size is reduced to 15 μm, the dissolution rate of total saponins from Panax notoginseng increases from 62% to 89% (Chinese pharmacopoeia method)

[0149] Analysis of the correlation between specific surface area and drug efficacy shows that when D90 ≤ 20 μm, the itching onset time is shortened to 8.3 ± 2.1 minutes

[0150] Visual verification of scar repair:

[0151] Using Imaging system:

[0152] After 8 weeks of treatment, the unevenness of the scar is reduced by 58%

[0153] The hemoglobin index decreases by 42% (P < 0.01)

[0154] Scientific basis for compatibility:

[0155] Network pharmacology analysis (Cytoscape 3.8.0):

[0156] Core target group: STAT3, VEGFA, IL6, MMP9

[0157] KEGG pathway enrichment: Jak-STAT signaling pathway (P = 3.2E-7), Scar formation pathway (P = 1.8E-5)

[0158] Multi-target synergistic treatment mechanism. Through network pharmacology analysis (Cytoscape 3.8.0), the composition can act on 12 skin pathological pathways such as IL-17A, JAK-STAT, and VEGF simultaneously, and the action range is expanded 4.2 times compared with single components.

[0159] Verification of the synergistic effect of key components:

[0160] Notoginsenoside R1 + Tanshinone IIA: The inhibition rate of TNF-α is increased to 89% (42% and 51% respectively when used alone).

[0161] Volatile oil of Cinnamomum cassia + Chitosan of Cryptotympana pustulata: The skin barrier repair speed is increased by 2.3 times (measured by TEWL value).

[0162] Breakthrough transdermal absorption efficiency. The specific surface area of the drug reaches 8.5 m 2 / g by ultrafine comminution technology (only 1.2 m 2 / g for traditional comminution).

[0163] Franz diffusion cell test shows that:

[0164] 24-hour cumulative penetration amount of Tanshinone IIA: 45.6 μg / cm 2 (only 12.3 μg / cm for traditional powder). 2 )

[0165] The onset time is shortened to 8.3 ± 2.1 minutes (traditional preparations require more than 25 minutes). Dual regulation of scar repair, molecular mechanism:

[0166] Up-regulate the expression of TGF-β3 (increased 2.7 times by Western blot detection).

[0167] Inhibit the activity of α-SMA in fibroblasts (decrease by 61%, P < 0.005).

[0168] Clinical verification:

[0169] The thickness of hypertrophic scars is reduced by ≥ 50% (12-week treatment, imaging).

[0170] The degree of orderliness of collagen fiber arrangement is increased by 3.2 times (observed by two-photon microscopy).

[0171] Balance of rapid and long-term effects. Pharmacokinetic studies show that:

[0172] The Tmax of puerarin, a rapid-acting component, is 0.9 h (rapidly relieves itching).

[0173] The AUC0-∞ of acid of Drynaria fortunei, a long-acting component, is 587.4 h·ng / mL (continuously anti-inflammatory).

[0174] The erythema regression rate of patients with acute eczema reached 91% within 24 hours (EASI scoring method)

[0175] Breakthrough innovation in microbial control. Pulse UV + electron beam combined sterilization enables the microbial load to be ≤ 50 CFU / g, a reduction of two orders of magnitude compared to traditional moist heat sterilization

[0176] Verified by 6-month accelerated test: No pathogenic bacteria detected (detection limit: 1 CFU / g)

[0177] Precision drug delivery for special populations, pediatric dosing system:

[0178] The error of the dosing spoon is ≤ ±5% (verified by ISO international standard)

[0179] Linear relationship R of blood drug concentration in the 1 / 4 dose group 2 = 0.987 (determined by LC-MS / MS)

[0180] Dosage reduction plan for patients with renal insufficiency:

[0181] When the clearance rate decreases by 35%, the dosage is adjusted to 6 g / day (calculated based on the PBPK model)

[0182] Revolutionary improvement in formulation stability, vacuum freeze-drying + nano-silica anti-caking technology:

[0183] The retention rate of the active ingredient is ≥ 97.5% after 36 months (detected by HPLC)

[0184] Flowability index: Angle of repose ≤ 35° (superior to the Chinese Pharmacopoeia standard for powder ≤ 40°). Multi-dimensional quality controllability, establishing a three-level quality control system:

[0185] Chemical marker: Notoginsenoside R1 ≥ 0.8 mg / g (quantification lower limit 0.1 μg / mL). Bioactivity index: Inhibition rate of IL-6 on HaCaT cells ≥ 65%

[0186] Physical property: Particle size distribution D90 ≤ 20 μm (verified by laser diffraction method)

[0187] Advantages in industrial production, dynamic continuous production process:

[0188] Energy consumption reduced by 42% (compared with traditional batch production)

[0189] The utilization rate of medicinal materials is increased to 98.7% (near-infrared on-line monitoring)

[0190] Intelligent control system:

[0191] Real-time feedback regulation of the comminution particle size (PID algorithm control accuracy ±1.5 μm)

[0192] Sterilization dose automatic compensation (irradiation intensity fluctuation ≤ ±3%)

[0193] Significant progress compared with the prior art:

[0194]

[0195]

[0196] The above describes the present invention and its implementation manners, and such description is not restrictive.

Claims

1. A Chinese medicine composition for treating skin diseases, characterized in that It consists of the following raw materials in parts by weight: 6 - 12 parts of Panax notoginseng, 8 - 15 parts of Salvia miltiorrhiza, 10 - 20 parts of Ligusticum chuanxiong, 8 - 15 parts of Curcuma longa, 15 - 35 parts of Angelica sinensis, 3 - 8 parts of Santalum album, 3 - 8 parts of Aurantii Fructus Immaturus, 40 - 60 parts of Cinnamomum cassia, 8 - 15 parts of Corydalis yanhusuo, 8 - 15 parts of Rhizoma zedoariae, 2 - 5 parts of Carthamus tinctorius, 5 - 12 parts of Pueraria lobata, 8 - 15 parts of Rehmannia glutinosa, 3 - 8 parts of Citrus reticulata Blanco, 8 - 15 parts of Prunella vulgaris, 3 - 8 parts of Trichosanthes kirilowii Maxim., 15 - 35 parts of Tribulus terrestris, 15 - 35 parts of Cryptotympana pustulata Fabricius, 5 - 12 parts of Bombyx batryticatus, 8 - 15 parts of Drynaria fortunei.

2. The traditional Chinese medicine composition according to claim 1, wherein The exact parts by weight of each raw material are: 9 parts of Panax notoginseng, 10 parts of Salvia miltiorrhiza, 15 parts of Ligusticum chuanxiong, 10 parts of Curcuma longa, 25 parts of Angelica sinensis, 5 parts of Santalum album, 5 parts of Aurantii Fructus Immaturus, 50 parts of Cinnamomum cassia, 10 parts of Corydalis yanhusuo, 10 parts of Rhizoma zedoariae, 3 parts of Carthamus tinctorius, 7.5 parts of Pueraria lobata, 10 parts of Rehmannia glutinosa, 5 parts of Citrus reticulata Blanco, 10 parts of Prunella vulgaris, 5 parts of Trichosanthes kirilowii Maxim., 25 parts of Tribulus terrestris, 25 parts of Cryptotympana pustulata Fabricius, 8 parts of Bombyx batryticatus, 10 parts of Drynaria fortunei.

3. The preparation method of the traditional Chinese medicine composition according to claim 2, characterized in that It includes: (1) Raw material pretreatment: Use an X-ray foreign object separator to remove impurities, with a removal accuracy of ≤ 0.3 mm 3 ; (2) Low-temperature grinding: Grind using an eddy current mill in a low-temperature environment of -15°C to 0°C, controlling the material temperature ≤ 25°C; (3) Particle size control: Classify through a 200-mesh vibrating screen and collect powders with a passing rate of ≥ 95%; (4) Dynamic sterilization: Implement pulsed ultraviolet irradiation sterilization during the powder transportation process, with an irradiation intensity of 120 - 150 μW / cm 2 .

4. The preparation method according to claim 3, characterized in that In step (2): Primary crushing is carried out using a shear - type crusher with a rotation speed of 800 - 1200 rpm and crushed to 80 - 100 mesh. Secondary crushing is carried out using a ball mill cooled by liquid nitrogen, with zirconia beads as the grinding medium, a particle size of 0.5 - 1 mm, and a grinding time of 30 - 60 min.

5. The preparation method according to claim 3, characterized in that In step (4): After sterilization, the powder is subjected to vacuum freeze - drying treatment. The pre - freezing temperature is maintained at - 40°C for 4 h, the pressure in the sublimation drying stage is 10 - 30 Pa, and the temperature in the desorption drying stage is 35°C.

6. The Chinese medicine composition according to claim 1, characterized in that It includes the following quality indicators: The content of notoginsenoside R1 ≥ 0.8 mg / g The content of tanshinone IIA ≥ 1.2 mg / g The content of puerarin ≥ 2.5 mg / g Microbial limit: The total number of aerobic bacteria ≤ 100 CFU / g, the total number of molds and yeasts ≤ 10 CFU / g.

7. Use of the traditional Chinese medicine composition according to claim 1 in the preparation of a drug for treating the following diseases: Use of the traditional Chinese medicine composition in the preparation of a drug for treating the following diseases: acute / chronic urticaria, eczema, pruritus of unknown etiology, dermatitis (such as: neurodermatitis, traumatic dermatitis, etc.), traumatic tissue hyperplasia (such as: keloid), acne, herpes virus, solar dermatitis, allergic dermatitis, contact dermatitis, intractable eczema, nodular prurigo, seborrheic dermatitis, atopic dermatitis, cutaneous amyloidosis, etc.

8. The traditional Chinese medicine composition according to claim 1, characterized in that It can be made into any one of the following: nano - suspension (particle size 100 - 300 nm), transdermal microneedle patch (needle height 500 - 800 μm), thermosensitive gel (phase transition temperature 32 - 35°C).

9. A traditional Chinese medicine external preparation, characterized in that It consists of the composition according to any one of claims 1 - 2 and a transdermal enhancer, wherein: The transdermal enhancer is a composite system of 1 - 3% azone, 0.5 - 1.5% menthol, and 2 - 5% propylene glycol, and the drug - loading amount is 15 - 25% (w / w).

10. A traditional Chinese medicine oral preparation, characterized in that It includes: 50 - 70% of the composition according to any one of claims 1 - 2, 20 - 30% of a prebiotic composition (fructooligosaccharide: inulin = 3:1), and 10 - 15% of an enteric - coated material (hydroxypropyl methylcellulose phthalate), and is made into sustained - release pellets with a gastric emptying time ≥ 2 h.

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