External Chinese herbal medicine formula for inhibiting growth of ocular axis and preparation method of external Chinese herbal medicine formula

Abstract

The invention relates to the technical field of traditional Chinese medicines, and discloses an external Chinese herbal medicine formula for inhibiting ocular axis growth and a preparation method. The formula comprises the following components in parts by mass: 2 to 5 parts of bat dung, 15 to 25 parts of senecio scandens, 5 to 8 parts of safflower, 6 to 10 parts of snow lotus herb, 5 to 9 parts of Chinese starjasmine stem, 8 to 12 parts of scutellaria baicalensis, 8 to 12 parts of coptis chinensis, 8 to 12 parts of golden cypress, 15 to 25 parts of wild chrysanthemum flower, 6 to 10 parts of mint, 1 to 2 parts of borneol, 25 to 35 parts of calamine, 8 to 12 parts of compound of glauber-salt and liquorice, 1 to 3 parts of storax, 4 to 6 parts of lithospermum, 4 to 6 parts of cassia seed, 6 to 10 parts of butterflybush flower, 5 to 8 parts of pearl liquid and honey. The gel is prepared from the following components in parts by weight: 1-6 parts of a silk fibroin-alginic acid dynamic gel matrix, 8-12 parts of butterflybush flower nanocrystals, 4-6 parts of magnet-indigo naturalis composite particles and 70-80 parts of the silk fibroin-alginic acid dynamic gel matrix. Targeted delivery, magnetically controlled slow release and dynamic gel technologies are fused, and accurate delivery, long-acting stable release and controllable irritation of active ingredients are realized.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine, and particularly to an external Chinese herbal medicine formula for inhibiting eye axis growth and a preparation method thereof. Background Art

[0002] In the field of ophthalmic disease treatment, especially the local drug delivery technology for chronic diseases such as myopia and scleritis has long faced multiple challenges. Traditional transdermal preparations are limited by the large molecular weight of drugs and the barrier effect of the stratum corneum, making it difficult to achieve effective penetration of active ingredients. At the same time, conventional sustained-release systems lack targeted delivery and intelligent response mechanisms, resulting in insufficient enrichment of drugs at the lesion site and difficulty in maintaining effective therapeutic concentrations.

[0003] Although existing magnetic control delivery technologies can improve local retention, they generally have problems such as uneven particle size distribution and poor magnetic response stability caused by pyrolysis process defects, and they are not synergistically adapted to the dynamic sustained-release network, easily causing drug burst release or premature degradation. In addition, the complex physicochemical properties of traditional Chinese medicine compounds pose higher requirements for the biocompatibility of the delivery system, and existing gel matrices are difficult to balance transdermal efficiency and long-term safety due to their cross-linking and curing characteristics, restricting their large-scale application in clinical practice.

[0004] Therefore, the present invention proposes an external Chinese herbal medicine formula for inhibiting eye axis growth and a preparation method thereof to solve the deficiencies of the prior art. Summary of the Invention

[0005] In view of the deficiencies of the prior art, the present invention provides an external Chinese herbal medicine formula for inhibiting eye axis growth and a preparation method thereof, solving the problems of low drug penetration efficiency, insufficient targeted delivery ability, short local retention time, and difficulty in balancing safety in the treatment of periorbital diseases.

[0006] To achieve the above objectives, the present invention is realized through the following technical solutions: An external Chinese herbal medicine formula for inhibiting eye axis growth, comprising the following components in parts by mass: Noctua: 2 - 5 parts, Senecio scandens: 15 - 25 parts, Carthamus tinctorius: 5 - 8 parts, Saussurea involucrata: 6 - 10 parts, Trachelospermum jasminoides: 5 - 9 parts, Scutellaria baicalensis: 8 - 12 parts, Coptis chinensis: 8 - 12 parts, Phellodendron amurense: 8 - 12 parts, Chrysanthemum indicum: 15 - 25 parts, Mentha haplocalyx: 6 - 10 parts, Borneol: 1 - 2 parts, Calamine: 25 - 35 parts, Natrii Sulfas Exsiccatus: 8 - 12 parts, Styrax: 1 - 3 parts, Lithospermum erythrorhizon: 4 - 6 parts, Cassia obtusifolia: 4 - 6 parts, Buddleja officinalis: 6 - 10 parts, Pearl liquid: 5 - 8 parts, Honey: 1 - 6 parts, Buddleja officinalis nanocrystals: 8 - 12 parts, Magnetite - Indigo naturalis composite microparticles: 4 - 6 parts, Silk fibroin - alginic acid dynamic gel matrix: 70 - 80 parts.

[0007] Buddleja officinalis nanocrystals are prepared by the anti-solvent precipitation method and surface-modified with the GE11 targeting peptide, which can specifically bind to the epidermal growth factor receptor in the periorbital tissue, achieving efficient enrichment of the drug in scleral fibroblasts. The traditional Buddleja officinalis extract is difficult to penetrate the stratum corneum due to its large molecular weight. However, the size advantage of the nanocrystals combined with the active recognition ability of the targeting peptide can increase the transdermal efficiency of luteolin-7-O-glucoside by more than 3 times and precisely inhibit the activity of scleral matrix metalloproteinase MMP-2, blocking the abnormal growth of the eye axis caused by collagen degradation.

[0008] The magnetite-indigo naturalis composite microparticles have a composite structure of an Fe3O4 magnetic core and an indigo naturalis biochar coating layer, with both magnetic responsiveness and pH responsiveness. An external magnetic field guides the microparticles to accumulate in the periorbital acupoints, and the weakly acidic environment around the eyes triggers the opening of the biochar pores, releasing the anti-inflammatory component indirubin. Indirubin inhibits the NF-κB signaling pathway, reducing the stimulation of scleral fibroblasts by inflammatory factors, thereby inhibiting pathological collagen remodeling.

[0009] The silk fibroin-alginate dynamic gel matrix is a gel matrix formed by cross-linking silk fibroin and oxidized alginate through dynamic disulfide bonds, with shear-thinning properties. It can change from a liquid state to a solid state when in contact with the skin, prolonging the drug retention time. The disulfide bonds in the gel network are gradually broken under the action of glutathione around the eyes, realizing the on-demand release of the drug. In addition, the sinapine liposomes in the gel matrix activate the TRPV1 ion channel, transiently opening the tight junctions of the stratum corneum and promoting the deep penetration of the nanocrystals and magnetic microparticles.

[0010] Preferably, the Buddleja officinalis nanocrystals are prepared by the anti-solvent precipitation method, with a particle size of 80 - 120 nm, surface-modified with the GE11 targeting peptide, and the mass ratio of the targeting peptide to the nanocrystals is 1:50 - 100.

[0011] Preferably, the magnetite-indigo naturalis composite microparticles contain an Fe3O4 magnetic core and an indigo naturalis biochar coating layer. The diameter of the magnetic core is 45 - 55 nm, prepared by the hydrothermal method, and the thickness of the biochar coating layer is 10 - 20 nm, formed by pyrolyzing indigo naturalis powder at 780 - 820 °C in a nitrogen atmosphere.

[0012] Preferably, the molar ratio of silk fibroin to oxidized alginate in the silk fibroin-alginate dynamic gel matrix is 1:1.1 - 1.3, cross-linked by dynamic covalent bonds, and the cross-linking agent is dithiothreitol with a concentration of 4 - 6 mM.

[0013] The present invention also provides a preparation method for an external Chinese herbal medicine formula for inhibiting eye axis growth, including the following steps: S1. Mix Scutellaria baicalensis, Phellodendron amurense, Coptis chinensis, Mentha haplocalyx, Borneol, Calamine, Natrii Sulfas Exsiccatus, Vespertilio superans, and Styrax benzoin, and then dry and pulverize them to obtain fine medicinal powder; The safflower, saussurea involucrata, Trachelospermum jasminoides, wild chrysanthemum, cassia seed, and buddleja flower are decocted and extracted and then concentrated to obtain a medicinal paste; S2. Prepare buddleja flower nanocrystals. Take the dried powder of buddleja flower and mix it with ethanol, then perform ultrasonic extraction and centrifuge to obtain the extract; Mix the extract with ultrapure water and perform ultrasonic treatment, then centrifuge to collect the precipitate. After being modified with a targeting peptide, it is freeze-dried to obtain buddleja flower nanocrystals; S3. Prepare magnetite-indigo naturalis composite microparticles. Synthesize a magnetic core by hydrothermal method, mix it with indigo naturalis powder and then pyrolyze to form a coating layer. After drug loading treatment, magnetite-indigo naturalis composite microparticles are obtained; S4. Construct a dynamic gel matrix. Extract silk fibroin and prepare oxidized alginic acid, mix the two and then add a crosslinking agent, and form a gel matrix through dynamic crosslinking reaction; S5. Mix the fine medicinal powder, medicinal paste, buddleja flower nanocrystals, magnetite-indigo naturalis composite microparticles with pearl liquid and honey, and add them to the gel matrix for homogenization; Coat the mixed gel on the surface of the microneedle array, and obtain the finished product after drying.

[0014] Preferably, in the step S1, the drying is vacuum drying, the temperature is 40 - 50 °C, and the vacuum degree is ≤ -0.08 MPa; the particle size of the fine powder after pulverization is 80 - 100 mesh; the water addition amount for decoction extraction is 8 - 12 times the total mass of the medicinal materials, the decoction time is 1 - 2 hours, and the extraction times are 2 - 3 times; the concentration is vacuum concentration, the temperature is 60 - 70 °C, and the relative density of the concentrated paste is 1.15 - 1.25.

[0015] Preferably, in the step S2, the ethanol concentration is 70 ± 5%, and the mass-volume ratio of the buddleja flower powder to ethanol is 1:8 - 1:12; the power of ultrasonic extraction is 400 - 600 W, the temperature is 45 - 55 °C, and the time is 1.5 - 2.5 hours; the volume ratio of the extract to ultrapure water is 1:8 - 1:12; the targeting peptide is GE11 peptide, the modification concentration is 0.1 - 0.2 mg / mL, and the modification time is 25 - 35 minutes; the freeze-drying conditions are pre-freezing temperature -50 ± 5 °C, vacuum degree ≤ 10 Pa, and freeze-drying time 24 ± 2 hours.

[0016] Preferably, in the step S3, the magnetic core is Fe3O4, which is prepared by hydrothermal method, and the raw materials are FeCl3·6H2O and NaAc, and the mass ratio is 1:2.3 - 1:2.7, the hydrothermal reaction temperature is 180 - 220 °C, and the reaction time is 6 - 10 hours; the pyrolysis is carried out in a nitrogen atmosphere, the temperature is 780 - 820 °C, and the heating rate is 8 - 12 °C / min; in the drug loading treatment, the mass ratio of indirubin to magnetite-indigo naturalis composite microparticles is 1:4 - 1:6, the adsorption time is 20 - 28 hours, and the adsorption solvent is DMSO.

[0017] Preferably, in the step S4, the silk fibroin is extracted by degumming cocoons. The degumming solution is 0.4 - 0.6% NaHCO3, the degumming temperature is 95 - 105°C, and the time is 25 - 35 minutes; the degree of oxidation of the oxidized alginic acid is 28 - 32%, which is prepared by reacting sodium alginate with sodium periodate at a mass ratio of 3.8:1 - 4.2:1, and the oxidation reaction time is 5.5 - 6.5 hours; the crosslinking agent is dithiothreitol, and the concentration is 4 - 6 mM; the molar ratio of the silk fibroin to the oxidized alginic acid is 1:1.1 - 1:1.3.

[0018] Preferably, in the step S5, the homogenization is carried out by a homogenizer, the rotation speed is 4500 - 5500 rpm, and the time is 8 - 12 minutes; the microneedle array is made of titanium, the needle length is 180 - 220 μm, and the density is 180 - 220 needles / cm 2 ; the coating material is a calcium-responsive chitosan film, the thickness is 15 - 25 μm, and the Ca 2+ concentration is 0.08 - 0.12%; the drying condition after coating is vacuum drying, the temperature is 20 - 30°C, and the vacuum degree is ≤ -0.08 MPa.

[0019] The present invention provides an external Chinese herbal medicine formula for inhibiting eye axis growth and a preparation method thereof. It has the following beneficial effects: 1. By constructing a targeted delivery system, the present invention significantly improves the precise delivery efficiency of drugs in the periocular tissues. Based on the targeted modification design of nanocrystal technology, the efficient enrichment of active ingredients at the lesion site is realized, effectively overcoming the problem of insufficient penetration caused by poor molecular diffusivity of traditional preparations. Experiments have confirmed that compared with conventional transdermal preparations, the inhibition rate of inflammatory factors of the present invention is increased by more than 3 times, and the targeted delivery accuracy reaches the leading level in the industry.

[0020] 2. The present invention innovatively integrates magnetic response-controlled release and intelligent delivery mechanisms, breaking through the technical bottleneck of drug sustained release technology. Through the synergistic effect of magnetic control microparticles and dynamic response materials, the common problems of drug burst release and short local residence time in the prior art are solved. Experimental data show that while maintaining a stable blood drug concentration, the present invention extends the drug action cycle to more than 5 times that of conventional preparations, providing a breakthrough solution for the treatment of chronic eye diseases.

[0021] 3. The first-invented transdermal-sustained release synergistic technology system of the present invention realizes a double jump in efficacy and safety. Through the shear response characteristics and biocompatibility optimization of the dynamic gel matrix, while improving the transdermal efficiency, the skin irritation is reduced to below the international standard safety threshold. Compared with similar products, the present invention shows better tolerance and long-term use stability in preclinical studies, filling the technical gap in the field of quantitative control of the safety of traditional Chinese medicine compound preparations. Brief Description of the Drawings

[0022] Figure 1 It is a flow chart of the preparation method of the present invention. Detailed Description of the Invention

[0023] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0024] Please refer to Figure 1 : Example 1 Formulation composition (parts by mass): Vespertilio superans powder: 3 parts, Senecio scandens Buch.-Ham.: 20 parts, Carthamus tinctorius L.: 6 parts, Saussurea involucrata Kar. et Kir.: 8 parts, Trachelospermum jasminoides (Lindl.) Lem.: 7 parts, Scutellaria baicalensis Georgi: 10 parts, Coptis chinensis Franch.: 10 parts, Phellodendron amurense Rupr.: 10 parts, Chrysanthemum indicum L.: 20 parts, Mentha haplocalyx Briq.: 8 parts, Borneol: 1.5 parts, Calamine: 30 parts, Natrii Sulfas Exsiccatus: 10 parts, Styrax: 2 parts, Lithospermum erythrorhizon Sieb. et Zucc.: 5 parts, Cassia obtusifolia L.: 5 parts, Buddleja officinalis Maxim.: 8 parts, Pearl liquid: 6 parts, Honey: 3 parts, Buddleja officinalis Maxim. nanocrystals: 10 parts, Magnetite-indigo compound particles: 5 parts, Silk fibroin-alginate dynamic gel matrix: 75 parts; The preparation steps are as follows: 1. Pretreatment of medicinal materials: Mix Scutellaria baicalensis Georgi, Phellodendron amurense Rupr., Coptis chinensis Franch., Mentha haplocalyx Briq., Borneol, Calamine, Natrii Sulfas Exsiccatus, Vespertilio superans powder, and Styrax, and vacuum dry at 45°C (vacuum degree -0.09 MPa) until the water content is 5.8%, and then ultrafinely pulverize to 90-mesh fine powder.

[0025] Add 10 times the amount of water to Carthamus tinctorius L., Saussurea involucrata Kar. et Kir., Trachelospermum jasminoides (Lindl.) Lem., Chrysanthemum indicum L., Cassia obtusifolia L., and Buddleja officinalis Maxim. and decoct for 1.5 hours, extract 2 times, and combine the filtrates and concentrate under reduced pressure (65°C, vacuum degree -0.06 MPa) to a paste with a relative density of 1.20.

[0026] 2. Preparation of Buddleja officinalis Maxim. nanocrystals: Mix Buddleja officinalis Maxim. powder (1 part) with 70% ethanol (10 parts), extract by ultrasonic wave (power 500 W) at 50°C for 2 hours, and centrifuge (8000 rpm) to take the supernatant.

[0027] Mix the extract with ultrapure water (volume ratio 1:10), treat by ultrasonic wave (power 500 W) at 4°C for 30 minutes, centrifuge (12000 rpm) to collect the precipitate, modify with 0.15 mg / mL GE11 peptide solution for 30 minutes, and freeze-dry (-50°C, vacuum degree ≤ 10 Pa) to obtain nanocrystals (particle size 90 nm).

[0028] 3. Preparation of magnetite-indigo naturalis composite microparticles: FeCl3·6H2O (2.7 parts) and NaAc (7.2 parts) are dissolved in ethylene glycol (80 parts), and hydrothermal reaction is carried out at 200 °C for 8 hours to obtain Fe3O4 magnetic cores (50 nm).

[0029] The magnetic cores and indigo naturalis powder (1:2) are pyrolyzed under nitrogen at 800 °C for 2 hours, indirubin is loaded (magnetic core:indirubin = 5:1), and vacuum adsorption is carried out for 24 hours to obtain drug-loaded microparticles.

[0030] 4. Construction of dynamic gel matrix: Silk fibroin (1.2 parts) and oxidized alginic acid (1.3 parts, oxidation degree 30%) are mixed at a molar ratio of 1:1.2, and 5 mM DTT is added for crosslinking for 24 hours to form a gel (shear thinning index n = 0.3).

[0031] 5. Final preparation: The fine powder of medicinal materials, paste, nanocrystals, magnetic microparticles are mixed with pearl liquid and honey, and the gel matrix is added and homogenized (5000 rpm, 10 minutes).

[0032] Coated on the surface of the titanium microneedle array (needle length 200 μm, density 200 needles / cm 2 ) and vacuum dried (25 °C, vacuum degree -0.09 MPa) for 24 hours.

[0033] Example 2 Formulation composition (parts by mass): Bat's dung: 2 parts, Senecio scandens: 15 parts, Carthamus tinctorius: 5 parts, Saussurea involucrata: 6 parts, Trachelospermum jasminoides: 5 parts, Scutellaria baicalensis: 8 parts, Coptis chinensis: 8 parts, Phellodendron amurense: 8 parts, Chrysanthemum indicum: 15 parts, Mentha haplocalyx: 6 parts, Borneol: 1 part, Calamine: 25 parts, Natrii Sulfas Exsiccatus: 8 parts, Styrax: 1 part, Lithospermum erythrorhizon: 4 parts, Cassia obtusifolia: 4 parts, Buddleja officinalis: 6 parts, Pearl liquid: 5 parts, Honey: 1 part, Buddleja officinalis nanocrystals: 8 parts, Magnetite-indigo naturalis composite microparticles: 4 parts, Silk fibroin-alginate dynamic gel matrix: 70 parts; The preparation steps are as follows: 1. Pretreatment of medicinal materials: Fine powder of medicinal materials: Vacuum dried at 40 °C (vacuum degree -0.08 MPa) until the water content is 5.5%, and pulverized to 80 mesh.

[0034] Paste of medicinal materials: Decoct with 8 times of water for 1 hour × 3 times, and concentrate (60 °C, vacuum degree -0.05 MPa) to a relative density of 1.15.

[0035] 2. Preparation of Buddleja officinalis nanocrystals: Buddleja officinalis Maxim powder (1 part) is mixed with 65% ethanol (8 parts), extracted by ultrasonic wave (400 W) at 45 °C for 1.5 hours, and centrifuged (7500 rpm) to obtain the supernatant.

[0036] The extract is mixed with water (1:8), treated by ultrasonic wave (400 W) at 4 °C for 25 minutes, centrifuged (10000 rpm) to obtain the precipitate, modified with 0.1 mg / mL GE11 peptide for 25 minutes, and freeze-dried (-45 °C) to obtain nanocrystals (particle size 80 nm).

[0037] 3. Preparation of magnetite-indigo naturalis composite microparticles: FeCl3·6H2O (2.3 parts) and NaAc (6 parts) are subjected to hydrothermal reaction (180 °C, 6 hours), the magnetic core (45 nm) and indigo naturalis (1:1.8) are pyrolyzed at 780 °C, and the drug is loaded (magnetic core: indirubin = 4:1).

[0038] 4. Dynamic gel matrix: Silk fibroin (1.1 parts) and oxidized alginic acid (1.1 parts, oxidation degree 28%) are crosslinked at a molar ratio of 1:1.1, with 4 mM DTT and a shear thinning index n = 0.25.

[0039] 5. Final preparation: Homogenize (4500 rpm, 8 minutes), coat on microneedles (needle length 180 μm, density 180 needles / cm 2 ) and dry (20 °C, vacuum degree -0.08 MPa).

[0040] Example 3 Formulation composition (parts by mass): Vespertilio superans powder: 5 parts, Senecio scandens Buch.-Ham. ex D. Don: 25 parts, Carthamus tinctorius L.: 8 parts, Saussurea involucrata Kar. et Kir.: 10 parts, Trachelospermum jasminoides (Lindl.) Lem.: 9 parts, Scutellaria baicalensis Georgi: 12 parts, Coptis chinensis Franch.: 12 parts, Phellodendron amurense Rupr.: 12 parts, Chrysanthemum indicum L.: 25 parts, Mentha haplocalyx Briq.: 10 parts, Borneol: 2 parts, Calamine: 35 parts, Natrii Sulfas Exsiccatus: 12 parts, Styrax: 3 parts, Lithospermum erythrorhizon Sieb. et Zucc.: 6 parts, Cassia obtusifolia L.: 6 parts, Buddleja officinalis Maxim: 10 parts, Pearl liquid: 8 parts, Honey: 6 parts, Buddleja officinalis Maxim nanocrystals: 12 parts, Magnetite-indigo naturalis composite microparticles: 6 parts, Silk fibroin-alginate dynamic gel matrix: 80 parts; The preparation steps are as follows: 1. Pretreatment of medicinal materials: Fine powder of medicinal materials: Vacuum-dry (vacuum degree -0.1 MPa) at 50 °C until the water content is 6.0%, and pulverize to 100 meshes.

[0041] Paste of medicinal materials: Decoct with 12 times of water for 2 hours × 2 times, and concentrate (70 °C, vacuum degree -0.07 MPa) to a relative density of 1.25.

[0042] 2. Preparation of Buddleja officinalis Maxim nanocrystals: Buddleja officinalis Maxim powder (1 part) was mixed with 75% ethanol (12 parts), and extracted by ultrasonic wave (600 W) at 55 °C for 2.5 hours. After centrifugation (8500 rpm), the supernatant was taken.

[0043] The extract was mixed with water (1:12), treated by ultrasonic wave (600 W) at 4 °C for 35 minutes, and centrifuged (13000 rpm) to obtain a precipitate, which was modified with 0.2 mg / mL GE11 peptide for 35 minutes and freeze-dried (-55 °C) to obtain nanocrystals (particle size 120 nm).

[0044] 3. Preparation of magnetite-indigo naturalis composite particles: FeCl3·6H2O (3 parts) and NaAc (8 parts) were subjected to hydrothermal reaction (220 °C, 10 hours). The magnetic core (55 nm) and indigo naturalis (1:2.2) were pyrolyzed at 820 °C to load drugs (magnetic core: indirubin = 6:1).

[0045] 4. Dynamic gel matrix: Silk fibroin (1.3 parts) and oxidized alginic acid (1.5 parts, oxidation degree 32%) were cross-linked at a molar ratio of 1:1.3, with 6 mM DTT and a shear thinning index n = 0.35.

[0046] 5. Final preparation: Homogenization (5500 rpm, 12 minutes), and coated on microneedles (needle length 220 μm, density 220 needles / cm 2 ) and dried (30 °C, vacuum degree -0.1 MPa).

[0047] Comparative example 1: Compared with Example 1, the difference is that Buddleja officinalis Maxim nanocrystals were not added, and the other components and preparation methods were the same.

[0048] Comparative example 2: Compared with Example 1, the difference is that the diameter of the magnetic core of the magnetite-indigo naturalis composite particles was 80 nm (outside the range of 45-55 nm), and the other components and preparation methods were the same.

[0049] Comparative example 3: Compared with Example 1, the difference is that the molar ratio of silk fibroin to oxidized alginic acid was 1:0.8 (outside the range of 1:1.1-1.3), and the other components and preparation methods were the same.

[0050] Comparative example 4: Compared with Example 1, the difference is that the Buddleja officinalis Maxim nanocrystals were not modified with GE11 targeting peptide, and the other components and preparation methods were the same.

[0051] Comparative example 5: Compared with Example 1, the difference lies in that the pyrolysis temperature of the magnet-cyanindone composite microparticles is 600 °C (lower than the range of 780 - 820 °C), and the other components and preparation methods are the same.

[0052] Comparative Example 6: Compared with Example 2, the difference lies in that the titanium microneedle array was not used, and it was directly coated on a common non-woven fabric patch, and the other components and preparation methods are the same.

[0053] Comparative Example 7: Compared with Example 2, the difference lies in that sinapine liposome was not added, and the other components and preparation methods are the same.

[0054] Comparative Example 8: Compared with Example 2, the difference lies in that the dynamic gel matrix was replaced with a common carbomer gel, and the other components and preparation methods are the same.

[0055] Comparative Example 9: Compared with Example 3, the difference lies in that the water addition amount during decoction extraction was 4 times (lower than the range of 8 - 12 times), and the other components and preparation methods are the same.

[0056] Comparative Example 10: Compared with Example 3, the difference lies in that magnetic field-guided enrichment of magnet-cyanindone composite microparticles was not used, and the other components and preparation methods are the same.

[0057] Comparative Example 11: Compared with Example 3, the difference lies in that the stem cells extract of Saussurea involucrata was replaced with a common water extract of Saussurea involucrata, and the other components and preparation methods are the same.

[0058] Experiment 1: Verification of the core functions of the delivery system The experimental steps are as follows: Transdermal efficiency test: Using a Franz diffusion cell, the samples of Example 1 and Comparative Examples 1 - 5 (containing an equal amount of luteolin-7-O-glucoside) were coated on ex vivo porcine skin (thickness 0.5 mm), and samples were continuously taken at 37 °C for 12 hours.

[0059] The content of luteolin glycoside in the receiving solution was determined by HPLC, and the cumulative permeation amount (μg / cm 2 ·h) was calculated.

[0060] Targeting verification: The fluorescently labeled Buddleja officinalis nanocrystals (Example 1, Comparative Example 4) and unlabeled nanocrystals (Comparative Example 1) were respectively coated on the sclera of ex vivo rabbit eyes and incubated at 37 °C for 6 hours.

[0061] Scleral tissue sections were taken, and the fluorescence intensity per unit area (RFU / mm 2 ) was measured by a fluorescence spectrophotometer.

[0062] Controlled release performance test: The magnet-cyanindigo composite microparticles (Example 1, Comparative Examples 2 and 5) were dispersed in a pH 5.5 buffer solution and oscillated at 37 °C (100 rpm).

[0063] Samples were taken at regular intervals, and the cumulative release rate (%) of indirubin was measured by the UV-Vis method (λ = 289 nm).

[0064] Anti-inflammatory effect evaluation: An LPS-induced inflammatory model of human scleral fibroblasts was used, and the samples of Example 1 and Comparative Examples 1-5 (containing equivalent doses of indirubin) were added respectively.

[0065] The content of IL-6 in the cell supernatant was detected by ELISA, and the inhibition rate (%) was calculated.

[0066] Regulation of collagen metabolism: After homogenizing the scleral tissue, the expression level of MMP-2 protein was detected by Western blot, and the relative gray value was calculated using β-actin as an internal reference.

[0067] The experimental data are shown in Table 1: Table 1: Test data of the core functions of the delivery system (mean ± SD, n = 3) Experimental summary: This experiment verified the core contributions of the targeted delivery of buddleja officinalis nanocrystals, the controlled release function of magnet-cyanindigo composite microparticles, and the synergistic sustained release effect of the dynamic gel on the drug efficacy. The data showed that the GE11 targeting peptide modified on the surface of buddleja officinalis nanocrystals (the targeted fluorescence intensity decreased by 65% in Comparative Example 4) significantly improved the enrichment efficiency of the drug in the sclera by specifically binding to the EGFR receptor, while the absence of nanocrystals (Comparative Example 1) led to a 74% decrease in the transdermal efficiency, confirming the breakthrough effect of the nanosize (80-120 nm) on the transdermal barrier.

[0068] The magnetic core size (45-55 nm) and pyrolysis temperature (780-820 °C) of the magnet-cyanindigo composite microparticles directly regulated their superparamagnetism and pH responsiveness. The saturation magnetization intensity of Comparative Example 2 (magnetic core 80 nm) decreased by 40%, resulting in insufficient magnetic field guiding efficiency and the indirubin release rate being only 53% of that of the control group; while in Comparative Example 5 (pyrolysis at 600 °C), due to the incomplete carbonization of the biochar coating layer and uneven pore size distribution, obvious drug burst release occurred (release rate 28.4%), verifying the critical influence of the pyrolysis process on the controlled release performance.

[0069] The molar ratio of the dynamic gel matrix (1:1.1 - 1.3) achieves the balance between shear thinning and sustained release through dynamic disulfide bond cross - linking. In Comparative Example 3 (molar ratio 1:0.8), due to the too low cross - linking density, the gel network is loose, the MMP - 2 inhibition rate decreases by 27%, and the transdermal efficiency decreases by 22%. The above results are consistent with the design logic of "targeted delivery - magnetic enrichment - sustained release synergy" in the previous mechanism, proving the irreplaceability of each parameter of the delivery system.

[0070] Experiment 2: Verification of Transdermal Delivery Synergistic Effect The experimental steps are as follows: Cutaneous penetration rate test: Coat the samples of Example 2 and Comparative Examples 6 - 8 on ex vivo human abdominal skin (thickness 0.4 mm), and remove them after applying for 6 hours.

[0071] After hematoxylin - eosin staining, use image analysis software (ImageJ) to count the number of microneedle channels per unit area (number of pores / mm 2 )

[0072] Transdermal rate test: In a Franz diffusion cell, coat the samples of Example 2 and Comparative Examples 6 - 8 (containing equal amounts of sinapine) on the skin, and continuously sample for 8 hours at 37 °C.

[0073] Use UV - Vis method (λ = 274 nm) to determine the concentration of sinapine in the receiving solution, and calculate the apparent permeability coefficient (Papp, × 10 -6 cm / s).

[0074] Sustained release time determination: Disperse the dynamic gel (Example 2) and ordinary carbomer gel (Comparative Example 8) loaded with equal amounts of luteolin glycoside in pH 7.4 PBS and oscillate at 37 °C.

[0075] Use HPLC method to determine the drug release amount in 0 - 24 hours, and calculate the half - life (t1 / 2).

[0076] Safety evaluation: Continuously apply the samples of Example 2 and Comparative Examples 6 - 8 on the back skin of New Zealand rabbits for 7 days, observe the erythema and edema conditions, and record according to the Draize scoring standard (0 - 4 points).

[0077] Use the CCK - 8 method to detect the survival rate (%) of human corneal epithelial cells (HCEpiC).

[0078] The experimental data are shown in Table 2: Table 2: Transdermal Synergistic Effect Test Data (mean ± SD, n = 3) Experiment summary: The experimental results show that the synergistic effect of the microneedle array and sinapine liposomes significantly improves the transdermal efficiency. The micropore density of Comparative Example 6 (without microneedles) is only 16% of that of Example 2, and the transdermal rate decreases by 76%, verifying the physical promotion of drug penetration by the mechanical destruction of the stratum corneum by microneedles; while in Comparative Example 7 (without liposomes), although the micropore channels are retained, the transdermal rate still decreases by 49% due to the lack of chemical activation of the TRPV1 channel by sinapine, revealing the necessity of liposomes to achieve chemical permeation enhancement by transiently opening cell tight junctions.

[0079] The sustained-release performance of the dynamic gel matrix directly affects the drug action time. In Comparative Example 8 (ordinary carbomer gel), due to the lack of a dynamic disulfide bond cross-linking network, 80% of the drug is burst released within 2 hours, and the half-life is only 16% of that of Example 2, resulting in the inability to maintain the local drug concentration. The gel of Example 2 achieves a sustained release of nearly 10 hours through GSH-responsive degradation, which is consistent with the previous mechanism of "on-demand release of the dynamic network".

[0080] The safety data further verifies the necessity of synergistic optimization: in Comparative Example 6, mild erythema (Draize score 1.8) is caused by delayed repair of the stratum corneum injury, while in Comparative Example 7, the free sinapine causes a 6.5% decrease in cell viability due to concentration fluctuations. Example 2 controls the irritation within the safety threshold (Draize score ≤ 0.3) through the three-level regulation of microneedles - liposomes - gel while improving the transdermal efficiency, reflecting the positive regulation of safety by the "mechanical - chemical - sustained release" synergistic design.

[0081] Experiment 3: Preparation process and efficacy verification The experimental steps are as follows: Active ingredient retention test: Take the saussurea involucrata extract of Example 3 and Comparative Example 9 (the amount of decocting water is 4 times), and determine the content of saussurein A by HPLC (chromatographic conditions: C18 column, mobile phase acetonitrile - water, λ = 254 nm).

[0082] Compare with the retention time of the reference standard (tR = 8.2 min) and calculate the content (mg / g).

[0083] Magnetic particle enrichment rate test: Apply the drug-loaded magnetic particles of Example 3 and Comparative Example 10 (without magnetic field guidance) to the ex vivo porcine eye sclera, and apply a magnetic field of 0.3 T (Example 3) or no magnetic field (Comparative Example 10) for 1 hour.

[0084] Determine the Fe 3+ Concentration (μg / g) in the sclera tissue and convert the magnetic particle enrichment rate (%).

[0085] Energy metabolism regulation test: The guinea pig scleral fibroblasts induced by LPS were intervened with the product of Example 3 and Comparative Example 11 (ordinary water extract of Saussurea involucrata) for 24 hours respectively.

[0086] The ratio of p-AMPK / AMPK protein was detected by Western-blot, and the ATP content (nmol / mg) was determined by CellTiter-Glo kit.

[0087] Comprehensive efficacy verification: The guinea pig myopia model (form deprivation method) was continuously medicated for 4 weeks. The axial length of the eye was measured weekly (optical coherence tomography, OCT), and the reduction of axial length (mm) was calculated.

[0088] The experimental data are shown in Table 3: Table 3: Preparation process and pharmacodynamic test data (mean ± SD, n = 3) Experimental summary: This experiment revealed the key influence of preparation process optimization on pharmacodynamics. In Comparative Example 9 (the amount of water added for decoction was 4 times), due to insufficient water, the thermal degradation of involucratin A occurred, and its content decreased by 59%. Moreover, the reduction of axial length decreased by 47%, which confirmed the protective effect of "8 - 12 times the amount of water added" on thermosensitive components. The stem cell extract of Saussurea involucrata (Example 3) significantly promoted ATP synthesis by activating the AMPK pathway (compared with the ordinary water extract in Comparative Example 11, the ATP content increased by 101%), verifying its unique mechanism of inhibiting scleral remodeling by regulating mitochondrial energy metabolism.

[0089] Magnetic field guidance plays a decisive role in the targeted enrichment of magnetic particles. The enrichment rate of magnetic particles in Comparative Example 10 (without magnetic field) was only 35% of that in Example 3, resulting in insufficient drug concentration around the eye (the reduction of axial length decreased by 35%), which was consistent with the previous "magnetic control spatio-temporal delivery" mechanism. For the ordinary water extract of Saussurea involucrata (Comparative Example 11), due to the lack of stem cell active components, the ratio of p-AMPK / AMPK decreased by 68%, further proving the irreplaceability of the stem cell extraction process in energy metabolism regulation.

[0090] The comprehensive efficacy data showed that Example 3 achieved multi-pathway synergistic intervention through process optimization (the amount of water for decoction, magnetic field guidance, extraction process): involucratin A inhibited the release of inflammatory factors, AMPK activation promoted collagen synthesis, and magnetic control delivery maintained a high local concentration. Due to the lack of a single process, the curative effects of Comparative Examples 9 - 11 were significantly inferior to that of Example 3, proving the creative value of the combination of process parameters and components.

[0091] Although embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. An external Chinese herbal medicine formula for inhibiting the growth of eye axis, characterized in that, It comprises components in the following parts by mass: Vespertilio superans faeces: 2 - 5 parts, Senecio scandens Buch.-Ham.: 15 - 25 parts, Carthamus tinctorius L.: 5 - 8 parts, Saussurea involucrata Kar. et Kir.: 6 - 10 parts, Trachelospermum jasminoides (Lindl.) Lem.: 5 - 9 parts, Scutellaria baicalensis Georgi: 8 - 12 parts, Coptis chinensis Franch.: 8 - 12 parts, Phellodendron amurense Rupr.: 8 - 12 parts, Chrysanthemum indicum L.: 15 - 25 parts, Mentha haplocalyx Briq.: 6 - 10 parts, Borneol: 1 - 2 parts, Calamine: 25 - 35 parts, Natrii Sulfas Exsiccatus: 8 - 12 parts, Styrax: 1 - 3 parts, Lithospermum erythrorhizon Sieb. et Zucc.: 4 - 6 parts, Cassia obtusifolia L.: 4 - 6 parts, Buddleja officinalis Maxim.: 6 - 10 parts, Pearl liquid: 5 - 8 parts, Honey: 1 - 6 parts, Buddleja officinalis Maxim. nanocrystals: 8 - 12 parts, Magnetite-indigo naturalis composite particles: 4 - 6 parts, Silk fibroin-alginate dynamic gel matrix: 70 - 80 parts.

2. The external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 1, characterized in that, The Buddleja officinalis Maxim. nanocrystals are prepared by the anti-solvent precipitation method, with a particle size of 80 - 120 nm, and the surface is modified with GE11 targeting peptide, and the mass ratio of the targeting peptide to the nanocrystals is 1:50 - 100.

3. An external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 1, characterized in that, The magnetite-indigo naturalis composite particles comprise an Fe3O4 magnetic core and an indigo naturalis biochar coating layer. The diameter of the magnetic core is 45 - 55 nm, and it is prepared by the hydrothermal method. The thickness of the biochar coating layer is 10 - 20 nm, which is formed by pyrolyzing indigo naturalis powder at 780 - 820 °C in a nitrogen atmosphere.

4. An external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 1, characterized in that, In the silk fibroin-alginate dynamic gel matrix, the molar ratio of silk fibroin to oxidized alginic acid is 1:1.1 - 1.3, and it is crosslinked by dynamic covalent bonds. The crosslinking agent is dithiothreitol, and the concentration is 4 - 6 mM.

5. A preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth, which is applied to the external Chinese herbal medicine formula for inhibiting eye axis growth described in any one of claims 1-4, characterized in that, It includes the following steps: S1. Mix Scutellaria baicalensis Georgi, Phellodendron amurense Rupr., Coptis chinensis Franch., Mentha haplocalyx Briq., Borneol, Calamine, Natrii Sulfas Exsiccatus, Vespertilio superans faeces, and Styrax, then dry and pulverize them to obtain fine medicinal powder. Decoct and extract Carthamus tinctorius L., Saussurea involucrata Kar. et Kir., Trachelospermum jasminoides (Lindl.) Lem., Chrysanthemum indicum L., Cassia obtusifolia L., and Buddleja officinalis Maxim., and then concentrate to obtain medicinal paste. S2. Prepare Buddleja officinalis Maxim. nanocrystals. Take the dry powder of Buddleja officinalis Maxim. and mix it with ethanol, then perform ultrasonic extraction and centrifuge to obtain the extract. Mix the extract with ultrapure water, perform ultrasonic treatment, centrifuge to collect the precipitate, and after modification with the targeting peptide, freeze-dry to obtain Buddleja officinalis Maxim. nanocrystals. S3. Prepare magnetite-indigo naturalis composite particles. Synthesize the magnetic core by the hydrothermal method, mix it with indigo naturalis powder, pyrolyze to form the coating layer, and after drug loading treatment, obtain magnetite-indigo naturalis composite particles. S4. Construct the dynamic gel matrix. Extract silk fibroin and prepare oxidized alginic acid, mix the two, add the crosslinking agent, and form the gel matrix through dynamic crosslinking reaction. S5. Mix the fine medicinal powder, medicinal paste, Buddleja officinalis Maxim. nanocrystals, magnetite-indigo naturalis composite particles with pearl liquid and honey, and add them to the gel matrix for homogenization. Coat the mixed gel on the surface of the microneedle array and dry to obtain the finished product.

6. The preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 5, characterized in that, In the step S1, the drying is vacuum drying, the temperature is 40 - 50 °C, and the vacuum degree ≤ -0.08 MPa; the particle size of the pulverized fine powder is 80 - 100 mesh; the water addition amount for the decoction extraction is 8 - 12 times the total mass of the medicinal materials, the decoction time is 1 - 2 hours, and the extraction times are 2 - 3 times; the concentration is vacuum concentration, the temperature is 60 - 70 °C, and the relative density of the concentrated paste is 1.15 - 1.

25.

7. The preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 5, characterized in that, In the step S2, the ethanol concentration is 70±5%, and the mass-volume ratio of Buddleja officinalis Maxim. powder to ethanol is 1:8 - 1:12; the power of the ultrasonic extraction is 400 - 600 W, the temperature is 45 - 55 °C, and the time is 1.5 - 2.5 hours; the volume ratio of the extract to ultrapure water is 1:8 - 1:12; the targeting peptide is GE11 peptide, the modification concentration is 0.1 - 0.2 mg / mL, and the modification time is 25 - 35 minutes; the freeze-drying conditions are a pre-freezing temperature of -50±5 °C, a vacuum degree of ≤10 Pa, and a freeze-drying time of 24±2 hours.

8. The preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 5, characterized in that, In the step S3, the magnetic core is Fe3O4, which is prepared by a hydrothermal method. The raw materials are FeCl3·6H2O and NaAc, and the mass ratio is 1:2.3 - 1:2.

7. The hydrothermal reaction temperature is 180 - 220 °C, and the reaction time is 6 - 10 hours; the pyrolysis is carried out in a nitrogen atmosphere, the temperature is 780 - 820 °C, and the heating rate is 8 - 12 °C / min; in the drug-loading treatment, the mass ratio of indirubin to the magnet-cyanobacteria composite particles is 1:4 - 1:6, the adsorption time is 20 - 28 hours, and the adsorption solvent is DMSO.

9. The preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 5, characterized in that, In the step S4, the silk fibroin is extracted by degumming silkworm cocoons. The degumming solution is 0.4 - 0.6% NaHCO3, the degumming temperature is 95 - 105 °C, and the time is 25 - 35 minutes; the oxidation degree of the oxidized alginic acid is 28 - 32%, which is prepared by reacting sodium alginate and sodium periodate in a mass ratio of 3.8:1 - 4.2:1, and the oxidation reaction time is 5.5 - 6.5 hours; the cross-linking agent is dithiothreitol, and the concentration is 4 - 6 mM; the molar ratio of silk fibroin to oxidized alginic acid is 1:1.1 - 1:1.

3.

10. The preparation method of an external Chinese herbal medicine formula for inhibiting eye axis growth according to claim 5, characterized in that, In the step S5, a homogenizer is used for homogenization, with a rotation speed of 4500 - 5500 rpm and a time of 8 - 12 minutes; the microneedle array is made of titanium, with a needle length of 180 - 220 μm and a density of 180 - 220 needles / cm 2 ; the coating material is a calcium-responsive chitosan film with a thickness of 15 - 25 μm and containing Ca 2+ at a concentration of 0.08 - 0.12%; the drying condition after coating is vacuum drying, with a temperature of 20 - 30°C and a vacuum degree of ≤ -0.08 MPa.

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