High drug loading and sustained release type artemisia vulgaris active ingredient composite polyacrylate hydrogel and preparation method thereof

Abstract

This invention discloses a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel, comprising: obtaining standardized Artemisia argyi powder; obtaining a hydrophilic Artemisia argyi active ingredient concentrate containing Artemisia argyi flavonoids and Artemisia argyi polyphenols; obtaining a volatile active ingredient inclusion dispersion; obtaining a hydrophilic active ingredient complex loading solution; forming a two-domain composite drug-loaded solution; obtaining an Artemisia argyi active ingredient composite acrylate prepolymer solution; obtaining a gel-forming composite prepolymer solution; obtaining an initial colloid of Artemisia argyi active ingredient composite polyacrylate; obtaining a two-network Artemisia argyi active ingredient composite polyacrylate initial hydrogel; and subjecting the two-network Artemisia argyi active ingredient composite polyacrylate initial hydrogel to short-time gradient purification, moisture balancing, sterilization, and sealed packaging treatment to obtain a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel. This invention can maintain the hydrogel's water content and flexibility while achieving a high drug loading capacity and sustained release capability.

Description

Technical Field

[0001] This invention relates to the field of polyacrylate hydrogel technology, and in particular to a high-drug-loaded sustained-release polyacrylate hydrogel containing Artemisia argyi active ingredients and its preparation method. Background Technology

[0002] Hydrogels, characterized by high water content, good softness, and the ability to load active substances, have been applied in wound covering, moisturizing dressings, and active ingredient release materials. Polyacrylate hydrogels exhibit good film-forming properties and structural stability; however, the single polyacrylate network has limited drug loading capacity for active ingredients of different polarities, making it prone to active ingredient release, initial burst release, and insufficient late release.

[0003] Artemisia argyi contains active ingredients such as volatile oils, flavonoids, and polyphenols. The volatile components are hydrophobic and easily volatilized, while flavonoids and polyphenols exhibit different water solubility and intermolecular interaction characteristics. Existing methods typically involve directly mixing Artemisia argyi extract into the hydrogel precursor solution or immersing the formed hydrogel in the extract, making it difficult to simultaneously achieve high loading ratios of both hydrophobic and hydrophilic active ingredients. Direct mixing can also easily disrupt the stability of the prepolymerization system, causing phase separation, local aggregation, and uneven cross-linking; immersion loading primarily concentrates the active ingredients on the hydrogel surface, easily leading to rapid release. Furthermore, the pore size and swelling behavior of a single chemical cross-linking network make it difficult to simultaneously achieve high drug loading and sustained release, and the hydrogel purification process may also cause the loss of already loaded active ingredients. Summary of the Invention

[0004] One objective of this invention is to provide a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel and its preparation method. This invention can maintain the hydrogel's water content and flexibility while achieving a high drug loading capacity and sustained release capability.

[0005] A method for preparing a high-drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel according to an embodiment of the present invention includes:

[0006] S1. Clean, dry at low temperature, crush and sieve the raw mugwort to obtain standardized mugwort powder;

[0007] S2. The standardized Artemisia argyi powder is subjected to steam distillation to collect the volatile active ingredients of Artemisia argyi. The Artemisia argyi residue after steam distillation is subjected to ultrasonic-assisted extraction, solid-liquid separation and vacuum concentration in an ethanol-water mixed solvent to obtain a hydrophilic Artemisia argyi active ingredient concentrate containing Artemisia argyi flavonoids and Artemisia argyi polyphenols.

[0008] S3. The volatile active ingredients of Artemisia argyi are added to a cyclodextrin derivative solution for inclusion reaction to obtain a volatile active ingredient inclusion dispersion.

[0009] S4. Add a hydrophilic polymer stabilizer containing carboxyl and hydroxyl groups to the hydrophilic Artemisia argyi active ingredient concentrate to obtain a hydrophilic active ingredient complex loading solution.

[0010] S5. The volatile active ingredient inclusion dispersion and the hydrophilic active ingredient complex loading solution are mixed and homogenized to form a dual-domain composite drug loading solution.

[0011] S6. Add acrylate monomers, hydrophilic comonomers, alginate and multifunctional unsaturated crosslinking agents to the dual-domain composite drug-carrying solution and mix them to obtain the Artemisia argyi active ingredient composite acrylate prepolymer solution.

[0012] S7. Adjust the pH and viscosity of the Artemisia argyi active ingredient composite acrylate prepolymer solution, and perform deoxygenation and defoaming treatment on it to obtain a gelatinizable composite prepolymer solution.

[0013] S8. Add a water-soluble redox initiator system to the gelatable composite prepolymer liquid to obtain a primary colloid of Artemisia argyi active ingredient composite polyacrylate.

[0014] S9. The mugwort active ingredient composite polyacrylate primary colloid is placed in an ion crosslinking liquid containing multivalent metal ions to obtain a double-network mugwort active ingredient composite polyacrylate primary hydrogel.

[0015] S10. The initial hydrogel of the dual-network Artemisia argyi active ingredient composite polyacrylate is subjected to short-time gradient purification, moisturizing balancing, sterilization and sealing packaging to obtain a high drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0016] Optionally, in step S1, the mugwort raw material is selected from one or more of mugwort leaves, tender stems, and inflorescences; the low-temperature drying temperature is 35-55℃, and the mugwort raw material is dried until the moisture content is not higher than 10%; the pulverization process adopts an intermittent low-temperature pulverization method, and the pulverized mugwort raw material is passed through a 40-100 mesh sieve to obtain the standardized mugwort powder.

[0017] Optionally, in step S2, the standardized Artemisia argyi powder is mixed with purified water at a solid-liquid ratio of 1g:(8-20)mL and subjected to steam distillation for 1-4 hours to obtain the volatile active ingredients of Artemisia argyi; the Artemisia argyi residue after steam distillation is mixed with a 40%-75% ethanol-water mixed solvent at a solid-liquid ratio of 1g:(10-30)mL, and ultrasonically extracted at 30-55℃ and 200-500W for 20-80 minutes. After solid-liquid separation, the mixture is concentrated under reduced pressure at 35-50℃ to obtain the concentrated hydrophilic Artemisia argyi active ingredient solution.

[0018] Optionally, in step S3, the cyclodextrin derivative is selected from one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methylated-β-cyclodextrin; the mass ratio of the volatile active ingredient of Artemisia argyi to the cyclodextrin derivative is 1:(3-15); the inclusion process is carried out at 25-50°C for 1-6 hours, and the volatile active ingredient inclusion dispersion is formed by high-speed shearing, ultrasonic dispersion, or a combination of both.

[0019] Optionally, in step S4, the hydrophilic polymer stabilizer includes polyvinyl alcohol and a carboxyl-containing hydrophilic polymer, wherein the carboxyl-containing hydrophilic polymer is selected from one or more of sodium carboxymethyl cellulose, sodium alginate, sodium hyaluronate, and sodium polyacrylate; the mass ratio of polyvinyl alcohol to the carboxyl-containing hydrophilic polymer is 1:(0.1-2.0); the dry matter mass ratio of the concentrated hydrophilic Artemisia argyi active ingredient solution to the hydrophilic polymer stabilizer is 1:(0.2-3.0); the pH value of the complexation stabilization treatment is 5.5-7.0, the temperature is 20-40℃, and the treatment time is 30-180 min.

[0020] Optionally, in step S5, the volatile active ingredient inclusion dispersion and the hydrophilic active ingredient complex loading liquid are mixed at a mass ratio of 1:(1-20) of the total amount of Artemisia argyi volatile active ingredients, Artemisia argyi flavonoids, and Artemisia argyi polyphenols; the homogenization treatment includes high-speed shearing at 3000-12000 rpm for 2-15 min and ultrasonic dispersion at 100-500 W for 1-10 min to obtain the dual-domain composite drug loading liquid.

[0021] Optionally, in step S6, the acrylate monomer is selected from one or more of hydroxyethyl acrylate, hydroxyethyl methacrylate, polyethylene glycol methacrylate, and methoxy polyethylene glycol acrylate; the hydrophilic comonomer is selected from one or more of acrylic acid, acrylamide, N-vinylpyrrolidone, and methacrylic acid; the alginate is sodium alginate; the multifunctional unsaturated crosslinking agent is selected from one or more of N,N'-methylenebisacrylamide, polyethylene glycol diacrylate, and polyethylene glycol dimethacrylate; and the amount of the multifunctional unsaturated crosslinking agent added is 0.05% to 2.0% of the total mass of the acrylate monomer and the hydrophilic comonomer.

[0022] Optionally, in step S7, the pH value of the prepolymerized solution of the Artemisia argyi active ingredient composite acrylate is adjusted to 6.0–7.2, and the viscosity is adjusted to 300–5000 mPa·s; in step S8, the water-soluble redox initiator system includes ammonium persulfate and N,N,N',N'-tetramethylethylenediamine, the amount of ammonium persulfate added is 0.05%–1.0% of the total mass of the acrylate monomers and hydrophilic comonomers, the amount of N,N,N',N'-tetramethylethylenediamine added is 0.02%–0.5% of the total mass of the acrylate monomers and hydrophilic comonomers, and the temperature of the free radical polymerization crosslinking reaction is 15–40°C, and the time is 0.5–6 h.

[0023] Optionally, in step S9, the multivalent metal ions are selected from one or more of calcium ions, zinc ions, and magnesium ions, the mass concentration of multivalent metal ions in the ion crosslinking solution is 0.1% to 3.0%, and the ion crosslinking time is 5 to 60 min; in step S10, the initial hydrogel of the double-network Artemisia argyi active ingredient complex polyacrylate is purified 2 to 5 times using physiological saline, phosphate buffer, or a combination of both, with each purification time being 5 to 30 min.

[0024] A high-drug-loaded sustained-release hydrogel of Artemisia argyi active ingredients, comprising, by weight of raw materials: 0.1-5 parts of volatile active ingredients of Artemisia argyi; 1-20 parts of Artemisia argyi flavonoids and polyphenols; 0.5-15 parts of cyclodextrin derivatives; 1-15 parts of hydrophilic polymer stabilizers containing carboxyl and hydroxyl groups; 10-40 parts of acrylate monomers; 2-25 parts of hydrophilic comonomers; 0.5-10 parts of alginate; 0.02-2 parts of multifunctional unsaturated crosslinking agents; 0.02-2 parts of a water-soluble redox initiator system; and 30-85 parts of purified water.

[0025] The volatile active ingredients of Artemisia argyi are encapsulated in the hydrophobic cavity of the cyclodextrin derivative, and the active ingredients of Artemisia argyi flavonoids and Artemisia argyi polyphenols are loaded in the hydrophilic complexation region formed by the hydrophilic polymer stabilizer, forming a dual-domain composite drug delivery system; the dual-domain composite drug delivery system is distributed and confined in the interpenetrating dual network composed of the polyacrylate chemical crosslinking network and the alginate ionic crosslinking network.

[0026] The volatile active ingredients of Artemisia argyi include one or more of eucalyptol, camphor, borneol, caryophyllene, and terpinene; the active ingredients of Artemisia argyi flavonoids and polyphenols include one or more of iso-eupatorin, apigenin, luteolin, chlorogenic acid, caffeic acid, and total polyphenols; the total loading of the active ingredients of Artemisia argyi based on the mass of the dried hydrogel is 3% to 20%.

[0027] The beneficial effects of this invention are:

[0028] The hydrophobic cavity of the cyclodextrin derivative in this invention encapsulates the volatile active ingredients of Artemisia argyi, reducing volatilization, flotation, and precipitation of these volatile components during mixing and polymerization. The hydrophilic polymer containing carboxyl and hydroxyl groups loads Artemisia argyi flavonoids and polyphenols through hydrogen bonding, electrostatic interactions, and molecular chain entanglement, ensuring that the hydrophilic active ingredients no longer exist as free small molecules. By introducing both types of active ingredients into drug-loaded regions compatible with their respective polarities before co-introducing them into the prepolymerization system, the compatibility and effective loading ratio of Artemisia argyi active ingredients of different polarities within the same hydrogel can be improved, reducing phase separation, localized precipitation, and uneven cross-linking caused by directly adding Artemisia argyi extract. The chemical cross-linking network of polyacrylate formed after polymerization provides stability to the main structure, while the ionic cross-linking network of alginate further compresses and separates the hydration diffusion channels, forming multi-level mass transfer resistance. When the active ingredient is released, it needs to overcome the dissociation of cyclodextrin or polymer complexation, the migration of the dual drug-loaded regions to the hydrogel network, and the diffusion of the dual network pores in sequence, thereby inhibiting the rapid release from the surface and prolonging the diffusion path of the internal active ingredient. The structure does not reduce the release rate by simply increasing the amount of cross-linking agent, so it can maintain the water content and flexibility of the hydrogel while taking into account both high drug loading capacity and continuous release capability. Detailed Implementation

[0029] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the protection scope of the present invention.

[0030] In the following examples and comparative examples, the Artemisia argyi raw materials used were a mixture of dried Artemisia argyi leaves and tender stems from the same batch; the ethanol, hydroxypropyl-β-cyclodextrin, polyvinyl alcohol, sodium carboxymethyl cellulose, sodium alginate, hydroxyethyl acrylate, acrylic acid, acrylamide, N,N'-methylenebisacrylamide, polyethylene glycol diacrylate, ammonium persulfate, N,N,N',N'-tetramethylethylenediamine, calcium chloride, and purified water used were all commercially available reagents.

[0031] The total loading of Artemisia argyi active ingredients refers to the percentage of the total mass of Artemisia argyi volatile active ingredients, Artemisia argyi flavonoids and Artemisia argyi polyphenols contained in the dried hydrogel to the mass of the dried hydrogel.

[0032] The cumulative release rate refers to the ratio of the cumulative release mass of the characteristic active ingredient of Artemisia argyi in the release medium within a specified release time to the total mass of the corresponding active ingredient initially loaded on the hydrogel.

[0033] Example 1

[0034] This embodiment provides a method for preparing a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0035] S1. Weigh 100g of Artemisia argyi raw material, remove hard roots and stems, withered yellow leaves, sand and other impurities, wash twice with flowing purified water, drain off the surface moisture, and place in a 45℃ hot air circulating drying oven to dry for 12 hours. The dried Artemisia argyi raw material is then subjected to intermittent low-temperature pulverization and passed through a 60-mesh sieve to obtain standardized Artemisia argyi powder.

[0036] S2. Weigh 50g of the standardized Artemisia argyi powder obtained in step S1, add it to 750mL of purified water for steam distillation for 2 hours, collect the oil-water mixture distillate, and obtain 0.45g of Artemisia argyi volatile active ingredients by oil-water separation.

[0037] The mugwort residue after steam distillation was dried at 45℃ until no obvious free water remained. It was then added to 500 mL of a 60% (v / v) ethanol-water mixture and soaked at room temperature for 30 min. Following this, it was ultrasonically extracted at 40℃ and 300 W for 40 min. After extraction, the mixture was filtered and centrifuged at 5000 rpm for 10 min. The supernatant was then concentrated under reduced pressure at 45℃ to 50 mL to obtain a concentrated hydrophilic mugwort active ingredient solution.

[0038] S3. Weigh 2.70g of hydroxypropyl-β-cyclodextrin and add it to 20mL of purified water. Stir and dissolve at 40℃. Slowly add 0.45g of Artemisia argyi volatile active ingredients to the hydroxypropyl-β-cyclodextrin solution, stir at 600rpm for 2h, and then sonicate at 300W for 5min to obtain a volatile active ingredient inclusion dispersion.

[0039] S4. Weigh 3.0g of polyvinyl alcohol and add it to 30mL of purified water. Stir and dissolve at 85℃. Then add 0.8g of sodium carboxymethyl cellulose and continue stirring until homogeneous. Cool to 35℃ to obtain a hydrophilic polymer stabilizer solution.

[0040] The hydrophilic Artemisia argyi active ingredient concentrate obtained in step S2 was slowly added to the hydrophilic polymer stabilizer solution. The pH of the system was adjusted to 6.2 using 0.1 mol / L sodium hydroxide solution. The mixture was stirred at 30°C in the dark for 60 min to obtain the hydrophilic active ingredient complex loading solution.

[0041] S5. Add the volatile active ingredient inclusion dispersion obtained in step S3 to the hydrophilic active ingredient complex loading solution obtained in step S4, shear at 6000 rpm for 5 min, and then perform ultrasonic dispersion at 200 W for 3 min to obtain a dual-domain composite drug loading solution.

[0042] S6. Add 18g of hydroxyethyl acrylate, 4g of acrylic acid, 5g of acrylamide, 2g of sodium alginate and 0.10g of N,N'-methylenebisacrylamide to the dual-domain composite drug loading solution obtained in step S5, and stir at 400rpm for 30min to obtain the Artemisia argyi active ingredient composite acrylate prepolymer solution.

[0043] S7. The pH of the Artemisia argyi active ingredient composite acrylate prepolymer solution obtained in step S6 was adjusted to 6.5 using 0.1 mol / L sodium hydroxide solution. The viscosity of the system was adjusted to a state that could be uniformly poured by adding purified water. Nitrogen gas was then introduced for 20 minutes and vacuum degassing was performed for 5 minutes to obtain a gel-forming composite prepolymer solution.

[0044] S8. Add 0.14g of ammonium persulfate and 0.07g of N,N,N',N'-tetramethylethylenediamine to the gelatinizable composite prepolymer liquid obtained in step S7. Stir at low speed for 2 minutes and then pour into a mold. Let it stand at 25°C for 2 hours under nitrogen atmosphere to obtain the initial colloid of Artemisia argyi active ingredient composite polyacrylate.

[0045] S9. The initial colloid of Artemisia argyi active ingredient composite polyacrylate obtained in step S8 is placed in a calcium chloride solution with a mass concentration of 0.5% for ionic cross-linking for 15 minutes, so that sodium alginate forms an ionic cross-linking network, and a double-network Artemisia argyi active ingredient composite polyacrylate initial hydrogel is obtained.

[0046] S10. The initial hydrogel of the double-network Artemisia argyi active ingredient complex polyacrylate obtained in step S9 is rinsed three times with physiological saline for 10 minutes each time, and then placed in phosphate buffer for 1 hour to maintain moisture equilibration. The equilibrated hydrogel is cut into sheets with a thickness of 2 mm, and then placed in a moisture-proof and light-proof packaging bag in a clean environment and sealed to obtain a high-drug-loaded sustained-release Artemisia argyi active ingredient complex polyacrylate hydrogel.

[0047] Example 2

[0048] This embodiment provides a method for preparing a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0049] S1. Weigh 100g of Artemisia argyi raw material, wash it, vacuum dry it at 40℃ for 16h, pulverize it at low temperature and pass it through an 80-mesh sieve to obtain standardized Artemisia argyi powder.

[0050] S2. Weigh 60g of standardized Artemisia argyi powder and add it to 900mL of purified water for steam distillation for 3 hours to obtain 0.65g of Artemisia argyi volatile active ingredients. Add the distilled Artemisia argyi residue to 720mL of 65% ethanol-water mixed solvent and extract by ultrasonication at 45℃ and 350W for 50min. After solid-liquid separation, concentrate the extract to 60mL under reduced pressure at 45℃ to obtain a concentrated hydrophilic Artemisia argyi active ingredient solution.

[0051] S3. Add 0.65g of Artemisia argyi volatile active ingredients to 30mL of aqueous solution containing 4.55g of hydroxypropyl-β-cyclodextrin, stir at 40℃ for 3h, and then sonicate for 5min to obtain a volatile active ingredient inclusion dispersion.

[0052] S4. Dissolve 4.0g of polyvinyl alcohol and 1.2g of sodium carboxymethyl cellulose in 45mL of purified water, add concentrated hydrophilic Artemisia argyi active ingredient solution, adjust the pH to 6.4, and stir at 30℃ for 90min to obtain hydrophilic active ingredient complex loading solution.

[0053] S5. Mix the volatile active ingredient inclusion dispersion with the hydrophilic active ingredient complex loading solution, shear at 8000 rpm for 6 min and sonicate for 4 min to obtain a dual-domain composite drug loading solution.

[0054] S6. Add 20g of hydroxyethyl acrylate, 5g of hydroxyethyl methacrylate, 5g of acrylic acid, 5g of N-vinylpyrrolidone, 3g of sodium alginate and 0.25g of polyethylene glycol diacrylate to the dual-domain composite drug-carrying solution, stir for 40min to obtain the Artemisia argyi active ingredient composite acrylate prepolymer solution.

[0055] S7. Adjust the pH of the prepolymer solution to 6.6, purge with nitrogen for 30 minutes and degas under vacuum to obtain a gel-forming composite prepolymer solution.

[0056] S8. Add 0.18g ammonium persulfate and 0.09g N,N,N',N'-tetramethylethylenediamine, and polymerize at 28℃ for 3h to obtain a primary colloid of Artemisia argyi active ingredient composite polyacrylate.

[0057] S9. The initial colloid was placed in a 1.0% calcium chloride solution for cross-linking for 20 min to obtain a double-network Artemisia argyi active ingredient composite polyacrylate initial hydrogel.

[0058] S10. Rinse three times with physiological saline for 15 minutes each time, then perform moisturizing balancing, cutting and sealing packaging to obtain a high-drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0059] Example 3

[0060] This embodiment provides a preferred method for preparing a high-drug-loaded, sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0061] S1. Weigh 100g of Artemisia argyi raw material, wash it, dry it at 45℃ for 14h, pulverize it at low temperature and pass it through an 80-mesh sieve to obtain standardized Artemisia argyi powder.

[0062] S2. Weigh 60g of standardized Artemisia argyi powder and add it to 900mL of purified water for steam distillation for 2.5h to obtain the volatile active ingredients of Artemisia argyi. Add the distilled Artemisia argyi residue to 600mL of 60% ethanol-water mixed solvent and extract by ultrasonication at 42℃ and 350W for 45min. After filtration and centrifugation, concentrate the extract under reduced pressure at 42℃ to 55mL to obtain a concentrated hydrophilic Artemisia argyi active ingredient solution.

[0063] S3. The obtained volatile active ingredients of Artemisia argyi were mixed with hydroxypropyl-β-cyclodextrin at a mass ratio of 1:6, stirred at 40℃ for 2.5h and ultrasonically dispersed for 5min to obtain a volatile active ingredient inclusion dispersion.

[0064] S4. Weigh 3.5g polyvinyl alcohol, 1.0g sodium carboxymethyl cellulose and 0.5g sodium hyaluronate, add to 40mL purified water to dissolve, cool to 30℃ and add hydrophilic Artemisia argyi active ingredient concentrate, adjust pH to 6.3, stir in the dark for 90min to obtain hydrophilic active ingredient complex loading solution.

[0065] S5. Mix the volatile active ingredient inclusion dispersion and the hydrophilic active ingredient complex loading solution, shear at 8000 rpm for 5 min, and then ultrasonically disperse at 250 W for 4 min to obtain the dual-domain composite drug loading solution.

[0066] S6. Add 20g hydroxyethyl acrylate, 4g hydroxyethyl methacrylate, 4g acrylic acid, 4g acrylamide, 2.5g sodium alginate, 0.06g N,N'-methylenebisacrylamide and 0.15g polyethylene glycol diacrylate to the dual-domain composite drug-carrying solution, stir for 40min to obtain the Artemisia argyi active ingredient composite acrylate prepolymer solution.

[0067] S7. Adjust the pH of the prepolymer solution to 6.5, purge with nitrogen for 25 minutes and degas under vacuum for 5 minutes to obtain a gel-forming composite prepolymer solution.

[0068] S8. Add 0.16g ammonium persulfate and 0.08g N,N,N',N'-tetramethylethylenediamine to the gel-forming composite prepolymer solution, and polymerize at 26℃ for 2.5h to obtain the initial colloid of Artemisia argyi active ingredient composite polyacrylate.

[0069] S9. The initial colloid was placed in a 0.8% calcium chloride solution for cross-linking for 20 minutes to obtain a double-network Artemisia argyi active ingredient composite polyacrylate initial hydrogel.

[0070] S10. Rinse three times with physiological saline for 10 minutes each time, and use phosphate buffer for moisturizing and balancing. Then cut, aseptically package and seal for preservation to obtain a high drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

[0071] Comparative Example 1

[0072] The difference between this comparative example and Example 3 is that hydroxypropyl-β-cyclodextrin is not used to encapsulate the volatile active ingredients of Artemisia argyi. Instead, the volatile active ingredients of Artemisia argyi are directly added to the hydrophilic active ingredient complexation loading solution. The amounts of other raw materials and preparation conditions are the same as in Example 3.

[0073] This comparative example was used to investigate the effects of cyclodextrin inclusion treatment on the retention rate of volatile active ingredients in Artemisia argyi, the stability of the prepolymerization system, and the release behavior.

[0074] Comparative Example 2

[0075] The difference between this comparative example and Example 3 is that polyvinyl alcohol, sodium carboxymethyl cellulose, and sodium hyaluronate are not added, and the hydrophilic Artemisia argyi active ingredient concentrate is not complexed and loaded. Instead, the hydrophilic Artemisia argyi active ingredient concentrate is directly added to the prepolymerization system. The amounts of other raw materials and preparation conditions are the same as in Example 3.

[0076] This comparative example was used to investigate the effect of hydrophilic polymer complexation loading on the retention rate and sustained-release behavior of flavonoid and polyphenol active ingredients.

[0077] Comparative Example 3

[0078] The difference between this comparative example and Example 3 is that sodium alginate is not added and the calcium chloride ion crosslinking treatment is omitted, only a polyacrylate chemical crosslinking network is formed, and the amounts of other raw materials and preparation conditions are the same as in Example 3.

[0079] This comparative example was used to investigate the effect of alginate ion crosslinking network on the hydrogel pore structure and the release rate of active ingredients.

[0080] Comparative Example 4

[0081] In this comparative example, a dual-network hydrogel without Artemisia argyi active ingredients was first prepared according to the amounts of acrylate monomers, hydrophilic comonomers, crosslinking agents, sodium alginate and initiator system in Example 3. The obtained dual-network hydrogel was then immersed in a dual-domain composite drug-loaded solution for 12 hours to obtain an immersed drug-loaded hydrogel.

[0082] This comparative example is used to investigate the effects of prepolymer confinement drug loading and post-gelation immersion drug loading on drug distribution and burst release.

[0083] Performance testing

[0084] 1. Test of total loading of active ingredients in Artemisia argyi

[0085] The hydrogel samples were freeze-dried and accurately weighed, and the active ingredients of Artemisia argyi were completely extracted using a suitable solvent. Gas chromatography was used to detect volatile marker components such as eucalyptol, camphor, or borneol, while high-performance liquid chromatography was used to detect hydrophilic marker components such as chlorogenic acid, caffeic acid, luteolin, or iso-eupatorin.

[0086] The total loading of active ingredients in Artemisia argyi is calculated using the following formula:

[0087] Total loading of Artemisia argyi active ingredients = Total mass of Artemisia argyi active ingredients in hydrogel / Mass of dried hydrogel × 100%.

[0088] 2. Active ingredient encapsulation rate test

[0089] Calculate the mass of volatile active ingredients and hydrophilic active ingredients that actually enter the hydrogel during the preparation process.

[0090] The encapsulation efficiency of the active ingredient is calculated using the following formula:

[0091] Encapsulation efficiency of active ingredient = actual mass of active ingredient loaded in hydrogel / mass of active ingredient added during preparation × 100%.

[0092] 3. In vitro release performance test

[0093] Hydrogel samples of uniform size were placed in phosphate buffer at pH 7.4 and released by shaking at 37°C and 60 rpm. Samples were taken at 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, 24 h, 48 h, and 72 h, and an equal volume of fresh buffer was added.

[0094] The cumulative release rates of volatile marker components, flavonoid marker components, and polyphenol marker components were detected separately, and cumulative release rate-time curves were plotted. The zero-order release model, first-order release model, Higuchi model, and Korsmeyer-Peppas model were used for fitting.

[0095] 4. Antibacterial performance test

[0096] Staphylococcus aureus and Escherichia coli were selected as test strains. The hydrogel samples were cultured in contact with bacterial solutions of a specified concentration. The number of colonies was detected by plate counting method, and the inhibition rate was calculated.

[0097] The antibacterial rate is calculated using the following formula:

[0098] Antibacterial rate = (number of colonies in blank control group - number of colonies in hydrogel sample group) / number of colonies in blank control group × 100%.

[0099] 5. Swelling performance test

[0100] After weighing the dried hydrogel, place it in phosphate buffer solution and swell at 37°C for the specified time. Remove it, absorb the free water on the surface, and then weigh it.

[0101] The equilibrium swelling ratio is calculated using the following formula:

[0102] Equilibrium swelling rate = (mass after swelling - dry mass) / dry mass × 100%.

[0103] 6. Mechanical property testing

[0104] The hydrogel was cut into uniform sizes, and its tensile strength, elongation at break, compressive strength, and cyclic compression recovery were measured using a universal testing machine to evaluate the mechanical stability and flexibility of the dual-network structure.

[0105] 7. Cell compatibility test

[0106] Fibroblasts were cultured using hydrogel extract, and the relative cell viability was detected by CCK-8 assay. Cell status was also observed by live-dead cell staining.

[0107] The tests showed that the total loading of Artemisia argyi active ingredient composite polyacrylate hydrogel with high drug loading capacity obtained in Example 1 was 10.8%, the encapsulation rate of volatile active ingredients was 83.6%, and the encapsulation rate of hydrophilic active ingredients was 88.9%. The cumulative release rate was 18.7% after 2 hours, 54.3% after 24 hours, and 81.6% after 72 hours. The antibacterial rate against Staphylococcus aureus was 93.8%, the antibacterial rate against Escherichia coli was 89.7%, and the relative survival rate of fibroblasts was 95.4%.

[0108] The total loading of Artemisia argyi active ingredient composite polyacrylate hydrogel with high drug loading and sustained release obtained in Example 2 was 13.9%, the encapsulation rate of volatile active ingredients was 88.7%, and the encapsulation rate of hydrophilic active ingredients was 92.4%. The cumulative release rate was 15.9% after 2 hours, 49.8% after 24 hours, and 78.2% after 72 hours. The inhibition rate against Staphylococcus aureus was 96.1%, the inhibition rate against Escherichia coli was 92.6%, and the relative survival rate of fibroblasts was 94.8%.

[0109] The total loading of Artemisia argyi active ingredient composite polyacrylate hydrogel with high drug loading and sustained release obtained in Example 3 was 15.6%, the encapsulation rate of volatile active ingredients was 91.8%, and the encapsulation rate of hydrophilic active ingredients was 94.6%. The cumulative release rate was 13.8% after 2 hours, 45.6% after 24 hours, and 74.9% after 72 hours. The inhibition rate against Staphylococcus aureus was 97.4%, the inhibition rate against Escherichia coli was 94.2%, and the relative survival rate of fibroblasts was 96.3%.

[0110] Comparative Example 1 did not use hydroxypropyl-β-cyclodextrin to encapsulate the volatile active ingredients of Artemisia argyi. The total loading of Artemisia argyi active ingredients in the resulting hydrogel was 10.2%, the encapsulation rate of volatile active ingredients was 52.4%, and the encapsulation rate of hydrophilic active ingredients was 93.8%. The cumulative release rate was 31.6% after 2 hours, 67.8% after 24 hours, and 87.9% after 72 hours. The inhibition rate against Staphylococcus aureus was 86.2%, the inhibition rate against Escherichia coli was 80.5%, and the relative survival rate of fibroblasts was 94.7%.

[0111] Comparative Example 2 did not use polyvinyl alcohol, sodium carboxymethyl cellulose, and sodium hyaluronate to complex and load the hydrophilic Artemisia argyi active ingredients. The total loading of Artemisia argyi active ingredients in the resulting hydrogel was 9.6%, the encapsulation rate of volatile active ingredients was 90.5%, and the encapsulation rate of hydrophilic active ingredients was 56.8%. The cumulative release rate was 35.4% after 2 hours, 71.2% after 24 hours, and 90.3% after 72 hours. The inhibition rate against Staphylococcus aureus was 82.7%, the inhibition rate against Escherichia coli was 77.1%, and the relative survival rate of fibroblasts was 91.6%.

[0112] Comparative Example 3 did not contain sodium alginate or undergo calcium chloride ion crosslinking; it only formed a polyacrylate chemical crosslinking network. The total loading of Artemisia argyi active ingredients in the resulting hydrogel was 14.9%, the encapsulation rate of volatile active ingredients was 90.7%, and the encapsulation rate of hydrophilic active ingredients was 93.5%. The cumulative release rate was 28.9% after 2 hours, 63.7% after 24 hours, and 88.1% after 72 hours. The inhibition rate against Staphylococcus aureus was 95.2%, the inhibition rate against Escherichia coli was 91.5%, and the relative survival rate of fibroblasts was 95.8%.

[0113] Comparative Example 4 involved first preparing a double-network hydrogel and then loading Artemisia argyi active ingredients onto it via an immersion method. The total loading of Artemisia argyi active ingredients in the resulting hydrogel was 7.4%, with an encapsulation rate of 61.3% for volatile active ingredients and 68.5% for hydrophilic active ingredients. The cumulative release rate was 46.8% after 2 hours, 82.4% after 24 hours, and 95.1% after 72 hours. The inhibition rate against Staphylococcus aureus was 88.9%, against Escherichia coli was 83.6%, and the relative survival rate of fibroblasts was 93.2%.

[0114] The test results above show that the hydrogels obtained in Examples 1-3 have higher total loading of Artemisia argyi active ingredients, higher encapsulation rates of volatile active ingredients and hydrophilic active ingredients than the control group, and lower cumulative release rates at 2h and 24h than the control group. This indicates that the obtained hydrogels can reduce early burst release and prolong the release time of active ingredients. Specifically, the total loading of Artemisia argyi active ingredients in Example 3 reached 15.6%, and the encapsulation rates of volatile and hydrophilic active ingredients reached 91.8% and 94.6%, respectively. Meanwhile, its cumulative release rate at 2h was only 13.8%, and its cumulative release rate at 72h was 74.9%, indicating that it has high drug loading capacity and relatively stable sustained release performance.

[0115] Comparative Example 1 did not involve cyclodextrin encapsulation of the volatile active ingredient, resulting in a lower encapsulation rate of 52.4%. This indicates that unencapsulated volatile components are prone to volatilization or precipitation from the prepolymerization system during mixing, degassing, and polymerization. Comparative Example 2 did not involve polymer complexation loading of the hydrophilic active ingredient, leading to a lower encapsulation rate of 56.8% and an increased cumulative release rate of 35.4% over 2 hours. This suggests that free flavonoids and polyphenols are easily lost during purification and diffuse rapidly in the initial stages of release.

[0116] Although Comparative Example 3 maintained a high active ingredient loading and encapsulation efficiency, its cumulative release rates at 2h and 24h increased to 28.9% and 63.7%, respectively, due to the lack of an alginate ionic cross-linking network. This indicates that the single polyacrylate chemical cross-linking network is insufficient in restricting the diffusion pathway of the active ingredient. Comparative Example 4, which used a post-gelation immersion loading method, had a total active ingredient loading of only 7.4%, and a cumulative release rate of 46.8% at 2h. This indicates that the active ingredient was mainly distributed on the surface of the hydrogel and had difficulty penetrating the interior of the cross-linking network, resulting in a reduced loading and significant early burst release.

[0117] In the description of this specification, the terms "an embodiment," "specific embodiment," and "example" indicate that a specific feature, structure, material, or condition associated with that embodiment or example is included in at least one embodiment of the invention. The aforementioned specific features, structures, materials, or conditions may be combined in a suitable manner without contradicting each other.

[0118] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, any equivalent substitutions or adjustments made to the types of raw materials, component ratios, processing sequence, and process parameters without departing from the concept of the present invention should fall within the protection scope of the present invention.

[0119] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A preparation method of a high drug-loaded slow-release type Artemisia vulgaris active ingredient composite polyacrylate hydrogel, characterized in that, include: S1. Clean, dry at low temperature, crush and sieve the raw mugwort to obtain standardized mugwort powder; S2. The standardized Artemisia argyi powder is subjected to steam distillation to collect the volatile active ingredients of Artemisia argyi. The Artemisia argyi residue after steam distillation is subjected to ultrasonic-assisted extraction, solid-liquid separation and vacuum concentration in an ethanol-water mixed solvent to obtain a hydrophilic Artemisia argyi active ingredient concentrate containing Artemisia argyi flavonoids and Artemisia argyi polyphenols. S3. The volatile active ingredients of Artemisia argyi are added to a cyclodextrin derivative solution for inclusion reaction to obtain a volatile active ingredient inclusion dispersion. S4. Add a hydrophilic polymer stabilizer containing carboxyl and hydroxyl groups to the hydrophilic Artemisia argyi active ingredient concentrate to obtain a hydrophilic active ingredient complex loading solution. S5. The volatile active ingredient inclusion dispersion and the hydrophilic active ingredient complex loading liquid are mixed and homogenized to form a dual-domain composite drug loading solution. S6. Add acrylate monomers, hydrophilic comonomers, alginate and multifunctional unsaturated crosslinking agents to the dual-domain composite drug-carrying solution and mix them to obtain the Artemisia argyi active ingredient composite acrylate prepolymer solution. S7. Adjust the pH and viscosity of the Artemisia argyi active ingredient composite acrylate prepolymer solution, and perform deoxygenation and defoaming treatment on it to obtain a gelatinizable composite prepolymer solution. S8. Add a water-soluble redox initiator system to the gelatable composite prepolymer liquid to obtain a primary colloid of Artemisia argyi active ingredient composite polyacrylate. S9. The mugwort active ingredient composite polyacrylate primary colloid is placed in an ion crosslinking liquid containing multivalent metal ions to obtain a double-network mugwort active ingredient composite polyacrylate primary hydrogel. S10. The initial hydrogel of the dual-network Artemisia argyi active ingredient composite polyacrylate is subjected to short-time gradient purification, moisturizing balancing, sterilization and sealing packaging to obtain a high drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel.

2. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S1, the mugwort raw material is selected from one or more of mugwort leaves, tender stems, and inflorescences; the low-temperature drying temperature is 35-55℃, and the mugwort raw material is dried until the moisture content is not higher than 10%; the pulverization process adopts an intermittent low-temperature pulverization method, and the pulverized mugwort raw material is passed through a 40-100 mesh sieve to obtain the standardized mugwort powder.

3. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S2, the standardized Artemisia argyi powder is mixed with purified water at a solid-liquid ratio of 1g:(8-20)mL and subjected to steam distillation for 1-4 hours to obtain the volatile active ingredients of Artemisia argyi. The Artemisia argyi residue after steam distillation is mixed with a 40%-75% ethanol-water mixed solvent at a solid-liquid ratio of 1g:(10-30)mL and ultrasonically extracted at 30-55℃ and 200-500W for 20-80 minutes. After solid-liquid separation, the mixture is concentrated under reduced pressure at 35-50℃ to obtain the concentrated hydrophilic Artemisia argyi active ingredient solution.

4. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S3, the cyclodextrin derivative is selected from one or more of hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin, and methylated-β-cyclodextrin; the mass ratio of the volatile active ingredient of Artemisia argyi to the cyclodextrin derivative is 1:(3-15); the inclusion process is carried out at 25-50°C for 1-6 hours, and the volatile active ingredient inclusion dispersion is formed by high-speed shearing, ultrasonic dispersion, or a combination of both.

5. The preparation method of a high-drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S4, the hydrophilic polymer stabilizer includes polyvinyl alcohol and a carboxyl-containing hydrophilic polymer, wherein the carboxyl-containing hydrophilic polymer is selected from one or more of sodium carboxymethyl cellulose, sodium alginate, sodium hyaluronate, and sodium polyacrylate; the mass ratio of polyvinyl alcohol to the carboxyl-containing hydrophilic polymer is 1:(0.1-2.0); the dry matter mass ratio of the concentrated hydrophilic Artemisia argyi active ingredient solution to the hydrophilic polymer stabilizer is 1:(0.2-3.0); the pH value of the complexation stabilization treatment is 5.5-7.0, the temperature is 20-40℃, and the treatment time is 30-180 min.

6. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S5, the volatile active ingredient inclusion dispersion and the hydrophilic active ingredient complex loading solution are mixed at a mass ratio of 1:(1-20) of the total amount of Artemisia argyi volatile active ingredients, Artemisia argyi flavonoids, and Artemisia argyi polyphenols. The homogenization process includes high-speed shearing at 3000-12000 rpm for 2-15 min and ultrasonic dispersion at 100-500W for 1-10 min to obtain the dual-domain composite drug loading solution.

7. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S6, the acrylate monomer is selected from one or more of hydroxyethyl acrylate, hydroxyethyl methacrylate, polyethylene glycol methacrylate, and methoxy polyethylene glycol acrylate; the hydrophilic comonomer is selected from one or more of acrylic acid, acrylamide, N-vinylpyrrolidone, and methacrylic acid; the alginate is sodium alginate; the multifunctional unsaturated crosslinking agent is selected from one or more of N,N'-methylenebisacrylamide, polyethylene glycol diacrylate, and polyethylene glycol dimethacrylate; the amount of the multifunctional unsaturated crosslinking agent added is 0.05% to 2.0% of the total mass of the acrylate monomer and the hydrophilic comonomer.

8. The preparation method of a high-drug-loaded sustained-release Artemisia argyi active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S7, the pH of the prepolymerized solution of the Artemisia argyi active ingredient composite acrylate is adjusted to 6.0–7.2, and the viscosity is adjusted to 300–5000 mPa·s. In step S8, the water-soluble redox initiator system includes ammonium persulfate and N,N,N',N'-tetramethylethylenediamine. The amount of ammonium persulfate added is 0.05%–1.0% of the total mass of the acrylate monomers and hydrophilic comonomers. The amount of N,N,N',N'-tetramethylethylenediamine added is 0.02%–0.5% of the total mass of the acrylate monomers and hydrophilic comonomers. The temperature of the free radical polymerization crosslinking reaction is 15–40°C, and the time is 0.5–6 h.

9. The preparation method of the high drug-loaded slow-release type artemisia active ingredient composite polyacrylate hydrogel according to claim 1, characterized in that, In step S9, the multivalent metal ions are selected from one or more of calcium ions, zinc ions, and magnesium ions, and the mass concentration of the multivalent metal ions in the ion crosslinking solution is 0.1% to 3.0%, and the ion crosslinking time is 5 to 60 min. In step S10, the initial hydrogel of the double-network Artemisia argyi active ingredient complex polyacrylate is purified by physiological saline, phosphate buffer, or a combination of both for 2 to 5 short-time gradient purifications, with each purification time being 5 to 30 min.

10. A high drug-loaded, slow-release type of Artemisia vulgaris active ingredient composite polyacrylate hydrogel, characterized by, Based on the mass fractions of the raw materials used in preparation, the following components are included: 0.1–5 parts of volatile active ingredients from Artemisia argyi; 1–20 parts of active ingredients from Artemisia argyi flavonoids and polyphenols; 0.5–15 parts of cyclodextrin derivatives; 1–15 parts of hydrophilic polymer stabilizers containing carboxyl and hydroxyl groups; 10–40 parts of acrylate monomers; 2–25 parts of hydrophilic comonomers; 0.5–10 parts of alginate; 0.02–2 parts of multifunctional unsaturated crosslinking agents; 0.02–2 parts of a water-soluble redox initiator system; and 30–85 parts of purified water. The volatile active ingredients of Artemisia argyi are encapsulated in the hydrophobic cavity of the cyclodextrin derivative, and the active ingredients of Artemisia argyi flavonoids and Artemisia argyi polyphenols are loaded in the hydrophilic complexation region formed by the hydrophilic polymer stabilizer, forming a dual-domain composite drug delivery system; the dual-domain composite drug delivery system is distributed and confined in the interpenetrating dual network composed of the polyacrylate chemical crosslinking network and the alginate ionic crosslinking network. The volatile active ingredients of Artemisia argyi include one or more of eucalyptol, camphor, borneol, caryophyllene, and terpinene; the active ingredients of Artemisia argyi flavonoids and polyphenols include one or more of iso-eupatorin, apigenin, luteolin, chlorogenic acid, caffeic acid, and total polyphenols; the total loading of the active ingredients of Artemisia argyi based on the mass of the dried hydrogel is 3% to 20%.