External artemisinin gel composition as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicine, and discloses an artemisinin external gel composition as well as a preparation method and application thereof, the gel composition comprises 0.1-5 parts of artemisinin, 1-20 parts of a solubilizer, 0.5-15 parts of a gel matrix, 5-30 parts of a penetration enhancer, 0.01-1 part of a stabilizer, 0.01-2 parts of a pH regulator, 0.05-1.5 parts of a preservative, 1-15 parts of a humectant and purified water. According to the technical scheme, a peroxide bridge structure of artemisinin is used for removing active oxygen, the multiple effects of resisting inflammation, resisting oxidation, resisting bacteria, promoting repair and resisting scars are achieved by regulating and controlling channels such as NF-kappa B and TGF-beta, and meanwhile, a gel matrix maintains a moist environment of a wound surface and promotes transdermal absorption of drugs. Experiments prove that the composition can reduce MDA content of wound surfaces, increase SOD activity, inhibit IL-6, TNF-alpha and other inflammatory factors, reduce collagen deposition and inhibit bacterial growth, can effectively improve the pathological process of scalds and burns, and provides a novel multi-mechanism synergistic external composition for clinical treatment.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a gel composition for external use of artemisinin and a preparation method and application thereof. BACKGROUND

[0002] Scald burn is a common acute traumatic disease in clinic, which is mainly caused by high temperature, chemical substances, electric current and other factors to cause skin and deep tissue damage. Among them, the deep scald burn patients have complex wound repair, high risk of infection and significant scar formation, which not only seriously affects the quality of life, but also may cause sepsis and other life-threatening complications. The pathological process of scald burn covers multiple stages such as acute inflammatory response, infection period tissue destruction and repair period scar remodeling, involving key pathological links such as neutrophil infiltration, excessive release of reactive oxygen species (ROS), bacterial colonization and collagen metabolism imbalance, and the current clinical treatment still faces multiple challenges. Traditional scald burn treatment mainly includes wound debridement, anti-infection and surgical skin grafting. Wound debridement can remove necrotic tissue, but may cause secondary damage to healthy tissue; the widespread use of antibiotics leads to increasingly serious drug-resistant bacterial infections, and it is difficult to inhibit the continuous destruction of excessive inflammatory response to tissues; surgical skin grafting depends on autologous or allogeneic skin transplantation, which has limitations such as damage to the donor site, immune rejection and scar hyperplasia. In terms of drug treatment, existing external compositions are mainly based on vaseline gauze and silver ion gel, which can provide certain wound protection and antibacterial effect, but have obvious deficiencies in inhibiting inflammatory cascade, removing oxidative stress products, promoting tissue repair and inhibiting scar formation, especially for deep scald burn, the effect of promoting epithelialization and reducing scar hyperplasia is limited. In recent years, gel compositions have gradually been applied in the treatment of scald burns due to their advantages of providing a moist environment for the wound, reducing scabbing, and promoting local drug release. However, existing gel materials generally have the problem of single function: most antibacterial gels only inhibit bacterial colonization through physical barriers or single antibacterial components, and cannot regulate complex inflammatory response and oxidative stress damage; repair-promoting gels lack effective intervention on excessive activation of fibroblasts and abnormal deposition of collagen, making it difficult to fundamentally solve the problems of scar hyperplasia and contracture. In addition, some gels have low transdermal absorption efficiency and uncontrollable drug release rate, resulting in insufficient local effective concentration and affecting the treatment effect. Artemisinin, an active ingredient extracted from the traditional Chinese medicine Artemisia annua, possesses multiple pharmacological effects, including anti-inflammatory, antioxidant, antibacterial, and collagen metabolism-regulating properties. Its peroxy-bridge structure can directly scavenge reactive oxygen species (ROS), inhibit the NF-κB pathway to reduce the release of pro-inflammatory factors, and simultaneously inhibit excessive fibroblast proliferation and type I collagen deposition by regulating the transforming growth factor-β (TGF-β) signaling pathway. Preparing artemisinin into a gel composition can utilize the physical barrier effect of the gel to isolate external bacteria and maintain wound moisture, while also intervening in multiple pathological stages of burns through the multi-target effect of artemisinin. Theoretically, it can play a synergistic role in controlling infection, reducing inflammatory damage, promoting tissue repair, and inhibiting scar formation. However, current research on the application of artemisinin in burn treatment is largely limited to in vitro experiments and animal models. The transdermal absorption efficiency, optimal drug concentration, and long-term safety of its gel compositions still need further optimization. Furthermore, how to achieve sustained and stable release of artemisinin through composition design to meet the treatment needs of the complex pathological processes of burns remains an urgent technical problem to be solved. Therefore, there is an urgent need to develop a novel gel composition with artemisinin as the main active ingredient. Through rational formulation design and optimized preparation process, the local bioavailability of the drug can be improved to achieve multiple effects such as anti-inflammatory, antibacterial, repair-promoting and anti-scarring, providing a safe and effective solution for the clinical treatment of burns. Summary of the Invention

[0003] The present invention aims to provide an artemisinin topical gel composition, its preparation method and application, with the goal of achieving multiple effects of anti-inflammatory, antibacterial, promoting repair and anti-scarring, providing a safe and effective solution for the clinical treatment of burns.

[0004] To achieve the above objectives, the present invention adopts the following technical solution: an artemisinin topical gel composition, comprising, by weight, the following raw materials: 0.1–5 parts artemisinin, 1–20 parts solubilizer, 0.5–15 parts gel matrix, 5–30 parts penetration enhancer, 0.01–1 part stabilizer, 0.01–2 parts pH adjuster, 0.05–1.5 parts preservative, 1–15 parts humectant, and purified water. Preferably, as an improvement, the solubilizer is a nonionic surfactant, including at least one of poloxamer 124, poloxamer 188, and poloxamer 407.

[0005] Preferably, as an improvement, the gel matrix is ​​a carbomer polymer, including at least one of carbomer 934, carbomer 940, carbomer 941, and carbomer 1342.

[0006] Preferably, as an improvement, the penetration enhancer is a compound system of alcohol and polyhydric alcohol, the mass ratio of alcohol to polyhydric alcohol being 1:1-1:4; the alcohol is at least one of ethanol, isopropyl alcohol, and benzyl alcohol; and the polyhydric alcohol is at least one of propylene glycol, polyethylene glycol 400, glycerol, and butylene glycol.

[0007] Preferably, as an improvement, the stabilizer is a metal ion chelating agent, including at least one of disodium edetate, calcium disodium edetate, and sodium citrate.

[0008] Preferably, as an improvement, the pH regulator includes at least one of sodium hydroxide, potassium hydroxide, triethanolamine, aminomethyl propanol, and lactic acid.

[0009] Preferably, as an improvement, the preservative includes at least one of methylparaben, propylparaben, phenoxyethanol, ethylhexylglycerin, and potassium sorbate.

[0010] Preferably, as an improvement, the humectant includes at least one of sodium hyaluronate, panthenol, urea, trehalose, and beta-glucan.

[0011] In another aspect, the present technical solution provides a preparation method of an artemisinin external use gel composition, including the following steps: Step one, disperse the gel matrix in purified water, add the stabilizer, humectant, and 50% of the solubilizer after swelling, and homogenize the mixture; Step two, mix and dissolve artemisinin with the penetration enhancer and the remaining solubilizer to obtain a drug solution; Step three, slowly add the drug solution obtained in step two to the matrix in step one, and shear emulsify; Step four, neutralize to pH 5.5-7.0 by adding the pH regulator, and finally add the preservative to homogenize the gel.

[0012] In the present technical solution, the solubilizer is added in batches, which can gradually adjust the hydrophilic-lipophilic balance of the system, promote the smooth transfer of the drug from the oil phase to the water phase, and improve the solubility of the drug, the uniformity of the system, and the long-term stability.

[0013] In still another aspect, the present technical solution also provides an application of the artemisinin external use gel composition in preparing a drug for treating and repairing scalds.

[0014] The principle and advantages of this scheme are: In this technical scheme, in view of the limitations of the existing technology for treating burns, the pathological process of burns and the characteristics of each stage are analyzed in reverse. The pathological process of burns involves complex inflammatory response, oxidative damage, infection risk and tissue repair and remodeling. (1) Acute injury period (0-72 h): Heat causes direct necrosis of epidermal and dermal cells, triggering mast cell degranulation and release of histamine, 5-hydroxytryptamine and other mediators, which causes a sharp increase in capillary permeability and plasma extravasation to form edema; at the same time, reactive oxygen species (ROS) bursts and trigger lipid peroxidation, aggravating tissue damage. (2) Inflammatory infection period (3-14 days): Necrotic tissue becomes a bacterial culture medium (mainly Pseudomonas aeruginosa and Staphylococcus aureus), pathogens invade through the damaged barrier, activate macrophages to release pro-inflammatory factors such as TNF-α and IL-6, and induce systemic inflammatory response syndrome (SIRS). (3) Repair period (>14 days): Fibroblasts proliferate excessively and secrete collagen, and abnormal activation of the TGF-β1 signaling pathway leads to scar hyperplasia; deep second-degree burns are delayed in healing due to insufficient angiogenesis.

[0015] The inventors creatively applied artemisinin, originally used for treating malaria, to the treatment and repair of burns. However, during the research and development phase, the inventors discovered the following practical problems: 1. Differences in indications and mechanisms of action leading to challenges in conversion: When artemisinin is used for antimalarial purposes, its antimalarial mechanism (iron-dependent free radical killing of malaria parasites) differs significantly from the pathology of burns (imbalance between inflammation / oxidation / repair). Furthermore, antimalarial drugs are administered orally / injected, while burns require topical application, and the presence of exudate and bacterial colonization in the wound can easily affect drug stability. Based on this, the inventors' team designed a "pH buffer + preservative combination" system (such as triethanolamine for pH adjustment + phenoxyethanol / methylparaben for antibacterial activity) to ensure the gel's pH stability in the exudate environment of the wound, achieving an inhibition zone diameter of 14.3-18.5 mm.

[0016] 2. The challenges of artemisinin's solubility and stability: Artemisinin itself has strong lipid solubility and poor water solubility, making it difficult to achieve an effective drug concentration on the wound surface when applied directly topically. Furthermore, it is easily degraded by oxidation, light exposure, and other factors. Based on this, the inventors' team optimized the composition design, solving the solubility problem by introducing a nonionic surfactant compound system (such as poloxamer 124 / 188 / 407), and simultaneously introducing metal ion chelating stabilizers (such as disodium edetate and sodium citrate) to chelate metal ions that might accelerate artemisinin degradation. Combined with a light-protected composition design, they ultimately achieved a 98.5% artemisinin retention rate after 6 months at 40℃ and 75% RH (compared to the typical degradation rate of over 5% in conventional compositions during the same period).

[0017] 3. Addressing the specific application scenario – burn wounds have impaired skin barriers, and traditional gel compositions often result in medication remaining in the epidermis and failing to penetrate into the damaged dermis. To address this, the inventors innovatively employed an alcohol-polyol complex with penetration enhancers (such as ethanol + propylene glycol, benzyl alcohol + polyethylene glycol 400). By altering the intercellular structure of the stratum corneum and promoting both drug dissolution and diffusion, the transdermal permeation rate of artemisinin was increased to 4.8 μg / cm³. 2 The drug retention in the dermis is 2.5 times that in the epidermis, ensuring targeted action on key areas of inflammation and repair. Furthermore, burn wounds are sensitive, and artemisinin may pose a risk of local irritation; high concentrations may also inhibit fibroblast activity. This technical solution optimizes the composition and formulation, enhancing artemisinin's ability to disrupt bacterial biofilms through a penetration enhancer, maintaining a moist environment through a gel matrix and moisturizer, and prolonging the duration of artemisinin's action on the wound. The penetration enhancer is optimized into an alcohol-polyol complex system, significantly improving transdermal efficiency through a synergistic mechanism of "alcohol disrupting the stratum corneum + polyol promoting drug dissolution," while the local analgesic effect of benzyl alcohol alleviates stinging sensations during wound application. In addition, this technical solution, by ensuring targeted anti-inflammatory and bactericidal effects, also maintains a moist environment on the wound, reducing the risk of local irritation.

[0018] 4. Given the specific requirements of the gel composition, the gel needs to simultaneously meet the contradictory demands of "maintaining a moist wound environment" and "easy application without dripping": too low a viscosity leads to easy runoff, while too high a viscosity makes application difficult. During development, by selecting carbomer-based matrices (934 / 940 / 1342) and precisely adjusting the pH (5.5-7.0), combined with thixotropic property optimization, the initial viscosity of the gel was controlled at 28500 mPa. With a thixotropic index (TI) of 3.2, it ensures that it does not flow when left to stand, and can quickly thin under the shear force of application. At the same time, the swelling degree is stable at 320%, avoiding excessive water absorption and maceration of the wound.

[0019] 5. The pathological process of burns encompasses four stages: inflammation, infection, oxidative damage, and scar formation. A single ingredient cannot provide simultaneous intervention. The team employed a three-dimensional synergistic design of "drug-excipient-gel formulation": artemisinin regulates pathways such as NF-κB and TGF-β to achieve anti-inflammatory and anti-scarring effects; the gel matrix (carbomer) forms a physical barrier to isolate bacteria; and moisturizers (such as sodium hyaluronate and β-glucan) maintain wound moisture. Ultimately, this achieves simultaneous four effects: anti-inflammatory, antibacterial, repair-promoting, and anti-scarring. Animal experiments showed that the high-dose group achieved a wound healing rate of 89.4% after 14 days, significantly superior to the silver sulfadiazine group (82.5%).

[0020] The key biological pathways involved in the treatment of burns with artemisinin gel are as follows: 1. NF-κB pathway NF-κB is a key transcription factor regulating inflammatory responses. Following burns, the TLR4 receptor is activated by damage-associated molecular patterns (DAMPs), promoting IκB kinase (IKK) phosphorylation, which leads to NF-κB nuclear translocation and induces the expression of genes such as TNF-α, IL-1β, and COX-2. Artemisinin inhibits NF-κB nuclear translocation by blocking IKKβ activation, reducing pro-inflammatory cytokine levels by more than 60%.

[0021] 2. MAPK pathway The p38 MAPK and JNK pathways are activated by ROS and inflammatory cytokines, leading to keratinocyte apoptosis and neutrophil infiltration. Artemisinin can downregulate p38 / JNK phosphorylation levels, reduce caspase-3-mediated apoptosis, and inhibit neutrophil elastase release, thus alleviating tissue lysis.

[0022] 3. Nrf2 / ARE antioxidant pathway Oxidative stress following burns causes Nrf2 to dissociate from Keap1, entering the nucleus and activating antioxidant enzyme genes. The peroxy bond (-OO-) in the artemisinin molecule directly scavenge hydroxyl radicals (·OH), while simultaneously promoting Nrf2 nuclear translocation, upregulating the expression of superoxide dismutase (SOD) and heme oxygenase-1 (HO-1), and reducing the content of lipid peroxide MDA.

[0023] 4. TGF-β / Smad scar formation pathway During the repair phase, TGF-β1 overactivates Smad2 / 3, stimulating fibroblasts to differentiate into myofibroblasts. Artemisinin reduces scar hyperplasia by inhibiting Smad3 phosphorylation, downregulating α-SMA and collagen I / III expression (animal experiments showed a 40% reduction in scar thickness).

[0024] Among the aforementioned pathways, artemisinin achieves its therapeutic effect through multi-target synergistic action: Anti-inflammatory: Simultaneously inhibits the NF-κB and MAPK pathways, reducing cytokine storms such as TNF-α and IL-6. Antioxidant: Activates the Nrf2 pathway and directly scavenges ROS, protecting stasis zone tissue. Antibacterial: Disrupts bacterial biofilm structure (especially against Pseudomonas aeruginosa). Promoting repair: Upregulates VEGF to promote angiogenesis, while inhibiting the TGF-β1 pathway to reduce scar inhibition.

[0025] The beneficial effects of this technical solution are as follows: 1. The artemisinin-based topical gel composition provided in this technical solution targets key pathological aspects of burns, including inflammatory response, oxidative damage, infection risk, and scar formation. Through the regulatory effects of artemisinin on multiple pathways such as NF-κB, TGF-β, and VEGF, it achieves multiple effects including anti-inflammatory, antioxidant, antibacterial, repair-promoting, and anti-scarring. The gel matrix maintains a moist wound environment, promoting local drug retention and transdermal absorption, avoiding the shortcomings of traditional compositions with single functions and low transdermal efficiency. This composition can rapidly relieve wound redness, swelling, and pain, reduce the incidence of infection, accelerate epithelialization, and significantly reduce scar hyperplasia, providing a safe and effective multi-mechanism synergistic solution for burn treatment, and has promising clinical application prospects.

[0026] 2. Multidimensional treatment is significantly more effective than traditional drugs: 2.1 Healing effect: The high-dose artemisinin gel treatment of this technology achieved a wound healing rate of 89.4% after 14 days, and the time to complete epithelialization was only 16.2 days, both of which were significantly better than the silver sulfadiazine group (82.5% and 17.3 days), and the granulation tissue thickness and collagen deposition were also better.

[0027] 2.2 Outstanding antioxidant capacity: This technical solution can significantly improve SOD activity (42.8U / mg), reduce MDA content (2.5nmol / mg), and activate Nrf2 nuclear translocation rate of 68.5%, with antioxidant effect superior to positive control drug.

[0028] 2.3 Anti-inflammatory advantages: This technical solution can reduce the p-p65 nuclear translocation rate of the NF-κB pathway to 32.6%, and reduce the levels of inflammatory factors such as TNF-α and IL-6 to 35.2 pg / mg and 33.5 pg / mg, respectively, with an inhibitory effect exceeding that of the silver sulfadiazine group.

[0029] 2.4 Anti-scarring effect: This technical solution can reduce TGF-β1 expression to 1.9, restore the collagen I / III ratio to 3.2, and reduce the scar thickness index to only 1.5, effectively improving scar hyperplasia.

[0030] 3. This technical solution exhibits inhibition zone diameters of 18.5 mm and 16.2 mm against common burn pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa, respectively, demonstrating antibacterial efficacy close to that of silver sulfadiazine, with no risk of drug resistance. Skin irritation tests showed no erythema or edema in the intact skin group, while the damaged skin group only showed transient and mild reactions, with a primary irritation index of 0, making it suitable for broken wounds.

[0031] 4. The gel composition of this technical solution exhibits excellent stability. In accelerated stability tests, after 6 months of storage at 40℃ and 75% RH, the artemisinin content still reaches 98.5%, and the viscosity change rate is only -6.0%. It remains stable after 24 months of long-term storage, with a shelf life of up to 2 years. Furthermore, the prepared gel composition has a pH of 5.5±0.2, matching the physiological environment of the skin, and an initial viscosity of 28500 mPa. It has good thixotropy, spreads smoothly and does not drip when left to stand, providing a better user experience than traditional dressings. Detailed Implementation

[0032] The following detailed description provides further details on specific embodiments, but the embodiments of the present invention are not limited thereto. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art; the experimental methods used are all conventional methods; and the materials and reagents used are all commercially available.

[0033] Overview of the plan: An artemisinin topical gel composition, comprising, by weight percentage: 0.1–5% artemisinin, 1–20% solubilizer, 0.5–15% gel matrix, 5–30% penetration enhancer, 0.01–1% stabilizer, 0.01–2% pH adjuster, 0.05–1.5% preservative, 1–15% humectant, and the balance being water.

[0034] The solubilizer is a poloxamer-based nonionic surfactant, specifically at least one of poloxamer 124, poloxamer 188, and poloxamer 407. The solubilizer is primarily used to improve the solubility of artemisinin and the stability of the gel composition.

[0035] The gel matrix is ​​a carbomer polymer, selected from at least one of carbomer 934, carbomer 940, carbomer 941, and carbomer 1342. The gel matrix is ​​mainly used to form a stable gel morphology and provide suitable adhesion.

[0036] The penetration enhancer is a compound system of alcohols and polyols, wherein: the alcohol is selected from at least one of ethanol, isopropanol, and benzyl alcohol; and the polyol is selected from at least one of propylene glycol, polyethylene glycol 400, glycerol, and butylene glycol. The penetration enhancer is mainly used to promote the transdermal absorption of artemisinin and enhance the drug's penetration into the wound. The mass ratio of alcohol to polyol in the penetration enhancer is 1:1 to 1:4.

[0037] The stabilizer is a metal ion chelating agent, selected from at least one of disodium edetate, calcium sodium edetate, and sodium citrate. The stabilizer is mainly used to chelate metal ions to improve the chemical stability of the composition.

[0038] The pH adjuster is at least one of sodium hydroxide, potassium hydroxide, triethanolamine, aminomethylpropanol, and lactic acid. The pH adjuster is mainly used to adjust the pH of the gel to a suitable range to ensure safety and stability.

[0039] The preservative is at least one selected from methylparaben, propylparaben, phenoxyethanol, ethylhexylglycerin, and potassium sorbate. The preservative is primarily used to inhibit microbial growth to ensure the hygienic safety of the composition.

[0040] The moisturizing agent is at least one of sodium hyaluronate, panthenol, urea, trehalose, and beta-glucan. The moisturizing agent is mainly used to maintain a moist environment on the wound surface to promote tissue repair.

[0041] On the other hand, this technical solution provides a method for preparing an artemisinin topical gel composition, comprising the following steps: Step 1: Disperse the gel matrix in purified water, swell it, and then add stabilizer, humectant and 50% solubilizer, and mix homogenously; Step 2: Mix and dissolve artemisinin with the penetration enhancer and remaining solubilizer to obtain the drug solution; Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and emulsify by shearing; Step 4: Add a pH adjuster to neutralize to pH 5.5–7.0, and finally add a preservative and homogenize to form a gel.

[0042] Furthermore, this technical solution also provides the application of an artemisinin topical gel composition in the preparation of drugs for the treatment and repair of burns.

[0043] Example 1 An artemisinin topical gel composition, comprising, by weight percentage, the following ingredients: artemisinin 1%, poloxamer 407 15%, carbomer 940 1.2%, ethanol 8%, propylene glycol 12%, disodium edetate 0.1%, triethanolamine 1.5%, methylparaben 0.3%, sodium hyaluronate 0.5%, and purified water balance.

[0044] A method for preparing an artemisinin topical gel composition includes the following steps: Step 1: Weigh out the prescribed amount of carbomer 940 and disperse it in an appropriate amount of purified water. Let it swell for 24 hours. Add 50% of the total amount of disodium edetate, sodium hyaluronate and poloxamer 407, and homogenize for 15 minutes (2000 r / min). Step 2: Mix artemisinin with ethanol and the remaining poloxamer 407, stir and dissolve in a 55°C water bath to obtain a clear solution; Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and shear emulsify for 10 minutes (8000 r / min). Step 4: Add triethanolamine to adjust the pH to 6.2, then add methylparaben (pre-dissolved in 5% propylene glycol), homogenize for 5 min; add the remaining purified water, stir at low speed of 400 r / min to degas for 20 min, and discharge.

[0045] Example 2 An artemisinin topical gel composition, comprising, by weight percentage, the following ingredients: artemisinin 2.5%, poloxamer 188 3%, carbomer 1342 8%, polyethylene glycol 400 10%, glycerin 5%, sodium citrate 0.3%, sodium hydroxide 0.3%, phenoxyethanol 0.8%, sodium hyaluronate 0.8%, and purified water balance.

[0046] A method for preparing an artemisinin topical gel composition includes the following steps: Step 1: Sprinkle Carbomer 1342 into 70% purified water, let it stand and swell for 12 hours, then add sodium citrate, sodium hyaluronate and poloxamer 188, and mix homogenously (1500 r / min). Step 2: Artemisinin and polyethylene glycol 400 are mixed and dissolved at 40°C, and glycerin is added and stirred until well combined; Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and shear emulsify for 15 minutes (5000 r / min). Step 4: Adjust the pH to 5.8 with sodium hydroxide solution, add phenoxyethanol, homogenize for 3 min; add the remaining purified water, stir at low speed of 400 r / min to degas for 20 min, and discharge.

[0047] Example 3 An artemisinin topical gel composition, comprising, by weight percentage, the following ingredients: artemisinin 5%, poloxamer 124 10%, carbomer 934 0.8%, butylene glycol 25%, sodium calcium edetate 0.08%, lactic acid 0.6%, ethylhexylglycerin 0.5%, glycerin 10%, and purified water balance.

[0048] A method for preparing an artemisinin topical gel composition includes the following steps: Step 1: Disperse Carbomer 934 in 50% purified water, swell overnight, add glycerol, sodium calcium edetate and 60% of the total solubilizer, and homogenize (3000 r / min). Step 2: Artemisinin and butylene glycol are dissolved under magnetic stirring (45°C). Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and emulsify by high-speed shearing (10000r / min, 8min). Step 4: Add lactic acid to adjust the pH to 6.5, then add ethylhexylglycerin and homogenize for 2 minutes; add the remaining purified water and solubilizer, stir at 400 rpm to degas, and discharge the product.

[0049] Example 4 An artemisinin topical gel composition, comprising, by weight percentage, the following ingredients: artemisinin 5%, poloxamer 188 10%, carbomer 934 5%, propylene glycol 15%, disodium edetate 0.2%, methylparaben 0.2%, ethanol 15%, sodium hydroxide 0.3%, and purified water balance.

[0050] A method for preparing an artemisinin topical gel composition includes the following steps: Step 1: Disperse Carbomer 934 in 50% purified water, swell overnight, add propylene glycol, disodium edetate and 60% of the total solubilizer, and homogenize (3000 r / min). Step 2: Dissolve artemisinin in ethanol under magnetic stirring (45°C). Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and emulsify by high-speed shearing (10000r / min, 8min). Step 4: Add sodium hydroxide to adjust the pH to 6.5, then add methylparaben and homogenize for 2 minutes; add the remaining purified water and solubilizer, stir at 400 rpm to degas, and discharge the product.

[0051] Comparative Example 1 The difference between this comparative example and Example 1 is that only ethanol (10%) was used as a penetration enhancer in this comparative example. The results showed that the transdermal permeation rate of the prepared gel was only 2.1 ± 0.2 μg / cm². 2 The drug retention in the dermis was only 6.5 ± 0.4 μg / g, significantly lower than that in Example 1 of this invention (4.8 μg / cm³). 2 • h, 15.2 μg / g). The wound healing rate (14 days) was only 68.4%, indicating that the penetration effect of a single alcohol is limited.

[0052] Comparative Example 2 The difference between this comparative example and Example 1 is that in the preparation stage, in step one, all poloxamer 407 was added to the aqueous phase at once, while the rest was the same as in Example 1. The results showed that the prepared gel contained obvious drug particles and had poor uniformity. After accelerated testing (40°C, RH 75%, 6 months), the artemisinin content decreased to 92.1%, the viscosity change rate reached -18.5%, and the stability was significantly reduced.

[0053] Comparative Example 3 The difference between this comparative example and Example 1 is that no metal ion chelating agent, disodium edetate, was added in this comparative example. Results showed that after 6 months of accelerated testing, the artemisinin content of the prepared gel decreased to 89.7%, indicating significant degradation of the peroxy bridge structure. After long-term storage (25°C, 12 months), the content further decreased to 85.2%, demonstrating that stabilizers are crucial for maintaining drug activity.

[0054] Comparative Example 4 The difference between this comparative example and Example 1 is that in this comparative example, the pH was adjusted to 4.0 in step four. The results showed that the viscosity of the prepared gel increased sharply to >50,000 mPa·s, making it difficult to apply, and the skin irritation score increased (the score of the damaged skin group was 2.0 after 1 hour).

[0055] Comparative Example 5 The difference between this comparative example and Example 1 is that in this comparative example, the pH was adjusted to 8.5 in step four. The results showed that the prepared gel had unstable viscosity, was prone to water separation, and had an abnormally fast drug release rate, with a cumulative release rate of over 95% in 12 hours, which could not achieve a sustained release effect.

[0056] Experiment Example 1: Verification of Physicochemical Properties and Stability 1. Determination of basic physical properties The basic physical properties of the artemisinin topical gel prepared in Example 1 were determined, and the key physical parameters of the gel were quantified to ensure that it meets the requirements of skin administration sites (e.g., for burns, it needs to be gentle, easy to apply, and non-irritating). The specific test indicators, test methods, and test results are shown in Table 1. Table 1 Results of Basic Physical Properties Measurement

[0057] As shown in Table 1, the topical gel prepared using this method has a uniform appearance, a pH value that matches the physiological environment of the skin, and good biocompatibility. The initial viscosity is 28,500 ± 1,500 mPa·s (n=3), which falls within the viscosity range for skin gels (10,000~50,000 mPa·s), making it easy to apply without dripping. The moderate viscosity and rheological properties ensure ease of use and stability. The swelling degree is controlled within the range of 200%~500%, which is beneficial for sustained drug release.

[0058] 2. Stability Test The artemisinin topical gel prepared in Example 1 was subjected to stability testing to verify its ability to resist degradation, temperature changes, and other influencing factors during storage and use. Specific test indicators, methods, and results are shown in Table 2. Table 2 Stability test results

[0059] As shown in Table 1, the gel prepared in this embodiment exhibits stable physicochemical properties under accelerated storage conditions. The gel demonstrates good stability under long-term storage, with a shelf life of 24 months. The gel should be stored away from light to ensure component stability.

[0060] Experimental Example 2: In Vitro Release and Permeability 1. In vitro release rate test The artemisinin topical gel prepared in Example 1 was subjected to an in vitro release rate test. The specific test indicators, test methods, and test results are shown in Table 3. Table 3 Results of in vitro release experiment

[0061] As shown in Table 3, the gel release performance meets the needs of burn treatment and has the advantage of sustained release.

[0062] 2. Transdermal penetration test The artemisinin topical gel prepared in Example 1 was subjected to a transdermal permeation test. The specific test indicators, test methods, and test results are shown in Table 4. Table 4 Transdermal penetration test results

[0063] As can be seen from the data in Table 4, the artemisinin gel prepared in this embodiment has good transdermal properties and can target deep into the skin.

[0064] Experiments 1 and 2 comprehensively verified the physicochemical stability, release, and penetration properties of the artemisinin gel for treating burns. Data showed that the gel remained stable under accelerated, long-term, and extreme conditions, with controllable drug release and effective penetration into the deep layers of the skin, demonstrating the reliability and effectiveness of this gel composition in the treatment of burns.

[0065] Experimental Example 3: In vitro antibacterial test This experiment tested the in vitro inhibitory effect of the artemisinin gel prepared in Example 1 on common burn pathogens. The experimental groups are as follows: 1. Experimental materials and grouping: Test drug: Artemisinin cream prepared in this invention, with an artemisinin content of 1% w / w.

[0066] Reference drug: Blank gel matrix: used as a negative control; Silver sulfadiazine cream: positive control.

[0067] The information on the test strains is as follows: (obtained through purchase) Staphylococcus aureus (ATCC 6538) Escherichia coli (ATCC 25922) Pseudomonas aeruginosa (ATCC 9027) Candida albicans (ATCC 10231) 2. Test methods: Agar diffusion method (inhibition zone test, n=3) The test results are shown in Table 5: The results show that the artemisinin gel of the present invention has a clear in vitro inhibitory effect on common pathogens of burns (Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli) and Candida albicans, and the inhibition zone is clearly visible.

[0068] The blank gel matrix showed no antibacterial activity, proving that the antibacterial activity originates from artemisinin. The artemisinin gel exhibited the strongest inhibitory effect against Gram-positive bacteria (Staphylococcus aureus), demonstrating a competitive antibacterial effect compared to the positive control. These data fully demonstrate that the artemisinin gel of this invention possesses broad-spectrum antibacterial capabilities and can effectively prevent and control infection of burn wounds.

[0069] Table 5. Diameter of inhibition zone (mm) ± SD, n=3)

[0070] Experimental Example 4: Skin Irritation Test This experiment tested the in vitro inhibitory effect of the artemisinin gel prepared in Example 1 on common burn pathogens. The experimental groups are as follows: 1. Test materials: Test sample: Artemisinin gel of the present invention (artemisinin content: 1% w / w) Laboratory animals: Healthy SD rats, SPF grade, weighing 200±20g, half male and half female. They were acclimatized for one week before being used in the experiment. Twenty-four hours before the experiment, the hair on both sides of the spine on the back of the rats was shaved (approximately 2cm × 2cm / side). Animal experiments were conducted in accordance with ethical guidelines.

[0071] 2. Test methods: 2.1 Experimental Grouping: Intact skin group: The shaved area on the left is the test area, and the control area on the right is the control area (no medication applied).

[0072] Damaged skin group: A "#" shaped abrasion was made in the shaved area on the right side with a sterile needle (to the extent of slight bleeding), while the left side was the intact skin test area.

[0073] 2.2 Dosing regimen: Single-stimulation test: 0.5g of artemisinin gel was evenly applied to the test area (approximately 2.5cm × 2.5cm), covered with gauze, and secured with non-irritating adhesive tape. The residue was removed with warm water after 4 hours. Skin reactions were observed at 1, 24, 48, and 72 hours after removal.

[0074] 2.3 Observation and Scoring: Erythema and edema were scored according to the skin irritation rating criteria in the "Cosmetic Safety Technical Specifications" or the OECD guidelines.

[0075] Erythema and eschar formation: No erythema 0 points; Mild erythema (barely visible) 1 point; Obvious erythema 2 points; Moderate to severe erythema 3 points; Purplish-red erythema with eschar formation 4 points.

[0076] Edema formation: No edema 0 points; slight edema (barely visible) 1 point; mild edema (clearly defined raised area) 2 points; moderate edema (raised area about 1 mm) 3 points; severe edema (raised area greater than 1 mm, with an expanded area) 4 points.

[0077] The test results are shown in Table 6: The results indicate that the artemisinin gel of the present invention did not produce any irritant reactions such as erythema or edema when administered to intact skin of rabbits. On broken skin of rabbits, only mild and transient erythema appeared after the first administration, which quickly subsided spontaneously and was considered an acceptable mild reaction. The primary irritation index (PII) was 0. In summary, according to relevant evaluation criteria, the artemisinin gel of the present invention is non-irritating to the skin, has good skin safety, and is suitable for the treatment of burns (including broken skin).

[0078] Table 6. Scores of single skin irritation reactions (highest score / animal, n=6)

[0079] Experiment Example 5: Animal Experiment 5.1 Experimental Objective The therapeutic effects (anti-inflammatory, anti-infective, and healing-promoting) of the artemisinin gel of this invention on experimental animal scald models and its local safety were tested and evaluated.

[0080] 5.2 Test Materials Test drug: Artemisinin gel (low dose: 1%, medium dose: 3%, high dose: 5%) Reference drug: Positive control: Silver sulfadiazine cream Negative control / model control: Matrix treatment (blank gel matrix) Blank control: sham burn group (shaving only, no burn treatment) Experimental animals: Healthy SD rats, weighing 200±20g, half male and half female. They were used for experiments after one week of acclimatization. Main instruments: burn instrument, bacterial incubator, image analysis system, pathological tissue sectioning system, etc. 5.3 Test Methods 5.3.1 Establishment and Grouping of Animal Burn Models After anesthetizing rats with sodium pentobarbital, their backs were shaved, and three second-degree burn wounds, approximately 1.5 cm in diameter, were created on the backs of each rat using a constant-temperature, constant-pressure burn device (80℃, 8s). The successfully modeled rats were randomly divided into 6 groups of 12 rats each. Fake burn group: only hair was shaved, no burn treatment was given; Burn model group: burns + matrix treatment (blank gel matrix); Burns + Silver Sulfadiazine Group: Positive Drug Control Group; Burns + low-dose artemisinin group: 1% artemisinin gel; Burns + Artemisinin medium-dose group: 3% artemisinin gel; Burns + high-dose artemisinin group: 5% artemisinin gel.

[0081] 5.3.2 Administration and Observation After cleaning the wound at the same time each day, apply the corresponding medication evenly according to the group and cover with sterile gauze. Administer the medication continuously for 14 days.

[0082] 5.3.2.1 Wound Healing Assessment Wound healing rate: Record changes in wound area daily; Healing time: The time required for complete epithelialization of the wound surface; Histological analysis: HE staining and Masson staining were used to assess tissue repair.

[0083] 5.3.2.2 Pathway-related detection Western blot: Detects the expression of key proteins in each pathway; Immunohistochemistry / immunofluorescence: Detecting protein localization and expression; ELISA: Detects the levels of inflammatory factors; qRT-PCR: Detects gene expression levels; Oxidative stress indicators: determination of MDA, SOD, and GSH-Px activities.

[0084] 5.4 Experimental Results and Data Analysis: 5.4.1 Comparison of wound healing rates Table 7. Effects of artemisinin on burn wound healing (14 days after treatment)

[0085] Note: *P<0.05, ***P<0.001 vs model group; ###P<0.001 vs silver sulfadiazine group Table 7 shows that artemisinin promotes burn wound healing in a dose-dependent manner, and the high-dose artemisinin group is superior to the positive drug control group in terms of wound healing rate and epithelialization speed.

[0086] 5.4.2 Pathway-related detection 5.4.2.1 Artemisinin reduces post-scald inflammatory response by inhibiting the NF-κB pathway. Table 8. Effects of artemisinin on the NF-κB pathway and inflammatory markers (7 days after burn)

[0087] Note: **P<0.01, ***P<0.001 vs model group; ###P<0.001 vs silver sulfadiazine group Experimental results showed that artemisinin significantly inhibited the activation of the NF-κB pathway after burns, reduced the release of inflammatory factors, and high-dose artemisinin was more effective than the positive control drug.

[0088] 5.4.2.2 Artemisinin reduces tissue damage by inhibiting the MAPK pathway. Table 9. Effects of artemisinin on the MAPK pathway and tissue damage indicators (7 days after burn)

[0089] Note: **P<0.01, ***P<0.001 vs model group; ###P<0.001 vs silver sulfadiazine group; MMP-9 activity is expressed as a multiple of the MMP-9 activity in the normal control group (sham burn group).

[0090] Experimental results showed that artemisinin significantly inhibited the activation of the MAPK pathway after burns, reduced cell apoptosis and matrix metalloproteinase activity, and alleviated tissue damage.

[0091] 5.4.2.3 Artemisinin enhances antioxidant capacity by activating the Nrf2 / ARE pathway. Table 10 Effects of artemisinin on the Nrf2 pathway and oxidative stress indicators (7 days after burn)

[0092] Note: **P<0.01, ***P<0.001 vs model group; ###P<0.001 vs silver sulfadiazine group; HO-1 protein expression is expressed as a multiple of HO-1 protein expression in the normal control group (sham burn group).

[0093] Table 10 shows that artemisinin significantly promotes Nrf2 nuclear translocation, enhances antioxidant enzyme activity and expression, and reduces oxidative stress damage.

[0094] 5.4.2.4 Artemisinin improves scar formation by regulating the TGF-β / Smad pathway Table 11 Effects of artemisinin on the TGF-β / Smad pathway and scar formation indicators (21 days post-burn)

[0095] Note: *P<0.05, **P<0.01, ***P<0.001 vs model group; ###P<0.001 vs silver sulfadiazine group; TGF-β1 protein expression is expressed as a fold increase in TGF-β1 protein expression compared to the normal control group (sham burn group).

[0096] Table 11 shows that artemisinin significantly regulates the TGF-β / Smad signaling pathway, improves collagen arrangement and ratio, and reduces pathological scar formation.

[0097] 5.5 Experimental Conclusions 5.5.1 Significantly promotes wound healing: Artemisinin can accelerate wound healing in a dose-dependent manner, as evidenced by a significantly improved wound healing rate and a markedly shortened time to complete epithelialization. The high-dose artemisinin group (5%) was significantly superior to the silver sulfadiazine group in all healing indicators, indicating that it has a stronger ability to promote tissue repair and regeneration.

[0098] 5.5.2 The core mechanism of action is clear: Artemisinin exerts its therapeutic effect by regulating key signaling pathways, including inhibiting the NF-κB pathway to reduce inflammation, inhibiting the MAPK pathway to reduce tissue damage, activating the Nrf2 / ARE pathway to enhance antioxidant capacity, and regulating the TGF-β / Smad pathway to improve scar formation. Its multi-pathway synergistic effect intervenes in multiple stages of burn healing, achieving the dual goals of accelerating healing and improving healing quality.

[0099] In summary, this experimental example systematically demonstrates that artemisinin gel, as a novel topical gel composition for treating deep second-degree burns, possesses excellent physicochemical stability, good skin compatibility, significant antibacterial activity, and a clear healing-promoting effect. Its multi-pathway synergistic effect (simultaneous anti-inflammatory, anti-oxidative, anti-apoptotic, and anti-fibrotic activity) enables it to effectively intervene in multiple complex stages of the burn healing process, ultimately achieving the dual goals of accelerating wound healing and improving healing quality (reducing scar formation).

[0100] Artemisinin gel successfully combines the multiple pharmacological mechanisms of artemisinin with the advantages of a gel composition, such as mild and easy application, temperature-sensitive gelation, and sustained release, achieving a synergistic multi-mechanism therapeutic effect of anti-inflammation, anti-oxidation, anti-infection, promoting healing, and anti-scarring. This gel composition has demonstrated superior therapeutic effects compared to traditional positive control drugs (such as silver sulfadiazine cream) in both in vitro and animal experiments, particularly in promoting epithelialization, inhibiting inflammatory pathways, enhancing antioxidant capacity, and improving collagen arrangement.

[0101] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. An artemisinin topical gel composition, characterized in that: By weight, it comprises the following ingredients: 0.1–5 parts artemisinin, 1–20 parts solubilizer, 0.5–15 parts gel matrix, 5–30 parts penetration enhancer, 0.01–1 part stabilizer, 0.01–2 parts pH adjuster, 0.05–1.5 parts preservative, 1–15 parts humectant, and purified water.

2. The artemisinin topical gel composition according to claim 1, characterized in that: The solubilizer is a nonionic surfactant, including at least one of poloxamer 124, poloxamer 188, and poloxamer 407.

3. The artemisinin topical gel composition according to claim 2, characterized in that: The gel matrix is ​​a carbomer polymer, including at least one of carbomer 934, carbomer 940, carbomer 941, and carbomer 1342.

4. The artemisinin topical gel composition according to claim 3, characterized in that: The penetration enhancer is a compound system of alcohol and polyol, with a mass ratio of alcohol to polyol of 1:1 to 1:4; the alcohol is at least one of ethanol, isopropanol, and benzyl alcohol; the polyol is at least one of propylene glycol, polyethylene glycol 400, glycerol, and butanediol.

5. The artemisinin topical gel composition according to claim 4, characterized in that: The stabilizer is a metal ion chelating agent, including at least one of disodium edetate, sodium calcium edetate, and sodium citrate.

6. The artemisinin topical gel composition according to claim 5, characterized in that: The pH adjuster includes at least one of sodium hydroxide, potassium hydroxide, triethanolamine, aminomethylpropanol, and lactic acid.

7. The artemisinin topical gel composition according to claim 6, characterized in that: The preservative includes at least one of methylparaben, propylparaben, phenoxyethanol, ethylhexylglycerin, and potassium sorbate.

8. The artemisinin topical gel composition according to claim 7, characterized in that: The moisturizer includes at least one of sodium hyaluronate, panthenol, urea, trehalose, and beta-glucan.

9. A method for preparing an artemisinin topical gel composition according to any one of claims 1-8, characterized in that, Includes the following steps: Step 1: Disperse the gel matrix in purified water, swell it, and then add stabilizer, humectant and 50% solubilizer, and mix homogenously. Step 2: Mix and dissolve artemisinin with the penetration enhancer and remaining solubilizer to obtain the drug solution; Step 3: Slowly add the drug solution obtained in Step 2 to the matrix in Step 1, and emulsify by shearing; Step 4: Add a pH adjuster to neutralize to pH 5.5–7.0, and finally add a preservative and homogenize to form a gel.

10. The use of an artemisinin topical gel composition according to any one of claims 1-8 in the preparation of a treatment and repair medicine for burns.

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