An active composition for treating atopic dermatitis and use thereof
By combining (+)-catechin hydrate, epicatechin, chlorogenic acid, and styracil alcohol with nanocarriers in specific ratios, the safety and stability issues of existing drugs were resolved, achieving multi-target synergistic effects, significantly alleviating atopic dermatitis, and improving the therapeutic efficacy and patient compliance.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- FOSHAN UNIVERSITY
- Filing Date
- 2026-02-27
- Publication Date
- 2026-05-19
AI Technical Summary
Existing medications for treating atopic dermatitis have issues with safety, side effects, and stability. Furthermore, their complex formulations make them difficult to effectively target multiple inflammatory pathways, resulting in poor patient compliance.
Using a specific ratio of (+)-catechin hydrate, epicatechin, chlorogenic acid and geraniol as active ingredients, combined with a nanocarrier prepared from chitosan, vinyl grafted modified gelatin and glyceryl monostearate, a highly stable and biocompatible active composition is formed for the preparation of topical drugs.
It significantly inhibits PDE4B, PDE4D and JAK1, with multi-target synergistic effects, improving the efficacy of treating atopic dermatitis, relieving itching and possessing skin repair function. It has high safety, low side effects, is suitable for processing into various dosage forms, and has high patient compliance.
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Figure CN121731318B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical technology, and more specifically, to an active composition for treating atopic dermatitis and its application. Background Technology
[0002] Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease clinically characterized by dry skin, erythema, papules, vesicles, and intense itching, severely impacting patients' quality of life. Current clinical treatment primarily involves anti-inflammatory drugs such as corticosteroids and calcineurin inhibitors; however, long-term use can lead to adverse reactions such as skin atrophy and pigmentation, and patient compliance is poor. Recent studies have shown that the pathogenesis of AD is closely related to immune dysregulation, with the JAK / STAT signaling pathway and the PDE4 / cAMP pathway playing crucial roles in inflammation regulation. JAK1 inhibitors and PDE4 inhibitors have become emerging targets for AD treatment, but existing synthetic drugs still present challenges related to safety, cost, and side effects.
[0003] Medication is a crucial treatment for atopic dermatitis (AD). Topical medications are first-line therapies, including topical corticosteroids, calcineurin inhibitors, and phosphodiesterase 4 (PDE4) inhibitors. For severe cases, systemic therapy is used clinically, including antihistamines, immunosuppressants, JAK inhibitors, and monoclonal antibodies. Although various medications are available clinically, surveys show that patient satisfaction with existing drugs is only 14%–42%. For example, Chinese patent application CN202511909029.6 discloses the application of *Helianthus altissima* extract in the preparation of drugs for treating atopic dermatitis. This extract can act on various stages of atopic dermatitis to relieve inflammation and improve itching symptoms, and it has higher safety and efficacy. For example, Chinese patent application CN202511032658.5 discloses a drug for treating atopic dermatitis, its preparation method, and its application. The method involves mixing sodium alginate and sodium polyacrylate with water and subjecting them to a swelling reaction to form a colloidal solution with a viscosity ≥5000 cP. Then, utpatinib, a preservative, glycerin, and azone are mixed to obtain the raw material phase. The colloidal solution is then mixed with the raw material phase and homogenized to obtain the drug for treating atopic dermatitis. This patent utilizes the swelling reaction of sodium alginate and sodium polyacrylate to significantly increase the viscosity of the colloidal solution through molecular chain entanglement, charge repulsion, and synergistic effects of water absorption. The combination of these components improves the transdermal efficiency of the drug, reduces drug irritation, and enhances the inhibitory efficiency against inflammatory factors in atopic dermatitis. However, the components in existing technologies are relatively complex, and there is still a need to develop safe, natural, and effective targeted active ingredients.
[0004] A search revealed few existing reports on the specific application of (+)-catechin hydrate, epicatechin, chlorogenic acid, and geraniol in the preparation of drugs for atopic dermatitis. Furthermore, the stability of the system after combining these four components presents new challenges, and the stability of the carrier also presents a technical problem that urgently needs to be solved. Therefore, developing a compound active composition and applying it to the preparation of drugs for atopic dermatitis that is safe, effective, and stable has significant clinical and market value. Summary of the Invention
[0005] In view of this, and in order to solve one of the above-mentioned technical problems, the present invention provides an active composition for treating atopic dermatitis and its application, the specific technical solution of which is as follows:
[0006] An active composition for treating atopic dermatitis, the active composition comprising an active ingredient and a carrier, wherein the active ingredient comprises (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of (0.2~1):(0.1~0.8):(0.1~0.5):(0.1~0.5).
[0007] Further, the carrier is prepared by the following method: adding chitosan to an acetic acid solution, adding modified gelatin and tannic acid, heating to 60℃~85℃, and stirring at 50r / min~100r / min for 1h~5h, then adding glyceryl monostearate, and continuing to stir for 20min~30min to obtain the carrier.
[0008] Further, by weight, the ratio of chitosan, acetic acid solution, modified gelatin, tannic acid and glyceryl monostearate is (7~15):(10~20):(3~7):(0.1~0.5):(1~2).
[0009] Furthermore, the modified gelatin is a vinyl-grafted modified gelatin.
[0010] Further, the preparation method of the active composition is as follows: the active ingredient is added to the carrier, stirred at a speed of 50 r / min to 100 r / min for 20 min to 60 min, and then freeze-dried to obtain the active composition.
[0011] Furthermore, the temperature of the freeze spray drying is -30℃ to 0℃, and the feeding rate is 20mL / min to 50mL / min.
[0012] Furthermore, the average particle size of the active composition is 30 nm to 80 nm.
[0013] Furthermore, the active ingredient accounts for 0.01% to 15% of the mass of the active composition.
[0014] In addition, the present invention provides the use of the active composition described herein in the preparation of a medicament for treating atopic dermatitis.
[0015] Furthermore, the medication for treating atopic dermatitis is a topical dosage form, including at least one of gels, creams, dressings, and sprays.
[0016] Compared with existing technologies, its beneficial effects include:
[0017] 1. This invention combines four natural ingredients—(+)-catechin hydrate, epicatechin, chlorogenic acid, and geraniol—in a specific ratio to exert a synergistic effect across multiple targets and pathways as active ingredients. The combined active ingredients can simultaneously act on multiple key aspects of atopic dermatitis pathogenesis, including inflammation, immunity, and oxidative stress. In particular, it specifically targets atopic dermatitis-related targets PDE4B, PDE4D, and JAK1. Compared to single ingredients or complex extracts, its mechanism of action is more clearly defined, exhibiting a significant inhibitory effect on atopic dermatitis, effectively relieving itching, and providing a certain degree of skin repair, thereby achieving a therapeutic goal. Furthermore, the raw materials are derived from natural products, ensuring high safety and low risk of side effects.
[0018] 2. This invention significantly improves the stability, skin permeability, and sustained-release performance of active ingredients by optimizing the carrier composition. The carrier is prepared by combining chitosan, vinyl-grafted modified gelatin, tannic acid, and glyceryl monostearate to form a nanocarrier with good biocompatibility and adhesion. This carrier can effectively encapsulate and protect the active ingredients, preventing oxidation or degradation and thus improving stability. Furthermore, the suitable nanoparticle size and the characteristics of the carrier material help enhance the transdermal penetration and target site accumulation of the active ingredients, achieving long-lasting sustained release and further improving the bioavailability of the active ingredients.
[0019] 3. This invention achieves better bioactivity of active ingredients through rapid molding at low temperatures, resulting in a more uniform particle size distribution and excellent reproducibility of the active composition. Furthermore, the prepared active composition can be easily reprocessed into various topical dosage forms such as gels, creams, dressings, and sprays according to clinical needs, leading to high patient compliance and flexible application.
[0020] 4. The active composition of the present invention is derived from natural plants, and the carrier is a biodegradable material with excellent biocompatibility. It has low or no irritation when applied topically, and can be used for a long time or repeatedly, avoiding the adverse reactions that may be caused by long-term use of traditional hormones or chemically synthesized drugs. It has good prospects for industrial transformation. Attached Figure Description
[0021] The invention will be further understood from the following description taken in conjunction with the accompanying drawings. The components in the drawings are not necessarily drawn to scale, but rather the emphasis is on illustrating the principles of the embodiments. In different views, the same reference numerals designate corresponding parts.
[0022] Figure 1 The diagrams show mouse experiments conducted on the blank group, model group, positive control group, and active composition creams prepared according to Examples 1-3 of this invention. Part A shows the mouse experiments on the blank group; Part B shows the mouse experiments on the model group; Part C shows the mouse experiments on the positive control group; Part D shows the mouse experiments on the active composition cream prepared according to Example 1; Part E shows the mouse experiments on the active composition cream prepared according to Example 2; and Part F shows the mouse experiments on the active composition cream prepared according to Example 3. Detailed Implementation
[0023] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to its embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the scope of protection of the invention.
[0024] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.
[0025] An active composition for treating atopic dermatitis according to one embodiment of the present invention includes an active ingredient and a carrier, wherein the active ingredient is composed of (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of (0.2~1):(0.1~0.8):(0.1~0.5):(0.1~0.5).
[0026] In one embodiment, the chemical structure of the (+)-catechin hydrate is as follows: .
[0027] In one embodiment, the chemical structural formula of epicatechin is as follows: .
[0028] In one embodiment, the chemical structural formula of the chlorogenic acid is as follows: .
[0029] In one embodiment, the chemical structural formula of the argan oil is as follows: .
[0030] In one embodiment, the carrier is prepared by the following method: adding chitosan to an acetic acid solution, adding modified gelatin and tannic acid, heating to 60°C to 85°C, and stirring at 50 r / min to 100 r / min for 1 h to 5 h, then adding glyceryl monostearate, and continuing to stir for 20 min to 30 min to obtain the carrier.
[0031] In one embodiment, the chitosan, acetic acid solution, modified gelatin, tannic acid and glyceryl monostearate are in the following weight ratios: (7~15):(10~20):(3~7):(0.1~0.5):(1~2).
[0032] In one embodiment, the acetic acid solution has a mass percentage concentration of 5% to 20%.
[0033] In one embodiment, the modified gelatin is a vinyl-grafted modified gelatin.
[0034] In one embodiment, the method for preparing the vinyl grafted modified gelatin is as follows: gelatin and vinyltrimethoxysilane are added to deionized water, heated to 60°C~70°C, and stirred at a speed of 50r / min~300r / min for 1h~5h.
[0035] In one embodiment, the weight ratio of the gelatin, vinyltrimethoxysilane and deionized water is (5~9):(1~3):(8~12).
[0036] In one embodiment, the active composition is prepared by adding the active ingredient to the carrier, stirring at a speed of 50 r / min to 100 r / min for 20 min to 60 min, and then freeze-spray drying to obtain the active composition.
[0037] In one embodiment, the temperature of the freeze spray drying is -30°C to 0°C, and the feeding rate is 20 mL / min to 50 mL / min.
[0038] In one embodiment, the average particle size of the active composition is 30 nm to 80 nm.
[0039] In one embodiment, the active ingredient accounts for 0.01% to 15% of the mass of the active composition.
[0040] In addition, the present invention provides the use of the active composition described herein in the preparation of a medicament for treating atopic dermatitis.
[0041] In one embodiment, the drug for treating atopic dermatitis is a topical dosage form, including at least one of gels, creams, dressings, and sprays.
[0042] The above-mentioned combination of (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol can more specifically target the atopic dermatitis-related targets PDE4B, PDE4D and JAK1, and achieve a significant therapeutic effect on atopic dermatitis. Furthermore, encapsulating them in a carrier can better preserve them as raw materials and reprocess them into corresponding dosage forms, resulting in excellent overall storage stability and efficacy stability.
[0043] The implementation schemes of the present invention will now be described in detail with reference to specific embodiments.
[0044] Example 1:
[0045] A method for preparing an active composition includes the following steps:
[0046] S1. According to the weight, 7 parts of gelatin and 3 parts of vinyltrimethoxysilane are added to 12 parts of deionized water, heated to 65°C, and stirred at 100 r / min for 1 h to obtain vinyl grafted modified gelatin.
[0047] S2. By weight, add 9 parts of chitosan to 15 parts of acetic acid solution with a mass percentage concentration of 8%, add 6 parts of vinyl grafted modified gelatin and 0.3 parts of tannic acid, heat to 65°C, and stir at 50 r / min for 3 h. Then add 2 parts of glyceryl monostearate and continue stirring for 25 min to obtain the carrier.
[0048] S3. Mix (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of 0.2:0.3:0.2:0.3 to obtain the active ingredient. Then, add 10% of the active ingredient by mass of the active composition to the carrier and stir at 50 r / min for 30 min. Then, freeze-dry at a temperature of -20°C and a feeding rate of 30 mL / min to obtain an active composition with an average particle size of 45 nm.
[0049] Example 2:
[0050] A method for preparing an active composition includes the following steps:
[0051] S1. According to the weight, 9 parts of gelatin and 3 parts of vinyltrimethoxysilane are added to 12 parts of deionized water, heated to 65°C, and stirred at 100 r / min for 1 h to obtain vinyl grafted modified gelatin.
[0052] S2. By weight, add 10 parts of chitosan to 15 parts of acetic acid solution with a mass percentage concentration of 8%, add 5 parts of vinyl grafted modified gelatin and 0.4 parts of tannic acid, heat to 70°C, and stir at 50 r / min for 3 h. Then add 2 parts of glyceryl monostearate and continue stirring for 25 min to obtain the carrier.
[0053] S3. Mix (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of 0.3:0.4:0.2:0.1 to obtain the active ingredient. Then, add 11% of the active ingredient by mass of the active composition to the carrier and stir at 50 r / min for 30 min. Then, freeze-dry at a temperature of -20°C and a feeding rate of 30 mL / min to obtain an active composition with an average particle size of 45 nm.
[0054] Example 3:
[0055] A method for preparing an active composition includes the following steps:
[0056] S1. According to the weight, 9 parts of gelatin and 3 parts of vinyltrimethoxysilane are added to 12 parts of deionized water, heated to 70°C, and stirred at 50 r / min for 1 h to obtain vinyl grafted modified gelatin.
[0057] S2. By weight, add 10 parts of chitosan to 15 parts of acetic acid solution with a mass percentage concentration of 8%, add 5 parts of vinyl grafted modified gelatin and 0.3 parts of tannic acid, heat to 75°C, and stir at 50 r / min for 3 h. Then add 2 parts of glyceryl monostearate and continue stirring for 25 min to obtain the carrier.
[0058] S3. Mix (+)-catechin hydrate, epicatechin, chlorogenic acid, and styracil alcohol in a weight ratio of 0.2:0.3:0.3:0.2 to obtain the active ingredient. Then, add 12% of the active ingredient by mass of the active composition to the carrier and stir at 50 r / min for 30 min. Then, freeze-dry at a temperature of -20°C and a feeding rate of 30 mL / min to obtain an active composition with an average particle size of 45 nm.
[0059] Comparative Example 1:
[0060] The difference between Comparative Example 1 and Example 3 is that the active ingredient in Comparative Example 1 is only a single (+)-catechin hydrate, while the rest is the same as in Example 3.
[0061] Comparative Example 2:
[0062] The difference between Comparative Example 2 and Example 3 is that the active ingredient in Comparative Example 2 is only epicatechin, while the rest is the same as in Example 3.
[0063] Comparative Example 3:
[0064] The difference between Comparative Example 3 and Example 3 is that the active ingredient in Comparative Example 3 is only chlorogenic acid, while the rest is the same as in Example 3.
[0065] Comparative Example 4:
[0066] The difference between Comparative Example 4 and Example 3 is that the active ingredient in Comparative Example 4 is only a single argan oil, while the rest is the same as in Example 3.
[0067] Comparative Example 5:
[0068] The difference between Comparative Example 5 and Example 3 is that the active ingredient in Comparative Example 5 is obtained by mixing (+)-catechin hydrate and epicatechin in a weight ratio of 0.2:0.3 (without the addition of chlorogenic acid and styracil alcohol), while the rest is the same as in Example 3.
[0069] Comparative Example 6:
[0070] The difference between Comparative Example 6 and Example 3 is that the active ingredient in Comparative Example 6 is obtained by mixing (+)-catechin hydrate, epicatechin and chlorogenic acid in a weight ratio of 0.2:0.3:0.3 (without adding styracil alcohol), and the rest is the same as in Example 3.
[0071] Comparative Example 7:
[0072] The difference between Comparative Example 7 and Example 3 is that the active ingredient in Comparative Example 7 is obtained by mixing (+)-catechin hydrate, epicatechin and styracil alcohol in a weight ratio of 0.2:0.3:0.2 (without adding chlorogenic acid), while the rest is the same as in Example 3.
[0073] Comparative Example 8:
[0074] The difference between Comparative Example 8 and Example 3 is that the active ingredient in Comparative Example 8 is obtained by mixing (+)-catechin hydrate, chlorogenic acid and styracil alcohol in a weight ratio of 0.2:0.3:0.2 (without adding epicatechin), while the rest is the same as in Example 3.
[0075] Comparative Example 9:
[0076] The difference between Comparative Example 9 and Example 3 is that Comparative Example 9 uses a common carrier (10 parts by weight of chitosan and 5 parts by weight of gelatin are added to 15 parts by weight of deionized water and stirred at 70°C and 100 r / min for 1 h), while the rest is the same as Example 3.
[0077] Comparative Example 10:
[0078] Compared with Example 3, Comparative Example 10 did not use a carrier for loading. Instead, a mixture of (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of 0.2:0.3:0.3:0.2 was used as a sample for testing.
[0079] Comparative Example 11:
[0080] Comparative Example 11 was a clinically approved dermatitis treatment drug (silomyst), which served as the control group.
[0081] I. The inhibition rates of the samples from Examples 1 to 3 and Comparative Examples 1 to 11 on the atopic dermatitis-related target phosphodiesterase 4B and phosphodiesterase 4D were tested, and the results are shown in Table 1.
[0082] The test method was as follows: all enzyme reactions were performed as follows: the reaction system was 50 µL, containing 40 mM MOPS (pH 7.5), 0.5 mM EDTA, 15 mM magnesium chloride, 0.15 mg / ml bovine serum albumin (BSA), 1 mM DTT, 0.05% Proclin 200, 15 ng / mL PDE 4CAT and 100 nM FAM-Cyclic-3',5'-AMP, and the enzyme amount was 0.05 ng.
[0083] Samples from Examples 1-3 and Comparative Examples 1-11 were used as test samples. 10g of each sample was added to 10% dimethyl sulfoxide (DMSO). 5µL of the diluent was added to 50µL of the reaction system to bring the final DMSO concentration to 1%. After incubating the reaction system at 25°C for 1 hour, 100µL of diluted phosphodiesterase-specific binding reagent was added to each well. The system was then incubated at 25°C with slow shaking for another hour. Fluorescence polarization values were detected using a 360 nm excitation filter and a 480 nm emission filter. The half-inhibition concentration (WIC) was calculated using Prism GraphPad software by fitting a normalized dose-response curve to the nonlinear regression. An in vitro enzyme activity detection system was established to evaluate and calculate the enzyme inhibitory activity.
[0084] Table 1: Enzyme Inhibition Rate
[0085]
[0086] Analysis of the data in Table 1 shows that the present invention, by combining natural components of (+)-catechin hydrate, epicatechin, chlorogenic acid, and argan oil in specific proportions, exhibits a synergistic effect. Compared with Example 3, the active ingredients in Comparative Examples 1-4 are single components. Although single active ingredients have certain inhibitory activity against the target PDE4, their efficacy is weak when used alone and insufficient to achieve the required inhibitory level for treatment. Comparative Example 5, Comparative Example 6, and Comparative Example 7 did not contain chlorogenic acid or argan oil; Comparative Example 8 did not contain epicatechin. The use of different active ingredients in Comparative Examples 5-8 failed to leverage the synergistic effect of the four active ingredients of the present invention. Consequently, the inhibition rates of phosphodiesterase 4B and phosphodiesterase 4D in Comparative Examples 5-8 were lower than those in Example 3, further demonstrating that the present invention, through component combination, can achieve superior inhibitory efficacy. Results: Comparative Example 9, using a common carrier, showed lower inhibition rates against atopic dermatitis-related targets phosphodiesterase 4B and phosphodiesterase 4D compared to Example 3. The introduction of vinyl-grafted modified gelatin, tannic acid, and glyceryl monostearate in this invention forms more stable and uniform nanoparticles, improving the dispersibility and bioavailability of the active ingredients, effectively enhancing their bioavailability and contributing to better efficacy. Comparative Example 10, lacking a carrier, posed a risk of oxidation and aggregation of the active ingredients, leading to activity loss and lower efficacy compared to Example 3. Comparative Example 11 used a clinically approved dermatitis treatment drug (silomysmet), a synthetically produced specific PDE4 inhibitor, while this invention, as a naturally derived compound, still achieved a similar inhibitory effect.
[0087] 2. The inhibitory activity of the samples from Examples 1 to 3 and Comparative Examples 1 to 11 on JAK1 enzyme was tested, and the results are shown in Table 2.
[0088] The assay method was as follows: all enzyme reactions were performed at 30°C for 40 min. The 50 µL reaction system contained: 40 mM Tris (pH 7.4), 10 mM magnesium chloride, 0.1 mg / mL bovine serum albumin (BSA), 1 mM DTT, 10 µM ATP, 0.2 μg / mL kinase (BPS Biosciences, San Diego, USA, catalog number 40449), and 100 μM lipid substrate.
[0089] Samples from Examples 1-3 and Comparative Examples 1-11 were used as test samples. Each sample (10g) was diluted with 10% dimethyl sulfoxide (DMSO). 5µL of the diluted solution was added to a 50µL reaction system to ensure a final DMSO concentration of 1% in all reaction systems. The Kinase-Glo Plus luminescent kinase assay kit was used to determine kinase activity by detecting the amount of residual ATP in the solution after the kinase reaction. The luminescent signal was positively correlated with ATP content and negatively correlated with kinase activity. The half-inhibitory concentration (WIC) was calculated using Prism GraphPad software through nonlinear regression analysis and standardized dose-response fitting.
[0090] Table 2: Inhibition rate of JAK1 enzyme
[0091]
[0092] Analysis of the data in Table 2 shows that the present invention, by combining a specific ratio of (+)-catechin hydrate, epicatechin, chlorogenic acid, and geraniol, exhibits superior phosphodiesterase inhibition rate while also showing JAK1 inhibition rate, indicating that the active composition of the present invention possesses the ability to regulate inflammation at multiple targets (PDE4 & JAK1). The pathogenesis of atopic dermatitis involves multiple signaling pathways; this multi-target mechanism helps to block inflammation at different levels, potentially producing a more comprehensive and lasting therapeutic effect, and reducing the risk of compensatory activation or drug resistance that may result from single-pathway inhibition. Furthermore, the combined active ingredients have a higher inhibition rate than single-target ingredients. Compared to single-target drugs such as silomycin, the active composition provided by the present invention is expected to more effectively control inflammation, relieve itching, and has better safety.
[0093] III. Mouse Experiment
[0094] Preparation of the cream: 2g of liquid paraffin, 2g of glyceryl monostearate and 2g of white petrolatum were mixed and heated to 80℃, and stirred to obtain phase A; 2mL of glycerin, 0.3mL of Lpan 80, 0.7mL of Tween 80 and 0.04g of ethylparaben were added to water, heated to 80℃ and stirred to obtain phase B; under continuous stirring, phase B was gradually added to phase A until uniformly mixed, then water was added to 20g, stirred and cooled to obtain the cream base;
[0095] 5g of each of the samples prepared in Examples 1-3 and Comparative Examples 1-10 were dispersed in 95% ethanol by mass percentage, and then added to the above-mentioned cream base. Water was added under stirring to bring the mixture to a volume of 20g, and homogenized to obtain the corresponding cream samples.
[0096] a. Fourteen experimental mice were used. Following the requirements of the "Technical Guidelines for the Study of Irritation and Hemolytic Properties of Traditional Chinese Medicine and Natural Drugs," a self-comparison was conducted between the left and right sides of the same body. The right side represented normal skin, and the left side represented damaged skin. The sides were divided using a marker. The upper end was the blank group coated with pure water, and the lower end represented the experimental groups (coated with 0.5 mL of samples from Examples 1-3 and creams prepared in Comparative Examples 1-10, respectively, with the product of Comparative Example 11 serving as the control group). The groups were then covered with two layers of gauze (3cm × 3cm) and secured with non-irritating adhesive tape. Hair was removed 24 hours before the experiment, with each side measuring 3cm × 3cm. Damaged skin was defined as a crisscross pattern drawn with sandpaper after hair removal, with bleeding as the criterion. A scoring standard was established according to the "Technical Guidelines for the Study of Irritation and Hemolytic Properties of Traditional Chinese Medicine and Natural Drugs," as shown in Tables 3 and 4 below. 72 hours after drug administration, the presence of erythema and edema at the application site was visually observed and recorded. The results are shown in Table 5.
[0097] Table 3: Skin Irritation Reaction Scoring Criteria
[0098]
[0099] Table 4: Evaluation Criteria for Skin Irritation Intensity
[0100]
[0101] Table 5: Results of Drug Irritation Evaluation
[0102]
[0103] As can be seen from the data analysis in Table 5, when the active composition of the present invention was used to prepare an ointment and applied to mice, no skin irritation reactions such as erythema or edema occurred, indicating that the ingredients are mild and have high safety.
[0104] b. Establishment of an atopic dermatitis model
[0105] BALB / c mice were randomly divided into four groups (n=6 per group): a control group, a model group, an experimental group, and a positive control group. 100 μL of 1% dichlorodiphenylethylamine solution was evenly applied to a sterile medical patch (1.8cm × 1.8cm) and attached to the mouse's back skin for 24 hours. Sensitization was confirmed by observing the appearance of erythema and exudation on the back skin after patch removal. On days 7, 11, 14, 18, 21, 25, and 27, 100 μL of 0.2% dichlorodiphenylethylamine solution was evenly applied to the back skin to induce an AD-like response. From day 15 onwards, mice received the following treatments daily for 14 consecutive days: the control group received only hair removal; the model group received the blank ointment base; the experimental groups received samples from Examples 1-3 and Comparative Examples 1-10, respectively; and the positive control group received the clinically approved PDE4 inhibitor silomysate described in Comparative Example 11. Mice were sacrificed at the end of the experiment, and back skin tissue was collected for subsequent analysis.
[0106] To assess the severity of atopic dermatitis and the corresponding therapeutic effects of creams, dermatitis scores were measured in experimental animals. Dermatitis scoring was performed using previously established methods, with the severity of skin lesions assessed every 4 days. Assessment indicators included characteristic symptoms such as erythema / hemoptysis, edema, scratch marks / erosions, and desquamation / dryness. Each symptom was scored according to the following criteria: 0 (none), 1 (mild), 2 (moderate), and 3 (severe). All symptom scores were summed to obtain a total dermatitis score for each mouse, ranging from 0 to 12. On day 28, skin lesion characteristics similar to atopic dermatitis, such as erythema, edema, dryness, exudation, and crusting, were compared between groups, and digital photographs were taken to record the observations. In addition, scratching behavior was recorded every 4 days, with the frequency of mice rubbing their backs, hind paws, noses, and ears recorded during a 10-minute observation period. The results of mouse scratching behavior are shown in Table 6 below, and the mouse skin inflammation scores are shown in Table 7.
[0107] Table 6: Results of Scratching Behavior in Mice
[0108]
[0109] Note: This indicates that on day 14 after modeling, there was a significant difference compared to the control group (p < 0.05). The value indicated that on day 14 after modeling, there was a highly significant difference compared with the blank control (p < 0.01); # indicated that on day 14 after drug administration, there was a significant difference compared with day 14 after modeling (p < 0.05); ## indicated that on day 14 after drug administration, there was a highly significant difference compared with day 14 after modeling (p < 0.01).
[0110] Analysis of the data in Table 6 shows that silomyst is a specific PDE4 inhibitor, and its antipruritic effect is mainly achieved by inhibiting PDE4 and increasing cAMP. The product of this invention not only strongly inhibits PDE4 but also moderately inhibits the JAK1 pathway. Itching involves multiple mediators (such as IL-31 and TSLP) and neuronal signals (such as the JAK-STAT pathway involved in itch signal transmission). Therefore, this invention, through a dual mechanism of PDE4 and JAK1 inhibition, more comprehensively blocks the generation and transmission of itch signals, thereby producing a stronger antipruritic effect. In summary, this invention, through the compounding of components and effective loading, improves the bioavailability of the active ingredients, effectively relieving the core symptoms of atopic dermatitis, with significant effects on itching.
[0111] Table 7: Results of Skin Inflammation Scores in Mice
[0112]
[0113] Note: This indicates that on day 14 after modeling, there was a significant difference compared to the control group (p < 0.05). The expression "#" indicates a highly significant difference between the control group and the control group on day 14 after drug administration (p < 0.01); "#" indicates a significant difference between the control group and the control group on day 14 after drug administration (p < 0.05); and "##" indicates a highly significant difference between the control group and the control group on day 14 after drug administration (p < 0.01).
[0114] As shown in Table 7, after 14 days of treatment, the active composition prepared in this invention has a significant effect on improving atopic dermatitis. The active composition of this invention can effectively inhibit PDE4 and JAK1, exhibiting dual activity. Furthermore, atopic dermatitis involves the release of multiple cytokines (such as IL-4, IL-13, IL-31, and TSLP), and the signal transduction of these cytokines depends on the JAK-STAT pathway. Therefore, the active composition of this invention synergistically blocks the inflammatory cascade reaction, thereby showing a more comprehensive and better effect in improving visible skin inflammation.
[0115] in addition, Figure 1This diagram illustrates mouse experiments of the preparation of the active composition cream from Examples 1-3, including the blank group, model group, positive control group, and experimental group. Part A represents the mouse experiment of the blank group; Part B represents the mouse experiment of the model group; Part C represents the mouse experiment of the positive control group; Part D represents the mouse experiment of the active composition cream from Example 1; Part E represents the mouse experiment of the active composition cream from Example 2; and Part F represents the mouse experiment of the active composition cream from Example 3. Figure 1 As can be seen from Part A (blank group): The skin on the backs of mice was intact, the hair was normal, and no signs of lesions such as erythema, edema, desquamation, or scratches were observed. The skin color and texture were healthy, representing normal skin condition. Part B (model group): Extensive and severe inflammatory lesions were visible on the skin on the backs of mice. These were manifested as obvious erythema, thickened and rough skin, local scratches and scabs, accompanied by a large amount of dandruff and hair loss areas. This part clearly reflects the AD-like skin lesions successfully induced by dichlorodiphenylethylamine. Part C (positive control group, silomyst): Compared with the model group, skin inflammation was improved, the erythema area was reduced and the color was lighter, and the degree of skin thickening and desquamation was reduced, but local mild redness and a small amount of dandruff were still visible. Parts D, E, and F (Experimental groups of Examples 1, 2, and 3): The appearance of the skin on the backs of mice in these three experimental groups showed significant improvement, and their degree of recovery was significantly better than that of the positive control group (Part C). The skin erythema basically subsided, approaching normal skin color, the skin surface was smooth, and the visible thickening, edema, erosion, and large amount of desquamation almost completely disappeared. The area covered by hair increased, with only occasional, slight dandruff or no dandruff at all. Overall, this invention demonstrates that the active compositions prepared in Examples 1-3 of this invention to prepare the cream can significantly alleviate visible inflammatory signs such as erythema, edema, and desquamation of the skin in AD model mice, with a clearer mechanism of action and more significant therapeutic effect.
[0116] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.
[0117] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.
Claims
1. An active composition for treating atopic dermatitis, characterized in that, The active composition includes an active ingredient and a carrier, and the active ingredient is composed of (+)-catechin hydrate, epicatechin, chlorogenic acid and styracil alcohol in a weight ratio of (0.2~1):(0.1~0.8):(0.1~0.5):(0.1~0.5); The chemical structural formula of epicatechin is as follows: ; The chemical structural formula of the chlorogenic acid is: ; The chemical structural formula of the aromatic resin alcohol is: ; The carrier is prepared by adding chitosan to an acetic acid solution, adding modified gelatin and tannic acid, heating to 60℃~85℃, and stirring at 50r / min~100r / min for 1h~5h, then adding glyceryl monostearate and continuing stirring for 20min~30min to obtain the carrier.
2. The active composition according to claim 1, characterized in that, The ratio of chitosan, acetic acid solution, modified gelatin, tannic acid and glyceryl monostearate by weight is (7~15):(10~20):(3~7):(0.1~0.5):(1~2).
3. The active composition according to claim 1, characterized in that, The modified gelatin is a vinyl-grafted modified gelatin.
4. The active composition according to claim 1, characterized in that, The active composition is prepared by adding the active ingredient to the carrier, stirring at a speed of 50 r / min to 100 r / min for 20 min to 60 min, and then freeze-spray drying to obtain the active composition.
5. The active composition according to claim 4, characterized in that, The temperature of the freeze spray drying is -30℃ to 0℃, and the feeding rate is 20mL / min to 50mL / min.
6. The active composition according to claim 4, characterized in that, The average particle size of the active composition is 30 nm to 80 nm.
7. The active composition according to claim 4, characterized in that, The active ingredient accounts for 0.01% to 15% of the mass of the active composition.
8. Use of the active composition according to any one of claims 1 to 7 in the preparation of a medicament for treating atopic dermatitis.
9. The application according to claim 8, characterized in that, Medications for treating atopic dermatitis are topical formulations, including at least one of gels, creams, dressings, and sprays.