Corydalis B eth O Ointment, Method and Application

Abstract

The application relates to a tetrahydropalmatine ointment, a preparation method and application. The tetrahydropalmatine ointment comprises the following components in percentage by weight: tetrahydropalmatine 0.01-1%, and auxiliary materials 99.00-99.99%. By comparing the ointment colors and impurity contents of different prescriptions, the screening of antioxidants, matrices and packaging materials in the ointment prescription is completed. The application proves that the tetrahydropalmatine ointment has no obvious toxicity and can effectively improve the symptoms of atopic dermatitis or children's atopic dermatitis.

Description

Technical Field

[0001] This invention relates to the field of drug formulation technology for atopic dermatitis, and particularly to a corydalis yanhusuo ointment, its method, and its application. Background Technology

[0002] Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease with a global incidence rate that is increasing year by year, seriously affecting patients' quality of life. Currently, treatments for atopic dermatitis mainly include corticosteroids, immunosuppressants, and biologics; however, these drugs have problems such as easy development of drug resistance, significant systemic adverse reactions, and high treatment costs, necessitating the development of safe and effective new treatments. Furthermore, the incidence of atopic dermatitis in children is also showing an increasing trend year by year.

[0003] Ointments, as an important dosage form for transdermal drug delivery, demonstrate significant advantages in local treatment. Firstly, ointments allow the monomeric compounds of traditional Chinese medicine to act directly on the affected skin, achieving highly efficient local penetration and avoiding the first-pass effect and gastrointestinal degradation associated with oral medications, thus significantly improving drug bioavailability. Secondly, the unique semi-solid form of ointments forms a protective film on the skin surface, preventing excessive moisture evaporation and blocking external irritants, creating a favorable environment for the repair of damaged skin. Furthermore, ointments are convenient to use, allow for easy dosage control, and enable adjustments to the dosing frequency according to the patient's condition, greatly improving patient adherence. Compared to other dosage forms, the base components of ointments have good compatibility with the monomeric compounds of traditional Chinese medicine, effectively maintaining drug stability. Moreover, the drug release rate can be optimized by adjusting the base formulation, achieving long-lasting therapeutic effects.

[0004] The information disclosed in the background section is only for enhancing the understanding of the background of this invention, and therefore may contain information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0005] This invention provides a corydalis ethyl ointment, which, based on the unique pharmacological activity of corydalis ethyl and combined with the advantages of ointment formulation, is developed for the treatment of atopic dermatitis and childhood atopic dermatitis, aiming to provide a safe, effective and convenient solution for patients with atopic dermatitis and childhood atopic dermatitis.

[0006] A corydalis yanhusuo ointment comprises the following components by weight percentage:

[0007] Corydaline: 0.01%–1%;

[0008] Excipients: 99.00%-99.99%; wherein, the Corydalis yanhusuo ointment has no obvious toxicity.

[0009] In the aforementioned corydalis ethyl ointment,

[0010] The Corydalis yanhusuo ointment is used for atopic dermatitis and is used to synergistically downregulate the mRNA expression levels of IL-4, IL-5, and IL-13.

[0011] In the aforementioned corydalis ethyl ointment,

[0012] The Corydalis yanhusuo ointment is also used for childhood atopic dermatitis, to: reduce acute itching and inflammation mediated by the release of histamine and other mediators, and to downregulate excessive local Th2 immune responses by blocking Th2 cytokines, as well as to inhibit adaptive immune responses triggered by specific antigens.

[0013] In the aforementioned corydalis yanhusuo ointment, the excipients comprise the following components by weight percentage:

[0014] White petrolatum: 75%–85%;

[0015] White beeswax: 3%–7%;

[0016] Glyceryl monostearate and glyceryl distearate: 5%–10%;

[0017] Transcutol P: 5%–10%;

[0018] Antioxidant BHT: 0.1%~0.2%.

[0019] The formula for the aforementioned corydalis ethyl ointment is as follows:

[0020] Corydalis rhizome: 0.10%;

[0021] White petrolatum: 76.00%;

[0022] White beeswax: 6.00%;

[0023] Glyceryl monostearate and glyceryl distearate: 7.70%;

[0024] Transcutol P: 10.00%;

[0025] Antioxidant BHT: 0.20%.

[0026] In the aforementioned corydalis ethyl ointment, the impurity growth of the corydalis ethyl ointment does not exceed 0.2% after being stored for 20 days.

[0027] The aforementioned corydaline ointment is packaged in an aluminum-plastic tube.

[0028] In the aforementioned corydalis ethyl ointment, after transdermal administration, the frequency of scratching and the severity of skin damage are reduced.

[0029] A method for preparing a corydalis yanhusuo ointment includes,

[0030] The molten matrix was obtained by heating and melting white petrolatum, white beeswax, and glyceryl mono- and di-stearate and clarifying the mixture.

[0031] The antioxidant BHT was dissolved in Transcutol P, and corydaline was added and sonicated to completely dissolve the solution.

[0032] The solution is added to the molten matrix under stirring conditions and homogenized.

[0033] Cool and stir at room temperature until a uniform ointment is formed.

[0034] An application of corydalis yanhusuo ointment, wherein the drug is administered by topical application.

[0035] Compared with existing technologies, this invention has the following advantages: Using corydaline as the main active ingredient and adding antioxidants and other excipients, the prepared ointment is used to treat atopic dermatitis and childhood atopic dermatitis, and has no significant toxicity. Through comparison of the color and impurity content of ointments with different formulations, the screening of antioxidants, base, and packaging materials in the ointment formulation was completed, and it was confirmed that the corydaline ointment disclosed in this invention has no significant toxicity and can effectively improve the symptoms of atopic dermatitis and childhood atopic dermatitis. Attached Figure Description

[0036] Various other advantages and benefits of the present invention will become apparent to those skilled in the art upon reading the detailed description of the preferred embodiments below. The accompanying drawings are for illustrative purposes only and are not intended to limit the invention. It is obvious that the drawings described below are merely some embodiments of the invention, and those skilled in the art can obtain other drawings based on these drawings without any inventive effort. Furthermore, the same reference numerals denote the same parts throughout the drawings.

[0037] In the attached diagram:

[0038] Figure 1 This is a schematic diagram showing the comparison of samples of prescriptions F1 and F2 after 20 days in different embodiments of the present invention;

[0039] Figure 2 This is a comparison chart showing the therapeutic effects of different treatments on atopic dermatitis in mice in terms of body weight, number of scratches, and skin observation in the embodiments and comparative examples of this invention;

[0040] Figure 3 This is a comparison chart of the mRNA expression levels of IL-4, IL-5, and IL-13 in mice treated with different regimens for atopic dermatitis in the embodiments and comparative examples of the present invention.

[0041] Figure 4 This is a data visualization comparison of the skin permeability and sustained-release properties of the corydaline ointment and the corydaline 40% ethanol solution disclosed in this invention in the epidermis, subcutaneous tissue and dermis.

[0042] Figure 5 This is a schematic diagram showing the distribution of the corydalis ethyl ointment disclosed in this invention in four application areas on the back of miniature pigs and the distal skin.

[0043] Figure 6 The figure shows the inhibitory effect of corydaline, the core active ingredient of corydaline ointment, on the epidermal barrier damage induced by ovalbumin and calcipotriol in newborn mice.

[0044] Figure 7 The figure shows the inhibitory effect of corydaline, the core active ingredient of corydaline ointment, on the weight loss of newborn mice induced by ovalbumin and calcipotriol.

[0045] Figure 8 The figure shows the inhibition of scratching frequency in newborn mice induced by ovalbumin and calcipotriol by tetrabumin, the core active ingredient of tetrabumin ointment.

[0046] Figure 9 The figure shows the inhibitory effect of corydaline, the core active ingredient of corydaline ointment, on the increase in spleen index induced by ovalbumin and calcipotriol in newborn mice.

[0047] Figure 10 The image shows the inhibitory effect of corydaline, the core active ingredient of corydaline ointment, on epidermal hyperplasia and inflammatory infiltration induced by ovalbumin and calcipotriol in newborn mice, magnified at 20x.

[0048] Figure 11 , Figure 12 These are schematic diagrams showing the relative expression levels of IL4 mRNA and IL13 mRNA in mice induced by ovalbumin and calcipotriol, respectively.

[0049] Figure 13 This diagram illustrates the effects of applying different grades of corydaline to inhibit serum IgE in mice induced by ovalbumin and calcipotriol, compared to the normal group and the ovalbumin and calcipotriol-induced model group.

[0050] The present invention will be further explained below with reference to the accompanying drawings and embodiments. Detailed Implementation

[0051] The following will refer to the appendix. Figures 1 to 13 Specific embodiments of the invention will be described in more detail below. While specific embodiments of the invention are shown in the accompanying drawings, it should be understood that the invention may be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the invention and to fully convey the scope of the invention to those skilled in the art.

[0052] It should be noted that certain terms are used in the specification and claims to refer to specific components. Those skilled in the art will understand that different terms may be used to refer to the same component. This specification and claims do not distinguish components based on differences in terminology, but rather on differences in function. The terms "comprising" or "including" used throughout the specification and claims are open-ended and should be interpreted as "comprising but not limited to." The following descriptions are preferred embodiments for carrying out the invention; however, these descriptions are for the purpose of understanding the general principles of the specification and are not intended to limit the scope of the invention. The scope of protection of this invention is determined by the appended claims.

[0053] To facilitate understanding of the embodiments of the present invention, further explanations and descriptions will be provided below with reference to the accompanying drawings and specific embodiments. The accompanying drawings do not constitute a limitation on the embodiments of the present invention.

[0054] In one embodiment, the present invention discloses a corydalis acetate ointment comprising the following components by weight percentage:

[0055] Corydaline: 0.01%–1%;

[0056] Excipients: 99.00%-99.99%; wherein, the Corydalis yanhusuo ointment has no obvious toxicity.

[0057] In a preferred embodiment of the aforementioned corydalis rhizome ointment,

[0058] The Corydalis yanhusuo ointment is used to treat or relieve atopic dermatitis and to synergistically downregulate the mRNA expression levels of IL-4, IL-5, and IL-13.

[0059] In a preferred embodiment of the aforementioned corydalis rhizome ointment,

[0060] The Corydalis yanhusuo ointment is also used to treat or relieve atopic dermatitis in children, by: reducing acute itching and inflammation mediated by the release of histamine and other mediators, by downregulating excessive local Th2 immune responses through blocking Th2 cytokines, and by inhibiting adaptive immune responses triggered by specific antigens.

[0061] In a preferred embodiment of the Corydalis yanhusuo ointment, the excipients comprise the following components by weight percentage:

[0062] White petrolatum: 75%–85%;

[0063] White beeswax: 3%–7%;

[0064] Glyceryl monostearate and glyceryl distearate: 5%–10%;

[0065] Transcutol P: 5%–10%;

[0066] Antioxidant BHT: 0.1%~0.2%.

[0067] In a preferred embodiment of the corydaline ointment, the formula of the corydaline ointment is as follows:

[0068] Corydalis rhizome: 0.10%;

[0069] White petrolatum: 76.00%;

[0070] White beeswax: 6.00%;

[0071] Glyceryl monostearate and glyceryl distearate: 7.70%;

[0072] Transcutol P: 10.00%;

[0073] Antioxidant BHT: 0.20%.

[0074] In a preferred embodiment of the corydalis ethyl ointment, the impurity growth of the corydalis ethyl ointment does not exceed 0.2% after being stored for 20 days.

[0075] In a preferred embodiment of the Corydalis Ethyl Corydalis Ointment, the Corydalis Ethyl Corydalis Ointment is packaged in an aluminum-plastic tube.

[0076] In a preferred embodiment of the corydalis ethyl ointment, after transdermal administration, the corydalis ethyl ointment reduces the frequency of scratching and alleviates the severity of skin lesions.

[0077] A method for preparing a corydalis ethyl ointment, comprising,

[0078] The molten matrix was obtained by heating and melting white petrolatum, white beeswax, and glyceryl mono- and di-stearate and clarifying the mixture.

[0079] The antioxidant BHT was dissolved in Transcutol P, and corydaline was added and sonicated to completely dissolve the solution.

[0080] The solution is added to the molten matrix under stirring conditions and homogenized.

[0081] Cool and stir at room temperature until a uniform ointment is formed.

[0082] An application of the aforementioned corydalis ethyl ointment in the preparation of a drug for treating atopic dermatitis, wherein the medication is administered via topical application.

[0083] In one embodiment, excipients include, but are not limited to, white petrolatum, white beeswax, glyceryl monostearate and glyceryl distearate, Transcutol P, and 2,6-di-tert-butyl-p-cresol. Based on data regarding the compatibility, solubility, and solution stability of the excipients for corydalis ethylstilbestrol, and through investigation of the ointment matrix, antioxidant content, and packaging materials, with ointment stability as the primary indicator, formulation screening was conducted to determine the optimal formulation. The effects of parameters such as temperature, homogenization, and cooling during the preparation process on the physicochemical properties of the ointment were investigated, and the ointment was prepared using a homogenization method.

[0084] In one embodiment, the ointment contains the antioxidant 2,6-di-tert-butyl-p-cresol (BHT). When the antioxidant content is 0.1%-0.5%, impurity formation is low. When treating atopic dermatitis, the active ingredient content is 0.01%-0.1%.

[0085] Example 1: Antioxidant Screening in Formulation Development

[0086] Based on the chemical properties of API and the results of pre-formulation studies, no significant increase in impurities was observed in the API-BHT mixture under high temperature (50°C). However, when API was mixed with other excipients such as cetyl alcohol, stearic acid, and white petrolatum, the impurities showed an increasing trend under high temperature conditions, suggesting that API may be undergoing oxidation in the formulation. Therefore, formulation F1 without antioxidants and formulation F2 containing the antioxidant dibutylhydroxytoluene (BHT) were prepared to compare the chemical stability of the formulations, as detailed in Table 1 below:

[0087]

[0088] It should be noted that the percentages of each ingredient or component in all the prescriptions disclosed in this invention are weight percentages.

[0089] Preparation method for F2 prescription sample: ① Mix the prescribed amounts of white petrolatum, white beeswax, and glyceryl monostearate and glyceryl distearate, heat in a 75°C water bath until the excipients melt and become clear, and stir evenly. ② Add BHT to Transcutol P solvent and sonicate to dissolve and clarify. Then add the prescribed amount of API and sonicate to dissolve and clarify. ③ While stirring, add ② to ①, turn on the homogenizer, and homogenize for 1.5 min at 2000 rpm. ④ Stir at room temperature until an ointment is formed. The preparation method for F1 prescription sample is basically the same as that for F2 prescription sample, except that the antioxidant BHT is not added. The preparation methods for other prescription samples described below are similar.

[0090] See Figure 1 The stability of the samples was observed by color: the F1 formulation sample turned pale yellow after 20 days; the F2 formulation sample remained unchanged in color after 20 days, remaining off-white. The test results showed that under the same sampling conditions, the F1 formulation exhibited a greater increase in impurities than the F2 formulation. Furthermore, at 30℃, new impurities with an RRT of 0.89 appeared; the impurity at RRT of 0.87 showed an increasing trend with increasing temperature.

[0091] Stability results showed that under the same sampling conditions, the F1 formulation sample exhibited a greater increase in impurities than the F2 formulation sample. After 40 days at 30℃ / 65%RH, the total impurities in the F1 and F2 formulation samples were 0.79% and 0.33%, respectively, while the known impurity, berberine, was 0.73% and 0.11%, respectively. This indicates that, based on chemical stability, the F2 formulation is superior to the F1 formulation. Antioxidants can slow down the oxidation reaction of compounds, and further optimization studies will be conducted on the F2 formulation containing antioxidants.

[0092] Example 2: Screening of Ointment Matrix in Formulation Development

[0093] Ointments F2 and F3 with different oily bases were prepared, and their physicochemical stability was compared. The formulation of F2 consisted of API (0.10%), white petrolatum (76.00%), white beeswax (6.00%), glyceryl mono- and di-stearates (7.70%), Transcutol P (10.00%), and BHT (0.20%). The formulation of F3 consisted of API (0.10%), white petrolatum (62.00%), white beeswax (6.00%), glyceryl mono- and di-stearates (7.70%), Transcutol P (10.00%), BHT (0.20%), cetyl alcohol (3.00%), octadecanol (2.00%), and lanolin (9.00%).

[0094] PLM results showed no drug crystallization in either formulation F2 or F3. Stability results showed that under all stability conditions, the impurity growth rate of formulation F2 was lower than that of formulation F3 after 40 days. At 30℃ / 65%RH for 40 days, the total impurities in F2 and F3 were 0.33% and 1.48%, respectively, and the known impurity berberine was 0.11% and 0.58%, respectively. The results are shown in the table below:

[0095]

[0096] Since formulation F2 has better chemical stability than F3, formulation F2 was chosen for further research.

[0097] Example 3: Packaging Material Screening in Formula Development

[0098] The F2 formulation was packaged using high borosilicate glass bottles and two common packaging materials for topical preparations: aluminum ointment tubes (hereinafter referred to as aluminum tubes) and polyethylene-aluminum-polyethylene composite ointment tubes (hereinafter referred to as aluminum-plastic tubes). Stability was then tested.

[0099] The results showed no significant difference in impurities between samples packaged in glass bottles and aluminum-plastic tubes. However, the aluminum-plastic tube samples had fewer impurities and a lower total impurity content compared to the aluminum tube samples. Therefore, aluminum-plastic tubes are planned to be used for packaging the formulation in the future.

[0100] Example 4: Preparation of samples with different antioxidant contents to further investigate the content of the antioxidant BHT, ranging from 0.10% to 0.20%.

[0101]

[0102] As mentioned above, with white beeswax, glyceryl monostearate and glyceryl distearate, and Transcuto1P all fixed, in order to study the effect of different antioxidant contents, F2, F6, and F7 formulation samples were prepared. At the same time, high-specification F5 and F8 formulations (1% specification) samples were prepared to specifically examine the effect of different antioxidant contents on the stability of different specification formulations.

[0103] The results showed that, under conditions of 25℃ / 60%RH and 30℃ / 65%RH for 60 days, samples with an antioxidant content of 0.2% (Formulas F2 and F8) exhibited better stability than samples with an antioxidant content of 0.1% (Formulas F7 and F5) and 0.15% (Formula F6). However, under conditions of 2–8℃ for 60 days, no significant differences were observed as all samples were relatively stable (see table below).

[0104]

[0105] Therefore, the preferred antioxidant content is 0.2%.

[0106] A mouse model of atopic dermatitis induced by MC903 was established, and tebuconazole ointment, anhydrous ethanol solution of tebuconazole, and 40% ethanol solution of tebuconazole were applied percutaneously. Changes in mouse body weight, scratching frequency, and skin lesion condition were recorded. The model induced significant thickening and desquamation of the ear skin in mice. The tebuconazole ointment showed significantly better improvement in skin lesions than the anhydrous ethanol solution and the 40% ethanol solution of tebuconazole. Furthermore, the ointment significantly reduced weight loss compared to the anhydrous ethanol solution. Simultaneously, the frequency of scratching was significantly reduced, superior to the positive control drug tacrolimus. The tebuconazole ointment showed no significant toxicity.

[0107] See results Figure 2 .

[0108] MC903, or calcipotriol, is a low-calcium analog of vitamin D3, widely used to treat psoriasis. Studies have found that topical application of MC903 can stimulate high expression of TSLP in mouse epithelial keratinocytes, promote the differentiation of CD4+ T cells into Th2 cells and activate and release inflammatory cytokines, inducing an atopic dermatitis phenotype in mice.

[0109] When the ointment of the present invention was prepared according to the prescription, the corydalis ointment showed the most significant inhibitory effect on atopic dermatitis in the ear tissue of mice with this type of inflammatory flare-up. Further combined with… Figure 3 It can be seen that, compared with the model group (i.e., the MC903-induced mouse model), the corydaline ointment disclosed in this invention has the best downregulation ability in synergistically downregulating the mRNA expression levels of IL-4, IL-5, and IL-13 to alleviate the inflammation of atopic dermatitis. It is also superior to the tacrolimus group and the 40% ethanol solvent group (corydaline dissolved in 40% ethanol), and only slightly higher than the blank control group. This further illustrates that the corydaline ointment has no obvious toxicity.

[0110] Example 5: Preparation and stability study of ointments with different corydaline contents

[0111] To verify the effect of different concentrations of corydaline (0.01%–1%) on the stability and efficacy of the ointment.

[0112]

[0113] Preparation method

[0114] The preparation of prescription samples F9, F2 and F11 shall be performed in accordance with the preparation methods of the preceding examples, such as Example 1.

[0115] Evaluation indicators

[0116] Changes in the appearance of the formulation (color, texture)

[0117] Total impurities (HPLC detection)

[0118] Evaluation of treatment efficacy in a mouse AD model (number of scratches, ear thickness)

[0119]

[0120] When the content of corydaline is 0.01% to 1%, the preparations all have good chemical stability and significant anti-inflammatory effects. Among them, 0.10% is the optimal concentration, that is, the F2 prescription has the best overall efficacy.

[0121] Example 6: Effect of different BHT contents on the stability of ointments

[0122] To verify the antioxidant protective effect of BHT on tebufenozide ointment in the range of 0.1% to 0.25%.

[0123]

[0124] High-temperature accelerated testing (40℃ / RH 75%, 6 months) was conducted to examine the growth of impurities and the retention rate of active ingredients. The results are as follows:

[0125]

[0126] In other words, based on the comparison of the above-mentioned prescription samples, the stability of the formulation significantly improved with increasing BHT content. Therefore, it is recommended to choose a BHT content of 0.1%–0.2% to meet long-term storage requirements, avoiding excessive addition of BHT and thus preventing an increased probability of skin side effects due to excessive BHT. Therefore, F2 remains the optimal prescription.

[0127] Example 7: Comparison of physical properties of ointments with different base ratios

[0128] To verify the effect of the content of base components such as white petrolatum (75%–85%) and white beeswax (3%–7%) on the physical properties of ointments.

[0129]

[0130] Ointment hardness (penetration test)

[0131] Stability (storage at room temperature of 25℃±2 for 6 months)

[0132] Drug release rate (in vitro transdermal assay)

[0133]

[0134] Therefore, the F2 formulation sample also possesses the most suitable hardness and optimal drug release performance, making it suitable for clinical topical administration. In conclusion, through multi-dimensional experiments and screening, the F2 formulation is the optimal formulation.

[0135] Example 8: Comparison of the effects of aluminum-plastic tube and glass bottle packaging on the stability of ointments

[0136] Purpose

[0137] To verify the effect of different packaging materials on the stability of corydalis yanhusuo ointment.

[0138]

[0139] Examination conditions

[0140] Room temperature (25℃±2)

[0141] Storage time: 12 months

[0142]

[0143] Aluminum-plastic tubes, as packaging materials for ointments, offer better sealing and barrier properties, helping to maintain the chemical stability of the formulation.

[0144] Example 9: Comparison of the efficacy of ointment (i.e., the corydaline ointment disclosed in this invention) and solution formulation (i.e., different solutions of corydaline, including: anhydrous ethanol solution of corydaline, 40% ethanol solution of corydaline, etc.) in a mouse AD model.

[0145] Purpose

[0146] To verify the advantages of corydalis rhizome ointment over traditional solution formulations in the treatment of Alzheimer's disease (AD).

[0147] Grouping and Processing

[0148]

[0149]

[0150] Corydalis yanhusuo ointment was significantly superior to the solution formulation in the treatment of Alzheimer's disease (AD), reducing scratching frequency by 63% and significantly improving skin lesions, such as a 38.7% reduction in ear thickness. See also Figure 4 This demonstrates that ointments achieve better therapeutic effects through their excellent skin penetration and sustained-release properties. Figure 4 This study visualizes data reflecting the skin permeability and sustained-release properties of corydaline ointment and corydaline 40% ethanol solution in the epidermis, subcutaneous tissue, and dermis.

[0151] Example 10: Skin dynamics study of ointment and solution formulations in miniature pigs

[0152] Clinically, this ointment / solution is intended for topical application to treat dermatitis, with a recommended frequency of every 4 hours. This study investigated the drug concentrations in the epidermis, dermis, subcutaneous tissue, and subcutaneous muscle of Bama miniature pigs after a single transdermal application of the F2 prescription ointment or solution. The study compared the skin dynamics of the ointment and solution in miniature pigs to provide a basis for subsequent experiments.

[0153] Administration method: Topical application, consistent with the clinically intended administration method;

[0154] Animals treated with DP158-O241001 ointment and DP158-O241002 ointment;

[0155] Dosing frequency: multiple times; administer the medication in the designated area on Days 1, 3, 4, and 5 respectively, and the dosing time for Days 3 to 5 is consistent with that of Day 1;

[0156] Administration site: Dorsal skin. The skin on both sides of the dorsal side of each miniature pig was divided into four administration areas. Each area had an application area of ​​6 cm × 5 cm, with an interval of at least 5 cm between adjacent areas. See the diagram showing the distribution of the four application areas and distal skin on the dorsal side of the miniature pig. Figure 5 In the image, the distal skin (approximately 6 cm × 5 cm) is more than 5 cm away from the two adjacent application areas (upper left and upper right). No medication is administered to the distal skin.

[0157] Therefore, the F2 formulation ointment significantly improves drug distribution in the epidermis and dermis of miniature pigs. (See the results below.) Figure 4 .

[0158] The following examples demonstrate the efficacy and safety of corydaline, the core active ingredient in corydaline ointment, in treating atopic dermatitis in children:

[0159] 1. Experimental Materials

[0160] Corydaline, ovalbumin (purchased from MCE), calcipotriol (purchased from MCE), and newborn C57 mice (purchased from the Experimental Animal Center of Xi'an Jiaotong University).

[0161] 2. Experimental Methods

[0162] This invention employs a combination of calcipotriol (MC903) and ovalbumin (OVA) to construct a model for childhood atopic dermatitis (AD), a combined model designed to better study drug candidates for childhood atopic dermatitis. Calcipotriol-induced AD models utilize TSLP-driven Th2 responses, meaning they are models for studying drugs targeting the Th2 pathway. However, childhood atopic dermatitis (AD) often involves antigen-specific immune responses. This combined model, by integrating barrier disruption with specific antigen exposure, more accurately reproduces the core pathological features of childhood AD: not only Th2-driven but also antigen-specific. This means that this combined model can simulate the core characteristics of childhood AD: skin barrier disruption, Th2-type immune responses, and sensitization to specific antigens (ovalbumin OVA).

[0163] In the specific experiment, mice were first divided into the NC group (blank control group), Vehicle group (negative control group), Dex group (positive drug dexamethasone group), and different concentrations of corydaline groups (0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL groups; the dosage form shown here is an aqueous solution or lotion, and other dosage forms can be calculated accordingly). Mice in the NC group received no treatment and were fed normally. Mice in the other groups were treated with calcipotriol (MC903) solution and ovalbumin (OVA) solution once daily on their backs for 13 consecutive days to establish a childhood atopic dermatitis model. Mice in the Vehicle group received no other medications besides the 13-day treatment. Mice in the positive drug group received glucocorticoids applied to their backs daily from day 8, and mice in each corydaline group received 0.01 mg / mL, 0.1 mg / mL, and 1 mg / mL corydaline solution applied to their backs daily from day 8. On day 13, the number of times mice scratched their ears (within 30 minutes) and the amount of scales were counted in each group. The mice were then euthanized, and their back tissues were collected for observation.

[0164] 3. Experimental Results

[0165] like Figure 6 As shown, the ear skin of mice in the NC group showed no significant changes, while mice in the Vehicle group, treated with calcipotriol and ovalbumin, exhibited increased scaling and damage to the skin's epidermal barrier. This is because calcipotriol and ovalbumin induced atopic dermatitis in the ears, causing itching and constant scratching. Applying corydalis solution to the ears of mice with atopic dermatitis symptoms reduced scaling and epidermal barrier damage compared to the Vehicle group, indicating that corydalis effectively inhibits the skin barrier damage caused by scratching induced by calcipotriol and ovalbumin. While applying glucocorticoids (a positive control drug) to the ears also reduced epidermal barrier damage, wrinkling of the ears was observed, indicating an adverse reaction to the positive control drug. Mice in the corydalis group did not exhibit wrinkling in the skin areas affected by childhood atopic dermatitis, meaning corydalis did not cause adverse reactions in mice, indicating that corydalis is non-toxic at concentrations below 0.1 mg / mL.

[0166] like Figure 7 As shown, the overall body weight of mice in the NC group increased, while the body weight of mice in the Vehicle group, which were treated with calcipotriol and ovalbumin, decreased significantly. The body weight of mice treated with corydaline was comparable to that of the Vehicle group, while the body weight of mice treated with the positive control drug decreased at a faster rate. This indicates that the positive control drug, glucocorticoids, exacerbated the body weight loss in mice, suggesting that glucocorticoids have some toxicity to mice, while corydaline has no toxicity.

[0167] like Figure 8 As shown, mice in the NC group scratched their ears very little, while mice in the Vehicle group, which were treated with calcipotriol and ovalbumin, scratched their ears more frequently, indicating that calcipotriol and ovalbumin increased the levels of pruritus mediators. Mice treated with tebufenozide scratched significantly less than the Vehicle group, indicating that tebufenozide can effectively inhibit the increase in pruritus mediator levels induced by calcipotriol and ovalbumin.

[0168] like Figure 9 As shown, compared with the NC group, the spleen index of the Vehicle group mice treated with calcipotriol and ovalbumin increased, indicating that calcipotriol and ovalbumin induced a systemic inflammatory response. Mice treated with corydaline showed a significantly lower spleen index compared to the Vehicle group, indicating that corydaline can effectively inhibit the systemic inflammatory response.

[0169] like Figure 10 As shown, compared with the NC group, the Vehicle group mice treated with calcipotriol and ovalbumin showed increased epidermal thickness and increased dermal inflammatory infiltration. Mice treated with corydaline showed significantly reduced epidermal thickness and decreased dermal inflammatory infiltration compared to the Vehicle group, indicating that corydaline can effectively inhibit the skin inflammatory response in children with atopic dermatitis.

[0170] See further Figure 11 , Figure 12 Compared with the normal group, mice in the model group treated with calcipotriol and ovalbumin showed a dramatic increase in IL4 mRNA and IL13 mRNA levels. Mice treated with corydaline showed a significant decrease in IL4 mRNA and IL13 mRNA levels compared with the model group, indicating that corydaline can effectively inhibit the Th2-type inflammatory response of the skin caused by atopic dermatitis in children.

[0171] comprehensive Figures 6 to 12 As can be seen, applying calcipotriol to the ears of mice induces significant atopic dermatitis symptoms, including increased scratching frequency, weight loss, damage to the skin's epidermal barrier, and elevated levels of inflammatory factors in the epidermis. Applying corydalis ethinylene to the ears of mice effectively inhibits damage to the skin's epidermal barrier, the release of pruritus mediators, and the release of inflammatory factors in the epidermis, alleviating atopic dermatitis symptoms and reducing scratching frequency. Corydalis ethinylene significantly improves atopic dermatitis symptoms in mice and has lower toxicity than commonly used clinical corticosteroids.

[0172] Further analysis reveals that, because the aforementioned combined model can simulate the core characteristics of childhood atopic dermatitis (AD): skin barrier disruption, Th2 immune response, and sensitization to specific antigens (such as ovalbumin OVA), corydaline, as an effective component of drugs for childhood atopic dermatitis, is used to: reduce acute itching and inflammation mediated by the release of histamine and other mediators, and to downregulate excessive local Th2 immune responses by blocking Th2 cytokines; see further... Figure 13 Compared with the normal group and the model group, applying different grades of corydaline to the mice could inhibit the increase of serum IgE. Among them, the concentration of 0.1 mg / mL had the best effect. This proves that corydaline, as an effective component of drugs for atopic dermatitis in children, can also inhibit the adaptive immune response triggered by specific antigens.

[0173] This invention marks the first application of corydaline to the treatment of atopic dermatitis in children, breaking through its traditional uses for analgesia and sedation, realizing a "new use for an old drug," exploring the potential value of corydaline in the field of immune dermatology, and improving the utilization rate of traditional Chinese medicine resources. Addressing the characteristics of children's fragile skin barrier and sensitivity to hormones, this invention provides a non-hormonal, low-toxicity alternative treatment. Corydaline is prepared into topical dosage forms such as gels, creams, and ointments for direct application to the affected area. Direct application to the diseased skin enhances efficacy, reduces systemic absorption, and lowers the risk of systemic side effects: avoiding adverse reactions such as central nervous system depression (e.g., drowsiness, hypotension) that may occur with oral administration, making it particularly suitable for children. Topical preparations are convenient to use, easy for parents to operate, and suitable for long-term maintenance treatment. Gels and creams have a gentle texture, are less likely to clog pores, and are suitable for children's sensitive skin.

[0174] Furthermore, it should be noted that dose gradient experiments have clearly demonstrated that corydaline has a therapeutic effect in the range of 0.01–1 mg / mL, and that: below a concentration of 0.1 mg / mL, corydaline has no toxicity; and no obvious toxicity was observed at 1 mg / mL.

[0175] This invention provides clear concentration guidance for clinical formulation development, avoiding ineffectiveness due to excessively low concentrations or irritation due to excessively high concentrations. It is effective at low concentrations, and no toxic effects such as skin wrinkling or weight loss were observed in experiments, making it superior to positive control drugs such as dexamethasone. Compared to single-factor models, it more realistically reflects the complex pathogenesis of childhood Alzheimer's disease (AD), enhancing the clinical reference value of experimental results.

[0176] In another embodiment, the present invention discloses the use of corydaline in a medicament for treating atopic dermatitis in children, the medicament being used to: reduce acute itching and inflammation mediated by the release of mediators such as histamine, downregulate excessive local Th2 immune responses by blocking Th2 cytokines, and inhibit adaptive immune responses triggered by specific antigens. The single active ingredient of the medicament for treating atopic dermatitis in children is corydaline.

[0177] In a preferred embodiment of the application, the drug is in the form of a topical preparation, including gels, ointments, creams, powders, solutions, or lotions. Furthermore, the drug does not contain any glucocorticoid components.

[0178] In a preferred embodiment of the application, the concentration of corydaline in the drug is 1, 0.1, or 0.01 mg / mL. More broadly, the concentration of corydaline is in the range of 0.01–1 mg / mL. More preferably, the concentration of corydaline is 0.01–0.1 mg / mL.

[0179] Furthermore, in another embodiment, the present invention also discloses a medicament for treating atopic dermatitis in children, the medicament comprising corydaline, the medicament being used to: reduce acute itching and inflammation mediated by the release of mediators such as histamine, downregulate excessive local Th2 immune responses by blocking Th2 cytokines, and inhibit adaptive immune responses triggered by specific antigens. The single active ingredient of the medicament for treating atopic dermatitis in children is corydaline.

[0180] In a preferred embodiment of the described drug, the drug is a topical preparation, including gels, ointments, creams, powders, solutions, or lotions. Furthermore, the drug does not contain any glucocorticoid components.

[0181] In a preferred embodiment of the drug, the concentration of corydaline in the drug is 0.01–1 mg / mL. More preferably, the concentration of corydaline is 0.01–0.1 mg / mL.

[0182] In a preferred embodiment of the drug, the corydaline is administered topically. Although embodiments of the invention have been described above in conjunction with the accompanying drawings, the invention is not limited to the specific embodiments and application fields described above. The specific embodiments described above are merely illustrative and instructive, not restrictive. Those skilled in the art can make many other modifications based on the guidance of this specification and without departing from the scope of the claims of this invention, and all such modifications are within the scope of protection of this invention.

Claims

1. A corydalis rhizome extract ointment, characterized in that, Includes the following components by weight percentage: Corydaline: 0.01%–1%; Auxiliary materials: 99.00%-99.99%; Among them, The Corydalis yanhusuo ointment has no obvious toxicity.

2. The corydalis rhizome ointment according to claim 1, characterized in that, Preferred, The Corydalis yanhusuo ointment is used for atopic dermatitis and is used to synergistically downregulate the mRNA expression levels of IL-4, IL-5, and IL-13.

3. The corydalis rhizome ointment according to claim 1, characterized in that, The Corydalis yanhusuo ointment is also used for childhood atopic dermatitis, to: reduce acute itching and inflammation mediated by the release of histamine and other mediators, and to downregulate excessive local Th2 immune responses by blocking Th2 cytokines, as well as to inhibit adaptive immune responses triggered by specific antigens.

4. The corydalis rhizome ointment according to claim 1, characterized in that, The excipients comprise the following components by weight percentage: White petrolatum: 75%–85%; White beeswax: 3%–7%; Glyceryl monostearate and glyceryl distearate: 5%–10%; Transcutol P: 5%–10%; Antioxidant BHT: 0.1%~0.2%.

5. The corydalis rhizome ointment according to claim 1, characterized in that, The formula for the Corydalis rhizome ointment is as follows: Corydalis rhizome: 0.10%; White petrolatum: 76.00%; White beeswax: 6.00%; Glyceryl monostearate and glyceryl distearate: 7.70%; Transcutol P: 10.00%; Antioxidant BHT: 0.20%.

6. The corydalis rhizome ointment according to claim 1, characterized in that, The impurity growth of the Corydalis Ethyl Corydalis ointment did not exceed 0.2% after 20 days of storage.

7. The corydalis rhizome ointment according to claim 1, characterized in that, The Corydalis Ethyl Ointment is packaged in an aluminum-plastic tube.

8. The corydalis rhizome ointment according to claim 1, characterized in that, The ointment containing corydalis yanhusuo, when administered transdermally, reduces the frequency of scratching and alleviates the severity of skin lesions.

9. A method for preparing a corydalis rhizome ointment according to any one of claims 1-8, characterized in that, It includes, The molten matrix was obtained by heating and melting white petrolatum, white beeswax, and glyceryl mono- and di-stearate and clarifying the mixture. The antioxidant BHT was dissolved in Transcutol P, and corydaline was added and sonicated to completely dissolve the solution. The solution is added to the molten matrix under stirring conditions and homogenized. Cool and stir at room temperature until a uniform ointment is formed.

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