Chenodeoxycholic acid and heparin sodium combined composition for acne treatment and application of chenodeoxycholic acid and heparin sodium combined composition

Abstract

The invention relates to an external composition for treating acne and application thereof. The composition comprises chenodeoxycholic acid or pharmaceutically acceptable salt thereof and heparin sodium. The composition achieves a multi-target synergistic effect by adjusting sebum secretion, inhibiting inflammatory response and improving local repair, significantly reduces the severity of acne lesions, and is high in safety and low in irritation.

Description

Technical Field

[0001] This invention relates to the fields of dermatology and pharmaceutical composition technology, specifically to a topical composition containing chenodeoxycholic acid (CDCA) and heparin sodium and its application in the treatment of acne. Background Technology

[0002] Acne vulgaris is a chronic inflammatory skin disease characterized primarily by abnormal function of the pilosebaceous unit. Its pathogenesis involves excessive sebum secretion, abnormal follicular keratinization, proliferation of Propionibacterium acnes (C. acnes), and local immune inflammatory responses. Current treatments mainly include retinoids, antibiotics, benzoyl peroxide, and hormones, but these have limitations such as limited efficacy, strong irritation, drug resistance, and high recurrence rates. Therefore, there is an urgent need to develop novel drugs with clear mechanisms of action and low side effects.

[0003] Chenodeoxycholic acid (CDCA) is a natural bile acid. Recent studies have shown that CDCA not only plays a role in lipid metabolism and cholesterol regulation, but also reduces the levels of inflammatory factors (such as TNF-α and IL-6) by activating receptor pathways like FXR and TGR5, and regulates fatty acid synthesis-related enzymes (FASN and SREBP1), thereby achieving anti-inflammatory effects, inhibiting excessive sebum secretion, and improving the hair follicle microenvironment. This makes CDCA a promising novel drug candidate with potential anti-acne effects.

[0004] Currently, the main drug treatment for acne involves retinoids, which work by reducing inflammation and keratinization and inhibiting sebum secretion. Side effects include dry skin, inflammation, and desquamation. Additionally, Chinese patent application number 202510157546.6 discloses the use of chenodeoxycholic acid in the treatment of acne; however, the therapeutic effect of chenodeoxycholic acid on acne remains unsatisfactory.

[0005] Sodium heparin is a commonly used anticoagulant in clinical practice. It also has anti-inflammatory, anti-fibrotic, and microcirculation-improving effects, and is frequently used in dermatology to prevent and improve scarring and reduce tissue edema. By inhibiting the release of inflammatory mediators, improving local blood circulation, and promoting tissue repair, it can help reduce fibrosis and scar formation after acne damage.

[0006] There are currently no literature reports on the combined use of chenodeoxycholic acid and heparin sodium for the treatment of acne. Summary of the Invention

[0007] (a) Technical problems to be solved The technical problem to be solved by this invention is to address the issues of strong irritation, drug resistance, and high relapse rate that exist in existing drugs such as retinoids, antibiotics, and hormones when used for a long time.

[0008] (II) Technical Solution To address the aforementioned problems in the prior art, this invention utilizes a rational combination of chenodeoxycholic acid or its pharmaceutically acceptable salts with heparin sodium to synergistically exert an anti-acne effect, filling the technological gap in existing anti-acne treatments that lack safety and low recurrence rates. This provides a topical composition for treating acne, and the use of a topical composition containing chenodeoxycholic acid or its pharmaceutically acceptable salts and heparin sodium in the preparation of acne treatment drugs.

[0009] The present invention aims to provide a topical composition for treating acne, comprising chenodeoxycholic acid or a pharmaceutically acceptable salt thereof and sodium heparin, wherein the mass percentage of chenodeoxycholic acid is 0.4% to 0.6% and the mass percentage of sodium heparin is 0.4% to 0.6%, wherein the mass percentage is a mass-volume ratio in g / mL.

[0010] According to the above-mentioned topical composition, the mass percentage of chenodeoxycholic acid is 0.4% and the mass percentage of heparin sodium is 0.6%.

[0011] According to the above-mentioned topical composition, the mass percentage of chenodeoxycholic acid is 0.5% and the mass percentage of heparin sodium is 0.5%.

[0012] According to the above-mentioned topical composition, the mass percentage of chenodeoxycholic acid is 0.6% and the mass percentage of heparin sodium is 0.4%.

[0013] According to the above-described topical composition, the topical composition is selected from gels or creams.

[0014] Another object of the present invention is to provide the use of a topical composition containing chenodeoxycholic acid or a pharmaceutically acceptable salt thereof and sodium heparin in the preparation of a medicament for treating acne.

[0015] According to the above uses, the mass percentage of chenodeoxycholic acid is 0.4%, and the mass percentage of heparin sodium is 0.6%.

[0016] According to the above uses, the mass percentage of chenodeoxycholic acid is 0.5%, and the mass percentage of heparin sodium is 0.5%.

[0017] According to the above uses, the mass percentage of chenodeoxycholic acid is 0.6%, and the mass percentage of heparin sodium is 0.4%.

[0018] According to the above-described uses, the drug is selected from gels or creams.

[0019] (III) Beneficial Effects The above-described technical solution of the present invention has the following advantages: (1) The chenodeoxycholic acid of the present invention acts directly on the sebaceous glands, reduces sebum secretion, improves sebum composition, and exerts anti-inflammatory effects to control the root cause of acne.

[0020] (2) The heparin sodium of the present invention alleviates inflammatory response, reduces scar formation, and improves the local tissue healing environment through anti-inflammatory and anti-fibrotic effects.

[0021] (3) The combined application of chenodeoxycholic acid and heparin sodium in the present invention showed significant superiority in the mouse acne model, achieving the triple effect of "anti-inflammatory + sebum secretion inhibition + skin repair improvement". The efficacy was significantly better than that of a single component. It not only controlled the inflammatory process of acne, but also reduced the risk of post-inflammatory pigmentation and scarring, thus improving the overall treatment effect and patient compliance.

[0022] (4) The composition of the present invention is for external use, avoiding systemic side effects caused by oral or injection, and the raw materials are safe. It has the potential to be developed into a drug or functional skin care product, meeting the market demand for mild and effective anti-acne products. Attached Figure Description

[0023] Figure 1 The changes in acne lesions in mice of different treatment groups on days 1, 3, and 5 after drug administration; Figure 2 This includes the acne lesion scores and statistical analysis for each treatment group; Figure 2 A shows the acne lesion scoring table and example images for different treatment groups on day 1 and day 3; Figure 2 B represents the total acne score for each group on day 1 and day 3. Figure 2 C represents the change in rating from day 1 to day 3. Figure 3 It is a scoring standard for acne lesions; Figure 4 These are images of acne lesions from different treatment groups acquired by the C-Cube system. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] The chenodeoxycholic acid of the present invention can be a naturally occurring compound or a synthetically produced compound.

[0026] The chemical formula of chenodeoxycholic acid is C1 24 H 40 O4, chemically named 3α,7α-dihydroxy-5β-cholanic acid, abbreviated as CDCA, has the following chemical structural formula: The topical composition of the present invention comprises chenodeoxycholic acid (CDCA) or a pharmaceutically acceptable salt thereof and sodium heparin, wherein the mass percentage of CDCA is 0.4% to 0.6% and the mass percentage of sodium heparin is 0.4% to 0.6%, wherein the mass percentage is a mass-volume ratio in g / mL.

[0027] The topical composition of the present invention is prepared by formulating phase A and phase B: phase A is a CMC-glycerol gel system composed of 1.5% sodium carboxymethyl cellulose (CMC), 5% glycerol and physiological saline; phase B is an active ingredient solution, in which heparin sodium is a ready-made preparation that does not require further processing and can be added according to the mass percentage; and the CDCA solution is prepared by adding CDCA of the appropriate concentration after adjusting the pH to 8.3, containing 18 mg benzyl alcohol, 2.84 mg disodium hydrogen phosphate, 8.76 mg sodium chloride and 2.86 mg sodium hydroxide per 1 mL.

[0028] Phase A and Phase B are mixed in proportion to obtain finished products of different concentrations. The pH is adjusted to the range of 6.0 to 7.0 to obtain a gel-type topical preparation. Specific Implementation To better understand the present invention, the following specific embodiments are provided to further explain or illustrate the content of the present invention, but these examples should not be construed as limiting the scope of protection of the present invention.

[0030] Example 1: Experimental Method 1.1 Drug Preparation Chenodeoxycholic acid (CDCA, CAS: 474-25-9, Macklin Biochemical Co., Ltd., Shanghai, China), purity ≥98%.

[0031] Heparin sodium (R28095, Yuanye Biotechnology Co., Ltd., CAS: 041-08-1, Shanghai, China) has a potency of 5000 IU / g and a purity of ≥98%.

[0032] CDCA solution preparation: Use water for injection as solvent. Each 1 mL of solution contains 18 mg benzyl alcohol, 2.84 mg disodium hydrogen phosphate, 8.76 mg sodium chloride, and 2.86 mg sodium hydroxide. Adjust the pH to 8.3, then add CDCA to the required concentration and mix well for later use.

[0033] Heparin sodium is a ready-made preparation, added according to a specified ratio.

[0034] The gel matrix consisted of sodium carboxymethyl cellulose (CMC, 1.5% w / w), glycerol (5% w / w), and physiological saline, and had no pharmacological activity. The final pH was adjusted to 6.0–7.0.

[0035] 1.2 Laboratory Animals Twenty-one male BALB / c mice (6–8 weeks old, weighing 20±2 g) were used in the experiment and housed in a controlled environment with a 12-hour light / dark cycle, provided with standard feed and free access to water.

[0036] 1.3 Establishment of an Acne Mouse Model The molding process includes the following steps: (i) Adaptive feeding: Mice were acclimatized for 7 days before the experiment; (ii) Hair removal: Hair removal on the back is performed one day before the model is made. First, use an electric shaver to remove most of the hair, and then use hair removal cream to remove the remaining hair to avoid skin damage. (iii) Preparation of artificial sebum: Artificial sebum was prepared on the day of modeling, with the following composition ratio: oleic acid (O815202, Macklin, China) 17%, trioleic acid glycerides (G810388, Macklin, China) 45%, jojoba oil (J885960, Macklin, China) 25%, and squalene (S817864, Macklin, China) 13%; (iv) C. acnes Intradermal injection and sebum application: Four fixed sites were selected on both sides of the spine on the back of mice for intradermal injection. C. acnes The suspension (concentration according to the experimental protocol) was injected for 3 consecutive days at an OD concentration of 0.5, and artificial sebum was evenly applied to the injection site daily to promote the formation of acne-like lesions.

[0037] 1.4 Experimental Grouping and Drug Treatment After modeling, the mice were randomly divided into 7 groups (n = 3 per group): blank group (smeared with blank gel), model group (smeared with physiological saline), CDCA single treatment group, heparin sodium single treatment group, 6:4 group, 4:6 group, and 5:5 group.

[0038] Prepare 100 mL of topical gel for each group. The specific groups and dosage designs are shown in the table below: The combined gel was prepared according to the ratio of CDCA to heparin sodium. Preparation method: First, prepare phase A (CMC 1.5%, glycerol 5%, physiological saline) as the gel matrix, then add phase B (CDCA solution and heparin sodium solution) and mix well.

[0039] Administration: Apply evenly to the acne lesions on the back of mice twice daily for 5 consecutive days.

[0040] 1.5 Imaging observation and recording Multimodal imaging of acne lesions on the back of mice was performed on the first, third, and fifth days after modeling: (1) Standard photography: used to record macroscopic changes in acne lesions; (2) C-Cube system imaging: including standard images, three-dimensional surface topography maps and color depth maps, used to assess skin undulations and lesion protrusions.

[0041] Example 2: Experimental Results 2.1 Changes in acne lesions on the back of mice from day 1 to day 5 Figure 1 The images show the changes in the appearance of acne lesions on the backs of mice in different treatment groups on days 1, 3, and 5 after drug administration. Red circles indicate typical acne lesions, and the right side shows a magnified image of the corresponding lesion.

[0042] Figure 1 The observation results showed that the severity of acne lesions was basically the same in all groups on the first day of drug administration, manifesting as obvious papules and inflammatory reactions. By the third day, the improvement of acne in the combination drug group was significantly better than that in the single drug group, and the CDCA:heparin sodium = 6:4 group showed the most outstanding efficacy, with a significant reduction in lesion area and degree of inflammation; the 5:5 group was second, followed by the 4:6 group. The CDCA and heparin sodium single drug groups showed slower improvement, and the model group showed no significant relief. By the fifth day, the acne in the 6:4 group had basically recovered, and the other combination groups were also close to complete healing, while residual lesions were still visible in the single drug groups. Overall, the observation showed that the most obvious effect was observed on the third day.

[0043] 2.2 Acne lesion scoring and statistical analysis The severity of acne was evaluated using the clinical scoring criteria of the reference Nat Commun. 2023;14(1):1005.doi: 10.1038 / s41467-023-36694-8. Topical phage therapy in a mouse model of Cutibacterium acnes-induced acne-like lesions. Six typical acne lesions were selected from the back of each mouse. Scoring was performed based on the diameter of the lesions, the degree of elevation, and the condition of the eschar. The indicators on day 1 and day 3 were recorded, and the total score and the mean within the group were calculated.

[0044] Figure 3 The scoring is based on the diameter of the acne lesion, the degree of elevation (double-blind assessment), the condition of the eschar (double-blind assessment), and the histological features, each assigned a score of 0–3. The final total score is obtained by summing up the scores of each lesion and is used to reflect the severity of the lesion.

[0045] Figure 2 The results showed that from day 1 to day 3, the lesion scores in the model group did not decrease and even increased slightly; the blank control group, due to the use of a glycerin-containing matrix, experienced some relief of acne, with better improvement than the model group.

[0046] In the treatment groups, the 6:4 combined formulation group showed the largest decrease in total score, indicating the best repair effect; followed by the 5:5 group, and then the 4:6 group; the CDCA monotherapy group and the heparin sodium monotherapy group showed the slowest improvement, with the heparin sodium monotherapy group showing the worst effect. The statistical results are consistent with the image observations, showing that combined medication has a significant advantage over monotherapy, and different ratios affect the efficacy, with the 6:4 group exhibiting the optimal formulation characteristics.

[0047] 2.3 C-Cube Imaging Results The C-Cube system was used to acquire images of acne lesions in mice in different treatment groups on the first and third days. Three image modes were displayed for each group: (1) Standard image: showing the appearance of the lesion surface; (2) Three-dimensional morphological reconstruction image: showing the undulation of the skin surface; (3) Color depth image: reflecting the degree of lesion protrusion, with red areas indicating higher elevation and blue-green areas indicating flatness or depression.

[0048] The C-Cube system was used to perform high-resolution imaging of typical acne lesions, generating standard images, three-dimensional skin surface morphology maps, and color depth maps, which visually presented the degree of lesion elevation and surface unevenness.

[0049] Figure 4The results showed that the imaging trends of each group on Day 3 were consistent with the scoring results: the 6:4 combination therapy group showed the most significant decrease in lesion elevation, with the surface appearing smoother in 3D images and a significant reduction in high-convex areas in the color depth map; the 5:5 and 4:6 groups followed, while the single-drug groups showed relatively limited changes. These results further validated the superiority of the combination therapy regimen.

[0050] The above experimental results show that the combined topical application of chenodeoxycholic acid (CDCA) and heparin sodium exhibits significant superiority in a mouse acne model. The combined group is significantly better than either CDCA or heparin sodium alone in improving acne lesions, and different ratios show different therapeutic effects. Among them, the CDCA:heparin sodium = 6:4 formulation is the most outstanding in terms of repair speed and degree of acne improvement. By the 3rd day of administration, the diameter, elevation, and eschar condition of the lesions in the formulation group have significantly improved, and by the 5th day, they have almost completely recovered. In contrast, the improvement in the single-drug group is slow, and the condition in the model group has even worsened.

[0051] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. An external composition for treating acne, comprising chenodeoxycholic acid or a pharmaceutically acceptable salt thereof and sodium heparin, wherein the mass percentage of chenodeoxycholic acid is 0.4% to 0.6% and the mass percentage of sodium heparin is 0.4% to 0.6%, the mass percentage being g / mL.

2. The external composition according to claim 1, wherein the mass percentage of chenodeoxycholic acid is 0.4% and the mass percentage of sodium heparin is 0.6%.

3. The external composition according to claim 1, wherein the mass percentage of chenodeoxycholic acid is 0.5% and the mass percentage of sodium heparin is 0.5%.

4. The external composition according to claim 1, wherein the mass percentage of chenodeoxycholic acid is 0.6% and the mass percentage of sodium heparin is 0.4%.

5. The external composition according to claims 1 to 4, which is selected from the group consisting of a gel or a cream.

6. Use of the external composition according to claim 1 for the manufacture of a medicament for treating acne.

7. The use according to claim 6, wherein the mass percentage of chenodeoxycholic acid is 0.4% and the mass percentage of sodium heparin is 0.6%.

8. The use according to claim 6, wherein the mass percentage of chenodeoxycholic acid is 0.5% and the mass percentage of sodium heparin is 0.5%.

9. The use according to claim 6, wherein the mass percentage of chenodeoxycholic acid is 0.6% and the mass percentage of sodium heparin is 0.4%.

10. The use according to claims 6 to 9, which is selected from the group consisting of a gel or a cream.

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