Application of ursodesoxychoberberine in preparation of medicine for preventing and / or relieving and / or treating pulmonary fibrosis
By studying the anti-inflammatory and metabolic regulatory properties of ursodeoxycholic acid, it was found that it can significantly inhibit pulmonary fibrosis. It was prepared into various dosage forms for treatment, filling the gap in the treatment of pulmonary fibrosis in the existing technology and achieving significant inhibition and improvement effects.
Patent Information
- Application Number
- CN202511892602.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-16
- Publication Date
- 2026-01-27
AI Technical Summary
Current technologies have not effectively utilized the anti-inflammatory and comprehensive metabolic regulation properties of ursodeoxycholic acid, have failed to effectively inhibit the progression of pulmonary fibrosis, and lack corresponding treatment methods.
Using ursodeoxycholic acid as the active ingredient, its role in inhibiting pulmonary fibrosis was studied through in vivo and in vitro experiments. It was found that it can significantly inhibit the progression of pulmonary fibrosis, and its inhibitory effect is dose-dependent. It was prepared into drug formulations in various dosage forms for prevention and treatment.
Ursodeoxycholic acid significantly improves inspiratory volume, tidal volume, and expiratory reserve volume, reduces collagen deposition, and improves pathological damage to lung tissue, demonstrating a good anti-pulmonary fibrosis effect. In particular, the high-dose group is superior to the existing drug pirfenidone.
Smart Images
Figure CN121401271A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to the use of ursodeoxycholic acid in the preparation of drugs for the prevention and / or relief and / or treatment of pulmonary fibrosis. Background Technology
[0002] Ursodeoxycholic acid berberine (HTD1801, BU) is a globally innovative molecular entity formed by ursodeoxycholic acid and berberine through ionic bonds. It targets the gut-hepatic system through a dual mechanism of activating AMPK and inhibiting the NLRP3 inflammasome, exerting anti-inflammatory and comprehensive metabolic regulatory effects. Its research and development progress mainly focuses on indications such as type 2 diabetes mellitus (T2DM) and metabolic-associated steatohepatitis (MASH). (1) In the treatment of type 2 diabetes mellitus (TDM): HTD1801 met the primary efficacy endpoint and multiple secondary endpoints in two Phase III clinical trials (SYMPHONY1 and SYMPHONY2) in China. Studies have shown that after 24 weeks of treatment, HTD1801 can significantly reduce glycated hemoglobin (HbA1c) by 1.2%-1.3%, and can improve blood lipids (such as reducing LDL-C) and reduce inflammation (such as reducing hs-CRP), demonstrating the characteristics of "one drug with multiple effects". Based on these positive data, Junshengtai Pharmaceutical plans to submit a New Drug Application (NDA) to the National Medical Products Administration (NMPA) in 2025.
[0003] (2) Regarding other metabolic diseases: HTD1801 has demonstrated efficacy in the Phase IIa study of MASH, and its global multicenter Phase IIb clinical trial results are expected to be released in 2025. Simultaneously, studies also suggest its therapeutic potential in weight loss, severe hypertriglyceridemia (SHTG), and primary sclerosing cholangitis (PSC). In terms of safety, HTD1801 is well-tolerated, with the most common adverse reactions being gastrointestinal reactions, and a low risk of hypoglycemia. Overall, HTD1801, as a multi-target drug with a novel mechanism of action, shows the potential to provide comprehensive benefits in the treatment of metabolic diseases. Its development is progressing smoothly, and its application for marketing authorization in the T2DM indication is nearing completion.
[0004] Pulmonary fibrosis is a chronic, progressive, fibrotic interstitial lung disease characterized by abnormal repair of lung tissue after repeated injury. This leads to the replacement of normal alveolar structures with scar tissue (fibrous connective tissue), resulting in hardening of the lungs and severe impairment of gas exchange. This disease is extremely harmful, causing progressively worsening dyspnea and persistent dry cough, severely impacting patients' quality of life. It can also lead to hypoxemia, potentially causing respiratory failure. Furthermore, pulmonary fibrosis significantly increases the risk of pulmonary hypertension, pulmonary heart disease, and even lung cancer, posing a serious threat to life. In terms of pathogenesis, inflammation is a key driver of pulmonary fibrosis. Multiple factors can activate immune cells, triggering inflammatory responses and releasing pro-inflammatory factors. This inflammatory microenvironment stimulates fibroblast activation and proliferation, thereby driving fibrosis formation. Metabolic reprogramming also plays a crucial role. Studies have found a metabolic imbalance in pulmonary fibrosis, characterized by enhanced glycolysis and weakened fatty acid oxidation. This metabolic shift disrupts extracellular matrix homeostasis, promoting fibrosis development.
[0005] Given the significant anti-inflammatory and comprehensive metabolic regulation activities demonstrated by ursodeoxycholic acid (BU), and considering the current lack of research on its application in the treatment of pulmonary fibrosis, expanding the application of BU in pulmonary fibrosis treatment has important scientific research significance and clinical translational value. This study systematically evaluates the inhibitory effect of BU on the progression of pulmonary fibrosis through in vivo and in vitro experiments, aiming to explore its mechanistic molecules and provide a theoretical basis and experimental evidence for developing new strategies for the treatment of pulmonary fibrosis with BU. Summary of the Invention
[0006] To comprehensively address the aforementioned problems, this invention proposes the use of ursodeoxycholic acid in the preparation of drugs for the prevention and / or alleviation and / or treatment of pulmonary fibrosis. Through research, this invention has found that ursodeoxycholic acid can significantly inhibit the progression of pulmonary fibrosis, and its inhibitory effect exhibits a clear dose-dependent relationship. To assess the degree of pulmonary fibrosis and the therapeutic effect, multiple indicators were analyzed. Compared with the model group, the above indicators were significantly improved in both the low-dose and high-dose ursodeoxycholic acid groups, with the high-dose group showing the best effect, especially in improving mouse body weight; the high-dose ursodeoxycholic acid group was significantly superior to the pirfenidone (PFD) positive drug group. These results demonstrate the promising development potential of ursodeoxycholic acid as a candidate drug for anti-pulmonary fibrosis.
[0007] To achieve the above objectives, the first aspect of the present invention provides the use of ursodeoxycholic acid in the preparation of medicaments for the prevention and / or relief and / or treatment of pulmonary fibrosis.
[0008] A second aspect of the present invention provides an formulation for the prevention and / or relief and / or treatment of pulmonary fibrosis, said formulation containing ursodeoxycholic acid.
[0009] Preferably, the formulation further includes one or more of a pharmaceutically acceptable carrier, excipients, and excipients.
[0010] Preferably, the dosage form of the preparation includes, but is not limited to, capsules, granules, tablets, pills, sprays, suppositories, aerosols, powder inhalers, patches, oral liquids, or injections.
[0011] Preferably, the preparation is any one of a drug, a drug composition, a health product, a food, or an additive.
[0012] Compared with the prior art, the beneficial effects of the present invention are: This invention proposes the use of ursodeoxycholic acid (BU) in the preparation of drugs for the prevention and / or alleviation and / or treatment of pulmonary fibrosis. Through research, this invention has found that BU can significantly inhibit the progression of pulmonary fibrosis, and its inhibitory effect exhibits a clear dose-dependent relationship. Studies have shown that both low-dose and high-dose BU groups significantly improved inspiratory volume, tidal volume, and expiratory reserve volume, with the high-dose group showing the best effect. Particularly in improving mouse body weight, the high-dose BU group was significantly superior to the pirfenidone (PFD) positive drug group. Pathological results showed that alveolar structure was better maintained and collagen deposition was reduced after BU intervention, thus confirming the positive therapeutic effect of BU in reducing pulmonary edema, inhibiting collagen production, and improving pathological damage in lung tissue. These results demonstrate the promising development potential of ursodeoxycholic acid as a candidate drug for anti-pulmonary fibrosis. Attached Figure Description
[0013] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof.
[0014] In the attached diagram: Figure 1 Body weight results in mice with ursodeoxycholic acid-based anti-pulmonary fibrosis treatment; Figure 2 a) Lung weight and b) Lung coefficient in ursodeoxycholic acid-resistant pulmonary fibrosis mice; Figure 3 Lung function test results of ursodeoxycholic acid in the treatment of pulmonary fibrosis: a) inspiratory volume, b) tidal volume, and c) expiratory volume reserve; Figure 4 Phenotypic and pathological results of the lungs in mice with pulmonary fibrosis after BU intervention (A. Phenotypic results of mouse lungs; B. HE staining results of mouse lungs; C. MASSON staining results of mouse lungs). Figure 5 Principal component analysis of three groups of differentially expressed proteins; Figure 6Partial least squares discriminant analysis of three groups of differentially expressed proteins; Figure 7 Enrichment analysis of three groups of differentially expressed proteins; Figure 8 Expression levels of the differentially expressed protein Itga3 in three groups of lung tissues. Detailed Implementation
[0015] The following combination Figures 1-8 The preferred embodiments of the present invention are described herein. It should be understood that the preferred embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the materials, reagents, etc., used in the following embodiments are commercially available. The following embodiments are provided to better understand the present invention, but do not limit the present invention. Example 1
[0016] Use of ursodeoxycholic acid in the preparation of drugs for the prevention and / or relief and / or treatment of pulmonary fibrosis. Example 2
[0017] A formulation for the prevention and / or relief and / or treatment of pulmonary fibrosis, the formulation containing ursodeoxycholic acid berberine. The formulation further includes one or more pharmaceutically acceptable carriers, excipients, and excipients. The dosage form of the formulation includes, but is not limited to, capsules, granules, tablets, pills, sprays, suppositories, aerosols, powder inhalers, patches, oral liquids, or injections. The formulation is any one of a drug, pharmaceutical composition, health product, food, or additive.
[0018] Experimental procedure: 1. Constructing an animal model of pulmonary fibrosis A pulmonary fibrosis model was established by intratracheal infusion of bleomycin (2 U / kg).
[0019] 1.1 Grouping: Eight-week-old male C57 mice, weighing 20-22g, were used and divided into a blank control group, a model group, a low-dose BU group (2.5mg / kg), a high-dose BU group (5mg / kg), and a pirfenidone (PFD) positive drug group, with six mice in each group.
[0020] 1.2 Experimental Procedure: Mice were placed in an animal room at a temperature of 22±2℃ and a humidity of 55±5%, with a 12h / 12h light-dark cycle for one week for acclimatization. Mice in all groups except the control group were induced into a bleomycin model via tracheal instillation (2U / kg): Mice anesthetized with isoflurane (Shanghai Abbott Laboratories Co., Ltd.) were placed in an upright position, their trunks gently held, and a surgical suture was wrapped around the upper incisors and fixed to both ends of a self-made manipulator to keep the mouth open. The tongue was gently pulled back with sterile forceps to expose the tracheal inlet under direct vision, and 50μl of bleomycin (2U / kg) solution was slowly instilled. After instillation, the mice were kept upright for 1 minute to allow the drug to distribute evenly in the lungs. The mice were then returned to their cages, and their respiratory rate and activity level were closely monitored.
[0021] On day 1 after modeling, BU was dissolved in 5% DMSO, 30% PEG300, 5% Tween-80, and 60% PBS, respectively. Ursodeoxycholic acid berberine (BU, TargetMol / Tao Shu; catalog number: T67974) was administered intraperitoneally in both low-dose and high-dose groups (100 μl / mouse). Pirfenidone (PFD) was administered by gavage in the positive control group (100 μl / mouse). The blank control group was administered intraperitoneally in a blank solvent composed of 5% DMSO, 30% PEG300, 5% Tween-80, and 60% PBS. Administration continued for 14 days, and daily body weight was measured. On day 15 after administration, mice were weighed and had their lung function tested. Animals were then sacrificed, serum was collected, organ weights were measured, and organ indices were recorded. Simultaneously, a portion of the lungs was fixed, sectioned, and stained with hematoxylin and eosin (HE).
[0022] 1.3 Experimental Results: In vivo experiments showed that compound BU significantly inhibited the progression of pulmonary fibrosis, and its inhibitory effect exhibited a clear dose-dependent relationship. To assess the severity of pulmonary fibrosis and the therapeutic effect, we analyzed several indicators. Compared with the control group, the body weight of mice in the model group ( Figure 1 ), inhalation volume ( Figure 3 a) Tidal volume ( Figure 3 (b) and expiratory volume (EV) Figure 3 The lung weight (c) was significantly lower than that of the blank control group. Figure 2 a) and lung coefficient ( Figure 2 Both (b) were significantly elevated, lung weight and lung coefficient were significantly higher than in the blank control group, and typical pathological features of pulmonary fibrosis such as alveolar structure destruction and massive collagen deposition were observed. Figure 4 , Figure 4 A. Phenotypic results of mouse lungs; Figure 4 HE staining results of lungs in mice (B12). Figure 4 (Results of MASSON staining of mouse lungs). In vivo experiments confirmed successful model establishment.
[0023] After treatment, compared with the model group, the above-mentioned indicators in both the low-dose and high-dose BU groups were significantly improved, with the high-dose group showing the best effect. Particularly in improving mouse body weight, the high-dose BU group was significantly superior to the pirfenidone (PFD) positive drug group. Pathological results showed that alveolar structure was better maintained and collagen deposition was reduced after BU intervention, thus confirming the positive therapeutic effect of BU in reducing pulmonary edema, inhibiting collagen production, and improving lung tissue pathological damage. These results demonstrate the promising development potential of BU as a candidate drug for anti-pulmonary fibrosis.
[0024] 2. Proteomic analysis of lung tissue samples 2.1 Sample pretreatment: Sample pretreatment includes protein extraction, denaturation, reductive alkylation, enzymatic digestion, and peptide desalting. This project used iST sample pretreatment reagents (PreOmics, Germany) to pretreat lung tissue sample proteins. An appropriate amount of lung tissue sample protein was taken, and 50 μL of lysis buffer was added. The mixture was heated at 95°C and 1000 rpm for 10 min. After cooling to room temperature, trypsin digestion buffer was added, and the mixture was incubated at 37°C and 500 rpm for 2 h with shaking. The enzymatic digestion reaction was terminated by adding stop buffer. Peptide desalting was performed using the iSTcartridge kit, followed by elution with 2 × 100 µL of elution buffer. The eluted peptides were then vacuum-dried and stored at -80°C.
[0025] 2.2 DIA Data Acquisition: The desalted lyophilized peptides were reconstituted in phase A (0.1% formic acid aqueous solution) and then analyzed by LC-MS / MS. The entire system was an Orbitrap Astral mass spectrometer (Thermo Fisher Scientific, MA, USA) equipped with FAIMS and a Vanquish NeoUHPLC ultra-high performance liquid chromatography system in series. A total of 200 ng of sample (AUR3-15075C18 analytical column: 15 cm × 75 μm·d, 1.7 μm particle size, IonOpticks) was loaded, and the sample was separated by a gradient of 8 min at a column temperature of 50°C. The gradient started with 8% of phase B (80% acetonitrile and 0.1% formic acid), increased to 15% at a flow rate of 700 nL / min over 1 min, increased to 40% at a flow rate of 400 nL / min over 5.5 min, increased to 99% at a flow rate of 700 nL / min over 0.5 min, and maintained at a flow rate of 1000 nL / min for 1 min.
[0026] The mass spectrometer was operated in data-independent acquisition (DIA) mode, and the mass spectrometry parameters were set as follows: (1) Orbitrap: scan range (m / z): 380-980; resolution: 240K; normalized AGC target: 500%; maximum injection time: 3 ms; (2) Astral: Precursor Massrange (m / z): 380-980; normalized AGC target: 500%; maximum injection time: 3ms; collision energy: 25%, isolationWindow: 2m / z, WindowOverlap: 0; loop time: 0.6s. FAIMS CV: -42.
[0027] 2.3 Database Retrieval: DIA data were analyzed using Spectronaut20 with default parameters (BGSFactory Settings (default)). The sequence database was uniprot-Mus musculus (version 2025, 21701 entries), and Trypsin digestion was set. Search parameters were fixed with Carbamidomethylation (C) 57.02 and variable with Oxidation (M) 15.9 and Acetyl (protein N-term) 42.01. The iRT peptide software automatically corrected retention time and quality windows, automatically determining the ideal extraction window. Protein qualitative standards were: Precursor Threshold 1.0% FDR, Peptide Threshold 1.0% FDR, and Protein Threshold 1.0% FDR. The Decoy database was generated using a mutated strategy, similar to shuffling a random number of amino acid sequences (at least 2 amino acids, up to half the total length of the polypeptide). Spectronaut performed automatic correction and used a local normalization strategy for data normalization. Peptides with less than 1.0% FDR were quantified using MaxLFQ for protein group analysis.
[0028] This invention utilizes proteomics analysis of lung tissue samples to identify differentially expressed proteins through principal component analysis (PCA). Figure 5 ) and Partial Least Squares Discriminant Analysis (PLS-DA) Figure 6The results showed a good separation trend among the normal group, model group, and high-dose BU group. The high-dose BU group was positioned closer to the normal group and farther from the model group in the score plot, suggesting that BU intervention may have caused the protein expression profile to revert from the model state towards the normal direction. Further KEGG enrichment analysis (…) Figure 7 The results showed that the anti-pulmonary fibrosis effect of BU was significantly correlated with signaling pathways related to extracellular matrix (ECM) deposition (P < 0.001), mainly involving cytoskeleton in muscle cells, tight junction, Focal adhesion, regulation of actin cytoskeleton, and the chemokine signaling pathway. Notably, the differentially expressed protein Itga3 was enriched in multiple of these pathways and may play a key role in the development and progression of pulmonary fibrosis. Proteomics data showed that Itga3 expression was significantly downregulated in the model group, while its expression was significantly upregulated after BU intervention. Figure 8 The above results suggest that BU may alleviate the progression of pulmonary fibrosis by upregulating Itga3 levels to inhibit excessive ECM deposition.
[0029] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.
Claims
1. Use of ursodeoxycholic acid in the preparation of drugs for the prevention and / or relief and / or treatment of pulmonary fibrosis.
2. An agent for the prevention and / or relief and / or treatment of pulmonary fibrosis, characterized in that, The formulation contains ursodeoxycholic acid.
3. The formulation according to claim 2, characterized in that, The formulation also includes one or more of pharmaceutically acceptable carriers, excipients, and excipients.
4. The formulation according to claim 3, characterized in that, The dosage forms of the preparations include, but are not limited to, capsules, granules, tablets, pills, sprays, suppositories, aerosols, powder inhalers, patches, oral liquids, or injections.
5. The formulation according to claim 4, characterized in that, The preparation is any one of a drug, a drug composition, a health product, a food, or an additive.