Use of sulfasalazine in the preparation of a drug for treating primary biliary cholangitis which is poorly responsive to ursodeoxycholic acid

Abstract

The application relates to the medical technical field, in particular to application of sulfasalazine in preparation of a medicine for treating primary biliary cholangitis (PBC) which is poorly responsive to ursodeoxycholic acid (UDCA), aiming at the clinical problem that about 40% of PBC patients are poorly responsive to the first-line drug UDCA, have high disease progression risk and limited second-line treatment options, and providing a new treatment use of the mature drug sulfasalazine. Through prospective clinical research, it is confirmed that, on the basis of UDCA standard treatment, combined use of sulfasalazine (1.5g / day, a treatment course of 48 weeks) can significantly improve liver biochemical indexes of UDCA non-responders, including alkaline phosphatase and gamma-glutamyltransferase, and 62.5% of the patients reach composite biochemical response. The application provides a new, effective, safe and highly accessible second-line treatment strategy for PBC patients who are poorly responsive to UDCA, and has a good clinical application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to the use of sulfasalazine in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid. Background Technology

[0002] Primary biliary cholangitis (PBC) is a chronic, progressive, autoimmune cholestatic liver disease characterized by immune-mediated destruction of intrahepatic small bile ducts. In untreated or improperly treated patients, the disease progresses to liver fibrosis, cirrhosis, and decompensated liver function, ultimately requiring liver transplantation or leading to death. PBC is significantly more prevalent in women than men, with a female-to-male ratio of approximately 9:1, and patients are typically diagnosed between the ages of 40 and 60.

[0003] According to international guidelines, the diagnosis of PBC is based on meeting at least two of the following three criteria: (1) abnormal biochemical markers reflecting cholestasis, primarily elevated alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT); (2) positive serum anti-mitochondrial antibody (AMA); and (3) histological examination of the liver indicating non-suppurative destructive cholangitis. Serum ALP levels are a key biomarker for assessing disease activity, treatment response, and long-term prognosis. Any persistent elevation in ALP levels is associated with a significantly increased risk of adverse clinical outcomes, such as liver transplantation and death.

[0004] Undextrinsic liver enzymes (UDCAs) have been approved by regulatory agencies worldwide for decades as first-line treatment for peripheral blood cancer (PBC). UDCAs can improve liver biochemical parameters, slow histological progression, and improve transplant-free survival. However, up to 40% of PBC patients do not respond adequately to UDCA treatment. Furthermore, up to 5% of PBC patients are intolerant to UDCAs. Currently, second-line treatments such as obeticholic acid (OCA) were withdrawn from the market in Europe and the United States between 2024 and 2025 due to post-marketing studies demonstrating a serious risk of liver injury and a lack of confirmed clinical benefit. The efficacy stability and long-term tolerability of fibrates and novel peroxisome proliferator-activated receptor (PPAR) agonists (such as Elafibranor) still require further validation. Therefore, developing a novel second-line treatment regimen with proven efficacy, good safety, and high clinical accessibility for PBC patients with poor UDCA response has become a critical issue urgently needing to be addressed in current clinical practice.

[0005] Sulfasalazine (SASP) is a prodrug with antibacterial, anti-inflammatory, and immunosuppressive activities. It is currently used clinically, either alone or in combination with other drugs, to treat various diseases, including inflammatory bowel disease, rheumatoid arthritis, and skin diseases. Its mechanism of action involves inhibiting the production of cytokines, prostaglandins, and leukotrienes, and reducing leukocyte adhesion and function. SASP parent compound and its metabolite, 5-aminosalicylic acid (5-ASA), can inhibit immune activity in multiple ways by suppressing lymphocyte production, activation, and differentiation. Furthermore, 5-ASA has strong antioxidant properties and can act directly as an antioxidant and free radical scavenger.

[0006] Currently, there are no reports on the use of sulfasalazine (SASP) for the treatment of polycystic pulmonary angina (PBC). In particular, for patients with refractory PBC who do not respond well to standard UDCA therapy, there is a lack of effective second-line treatment options, and no studies have revealed whether SASP has therapeutic potential for this specific patient subgroup. Therefore, this invention aims to provide a novel use of sulfasalazine in the preparation of drugs for treating PBC that do not respond well to UDCA. Summary of the Invention

[0007] The purpose of this invention is to provide the application of sulfasalazine in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid. SASP combined with UDCA can effectively treat PBC patients with poor response to UDCA, significantly improve their liver biochemical indicators, and has a high biochemical response rate and good safety.

[0008] To achieve the above objectives, the present invention provides the use of sulfasalazine in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, wherein sulfasalazine or a pharmaceutically acceptable salt thereof is used in the preparation of a pharmaceutical composition for treating primary biliary cholangitis with poor response to ursodeoxycholic acid.

[0009] The pharmaceutical composition is administered in combination with ursodeoxycholic acid.

[0010] The definition of poor response to ursodeoxycholic acid is: in patients with primary biliary cholangitis, after continuous treatment with ursodeoxycholic acid at a dose of 13-15 mg / kg / day for at least 12 months, their serum alkaline phosphatase level is still higher than 1.67 times the upper limit of normal.

[0011] The daily dose of sulfasalazine is 0.5g to 3.0g.

[0012] The daily dose of sulfasalazine is 1.5g, administered orally in divided doses.

[0013] The pharmaceutical composition is used to prepare an oral formulation, which is selected from tablets, capsules, granules or enteric-coated formulations.

[0014] Among them, a composite biochemical response was achieved at week 48 of combined therapy.

[0015] The composite biochemical response refers to the simultaneous fulfillment of the following conditions: Condition 1: Serum alkaline phosphatase level ≤ 1.67 times the upper limit of normal; Condition 2: Serum alkaline phosphatase level decreased by ≥15% compared to baseline; Condition 3: Serum total bilirubin level ≤ upper limit of normal.

[0016] The present invention also provides a pharmaceutical composition comprising sulfasalazine and ursodeoxycholic acid for the treatment of primary biliary cholangitis with poor response to ursodeoxycholic acid.

[0017] The pharmaceutical composition is prepared into an oral dosage form.

[0018] This invention relates to the application of sulfasalazine in the preparation of a drug for treating primary biliary cholangitis (PBC) with poor response to ursodeoxycholic acid (UDCA). Addressing the clinical challenge of approximately 40% of PBC patients having poor response to first-line UDCA, a high risk of disease progression, and limited second-line treatment options, this invention provides a novel therapeutic use for the established drug sulfasalazine. Prospective clinical studies have demonstrated that the combined use of sulfasalazine (1.5 g / day for 48 weeks) with standard UDCA treatment significantly improves liver biochemical parameters, including alkaline phosphatase (ALP) and gamma-glutamyl transferase (γ-GGT), in patients with poor UDCA response, and achieves a composite biochemical response in 62.5% of patients. This invention provides a novel, effective, safe, and accessible second-line treatment strategy for PBC patients with poor UDCA response, and has promising clinical application prospects. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of this application or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0020] Figure 1 The present invention provides a schematic diagram of the composite biochemical response rate, ALP normalization rate, and individual ALP changes when sulfasalazine is used to treat patients with primary biliary cholangitis who have poor response to ursodeoxycholic acid.

[0021] Figure 2 This diagram illustrates the changes in key liver biochemical indicators and the stratified comparison of responders / non-responders during SASP combination therapy.

[0022] Figure 3 This is a schematic diagram illustrating the dynamic changes in serum markers related to the intestinal barrier and FGF19 levels.

[0023] Figure 4 This is a schematic diagram illustrating the dynamic changes of key bacterial genera / species during SASP treatment.

[0024] Figure 5 A schematic diagram comparing the characteristics of key bacterial species in patients with different treatment outcomes. Detailed Implementation

[0025] Exemplary embodiments will now be described in detail, examples of which are illustrated in the accompanying drawings. When the following description relates to the drawings, unless otherwise indicated, the same numbers in different drawings represent the same or similar elements. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with this application.

[0026] The terminology used in this application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. The singular forms “a,” “the,” and “the” used in this application and the appended claims are also intended to include the plural forms unless the context clearly indicates otherwise. It should also be understood that the term “and / or” as used herein refers to and includes any or all possible combinations of one or more of the associated listed items.

[0027] It should be understood that although the terms first, second, third, etc., may be used in this application to describe various information, such information should not be limited to these terms. These terms are only used to distinguish information of the same type from one another. For example, without departing from the scope of this application, first information may also be referred to as second information, and similarly, second information may also be referred to as first information. Depending on the context, the word "if" as used herein may be interpreted as "when," "when," or "in response to determination."

[0028] The present invention provides the use of sulfasalazine or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating primary biliary cholangitis that is poorly responsive to ursodeoxycholic acid, said pharmaceutical composition being administered in combination with ursodeoxycholic acid.

[0029] Eight patients with primary biliary cholangitis (PBC) who met the international diagnostic criteria and had an inadequate response (serum alkaline phosphatase ALP > 1.67 × upper limit of normal ULN) after at least 12 months of treatment with ursodeoxycholic acid (UDCA, 13-15 mg / kg / day) were selected. In addition to maintaining the original UDCA dose, sulfasalazine enteric-coated tablets were added, 1.5 g orally daily in divided doses, for 48 weeks.

[0030] Patients were followed up and assessed before treatment (week 0, W0), at week 24 (W24), and at week 48 (W48), and liver biochemical markers, including ALP, gamma-glutamyl transferase (γ-GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and total bile acids (TBA), were measured. Serum intestinal barrier-related markers, including diamine oxidase (DAO), lipopolysaccharide (LPS), D-lactic acid, and fibroblast growth factor 19 (FGF19) levels, were also measured. Fecal samples were collected for metagenomic analysis, with a good UDCA response group (B0) included as a reference control. Changes in key bacterial genera and species before and after SASP treatment were compared, and further stratified analysis was performed based on whether a composite biochemical response was achieved at week 48.

[0031] The changes in liver biochemical parameters before and after treatment are shown in Table 1. The results showed that after 48 weeks of treatment, serum ALP, ALT, and AST levels were significantly lower than baseline (P<0.05), and γ-GGT levels also showed a significant decreasing trend (P<0.05), indicating a significant improvement in intrahepatic cholestasis and hepatocellular damage. The combined biochemical response and ALP normalization status are shown in Table 1. Figure 1 As shown in Figure A, the vertical axis represents the percentage of patients (%), and the horizontal axis represents the treatment time (week 4, week 12, week 24, week 36, and week 48). Purple bars represent the composite biochemical response rate, and blue bars represent the ALP normalization rate. Values ​​above the bars represent the corresponding percentages, and scores within the bars represent the number of patients achieving the standard / total number of patients. By week 48, 62.5% (5 / 8) of patients had achieved the composite biochemical response standard, with 25% (2 / 8) of these patients having their ALP levels return to normal. The percentage change in ALP levels from baseline to week 48 for individual patients is shown in Figure A. Figure 1 As shown in Figure B, the vertical axis represents the percentage change in alkaline phosphatase (ALP) from baseline, and the horizontal axis represents different patient numbers. The dashed line represents the response threshold of a 15% decrease in ALP. All patients experienced a decrease in ALP from baseline, with 87.5% (7 / 8) of patients showing a decrease of more than 15%. The dynamic changes of key liver biochemical indicators at different time points are shown in Figure B. Figure 2 As shown, the indicators exhibit a continuous improvement trend with prolonged treatment. The upper part is a bar chart, representing the overall changes in key liver biochemical indicators (including ALP, ALT, AST, and γ-GGT) at baseline, week 24, and week 48; the lower part is a line graph, representing the individual follow-up trend after stratification by treatment outcome. In the line graph, red lines represent patients who did not achieve a composite biochemical response at week 48 of treatment, while blue lines represent patients who achieved a biochemical response at week 48 of treatment.

[0032] Further analysis of intestinal barrier-related serum markers and FGF19 levels, such as Figure 3As shown in the figure, the serum D-lactic acid, diamine oxidase (DAO), lipopolysaccharide (LPS), and FGF19 levels were measured at baseline (week 0), week 24, and week 48. Different colored bars represent data at different follow-up time points (baseline, week 24, and week 48); dashed lines represent the upper limits of normal for the corresponding indicators (the upper limits of normal are based on the reference range of the Department of Laboratory Medicine, Second Affiliated Hospital of Chongqing Medical University). The results showed that after 48 weeks of treatment, serum DAO levels decreased significantly from baseline (P<0.05), indicating a reduction in intestinal mucosal damage; serum LPS levels decreased from 19.79 EU / mL at baseline to 15.35 EU / mL, with all patients with elevated baseline LPS (>20 EU / mL) returning to the normal range (≤20 EU / mL), indicating reduced bacterial translocation and improved intestinal barrier function. No significant changes were observed in serum D-lactic acid levels.

[0033] Simultaneously, serum fibroblast growth factor 19 (FGF19) levels decreased significantly from baseline (P<0.05). FGF19, a key regulator in the bile acid-gut-hepatic feedback axis, has an expression level closely related to bile acid composition and intestinal environmental status. The changes in FGF19 levels in this study were consistent with the improvement trend of liver biochemical indicators, suggesting that SASP treatment may be accompanied by bile acid metabolism regulation and gut-hepatic axis functional remodeling. These results support the therapeutic effect of SASP in PBC patients with poor response to UDCA from both the intestinal barrier and bile acid feedback regulation perspectives.

[0034] Further analysis of the dynamic changes in key bacterial genera / species during treatment, such as... Figure 4As shown in the figure, the left side of the graph represents the relative abundance distribution of representative genera (Klebsiella, Fusobacterium, Prevotella, Dorea, Faecalibacterium, Bifidobacterium, and Blautia), while the right side represents the relative abundance distribution of representative species (Ruminococcus bromii, Klebsiella pneumoniae, Faecalibacterium prausnitzii, Bifidobacterium longum, Blautia wexlerae, and Blautia obeum). The vertical axis represents the names of different genera or species, and the horizontal axis represents the relative abundance of the corresponding genera or species. In the figure, different colors represent different groups. B0 represents the baseline control group of primary biliary cholangitis (PBC) patients with a good response to ursodeoxycholic acid (UDCA) treatment. W0, W24, and W48 represent samples from patients with poor UDCA response at baseline (week 0), week 24, and week 48 of SASP treatment, respectively. The bins and scatter plots in the figure represent the distribution of the abundance of corresponding genera or species in each group. The results show that compared with B0 and the baseline before treatment, some representative genera / species exhibited dynamic changes during SASP treatment, suggesting that SASP combined with UDCA treatment may be accompanied by remodeling of the gut microbiota. The gut microbiota, as an important component of the gut-hepatic axis, is closely related to bile acid metabolism, intestinal barrier function, and the state of liver immune inflammation. The changes in the microbiota observed in this invention are consistent with the improvement trends of liver biochemical indicators and intestinal barrier-related indicators, suggesting that gut microbiota remodeling may participate in the therapeutic effect of SASP on PBC patients with poor UDCA response.

[0035] Further analysis was conducted on the changes in key bacterial species characteristics before and after treatment in patients with different treatment outcomes, such as... Figure 5As shown in the figure, the average abundance levels of key bacterial species after CLR (centered log-ratio) transformation at different groupings and time points are displayed in heatmap form (Blautia obeum, Roseburia intestinalis, Mediterranean butyrica butyrica genes, Anaerostipes hadrus, Phocaeicolavulgatus, Bacteroides uniformis, Alistipes putredinis, Ruminococcus gnavus, Escherichia coli, Klebsiella pneumoniae, Bifidobacterium adolescentis, and Enterococcus faecalis). The vertical axis represents the names of different key bacterial species, and the horizontal groups represent the detection results of patients with different treatment outcomes at baseline and treatment endpoint. The color intensity in the heatmap represents the average abundance level of the corresponding bacterial species after CLR conversion, and different color gradients reflect the trend of bacterial abundance from low to high. The different colored annotation bars on the left side of the figure indicate the taxa to which the corresponding bacterial species belong.

[0036] The figure shows that patients were divided into a responder group (SASP.R) and a non-responder group (SASP.NR) based on whether they achieved a composite biochemical response at 48 weeks of treatment; where 0W represents the baseline before treatment and 48W represents week 48 of treatment. The results showed that responders and non-responders exhibited different abundance distribution characteristics at several key bacterial species levels, and the trends of changes in related bacterial species before and after treatment were not entirely consistent, suggesting that SASP treatment response may be related to specific gut microbiota characteristics. These results further indicate that, in addition to improvements in overall liver biochemistry and intestinal barrier-related indicators, SASP treatment may also be accompanied by changes in response-related microbiota characteristics. These results provide supplementary evidence for understanding the therapeutic role of SASP in PBC patients with poor UDCA response.

[0037] It should be noted that, Figure 4 and Figure 5 The genera / species names listed are all known genera / species names obtained from annotations in public databases during metagenomic sequencing analysis. Figure 4 and Figure 5Both figures are derived from sequencing analysis of the same group of research subjects, but due to the different analytical purposes of the two figures, the representative bacterial communities screened and displayed are not entirely consistent. Among them, Figure 4 This mainly reflects the dynamic changes of representative bacterial communities at different time points during the treatment process. Figure 5 This primarily reflects the key bacterial species characteristics associated with treatment outcomes after stratification based on whether a composite biochemical response was achieved at 48 weeks of treatment. Therefore, the differences in bacterial communities shown in the two figures represent representative results obtained from the same group of study subjects under different analytical dimensions.

[0038] Table 1 Changes in biochemical indicators before and after treatment Clinical studies have confirmed that SASP combined with UDCA can effectively treat PBC patients who do not respond well to UDCA, significantly improve their liver biochemical indicators, and has a high biochemical response rate and good safety.

[0039] A pharmaceutical composition for treating PBC with poor response to UDCA comprises a therapeutically effective amount of SASP as the active ingredient and a therapeutically effective amount of UDCA, wherein the daily dose of SASP is 0.5 g to 3 g, for example 1.5 g. The daily dose of UDCA is 10 mg / kg body weight to 15 mg / kg body weight. This pharmaceutical composition can be prepared into oral dosage forms such as tablets, capsules, and granules using conventional pharmaceutical excipients and techniques. Specifically, the SASP and UDCA can be co-prepared into a single fixed-dose combination formulation; or they can be prepared as separate formulations and packaged together in a kit to form a combined drug delivery system.

[0040] Based on the synergistic therapeutic effect and proven efficacy demonstrated in the selected patients, this composition provides a directly corresponding product form for the clinical treatment of PBC with poor response to UDCA.

[0041] The sulfasalazine or a pharmaceutically acceptable salt thereof described in this invention can be prepared into an oral formulation using conventional pharmaceutical methods for the treatment of patients with primary biliary cholangitis who have an inadequate response to ursodeoxycholic acid. The oral formulation includes, but is not limited to, tablets, capsules, granules, or enteric-coated preparations.

[0042] In one embodiment, the sulfasalazine pharmaceutical preparation is a tablet. The preparation method includes: mixing sulfasalazine active pharmaceutical ingredient with a pharmaceutically acceptable diluent, adding a binder to form a soft mass, granulating, drying, and sizing the mass, then adding a disintegrant and a lubricant and mixing thoroughly, followed by compression to obtain a tablet; if necessary, the obtained tablets can be coated to obtain film-coated tablets or enteric-coated tablets.

[0043] In another embodiment, the sulfasalazine pharmaceutical preparation is a capsule. The preparation method includes: mixing sulfasalazine active pharmaceutical ingredient with a pharmaceutically acceptable filler and a flow aid, and then filling the mixture into hard capsules to obtain the capsule formulation.

[0044] In a further embodiment, the sulfasalazine pharmaceutical preparation can be prepared separately from the ursodeoxycholic acid preparation and co-packaged to form a kit for combined administration; or, sulfasalazine and ursodeoxycholic acid can be co-prepared into a compound preparation using a pharmaceutically acceptable formulation.

[0045] Other embodiments of this application will readily occur to those skilled in the art upon consideration of the specification and practice of the disclosure herein. This application is intended to cover any variations, uses, or adaptations of this application that follow the general principles of this application and include common knowledge or customary techniques in the art not disclosed herein.

[0046] It should be understood that this application is not limited to the precise structure described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope.

Claims

1. The use of sulfasalazine in the preparation of drugs for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, Sulfasalazine or a pharmaceutically acceptable salt thereof is used in the preparation of pharmaceutical compositions for treating primary biliary cholangitis that is poorly responsive to ursodeoxycholic acid.

2. The use of sulfasalazine as described in claim 1 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, The pharmaceutical composition is administered in combination with ursodeoxycholic acid.

3. The use of sulfasalazine as described in claim 1 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, Poor response to ursodeoxycholic acid is defined as: in patients with primary biliary cholangitis, serum alkaline phosphatase levels remain 1.67 times higher than the upper limit of normal after continuous treatment with ursodeoxycholic acid at a dose of 13-15 mg / kg / day for at least 12 months.

4. The use of sulfasalazine as described in claim 3 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, The daily dose of the sulfasalazine is 0.5g to 3.0g.

5. The use of sulfasalazine as described in claim 4 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, The daily dose of the sulfasalazine is 1.5g, administered orally in divided doses.

6. The use of sulfasalazine as described in any one of claims 1-5 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, The pharmaceutical composition is used to prepare an oral formulation, which is selected from tablets, capsules, granules or enteric-coated formulations.

7. The use of sulfasalazine as described in claim 1 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, A composite biochemical response was achieved at week 48 of combined therapy.

8. The use of sulfasalazine as described in claim 7 in the preparation of a drug for treating primary biliary cholangitis with poor response to ursodeoxycholic acid, characterized in that, The composite biochemical response refers to the simultaneous fulfillment of the following conditions: Condition 1: Serum alkaline phosphatase level ≤ 1.67 times the upper limit of normal; Condition 2: Serum alkaline phosphatase level decreased by ≥15% compared to baseline; Condition 3: Serum total bilirubin level ≤ upper limit of normal.

9. A pharmaceutical composition, characterized in that, These include sulfasalazine and ursodeoxycholic acid, used to treat primary biliary cholangitis that does not respond well to ursodeoxycholic acid.

10. The pharmaceutical composition according to claim 9, characterized in that, The pharmaceutical composition is prepared into an oral dosage form.

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