Synergist and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a group of synergists for anti-tuberculosis infection medicines and application of the synergists. In the invention, Vortioxetine (Vor) shows obvious activity for enhancing mycobacterium infection resistance: under the concentration of 2 mu g / mL, the MIC (minimal inhibitory concentration) of Bedaquiline to H37Rv can be reduced by about 64 times (from 0.06 mu g / mL to 0.0009375 mu g / mL), and the MIC of Bedaquiline to an Rv0678 mutant strain can be reduced by about 64 times (from 1 mu g / mL to 0.0156 mu g / mL). And the content of sertraline hydrochloride (STL) can be reduced by about 16 times and 8 times respectively. The synergistic effect of fluoxetine (FXT) is weakest and is only reduced by two times. The synergist disclosed by the invention is a drug which has been sold on the market, so that the synergist has safety and complete medication guidance. The preparation process and the production process are both perfect, the product can be quickly sold on the market, the selling price is reasonable, the market acceptability is good, and the patient compliance is high. The votioxetine or the sertraline can be used as a synergist of a medicine for resisting mycobacterium tuberculosis infection.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of biological medicine, and particularly relates to a group of synergists of anti-tuberculosis infection drugs and application thereof. BACKGROUND

[0002] Mycobacteria include the Mycobacterium tuberculosis complex (including Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium caprae, Mycobacterium pinnipedii, Mycobacterium suricattae and Mycobacterium mungi), non-tuberculous Mycobacteria (NTM) and Mycobacterium leprae. Tuberculosis caused by Mycobacterium tuberculosis (MTB) is a chronic respiratory infectious disease that seriously endangers human health. The drug resistance of tuberculosis is serious, the drug selection for treating drug-resistant tuberculosis is limited, the treatment course is long, and the cure rate is low, about 63%.

[0003] Bedaquiline (Bdq, TMC207) is the first drug approved by FDA for clinical treatment of multidrug-resistant tuberculosis (MDR-TB) since 1971. Bedaquiline is a representative drug of diarylquinoline, which affects the activity of ATP synthase proton pump to block ATP synthesis, thereby playing a role in anti-mycobacterium tuberculosis (Andries K, Verhaeghst P, Guillemont J, et al. A diarylquinoline drug active on the ATP synthase of Mycobacterium tuberculosis[J]. Science, 2005, 307(5707): 223-227.; WANG Qingqing, YUAN Cheng, WANG Jiating, et al. Antituberculosis activity of quinoline hybrids[J]. Foreign Medicine (Antibiotics), 2023, 44(5): 337-345.). Related studies have shown that bedaquiline anti-drug tuberculosis long-term treatment regimen can significantly reduce the mortality of drug-resistant tuberculosis patients, and the efficacy is significantly better than that of treatment regimen without bedaquiline, and its safety has been proved by many countries' researches (Shi Zhengyu, Wu Guihui, Zou Liping, et al. Systematic review of the effectiveness and safety of bedaquiline and delamanid in the treatment of multidrug-resistant / extensively drug-resistant tuberculosis[J]. Chinese Journal of Infectious Diseases, 2021, 39(10): 625-630.; Hu Chunmei, Fang Gang, Zhang Xiangrong, et al. Long-term efficacy and safety of bedaquiline combined with conventional anti-tuberculosis drugs in the treatment of patients with multidrug-resistant pulmonary tuberculosis[J]. International Medicine and Health Guide, 2018, 24(5): 711-715.). WHO's 2019 Drug-Resistant Tuberculosis Treatment Integration Guidelines and 'Chinese Expert Consensus on Treatment of Multidrug-Resistant and Rifampicin-Resistant Tuberculosis (2019 Edition)' (Tuberculosis Branch of Chinese Medical Association. Chinese Expert Consensus on Treatment of Multidrug-Resistant and Rifampicin-Resistant Tuberculosis (2019 Edition)[J]. Chinese Journal of Tuberculosis and Respiratory Diseases, 2019, 42(10): 733-749.) include bedaquiline as a group A drug for the treatment of drug-resistant tuberculosis. However, with the wide clinical application of bedaquiline, its drug resistance problem has become increasingly prominent. Among them, the mutation of Rv0678 gene is one of the main mechanisms of bedaquiline resistance. Rv0678 gene encodes a negative regulatory protein, and its mutation can cause overexpression of MmpS5-MmpL5 efflux pump system, thereby reducing the accumulation concentration of intracellular bedaquiline and producing drug resistance. Once drug resistance occurs, it will greatly limit the clinical efficacy of bedaquiline, threaten the lives of patients, and exacerbate the difficulty of tuberculosis prevention and control.

[0004] Clofazimine was first synthesized in 1954 by a team of scientists at the University of Dublin, Trinity College, in the process of searching for a treatment for tuberculosis. In 2010, it was found that clofazimine had a significant inhibitory effect on drug-resistant Mycobacterium tuberculosis, and interest in exploring it as an antituberculosis drug has revived. This makes clofazimine one of the core drugs for treating multidrug-resistant tuberculosis (MDR-TB). The drug resistance of Mycobacterium tuberculosis to clofazimine is related to the mutation of the Rv0678 gene of the MmpR5 repressor protein, and in addition, the Rv1453, Rv2535c (pepQ) and Rv1979c genes were also found to be mutated in the clofazimine-resistant strain.

[0005] At present, the strategy to solve drug resistance is limited. The development of new drugs is long and costly, while the use of drug combinations to enhance the efficacy of existing drugs and reverse drug resistance is a more cost-effective and timely strategy. Therefore, it is of great clinical significance and urgent practical need to find a drug potentiator that can effectively enhance the antibacterial activity of bedaquiline or clofazimine and reverse its drug resistance.

[0006] Vortioxetine is an arylpiperazine derivative, which was approved by the US FDA in 2013 as a new antidepressant and was listed in China in 2017. Vortioxetine has different functional activities at different (5-HT) neuronal targets, such as inhibiting 5-HT reuptake and enhancing 5-HT activity in the central nervous system. Through its unique multi-modal mechanism of action, it not only can improve depressive symptoms, but also has a unique advantage in improving the cognitive function of MDD patients. It is also the only antidepressant that shows positive effects in multiple cognitive domains (Baldwin D S, Necking O, Schmidt S N, et al. Efficacy and safety of vortioxetine in treatment of patients with major depressive disorder and common comorbid physical illness [J]. Journal of Affective Disorders, 2022, 311: 588- 594.). So far, there is no public literature or patent indicating that vortioxetine has antituberculous Mycobacterium activity or can be used as an antibiotic potentiator.

[0007] Sertraline hydrochloride: (1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine; hydrochloride salt. Trade name: Zoloft or Luvox, is a selective serotonin reuptake inhibitor, an antidepressant. It inhibits platelet function, showing anti-platelet and endothelial protective functions. Relieves depression, improves the quality of life of patients with cardiovascular disease. It can also be prescribed to treat depression in patients with Parkinson's disease. So far, no public literature or patents have shown that sertraline hydrochloride has anti-mycobacterium tuberculosis activity or can be used as an antibiotic potentiator.

[0008] With the increasing problem of drug resistance of tuberculosis, it is urgent to develop new treatment strategies, enhance the activity of bedaquiline against mycobacterial infection, and reduce the occurrence of drug resistance of new drugs. SUMMARY

[0009] The present application finds that the combination of fluvoxamine or sertraline and anti-mycobacterium tuberculosis infection drugs can enhance the anti-mycobacterium tuberculosis activity of anti-mycobacterium tuberculosis infection drugs, and the combination of drugs after combination can resist mycobacterium tuberculosis infection. Based on this, the present application is completed.

[0010] In a first aspect, the present application provides the use of fluvoxamine in the preparation of a potentiator for anti-mycobacterium infection drugs, wherein the potentiator increases the effect of fluvoxamine on anti-mycobacterium infection drugs against mycobacterium infection.

[0011] Further, the anti-mycobacterium infection drug is selected from one or more of bedaquiline, clofazimine and / or PBTZ-169.

[0012] Further, the mycobacterium is selected from Mycobacterium tuberculosis.

[0013] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis clinical isolates, Mycobacterium tuberculosis standard strains and / or Mycobacterium tuberculosis carried by patients infected with Mycobacterium tuberculosis.

[0014] Further, the Mycobacterium tuberculosis infection includes primary infection, secondary infection, extrapulmonary infection and pulmonary infection.

[0015] Further, the Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis.

[0016] Further, the Mycobacterium tuberculosis includes human Mycobacterium tuberculosis, bovine Mycobacterium tuberculosis, African Mycobacterium tuberculosis, Kana Mycobacterium tuberculosis and mouse Mycobacterium tuberculosis.

[0017] Further, the fluvoxamine includes a pharmaceutically acceptable salt.

[0018] Further, the drug is introduced into the body by intramuscular, intradermal, subcutaneous, and intravenous injection.

[0019] In a second aspect, the present application provides a combined synergistic pharmaceutical composition against mycobacterial infection, the pharmaceutical composition is a combination of volisiidine and bedaquiline, clofazimine or PBTZ-169, the pharmaceutical composition has at least one of the following effects: a) inhibiting mycobacterial activity; b) against mycobacterial infection; c) preventing and / or treating diseases caused by mycobacterial infection.

[0020] Further, the mycobacterium is selected from Mycobacterium tuberculosis.

[0021] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis clinical isolates, Mycobacterium tuberculosis standard strains and / or Mycobacterium tuberculosis carried by patients infected with Mycobacterium tuberculosis.

[0022] Further, the Mycobacterium tuberculosis infection includes primary infection, secondary infection, extrapulmonary infection and pulmonary infection.

[0023] Further, the disease caused by Mycobacterium tuberculosis includes drug-resistant tuberculosis, non-drug-resistant tuberculosis, pulmonary tuberculosis and extrapulmonary tuberculosis.

[0024] Further, the drug-resistant tuberculosis includes single-drug-resistant tuberculosis, multi-drug-resistant tuberculosis, multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis.

[0025] Further, the pulmonary tuberculosis includes primary pulmonary tuberculosis, secondary pulmonary tuberculosis, blood type disseminated pulmonary tuberculosis, trachea-bronchus tuberculosis, tuberculous pleurisy and bacterium-negative pulmonary tuberculosis.

[0026] Further, the extrapulmonary tuberculosis includes lymph node tuberculosis, intestinal tuberculosis, kidney tuberculosis and bone and joint tuberculosis.

[0027] Further, the Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis.

[0028] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canni and Mycobacterium microti.

[0029] Further, the pharmaceutical composition can also contain other active ingredients against mycobacterial infection.

[0030] Further, one or more pharmaceutically acceptable carriers can be added to the pharmaceutical composition.

[0031] Further, the pharmaceutical composition can be prepared in various forms such as tablets, powders, granules, capsules, oral solutions, injection preparations, or aerosols, etc.; and each of the above-mentioned various forms of the pharmaceutical composition can be prepared according to a conventional method in the pharmaceutical field.

[0032] Further, the tablet can widely use various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and / or lubricants.

[0033] Still further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0034] Further, the wetting agents and binders include, but are not limited to, one or more of water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, sugar syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and / or polyvinylpyrrolidone.

[0035] Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, fucoidin, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, and / or ethyl cellulose.

[0036] Further, the disintegration inhibitors include, but are not limited to, sucrose, glycerol triestearate, cocoa butter, and / or hydrogenated oil, etc.

[0037] Further, the absorption promoters include, but are not limited to, one or more of quaternary ammonium salts and / or sodium dodecyl sulfate.

[0038] Further, the lubricants include, but are not limited to, one or more of talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0039] Further, if necessary, the various preparations can be added to the pharmaceutical preparation with colorants, preservatives, fragrances, flavoring agents, sweetening agents, or other materials.

[0040] Still further, the pharmaceutical composition can be introduced into the body in a manner of intramuscular, intradermal, subcutaneous, and intravenous.

[0041] Further, the vortioxetine includes a pharmaceutically acceptable salt.

[0042] Thirdly, the present invention provides the use of vortioxetine in combination with bedaquiline, clofazimine, or PBTZ-169 in the preparation of a combined synergistic drug composition for anti-mycobacterial infection, wherein the combination of vortioxetine with bedaquiline, clofazimine, or PBTZ-169 exerts an anti-mycobacterial infection effect, and wherein vortioxetine enhances the anti-mycobacterial infection activity of bedaquiline, clofazimine, or PBTZ-169.

[0043] Furthermore, the mycobacterium is selected from Mycobacterium tuberculosis.

[0044] Furthermore, the Mycobacterium tuberculosis includes clinical isolates of Mycobacterium tuberculosis, standard strains of Mycobacterium tuberculosis, and / or Mycobacterium tuberculosis carried by patients infected with Mycobacterium tuberculosis.

[0045] Furthermore, the Mycobacterium tuberculosis infection includes: primary infection, secondary infection, extrapulmonary infection, and pulmonary infection.

[0046] Furthermore, the tuberculosis mycobacteria include Mycobacterium humanis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium cannerae, and Mycobacterium villiformis.

[0047] Furthermore, the pharmaceutical composition may also contain other active ingredients that combat mycobacterial infections.

[0048] Furthermore, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.

[0049] Furthermore, the pharmaceutical composition can be formulated into various forms such as tablets, powders, granules, capsules, oral liquids, injectable preparations, or aerosols; all of the above dosage forms can be prepared according to conventional methods in the pharmaceutical field.

[0050] Furthermore, the tablets can widely utilize a variety of carriers known in the art, including one or more of diluents and absorbents, humectants and binders, disintegrants, disintegration inhibitors, absorption promoters and / or lubricants.

[0051] Furthermore, the diluent and absorbent include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0052] Furthermore, the wetting agent and adhesive include, but are not limited to, one or more of water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and / or polyvinylpyrrolidone.

[0053] Further, the disintegrating agent includes, but is not limited to, one or more of dry starch, alginic acid, powdered agar, alginic acid sodium salt, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium lauryl sulfate, methyl cellulose and / or ethyl cellulose.

[0054] Further, the disintegrating inhibitor includes, but is not limited to, one or more of sucrose, glycerol triestearate, cocoa butter and / or hydrogenated oil, etc.

[0055] Further, the absorption promoter includes, but is not limited to, one or more of quaternary ammonium salt and / or sodium lauryl sulfate.

[0056] Further, the lubricant includes, but is not limited to, one or more of talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin and / or polyethylene glycol.

[0057] Further, the various formulations, if necessary, can also add coloring agents, preservatives, flavors, flavoring agents, sweeteners or other materials to the pharmaceutical formulations.

[0058] Further, the pharmaceutical composition is introduced into the body in a manner including intramuscular, intradermal, subcutaneous and intravenous.

[0059] Further, the vortioxetine includes a pharmaceutically acceptable salt.

[0060] Further, the sertraline includes a pharmaceutically acceptable salt.

[0061] In a fourth aspect, the present application provides use of sertraline in the preparation of a pharmaceutical potentiator against mycobacterial infection, wherein the potentiator potentiates the effect of sertraline on bedaquiline against mycobacterial infection.

[0062] Further, the mycobacterium is selected from Mycobacterium tuberculosis.

[0063] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis clinical isolates, Mycobacterium tuberculosis standard strains and / or Mycobacterium tuberculosis carried by patients infected with Mycobacterium tuberculosis.

[0064] Further, the Mycobacterium tuberculosis infection includes primary infection, secondary infection, extrapulmonary infection and pulmonary infection.

[0065] Further, the Mycobacterium tuberculosis includes multidrug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis.

[0066] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti and Mycobacterium microti.

[0067] Further, the sertraline includes pharmaceutically acceptable salts.

[0068] Further, the way of introducing the drug into the body includes intramuscular, intradermal, subcutaneous and intravenous.

[0069] In a fifth aspect, the present application provides a combined synergistic pharmaceutical composition against mycobacterial infection, the pharmaceutical composition being a combination of sertraline and bedaquiline, the pharmaceutical composition having at least one of the following effects: a) inhibiting mycobacterial activity; b) resisting mycobacterial infection; c) preventing and / or treating diseases caused by mycobacterial infection.

[0070] Further, the mycobacterium is selected from Mycobacterium tuberculosis.

[0071] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis clinical isolates, Mycobacterium tuberculosis standard strains and / or Mycobacterium tuberculosis carried by patients infected with Mycobacterium tuberculosis.

[0072] Further, the Mycobacterium tuberculosis infection includes primary infection, secondary infection, extrapulmonary infection and pulmonary infection.

[0073] Further, the diseases caused by Mycobacterium tuberculosis include drug-resistant tuberculosis, non-drug-resistant tuberculosis, pulmonary tuberculosis and extrapulmonary tuberculosis.

[0074] Still further, the drug-resistant tuberculosis includes single-drug-resistant tuberculosis, multi-drug-resistant tuberculosis, multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis.

[0075] Further, the pulmonary tuberculosis includes primary pulmonary tuberculosis, secondary pulmonary tuberculosis, blood type disseminated pulmonary tuberculosis, trachea-bronchus tuberculosis, tuberculous pleurisy and bacterium-negative pulmonary tuberculosis.

[0076] Further, the extrapulmonary tuberculosis includes lymph node tuberculosis, intestinal tuberculosis, kidney tuberculosis and bone and joint tuberculosis.

[0077] Further, the Mycobacterium tuberculosis includes multi-drug-resistant Mycobacterium tuberculosis and extensively drug-resistant Mycobacterium tuberculosis.

[0078] Still further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti and Mycobacterium microti.

[0079] Further, the pharmaceutical composition can also contain other active ingredients against mycobacterial infection.

[0080] Further, one or more pharmaceutically acceptable carriers can be added to the pharmaceutical composition.

[0081] Further, the pharmaceutical composition can be prepared in various forms such as tablets, powders, granules, capsules, oral solutions, injection preparations, or aerosols, etc.; and each of the above-mentioned various forms of the pharmaceutical composition can be prepared according to a conventional method in the pharmaceutical field.

[0082] Further, the tablet can widely use various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption accelerators, and / or lubricants.

[0083] Still further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0084] Further, the wetting agents and binders include, but are not limited to, one or more of water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, sugar syrup, honey, glucose solution, acacia paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and / or polyvinylpyrrolidone.

[0085] Further, the disintegrants include, but are not limited to, one or more of dry starch, alginate, agar powder, fucoidin, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, and / or ethyl cellulose.

[0086] Further, the disintegration inhibitors include, but are not limited to, one or more of sucrose, glycerol triestearate, cocoa butter, and / or hydrogenated oil, etc.

[0087] Further, the absorption accelerators include, but are not limited to, one or more of quaternary ammonium salts and / or sodium dodecyl sulfate.

[0088] Further, the lubricants include, but are not limited to, one or more of talc, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0089] Further, the various preparations can also add coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, or other materials to the pharmaceutical preparations, if necessary.

[0090] Still further, the pharmaceutical composition can be introduced into the body in various ways, including intramuscularly, intradermally, subcutaneously, and intravenously.

[0091] Further, the sertraline includes a pharmaceutically acceptable salt.

[0092] In a sixth aspect, the present application provides the use of sertraline and bedaquiline in combination for the preparation of a combined synergistic pharmaceutical composition for the treatment of mycobacterial infection, wherein the sertraline and bedaquiline in combination exert an effect against mycobacterial infection, and the sertraline enhances the activity of bedaquiline against mycobacterial infection.

[0093] Further, the mycobacterium is selected from the group consisting of Mycobacterium tuberculosis.

[0094] Further, the Mycobacterium tuberculosis includes a clinical isolate of Mycobacterium tuberculosis, a standard strain of Mycobacterium tuberculosis, and / or Mycobacterium tuberculosis carried by a patient infected with Mycobacterium tuberculosis.

[0095] Further, the Mycobacterium tuberculosis infection includes a primary infection, a secondary infection, an extrapulmonary infection, and a pulmonary infection.

[0096] Further, the Mycobacterium tuberculosis includes Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium canetti, and Mycobacterium microti.

[0097] Further, the pharmaceutical composition can further contain other active ingredients against mycobacterial infection.

[0098] Further, one or more pharmaceutically acceptable carriers can be added to the pharmaceutical composition.

[0099] Further, the pharmaceutical composition can be prepared in the form of tablets, powders, granules, capsules, oral solutions, injection preparations, or aerosols, etc.; and the above-mentioned various dosage forms of the pharmaceutical composition can be prepared according to conventional methods in the pharmaceutical field.

[0100] Further, the tablets can widely use various carriers known in the art, including one or more of diluents and absorbents, wetting agents and binders, disintegrants, disintegration inhibitors, absorption promoters, and / or lubricants.

[0101] Further, the diluents and absorbents include, but are not limited to, one or more of starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, and / or aluminum silicate.

[0102] Further, the wetting agents and binders include, but are not limited to, one or more of water, glycerol, polyethylene glycol, ethanol, propanol, starch paste, dextrin, sugar syrup, honey, glucose solution, acacia mucilage, gelatin mucilage, sodium carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and / or polyvinylpyrrolidone.

[0103] Furthermore, the disintegrant includes, but is not limited to, one or more of the following: dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecyl sulfonate, methylcellulose and / or ethylcellulose.

[0104] Furthermore, the disintegration inhibitors include, but are not limited to, sucrose, tristearate, cocoa butter, and / or hydrogenated oils.

[0105] Furthermore, the absorption enhancer includes, but is not limited to, one or more of quaternary ammonium salts and / or sodium dodecyl sulfate.

[0106] Furthermore, the lubricant includes, but is not limited to, one or more of talc, silica, corn starch, stearate, boric acid, liquid paraffin, and / or polyethylene glycol.

[0107] Furthermore, colorants, preservatives, flavorings, tasters, sweeteners, or other materials may be added to the pharmaceutical preparations if necessary.

[0108] Furthermore, the drug composition can be delivered to the body via intramuscular, intradermal, subcutaneous, and intravenous routes.

[0109] Furthermore, the sertraline includes pharmaceutically acceptable salts.

[0110] Beneficial effects In this invention, vortioxetine (Vor) exhibited a significant enhancement of activity against mycobacterial infections: at a concentration of 2 μg / mL, it reduced the MIC of bedaquiline against H37Rv by approximately 64-fold (from 0.06 μg / mL to 0.0009375 μg / mL) and against the Rv0678 mutant strain by approximately 64-fold (from 1 μg / mL to 0.0156 μg / mL). Sertraline hydrochloride (STL) showed the next best effect, reducing the MIC by approximately 16-fold and 8-fold, respectively. Fluoxetine (FXT) had the weakest synergistic effect, reducing the MIC by only 2-fold in both cases.

[0111] The synergist of this invention is a marketed drug, possessing safety and complete usage instructions. Its preparation and production processes are well-established, enabling rapid market launch, reasonable pricing, good market acceptance, and high patient compliance. Attached Figure Description

[0112] Figure 1 It is the structural formula of vortioxetine.

[0113] Figure 2 It is the structural formula for sertraline hydrochloride. Detailed Implementation

[0114] The specific embodiments of the present application are further described below. It is to be understood that the description of these embodiments is intended to help understand the present application and is not intended to limit the present application. In addition, the technical features involved in the following described embodiments can be combined with each other as long as they do not conflict with each other.

[0115] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available unless otherwise specified.

[0116] The term Vortioxetine: Chemical formula is C 18 H 22 N2S is a new multi-mode antidepressant developed by Denmark Lundbeck and Japan Takeda. It is different from traditional monoamine drugs, and can improve depressive symptoms and has significant cognitive enhancement effect through unique dual mechanism of inhibiting serotonin reuptake and regulating the activity of multiple serotonin receptors.

[0117] Bedaquiline (BDQ): Chemical name is 1-(6-bromo-2-methoxyquinoline-3-yl)-4-dimethylamino-1-phenyl-2-(1-naphthyl)-2-butanol, and the trade name is Sirturo. It is a new type of diarylquinoline anti-mycobacterial drug, which can affect the ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of Mycobacterium tuberculosis ATP synthase proton pump, thereby playing an antibacterial and bactericidal effect. It is clinically used for the treatment of adult multidrug-resistant pulmonary tuberculosis (MDR-PTB).

[0118] The synergist in the present application refers to vortioxetine or sertraline. When vortioxetine and bedaquiline are used together, the activity of bedaquiline against mycobacterial infection is enhanced, and the drug composition after the combination of vortioxetine and bedaquiline has stronger anti-tuberculosis ability than bedaquiline alone; MIC (minimum inhibitory concentration): minimum inhibitory concentration, is an index for measuring the antibacterial activity of antibacterial drugs, refers to the minimum drug concentration that can inhibit the growth of pathogens in the culture medium after culturing Mycobacterium tuberculosis in vitro for 7 to 10 days. Pharmacodynamic interactions in vitro refer to the evaluation of the interaction of the study drug and the effective dose, so as to determine the feasibility of further development as a pulmonary tuberculosis treatment regimen drug. The commonly used quantitative method is the checkerboard dilution method. Taking the interaction of two drugs as an example, first, the MIC of the two study drugs for Mycobacterium tuberculosis is determined, and according to the MIC value, the highest concentration is set as 2xMIC of the single drug, and then 2-fold dilution is carried out one by one (in the vertical column and horizontal column of the square respectively), each tube (well) contains a mixture of different concentrations of the two drugs, generally 6-8 dilution degrees are designed. The initial inoculum is 5x10 5 CFU / mL, incubated at 37°C for 7 days, the results were observed and the fractional inhibitory concentration index (FICI) was calculated. The FICI index calculation formula is (MIC of drug A when used in combination) / (MIC of drug A when used alone)+(MIC of drug B when used in combination) / (MIC of drug B when used alone). According to the FICI value, it is judged as synergistic effect (≤0.5), additive effect (0.5-1), irrelevant effect (1-2) and antagonistic effect (>2). FICI is one of the pharmacodynamic (PD) parameters of antibacterial drugs, and is an index for combined drug sensitivity of two antibacterial drugs (when two antibacterial drugs are used at the same time, synergistic, additive, irrelevant and four situations may occur).

[0119] Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) antidepressant, its drug form is fluoxetine hydrochloride, and its trade name is "Prozac" or "Prozac" (Prozac). It is used in the treatment of adult depression, obsessive-compulsive disorder and anorexia nervosa, and is also used in the treatment of panic disorder with or without agoraphobia. Fluoxetine is a selective serotonin reuptake inhibitor that inhibits the reuptake of serotonin in nerve synapses to increase the level of extracellular serotonin that can bind to postsynaptic receptors. Fluoxetine has little binding to other receptors such as alpha-adrenergic, beta-adrenergic, 5-hydroxytryptaminergic, and dopaminergic receptors.

[0120] Isoniazid: chemical name 4-pyridine carboxylic acid hydrazide; drug name Remifen, isonicotinic acid hydrazide, belongs to monoamine oxidase inhibitor.

[0121] It has good antibacterial effect on tubercle bacillus, better curative effect, smaller dosage, relatively lower toxicity and is easily accepted by patients. It is often used in combination with other anti-tuberculosis drugs to enhance efficacy and overcome drug-resistant bacteria. In addition, it also has certain effect on dysentery, pertussis, granuloma, etc.

[0122] Rifampicin (RFP), also known as rifampin, rifampicin, rifampicin, and rifampicin. The chemical name is 3-(4-methyl-1-piperazinyl) imino methyl-rifamycin. Rifampicin binds firmly to the b subunit of DNA-dependent RNA polymerase, inhibits the synthesis of bacterial RNA, prevents the enzyme from connecting with DNA, and blocks the RNA transcription process, so that the synthesis of DNA and protein is stopped. It has obvious bactericidal effect on tubercle bacillus and other mycobacteria (including leprosy bacillus, etc.), both in host cells and outside. It also has certain antibacterial effect on meningococcus, Haemophilus influenzae, Staphylococcus aureus, Streptococcus epidermidis, Legionella pneumophila, etc. It is also effective against some viruses and chlamydia.

[0123] Example 1 Screening of Vortioxetine Tuberculosis mycobacterium (Rv0678 mutant strain: BDQMIC = 1 μg / ml) through Rv0678 mutant strain (MmpL5-MmpS5 overexpression) as a functional screening model, from the drug library Screening of compounds that can reduce the MIC of bedaquiline.

[0124] From the screening of 2863 compounds in the compound library, the most active vortioxetine for synergizing bedaquiline against mycobacterial infection was found, and its structural formula is shown as Figure 1 .

[0125] Example 2 Determination of the minimum inhibitory concentration and synergistic activity of vortioxetine by MABA method 2.1 Test method This part uses Microplate Alamar Blue Assay (MABA) to determine the minimum inhibitory concentration (MIC) of vortioxetine (Vortioxetine, VOR) on Mycobacterium tuberculosis standard strain H37Rv and its Rv0678 mutant strain, and to evaluate its in vitro synergistic activity on bedaquiline (Bedaquiline, BDQ).

[0126] Add culture medium and drug stock solution in microwells: Drug powder was weighed and liposoluble drug was added to DMSO to make a drug stock solution with a concentration of 2 mg / ml. The bacterial solution of M. tuberculosis in the logarithmic growth phase was added to the culture in the well plate. The OD value of each well was measured at a wavelength of 570 nm, wherein OD (strain) = OD (bacterial solution) - OD (7H9 medium). OD = 0.1 corresponds to 1 x 10 7 CFU / mL, and each bacterial solution was diluted so that the final concentration of each strain was set to 1 x 10 5 CFU / mL.

[0127] The drug in the first column of microwells was diluted to the tenth column by the double dilution method, and the final concentration of each microwell bacterial solution was 1 x 10 5 CFU / mL. After 7 days of culture, the addition of Tween-80 solution and 20 μl Alamar blue indicator to each microwell continued to incubate. The next day, the color change was observed, the fluorescence value of each well was measured at an excitation wavelength of 530 nm and 590 nm, and the color of each well was recorded, with blue indicating no growth of the strain and red indicating growth of the strain; the MIC indicates the lowest drug concentration that changes from blue to red.

[0128] Combined drug activity determination: To evaluate the combined effect of fluvoxamine and bedaquiline, the following groups were set up: Single drug control group: fluvoxamine alone (concentration gradient), bedaquiline alone (concentration gradient).

[0129] Bacterial solution growth control and medium blank control. In the 96-well plate, drug-containing medium (final concentration: fluvoxamine 48 μg / mL, bedaquiline 2 μg / mL) was added to the first column, followed by serial double dilution to the tenth column, the eleventh column was the bacterial solution growth control without drug, and the twelfth column was the medium blank control without bacteria. The prepared bacterial solution was finally added to each well to make the final volume of each well 200 μL, and the final concentration of the bacterial solution was 1 x 10 5 CFU / mL. The microwell plate was incubated in a 37°C, 5% CO2 incubator for 7 days.

[0130] Fixed concentration combination group: The fixed concentration of fluvoxamine was 1 μg / mL, and it was combined with different concentrations of bedaquiline.

[0131] The fixed concentration of fluvoxamine was 4 μg / mL, and it was combined with different concentrations of bedaquiline.

[0132] 1 μg / mL of fluvoxamine alone and 4 μg / mL of fluvoxamine were added to the medium, and the synergistic effect of fluvoxamine at a fixed concentration on BDQ was determined according to the above-mentioned BDQ single dilution gradient determination.

[0133] 2.2 Test results Table 1. Minimum inhibitory concentration of bedaquiline combined with vorucicline against H37Rv, Rv0678 mutant Note: Bedaquiline: BDQ; Vorucicline: Vor.

[0134] The MIC of vorucicline against H37Rv and Rv0678 mutant was 6 μg / ml. In the presence of vorucicline at sub-inhibitory concentrations (1 μg / mL and 4 μg / mL), the MIC of bedaquiline against both strains was significantly reduced (by 16, 128-fold), indicating that vorucicline can significantly enhance the anti-tuberculosis activity of bedaquiline and has a synergistic effect of restoring the sensitivity of Rv0678 mutant strains resistant to bedaquiline.

[0135] Example 3. Determination of the synergistic activity of different antidepressants combined with anti-tuberculosis drugs 3.1 Test method In order to evaluate the synergistic effect of different antidepressants, the following groups were set up: Anti-tuberculosis drug single drug control group: The individual MIC of bedaquiline, isoniazid and rifampicin against the two strains was determined respectively.

[0136] Fixed concentration antidepressant combination group: The concentration of the three antidepressants (vorucicline-Vor, fluoxetine-FXT, sertraline hydrochloride-STL) was fixed at 2 μg / mL (this concentration is lower than the respective inhibitory concentration, aiming to observe the sensitization effect rather than direct killing). In this fixed background, they were combined with serially diluted three anti-tuberculosis drugs respectively.

[0137] Control: Bacterial liquid growth control, containing 2 μg / mL of each antidepressant but no anti-tuberculosis drug (used to confirm that the single drug has no inhibitory effect at this concentration), medium blank control.

[0138] In a 96-well plate, a fixed concentration (2 μg / mL) of antidepressants or an equal volume of solvent was added in advance, then serially diluted anti-tuberculosis drugs were added, and finally bacterial liquid was inoculated to make the final volume 200 μL / well, with a final concentration of 1 x 10 5 CFU / mL. After 7 days of culture at 37°C, Alamar Blue indicator was added, and the results were read after 24 hours of further incubation. The MIC was defined as the lowest concentration of anti-tuberculosis drug that completely inhibited bacterial growth (blue color remained in the well).

[0139] 3.2 Test results Table 2. MIC of compounds against H37Rv (μg / mL) The MIC of vorinostat (Vor) against H37Rv was 6 μg / mL, the MIC of fluoxetine (FXT) against H37Rv was 12 μg / mL, and the MIC of sertraline hydrochloride (STL) against H37Rv was 3 μg / mL.

[0140] Table 3. MIC of compounds against Rv0678 mutant (μg / mL) The MIC of vorinostat (Vor) against Rv0678 mutant was 6 μg / mL, the MIC of fluoxetine (FXT) against Rv0678 mutant was 12 μg / mL, and the MIC of sertraline hydrochloride (STL) against Rv0678 mutant was 6 μg / mL.

[0141] As shown in Tables 2 and 3, there were significant differences in the potentiating effect of bedaquiline: vorinostat (Vor) showed the strongest potentiating activity. At a concentration of 2 μg / mL, it reduced the MIC of bedaquiline against H37Rv by about 64-fold (from 0.06 μg / mL to 0.0009375 μg / mL) and against Rv0678 mutant by about 64-fold (from 1 μg / mL to 0.0156 μg / mL). Sertraline hydrochloride (STL) was second, reducing by about 16-fold and 8-fold, respectively. Fluoxetine (FXT) had the weakest potentiating effect, reducing by only 2-fold.

[0142] As shown in Tables 2 and 3, the effects on isoniazid and rifampicin were limited: the three antidepressants had little or no effect on the in vitro MIC of isoniazid and rifampicin at a concentration of 2 μg / mL. Only vorinostat reduced the MIC by 2-fold, which may not be biologically significant, indicating that such synergy is drug-specific rather than broad-spectrum enhancement.

[0143] Among the three types of antidepressants selected, vorinostat showed a unique and significant advantage in enhancing the activity of bedaquiline, especially against its drug-resistant mutant. This effect is not shared by all antidepressants, suggesting that vorinostat may produce synergy with bedaquiline through its specific pharmacological mechanism, providing an important basis for the development of vorinostat as an anti-tuberculosis potentiator.

[0144] Example 4 Checkerboard assay to determine the combined activity of vorinostat and different anti-tuberculosis drugs against different strains 4.1 Test method The in vitro activity of vorinostat combined with different anti-tuberculosis drugs and the activity against Mycobacterium tuberculosis with different sensitivity to bedaquiline were determined by the checkerboard method.

[0145] Drug and concentration design: Drug A (Vorinostat, Vor): 7 two-fold dilution concentrations (X1-X7) were set for the concentration range of 4xMIC to 1 / 16xMIC (i.e. 48 µg / mL to 0.375 µg / mL, based on its single-agent MIC = 6 µg / mL).

[0146] Drug B (including Bedaquiline BDQ, Clofazimine CFZ, Rifampicin RFP, Isoniazid INH, Linezolid LZD, Moxifloxacin MXF, PBTZ169): 7 two-fold dilution concentrations (Y1-Y7) were set for each B drug for the concentration range of 4xMIC to 1 / 16xMIC. The specific concentrations were designed based on the respective single-agent MICs in Table 3.2 results.

[0147] Control: MIC well column for single-agent A, MIC well row for single-agent B, bacterial solution growth control well, medium blank control well. After 7 days of incubation, Alamar Blue indicator was added, and after 24 h, the color change of single-agent A and single-agent B was observed to determine their respective MIC wells. The combined effect of the two drugs was determined by calculating the FICI value according to the formula: FICI = MICA combined / MICA alone + MICB combined / MICB alone where MICA alone and MICB alone represent the MIC of A drug and B drug alone against Mycobacterium tuberculosis, respectively, and MICA combined and MICB combined represent the lowest concentrations of A drug and B drug after combined application that prevent the color change from blue to pink.

[0148] Table 4. Two-dimensional checkerboard design Note: X is Drug A, i.e. Vorinostat: Vor; X1-X7 are 7 concentration gradients of Vorinostat: 4xMIC-1 / 16xMIC; Y is Drug B, which is Bedaquiline BDQ, Clofazimine CFZ, Rifampicin RFP, Isoniazid INH, Linezolid LZD, Moxifloxacin MXF, and PBTZ169, respectively; Y1-Y7 are 7 concentration gradients of B drugs: 4xMIC-1 / 16xMIC.

[0149] 4.2 Test results Table 5. Checkerboard method for determining the combined activity of Vorinostat and different anti-tuberculosis drugs against H37Rv strain Table 6. Checkerboard method for determining the combined activity of Vorinostat and different anti-tuberculosis drugs against Rv0678 strain As shown in Table 5 and Table 6, the synergistic effect: fluoxetine combined with bedaquiline (BDQ), clofazimine (CFZ) and the new drug PBTZ-169, both on H37Rv and Rv0678 mutant strains showed significant synergistic effect (FICI ≤ 0.5). The three drugs are cross-resistant on Rv0678 mutant strains.

[0150] As shown in Table 5 and Table 6, the irrelevant effect: fluoxetine combined with rifampicin (RFP), isoniazid (INH), linezolid (LZD), moxifloxacin (MXF), the FICI value is about 1, showing no effect, indicating that its antibacterial mechanism has no significant cross or synergy with these drugs acting on RNA synthesis, cell wall synthesis, protein synthesis or DNA replication.

Claims

1. The use of vortioxetine in the preparation of potentiators for antimycobacterial infection drugs, wherein the potentiator enhances the antimycobacterial infection effect of vortioxetine; wherein the antimycobacterial infection drug is selected from one or more of bedaquiline, clofazimine, and / or PBTZ-169.

2. The application as described in claim 1, wherein the mycobacterium is selected from Mycobacterium tuberculosis; and the vortioxetine comprises a pharmaceutically acceptable salt.

3. A combined synergistic drug composition for combating mycobacterial infections, said drug composition being a combination of vortioxetine and bedaquiline, clofazimine, or PBTZ-169, said drug composition having at least one of the following effects: a) Inhibits mycobacterial activity; b) Antibacterial infection; c) Prevention and / or treatment of diseases caused by mycobacterial infection.

4. The composition of claim 3, wherein the mycobacterium is selected from Mycobacterium tuberculosis; and the vortioxetine comprises a pharmaceutically acceptable salt.

5. The use of vortioxetine in combination with bedaquiline, clofazimine, or PBTZ-169 in the preparation of a combined synergistic drug composition for the treatment of mycobacterial infections, wherein the combination of vortioxetine and bedaquiline, clofazimine, or PBTZ-169 exerts an anti-mycobacterial effect, wherein vortioxetine enhances the anti-mycobacterial activity of bedaquiline, clofazimine, or PBTZ-169; wherein the mycobacteria are selected from Mycobacterium tuberculosis; and wherein vortioxetine comprises a pharmaceutically acceptable salt.

6. The use of sertraline in the preparation of potentiators for antimycobacterial infection drugs, wherein the potentiator enhances the antimycobacterial infection effect of bedaquiline with sertraline; wherein the mycobacteria are selected from Mycobacterium tuberculosis; and wherein the sertraline comprises a pharmaceutically acceptable salt.

7. A combined synergistic pharmaceutical composition for combating mycobacterial infections, said pharmaceutical composition being a combination of sertraline and bedaquiline, said pharmaceutical composition having at least one of the following effects: a) Inhibits mycobacterial activity; b) Antibacterial infection; c) Prevention and / or treatment of diseases caused by mycobacterial infection.

8. The composition of claim 7, wherein the mycobacterium is selected from Mycobacterium tuberculosis; and the sertraline comprises a pharmaceutically acceptable salt.

9. The use of sertraline and bedaquiline in the preparation of a combined synergistic pharmaceutical composition for the treatment of mycobacterial infections, wherein the combination of sertraline and bedaquiline exerts an anti-mycobacterial effect, wherein sertraline enhances the anti-mycobacterial activity of bedaquiline; wherein the mycobacteria are selected from Mycobacterium tuberculosis; and wherein the sertraline comprises a pharmaceutically acceptable salt.

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