Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4965—Non-condensed pyrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
  • A61P31/06—Antibacterial agents for tuberculosis

Definitions

• the present invention relates to a new use of medicine, in particular to the application of nintedanib in the preparation of medicines for treating tuberculosis.
• Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) infection. It is still the single infectious disease that causes the largest number of deaths. Mycobacterium tuberculosis infection usually results in lesions characterized by granulomatous inflammation, destruction of lung parenchyma, and interstitial fibrosis.
• Existing chemotherapy regimens have problems such as long treatment courses, many side effects, and poor results.
• standard anti-tuberculosis treatment regimens are highly effective against drug-susceptible TB and can achieve microbiological cure, more than two-thirds of patients develop extensive structural lung changes after treatment, and more than half have permanent lung function. damage.
• pulmonary tuberculosis Secondary fibrosis of pulmonary tuberculosis is a common pulmonary impairment after TB (PIAT). Extensive pulmonary fibrosis not only seriously affects the patient's lung function, but also makes tuberculosis bacteria wrapped in fibers, making it difficult for drugs to completely kill the bacteria and prone to recurrence.
• Mycobacterium tuberculosis co-evolves with the human immune system and persists in infected cells through multiple pathways, causing severe pathology and tissue damage to the host, thereby reducing the therapeutic efficacy of existing antibiotics and conducive to the development of drug resistance.
• Host-directed therapy is an emerging treatment method in the field of anti-infection and a new and effective auxiliary treatment method for tuberculosis.
• the HDT approach can (1) enhance the effect of antibiotics, (2) shorten the duration of TB treatment, (3) prevent relapse, and (4) improve immunopathology, including TB-related matrix destruction and fibrosis, which interfere with Penetration and efficacy of antituberculosis drugs.
• cytokines such as tumor necrosis factor alpha (TNF- ⁇ ), transforming growth factor beta (TGF ⁇ ), and interleukin 1 ⁇ (IL-1 ⁇ ) mediate the development of fibrosis and may contribute to the development of fibrosis in patients with advanced chronic tuberculosis of respiratory failure. This data highlights the need for HDT approaches targeting collagen deposition and fibrosis formation.
• Nintedanib (BIBF1120) is a potent intracellular inhibitor of tyrosine kinase. Its ethyl sulfonate is used clinically. Its structural formula is as follows:
• nintedanib ethyl sulfonate is a soft capsule preparation and is clinically used to treat idiopathic pulmonary fibrosis (IPF).
• IPPF idiopathic pulmonary fibrosis
• TGF transforming growth factor
• PDGF platelet-derived growth factor
• FGF fibroblast growth factor
• VEGF vascular endothelial growth factor
• PDGFR platelet-derived growth factor receptor
• FGFR fibroblast growth factor receptor
• VAGFR vascular endothelial growth factor receptor
• Nintedanib inhibits PDGFR, FGFR, and VEGFR, thereby limiting the effects of profibrotic mediators released from damaged ECM.
• Nintedanib may have dual beneficial effects in reducing fibrosis and granulomatous angiogenesis because it acts as a VEGFR inhibitor.
• nintedanib can be used for the treatment of tuberculosis.
• the present invention provides the use of nintedanib or its pharmaceutically acceptable salts alone or in combination with other anti-tuberculosis drugs in the preparation of drugs for the treatment of tuberculosis.
• the medicinal salt of nintedanib is nintedanib ethyl sulfonate.
• Tuberculosis in the present invention is an infectious disease caused by Mycobacterium tuberculosis infection. Tuberculosis that occurs in the lungs is pulmonary tuberculosis, and tuberculosis that occurs outside the lungs is extrapulmonary tuberculosis.
• anti-tuberculosis drugs are selected from: rifampicin, isoniazid, pyrazinamide, ethambutol, fluoroquinolones, streptomycin, fluoroquinolones, kanamycin , amikacin, capreomycin, sodium para-aminosalicylate, ethionamide, cycloserine, clofazimine, linezolid.
• nintedanib ethyl sulfonate is: 50-300 mg/d; taken orally, 1-3 times a day.
• Another object of the present invention is to provide a pharmaceutical composition composed of nintedanib and other anti-tuberculosis drugs, specifically composed of nintedanib ethyl sulfonate and isoniazid, rifampicin, pyrazinamide Prepared by mixing several drugs.
• the present invention unexpectedly finds that the nintedanib of the present invention has the effect of treating tuberculosis.
• the present invention found in further experiments that the combination of nintedanib ethyl sulfonate and rifampicin, or nintedanib ethyl sulfonate and isoniazid (H), rifampicin (R), pyridoxine,
• H isoniazid
• R rifampicin
• pyridoxine pyridoxine
• the present invention provides a combined application of nintedanib ethyl sulfonate and rifampicin, or nintedanib ethyl sulfonate and isoniazid (H), rifampicin (R) ), a combination of pyrazinamide to treat tuberculosis.
• the combination includes taking both at the same time or one after another.
• the dosage is the effective dose of each, such as taking 150 mg of nintedanib ethyl sulfonate. Fuping 450mg-600mg, once a day. If nintedanib ethyl sulfonate is used in combination with isoniazid (H), rifampicin (R), or pyrazinamide (Z), each drug can be administered according to the standard administration method.
• the present invention further provides a compound pharmaceutical preparation prepared from nintedanib ethyl sulfonate and rifampicin as active pharmaceutical ingredients.
• the compound pharmaceutical preparation can be any oral preparation form, such as tablets dosage forms, capsules, granules, etc., and can also be in the form of soft capsules.
• both contents are their respective effective doses.
• each tablet contains 50-300 mg of nintedanib ethyl sulfonate and 50-300 mg of rifampicin.
• each tablet contains 150 mg of nintedanib ethyl sulfonate and 450 mg-600 mg of rifampicin.
• the present invention also provides relevant experimental effects of nintedanib.
• the present invention Compared with existing tuberculosis drug treatment, the present invention has the following advantages:
• nintedanib has anti-tuberculosis activity
• 3Shortened treatment course sensitive tuberculosis is expected to be shortened to 4-5 months;
• Figure 3 Alveolar inflammation score at 4W of treatment and alveolar inflammation score at 8W of treatment
• Row AF is the positive/negative control well, INH, RFP, PFD, SC1011, and BIBF1120. Take a 96-well plate and dilute each drug-containing well one-fold. After culturing for 7 days at 37°C, add 20 ⁇ l of Alma Blue and 12.5 ⁇ l of 20% Tween-80 to each well, continue culturing at 37°C for 24 hours, and record the color of each well. Blue indicates no bacterial growth, red indicates bacterial growth, and MIC Indicates the lowest drug concentration that changes from blue to red. Repeat the test 3 times. The results show that nintedanib has antibacterial activity, and the MIC value against the H37Rv standard strain is: 24.567ug/ml.
• the microbroth dilution method was used to determine the minimum drug concentration (MIC90) when the drug inhibits 90% of the growth of Mycobacterium tuberculosis. Then, based on the MIC value of each drug when used alone, the two-fold dilution method was used to dilute BIBF1120 and RFP to 6 concentrations, from 2 ⁇ MIC-1/16 ⁇ MIC. Add 50 ⁇ l of 2MIC-1/16MIC A solution (BIBF1120) to the second column of the 96-well plate, and add 50 ⁇ l of 2 ⁇ MIC-1/16 ⁇ MIC B solution (RFP) to the first 7 wells of rows 2-7.
• MIC90 minimum drug concentration
• FICI 0.5
• FICI 1, the two drugs have a synergistic effect;
• the results showed that the combination of the two drugs showed antibacterial activity.
• the intracellular bactericidal activity of macrophages was used to evaluate the anti-tuberculosis activity of BIBF1120 single drug and BIBF1120+RFP combination.
• the specific operation method is as follows: collect J774A.1 macrophages into a 50ml centrifuge tube, take 100ul of macrophages and 900ul of cell culture medium, and add them to a 1.5ml sterile centrifuge tube for a 10-fold dilution. Count under microscope. Dilute the macrophages to 4* 105 cells/ml and spread them gently in a 48-well transparent microplate, with 1ml per well.
• the H37Rv strain in the logarithmic growth phase was diluted with 20 ml 1 ⁇ PBS to a bacterial concentration of 1 ⁇ 10 7 CFU/ml, and 6-8 week old female C57BL/6 mice were aerosol infected.
• a chronic mouse tuberculosis model of aerosol infection was established, and the antibacterial activity of each treatment group was evaluated using this model.
• D-32 3 mice were randomly selected and sacrificed, and on the day of administration and treatment (D0), 6 mice were randomly selected and sacrificed.
• the spleen and lung tissues were dissected and homogenized, and the spleen and lung tissues were homogenized on 7H10 plates.
• CFU Lung colony-forming unit
• D day; W: weekly isoniazid: 10mg/kg/d; rifampicin: 10mg/kg/d; pyrazinamide: 150mg/kg/d; pirfenidone PFD: 100mg/kg/d; BIBF1120: 50mg /kg/d; RFP and other drugs should be administered at least 1 hour apart
• BIBF1120+HRZ treatment group and the HRZ treatment group had significant bactericidal effects at 4 and 8 weeks after administration. Among them, BIBF1120 can achieve sterility of the spleen and lungs after 8 weeks of administration. In addition, the addition of BIBF1120 may shorten the treatment time of tuberculosis and achieve sterility earlier.
• the BIBF1120+HRZ treatment group can reduce the recurrence rate of mice compared with the HRZ treatment group.
• Assay using HYP detection kit Determination of hydroxyproline content in right lung tissue. Dissect and separate fresh lung tissue, weigh it, place it in a test tube, and add exactly 1 ml of hydrolyzate. Water bath in water bath for 20 minutes. Adjust the pH to about 6.0-6.8. Then add distilled water to 10ml, take 4ml of the diluted hydrolyzate and add an appropriate amount of activated carbon. Centrifuge at 3500r/min for 10min, and take 1ml of the supernatant for detection. Blank tubes and standard tubes represent distilled water and standard products respectively. Add each reagent in sequence according to the instructions.
• a test the absorbance of the measurement tube;
• a blank the absorbance of the blank tube;
• a standard the absorbance of the standard tube.
• a mark absorbance of standard tube.
• Lung histopathological observation The left lung tissue of the mouse was trimmed and fixed in 4% paraformaldehyde. After the fixation was in good condition, it was washed with physiological saline and fixed in 4% paraformaldehyde solution, embedded in conventional paraffin, and made into 3 ⁇ m Paraffin sections were sectioned and HE stained to observe the pathological changes of the lung tissue. The pathological changes of the lung tissue were observed under a light microscope. The degree of inflammatory infiltration was described and the pathological lung injury score was performed.
• Masson staining was performed according to the instructions in the kit instructions.
• the sections were routinely dewaxed to water, soaked in Masson A liquid overnight, mixed with Masson B liquid and Masson C liquid in equal proportions and soaked for 1 min, soaked in Masson D liquid for 6 min, Masson E liquid for 1 min, Masson F liquid for 2-30 s, rinsed and differentiated with 1% glacial acetic acid , dehydrated with anhydrous ethanol, transparent with xylene, mounted with neutral gum, and observed with an ordinary optical microscope.
• Collagen fibers are blue; muscle fibers, cellulose and red blood cells are red.
• the immunohistochemistry results show that the expression of CD31 in the BIBF1120+HRZ treatment group is reduced compared to the HRZ treatment group; it can be initially speculated that the auxiliary anti-tuberculosis treatment effect of BIBF1120 may be through inhibiting abnormal vascular proliferation. , increasing the delivery of small molecule compounds (anti-tuberculosis drugs) to exert better anti-tuberculosis activity.

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