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CN-121987640-A - Application of combination composition nano particles in preparation of medicines for resisting fungal and bacterial infection

CN121987640ACN 121987640 ACN121987640 ACN 121987640ACN-121987640-A

Abstract

The invention relates to application of a combination composition nanoparticle in preparing medicines for resisting fungal and bacterial infection, wherein the active components of the combination composition nanoparticle are antibiotics and antibiotic adjuvants, and the antibiotic adjuvants are tripterine or pharmaceutically acceptable salts thereof. According to the invention, the tripterine or the pharmaceutically acceptable salt thereof and the antibiotics are prepared into nano particles by utilizing a nano technology, so that the solubility of the fat-soluble antibiotics is effectively improved, the biocompatibility of the tripterine or the pharmaceutically acceptable salt thereof is improved, and the tripterine or the pharmaceutically acceptable salt thereof has excellent effects in resisting fungal and bacterial infections. Wherein the tripterine or the pharmaceutically acceptable salt thereof can enhance the antibacterial effect of antibiotics, especially antifungal effect, increase the antibacterial sensitivity of antibiotics and inhibit the occurrence of fungal or bacterial drug resistance.

Inventors

  • LIU JING
  • WANG MINGGE

Assignees

  • 国家纳米科学中心

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. The application of the combination composition nano-particles in preparing medicines for resisting fungal and bacterial infection is characterized in that the active components of the combination composition are antibiotics and antibiotic adjuvants, and the antibiotic adjuvants are tripterine or pharmaceutically acceptable salts thereof.
  2. 2. The use according to claim 1, wherein the fungus comprises any one or a combination of at least two of candida albicans, candida glabrata, candida tropicalis, candida krusei, aspergillus fumigatus, aspergillus niger, aspergillus flavus, aspergillus oryzae, fusarium, cryptococcus neoformans, candida, mucor, histoplasma capsulatum, cercospora, coccidioides, cryptococcus gatus, or paracoccidioidosporic; The bacteria include any one or a combination of at least two of klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, escherichia coli, salmonella, shigella, streptococcus pneumoniae, staphylococcus aureus, mycobacterium tuberculosis or clostridium difficile.
  3. 3. The use according to claim 1, wherein the combination composition nanoparticle comprises a carrier-free nanoparticle formed from an antibiotic and an antibiotic adjuvant, wherein the antibiotic adjuvant is tripterine or a pharmaceutically acceptable salt thereof; Preferably, the antibiotic is selected from any one or a combination of at least two of amphotericin B, nystatin, miconazole, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, terbinafine, caspofungin, micafungin, anidulafungin, griseofulvin, penicillin, amoxicillin, ampicillin, cefradine, ceftazidime, imipenem, amikacin, gentamicin, doxycycline, tetracycline, minocycline, erythromycin, clarithromycin, azithromycin, sulfadiazine, ciprofloxacin, levofloxacin, metronidazole, clindamycin or fosfomycin; Preferably, the molar ratio of the antibiotic to the antibiotic adjuvant is 1 (0.001-500).
  4. 4. The use according to claim 3, wherein the unsupported nanoparticles are prepared by a preparation process comprising the steps of: (1) Dissolving tripterine or pharmaceutically acceptable salts thereof and hydrophobic antibiotics in a good solvent to obtain a solution A; (2) Adding the solution A into a poor solvent of tripterine or pharmaceutically acceptable salt and hydrophobic antibiotics to obtain a solution B; (3) And (3) stirring the solution B, and separating the free drug to obtain the carrier-free nano-particles.
  5. 5. The use according to claim 4, wherein the good solvent comprises any one or a combination of at least two of methanol, ethanol, propanol, isopropanol, acetone, tetrahydrofuran or dimethyl sulfoxide; preferably, the poor solvent comprises deionized water and/or phosphate buffer; preferably, the stirring time is 5-60min; preferably, the separation of free medicine adopts ultrafiltration centrifugation, and the condition of ultrafiltration centrifugation is that the rotating speed is 8000-10000g, and the duration is 10-30min.
  6. 6. The use according to claim 1, wherein the combination composition nanoparticle comprises a complex liposome prepared from an antibiotic, an antibiotic adjuvant, a lipid, and cholesterol as raw materials, wherein the antibiotic adjuvant is celastrol or a pharmaceutically acceptable salt thereof; Preferably, the antibiotic is selected from any one or a combination of at least two of amphotericin B, nystatin, miconazole, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, terbinafine, caspofungin, micafungin, anidulafungin, griseofulvin, penicillin, amoxicillin, ampicillin, cefradine, ceftazidime, imipenem, amikacin, gentamicin, doxycycline, tetracycline, minocycline, erythromycin, clarithromycin, azithromycin, sulfadiazine, ciprofloxacin, levofloxacin, metronidazole, clindamycin or fosfomycin; preferably, the molar ratio of the antibiotic to the antibiotic adjuvant is 1 (0.001-500); preferably, the lipid comprises any one or a combination of at least two of phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidic acid, cardiolipin, sphingomyelin, phosphatidylserine, DSPE-PEG, or fluorinated modified DSPE-PEG.
  7. 7. The use according to claim 6, wherein the complex liposome is prepared by a preparation method comprising the steps of: (1) Mixing the first solvent, the tripterine or the pharmaceutically acceptable salt thereof, the hydrophobic antibiotics, the phospholipids and the cholesterol to obtain a solution A; (2) Removing the first solvent in the solution A, mixing with the solution B for hydration to obtain a solution C; (3) Performing ultrasonic and gradient extrusion on the solution C to obtain the composite liposome; preferably, the first solvent comprises any one or a combination of at least two of methanol, ethanol, propanol or chloroform, and the second solvent comprises deionized water and/or phosphate buffer solution; preferably, the hydration time is 10-60min and the temperature is 15-35 ℃; preferably, the pore diameter of the gradient extruded filter membrane is 400nm and 200nm in sequence; preferably, the ultrasonic treatment in the step (3) is carried out at 0-10 ℃, the power of ultrasonic treatment is 80-250W, and the time of ultrasonic treatment is 3-30min.
  8. 8. The use according to claim 6, wherein the complex liposome is prepared by a preparation method comprising the steps of: (1) Mixing the first solvent, phospholipid and cholesterol to obtain solution A, mixing tripterine or pharmaceutically acceptable salt thereof, antibiotics and organic solvent, and dropwise adding into the second solvent to obtain solution B; (2) Removing the first solvent in the solution A, mixing with the solution B for hydration to obtain a solution C; (3) Performing ultrasonic and gradient extrusion on the solution C to obtain the composite liposome; Preferably, the first solvent comprises any one or a combination of at least two of methanol, ethanol, propanol or chloroform, the organic solvent comprises any one or a combination of at least two of methanol, ethanol, DMF or DMSO, and the second solvent comprises deionized water and/or phosphate buffer; preferably, the hydration time is 10-30min and the temperature is 15-35 ℃; preferably, the ultrasonic treatment in the step (3) is carried out at 0-10 ℃, the power of ultrasonic treatment is 80-250W, and the time of ultrasonic treatment is 3-30min; preferably, the pore size of the gradient extruded filter membrane is 400nm and 200nm in sequence.
  9. 9. The use according to claim 1, wherein the combination composition nanoparticles comprise composite polymer nanoparticles prepared from antibiotics, antibiotic adjuvants and pharmaceutically degradable polymers, wherein the antibiotic adjuvants are tripterine or pharmaceutically acceptable salts thereof; Preferably, the antibiotic is selected from any one or a combination of at least two of amphotericin B, nystatin, miconazole, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, flucytosine, terbinafine, caspofungin, micafungin, anidulafungin, griseofulvin, penicillin, amoxicillin, ampicillin, cefradine, ceftazidime, imipenem, amikacin, gentamicin, doxycycline, tetracycline, minocycline, erythromycin, clarithromycin, azithromycin, sulfadiazine, ciprofloxacin, levofloxacin, metronidazole, clindamycin or fosfomycin; preferably, the molar ratio of the antibiotic to the antibiotic adjuvant is 1 (0.001-500); Preferably, the pharmaceutically degradable polymer comprises any one or a combination of at least two of PLGA, PEG, mPEG-PLGA or DSPE-PEG.
  10. 10. The use according to claim 9, wherein the composite polymer nanoparticle is prepared by a preparation method comprising the steps of: (1) Mixing the first solvent with pharmaceutically-degradable polymer to obtain solution A, mixing tripterine or pharmaceutically-acceptable salt thereof, antibiotics and organic solvent, and dropwise adding into a second solvent containing emulsifying agent to obtain solution B; (2) Mixing the solution A with the solution B to obtain a solution C; (3) Adding the solution C into a third solvent containing an emulsifier, and mixing to obtain a solution D; (4) Removing the residual first solvent in the solution D to obtain the composite polymer nano-particles; Preferably, the first solvent comprises any one or a combination of at least two of methanol, ethanol, propanol or dichloromethane, the organic solvent comprises any one or a combination of at least two of methanol, ethanol, DMF or DMSO, the second solvent comprises deionized water and/or phosphate buffer solution, and the third solvent comprises deionized water and/or phosphate buffer solution; preferably, each group of emulsifiers in the second solvent, third solvent independently comprises any one or a combination of at least two of polyvinyl alcohol, tween-80 or vitamin E polyethylene glycol succinate; preferably, the mass fraction of the emulsifier in the second solvent is 3% -15%, and the mass fraction of the emulsifier in the third solvent is 30% -60%.

Description

Application of combination composition nano particles in preparation of medicines for resisting fungal and bacterial infection Technical Field The invention belongs to the field of biological medicine, and relates to application of a combination composition nanoparticle in preparation of a medicament for resisting fungal and bacterial infection. Background Bacterial and fungal infections are important causes of human death, and the discovery of antibiotics greatly reduces the death of patients with bacterial and fungal infections. However, the abuse of antibiotics has led to the rapid development of multi-drug resistant bacteria, which constitutes a long-term threat to human health, sustainable production and development of food. The development difficulty of the novel antibiotics is high, the development period is long, and the clinical treatment of drug-resistant bacteria infection is severely limited. The advent of the latter antibiotic era has prompted us to develop new therapeutic regimens to address the state of optimistically ill-antibiotic resistance. The discovery of antibiotic adjuvants brings hopes for coping with the current situation that the development of novel antibiotics is hindered and the existing medicines are difficult to cope with drug-resistant bacteria infection. The antibiotic adjuvant plays a role in enhancing the curative effect of antibiotics by being combined with the antibiotics, provides new hope for restoring the pharmaceutical activity of the existing antibiotics and inhibiting the generation of drug resistance, and provides an orthogonal strategy for the discovery of novel antibiotics. The nanometer technology has the effects of improving the bioavailability of the medicine and reducing the toxic and side effects of the medicine. The advent of nanotechnology has brought new strategies to increase the water solubility and bioavailability of hydrophobic drugs. The tripterygium wilfordii also called Huang Lateng and shikimia aquatica have various effects of dispelling wind and removing dampness, activating blood and removing obstruction in collaterals, relieving swelling and pain, diminishing inflammation and detoxifying and the like. Tripterine (Celastrol, CST), also known as celastrol, is a triterpene active ingredient in Tripterygium wilfordii extract, and has various biological activities. The research shows that the tripterine has the functions of resisting tumor, rheumatoid disease, parkinsonism and the like. Disclosure of Invention Aiming at the defects of the prior art, the invention aims to provide an application of a combination composition nanoparticle in preparing medicines for resisting fungal and bacterial infection. In order to achieve the aim of the invention, the invention adopts the following technical scheme: In a first aspect, the invention provides an application of a combination composition nanoparticle in preparing a medicament for resisting fungal and bacterial infection, which is characterized in that the active components of the combination composition are antibiotics and antibiotic adjuvants, and the antibiotic adjuvants are tripterine or pharmaceutically acceptable salts thereof. According to the invention, the tripterine or the pharmaceutically acceptable salt thereof and the antibiotics are prepared into nano particles by utilizing a nano technology, so that the solubility of the fat-soluble antibiotics is effectively improved, the biocompatibility of the tripterine or the pharmaceutically acceptable salt thereof is improved, and the tripterine or the pharmaceutically acceptable salt thereof has excellent effects in resisting fungal and bacterial infections. Wherein the tripterine or the pharmaceutically acceptable salt thereof can enhance the antibacterial effect of antibiotics, especially antifungal effect, increase the antibacterial sensitivity of antibiotics and inhibit the occurrence of fungal or bacterial drug resistance. Preferably, the fungus comprises any one or a combination of at least two of candida albicans, candida glabrata, candida tropicalis, candida krusei, aspergillus fumigatus, aspergillus niger, aspergillus flavus, aspergillus oryzae, fusarium, cryptococcus neoformans, candida, mucor, histoplasma capsulatum, cercospora, coccidioides, cryptococcus garteus, or paracoccidiosis. Preferably, the bacteria include any one or a combination of at least two of klebsiella pneumoniae, acinetobacter baumannii, pseudomonas aeruginosa, escherichia coli, salmonella, shigella, streptococcus pneumoniae, staphylococcus aureus, mycobacterium tuberculosis, or clostridium difficile. The combined composition nano-particles related to the invention comprise the following three forms: the combined composition nano-particles comprise carrier-free nano-particles formed by antibiotics and antibiotic adjuvants, wherein the antibiotic adjuvants are tripterine or pharmaceutically acceptable salts thereof. Preferably, the antibiotic is selected from any one o