18 results about "Daptomycin" patented technology

The present disclosure provides daptomycin formulations which have improved chemical stability, faster reconstitution times when reconstituted from the solid state and longer in-use stability. The compositions comprise daptomycin, one basic amino acid or its salt and optionally one or more pH adjusting agents.

The application belongs to the technical field of biological medicine, and particularly relates to a biomimetic nano delivery system based on MRSA outer vesicle coating and application thereof. The application first couples chitosan oligosaccharide and monocarboxylated curcumin through an amide reaction to synthesize an amphiphilic polymer carrier, then loads vancomycin, daptomycin and other drugs through self-assembly to obtain a drug micelle, and finally coats the drug micelle with MRSA outer vesicle to successfully prepare a targeted biomimetic nano delivery system. The prepared biomimetic nano delivery system has excellent antibacterial effect, can realize targeted delivery and long-acting release of antibacterial drugs at an infection site, and is expected to overcome the bottleneck of drug resistance and insufficient drug penetration in traditional treatment, and provides a potential solution for the treatment of diseases such as periprosthetic infection.

The present invention relates to the field of pharmaceutical technology, and in particular, to a daptomycin nano-FORMULATION, a method for preparing same, and use thereof. The method comprises: A, encapsulating daptomycin with a copolymer poly(lactic-co-glycolic acid) to give a nanoparticle (NP); and B, sonicating a cell membrane vesicle overexpressing RANK and the nanoparticle (NP) in a water bath for 3 min, and then sequentially extruding the mixture through polycarbonate membranes of 800 nm, 400 nm, and 200 nm to give the daptomycin nano-formulation. The weight ratio of the membrane protein to PLGA is 0.25. By the method of the present invention, a daptomycin nano-formulation targeting rheumatoid arthritis is successfully prepared. The daptomycin nano-formulation prepared by the present invention has good stability. The daptomycin nano-formulation of the present invention has good therapeutic effects against RA.

The present disclosure relates to a solid formulation of daptomycin comprising at least one branched aliphatic amino acid. Solid daptomycin formulation of the present disclosure shows improved reconstituted time. The disclosure further relates to a method of preparation of the solid daptomycin formulation according to this disclosure.

The application belongs to the technical field of biological medicine, and particularly relates to application of pantothenic acid or a pharmaceutically acceptable salt thereof in preparation of a medicine for enhancing sensitivity of pathogenic bacteria to daptomycin. It is found for the first time that addition of pantothenic acid or a pharmaceutically acceptable salt thereof can improve the sensitivity of gram-positive bacteria including Staphylococcus aureus, Streptococcus agalactiae and Corynebacterium diphtheriae to daptomycin, significantly improve the bactericidal effect, and further research shows that pantothenic acid or a pharmaceutically acceptable salt thereof can promote the clearance, formation and reduction of pathogenic bacteria biofilm by daptomycin. The finding opens up a new way for overcoming antibiotic resistance and optimizing anti-infection treatment strategies.

A preparation method for a stable crystal form of daptomycin, comprising the following steps: (1) dissolving a daptomycin raw material in water and mixing evenly to obtain a daptomycin aqueous solutio

The invention belongs to the technical field of biological medicines, and particularly relates to application of daptomycin in preparation of a non-small cell lung cancer KRAS G12C inhibitor drug resistance reversal agent. It is found that the problem of drug resistance of non-small cell lung cancer to a KRAS inhibitor can be solved through combination of daptomycin and adagraxib, an excellent anti-tumor effect is shown, the drug resistance phenotype mediated by an acquired drug resistance mechanism can be remarkably reversed, no obvious toxic or side effect is observed in an experimental animal body, and the safety characteristic is good. In order to overcome the problem of drug resistance of targeted drugs such as KRAS inhibitors, the invention provides a novel combined treatment solution with high efficiency and safety.

This invention belongs to the field of biomedicine, and specifically relates to a purification method for daptomycin. The purification method includes loading a sample solution onto a C18 resin chromatography column equilibrated with an equilibration buffer, and eluting the C18 resin chromatography column with an eluent; wherein the sample solution, the equilibration buffer, and the eluent contain a sodium salt at a concentration of 0.1–1.0 (w / v)%, and the pH of the sample solution, the equilibration buffer, and the eluent is 6–8; the ethanol content of the sample solution, the equilibration buffer, and the eluent is 5–40%; and the sodium salt is selected from sodium sulfate, sodium phosphate, and sodium chloride. The purification method provided by this invention can achieve efficient removal of impurity 4 and unknown impurities from daptomycin, and the obtained product meets market demand.

The application belongs to the technical field of separation and crystallization, and relates to a preparation method of a stable crystal form of daptomycin. Daptomycin raw materials are dissolved in water and mixed to obtain a daptomycin aqueous solution, acetic acid buffer is added to the daptomycin aqueous solution and mixed to obtain a mixed solution, the mixed solution is vacuum concentrated to obtain a concentrated solution, the concentrated solution is heated and dissolved to obtain a saturated solution system, the saturated solution system is cooled, and after solid is precipitated, stirring is performed at the current crystallization temperature to crystallize; after the crystallization is completed, the system is continuously cooled to obtain a crystallization mother liquor containing daptomycin crystals; finally, the daptomycin crystals are washed at low temperature, daptomycin crystal crude products are collected by centrifugation, and the crude products are dried to obtain daptomycin crystals. The order of the daptomycin crystals prepared by the method is obviously better than that of the daptomycin crystals prepared by the crystallization method reported in the prior art.

The invention discloses a preparation method of a high-purity daptomycin finished product. The method comprises the following steps: firstly, pre-treating and flocculating daptomycin fermentation liquor, and then filtering; separating and purifying the filtrate through macroporous resin adsorption and desorption and ion exchange resin adsorption and desorption, then carrying out nanofiltration concentration, and then carrying out crystallization, suction filtration and drying to obtain a daptomycin crystal crude product; and dissolving the crystallized crude product with purified water, desalting on a column, and separating and purifying through a C18 filler high-pressure preparative column. By using the method, the daptomycin with the purity higher than 98% can be separated and purified from the daptomycin fermentation liquor; the method is simple and convenient in process flow, high in purification and crystallization process purity, high in yield, short in period and strong in operability; solvent materials are low in consumption and non-toxic; the production and operation cost is relatively low, and the obtained product is relatively high in purity and stable in yield; and the method has a good medical industrial enlarged application prospect.

The present disclosure provides daptomycin formulations which have improved chemical stability, faster reconstitution times when reconstituted from the solid state and longer in-use stability. The compositions comprise daptomycin, one basic amino acid or its salt and optionally one or more pH adjusting agents.

The invention belongs to the technical field of biological medicines, and particularly relates to application of daptomycin in preparation of a non-small cell lung cancer EGFR-TKI drug resistance reversal agent. The invention discloses that daptomycin can effectively reverse drug resistance for the first time: in-vitro experiments show that evaluation is performed by adopting an HSA model of SynergyFinder software, and it is found that the drug combination synergy score of daptomycin and osimertinib in H1975 drug-resistant cells is 18.166, which indicates that daptomycin and osimertinib have a strong synergistic effect, and the drug resistance of daptomycin and osimertinib can be effectively reversed. Cloning formation experiments show that the cell proliferation inhibition rate of a drug combination group is increased by more than 80% compared with that of a single drug group, and a strong synergistic effect is achieved. An in-vivo experiment further verifies that the tumor volume of a combined drug group is reduced by about 80% compared with that of an osimertinib single drug group, the tumor weight is obviously reduced, drug-resistant relapse does not occur in a treatment period of 22 days, and meanwhile, the stability of the weight of a mouse shows that the safety is good. The invention provides a combined treatment scheme with high efficiency and safety for overcoming EGFR-TKI drug resistance, and has important clinical transformation value.

The application discloses a synthesis method of daptomycin, and the daptomycin is prepared through a full liquid-phase fragment method; two full-protection fragments are prepared through the liquid-phase method by using two glycine sites contained in the daptomycin; the two full-protection peptide segments are condensed to form full-protection daptomycin; and after the protection groups are removed through acid cutting, the daptomycin is formed through an STL ring closing technology. The application solves the problems of low ring closing efficiency, low product purity after ring closing and many polymeric impurities of other ring closing technologies, so that the efficient preparation of the daptomycin is realized, and the application has the characteristics of less reagent and amino acid usage, less by-product and impurity production in the preparation process, high product purity and high yield compared with other preparation methods.

When employed, a recombinant expression vector carrying a daptomycin production gene including a foreign fatty acyl AMP ligase (FAAL) gene, a thioesterase (TE) gene, and a fatty acid synthase (FAS) gene according to the present invention can enhance specificity for decanoic acid, and produce daptomycin without supplementation of lipopeptides, such as decanoic acid, from the outside of the strain. In addition, no by-products are generated during the production process, thereby enabling production of daptomycin with high purity and high yield.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a daptomycin beta isomer. The invention discloses a preparation method of a daptomycin beta isomer, which comprises the following steps: S1, dissolving a crude product containing the daptomycin beta isomer to obtain a loading solution; s2, separating and purifying the loading solution through preparative chromatography to obtain a primary preparation solution; s3, concentrating the primary preparation solution to obtain a primary concentrated solution, and separating and purifying the primary concentrated solution through preparative chromatography to obtain a secondary preparation solution; s4, concentrating the secondary preparation solution to obtain a secondary concentrated solution, and separating and purifying the obtained secondary concentrated solution through preparative chromatography to obtain a third preparation solution; and S5, sequentially desalting, concentrating and freeze-drying the tertiary preparation solution to obtain the high-purity daptomycin beta isomer. The method disclosed by the invention is rapid, simple, convenient and low in cost, and the purity of the obtained daptomycin beta isomer is higher than 99%.

The invention relates to the technical field of food safety detection, in particular to a method for rapidly detecting daptomycin in meat food. The core of the method comprises the following steps: a chimeric probe composed of a daptomycin aptamer sequence, a DNA enzyme sequence and a flexible joint sequence is utilized, the probe generates conformational change in the presence of daptomycin and activates the cleavage activity of DNA enzyme, and then a quenching-reporter group labeled substrate chain is cleaved to generate a fluorescence signal; the method also optionally comprises the step of purifying and separating the reacted system by using a magnetic microsphere modified with a capture chain so as to reduce background interference. According to the method, high-specificity and high-sensitivity rapid quantitative detection on the daptomycin in the meat sample is realized under the condition that a complex instrument and a tedious process are not needed.

The invention provides a method for synergistically improving fermentation yield of daptomycin based on metabolic flux regulation and control, which comprises the following steps: inoculating a daptomycin seed solution into a daptomycin fermentation culture medium for fermentation, supplementing a capric acid precursor in stages in the fermentation process, coupling a carbon source for starvation induction, adding acetyl coenzyme A to relieve a metabolic bottleneck at the same time, and carrying out fermentation to obtain the daptomycin fermentation yield. And feeding the corn steep liquor and the amino acid powder in a fermentation secondary metabolism stage, and controlling the synthesis direction in combination with feeding, so that the metabolic flux and the precursor utilization rate are improved, and the daptomycin is obtained. In the fermentation process, capric acid precursors are supplemented in stages, carbon source starvation induction is coupled, meanwhile, acetyl coenzyme A is added to relieve the metabolic bottleneck, corn steep liquor and amino acid powder are fed in the fermentation secondary metabolism stage, the synthesis direction is controlled in combination with material supplementation, the metabolic flux and the precursor utilization rate are improved, and therefore main components are increased, and impurities are reduced.

The invention discloses a daptomycin modifier as well as a synthesis method and application thereof, and the daptomycin modifier is obtained by modifying a Trp1 site of daptomycin. The structure is shown as a general formula (I). Wherein R is an aromatic group or an aromatic sulfur group with alkyl, alkyl substituent, alkoxy, hydroxyl, nitryl or halogen substituent. The synthesis method is simple and easy to obtain, the synthesis efficiency is high, and the time cost and raw material cost are reduced. An in-vitro antibacterial experiment, a hemolytic activity experiment and an in-vitro serum stability experiment show that the synthesized daptomycin modifier is more effective in resisting gram-positive bacteria, particularly MRSA and biological membrane infection caused by the MRSA, is safe, low in toxicity and good in stability, has a good application prospect in the aspect of preparing clinical antibacterial drugs, and has a wide application prospect. The compound is expected to become a novel antibiotic candidate drug.