39 results about "Amethopterin" patented technology

The invention discloses a methotrexate-cationic polypeptide conjugate as well as a preparation method and application thereof, and belongs to the technical field of medicinal chemistry. According to the conjugate, MTX and cationic polypeptide with the amino acid sequence shown as SEQ ID NO: 1 are connected through chemical bonding, the membrane binding characteristic of oligomeric lysine and the transmembrane capacity of TAT cell-penetrating peptide are creatively fused, and a polypeptide carrier system with efficient cell penetrating capacity is constructed; mTX obtains amphipathy and electropositivity through peptide fragment modification, stable nanoparticles can be spontaneously formed, and the problems of poor water solubility and instable acidity of raw material medicines are effectively improved; according to the conjugate, the accumulation efficiency of the medicine at a diseased region is remarkably improved by utilizing the targeting characteristic of the polypeptide carrier, the action time of the medicine is prolonged through a precise delivery mechanism, and meanwhile, the system toxicity is reduced. The preparation method adopts mild coupling reaction conditions, and the product is high in purity and excellent in stability; the compound is suitable for treating immune-mediated inflammatory diseases and specific malignant tumors, and provides an innovative solution thought for treating related diseases.

The invention discloses an SNP (Single Nucleotide Polymorphism) site related to the risk of liver injury caused by methotrexate and application of the SNP site. The SNP is located at 31, 356 and 966bp positions of a No.6 chromosome of a human GRCh38 genome, and the basic group of the SNP is C or G. According to the scheme, the SNP site related to the methotrexate liver injury is provided, the risk of the liver injury caused by methotrexate can be effectively predicted, and the SNP site serves as a marker for predicting the liver injury caused by methotrexate.

The object of the invention is to search for novel drug or method for treating autoimmune diseases by means of a combination of methotrexate and 5-ALAs.[Selected Drawings] None.

The invention relates to the technical field of biological medicine, in particular to a multifunctional ternary complex based on cyclodextrin and a preparation method thereof. The invention provides a multifunctional curcumin / methotrexate ternary complex based on beta-cyclodextrin. The ternary complex can realize synergistic delivery and controlled-release release of natural polyphenol and synthetic drugs in a medication mode of'one dose with multiple effects'. Meanwhile, the problems that a traditional medicine is poor in water solubility and low in bioavailability, the treatment effect of a single medicine is limited, and an existing nano delivery system is complex in structure, tedious in preparation and the like are solved, and the technical requirements of modern medicine preparations are met.

The invention relates to the technical field of pharmaceutical analysis, in particular to a method for detecting the content of chloride ions in methotrexate injection. According to the method, ion chromatography is adopted for detection, a chromatographic column is an anion chromatographic column, a mobile phase is 0.015 mol / L anhydrous sodium carbonate solution, and the mobile phase is subjected to isocratic elution. By adopting the method disclosed by the invention, the content of chloride ions in the methotrexate injection can be effectively detected, the method has the advantages of strong specificity, high sensitivity and the like, and the quality of the methotrexate injection is effectively guaranteed.

This invention discloses a hyaluronic acid-phenylboronic acid-methotrexate antitumor conjugate and its preparation method in the field of drug preparation technology. First, hyaluronic acid is activated with carboxylic acid, then subjected to an amidation reaction with 3-aminophenylboronic acid to obtain a hyaluronic acid-phenylboronic acid conjugate. Next, methotrexate is activated and added to the hyaluronic acid-phenylboronic acid mixture, followed by stirring to obtain the hyaluronic acid-phenylboronic acid-methotrexate antitumor conjugate. The preparation method of this invention is simple. While the three drugs exert their respective effects, the introduction of phenylboronic acid enhances the targeted antitumor effect of the drug. The combined use of hyaluronic acid and phenylboronic acid further reduces the toxic side effects of methotrexate and improves the biocompatibility, bioavailability, and degradability of the resulting drug, making it suitable for application in the preparation of antitumor drugs.

The present application is a dry granulation method of methotrexate tablets, comprising: mixing methotrexate and excipients by geometric dilution method, and adopting roll pressing method and directly pressing to obtain methotrexate tablets. The excipients include anhydrous lactose, microcrystalline cellulose, pre-gelatinized starch and sodium carbonate. The content of methotrexate in each methotrexate tablet is 2-3%. The present application has the advantages that the components and method design are reasonable, the cost and energy can be effectively saved, the solvent contact in the granulation process is reduced, the time is saved, the stability of the pharmaceutical preparation components can be effectively improved, and the production efficiency is improved.

According to the preparation method of the chlorogenic acid-methotrexate soluble microneedle, chondroitin sulfate and a methyl vinyl ether-maleic anhydride copolymer are adopted as matrix materials, and the drug-loaded microneedle is prepared through a two-step centrifugation method. The length of a needle body of the prepared microneedle is about 500 microns, the microneedle has good mechanical strength and skin puncture performance, the microneedle can be basically dissolved within 2 hours, the average drug content of chlorogenic acid is 57.97 + / -1.76 mu g / tablet, and the average drug content of methotrexate is 56.32 + / -1.67 mu g / tablet. An in-vitro percutaneous penetration test shows that the 6-hour cumulative transdermal rate of chlorogenic acid reaches 93.96%, the 6-hour cumulative transdermal rate of methotrexate reaches 86.92%, which are respectively 22.1 times and 3.0 times that of a control solution group, so that the efficient percutaneous delivery of the medicine is realized. The microneedle is small in skin irritation, the skin barrier can be naturally repaired within 15 minutes after puncture, and a new administration approach is provided for treatment of skin diseases such as psoriasis.

Provided herein are compositions comprising disodium levofolinate. Also provided are processes for preparing compositions comprising disodium levofolinate. Also provided are compositions comprising disodium levofolinate prepared by the processes provided herein. Also provided are methods of treating folic acid deficiency in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering 5-fluorouracil and a composition provided herein to the subject. Also provided are methods of reducing the immediate toxic effects of methotrexate overdose in a subject in need thereof, comprising administering a composition provided herein to the subject. Also provided are methods of treating cancer in a subject in need thereof, comprising administering high-dose methotrexate and a composition provided herein to the subject. Also provided are methods of treating megaloblastic anemia in a subject in need thereof, comprising administering a composition provided herein to the subject.

The application discloses a method for efficiently synthesizing methotrexate, and relates to the technical field of methotrexate preparation. The method comprises the following steps: preparing three intermediates, and then preparing methotrexate by using the three intermediates. In the process of preparing the intermediates, a step of improving the purity of tribromoacetone is added, so that the content of the tribromoacetone is increased from 89-90% to more than 98%, thereby reducing the separation difficulty of the product, reducing the generation of impurities, and improving the yield; in the step of preparing the methotrexate, a new catalyst is used, sodium acetate trihydrate and potassium dihydrogen phosphate are used as a composite catalyst, and the yield of the methotrexate is improved.

The invention discloses a method for determining related substances in methotrexate, which comprises the following steps: firstly preparing an impurity C positioning solution, a system applicability solution and a test solution, then respectively carrying out liquid chromatography detection on the impurity C positioning solution, the system applicability solution, a reference substance solution and the test solution, recording chromatograms, and determining the content of the related substances in methotrexate according to the chromatograms. And performing quantitative analysis on the impurity C and other impurities in the test solution by comparing the chromatograms. According to the method, a system applicable solution is prepared by destroying a main component reference substance solution, the solution is a mixed solution containing an impurity B, an impurity C and methotrexate, the impurity C can be positioned, and the separation degree between the impurity B and the impurity C is controlled to be not less than 1.5.

A composition for preventing or treating a TNF-α-related disease is disclosed. The composition includes hydroflumethiazide or a pharmaceutically acceptable salt thereof as an active ingredient. The composition can effectively inhibit the expression or activity of TNF-α and exhibits an excellent treatment effect compared to methotrexate (MTX) or hydroxychloroquine (HCQ), which are rheumatoid arthritis treatment agents currently on the market, and, thus, can be effectively used for prevention or treatment of a TNF-α-related disease.

The invention belongs to the technical field of medicine, and particularly relates to a method for identifying skin mucosal lesions of ALL patients after HD-MTX treatment based on a column diagram, and the column diagram for predicting the skin mucosal lesions after acute lymphocytic leukemia patients receive high-dose methotrexate scheme treatment is established based on a multi-element logistic regression model, a decision tree and a neural network result. The method comprises the following steps: (1) determining risk factors of treating the skin mucosal lesion of an acute lymphocytic leukemia (ALL) patient by a large dose of methotrexate through a multivariate logistic regression model; (2) establishing the occurrence conditions of the skin mucosal lesion of the acute lymphocytic leukemia patient by using a decision tree model; and (3) the primary and secondary relationship between the 48-hour methotrexate blood concentration and the acute lymphocytic leukemia patient is found by using a neural network. The method provided by the invention has an accurate prediction capability, finds a lower and more accurate critical concentration for the first time, and can timely and effectively send out an early warning signal of skin mucosa injury of the acute lymphocytic leukemia patient.

This invention relates to a novel method for purifying methotrexate. This invention is the first to utilize an alkaline ionic liquid as a catalyst in the methotrexate purification process, aligning with the trend towards green chemistry. The purification method of this invention features a simple post-processing procedure, eliminating the need for complex post-processing operations, thus saving operating costs and facilitating industrial production. The alkaline ionic liquid of this invention is readily available, its preparation method is mature, and the ionic liquid is easily separated and can be reused after simple activation, further saving production costs and facilitating industrial production. The purification method of this invention yields methotrexate with high purity, low C impurity content, and a significantly improved overall reaction yield compared to existing technologies.

The present application relates to a kind of diclofenac-methotrexate co-amorphous substance and its preparation method and application, in the diclofenac-methotrexate co-amorphous substance, the molar ratio of diclofenac and methotrexate is 1:2, its X-ray powder diffraction pattern has no sharp diffraction peak, indicating the formation of co-amorphous form.The present application is obtained by using rotary evaporation method to obtain co-amorphous substance, and the results of pharmacokinetics and in vitro and in vivo pharmacodynamics experiments show that the performance indicators such as DIC-MTX co-amorphous system are superior to physical mixture in bioavailability, anti-inflammatory effect, etc., which embodies its potential application value, and shows that there is positive effect between the two drugs for treating rheumatoid arthritis, which provides a research basis for realizing the combination of DIC and MTX.

The present application relates to the technical field of rheumatoid arthritis drugs, and particularly relates to methotrexate-baiji polysaccharide nanoparticles and a preparation method and application thereof.The present application provides methotrexate-baiji polysaccharide nanoparticles, which have a structure shown in formula 1.The nanoparticles are formed by connecting methotrexate and baiji polysaccharide through a disulfide bond, and in theory, can realize drug release in response to high active oxygen stimulation in the microenvironment of rheumatoid arthritis.In addition, the present application researches and proves that the nanoparticles can effectively inhibit the proliferation and migration of fibroblast-like synoviocytes, regulate the polarization of M1 macrophages to M2 macrophages, and reduce synovial inflammation.The methotrexate-baiji polysaccharide nanoparticles of the present application have simple preparation process operation, are convenient to use, and have a good development and utilization prospect.Formula 1

The present application belongs to the technical field of medicine, and particularly relates to a refining method of methotrexate intermediate (i.e. methotrexate disodium salt). The finished product of methotrexate contains stubborn impurity C (the limit of impurity C in European Pharmacopoeia EP9.0 is ≤0.5%), which is difficult to remove by ordinary refining method. The inventors surprisingly found that, by adding sodium chloride to the reaction solution of methotrexate disodium salt for crystallization, the content of stubborn impurity C precursor can be greatly reduced, the number and content of impurity peaks are reduced, the pigment in the methotrexate intermediate is removed, and then the content of stubborn impurity C in the methotrexate bulk drug is reduced, so that the purity meets the requirements of European Pharmacopoeia.

The invention relates to the technical field of rheumatoid arthritis medicines, in particular to methotrexate-bletilla striata polysaccharide nanoparticles as well as a preparation method and application thereof. The invention provides methotrexate-bletilla striata polysaccharide nanoparticles. The methotrexate-bletilla striata polysaccharide nanoparticles have a structure as shown in a formula 1. The nanoparticle is formed by connecting methotrexate and bletilla striata polysaccharide through a disulfide bond, and theoretically, the nanoparticle can respond to high active oxygen stimulation in a rheumatoid arthritis microenvironment to realize drug release. In addition, the research proves that the nanoparticles can effectively inhibit proliferation and migration of fibroblast-like synovial cells, adjust polarization of M1 type macrophages to M2 type macrophages and relieve synovial inflammation. The methotrexate-bletilla striata polysaccharide nanoparticles are simple in preparation process operation and convenient to use, and have good development and utilization prospects. Formula 1

The invention relates to a diclofenac-methotrexate co-amorphous substance and a preparation method and application thereof, in the diclofenac-methotrexate co-amorphous substance, the molar ratio of diclofenac to methotrexate is 1: 2, and the X-ray powder diffraction pattern of the diclofenac-methotrexate co-amorphous substance has no sharp diffraction peak, indicating the formation of the co-amorphous state. The co-amorphous substance is obtained through a rotary evaporation method, pharmacokinetic and in-vivo and in-vitro pharmacodynamic experiment results show that the DIC-MTX co-amorphous system is superior to a physical mixture in bioavailability, anti-inflammatory effect and other performance indexes, the potential application value of the DIC-MTX co-amorphous system is embodied, and the DIC-MTX co-amorphous system has good application prospects. Moreover, the two medicines have a positive effect of treating rheumatoid arthritis, and a research basis is provided for realizing the drug combination of the DIC and the MTX.

The application discloses a method for determining related substances in methotrexate, which comprises the following steps: preparing an impurity C positioning solution, a system suitability solution and a test sample solution, and then respectively detecting the impurity C positioning solution, the system suitability solution, a reference substance solution and the test sample solution by using liquid chromatography, recording chromatograms, and quantitatively analyzing impurity C and other impurities in the test sample solution by comparing the chromatograms. The system suitability solution is prepared by destroying the main component reference substance solution, and the solution is a mixed solution containing impurity B, impurity C and methotrexate, so that impurity C can be positioned, and the separation degree between impurity B and impurity C should be not less than 1.5.

The invention discloses a layered screening method for acute lymphocytic leukemia patients based on methotrexate medication and application thereof, and the layered screening method for acute lymphocytic leukemia is characterized in that the patients are divided into three types of GG, AG and AA by detecting the genotype of the rs1544105 site of an FPGS gene in an in-vitro sample. Based on Meta analysis data of 1760 patients in 11 studies, the GG type is judged as a methotrexate standard dose suitable crowd, the AG or AA type needs to be adjusted, and the AG type corresponds to gt; 20 mg / m < 2 > high-dose methotrexate preparation and AA type corresponding non-folic acid medicine preparation. The invention also includes monitoring somatic mutation in recurrent patients, and switching to a non-methotrexate regimen if GG type mutation is AG / AA type. According to the method, precise layering is achieved, the disease progress risk is reduced, and technical support is provided for pharmaceutical enterprises to prepare personalized drugs and clinical test layering.

Disclosed are methods of treating cancer by administering a first agent comprising an antibody or fragment thereof that binds CD206 present on tumor associated macrophages conjugate to a mutant of human carboxypeptidase A (hCPA), followed by administering second agent comprising 3-cyclopentyl-alpha-phenylalanine-methotrexate.

A system for the production of methotrexate amino acid methyl ester-loaded lipid nanocapsules (LNCs) for the treatment of methotrexate-resistant breast cancer cells, consisting of: a) a conjugate synthesis unit configured to synthesize methotrexate-amino acid methyl ester conjugates selected from the group consisting of methotrexate-alanine methyl ester (MAME), methotrexate-cysteine methyl ester (MCME), and methotrexate-aspartic acid methyl ester (MADE) conjugates; b) a nanocapsule manufacturing unit used to formulate lipid nanocapsules (LNCs) derived from MCME and MADE conjugates; c) a homogenization unit configured to process the lipid acid nanocapsules to obtain a uniform dispersion at the nanoscale; and d) a purification unit configured to purify the lipid nanocapsules.

The invention discloses a layered screening method for acute lymphocytic leukemia patients based on methotrexate medication and application thereof, and the layered screening method for acute lymphocytic leukemia is characterized in that the patients are divided into three types of GG, AG and AA by detecting the genotype of the rs1544105 site of an FPGS gene in an in-vitro sample. Based on Meta analysis data of 1760 patients in 11 studies, the GG type is judged as a methotrexate standard dose suitable crowd, the AG or AA type needs to be adjusted, and the AG type corresponds to gt; 20 mg / m < 2 > high-dose methotrexate preparation and AA type corresponding non-folic acid medicine preparation. The invention also includes monitoring somatic mutation in recurrent patients, and switching to a non-methotrexate regimen if GG type mutation is AG / AA type. According to the method, precise layering is achieved, the disease progress risk is reduced, and technical support is provided for pharmaceutical enterprises to prepare personalized drugs and clinical test layering.

The invention aims to provide an acid response type rheumatoid arthritis targeted therapy nano preparation as well as a synthesis method and application thereof, and belongs to the technical field of preparation of nano biomedical materials. The preparation method comprises the following steps: synthesizing Zn / SiO nano-particles with a dandelion-shaped structure through an oil-water two-phase method, loading methotrexate by utilizing the large-aperture characteristic of the particles, and coating an M2 macrophage membrane on the outer layer to prepare the methotrexate-loaded Zn / SiO nano-particles. The nano preparation has good biocompatibility, stability and capability of targeting rheumatoid arthritis parts by virtue of inflammation chemotaxis and homologous targeting effects of M2 macrophage membranes. In an acidic microenvironment, the nanoparticles can respond to release zinc ions and drugs, so that safe and effective treatment of rheumatoid arthritis is realized.

The invention relates to a methotrexate immunodetection reagent as well as a preparation method and a detection method thereof, in particular to a methotrexate chemiluminescence immunodetection reagent as well as a preparation method and a detection method thereof, and the methotrexate chemiluminescence immunodetection reagent comprises an anti-methotrexate specific antibody and an indicating reagent for detecting an anti-methotrexate specific antibody-methotrexate conjugate, the anti-methotrexate specific antibody is obtained by immunizing an animal with methotrexate immunogen. The methotrexate immunogen has the beneficial effects that the methotrexate immunogen has strong specificity and high immunogenicity, and the prepared anti-methotrexate specific antibody has strong specificity and high titer; the chemiluminescence immunoassay reagent containing the anti-methotrexate specific antibody can conveniently, quickly and accurately determine the methotrexate content in a sample, can simultaneously determine a plurality of samples on a full-automatic chemiluminescence immunoassay instrument, realizes high-throughput quick determination of methotrexate, and has the advantages of high accuracy, strong specificity, high sensitivity, high sensitivity, high sensitivity and high sensitivity. And the accuracy and the detection efficiency are greatly improved.

The invention belongs to the field of biological medicine, and particularly relates to a cascade catalytic reactor based on Pickering emulsion as well as a preparation method and application of the cascade catalytic reactor. The cascade catalytic reactor is composed of active ingredients of uricase (Uri), active ingredients of catalase (Catalase, CAT), methotrexate and DSPE-PEG-Mannose (distearoyl phosphorylase-polyethylene glycol-Mannose). The self-cascade catalytic reactor provided by the invention can induce thorough removal of MUS crystals in an articular cavity and cells under reasonable assembly of various components, remarkably reduces ROS, polarizes M1 cells into M2 cells, and thoroughly turns the immunosuppression state of an inflammatory microenvironment. The self-cascade catalytic reactor relieves joint swelling, improves gait claudication and promotes tissue repair in vivo, shows the potential of serving as a treatment dosage form for effectively treating gouty arthritis, and provides a new strategy for developing a bioreactor with enzyme cascade catalysis and multi-stage component synergistic effect.

The invention specifically discloses a tumor-targeted biological membrane coated nano self-assembly and application thereof, and relates to the technical field of biological medicines. The invention provides a biological membrane coated nano self-assembly body. The biological membrane coated nano self-assembly body comprises a nano self-assembly body and a cell membrane, the nanometer self-assembly body comprises bivalent copper ions, methotrexate and adriamycin, additional nanometer carriers and auxiliary materials are not needed, the preparation process is simple, consumed time is short, the nanometer self-assembly body can be accurately delivered to a focus position by coating a tumor cell membrane with the homologous targeting characteristic, and therefore the anti-tumor treatment effect is improved.

The application belongs to microneedle, and particularly relates to soluble microneedle based on metal-amino acid / peptide / drug coordination nanoparticles and a preparation method and application thereof. 2+ The coordination center ion of the nanoparticles is selected from Zn 2+ , the ligand is selected from a mixture of 9-fluorenylmethyl oxycarbonyl modified histidine (Fmoc-H) and macrophage targeting peptide (Fmoc-HTKPR) modified by 9-fluorenylmethyl oxycarbonyl modified histidine derivatives, and methotrexate (MTX), a rheumatoid arthritis treatment drug containing a carboxyl group, and the microneedle carrier material is selected from a soluble polymer PVP. The application provides a scheme for realizing metal-drug coordination at normal temperature, and the nanoparticles are released by the microneedle in vivo, the nanoparticles can be actively targeted to inflammatory sites through the targeting peptide, and high-load MTX and active oxygen scavenging drugs are responsively released, so that high-efficiency and safe rheumatoid arthritis treatment is realized based on the synergistic effect of eliminating inflammatory macrophages and converting the same into an anti-inflammatory phenotype.