51 results about "Amethopterin" patented technology

The invention belongs to the technical field of analysis and detection of medicine related components, and particularly relates to a method for determining related substances of a methotrexate oral solution, the related substances comprise methotrexate impurity B, impurity C, impurity E, impurity D, impurity H and impurity I. The determination method adopts a high performance liquid chromatography method. A mobile phase of the high performance liquid chromatography comprises a mobile phase A and a mobile phase B, the mobile phase A is a buffer salt solution, the mobile phase B is acetonitrile, and gradient elution is adopted. According to the method, a plurality of known impurities in the methotrexate oral solution can be measured at the same time by utilizing the high performance liquid chromatography, interference generated by a blank solvent and an auxiliary material solution is eliminated, and the method can be used for accurately and quantitatively detecting related substances in the preparation process and the storage process of the methotrexate oral solution and serves as an important component for medicine quality control. The clinical use risk is reduced. The method is good in specificity, good in separation degree, good in accuracy and high in practicability in actual quality control work.

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 invention relates to a novel methotrexate purification method. According to the method, the basic ionic liquid is used as the catalyst for the first time and is used in the methotrexate purification process, and the development trend of green chemistry is met. The purification method disclosed by the invention is simple in post-treatment process, does not need complicated post-treatment operation, saves the operation cost and is beneficial to industrial production. The alkaline ionic liquid is simple and easy to obtain, the preparation method is mature, the ionic liquid is easy to separate and can be repeatedly used after being simply activated, the production cost is saved, and industrial production is facilitated. The methotrexate prepared by the purification method disclosed by the invention is high in purity and low in impurity C content, and the total reaction yield is greatly improved compared with the prior art.

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.

The present invention discloses a method for refining methotrexate intermediate Int1, namely diethyl p-(methylamino)benzoylglutamate. The method comprises crystallizing the intermediate Int1 from a mixed solvent of an organic solvent and water. This refining method has a good effect on removing key impurity 1 and impurity 2 in diethyl p-(methylamino)benzoylglutamate, the methotrexate intermediate. The process operation is simple, the yield is high, and it is suitable for industrial production.

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 disclosure relates generally to alpha polyglutamated aminopterin, formulations containing liposomes filled with alpha polyglutamated aminopterin, methods of making the alpha polyglutamated aminopterin and liposome containing formulations, and methods of using polyglutamated alpha polyglutamated aminopterin and liposome containing formulations to treat hyperproliferative disorders (e.g., cancer) and disorders of the immune system (e.g., an autoimmune disease such as rheumatoid arthritis).

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.

The invention provides a methotrexate derivative shown in a formula (I) or pharmaceutically acceptable salt thereof, a preparation method thereof and application of the methotrexate derivative to treatment and prevention of ophthalmic diseases such as retinopathy. # imgabs0 #

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 invention discloses a methotrexate tablet and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, and the preparation method comprises the following steps: step 1, respectively sieving a diluent and an adhesive through a shaking screen provided with a screen mesh to obtain an auxiliary material; the preparation method comprises the following steps: 1, preparing a methotrexate raw material medicine, 2, dissolving sodium carbonate in purified water to obtain a sodium carbonate solution, adding the methotrexate raw material medicine into the sodium carbonate solution, and carrying out a reaction on methotrexate and sodium carbonate to obtain a methotrexate disodium salt solution, and 3, mixing the methotrexate disodium salt solution and auxiliary materials, carrying out granulation, and carrying out drying treatment to obtain medicine particles. And 4, uniformly mixing the medicine particles with a lubricant, and tabletting to obtain the methotrexate tablets. The methotrexate disodium salt is prepared through reaction of methotrexate and sodium carbonate, the methotrexate tablet is prepared through wet granulation, and experiments prove that the improved methotrexate tablet is good in storage stability, few in impurities, high in drug solubility, high in dissolution rate, high in drug absorbance and capable of reducing side effects of drugs.

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

Provided is a therapy comprising a compound of formula (I), such as AP1189, and methotrexate for the treatment of rheumatoid arthritis in subjects having active systemic inflammation.

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 belongs to the technical field of adverse drug reaction prediction, and particularly relates to a risk prediction model for large-dose methotrexate excretion delay of central nervous system lymphoma patients and a construction method thereof, and the method comprises the steps: collecting clinical data of the central nervous system lymphoma patients which are treated by large-dose methotrexate and are subjected to plasma concentration monitoring; screening independent influence factors of excretion delay of methotrexate through single factor analysis and an AIC principle; the screened factors are incorporated into the Nomogram model, and the Nomogram model is constructed; and analyzing and evaluating the prediction capability and clinical effectiveness of the model through an ROC curve, a calibration curve and a decision curve, and performing internal verification of the model by adopting a Bootstrap (n = 1000) method. According to the risk prediction model for the large-dose methotrexate excretion delay of the patient with the central nervous system lymphoma, the probability of methotrexate excretion delay of the patient is evaluated through two independent influence factors, namely, the age is larger than 60 years old and ALB, assistance is provided for reducing adverse reactions of large-dose methotrexate, and support is provided for achieving clinical individualized drug delivery.

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.