39 results about "Candesartan cilexitil" patented technology

The present invention is directed to compositions comprising a candesartan, such as candesartan cilexitil. The candesartan particles of the composition have an effective average particle size of less than about 2000 nm. The candesartan compositions of the invention are useful in the treatment of hypertension or related cardiovascular conditions.

The present invention is directed to compositions comprising a candesartan, such as candesartan cilexitil. The candesartan particles of the composition have an effective average particle size of less than about 2000 nm. The candesartan compositions of the invention are useful in the treatment of hypertension or related cardiovascular conditions.

The present invention is directed to the preparation of substantially pure candesartan cilexetil by the deprotection of trityl candesartan cilexetil and crystallization and / or recrystallization of candesartan cilexetil.

The invention encompasses sable candesartan cilexetil of fine particle size, wherein desethyl-candesartan (desethyl-CNS) within the stable candesartan cilexetil does not increase to more than about 0.1% w / w by HPLC relative to the initial amount of candesartan cilexetil, when the stable candesartan cilexetil is maintained at a temperature of about 55° C. for at least 2 weeks, methods of making the same and pharmaceutical compositions thereof.

The invention relates to a stable candesartan cilexetil and amlodipine pharmaceutical-containing composition and its preparation method. The invention is characterized in that a) each tablet contains 4mg-8mg of candesartan cilexetil, b) each tablet contains 2-10mg of amlodipine or its pharmaceutically acceptable salt, c) each tablet contains polyethylene glycol, wherein the weight of polyethylene glycol accounts for 2-10% of the tablet, and d) the tablet is prepared by a compressed tablet technology by using a dry method.

The invention discloses a detection method of nitrosamine impurities in candesartan cilexetil. The method comprises the following steps of: S1, preparing a solution: respectively preparing a test solution and a standard curve solution; and S2, detecting: detecting and analyzing the test solution and the standard curve solution in the step S1 by adopting liquid chromatography and mass spectrometry.According to the detection method disclosed by the invention, nitrosamine compounds in the candesartan cilexetil can be more comprehensively detected, and simultaneous detection of seven nitrosaminecompounds can be realized on the premise of adopting one ion source, so that the quality and medication safety of the candesartan cilexetil are ensured. The detection limit of the detection method fordetecting the nitrosamine compounds in the candesartan cilexetil can reach a trace level; the detection method disclosed by the invention has good system adaptability, specificity, quantification limit and detection limit, linearity and range, accuracy, precision, durability and solution stability on detection of seven nitrosamines in the candesartan cilexetil.

Provided are candesartan cilexetil forms and methods of their preparation. Also provided are pharmaceutical compositions prepared by combining at least one pharmaceutically-acceptable excipient with at least one candesartan cilexetil form of the invention.

The present invention provides an improved synthesis for the manufacture of candesartan and pharmaceutically acceptable salts and esters thereof as active ingredients of a medicament for the treatment of hypertension and related diseases and conditions which comprises the removal of the tetrazolyl protecting group in an organic solvent, and in the presence of a Lewis acid.

The invention relates to a process improving method of candesartan cilexetil; 1-[(2'-cyano-1, 1'-xenyl-4-) methyl]-2-ethyoxyl-7-benzimidazole carboxylic acid ethyl ester and sodium azide serve as raw materials, N,N-dimethyl formamide serves as solvent, MC1 serves as catalyst, and the materials are synthesized into candesartan cilexetil at the temperature of 130DEG C to 160DEG C, wherein M is alkali metal or an ammonium cation. According to the method, the price of the used catalyst is low, no toxin or little toxin is produced, the production cost and the environmental treatment cost are reduced, the treatment after reaction is simple, the yield is higher, and the industrialized production is facilitated.

The invention relates to a preparation method of a candesartan cilexetil crystal form I spherical crystal, and belongs to the technical field of crystallization. The technical scheme adopted by the invention is that the preparation method comprises the following steps: firstly, adding candesartan cilexetil into ketone solvents, wherein the solid-liquid ratio of a solution is 0.01 to 0.1g / ml; stirring and dissolving at the temperature of 20 to 30DEG C, and continuously stirring for 30 to 60 minutes; secondly, filtering and decoloring; transferring filtrate into a crystallizer, controlling the temperature of a system to be 10 to 20DEG C, adding alcohol organic solvents, performing dilution crystallization, filtering, washing and drying to obtain a finished product disclosed by the invention. The candesartan cilexetil crystal form I spherical crystal by the preparation method provided by the invention is good in flowability and facilitates stable production of a preparation process.

The invention discloses an oral candesartan cilexetil solid preparation and a preparation method thereof. The oral solid preparation is prepared from candesartan cilexetil, stabilizer and pharmaceutically acceptable auxiliary ingredients, wherein the stabilizer is beta-cyclodextrin, and the weight of the stabilizer is 0.3 to 3 times that of the candesartan cilexetil. The preparation method comprises the steps of mixing candesartan cilexetil, beta-cyclodextrin or derivatives thereof and red iron oxide and sieving twice with a 100-mesh sieve, and then adding proper pharmaceutical auxiliary ingredients to obtain the candesartan cilexetil preparation. According to the oral candesartan cilexetil solid preparation and the preparation method thereof, the candesartan cilexetil can be inhibited from decomposing and keep long-time stabilizing and the expiry date of the candesartan cilexetil preparation can be prolonged.

The invention discloses an application of candesartan cilexetil or a pharmaceutically acceptable salt thereof in preparation of a drug for preventing and / or treating COVID-19. The candesartan cilexetil and hydrolysate candesartan have stronger binding strength with SARS-CoV-2 target 3CL hydrolase (MPro) that causes inflammation in the lung, and can significantly inhibit the activity of the 3CL hydrolase, wherein the IC50 of the candesartan cilexetil and the hydrolysate candesartan against the 3CL hydrolase (Mpro) is 2.78+ / -0.31 [mu]M and 9.45+ / -0.73 [mu]M, respectively, and the results indicate that the candesartan cilexetil and the hydrolysate candesartan have the effect of preventing and treating pneumonia caused by the SARS-CoV-2, and can be used to prepare an anti-pneumonia drug for application.

The present invention is directed to nanostructured (nanoparticulated) Candesartan or its pharmaceutically acceptable ester, preferable Candesartan Cilexetil, or co-crystal compositions, process for the preparation thereof and pharmaceutical compositions containing them. The nanoparticles of Candesartan or its pharmaceutically acceptable ester, preferable Candesartan Cilexetil, or co-crystal according to the invention have an average particle size of less than about 500 nm. Candesartan Cilexetil is a prodrug, is hydrolyzed to Candesartan during absorption from the gastrointestinal tract. Candesartan is a selective AT1 subtype angiotensin II receptor antagonist.

The invention belongs to the technical field of medicines and in particular discloses a capsule preparation containing candesartan cilexetil and a preparation method of the capsule preparation. The preparation method comprises the following steps: mixing the following components in parts by weight: 2-32 parts of candesartan cilexetil, 10-150 parts of a diluent 1, 10-150 parts of a diluent 2, 0.5-8parts of a disintegrant, 1-10 parts of an adhesive and 0.5-10 parts of a low melting point oily compound, preparing pellets by using an extrusion and rolling method, mixing 0.05-4 parts of a lubricant with the pellets, and filling a capsule shell with the mixture, so as to obtain the capsule preparation. The capsule preparation containing candesartan cilexetil, which is disclosed by the invention, is prepared by using an extrusion and rolling preparation process and has good dissolution performance, and the bioavailability of candesartan cilexetil of the capsule preparation is greatly improved when being compared with that of a candesartan cilexetil preparation in the market.

The invention relates to a hypotensive tablet containing a sodium chloride medicine carrier, which is suitable for a pharmaceutical enterprise. The disclosed tablet comprises the sodium chloride, candesartan cilexetil, and pharmaceutically acceptable adjuvants. The sodium chloride is stable in property and good in water solubility and compressibility, and is well compatible with the candesartan cilexetil. The sodium chloride is taken as the carrier for the candesartan cilexetil; by injecting polyethylene glycol 6000 solution or polyethylene glycol 8000 solution, a medicine is loaded on the sodium chloride and the mixed carrier containing other pharmaceutically acceptable adjuvants of the medicine; the adjuvants, such as a lubricant, are added to mix uniformly, and the mixture is subjected to tabletting and can be molded by compression under a pretty low pressure; and, by reducing the pressure in the tabletting process, the transformation of the candesartan cilexetil to an unstable crystal form due to over-high pressure in the tabletting process can be prevented so that the reduction of the candesartan cilexetil content and the increasing of the impurity content in the storage process can be prevented. The candesartan cilexetil tablet prepared by the invention has good stability and is released quickly.

The invention relates to a continuous-flow production process for synthesizing a candesartan cilexetil intermediate, belonging to the technical field of fine chemical engineering. The invention particularly relates to a process for continuously preparing 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate by using a microchannel reactor. The process comprises the following steps: carrying out staying reaction on 2-(chlorocarbonyl)-3-nitrobenzoate and sodium azide in a first reaction module; then allowing reaction liquid and water to simultaneously enter a continuous separator for separation; and subjecting an organic layer obtained through separation to reacting with tert-butyl alcohol in a second reaction module to obtain a target product. The method provided by the invention is safe, simple to operate, efficient and easy for large-scale production.

The invention provides a candesartan cilexetil compound and a novel preparation method thereof. Through absorption of active carbon, crystallization and adsorptive separation of macroporous absorption resin, the purpose of refined purification is achieved, and finally, the high-purity candesartan cilexeti is obtained, thereby greatly improving the purity and content of the candesartan cilexeti, improving the product quality of the preparation, reducing toxic and side effects and guaranteeing the clinical pharmacy safety of the candesartan cilexeti in preparing anti-hypertension medicaments. The novel preparation method has the advantages of simple process, low cost and high yield, and is suitable for industrial production.

The invention provides a candesartan cilexetil intermediate and a preparation method thereof. The intermediate is synthesized through the following route. The intermediate is synthesized, so that theformation of many byproducts in the reduction step in the prior art is effectively avoided, oxalic acid salifying crystallization is adopted for diamine purification in the subsequent step of synthesizing candesartan cilexetil through the intermediate, and a high-quality candesartan cilexetil bulk drug can be obtained.

The invention relates to a candesartan cilexetil self-microemulsion soft capsule and a preparation method thereof. The soft capsule comprises capsule liquid and content medicine liquid. The preparation method is as follows: 100-130 parts of gelatin is arranged in mixing solution for swelling, wherein the mixing solution is formed by 18-30 parts of glycerol, 20-30 parts of sorbic alcohol and 100-120 parts of water; then 0.1-0.3 part of ethylparaben is added, heating is carried out until the gelatin is dissolved, the mixture is stirred uniformly and is filtered, and vacuum defoaming and heat insulation are carried out, thus obtaining the capsule liquid; 1-2 parts of candesartan cilexetil, 20-40 parts of assistant emulsifiers, 10-30 parts of oil phase and 80-100 parts of emulsifiers are mixed uniformly, and then the mixture is heated and stirred until the uniform and transparent content solution is formed; and the prepared capsule liquid and the prepared content solution the weight percentage ratio of which is 4:3 are moulded and pressed into soft capsules by rotating a mould press, and then drying and surface treatment are carried out on the soft capsules, thus obtaining the finished products. In the invention, the bioavailability of the candesartan cilexetil is improved, and the preparation method is simple relatively, the production is easy, thus the application prospect is wide.

The invention discloses a candesartan cilexetil and hydrochlorothiazide co-amorphous substance formed by combining candesartan cilexetil and hydrochlorothiazide. According to a powder X-ray diffraction spectrum, a DSC spectrum and an infrared spectrum, the co-amorphous substance is a novel solid form completely different from each monomer and a physical mixture thereof. The candesartan cilexetil and the hydrochlorothiazide are used for preparing the co-amorphous substance, so that the solubility and the dissolution rate of the candesartan cilexetil can be significantly improved, and the co-amorphous substance is expected to become a new raw material solid form of a candesartan cilexetil / hydrochlorothiazide compound tablet and has good application development prospects.

The invention provides a method for preparing candesartan cilexetil, which can solve the problems of longer reaction route, easy remaining of toxic substances in medicines and lower total yield existing in the prior art. In the method, the candesartan cilexetil is finally prepared by using 2-amino-3-nitrobenzoic acid as an initial raw material through esterification reaction, N-alkylation reaction, nitro reduction reaction, cyclization reaction, hydrolysis reaction, esterification reaction and tetrazole protecting group deprotection reaction. The synthetic method has simple steps and high yield, greatly reduces the participation and generation of toxic products in the reaction process, reduces the release of waste and is beneficial to clean production.

The invention relates to a method for analyzing the genotoxic impurity 1-chloroethylcyclohexyl carbonate of candesartan cilexetil, belonging to the technical field of crude drug analysis. The present invention utilizes the impurity 1-chloroethyl cyclohexyl carbonate existing in candesartan cilexetil and the pre-column derivation method of the derivation reaction with candesartan cilexetil itself to measure the impurity 1-chloroethyl cyclohexyl carbonate content, to achieve the control of genotoxic impurity 1-chloroethyl cyclohexyl carbonate in candesartan cilexetil. The invention provides a detection method for the genotoxic impurity in candesartan cilexetil, which provides guarantee for the quality control of candesartan cilexetil preparations.

The preparation method of candesartan cilexetil and its precursor compound. The precursor compound is 2-ethoxy-1-[[2′-(1-R-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H -Benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl ester (III), from 2-ethoxy-1-(4'-halophenyl)methyl-1H-benzene Imidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester (I) and 2-(1-R-1H-tetrazol-5-yl)phenylboronic acid or 2- (1-R-1H-tetrazol-5-yl) phenyl borate (II) reacts in a soluble organic reaction medium and in the presence of a catalyst and a water-soluble basic compound allowed by the Suzuki reaction get. The precursor compound can be further hydrolyzed under acidic conditions to obtain candesartan cilexetil which can be used as medicine. The method can conveniently and advantageously prepare the candesartan cilexetil compound.

The invention discloses a nephropathy treating or preventing effect enhancer of candesartan cilexetil and other renin-angiotensin system inhibitors. The enhancer contains specific prostaglandin I derivatives such as bereprosodium as active ingredients.

The invention discloses a hydrochlorothiazide crystal and a candesartan cilexetil hydrochlorothiazide medicinal combination thereof. The characteristic peaks of the hydrochlorothiazide crystal in an X-ray powder diffraction pattern, which are measured and obtained by using a Cu-K[alpha] ray, are displayed when 2[theta] is 4.1 degrees, 8.2 degrees, 9.8 degrees, 12.1 degrees, 15.1 degrees, 16.7 degrees, 19.3 degrees, 20.0 degrees, 22.1 degrees, 23.3 degrees and 26.8 degrees. The combination comprises 4-20 parts of candesartan cilexetil, 10-15 parts of the hydrochlorothiazide crystal, 10-50 parts of pregelatinized starch, 15-35 parts of microcrystalline cellulose PH102, 10-45 parts of crosslinked polyvinylpyrrolidone and 0.5-1 part of magnesium stearate. The medicinal combination has a reasonable prescription, stable and reliable quality, and better disintegration time limit and dissolution rate; a direct powder tabletting process is adopted; the process is simple; the production period is short; the production cost is low; and the industrialized production is facilitated.

The invention relates to the technical field of chemical drug analysis, in particular to a method for detecting azide compounds in candesartan cilexetil. The detection method of the present invention is to take candesartan cilexetil raw material drug to be tested, add acetonitrile for ultrasonic dissolution, and then dilute with sulfuric acid aqueous solution; the volume ratio of the acetonitrile and sulfuric acid water is 40:60~60:40; after fully shaking Filtrate, get the filtrate and stand-by as need testing solution; Chromatographic column uses octadecylsilane bonded silica gel as stationary phase, adopts acetonitrile-sulfuric acid aqueous solution as mobile phase A, acetonitrile-water as mobile phase B to carry out gradient elution, carry out HPLC detection, record spectrum. The detection method of the invention can quickly and conveniently separate and quantitatively determine the sodium azide in the candesartan cilexetil, thereby effectively controlling the quality of the candesartan cilexetil product.

The invention provides a recovery method of candesartan cilexetil intermediate mother liquor. The candesartan cilexetil intermediate mother liquor obtained in real production comprises candesartan tert-butyl ester, candesartan tert-butyl ester decomposition impurities and candesartan tert-butyl ester diester impurities; and the mother liquor is not treated in conventional production procedures and is directly treated as waste liquor, so resources are wasted and cost is increased. The method for recovering the mother liquor provided by the invention can recover candesartan cilexetil in the mother liquor, convert decomposed impurities and diester impurities into candesartan cilexetil for recovery, and recover more than 90% of substances in the mother liquor, so the production cost of candesartan cilexetil is greatly reduced. According to the recovery method, interference of diester impurities can be avoided when the decomposed impurities are recycled, and generation of byproduct diester impurities is avoided as much as possible when the diester impurities are recycled; and operation is easy and convenient, and raw materials are low in price, so the method is suitable for industrial production and popularization.

The invention discloses a method for determining impurities in candesartan cilexetil. The method comprises the following steps: S1, heating a candesartan cilexetil standard substance solution at 70-100 DEG C for 1.5-3 hours, cooling, and adding acetonitrile to obtain a degradation solution 1; besides, adding the candesartan cilexetil standard substance solution into an alkaline solution, performing standing for 5-30 minutes, and adding an acid solution for neutralization to obtain a degradation solution 2; mixing the degradation solution 1 and the degradation solution 2 to obtain a system applicability solution; S2, dissolving candesartan cilexetil to be detected, and quantitatively preparing a test solution; diluting the test solution as a control solution; and S3, respectively carrying out liquid chromatography detection on the system suitability solution obtained in the step S1, the test solution obtained in the step S2 and the control solution, and determining the impurities A, B,C, D, E, F or G in candesartan cilexetil by comparing liquid chromatograms. The method is strong in pertinence, high in accuracy and easy to popularize, and has good application value in the aspect ofdetermining the impurities in candesartan cilexetil.