21 results about "Sacubitril" patented technology

The application relates to application of a transaminase mutant in synthesis of a key chiral intermediate D-4,4'-diphenylalanine of sacubitril valsartan sodium salt (LCZ696), and belongs to the technical field of biocatalytic synthesis.The mutant is a quadruple mutant of the amino acid sequence shown in SEQ ID NO:1, the amino acid sequence of the transaminase mutant is shown in SEQ ID NO:3, and the corresponding amino acid sequence is shown in SEQ ID NO:4.Compared with a wild-type transaminase parent, the unit enzyme activity is increased by about 30 times under the condition of ensuring the chiral purity of a product, the transaminase has very high stereoselectivity and conversion rate, the industrial production cost of sacubitril and LCZ696 can be further reduced, and the transaminase has good industrial application value.

A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and melsartan (or a salt of melsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.

This invention provides a method for preparing a sacubitril intermediate, relating to the field of pharmaceutical synthesis technology. Using (2R)-4-nitro-2-methyl-butyrate ethyl ester and 4-bromomethylbiphenyl as initial raw materials, the method involves condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salt formation and resolution reaction with R(+)-α-methylbenzylamine, and acidification to liberate the sacubitril intermediate. The preparation method provided by this invention is simple, easy to operate, has a high yield of the target product (36.5% overall yield in Example 1), high purity, low raw material cost, low production cost, and generates minimal waste, making it suitable for industrial production.

The invention discloses a detection method of sacubitril valsartan sodium tablet isomer impurities, and belongs to the technical field of pharmaceutical analysis. According to the method, sacubitril enantiomer and diastereoisomer impurities and valsartan optical isomer impurities in sacubitril and valsartan sodium tablets are detected by adopting HPLC (High Performance Liquid Chromatography), and under chromatographic conditions, a chromatographic column is a polysaccharide derivative reverse-phase coating type chiral chromatographic column, and the surface of silica gel is coated with cellulose-tri (4-methyl benzoate); a mobile phase is composed of a mobile phase A and a mobile phase B, the mobile phase A comprises water, acetonitrile and trifluoroacetic acid, and the volume ratio of the water to the acetonitrile to the trifluoroacetic acid is (790-810): (190-210): (0.9-1.1); a mobile phase B: methanol-acetonitrile, wherein the volume ratio of methanol to acetonitrile is (500-600): (500-400); a gradient elution mode is adopted. The method uses a reversed-phase system, is simple and convenient to operate, and can effectively realize separation and detection of sacubitril, valsartan and various isomer impurities, thereby realizing the purpose of controlling the quality of sacubitril and valsartan sodium tablets.

The invention discloses a Sacubitril-based compound as well as a pharmaceutically acceptable salt, an ester, a solvate, a pharmaceutical composition and a preparation method of the Sacubitril-based compound and the pharmaceutically acceptable salt, the ester, the solvate, the pharmaceutical composition and the preparation method of the Sacubitril-based compound. The sacubitril-based compound is a monoester compound or a monoamide compound, which can be obtained by reacting sacubitril with panoxadiol or 1, 3-diaminoadamantane. The pharmaceutically acceptable salts, esters, solvates, and pharmaceutical compositions include a sacubitril-based compound. All the components can be used for treating cardiovascular diseases including heart failure and hyperlipidemia.

The present invention relates to a pharmaceutical compound formulation that contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby having a synergistic effect in the treatment of heart failure, while minimizing the effects of drug dissolution between each drug to ensure bioequivalence, suppressing the generation of related substances, and exhibiting excellent stability of the active ingredients.

This invention discloses a compound tablet containing sacubitril / valsartan and rosuvastatin calcium, and its preparation method, belonging to the field of pharmaceutical preparation technology. The technical solution comprises: an active ingredient and pharmaceutical excipients; the active ingredient includes sacubitril / valsartan sodium and rosuvastatin calcium; the pharmaceutical excipients include fillers, binders, disintegrants, stabilizers, glidants, lubricants, and a gastrointestinal film-coating premix; the tablets are prepared using a dry granulation process. This invention solves the problems of poor adherence to single-drug use, asynchronous dissolution, and insufficient stability, achieving a synergistic effect of lowering blood pressure and lipids. Furthermore, the preparation process is simple, efficient, and suitable for industrial production.

The application provides a preparation method of a sacubitril intermediate compound III, which comprises the following steps: performing ring opening reaction on a compound of formula IV and a compound of formula V under the action of CuX, and the reaction formula is shown in the following formula: wherein X and X1 are independently selected from Cl, Br and I; the chiral 2-methyl pentanoic acid group is directly introduced into the chiral raw material compound of formula IV, the reaction route is short, time is saved, the purity of the chiral isomer is improved, and the post-treatment operation is simple; and the method has obvious technical advantages compared with the prior art.

The application provides an improved engineered transaminase polypeptide which can asymmetrically prepare a chiral amine compound with extremely high stereoselectivity, in particular, more effectively catalyzes the generation of an intermediate of sacubitril, has higher activity and stability, and has application value for the industrialization of sacubitril.

This invention relates to a sacubitril / valsartan sodium tablet composition and its preparation method, belonging to the field of pharmaceutical formulation technology. The technical solution of this invention is: a tablet composition containing sacubitril / valsartan sodium, comprising 50 parts of sacubitril / valsartan sodium, 4-16 parts of chitosan, 30-45 parts of microcrystalline cellulose, 3-8 parts of croscarmellose sodium, and 0.7-2 parts of magnesium stearate. This invention provides a stable sacubitril / valsartan sodium tablet and its preparation method. The tablets obtained by the preparation method have advantages such as rapid dissolution, smooth surface, and good stability, solving the sticking and punching problem in the preparation process of sacubitril / valsartan sodium tablets, and are suitable for large-scale industrial production.

The invention provides a sacubitril-valsartan sodium indapamide sustained-release tablet and a preparation method thereof, the sacubitril-valsartan sodium indapamide sustained-release tablet is of a double-layer tablet structure and comprises a first indapamide sustained-release layer and a second sacubitril-valsartan sodium quick-release layer, and the sacubitril-valsartan sodium indapamide sustained-release tablet can be prepared by adjusting the type and dosage of sustained-release materials in the indapamide sustained-release layer. According to the type and dosage of the disintegrating agent and the dosage of the adhesive in the sacubitril valsartan sodium quick release layer, the process of the double-layer tablet is stable, the release behavior of the double-layer tablet is similar to that of a single preparation, and the consistency of the curative effect of the medicine is ensured.

The present invention discloses high-purity oral solid dosage forms comprising sacubitril, valsartan, its complex or pharmaceutically acceptable salts thereof, and an SGLT-2 inhibitor or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable excipients, wherein the active ingredients are in a single-compartment form, without physical separation between them, distributed uniformly and homogeneously.

The present invention comprises sacubitril or pharmaceutically acceptable salts thereof in crystalline form, valsartan or pharmaceutically acceptable salts thereof in amorphous form and a disintegrant, wherein the disintegrant is comprised only in the internal phase.

This invention belongs to the field of pharmaceutical synthesis, specifically relating to a method for preparing sacubitril intermediates. The method uses intermediate compound 3 and an organic ammonium salt as raw materials, reacting them in the presence of an iridium catalyst and ligand to generate the sacubitril intermediate. This invention achieves high yield and chiral purity, with an ee value as high as 99.7%, and utilizes mild reaction conditions, avoiding the use of hazardous raw materials such as hydrogen and sodium borohydride.

The invention provides a sacubitril sodium spherical crystal and a preparation method thereof, the sacubitril sodium spherical crystal has excellent flowability and filterability, and has no obvious solvent residue; and the spherical crystal of sacubitril sodium has uniform particle size distribution, is beneficial to improving the product quality, is suitable for being prepared into various preparations, is simple and feasible in preparation process and is suitable for industrial production.

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and azilsartan (or a salt of azilsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.

The application belongs to the technical field of medicine and relates to a preparation method of a key intermediate of sacubitril, in particular to a preparation method of (R)-tert-butyl (1-([1,1'-biphenyl]-4-yl)-3-hydroxypropan-2-yl) carbamate. The method takes D-phenylalanine as a starting material, realizes C(sp 2 )-C(sp 2 ) coupling through Boc anhydride protection, sodium borohydride reduction and palladium-catalyzed remote C(sp 2 )-H bond activation to obtain the target compound. The raw material of the application is cheap and easy to obtain, the steps are short, the operation is simple, the pollution is small, the product yield is high, reaches more than 78%, and the application is beneficial to continuous large-scale industrial production. The synthetic route is as follows:

The invention belongs to the technical field of biology, and discloses an olefin reductase mutant and application thereof in catalytic synthesis of a sacubitril intermediate. According to the invention, olefin reductase derived from Clavisporaaluitaniae is modified through methods such as a gene mining technology, molecular docking, rational and semi-rational design, site-specific mutagenesis and the like, so that a mutant with relatively high yield aiming at the key intermediate of sacubitril is obtained. The sacubitril key intermediate is produced from a recombinant vector and recombinant genetically engineered bacteria constructed by the mutant in a whole-cell catalysis and pure enzyme catalysis mode, and the yield is remarkably improved and is 1.2-3 times that of an original strain. Therefore, the method for producing the sacubitril intermediate, provided by the invention, has the advantages of mild reaction conditions, simplicity in operation, short production period, environmental friendliness, reduction of production cost and the like.

The invention relates to the field of pharmaceutical preparations, in particular to a sacubitril and valsartan sodium controlled-release composition, a preparation method and application thereof, and a medicine. The invention provides a double-layer osmotic pump controlled release tablet of sacubitril and valsartan sodium, the tablet can continuously release medicine within 24 hours, and the oral administration of the original developed preparation on the market is changed into the oral administration of the original developed preparation once every two days, so that the medication compliance of a patient is greatly improved. Besides, the drug release of the preparation is characterized by zero-order release, the influence of the pH value of the environment is small, the influence of the complex environment of the gastrointestinal tract in the gastrointestinal tract is small, the safety of the drug is greatly improved, the fluctuation of the blood concentration caused by the peak valley effect of a common quick-release tablet is avoided, the steady-state blood concentration can be achieved after the preparation is taken once, and the preparation is safe and reliable. The effectiveness of the medicine is improved.

To provide a composition that can achieve synchronous sustained release of sacubitril and valsartan, and a method for producing the same. [Solution] A sustained-release composition of sacubitril valsartan sodium, comprising a drug-containing layer core having a pore on one side of the drug-containing layer, a booster layer core, and a coating film; The drug-containing layer core comprises a pharmacoactive ingredient and a carrier, the pharmacoactive ingredient being selected from sacubitril valsartan sodium or other pharmaceutically acceptable salt forms thereof; the content of the pharmacoactive ingredient in the drug-containing layer core is 10.00% to 80.00%; The composition is a 24-hour sustained-release drug. The dissolution of sacubitril and valsartan is A) Dissolve 40% or less of the drug active ingredient within 2 hours. B) 20% to 75% of the drug active ingredient is eluted within 8 hours. It simultaneously satisfies three characteristics: C) It releases more than 65% of the drug active ingredient within 24 hours.