33 results about "Apixaban" patented technology

The invention provides an anticoagulant coating for medical instruments, which can be used in the field of regenerative medical instruments. The prepared anticoagulant coating has short-term and long-term anticoagulant performance, and in addition, the thrombin responsive nanoparticles wrapped in the hydrogel coating can selectively release a factor Xa (FXa) inhibitor apixaban according to needs, so that thrombosis is inhibited in the middle stage of implantation. In-vitro and in-vivo experimental evidences show that after the material is implanted for a long time, an organized endodermis can be seen on the surface of the material, and the material has a special antithrombotic characteristic. The dynamic adjusting system has a multi-layer protection mechanism, and a new thought can be provided for designing the surface of a contact blood material adapting to environmental conditions.

The invention provides a preparation method of apixaban, and belongs to the technical field of raw material medicine synthesis. The intermediate product 5 is prepared by adopting continuous flow equipment, so that the defect of low heat and mass transfer efficiency of an intermittent reaction kettle is overcome, the reaction danger coefficient is reduced, the reaction time is shortened, the product quality is improved, and the product yield is increased; a ferric trichloride / activated carbon-hydrazine hydrate system is adopted for nitro reduction, so that the selectivity is good, and the product purity and yield are improved; the ethanol solution of ammonia is adopted to replace ammonia water, CH3ONa / HCOONH2, mixed anhydride-ammonia water and the like in the prior art, the defects that in the prior art, the content of acid impurities is high, and the amount of post-treated ammonia-containing wastewater is large are overcome, and the environmental protection pressure is reduced while the product quality is improved.

The invention relates to the field of chemical pharmacy, and in particular to a synthesis process of apixaban, comprising the following steps: using 3-chloro-1-(4-(2-oxopiperidin-1-yl)phenyl-5,6-dihydropyridine-2(1H)-one (intermediate A) to react with oxalyl chloride monoester to obtain compound B, then reacting with p-methoxyphenylhydrazine hydrochloride to form a ring through condensation and coupling to obtain compound D, and finally preparing apixaban through amine ester exchange of compound D. Compared with the prior art, the invention has the advantages of: 1. The synthesis process is more efficient and mild, the operation is simple, and the raw materials are easy to obtain; 2. It avoids the use of expensive or toxic and irritating reagents; 3. The total yield is high and is suitable for industrial production.

New derivatives of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl) phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo [3,4c] pyridine-3-carboxamide (Apixaban) able to increase its water solubility. These derivatives are cocrystals derivatives ofApixaban of different acids, from which the most outstanding are the following: Apixaban Malonic Acid derivative, Apixaban-a-Ketoglutaric Acid derivative, Apixaban-Gallic Acid derivative, Apixaban-Maleic Acid derivative, Apixaban-L-Tartaric Acid derivative, and Apixaban Citric Acid derivative.

The invention describes a buffered oral aqueous apixaban suspension comprising 0.08-0.20 w / v % micronized apixaban having a pH of 1.5-6.5 and a method for the preparation thereof.

The invention provides a synthesis method of apixaban. According to the synthesis method, a heterogeneous Pd monatomic catalyst is adopted to catalyze 1-(4-iodophenyl) piperidine-2-ketone and 1-(4-methoxyphenyl)-7-oxo-4, 5, 6, 7-tetrahydro-1H-pyrazolo [3, 4-c] pyridine-3-formamide to be subjected to a reaction, and apixaban is obtained. According to the method, the operation process is simple, the used Pd monatomic catalyst has high reaction selectivity on an N-H substrate, and the yield of apixaban is 94% or above. Compared with the traditional method, the synthesis method provided by the invention can select water as a solvent, can react under normal pressure, directly utilizes the Pd monatomic catalyst to synthesize the target product in one step, is faster and more efficient, and is environment-friendly and mild.

This invention relates to the field of pharmaceutical impurity preparation technology, and discloses a method for synthesizing apixaban genotoxic impurity I. The steps include: S1. performing an addition reaction of compound II in an alkaline system to generate compound III; S2. subjecting the product of S1 to elimination and isomerization reactions under heating, separating the reaction product to obtain apixaban genotoxic impurity I. The synthesis method of this invention has high safety, low raw material cost, and can achieve a one-pot reaction while ensuring yield and product purity (no product separation and purification is required between each reaction step; only one separation and purification is needed after obtaining the final product).

A method for administering a dosage of Apixaban to a patient for the treatment or prevention of thrombosis, the method comprising: administering a dosage of Apixaban to the patient, wherein the dosage of apixaban is determined by: receiving patient data relating to a patient, wherein the patient data includes a kidney function metric of the patient; and processing, using one or more processors, the patient data with a dosage calculator to determine the dosage of Apixaban for the patient, wherein the dosage calculator is derived from a plasma level prediction model that predicts Apixaban drug plasma levels, and the dosage calculator determines the dosage for the patient based in part on the kidney function metric of the patient.

This invention provides a solid preparation containing apixaban that exhibits stable dissolution properties and suppresses the formation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Solution] An apixaban-containing composition comprising crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent; and a dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant; a granulation step of granulating the dispersion and an excipient as raw materials after the dispersion preparation step; and a formulation step of manufacturing a solid preparation using the obtained granulated powder as raw materials after the granulation step, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent.

The application provides a synthesis method of apixaban. The synthesis method adopts a heterogeneous Pd monatomic catalyst to catalyze the reaction of 1-(4-iodophenyl)piperidin-2-one and 1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide to obtain apixaban. The method is simple in operation process, the Pd monatomic catalyst has high reaction selectivity to N-H substrates, and the yield of apixaban is more than 94%. Compared with the traditional method, the synthesis method provided by the application can select water as a solvent, can also react under normal pressure, directly utilizes a Pd monatomic catalyst to synthesize a target product in one step, is more fast and efficient, and is environment-friendly and mild.

The present invention discloses a new formulation composition of apixaban with obvious clinical advantages and a preparation method thereof, belonging to the field of pharmaceutical preparations. The new formulation composition of apixaban comprises the following components: apixaban, a filler, a binder, a disintegrant, a solubilizer, a glidant, a lubricant and a flavoring agent; wherein, the binder is hydroxypropyl cellulose, and calculated by weight percentage, the proportion of the binder is 1.0-3.0%. The new formulation composition of apixaban provided by the present invention has a short disintegration time in the oral cavity and does not need to be swallowed with water, thereby improving the convenience and compliance of administration, improving the medication safety of special populations, and providing a better choice for patients with dysphagia and / or those who need to crush tablets and then take them orally or by nasogastric feeding after surgery.

The invention provides an apixaban oral soluble film and a preparation method thereof, and belongs to the field of apixaban preparations. The apixaban oral soluble film is prepared from apixaban, copovidone, polyoxyethylene, polyethylene glycol and sucralose. The preparation method comprises the following steps: weighing raw materials according to a formula ratio, and sieving to obtain a sieved material; uniformly mixing the sieved material to obtain a mixture; and preparing the apixaban oral soluble film from the mixture in a hot melt extrusion manner. Compared with the prior art, the apixaban injection can meet the requirements of postoperative patients with poor health and dysphagia or patients needing to be deprived of water on apixaban administration; the apixaban oral soluble film prepared according to the formula and the preparation method disclosed by the invention is good in film-forming property, smooth in surface, uniform in color and luster and high in disintegration speed; under different dissolution conditions, the apixaban oral soluble film shows the same dissolution amount, and it can be ensured that the product has the same treatment effect in different crowds.

The invention discloses a fully continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate. The fully continuous flow chemical synthesis method comprises the following steps: introducing a sodium nitrite solution, a solution of a compound as shown in a formula (I) and acid into a dynamic tubular reactor, and carrying out diazotization reaction under the condition that the temperature is not higher than 0 DEG C; and introducing a sodium acetate solution and an ethyl 2-chloroacetoacetate solution into the microchannel reactor, mixing with the diazotization reaction solution, carrying out a Jappp-Klingemann reaction at-5-2 DEG C, and concentrating to obtain the apixaban intermediate compound shown in the formula (II). The invention provides a full-continuous flow chemical synthesis method of an apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate. The target product can be efficiently prepared in dozens of seconds in a high-purity and high-yield manner.

The invention belongs to the technical field of medicine synthesis, and particularly relates to an apixaban intermediate as well as a preparation method and application thereof. N-(4-aminophenyl)-2-piperidone is used as a raw material to react with 5-bromine-2-ethyl oxovalerate to obtain a new intermediate compound 3, and the intermediate compound 3 further reacts with ethyl oxalyl chloride to obtain a new intermediate compound 2. The preparation method comprises the following steps: preparing a compound 4, namely a key intermediate {5-hydroxy-6-oxo-1-[4-(2-oxopiperidine-1-yl) phenyl]-1, 2, 3, 6-tetrahydropyridine-4-yl} (oxo) ethyl acetate, namely a compound 4; the novel intermediate compound 3 and the compound 4 are simple in preparation method, high in yield and purity and suitable for industrial production.

The present invention relates to an orally disintegrating pharmaceutical dosage forms of apixaban or a pharmaceutically acceptable salt or prodrug thereof. The present invention specifically relates to a stable orally disintegrating pharmaceutical composition comprising apixaban and one or more pharmaceutically acceptable excipients. Further, the present invention relates to an orally disintegrating dosage form comprising apixaban, at least one disintegrating excipient and optionally one or more pharmaceutically acceptable excipients for treatment of disorders associated with Factor Xa.

The application provides a synthesis method of apixaban and a preparation method of an intermediate thereof. The method takes a key intermediate IX as a raw material, and obtains apixaban (formula I) through oxidation, elimination, addition, reduction and aminolysis successively. The synthesis route of the application is rationally designed, reaction conditions are mild, operation is simple, the yield is high, the process is economical, and the route is easy to be produced on an industrial scale.

The present invention is related to an oral liquid formulation of apixaban. The present invention is specifically related to an oral liquid formulation of apixaban which is comprising a therapeuticall

An oral liquid formulation of apixaban comprising a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of 3.5 to 4.5, and one or more pharmaceutically acceptable excipients. The present invention also relates to process of preparation of an oral liquid formulation of apixaban. The viscosifying agent may be sorbitol (10-500 mg / ml), the buffer may be citrate (0.5-50 mg / ml), further components include anti-foaming agents, thickening agents, humectants, sweetening agents, preservatives and flavourings.

The present invention relates to a stable aqueous solution composition of apixaban. The present disclosure also relates to a process for preparing stable aqueous solution compositions comprising apixaban and use of the composition.

The invention discloses a preparation method of an apixaban pyridone intermediate. The preparation method comprises the following steps: with 1, 4-dioxane as a solvent and iodide as a catalyst, carrying out a condensation-elimination reaction on a compound 1c and morpholine at 50-90 DEG C to prepare a compound 1d. According to the preparation method provided by the invention, a condensation-elimination reaction can be carried out at a relatively low temperature, an apixaban pyridone intermediate compound 1d is efficiently synthesized, excessive morpholine does not need to be adopted, byproducts are few in the reaction process, the product separation yield is high, and the purity is high; as the reaction temperature is lower, the safety risk level is lower than third level, and the safety risk is almost avoided.

To provide an orally disintegrating tablet containing apixaban that maintains its disintegration properties even after storage. [Solution] A pharmaceutical composition containing the following components (a) and (b). (a) Apixaban or its salt or solvate (b) D-mannitol characterized by having a D90 of 200-400 μm

The present invention relates to an injectable pharmaceutical composition comprising apixaban. The invention particularly relates to a ready to dilute injectable composition comprising apixaban, and pharmaceutically acceptable excipients. The present invention also relates to a ready to use injectable composition comprising apixaban, and pharmaceutically acceptable excipients The invention also particularly relates to a process of preparing the composition.

The utility model discloses a novel high-precision purification device for an apixaban intermediate, and relates to the technical field of medicine preparation. The device comprises a base, a purification tank is fixedly mounted on the base, a mounting cover is mounted at the top of the purification tank, a vertically-arranged rotating shaft is rotatably arranged at the middle end of the mounting cover, and a plurality of stirring pieces distributed at equal intervals are fixedly mounted at the end, located in the purification tank, of the rotating shaft. A horizontally-arranged cross rod is fixedly arranged at the top of the rotating shaft, a vertically-arranged first scraping plate is fixedly arranged at the end, away from the rotating shaft, of the cross rod, and an obliquely-arranged second scraping plate is fixedly arranged at the bottom of the first scraping plate; high-pressure water flow flushing of the fancy spraying head is combined with mechanical scraping of the first scraping plate and the second scraping plate, the double functions of spraying flushing and physical stripping are achieved, compared with a traditional single spraying mode, medicine impurities attached to the inner wall can be more thoroughly removed, and the cleaning efficiency is improved.

The invention discloses an apixaban intermediate and a synthesis method thereof, and relates to the technical field of pharmaceutical manufacturing intermediates. The synthesis method of the apixaban intermediate comprises the following steps: dissolving a compound as shown in a formula I in a solvent 1, adding an acid-binding agent and 5-chlorovaleryl chloride for reaction, and then adding an inorganic base 1 for reaction to obtain a compound as shown in a formula II; dissolving the compound as shown in the formula II in a solvent 2, adding a phase transfer catalyst, bromine and an inorganic base 2, and reacting to prepare a compound as shown in a formula III; dissolving the compound as shown in the formula III in a solvent 3, adding iron nitrate nonahydrate, a catalyst 1 and salt, and continuously introducing a catalyst 2 for reaction to prepare a compound as shown in a formula IV; dissolving the compound as shown in the formula IV in a solvent 4, adding morpholine and inorganic alkali 3, and reacting to obtain a compound as shown in a formula V; the invention solves the problems of harsh synthesis conditions and high cost of the existing apixaban intermediate.

Modified Factor Xa polypeptides having functional activity and reduced affinity for apixaban are provided. Nucleic acids encoding the modified Factor Xa polypeptides and vectors and host cells including the nucleic acids are also provided. Methods of reducing or inhibiting bleeding, such as in a subject being treated with a direct oral anticoagulant are provided.

This invention provides a solid preparation containing apixaban that exhibits stable dissolution properties and suppresses the formation of related substances, a method for producing the solid preparation, and an apixaban-containing composition that serves as a raw material for the solid preparation. [Solution] An apixaban-containing composition comprising crystalline apixaban particles, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent; and a dispersion preparation step of preparing a dispersion containing crystalline apixaban particles and a surfactant; a granulation step of granulating the dispersion and an excipient as raw materials after the dispersion preparation step; and a formulation step of manufacturing a solid preparation using the obtained granulated powder as raw materials after the granulation step, wherein the primary particles of the crystalline apixaban particles comprise crystalline apixaban and a swelling agent.

The application provides a high-purity apixaban and a preparation method thereof, and relates to the technical field of bulk drug synthesis. Specifically, compound 1 and compound 2 are used as raw materials, a phase catalyst is used, compound 1 is reacted with compound 2 in a reaction solvent under heterogeneous conditions, and amine ester exchange reaction is used to prepare crude apixaban; then the crude product is purified and crystallized to obtain apixaban products which are easy to prepare and high in purity. The raw material formula used in the application is simple, the amount of raw materials is small, the overall preparation method is simple and easy to operate, the requirements for equipment and energy consumption are low, and the application is especially suitable for large-scale industrial production. The prepared apixaban products are all above 99.94% in purity and above 98% in yield, and have the beneficial effects of high yield and high quality.

Disclosed herein relates to an oral liquid formulation of apixaban and more specifically an oral liquid formulation of apixaban comprising a therapeutically effective amount of apixaban, a salt or prodrug thereof; one or more viscosifying agents; one or more buffering agents to provide a formulation pH of from about 3.5 to about 4.5, and one or more pharmaceutically acceptable excipients. Also disclosed herein relates to a process for preparing an oral liquid formulation of apixaban and a method of using the same.

The application discloses a kind of full continuous flow chemical synthesis methods of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate.The full continuous flow chemical synthesis method includes the following steps: sodium nitrite solution, formula (I) compound solution, acid is passed into dynamic tubular reactor, and diazotization reaction occurs under the condition that temperature is not higher than 0 DEG C;Sodium acetate solution, 2-chloroacetoacetic acid ethyl ester solution is passed into microchannel reactor, and Japp-Klingemann reaction occurs with diazotization reaction liquid mixture under the condition that temperature is-5~2 DEG C, concentration, to obtain apixaban intermediate formula (II) compound.The application provides a kind of full continuous flow chemical synthesis method of apixaban intermediate (Z)-2-chloro [(4-methoxyphenyl) hydrazono] ethyl acetate, can be efficiently, high purity, high yield in a few tens of seconds to prepare target product.