32 results about "Vonoprazan" patented technology

The present invention relates to a method for preparing nitrosamine impurities in vonoprazan fumarate, belonging to the technical field of chemical synthesis. By mixing vonoprazan with an organic solvent and reacting the mixture with a nitrosating agent at room temperature, the nitrosamine impurities prepared by this method have a purity exceeding 85%. This method solves the problem of preparing nitrosamine impurities and also provides a reference substance for the study of impurities in vonoprazan fumarate.

This invention relates to the crystal form of vonorazine pyroglutamate and its preparation method. The vonorazine pyroglutamate crystal form obtained by this invention not only has good solubility but also excellent storage stability; in vitro activity experiments show that crystal form I of this invention is effective against H+. + K + The inhibitory effect of ATPase is comparable to that of TAK-438; animal experiments show that the crystal form of the present invention, when administered intravenously, can significantly inhibit histamine-induced gastric acid secretion in rats, and can exert its pharmacological effect faster than that of TAK-438 administered duodenally.

The invention belongs to the technical field of medicines, and particularly relates to a bifunctional compound with anti-helicobacter pylori and acid inhibition activity, a preparation method of the bifunctional compound and application of the bifunctional compound in preparation of medicines for treating peptic ulcer and helicobacter pylori infection. According to the compound, a potassium ion competitive acid blocker vonoprazan is used as an acid inhibition unit, and rifobetine is used as an anti-helicobacter pylori unit; the two compounds are respectively subjected to covalent modification through linking groups Linker 1 and Linker 2, and then are connected by virtue of a triazole ring to form a series of bifunctional compounds shown as a general formula (I). The compound can simultaneously and synergistically act on two key targets of gastric acid secretion and helicobacter pylori, so that not only is the treatment effect remarkably enhanced, but also better safety is shown due to the fact that the same curative effect can be achieved at a lower dosage.

The invention discloses vonoprazan fumarate, intragastric retention tablets of the vonoprazan fumarate and application of the vonoprazan fumarate to gastrointestinal tracts, and relates to the technical field of medicines.The vonoprazan fumarate is prepared through a synthesis method comprising the following steps that in the presence of an organic solvent and alkali, 5-(2-fluorophenyl) pyrrole-3-formaldehyde and pyridine-3-sulfonyl chloride are subjected to a reaction, and the vonoprazan fumarate is obtained. Hydroxypropyl-beta-cyclodextrin is added into a reaction system, and a compound WNLZ-1 is generated; reacting the compound WNLZ-1 with methylamine, and then reducing to obtain a compound WNLZ-3; the compound WNLZ-3 and fumaric acid are subjected to a salt forming reaction, and vonoprazan fumarate is obtained. According to the preparation method, hydroxypropyl-beta-cyclodextrin is introduced as a reaction accelerant in the synthesis step, the yield and purity of an intermediate are improved, meanwhile, hydroxypropyl-beta-cyclodextrin and xanthan gum are jointly used in the preparation, and the whole process optimization from raw material medicine synthesis to preparation performance is achieved.

Disclosed are: a pharmaceutical composition capable of inhibiting the generation of a nitrosamine impurity of a vonoprazan drug product by means of an antioxidant; and a preparation method therefor.

The application provides a preparation method of low-impurity vonerogefumate. The application provides a method for removing impurities A-E in the preparation of vonerogefumate, wherein vonerogefumate is reacted with hydrobromic acid to obtain vonerogefumate hydrobromide, and the method specifically comprises the following steps: (1) dissolving vonerogefumate and hydrobromic acid in a solvent; (2) cooling or directly precipitating a solid; and (3) separating to obtain vonerogefumate hydrobromide. The method can remove impurities A-E which are difficult to remove by a recrystallization refining method, and the method has good selectivity for impurities A-E. The application provides an impurity D, a preparation method thereof and application of the impurity D as an impurity control sample of vonerogefumate.

The present invention discloses a method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor. In the method of the present invention, α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile is used as the starting material, which attacks a series of Michael acceptors under basic conditions and undergoes cyclization to form a series of 3-substituted 5-(2-fluorophenyl)-1H-pyrroles. These 3-substituted pyrrole intermediates can be further chemically transformed to prepare vonoprazan. Compared with the prior art, the technical means of the present invention are characterized by a short synthetic route, high overall yield, simple post-treatment, and low cost.

The invention belongs to the technical field of drug analysis and detection, and particularly relates to a method for detecting potential genotoxic impurities in Vonoprasone fumarate and application. The invention discloses a high performance liquid chromatography method for detecting potential genotoxic impurities of Vonoprazan fumarate, which adopts a chromatographic column with octadecylsilane chemically bonded silica as a filler and adopts phosphate buffered solution-acetonitrile as a mobile phase for gradient elution. The potential genotoxic impurities in the Vonoprasone fumarate can be rapidly and effectively separated. The method has the advantages that the separation degree of each chromatographic peak and an adjacent impurity peak is good, the detection limit and the quantitation limit also meet the analysis requirements, the sensitivity and the accuracy are high, the detection of the potential genotoxic impurities of the Vonoprazan fumarate can be met, and the product quality is ensured.

Providing granules or solid formulations with reduced dissolution delay of Vonoprazan Fumarate after storage SOLUTION: The disclosed granules or solid formulations comprise Vonoprazan Fumarate, carbonate and aspartic acid.SELECTED DRAWING: Figure 2

The application belongs to the technical field of preparation of pharmaceutical compounds, and particularly relates to a preparation method of an intermediate for preparing vonomacarbazone fumarate, wherein compound S1 and compound S2 are used as raw materials to synthesize compound S3, and then the intermediate S4 is synthesized from the compound S3, wherein the structural formulae of the compounds S1 and S2 are as follows: S1: S2: S3: The above technical scheme of the application fundamentally changes the construction strategy of the key pyrrole ring skeleton of vonomacarbazone fumarate, and two open-chain molecules S1 and S2 with simple structures, which are commercially available or easy to prepare, are used to efficiently and selectively construct the target pyrrole ring structure (S4) on site through a simple addition-electrophilic cyclization reaction. The method not only greatly reduces the cost of raw materials, but also avoids the dependence on unstable intermediates, and simplifies the synthesis path from the source.

The present invention relates to a compound pharmaceutical composition and its application in preventing Helicobacter pylori infection, and more specifically, to the compound pharmaceutical composition, pharmaceutical preparation, preparation method and use. The composition comprises at least two selected from the following components: (I) vonoprazan or a pharmaceutically acceptable salt thereof; (II) amoxicillin or a pharmaceutically acceptable salt thereof; (III) clarithromycin; and (IV) a bismuth agent. The composition prepared by compounding different anti-infective active ingredients can not only effectively solve the problems of patient compliance and medication convenience, such as reducing the dosage of tablets and avoiding patients from taking the wrong tablets, missing a dose, or taking more than one dose, but also unexpectedly improve the stability and safety of the preparation, and is particularly conducive to reducing the content of harmful impurities.

The present invention relates to stabilization of non-peptidic pharmaceutically active agent or salt thereof. The pharmaceutical compositions comprise non-peptidic pharmaceutically active agent preferably vonoprazan or salt thereof along with glycerophosphoric acid (GPA) for the treatment of healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults.

The invention relates to the technical field of medicines, and particularly discloses a fumaric acid Vonoprazan tablet and a preparation method of the fumaric acid Vonoprazan tablet. The invention relates to a fumaric acid Vonoprazan tablet, which is prepared from the following raw materials in parts by weight: 5 to 8 parts of fumaric acid Vonoprazan, 0.5 to 1.5 parts of lubricating agents, 5 to 10 parts of disintegrating agents, 10 to 20 parts of filling agents and 1 to 3 parts of bonding agents. The fumaric acid vonorbitan tablet is coated with a polymethylacrylic acid composite material; according to the preparation method, the fumaric acid vonorbitan tablet is coated by adopting the polymethylacrylic acid composite material, moisture and illumination are isolated, degradation of active components of the fumaric acid vonorbitan tablet is reduced, and the dissolution rate and stability of the fumaric acid vonorbitan tablet are improved.

Described herein is a method for purifying vonoprazan fumarate of formula (I).

The invention discloses a fumaric acid Vonoprazan suspension and a preparation method thereof, the fumaric acid Vonoprazan suspension is prepared from fumaric acid Vonoprazan, a suspending aid, a wetting agent, an acidifying agent, a flavoring agent and essence, the prepared preparation is easier to swallow compared with tablets, proper auxiliary materials are screened and added through a prescription, the bitter taste of the fumaric acid Vonoprazan during oral administration is obviously reduced, and the oral administration effect of the fumaric acid Vonoprazan is improved. The clinical compliance of a patient is improved; and the defects that the tablet is taken after being broken apart, the dosage is not accurate enough, the coating is damaged and the taste masking effect is influenced are overcome. The oral suspension is packaged in unit dose, and is accurate in dose and convenient to administrate.

The present invention provides a vonoprazan fumarate composition and a preparation method thereof, belonging to the field of medical technology. Specifically, a vonoprazan fumarate composition is provided, comprising the following components: vonoprazan fumarate, vitamin C, an oil phase, and sodium bicarbonate or calcium carbonate; a preparation method of the vonoprazan fumarate composition is also provided. The vonoprazan fumarate composition provided by the present invention greatly improves the efficacy of treating gastric diseases, reduces the dosage of vonoprazan fumarate, and effectively solves the problem of large toxic and side effects of existing vonoprazan fumarate agents.

The present invention relates to stabilization of non-peptidic pharmaceutically active agent or salt thereof. The pharmaceutical compositions comprise non-peptidic pharmaceutically active agent preferably vonoprazan or salt thereof along with glycerophosphoric acid (GPA) for the treatment of healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults.

This invention belongs to the field of pharmaceutical technology and relates to a method for preparing vonoprazan fumarate. Compound 3 reacts with a methylamine alcohol solution and a reducing agent at low temperature, followed by quenching, and then forms a salt with fumaric acid to generate vonoprazan fumarate. In this method, the amination-reduction step is performed under mild conditions, and the product can be directly obtained by salt formation with fumaric acid after simple post-treatment following quenching, without the need for pre-preparing other intermediate salts. This method is simple to operate, low in cost, and yields a product with few impurities, making it suitable for industrial production.

The present invention provides a method for producing vonoprazan fumarate with a purity of 99.9% or higher in high yield. Specifically, the present invention relates to a method for producing vonoprazan fumarate with a purity of 99.9% or higher in high yield by forming vonoprazan hydrochloride using a specific amount of hydrochloric acid, and then converting it into a fumarate form to form vonoprazan fumarate. Furthermore, the present invention provides a specific crystalline form of vonoprazan hydrochloride that can be usefully used in the above production method.

The present invention relates to pharmaceutical composition comprises vonoprazan or pharmaceutically acceptable salts thereof.

According to the preparation method, the oral liquid is prepared into an oral liquid dosage form by taking a cosolvent, an acidifying agent, a pH regulator, a flavoring agent, a buffer solution and a solvent as auxiliary materials, the clinical compliance of a patient is improved, and meanwhile, the oral dosage form of the fumarate directly acts on gastric parietal cells, so that the oral dosage form of the fumarate directly acts on the gastric parietal cells; compared with tablets, active substances in the stomach can be released and act on gastric wall cells only after being disintegrated and dissolved, the solution reaches the stomach after being orally taken, the active substances can directly act on the gastric wall cells, the medicine effect can be quickly exerted, and a better treatment effect is provided for patients with acute gastrointestinal discomfort.

The present invention discloses a method for preparing a series of vonoprazan intermediates using an isonitrile and a Michael acceptor. In the method of the present invention, α-(p-toluenesulfonyl)-2-fluorobenzylisonitrile is used as the starting material, which attacks a series of Michael acceptors under basic conditions and undergoes cyclization to form a series of 3-substituted 5-(2-fluorophenyl)-1H-pyrroles. These 3-substituted pyrrole intermediates can be further chemically transformed to prepare vonoprazan. Compared with the prior art, the technical means of the present invention are characterized by a short synthetic route, high overall yield, simple post-treatment, and low cost.

This invention belongs to the field of pharmaceutical content detection, specifically relating to a method for determining the content of vonoprazan fumarate tablets. The vonoprazan fumarate tablets of this invention are prepared using mannitol, fumaric acid, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, and magnesium stearate as excipients. The preparation method described in this invention simplifies the preparation process and reduces production costs. This invention also provides the above-mentioned method for determining the content of vonoprazan fumarate tablets. High-performance liquid chromatography (HPLC) is used to accurately determine the content of the active ingredient vonoprazan in the prepared vonoprazan fumarate tablets. This method effectively eliminates the influence of added excipients and impurities on the determination of the active ingredient vonoprazan content, providing important assurance for clinical medication safety and offering a new method for the quality control of vonoprazan fumarate tablets.

The invention discloses a photochemical synthesis method of a vonoprazan intermediate, and belongs to the technical field of drug intermediate synthesis, the synthesis method comprises the following steps: (1) 2-bromo-1-(2-fluorophenyl) ethyl-1-ketone and acetaldehyde are subjected to a white light irradiation reaction under the action of a photosensitizer and alkali to obtain 4-(2-fluorophenyl)-4-oxobutyraldehyde; (2) carrying out a Paal-Knorr condensation reaction on the 4-(2-fluorophenyl)-4-oxobutyraldehyde and ammonium acetate under the action of an acid catalyst and a dehydrating agent, so as to obtain 2-(2-fluorophenyl)-1H-pyrrole; (3) carrying out formylation reaction on the 2-(2-fluorophenyl)-1H-pyrrole and 1, 1-dichloromethoxymethane under the action of a Lewis acid catalyst, so as to obtain a vonoprazan intermediate; the method has the advantages of cheap and easily available raw materials, high product yield, safe and simple process, mild reaction conditions and low cost, and is suitable for industrial production.

The invention provides a vonoprazan fumarate intermediate, a preparation method of the vonoprazan fumarate intermediate through photocatalytic propionaldehyde alpha-position alkylation reaction and application of the vonoprazan fumarate intermediate, and belongs to the field of organic synthesis. According to the preparation method disclosed by the invention, two cheap substrates, namely propionaldehyde and alpha-bromo-o-fluoroacetophenone or alpha-chloro-o-fluoroacetophenone, are efficiently converted into a 4-(2-fluorophenyl)-2-methyl-4-oxobutyraldehyde product through a photocatalysis strategy, and the 4-(2-fluorophenyl)-2-methyl-4-oxobutyraldehyde product is used as an important vonoprazan fumarate intermediate. The vonoprazan fumarate is taken as an intermediate and can be used for preparing vonoprazan fumarate; moreover, two important intermediates, namely 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde and 5-(2-fluorophenyl)-1-[(pyridine-3-yl) sulfonyl]-1H-pyrrole-3-formaldehyde, can be synthesized, so that the two important intermediates are used for preparing vonoprazan fumarate, and an important means and method are provided for reducing the industrial production cost of vonoprazan fumarate.

The invention relates to a preparation method of a Vonoprazan intermediate. According to the preparation method, pyridine-3-sulfonyl fluoride is taken as a raw material, and the pyridine-3-sulfonyl fluoride and 5-(2-fluorophenyl)-1H-pyrrole-3-formaldehyde are subjected to a reaction, such that the Vonoprazan intermediate 5-(2-fluorophenyl)-1-[(pyridine-3-yl) sulfonyl]-1H-pyrrole-3-formaldehyde is obtained. The pyridine-3-sulfonyl fluoride has good stability, is convenient to store and weigh, is easier to carry out quality research as a starting material than pyridine-3-sulfonyl chloride, can be directly analyzed and detected by a liquid phase, is simple and convenient to operate in the reaction process, and can overcome the problems existing in synthesis of the Vonorazan intermediate by taking pyridine-3-sulfonyl chloride as a raw material at present. The yield of the Vonoprazan intermediate prepared by the preparation method can reach 75-85%, and the preparation method is suitable for large-scale production.

The invention relates to a fumaric acid Vonoprazan freeze-dried sublingual tablet and a preparation method thereof. According to the freeze-dried sublingual tablet, the bulk drugs are nanocrystallized, the stability of a bulk drug nanocrystal system is kept by adding the special stabilizer, and the freeze-dried sublingual tablet can be rapidly disintegrated and absorbed under the tongue and is good in stability.

The present invention relates to a compound pharmaceutical composition, and use thereof in anti-helicobacter pylori infection, and particularly relates to the compound pharmaceutical composition, a pharmaceutical formulation, a preparation method, and use. The composition comprises at least two components selected from the following: (I) vonoprazan or a pharmaceutically acceptable salt thereof; (II) amoxicillin or a pharmaceutically acceptable salt thereof; (III) clarithromycin; and (IV) a bismuth agent. A composition prepared by compounding different anti-infective active ingredients can not only effectively address patient compliance and medication convenience issues, such as reducing tablet dosage to prevent patients from incorrect administration, missed doses, or overdoses, while unexpectedly enhancing formulation stability and safety, and particularly helping to reduce harmful impurity content.

The invention relates to a method for detecting related substances of Vonoprazan fumarate. The method comprises the following steps: (1) pretreating a sample to be detected by using a formic acid methanol solution; (2) determining related substances in the pretreated sample by liquid chromatography-mass spectrometry; the high performance liquid chromatography detection conditions are as follows: octadecylsilane chemically bonded silica is used as a filler, a 0.2% formic acid aqueous solution is used as a mobile phase A, a 0.2% formic acid methanol solution is used as a mobile phase B, and gradient elution is performed; the mass spectrum conditions are as follows: an ion source is an electrospray ion source, an acquisition mode is a positive ion mode, a monitoring mode is multi-reaction monitoring, the parent ion is 375.3, the daughter ion is 315.4, and the collision voltage is 15V. The method for detecting the impurities of the Vonoprazan fumarate NVP, provided by the invention, has the advantages of high sensitivity and high recovery rate.

The present invention relates to pharmaceutical composition comprises vonoprazan or pharmaceutically acceptable salts thereof.