73 results about "Dapagliflozin" patented technology

The invention relates to a method for continuously synthesizing a dapagliflozin intermediate, and belongs to the technical field of drug intermediate synthesis. The method comprises the following steps: mixing 5-bromo-2-chloro-4 '-ethoxydiphenylmethane, a photocatalyst and THF (tetrahydrofuran), introducing the mixture into an ultraviolet light catalytic micro-channel for pre-activation to generate an aryl free radical intermediate, namely a pre-activation solution, carrying out contact reaction on the pre-activation solution and a THF solution of 2, 3, 4, 6-tetra-O-trimethylsilyl-D-glucolactone in a low-temperature coupling area of a micro-reactor, and carrying out purification, purification and purification to obtain the aryl free radical intermediate. The reaction liquid is introduced into a dynamic quenching zone and is mixed with supercritical CO2 on line, an intermediate I is obtained through supercritical fluid extraction and separation, and the photocatalyst is recycled; the method has the advantages of high reaction efficiency, convenience in catalyst recovery and simplicity in product separation.

The present invention discloses modified-release bilayer tablets consisting of two layers, layer 1 consisting 500 mg sustained release metformin and layer 2 consisting 250 mg normal release metformin and 5mg / 10mg delayed-release dapagliflozin. This formulation is meticulously designed to regulate blood glucose levels effectively over an extended period. Immediate-release metformin swiftly addresses acute glucose spikes, while sustained-release metformin ensures prolonged glucose control, minimizing fluctuations throughout the day. The delayed-release dapagliflozin component allows for controlled and timed release, managing persistent hyperglycemia synergistically with metformin. By optimizing efficacy and minimizing glucose fluctuations, this innovative formulation offers a promising solution for stable glycemic control in individuals with diabetes. Present invention aims to improve patient outcomes and enhance overall quality of life by maintaining stable glucose levels and reducing the risk of complications associated with uncontrolled diabetes.

The present disclosure relates to the endothelin receptor antagonist (ERA) zibotentan in combination with the sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin for use in the treatment of certain endothelin related diseases.

The application discloses a preparation method of a key intermediate of dapagliflozin, and belongs to the technical field of preparation of medical intermediates. The preparation method of the key intermediate of dapagliflozin comprises the following steps: 1, 1-ethoxy-4-methylbenzene is prepared by using p-cresol, sodium hydroxide and diethyl sulfate; 2, (4-ethoxybenzyl) phenyl sulfide is prepared by using 1-ethoxy-4-methylbenzene, thiophenol, a palladium catalyst, an alkali and an oxidant; 3, 1-benzyl-4-ethoxybenzene is prepared by using (4-ethoxybenzyl) phenyl sulfide under a hydrogen atmosphere; 4, 4-ethoxy-2'-chlorobenzhydrol is prepared by carrying out chlorination reaction on 1-benzyl-4-ethoxybenzene; and 5, 5-bromo-2-chloro-4'-ethoxybenzhydrol is prepared by carrying out bromination reaction on 4-ethoxy-2'-chlorobenzhydrol. The yield and purity of 5-bromo-2-chloro-4'-ethoxybenzhydrol prepared by the method are higher, the process is safer, and the production cost is reduced.

Provided are a composite tablet comprising a first layer containing dry granules containing sitagliptin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and dapagliflozin, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, and a second layer containing wet granules containing metformin, or a pharmaceutically acceptable salt thereof, and colloidal silicon dioxide, and a method for producing the same.

The invention discloses a preparation method of a dapagliflozin intermediate 5-bromine-2-chlorine-4 '-ethyoxyl diphenylmethane, which comprises the following steps: carrying out nucleophilic substitution reaction on 4-bromine-1-chlorine-2-fluorobenzene and 4-ethyoxyl phenylacetate, and then hydrolyzing and decarboxylating to obtain the dapagliflozin intermediate 5-bromine-2-chlorine-4'-ethyoxyl diphenylmethane. By optimizing the preparation route, the reaction utilization rate, the product yield and the product purity of the raw materials are improved, high-risk and high-pollution chemicals are prevented from being used, and the method is convenient to operate, safe, environmentally friendly, efficient in reaction and beneficial to industrial implementation.

A stable pharmaceutical composition for oral administration, comprising sitagliptin and dapagliflozin, wherein said active ingredients are substantially free of contact from each other. A process for the preparation of a stable pharmaceutical dosage form for oral administration, comprising: Step 1: Weigh sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose and sieve; Step 2: Wet granulation Step 3: Drying the granules in fluid bed dryer; Step 4: Sizing the granules; Step 5: Weigh dapagliflozin base, lactose monohydrate, and sodium starch glycolate, premix them and sieve; Step 6: Mixing granules from step 4 with excipients from step 5; Step 7: Lubrication with magnesium stearate, and Step 8: Compression of the homogeneous powder obtained from step 7 under controlled humidity in mono-layer tablets in a rotary tabletting machine. An alternative process comprising the following steps: Step 1: Weigh sitagliptin hydrochloride monohydrate and Microcrystalline Cellulose and sieve; Step 2: Wet granulation Step 3: Drying the granules in fluid bed dryer; Step 4: Sizing the granules; Step 5: Weigh dapagliflozin base, lactose monohydrate, and hydroxypropylcellulose and sieve; Step 6: Dry granulation of second active ingredient and the intra-granular excipients of step 5 and mix; Step 7: Sizing the slugs or flakes obtained from step 6; Step 8: Pre-Mixing the granules from step 4 and step 7; Step 9: Weigh sodium starch glycolate and sieve; Step 10: Mixing; Step 11: Lubrication with magnesium stearate, and Step 12: Compression of the homogeneous powder obtained from step 11.

Disclosed is a method of treating patients with microvascular angina by using a combination of zibotentan and dapagliflozin.

The invention relates to a dapagliflozin impurity and a preparation method thereof, 5-bromo-2-chlorobenzoic acid (IV) is used as a raw material, (5-bromo-2-chlorphenyl) (4-ethyoxyl phenyl) ketone (III) is prepared through chlorination and Friedel-Crafts acylation, (5-bromo-2-chlorphenyl) (4-ethyoxyl phenyl) methanol (II) is obtained through reduction, and the benzhydryl ether impurity (I) is obtained through condensation under the catalysis of iodine. The preparation method has the advantages of simple operation, low cost, easily available raw materials and good product purity.

The invention relates to a dapagliflozin and metformin sustained-release tablet and a preparation method thereof, corresponding anti-spallation stabilizers are respectively added into dapagliflozin and metformin layer materials in a prescription, and the problems of temperature, humidity and spallation generated in the storage process can be reduced.

The present invention relates to a stable pharmaceutical composition comprising amorphous form of dapagliflozin base presenting proper in vivo and in vitro dissolution profiles.

Methods for treating high proteinuria chronic kidney disease and / or at least one disease, disorder, or condition associated therewith in patients by the use of a fixed-dose combination of zibotentan and dapagliflozin are disclosed.

The utility model discloses a dapagliflozin preparation reaction device with a protection function, and relates to the technical field of chemical medicine production equipment. Comprising a reaction kettle body, a protection part is rotatably arranged in an inner cavity of the reaction kettle body, a main material enters the reaction kettle body through a main material pipe, an ingredient enters an ingredient barrel in the reaction kettle body through an ingredient pipe, and at the moment, a sealing disc is tightly attached to the bottom of an inner cavity of the ingredient barrel to seal the bottom of the ingredient barrel. The main material and the auxiliary material do not react immediately, so that the material and the auxiliary material are prevented from violently reacting to generate material flushing, and liquid medicine in the reaction kettle body is prevented from being sprayed out through the auxiliary material pipe and the main material pipe to injure personnel.

The present disclosure relates to methods of treating patients with chronic kidney disease (CKD) with or without type 2 diabetes using an SGLT2 inhibitor such as dapagliflozin.

The present disclosure is directed to methods of treating patients with heart failure with reduced ejection fraction (HFrEF), with and without Type 2 diabetes, with an SGLT2 inhibitor, such as dapagliflozin. The methods disclosed herein can reduce the risk of a composite outcome of a first episode of worsening heart failure (hospitalization for heart failure or an urgent heart failure visit) or death from cardiovascular causes. Each of the three components of this composite outcome can also be reduced, as well as the total number of heart failure hospitalizations and deaths from cardiovascular causes. SGLT2 inhibitors, such as dapagliflozin, can also reduce a worsening of heart failure symptoms. The methods disclosed herein can also improve heart failure symptoms, health status, and quality of life.

The invention discloses a dapagliflozin-propylene glycol monohydrate pharmaceutical composition and a preparation method thereof, and relates to the technical field of medicine preparation, the pharmaceutical composition is composed of dapagliflozin-propylene glycol monohydrate, microcrystalline cellulose, lactose anhydrous, polyvinylpolypyrrolidone, silica, magnesium stearate and a coating agent; in the preparation process, firstly, the raw material medicines are sieved by a 120-mesh sieve, so that the in-vitro dissolution capacity is fully improved, and then granulation and coating are performed; the dapagliflozin propylene glycol monohydrate has the advantages that the coating rate of the prepared dapagliflozin propylene glycol monohydrate is high and reaches 95% or above through the unique ingredient proportion of the auxiliary materials and the coating agent, the disintegration time is short under various pH medium conditions, the dapagliflozin propylene glycol monohydrate can be completely disintegrated within 30 seconds, and the dissolution rate in 15 minutes reaches 85% or above. The sample content is uniform and reaches 100%; the prepared dapagliflozin and propylene glycol monohydrate composition has better stability under the conditions of high temperature, high humidity and illumination, and meanwhile, the tablet surface is smooth, so that the compliance of a patient can be improved.

The invention discloses a method for preparing dapagliflozin based on a microchannel reaction technology, which comprises the following reaction steps: (1) reacting a 5-bromo-2-chloro-4 '-ethoxydiphenylmethane solution, a 2, 3, 4, 6-tetraacetoxy-alpha-D-glucopyranose bromide solution and an organic metal reagent solution in a microchannel reactor 1 to obtain a compound as shown in a formula IV; and (2) reacting the compound solution as shown in the formula IV and the deacetylation reagent solution in a micro-channel reactor 2 to obtain dapagliflozin. According to the method, acetyl-protected bromoglucose is adopted as a reaction material, multiple derivatization of hydroxyl in a traditional process and a reduction reaction step in the traditional process are avoided, the dapagliflozin is prepared by adopting a micro-channel reaction technology, the synthesis steps are simple, the yield is high, and the method is suitable for industrial production. A target product can continuously flow out while reaction raw materials are continuously pumped, the operation is convenient, and the reaction safety is high.

The present disclosure relates to the endothelin receptor antagonist (ERA) zibotentan in combination with the sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin for use in the treatment of certain endothelin related diseases.

Provided is a preparation method for a dual sustained-release dapagliflozin tablet. The dapagliflozin tablet consists of an enteric-soluble inner core, a gastric-soluble middle core, and a coating. The gastric-soluble middle core consists of the following raw and auxiliary materials, in percentage by weight: 5-7% of dapagliflozin, 10% of voglibose, 69-73% of a microcrystalline cellulose complex, 2-4% of a disintegrating agent, and 10% of an HPMC coating solution; and the enteric-soluble inner core consists of the following raw and auxiliary materials, in percentage by weight: 5-7% of dapagliflozin, 8% of Yuanzhen sugar, 63-77% of a microcrystalline cellulose complex, 4-8% of a disintegrating agent, 8% of an HPMC coating solution, and 6% of alginic acid. The prepared dapagliflozin tablet has the advantages of high dissolution rates of the pharmaceutical ingredients, good release effect, and low pressure on the kidneys.

The invention relates to the technical field of biological medicine, in particular to application of tripterine or medicinal salt thereof in preparation of medicine for treating ketoacidosis or symptoms caused by ketoacidosis. The invention provides application of tripterine or medicinal salt thereof in preparation of a medicine for treating ketoacidosis or symptoms caused by ketoacidosis. The result of the specific embodiment of the invention shows that the tripterine can obviously reduce the mouse serum beta-hydroxybutyric acid level caused by hunger; the tripterine can be used for remarkably reducing the expression of HMGCS2 in the liver of a mouse; the dapagliflozin remarkably promotes the level of beta-hydroxybutyric acid, and the tripterine remarkably reduces the level of mouse serum beta-hydroxybutyric acid caused by treatment of the dapagliflozin. Therefore, tripterine can be used for treating or improving ketoacidosis or symptoms caused by ketoacidosis. The invention provides a new technical scheme for treatment and improvement of ketoacidosis or symptoms caused by ketoacidosis.

The present disclosure provides methods of preparing pharmaceutical formulations containing dapagliflozin and uses thereof. The method for preparing the dapagliflozin-containing pharmaceutical preparation comprises the following steps: dissolving dapagliflozin and / or a hydrate thereof and lactose in an aqueous solution of alcohol and / or ketone to ensure that the mass ratio of the dissolved lactose to the dapagliflozin is (1-9.4): 1 to obtain a coating solution; and preparing an upper drug coating layer by using the coating liquid. Therefore, the dissolution stability of dapagliflozin in the pharmaceutical preparation in the storage process can be improved.

The invention discloses a detection method of dapagliflozin peroxide genotoxic impurities, and belongs to the technical field of pharmaceutical analysis. According to the detection method, high performance liquid chromatography is adopted, and the detection conditions of the high performance liquid chromatography are as follows: an octadecyl bonded silica gel column is used as a chromatographic column; the mobile phase A is any one of water, a trifluoroacetic acid aqueous solution and an ammonium acetate buffer solution; the mobile phase B is a mixed solution of methanol and acetonitrile, and the volume ratio of methanol is not less than 40%; and carrying out gradient elution. According to the method, the peroxide genotoxic impurities in dapagliflozin are detected through the high performance liquid chromatography, an LC / MS (Liquid Chromatography / Mass Spectrometry) coupling technology is not needed, and the detection cost is greatly reduced. According to the present invention, the high performance liquid chromatography is adopted, the water or the buffer solution is adopted as the mobile phase A, the methanol and acetonitrile mixed solution is adopted as the mobile phase B, such that the method has characteristics of strong specificity, high sensitivity and high accuracy, and the guarantee is provided for the dapagliflozin medication safety.

The invention discloses a composition containing dapagliflozin and fenerenone and a preparation method thereof, and relates to the technical field of medicines, the composition is composed of dapagliflozin, fenerenone, a traditional Chinese medicine synergistic component, a bioactive substance, probiotic freeze-dried powder, a slow-release carrier and functional auxiliary materials; through the elaborately designed composition proportion, the treatment effect of the medicine and the patient experience are remarkably improved, the composition fuses the two effective components of dapagliflozin and fenerenone, and traditional Chinese medicine synergistic components of astragaloside and berberine are matched, so that the blood glucose reducing effect of the medicine is enhanced, and through the adjusting effect of traditional Chinese medicine, the blood glucose reducing effect of the medicine is improved. The traditional Chinese medicine composition effectively relieves possible adverse reactions of patients, and meanwhile, due to the addition of bioactive substances coenzyme and vitamin D, the overall efficacy of the medicine is further improved, the body function and metabolic level of the patients can be improved, and the traditional Chinese medicine composition has remarkable advantages in treatment effect compared with a traditional single-component medicine and is worthy of popularization and application. And the treatment requirements of patients can be better met.

Provided herein are compositions and methods for reducing or preventing ovarian aging comprising: administering to a subject in need of a reduction or prevention of ovarian aging an effective amount of an SGLT2 antagonist. Examples of SGLT2 antagonists include canagliflozin, bexagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin, phlorizin, or combinations thereof.

The invention relates to the field of medicines, and particularly discloses application of dapagliflozin to preparation of a medicine for preventing and / or treating obesity-related salt-sensitive hypertension. According to the application, the new application of dapagliflozin in prevention and treatment of a specific and high-risk disease subtype of obesity-related salt-sensitive hypertension is defined for the first time. Experiments prove that dapagliflozin can improve the sodium treatment function of the kidney and promote urine sodium excretion by inhibiting abnormal continuous coupling of a Na / K-ATPase / c-Src signal axis in the kidney. The discovery reveals a new kidney protection mechanism of dapagliflozin independent of the hypoglycemic effect, and provides a new drug use and a treatment scheme for clinical prevention and treatment of obesity-related renal sodium metabolism disorders and salt-sensitive hypertension.

Disclosed are methods for treating high proteinuria chronic kidney disease and / or at least one disease, disorder or condition associated therewith in a patient by using a fixed dose combination of zipotentan and dapagliflozin.

The invention relates to a bilayer tablet comprising metformin in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph thereof and dapagliflozin in the form of the free base or in the form of pharmaceutically acceptable salts, crystalline polymorph thereof, and at least one pharmaceutically acceptable excipient, wherein the bilayer tablet has a hardness of more than 253 N.