62 results about "Sitagliptin" patented technology

The present invention relates to a bilayer tablet comprising extended-release formulation having metformin or a pharmaceutically acceptable salt thereof and at least one cellulose derivates as binder and immediate release formulation having sitagliptin or a pharmaceutically acceptable salt thereof and at least one antioxidant. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process of preparing the bilayer tablet.

To provide a sitagliptin preparation in which the production of nitrosamines is suppressed, and to provide a method of storage of a sitagliptin preparation to suppress the production of nitrosamines.SOLUTION: According to an embodiment of the present invention, a sitagliptin preparation is provided, comprising a sitagliptin-containing tablet, and a case or a packing sealing the sitagliptin-containing tablet, wherein the equilibrium relative humidity of the sitagliptin-containing tablet, as converted to 24°C, is 50.3% or less when the sitagliptin preparation is stored for one month under conditions of 25°C and 60% relative humidity.SELECTED DRAWING: Figure 1A

The present invention relates to a tablet formulation comprising a core tablet having metformin and at least one matrix agent and a coating solution having sitagliptin surrounding the core tablet and a film coating wherein the coating solution further comprises at least one antioxidant and at least one coating agent. Further, the present invention provides a method for the preparation of said composition.

The present invention provides an oral dosage form for, and a therapeutically effective dose for the management and / or treatment of muscular dystrophy using Sitagliptin or its pharmaceutically acceptable salt, alone or in combination with other therapeutically effective agents.

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.

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.

According to the method, an enamine intermediate (2Z)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7 (8H)-yl]-1-(2, 4, 5-trifluorophenyl) butyl-2-ene-2-amine is used as an initial raw material, and the Sitagliptin is synthesized through synergistic catalysis asymmetric hydrogenation of a cobalt catalyst and a chiral ligand. The R-configuration sitagliptin is prepared by one step, the reaction yield and stereoselectivity are high, the catalytic reaction effect is good, the cost is low, and the method is suitable for industrial large-scale production.

The invention relates to two sitagliptin pharmaceutical co-crystals as well as a preparation method and application thereof. The sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal) is formed by combining the sitagliptin pharmaceutical co-crystal 1 (sitagliptin-CaCl2 co-crystal) according to the molar ratio of 2: 1, and the molecular formula of the sitagliptin pharmaceutical co-crystal 1 is C32H30CaCl2F12N10O2; the sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal) is formed by combining the sitagliptin pharmaceutical co-crystal 2 (sitagliptin-ZnBr2 co-crystal) according to the molar ratio of 1: 1, and the molecular formula of the sitagliptin pharmaceutical co-crystal 2 is C16H15ZnBr2F6N5O. The two Sitagliptin pharmaceutical co-crystals prepared by the invention are characterized by means of X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential scanning calorimetry (DSC), thermogravimetric analyzer (TGA) and the like. Compared with the prior art, the sitagliptin pharmaceutical co-crystal prepared by the invention has one or more improved characteristics compared with the existing compound, and has important value for optimization and development of the medicine in the future.

An oral dosage form of an antidiabetic pharmaceutical composition comprises a metformin-containing core portion, an outer portion that comprises a non-biguanide antidiabetic agent such as sitagliptin, and a controlled membrane film sandwiched therebetween. The controlled membrane film is provided with at least one passageway allowing core-residing metformin to release out when the oral dosage form is in an aqueous environment, such as in the gastrointestinal (GI) tract of a subject. The oral dosage form has a dissolution profile such that upon dissolving in a medium with a pH of approximately 6.8 at approximately 37° C., less than 15% of the metformin is released at approximately 1 hours, and approximately 45-99% of the metformin is released at approximately 12 hours. The oral dosage form can provide a maximum plasma concentration of the metformin from approximately 7.5 to 15 hours after single-dose oral administration.

The present invention relates to a bilayer tablet comprising extended-release formulation having metformin or a pharmaceutically acceptable salt thereof and at least one cellulose derivates as binder and immediate release formulation having sitagliptin or a pharmaceutically acceptable salt thereof and at least one antioxidant. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient process of preparing the bilayer tablet.

The present invention relates to sitagliptin or a pharmaceutically or veterinary acceptable salt thereof for use in the local eye treatment of neovascular retinal diseases. The invention also encompasses pharmaceutical or veterinary compositions for use in the local treatment of these diseases.

The invention relates to a preparation method of a gemigliptin intermediate compound. The method specifically comprises the following steps: by taking (3S)-4-amino-3-((t-butyloxycarboryl) amino) tert-butyl butyrate as a starting raw material, carrying out amidation cyclization reaction, and hydrolyzing under an alkaline condition to prepare a target intermediate (S)-3-tert-butoxycarbonyl amino-4-(5, 5-difluoro-2-oxopiperidine-1-yl)-butyric acid. The method is simple and convenient to operate, controllable, high in atom economy, high in reaction yield and purity and suitable for industrial production.

The present invention provides a microbial strain for preparing sitagliptin compounds and its application, belonging to the field of bioengineering technology. A microbial strain for preparing sitagliptin compounds, wherein the microbial strain is Pseudomonas aeruginosa NESita-5, and the Pseudomonas aeruginosa NESita-5 is deposited in the China Center for Type Culture Collection, with the deposit address being Wuhan University, Wuhan, China, the deposit date being June 21, 2024, and the deposit number being CCTCC NO: M 20241336. The present invention uses a simple and visual result analysis method, uses the culture solution containing microbial cells as a catalyst, observes the color depth of the reaction solution, and quickly judges whether there is enzyme activity and the level of enzyme activity. Through this method, a microbial strain containing transaminase is obtained, which can be used for catalytic production of the drug sitagliptin and has good application prospects.

The invention discloses a synthetic method of a gemigliptin chiral intermediate, and relates to the technical field of organic synthesis of drugs, t-butyloxycarboryl-L-aspartic acid-4-tert-butyl ester and 5, 5-difluoropiperidine-2-ketone are used as reaction raw materials, a condensation reaction is firstly performed, then a reduction reaction is performed, and the gemigliptin chiral intermediate is obtained. The gemigliptin chiral intermediate (S)-3-(t-butyloxycarboryl amino)-4-(5, 5-difluoro-2-oxopiperidine-1-yl)-tert-butyl butyrate can be synthesized through a fractional step method or a one-pot method, the synthesis method is short in route, mild in reaction condition and safe, simple and convenient to operate, the obtained target product is high in yield and purity, and the method is suitable for industrial production. The compound can be used as a high-quality intermediate for synthesizing gemigliptin.

The present invention discloses a pharmaceutical combination formulation comprising sitagliptin and empagliflozin and a preparation method thereof.

The invention discloses application of sitagliptin in preparation of a medicine for treating Graves eye diseases, and belongs to the field of biological medicine. The invention discloses the application of sitagliptin in preparation of the medicine for treating Graves eye diseases for the first time, and sitagliptin can improve expression of CD4 + CTL cytotoxic functional molecules and improve eye symptoms, extraocular muscle thickening and fibrosis, orbit fat neogenesis and orbit T lymphocyte infiltration of mice; the mouse spleen CD4 + CTL cell proportion is improved; in addition, the thyroid hormone level, thyroid hyperplasia and hypertrophy and lymphocyte infiltration of mice can be improved. Sitagliptin is a clinically common hypoglycemic drug, and is perfect in safety database, small in side effect and easy to popularize clinically. Therefore, the experimental result of the invention fully supports the new application of sitagliptin in treating Graves eye diseases, and is a new direction worthy of exploration for treating Graves eye diseases due to strong clinical operability.

The present invention relates to a method for synthesizing sitagliptin through cobalt-catalyzed asymmetric hydrogenation. The method uses an enamine intermediate (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine as a starting material, and carries out asymmetric hydrogenation through the coordinated catalysis of a cobalt catalyst and a chiral ligand to prepare R-configured sitagliptin in one step. The method has high reaction yield and stereoselectivity, good catalytic reaction effect, low cost, and is suitable for industrial scale-up production.

The application provides a transaminase, the amino acid sequence of which is shown as SEQ ID NO. 3, which can catalyze the conversion of (2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7-(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one into sitagliptin in a methanol solution reaction system.

The utility model belongs to the technical field of medicine preparation, particularly relates to a micro-channel reactor for producing sitagliptin intermediates, and provides the following scheme aiming at the efficiency problem: the micro-channel reactor comprises a support frame, a first connecting plate is fixedly connected to the lower side of the outer surface of the supporting frame. A second connecting plate is fixedly connected to one side of the outer surface of the supporting frame. A first sliding groove is formed in the upper surface of the first connecting plate. A second sliding groove is formed in the outer surface of one side of the second connecting plate. A fixing frame is slidably mounted on the inner surface of the first sliding groove. A first sliding block is fixedly connected to the outer surface of one side of the fixing frame. A second sliding block is fixedly connected to the lower surface of the fixing frame. And a fixed rotating block is rotationally mounted on the inner surface of the first sliding block. And through the arrangement of the fixer, the connector can be quickly mounted and dismounted, and the efficiency is improved.

The invention discloses a small sitagliptin-metformin sustained release tablet and a preparation method thereof, and belongs to the technical field of medical products, the sitagliptin-metformin sustained release tablet sequentially comprises a sustained release tablet core, an isolation layer, a quick release layer and an outer coating from inside to outside; the sustained release tablet core comprises metformin, resistant starch, microcrystalline cellulose and sodium bicarbonate; the isolating layer comprises an enteric coating. The sustained-release tablet core is coated with the enteric coating, so that the dissolution property is greatly reduced under the acidic condition in the stomach, the stimulation of metformin to the stomach is reduced, and the comfort level of the stomach is improved; and the metformin is gradually released in intestines. The product is small in size and weight, the swallowing experience is improved, and the situation that swallowing is difficult is reduced. The resistant starch and the microcrystalline cellulose have a slow release effect, promote intestinal tract movement and improve the comfort of intestinal tracts; meanwhile, lactic acid rise caused by metformin accumulation can be absorbed.

The present application relates to the technical field of enzyme engineering, and discloses an amino transferase mutant and application thereof.The present application provides a wild-type amino transferase mutant derived from Aspergillus avenaceus.The amino transferase mutant is obtained by carrying out single-point or multi-point combined mutation on the 20th, 60th, 92nd and 186th positions of the amino acid sequence shown in SEQ ID NO.2, and can directly take the sitagliptin intermediate precursor ketone as a substrate, take isopropylamine as an amino donor, take phosphopyridoxyl as a coenzyme, take dimethyl sulfoxide as a substrate solvent, catalyze the preparation of a sitagliptin intermediate with high optical purity, and the specific enzyme activity reaches 139.3 U / g in a reaction system with a final concentration of 50% DMSO, greatly improves the catalytic efficiency, and the product has high stereoselectivity (the e.e. value of the product reaches 99%), and has a wide industrial application prospect.

The invention belongs to the technical field of bioengineering, and particularly relates to a transaminase mutant and application thereof.The transaminase mutant SEQ ID NO: 37 prepared through the method has higher enzyme activity compared with an existing transaminase mutant, sitagliptin can be prepared with sitagliptin precursor ketone as a substrate, the use cost of enzyme is directly reduced, the reaction time is directly shortened, and the yield of sitagliptin is increased. And the production efficiency is improved.

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an endocrine drug-derived anti-cancer composition as well as a preparation method and application thereof. The composition comprises a composite solid dispersion composed of an endocrine disease treatment drug metformin, pioglitazone or sitagliptin, a hydrophilic carrier material and a pretreated functional ion exchange resin. The preparation method mainly comprises the following steps: carrying out alkaline swelling and surface modification pretreatment on ion exchange resin, forming a uniform compound from the medicine, the carrier and the resin through a melting-adsorption-curing process, and carrying out nanocrystallization treatment and structure stabilization drying to obtain the nano composite powder. The composition can be used for preparing an oral solid preparation for inhibiting breast cancer, prostatic cancer, endometrial cancer or colorectal cancer, and has the potential advantage of improving drug dissolution and release behaviors by utilizing a composite structure; the preparation method can effectively guarantee the structural integrity and the performance consistency of the preparation, and the operation controllability is high.

The present invention relates to a pharmaceutical composition for treatment of Parkinson's disease, containing sitagliptin as an active ingredient. It has been identified that, among patients with Parkinson's disease with comorbid diabetes, a sitagliptin-administered group exhibited less dopaminergic neuron loss at the time of diagnosis in comparison to a non-administered group, and in comparison even to a group without diabetes, the loss of dopaminergic neurons was milder. It has been also identified that oral administration of the sitagliptin in an animal model of Parkinson's disease improves intestinal inflammation and microbial groups, alleviates deposition of α-synuclein in the intestine, and alleviates deposition of α-synuclein in brain tissue, and thus the sitagliptin is provided as a novel treatment for Parkinson's disease on the basis of the gut-brain axis.

The present invention relates to a tablet formulation comprising a core tablet having metformin and at least one matrix agent and a coating solution having sitagliptin surrounding the core tablet and a film coating wherein the coating solution further comprises at least one antioxidant and at least one coating agent. Further, the present invention provides a method for the preparation of said composition.

The invention provides application of sitagliptin and related compounds thereof to preparation of a medicament for resisting microbial infection. The inventor of the invention finds that sitagliptin has a remarkable inhibition effect on microbial infection, especially infection caused by staphylococcus aureus, MRSA, enterococcus faecalis, MRSE and escherichia coli. Under the same dosage, the antibacterial effect of sitagliptin on staphylococcus aureus and MRSA exceeds that of a positive control drug linezolid. The biofilm inhibition effect of sitagliptin on MRSA is higher than that of linezolid under the same dosage. In addition, the sitagliptin sodium also has the effects of resisting staphylococcus aureus and MRSA (Methicillin Resistant Staphylococcus Aureus). Oral administration of the sitagliptin sodium can significantly reduce the level of MRSA in the heart, liver, spleen, lung, kidney and abdominal cavity of MRSA systemically infected mice. In addition, administration of sitagliptin at wounds promotes healing of MRSA infectious wounds. And a new thought is provided for the preparation of antibacterial drugs.

The application belongs to the technical field of preparation of pharmaceutical intermediates, and particularly relates to a one-pot method for preparing a sitagliptin intermediate. The one-pot method for preparing the sitagliptin intermediate comprises the following steps: at room temperature, 2,4,5-trifluorophenylacetic acid is dissolved in an organic solvent A, the temperature is lowered to 0-5 DEG C, thionyl chloride is added dropwise, after the dropwise addition is completed, the temperature is raised to 25-30 DEG C, and reaction is carried out for 2 hours; thin layer chromatography analysis is used for monitoring; vacuum concentration is carried out; an intermediate oil is obtained; solvent B is added; ketene is charged; the temperature is lowered to -78 DEG C to room temperature; reaction is carried out for 3 hours; thin layer chromatography is used for monitoring; after the reaction is completed, the temperature is raised to room temperature; stirring is continuously carried out for 12 hours; water is added; the liquid is left to stand and is separated into layers; the organic phase is collected; extraction is carried out; rotary evaporation is carried out; and the sitagliptin intermediate II is obtained. The preparation method of the sitagliptin intermediate provided by the application has the advantages that raw materials are low in price and easy to obtain, reaction conditions are mild, industrial production can be easily realized, the prepared intermediate is high in purity and high in yield.

A mutant transaminase and its use in the preparation of a sitagliptin intermediate are provided. The mutant is obtained by substituting tyrosine at position 74 with proline, glutamic acid at position 228 with aspartic acid, leucine at position 254 with alanine, and methionine at position 290 with threonine in the amino acid sequence shown in SEQ ID NO: 2. The sitagliptin intermediate or sitagliptin ester is prepared using wet thallus or a pure enzyme obtained by fermentation and culture of genetically modified bacteria containing a gene encoding the mutant transaminase as a biocatalyst, and using a ketone precursor of the sitagliptin intermediate or a prochiral carbonyl compound as a substrate. The overall yield is approximately 82%, and the ee value of the product can reach up to 99%.

The present invention discloses an improved method for preparing sitagliptin by transaminase catalysis, which is characterized in that: 1) feeding and reacting, using a low-concentration cosolvent-water buffer medium system for the transaminase-catalyzed reaction, and directly putting the crushed sitagliptin precursor ketone into the reaction system without dissolving it with a solvent; 2) reaction process control, using a pH automatic control liquid adding machine to automatically regulate the pH during the enzyme reaction process; 3) reaction treatment, after the reaction ends, the enzyme reaction solution is acidified and then the product is separated by a nano-ceramic membrane, the membrane filtrate is alkalized to precipitate the product, and then the product sitagliptin is prepared by recrystallization. The present invention greatly reduces the solvent consumption, effectively improves the preparation efficiency of sitagliptin, is easy to operate in industrial production, and reduces the production cost.

The present application relates to two kinds of sitagliptin pharmaceutical cocrystals and preparation methods and applications thereof. The sitagliptin pharmaceutical cocrystal 1 (sitagliptin-CaCl2 cocrystal) is combined according to a molar ratio of 2:1, and has a molecular formula of C 32 H 30 CaCl2F 12 N 10 O2; the sitagliptin pharmaceutical cocrystal 2 (sitagliptin-ZnBr2 cocrystal) is combined according to a molar ratio of 1:1, and has a molecular formula of C 16 H 15 ZnBr2F6N5O. The two kinds of sitagliptin pharmaceutical cocrystals prepared by the present application are characterized by X-ray powder diffraction (PXRD), single crystal X-ray powder diffraction (SCXRD), differential scanning calorimetry (DSC), and thermogravimetric analyzer (TGA). Compared with the prior art, the sitagliptin pharmaceutical cocrystals prepared by the present application have one or more improved properties compared with the prior art, and have important value for the optimization and development of the drug in the future.