43 results about "Sitagliptin" patented technology

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.

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 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 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 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 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 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 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.

The invention discloses a preparation method of sitagliptin base, and relates to the technical field of compound preparation, and the preparation method comprises the following steps: S1, adding 75 parts of water and 16 parts of hydrochloric acid into a three-neck bottle, and cooling to 0 DEG C; s2, the pH is adjusted to 7.5, 42.5 parts of a triethanolamine solution, 0.2 part of pyridoxal phosphate and 57 parts of DMSO are added, and the temperature is controlled to be lower than 10 DEG C; s3, adjusting the pH value to 8.5, adding 40 parts of liquid transaminase, and slowly heating to 40-45 DEG C; s4, when the temperature rises to 45 DEG C, 20 parts of diketone is dropwise added, the temperature is controlled to be 45 DEG C, the pH is adjusted to 8.5, and heat preservation is conducted for 24 h; s5, performing suction filtration and extraction, cooling and crystallizing through methyl tert-butyl ether to obtain a white solid, and drying to obtain a finished product sitagliptin base; preparation equipment adopted in the preparation method comprises a closed cylinder, a liquid separation mechanism, an organic phase receiving box, a water phase receiving box and the like, closed control in the liquid separation extraction process is achieved, recycling of the extraction agent is achieved, and the volatilization and dissipation amount of the extraction agent in the preparation process is effectively reduced.

The present invention provides a pharmaceutical product containing sitagliptin or a salt thereof, wherein the generation of nitroso compounds derived from sitagliptin or a salt thereof is reduced. [Solution] A pharmaceutical according to one aspect of the present invention is a pharmaceutical containing sitagliptin or a salt thereof. This pharmaceutical has a water content of 2.8% by weight or less as measured by the Karl Fischer method, and a content of nitroso compounds derived from sitagliptin or a salt thereof of 1.0 ppm or less.

The invention discloses a preparation method of sitagliptin, and belongs to the technical field of medicine synthesis. The method takes decarboxylation condensation and asymmetric reduction as core reaction steps, and comprises the following steps: firstly, decarboxylation condensation is performed on a cyano compound I and a compound II in an organic solvent A under the action of metal salt and alkali to generate an enamine intermediate III; the intermediate III is subjected to asymmetric reduction in an organic solvent B through a reducing agent, a reaction accelerant and a chiral catalyst, and sitagliptin is obtained. By optimizing raw material selection, a catalytic system and process conditions, the method remarkably shortens the synthesis route, simplifies the operation process, effectively avoids potential safety hazards and environmental protection problems of a traditional process, and reduces the production cost. After the process is optimized, the raw material utilization rate is increased, the catalyst cost is reduced, the single-batch production cost is remarkably reduced, the product yield reaches 88% or above, the purity exceeds 99.5%, and the optical purity gt is obtained; therefore, the requirements of industrial production on high efficiency, economical efficiency and green sustainability are completely met.

The invention provides a sitagliptin and metformin fixed-dose composition and a preparation method thereof, and relates to the technical field of medicines, and the sitagliptin and metformin fixed-dose composition comprises the following components in percentage by weight: 1-10% of sitagliptin, 1-10% of metformin and the balance of water. 50%-85% of metformin hydrochloride; 2%-10% of an adhesive and polymer; 0.5%-3% of a lubricant; 10%-40% of a filling agent; and 5%-20% of a stabilizer. The fixed-dose composition of sitagliptin and metformin and the preparation method of the fixed-dose composition are high in bioavailability, low in hygroscopicity, good in stability and easy for industrial production.

Disclosed are compositions, including pharmaceutical compositions, wherein the compositions comprise sitagliptin or a pharmaceutically acceptable salt and / or hydrate thereof in combination with an antioxidant.

Provided is an omega-transaminase mutant acquired by a single-point mutation or multi-point mutation at positions 275, 115, and 97 of the amino acid sequence set forth in SEQ ID NO. 2. The transaminase mutant is derived from Aspergillus lentulus. It catalyzes bioreactions with a ketone precursor of a sitagliptin intermediate as the substrate, isopropylamine as the amino donor, pyridoxal phosphate as the coenzyme, and a protonic polar solvent as the cosolvent, thus separating and purifying sitagliptin or the sitagliptin intermediate with high optical purity.

The present invention relates to a composition, a combination, and a combination therapy for treating type 2 diabetes mellitus. The composition, combination, and combination therapy effectively reduce blood glucose level by administering 10 mg or 25 mg of empagliflozin to a patient with type 2 diabetes mellitus whose blood glucose level is not adequately controlled by a combination therapy of metformin and sitagliptin, and maintains the controlled blood glucose level for a long period of time with symptoms mostly confirmed to be moderate or lower, and most of the adverse drug reactions are known adverse reactions that have been previously reported in previous clinical trials of clinical trial drugs, and therefore, a new three-drug composition, a combination, and a combination therapy with ensured safety may be provided.

Provided is use of immobilized transaminase in preparation of sitagliptin and / or (R)-3-amino-1-morpholine-4-(2,4,5-trifluorophenyl)-1-butanone. The immobilized transaminase comprises resin and a transaminase mutant, the amino acid sequence of the transaminase mutant is as shown in SEQ ID NO: 3 or SEQ ID NO: 7. Also provided is an immobilized transaminase, a transaminase mutant, a preparation method therefor and use thereof. The enzyme activity of the transaminase mutant in the catalysis of a ketoamide substrate is high, and the enzyme activity is still high after the transaminase mutant is prepared into the immobilized transaminase. When the transaminase mutant is used for catalyzing the ketoamide substrate to produce sitagliptin or an intermediate thereof, a screened solvent reaction system is combined, the immobilized transaminase is high in conversion rate and good in stereoselectivity and stability, the repeatability rate is improved, and the operation is simpler, thereby reducing the cost of production, and it is beneficial to industrial production.

The invention relates to the field of diabetic wound treatment, and particularly discloses a medicine for treating diabetic wound healing and a preparation method thereof.The medicine comprises active ingredients and a pharmaceutically acceptable carrier, the active ingredients are composed of epigallocatechin gallate, recombinant human epidermal growth factors and sitagliptin, and the carrier is composed of chitosan, chitosan and chitosan. The mass ratio of the three components is (20-50): (1-5): (5-15); according to the invention, through innovative compatibility of the active components epigallocatechin gallate (EGCG), recombinant human epidermal growth factor (rhEGF) and sitagliptin, the three components generate a synergistic interaction effect exceeding simple addition; eGCG strongly clears active oxygen and inhibits formation of advanced glycosylation end products, sitagliptin regulates immune response and improves local microenvironment, and clears obstacles for efficient playing of cell proliferation and migration promoting functions of rhEGF, so that drugs can synchronously intervene from three dimensions of oxidation resistance, inflammation resistance and growth promotion.

The invention relates to the technical field of drug analysis and detection, and particularly discloses a method for detecting related substances in trelagliptin succinate. According to the method, high performance liquid chromatography is adopted for detection, and chromatographic conditions are as follows: a chromatographic column is Kromsil 100-5-C18, 250 mm * 4.6 mm, 5 [mu] m; the detection wavelength is 214-234 nm, a mobile phase A is a monopotassium phosphate solution with the pH value of 3.0-5.0, a mobile phase B is acetonitrile, and gradient elution is carried out. The trelagliptin succinate can be effectively separated from various impurities (the impurity Q, the impurity E and the impurity F), the condition of the impurities in the trelagliptin succinate can be accurately detected, a reliable guarantee is provided for improving and better controlling the quality of a trelagliptin succinate product, and the method has very important significance for improving medication safety.

The invention belongs to the technical field of medicinal chemistry, and relates to a sitagliptin derivative, a preparation method thereof and application of the sitagliptin derivative in blood glucose reduction. The chemical structural formula of the sitagliptin derivative is shown in the specification, in the formula, R is propionyl, valeryl, hexanoyl, heptanoyl, capryloyl, isobutyryl, 3, 3-dimethyl butyryl or isovaleryl; the hypoglycemic activity of the Sd-05 prepared from hexanoyl chloride is obviously superior to that of sitagliptin, the acute safety is high, the Sd-05 can obviously improve the glucose tolerance of normal mice under the low-dosage condition, and the Sd-05 is obviously superior to that of existing sitagliptin in the aspects of improving glucose metabolism disorder and maintaining blood glucose stability.