23 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.

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 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.

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 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.

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 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.

A nanosystem and methods of treating, including prophylactically, coronavirus infections, such as those caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), by administering such nanosystem to a patient is presented. The nanosystem may be comprised of a single or a combination of therapeutic agents, optionally encapsulated in a nanoparticle having a targeting moiety directed to the particular coronavirus. For CoV-2 infections, at least one therapeutic agent, such as the dual DPP4 / ACE2 inhibitor sitagliptin, may optionally be encapsulated within a nanoparticle having a fatty acid such as linoleic acid, as the targeting moiety. Administration can occur intranasally prior to infection for prophylactic treatment or post-infection for treatment of the viral infection.

The invention relates to the field of chemical synthesis of medicines, and discloses a synthesis method of sitagliptin, which comprises the following steps: carrying out asymmetric hydroamination reaction on (E)-4-(2, 4, 5-trifluorophenyl)-butyl-2-ethyl olefine acid and an ammonia source at room temperature in the presence of a copper (I) catalyst, a chiral ligand, a hydrogen source, a strong base and a solvent to obtain a chiral hydroamination intermediate; carrying out hydrolysis reaction on ethyl ester in the chiral hydroamination intermediate to obtain a hydrolysis intermediate; the hydrolysis intermediate and 3-(trifluoromethyl)-5, 6, 7, 8-tetrahydro-[1, 2, 4] triazolo [4, 3-a] pyrazine are subjected to an amidation reaction in the presence of a condensation reagent, and an amidation intermediate is obtained; and carrying out debenzylation reaction on the amidation intermediate under the action of a catalyst and hydrogen to obtain sitagliptin. By introducing a brand-new catalytic system, the total yield is increased, and the enantioselectivity is remarkably improved.

The invention relates to the technical field of pharmacy, in particular to a synthesis method of sitagliptin related impurities, which comprises the following steps: step one, taking 4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro-[1, 2, 4] triazolo [4, 3-a] pyrazine-7-(8H)-yl]-1-(2, 4, 5-trifluorophenyl)-2-butanone as a raw material, taking (S)-phenylethylamine as a raw material, and performing ammonification reaction to obtain the sitagliptin related impurities. Synthesizing a compound III; 2, synthesizing a compound IV by taking the compound III as a raw material through a carbon-carbon double bond reduction reaction; and 3, synthesizing a compound I, namely the sitagliptin related impurity, by taking the compound IV as a raw material through deamination protection reaction. The invention provides a brand-new directional synthesis method, the target chiral impurity is directly obtained, complex post-treatment such as chiral resolution and preparative chromatography purification is not needed, and a large number of impurity reference substances can be rapidly, simply, conveniently and efficiently obtained.

The invention discloses application of sitagliptin in preparation of a medicine for treating benign prostatic hyperplasia, and relates to the technical field of biological medicine. The invention discloses application of sitagliptin in preparation of a medicine for treating benign prostatic hyperplasia. The invention focuses on BPH, such as a core pathological target LAMA5 of collagen sedimentary BPH, screens an intervention drug with drug properties, and finds that the inhibition effect of a dipeptidyl peptidase 4 (DPP4) inhibitor sitagliptin on LAMA5 expression, collagen deposition and cell migration in a cell experiment is obviously superior to that of candidate drugs such as SB-525334 and olantinib. More importantly, sitagliptin is widely applied to treatment of type 2 diabetes in clinic as a classic hypoglycemic drug, is clear in safety and tolerance, is highly matched with clinical characteristics of high incidence of diabetes of patients with BPH, such as collagen sedimentary BPH, and has the unique advantage of taking both hypoglycemic and BPH treatment into consideration. And an ideal drug candidate is provided for solving the treatment dilemma of the subtype.

The present application relates to a kind of siglitin metformin sustained-release tablets combined drug effect detection method in the field of pharmaceutical testing, in the application, by introducing intelligent terminal and monitoring terminal, real-time observation is realized using mechanical vision technology in the experiment process, the observation pressure of experimental personnel is reduced, the labor cost of experimental detection is greatly reduced, the detection efficiency is improved, at the same time, the identity of experimental personnel is identified using intelligent terminal, all experimental operations are bound with its experimental personnel, it is convenient to subsequent summary when experiment is summarized, the traceability work is carried out, the standardization of experimental detection is improved, at the same time, protection unit is set for monitoring terminal, when experimental organism touches trigger lever, a part of stored stimulating smell in slow-release unit is released, the expelling effect is strengthened, and experimental organism is formed to expel domestication, so that experimental organism forms the habit of keeping away from monitoring terminal.

The application discloses a dual-unit fluorescent sensor array for detecting oral anti-diabetic drugs and application thereof, and relates to a supramolecular fluorescent sensor array which comprises a PAL@Q[8] sensing unit and a bpep-Am@Q[8] sensing unit, wherein the PAL@Q[8] sensing unit is composed of palmatine and Q[8], and the bpep-Am@Q[8] sensing unit is composed of a derivative of 1,4-bis[2-(4-pyridyl)vinyl]benzene and Q[8]. The dual-unit fluorescent sensor array can be used for qualitative detection and quantitative detection of metformin, phenformin, buformin hydrochloride, rosiglitazone and sitagliptin in serum or urine, and the method provides a simple and reliable analysis tool for rapid screening of oral hypoglycemic drugs, clinical blood drug concentration monitoring and identification of hypoglycemia causes, so as to realize on-site rapid visual analysis of oral hypoglycemic drugs.

The invention relates to an improved method for detecting sitagliptin related substances in sitagliptin and metformin sustained-release tablets, which is characterized in that the auto-polymerization rate of a mobile phase B is delayed by increasing the proportion of a phosphate buffer solution in the mobile phase B, and after the improved method is continuously operated for 168 hours, no system pressure abnormity shown in Figure 1 occurs. Besides, by selecting a proper mobile phase, controlling the concentration and the flow velocity of the mobile phase, the column temperature of a chromatographic column and other conditions and adjusting a gradient elution procedure, the sitagliptin related substances in the sitagliptin metformin sustained release tablet are quantitatively analyzed, and the method can effectively reduce the probability of abnormal pressure of a high performance liquid chromatography system and improve the detection accuracy of the sitagliptin related substances in the sitagliptin metformin sustained release tablet. According to the method, the sitagliptin related substances in the sitagliptin metformin sustained-release tablets can be continuously detected for a long time, meanwhile, the sitagliptin and other impurities can be effectively separated, and the method is high in separation degree, good in accuracy and good in durability.