136 results about "Duloxetine" patented technology

Novel enteric compositions suitable for oral administration comprising Duloxetine or its pharmaceutical derivatives thereof and methods for preparing such compositions are disclosed. Such compositions contain a core consisting of a Duloxetine or its pharmaceutical derivatives thereof, the said core comprised of a pharmaceutically inert nuclei and the Duloxetine or its pharmaceutical derivatives thereof compressed together, an intermediate and an enteric layer. Duloxetine or its pharmaceutical derivatives thereof may be any pharmaceutically acceptable prodrug, salt, solvate or derivative of Duloxetine. The novel compositions prepared according to the present invention have enhanced stability and bioavailability.

The invention provides a pharmaceutical composition of duloxetine or its pharmaceutically equivalent derivatives like salts, isomers, complexes, polymorphs, hydrates or esters thereof and at least one buffering agent. The duloxetine or its pharmaceutically equivalent derivative is present from about 2 mg to approximately 200 mg; and the buffering agent is present in an amount of approximately 0.1 mEq to approximately 2.5 mEq per mg of duloxetine. Also provided is a method for treating of major depressive disorder and or diabetic peripheral neuropathic pain comprising administering to a mammal in need of such treatment a therapeutically effective amount of a composition.

This invention provides an improved asymmetric process for the synthesis of duloxetine involving arylation of Compounds of Formula I.

The present invention relates to solid oral pharmaceutical compositions of duloxetine, process for preparing such compositions and method of using such compositions. Preferably, the invention relates to a delayed release composition of duloxetine comprising a core comprising duloxetine, optional separating coat and an enteric coat, wherein the enteric coat comprises methacrylic acid copolymer.

The invention relates to a preparation method of duloxetine, which takes 2-acetyl phenol, paraformaldehyde and dimethylamine hydrochloride as raw materials to obtain the target product by five steps of Mannich reaction, reduction, resolution, etherification and demethylation, and optimizes the reaction conditions of resolution and etherification, wherein, the resolution reaction comprises the steps of one-time resolution, racemization-resolution and secondary racemization-resolution. The invention can improve the yield of the duloxetine and reduce the production cost, and is easy for industrial production.

The present invention relates to solid oral pharmaceutical compositions of duloxetine, process for preparing such compositions and method of using such compositions. Preferably, the invention relates to a delayed release composition of duloxetine comprising a core comprising duloxetine, optional separating coat and an enteric coat.

The invention provides a kit for detecting anti-depressant drugs in serum and plasma by liquid chromatography tandem mass spectrometry. The kit comprises drug standard substances, drug internal standardization compounds, drug extraction compositions, negative plasma and a diluent. The drug standard substances comprise amfebutamone, oxybupropion, citalopram, Escitalopram, venlafaxine, O-desmethylvenlafaxine, duloxetine, fluoxetine, norfloxetine, fluvoxamine, mirtazapine, paroxetine, sertraline and trazodone. The drug internal standardization compounds comprise amfebutamone-d9, oxybupropion-d6,citalopram-d6, venlafaxine-d6, O-desmethylvenlafaxine-d6, duloxetine-d3, fluoxetine-d6, norfloxetine-d6, fluvoxamine-d4, mirtazapine-d3, paroxetine-d6, sertraline-d3 and trazodone-d6. The drug extraction compositions comprise, by volume, 60% of methanol solution, 20% of acetonitrile solution, 10% of isopropyl alcohol solution and 10% of purified water. The diluent comprises 50 % of methanol waterfluid. The kit can be used for simultaneous detection of the anti-depressant drugs and active metabolites, the detection time is short, and flux is high.

Disclosed is a process for commercial preparation of 3-(methylamino)-1-(2-thienyl)propan-1-ol (hereinafter abbreviated as “MMAA”) of the formula below:

The process is carried out by the diastereomeric salt formation method using optically active mandelic acid or its derivatives, or an optically active tartaric acid derivative as the resolving agent. The product compound, diastereomeric satls, is useful as the intermediate for producing pharmaceuticals, such as duloxetine.

The invention discloses a carbonyl reductase (i)Ch (/i) KRED15 derived from Chryseobacterium ((i) Chryseobacterium (/i) (i) (/i) sp. CA49), and a coding gene thereof; the invention also discloses application of the carbonyl reductase as a biocatalyst in preparing a Duloxetine chiral intermediate ((i) S (/i))-N-methyl-3-hydroxy-3-(2-thienyl) propanamide. The enantiomer excess of products is greater than 99.9%. 20 g/L of substrate can be catalyzed by Ch(/i) KRED15 crude enzyme (2U/mL), and the conversion rate of over 99% can be obtained in 2 hours; a coenzyme circulation system is simple, and has large industrial application prospect.

The invention provides an alcohol dehydrogenase with high catalytic activity, strong enantiotropic selectivity and good substrate tolerance, and provides an enzymatic synthesis method of employing the alcohol dehydrogenase to catalyze and synthesize (s)-3-substituted amido-1-(thiophenyl-2-yl)-1- propanol and furthermore Duloxetine. The invention also provides a nucleic acid sequence for encoding the alcohol dehydrogenase, a recombinant expression vector including the nucleic acid sequence, and a recombinant expression transformant, and a preparation method of the alcohol dehydrogenase, and uses of the alcohol dehydrogenase in catalyzing asymmetric reduction of carbonyl substrates. The invention has advantages that the product concentration is high, the optical purity of the product is high, the reaction condition is mild and environment-friendly, the operation is convenient and is easy to industrialize, and an extra expensive coenzyme NADP<+>/NAD<+> is not necessary.

The pharmaceutical composition of the present invention comprises (1) a carbostyril derivative and (2) a serotonin reuptake inhibitor in a pharmaceutically acceptable carrier. The carbostyril derivative may be aripiprazole or a metabolite thereof, which is a dopamine-serotonin system stabilizer. The serotonin reuptake inhibitor may be fluoxetine, duloxetine, venlafaxine, milnacipran, citalopram, fluvoxamine, paroxetine, sertraline or escitalopram. The pharmaceutical composition of the present invention is useful for treating patients with mood disorders, particularly depression or major depressive disorder.

A compound of formula 10 is useful in making duloxetine.

The invention provides for the first time an oral liquid composition of duloxetine or its pharmaceutically equivalent derivatives like salts, isomers, complexes, polymorphs, hydrates or esters thereof. The duloxetine or its pharmaceutically equivalent derivative is present from about 2 mg to approximately 200 mg; and a buffering agent was used to stabilize the acid sensitive duloxetine. The composition has duloxetine from about 0.1 meq to about 2.5 mEq per mg of duloxetine. The invention further discloses an oral liquid composition of duloxetine or its pharmaceutically equivalent derivative wherein the degradation product 1-Naphthol is less than 0.01%. Also provided is a method for treating of major depressive disorder and or diabetic peripheral neuropathic pain comprising administering to a mammal in need of such treatment a therapeutically effective amount of a composition.

The invention relates to a duloxetine derivative and a method for preparing the same, which belongs to the chemistry field of medicine with antidepressant activity. The structural formula is as shown in the right formula, wherein R is aryl radical or tertiary butyl. The method for preparing the duloxetine derivative comprises the following steps: step one, dissolving duloxetine in dichloromethane in a reactor, adding an acid-binding agent into the mixture, stirring the mixture at room temperature for 20 minutes, and then dripping chloroacetic chloride into the mixture to react at a temperature of between 0 and 30 DEG C for 1 to 5 hours to generate an amide compound 1; and step two, dissolving the amide compound 1 generated in the step one in acetonitrile in the reactor, adding sodium iodide and triethylamine into the mixture of which the mol ratio of the amide compound 1 to the odium iodide to the triethylamine is 1 to 0.003 to (1.5 to 3), and then adding a piperazine compound into the mixture of which the mol ratio of the amide compound 1 to the piperazine compound is 1 to 1 to react at a temperature of 80 DEG C for 4 to 10 hours so as to obtain the target product. The duloxetine derivative prepared by the method has multiple mechanisms of action simultaneously, and can be used for preparing antidepressant drugs. Besides, the preparation process is simple and easy to operate.

The invention belongs to the technical field of biocatalysis and discloses a method for asymmetric synthesis of duloxetine intermediate by carbonyl reductase.In a pure enzyme catalytic system, by control of reaction pH, reaction temperature and metal ions, biocatalysis performance is improved.N,N-dimethyl-3-keto-3-(2-thienyl)-1-propylamine (DKTP) serves as a reaction substrate, a recombinant strain refers to E.coli BL21/Pet21c-cr2 expressing an aldo-keto reductase gene, a carbonyl reductase gene cr2 is derived from Candida macedoniensis AKU4588 and codes carbonyl reductase CR2, and catalysis of asymmetric reduction of DKTP is realized to obtain (S)-DHTP.By pure enzyme catalytic reaction and optimal control of the reaction pH, the reaction temperature and the metal ions, properties and functions of DKTP catalyzed by CR2 can be known, highly-stereoselective DKTP catalysis is realized, and optically-pure duloxetine key intermediate (S)-DHTP is prepared through asymmetric conversion reaction.

The invention discloses a method for detecting the concentration of antidepressant drugs in serum by an ultra-high performance liquid chromatography-tandem mass spectrometry technology. The antidepressant drugs comprise bupropion, agomelatine, hydroxybupropion, nortriptyline, o-desmethylvenlafaxine, mianserin, mirtazapine, venlafaxine, amitriptyline, doxepin, norfluoxetine hydrochloride, duloxetine, fluoxetine, fluvoxamine, citalopram, paroxetine, trazodone and vortioxetine. After a serum sample is pretreated, a to-be-detected substance is separated from a serum matrix by utilizing ultra-highperformance liquid chromatography, a calibration curve is established by utilizing a mass spectrum isotope internal standard quantitative method and taking a concentration ratio of the standard substance to an internal standard substance as an X axis and a peak area ratio of the standard substance to the internal standard substance as a Y axis, and the content of the drugs in serum is calculated.The method is high in sensitivity, high in specificity, accurate and simple in pretreatment process, separation and detection can be completed within 4.5 min, and the accuracy degree and precision basically meet the requirements.

The invention relates to the technical field of chemical synthesis, particularly to a duloxetine preparation method. The duloxetine preparation method comprises the following steps: choosing thiophene and 2-chloroacetyl chloride as raw materials, sealing and storing at 20-25 DEGC for standby application, putting 2-chloroacetyl chloride into a reaction vessel, heating to 60-65 DEGC, adding thiophene, slightly shaking evenly, continuing to heat, stirring for 10 minutes, obtaining 2-chloracetyl-thiophene through a friedel-crafts reaction, heating the produced 2-chloracetyl-thiophene to 80-100 DEGC, adding sodium cyanide into the reaction vessel, continuing to stir, heating for 10 minutes, conducting a cyano substitution reaction, and obtaining 3-hydroxy-3-(2-thiophene)-propionitrile. The cheap thiophene and 2-chloroacetyl chloride are chosen as the raw materials, the preparation is easy, the cost is low, the preparation is conducted through the conventional reactions, and the method has the advantages of low cost, easy preparation and high reaction speed.