66 results about "Duloxetine Hydrochloride" patented technology

Processes for preparing DNT-base, duloxetine alkyl carbamate, duloxetine-base and duloxetine hydrochloride, are provided. Also provided, are processes for converting DNT-base, duloxetine alkyl carbamate and duloxetine-base into pharmaceutically acceptable salts of duloxetine.

Delayed release formulations of duloxetine hydrochloride and methods for its manufacture are described. A preferred formulation includes an inert core, a drug layer comprising duloxetine hydrochloride, a separating layer and an enteric layer comprising at least one of methacrylic acid copolymer and hydroxypropyl methyl cellulose phthalate.

The present invention relates to a duloxetine hydrochloride slow-released medicine. Said slow-released medicine is formed from duloxetine hydrochloride and acceptable auxiliary components in oral medicine, in which the duloxetine hydrochloride content is 15-65% of total weight of said medicine. The described auxiliary components at least include (by wt%) 1%-80% of high-molecular skeleton slow-release material, 0.1%-50% of releasing speed regulation component and 1.5%-10% of enteric solubility external coating material.

The invention belongs to the field of medicine synthesis, relates to a process for synthesizing duloxetine hydrochloride, and solves the technical problem to provide a new process for synthesizing the duloxetine hydrochloride, which makes raw materials dissolved completely and reduced thoroughly. The synthetic process comprises the following steps of: 1, preparing 2-thienyl-2-dimethylaminomethyl butanone hydrochloride; 2, preparing N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine; 3, preparing (S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine; 4, preparing (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine; 5, preparing (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine; and 6, preparing (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride. By the six steps of the process, the total synthetic yield is 24.1 percent.

The invention relates to the technical field of medicinal preparations, in particular to duloxetine hydrochloride-containing enteric capsules and a preparation method thereof. The enteric capsules consist of capsule shells and coated pellets, wherein the coated pellets also comprise duloxetine hydrochloride-containing medicine carrying pellet cores and coating layers; and the medicine carrying pellet cores contain a disintegrating agent. In preparation of the medicine carrying pellet cores, the duloxetine hydrochloride raw material is subjected to super micronization, so that the particle size distribution that the diameter of 99 percent is not greater than 50 mum, the diameter of 90 percent is not greater than 35 mum, the diameter of 50 percent is not greater than 20 mum and the diameter of 5 percent is not greater than 10 mum is achieved; and after the disintegrating agent is added into the medicine carrying pellet cores, the release speed of the medicine in intestines is increased. According to the duloxetine hydrochloride-containing enteric capsules and the preparation method thereof, a method of directly preparing the medicine carrying pellet cores is adopted, so that the complexity for loading a medicine on blank pellets of the existing domestic and foreign similar products is reduced, the technological process is simplified, and the duloxetine hydrochloride raw material is firstly crushed to a certain particle size range and then prepared into the medicine carrying pellet cores; and the prepared capsules have uniform medicine content and high reproducibility and are suitable for industrial production.

A crystalline form of duloxetine hydrochloride, pharmaceutical compositions of the crystalline form of duloxetine hydrochloride, and methods of preparing the crystalline form of duloxetine hydrochloride are provided.

The invention relates to a duloxetine hydrochloride enteric pellet and a preparation method thereof. The pellet comprises a blank cane sugar pellet core, a protection layer, a drug layer, an isolating layer, an enteric layer and an optional modification layer. The method comprises the following steps: coating the blank pellet core with the protection layer; and then carrying out coating by successively using the drug layer, the isolating layer, the enteric layer and the optional modification layer so as to prepare the duloxetine hydrochloride enteric pellet. According to the invention, the blank cane sugar pellet core with a small particle size is employed, coating with the protection layer is carried out at first, so the problems of fragmentation and powder falling of the pellet core in the process of coating are effectively overcome; the prepared enteric pellet has a small particle size, a capsule filled with the enteric pellet has good content uniformity, and industrial mass production of the enteric pellet is facilitated.

The invention relates to a duloxetine hydrochloride enteric micropill preparation which is composed of a drug-carrying pill core, an isolating coating layer and an enteric coating layer. When the enteric materials in the prescription adopt common methacrylic acid copolymers, sugar alcohol can be added into the isolating layer to achieve the goal that the active component in-vitro dissolution curve is consistent with a positive control drug (Cymbalta of Eli Lilly and Company). The product has the advantages of high acid resistance, high dissolution speed, high rate and the like; the methacrylic acid copolymers used as the enteric material are easy to purchase and low in cost; and the adopted conventional preparation method is simple in technique and suitable for industrial production, thereby providing a drug with reasonable price and reliable curative effect for patients with melancholia.

The present invention relates to a pharmaceutical composition comprising an active core comprising duloxetine or its pharmaceutically acceptable derivatives, a separating layer comprising a pH modifier and a gastro-resistant coating comprising a gastro-resistant polymer selected from methacrylic acid copolymers and optionally an over-coating layer. The present invention also relates to a process for the preparation of duloxetine hydrochloride. It also relates to a packaged medicament.

The invention belongs to the technical field of medicines, and in particular relates to a preparation method of duloxetine hydrochloride enteric coated drugs. The duloxetine hydrochloride is prepared by wrapping four layers of coating on a blank mini-pill, wherein the four layers of coatings are respectively a drug carrier layer, an isolation layer, a enteric coating layer and a film coating layer.

The invention relates to a new preparation process of the medicinal raw material duloxetine hydrochloride of an antidepressant drug and belongs to the technical field of drug synthesis. The new preparation process is characterized in that N-methyl benzylamine hydrochloride but not dimethylamine hydrochloride is used in Mannich reaction; because benzyl is easier to remove as compared with methyl, dealkylation in a subsequent step has better effect and higher yield; an expensive chiral catalyst or a phase-transfer catalyst is not used; a better solvent crystallizing and removing method is adopted, so that the harm of a residual crystallizing solvent to a human body is prevented; the splitting of a chiral compound is carried out after dealkylation, and a mixture obtained after splitting is separated by adopting a unique recrystallization technology to prepare (S)-N-methyl-3-(1-naphthoxy)-3-(2-thienyl) propylamine/tartrate with high purity and high optical activity, so that a finally obtained duloxetine hydrochloride product can achieve better treatment effect. The new preparation process disclosed by the invention has the advantages of mildness in reaction condition, clear process, good easiness and convenience in operation and low production cost and is extremely favorable for industrial production.

The invention relates to a method for preparing an intermediate of duloxetine hydrochloride. The method comprises the following steps: adding 2-acetylthiophene into concentrated hydrochloric acid for reacting, preparing a compound of a formula II, adding NaBH4 for reacting, and refining to prepare a compound of a formula III; taking the compound of the formula III and methyl tertiary butyl ether, adding S-mandelic acid for reacting, filtering, spraying, drying to obtain a white granular solid, dissolving the white granular solid in water, regulating a pH value, extracting by using dichloromethane, drying, and preparing S-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl) propylamine (a compound of a formula I) after drying. The invention provides a simple method, so that the raw materials are completely dissolved, namely the consumption of NaBH4 is reduced, a reduction reaction can be completely carried out, and the maximum reaction rate can be 95.6 percent. Meanwhile, the invention provides a method for improving resolution yield and purity, and the maximum yield can be 47.6 percent. According to the improved process, the reaction time is greatly reduced, the operation is simplified, and the total yield of the compound of the formula I which is synthesized in three steps is more than 36 percent.

The invention belongs to the fields of organic chemistry and pharmaceutical chemistry, and particularly relates to a synthesis technique of duloxetine hydrochloride. By converting the R configuration compound into S configuration, compared with the duloxetine hydrochloride prepared from the single S-configuration compound, the total yield is enhanced by nearly 47%, and the production cost is lowered. 1-chloroethylchloroformate is used instead of phenyl chloro-formate to directly generate the duloxetine hydrochloride during demethylation, thereby reducing the salification step, shortening the production cycle and saving the cost.

The invention provides a preparation method of a duloxetine hydrochloride enteric micro-pellet capsule. The preparation method comprises following steps: (1) performing air jet pulverization to duloxetine hydrochloride to obtain duloxetine hydrochloride micro-particles; (2) mixing the duloxetine hydrochloride micro-particles with a medicinal excipient and preparing duloxetine hydrochloride micro-pellets through an extrusive granulation technology; (3) wrapping the duloxetine hydrochloride micro-pellets with an isolating layer for reducing mutual influence between main drugs and an enteric coating material; and (4) wrapping the isolating layer on the duloxetine hydrochloride micro-pellets by an enteric coating layer for achieving the enteric effect.

The invention discloses enteric sustained release granules containing duloxetine hydrochloride and a preparation method of the enteric sustained release granules. According to the preparation disclosed by the invention, duloxetine hydrochloride is prepared into a clathrate compound, and then the clathrate compound is prepared into enteric granules. The enteric sustained release granules comprise the duloxetine hydrochloride clathrate compound and acceptable auxiliary materials, wherein the auxiliary materials at least comprise a macromolecular sustained-release material, a release speed regulating ingredient and an enteric outer-layer coating material, the medicine has erosion and release in the intestinal tract, the action time is lasting, the side reaction occurrence rate caused by rapid release of the medicines after medicine taking is remarkably reduced, so that the blood drug concentration and the drug effect are stable and durable, and the medication compliance and clinical treatment effect of patients are enhanced.

The invention provides a synthesis method of a key intermediate for preparing duloxetine hydrochloride from 2-acetylthiophene and belongs to the technical field of chemical synthesis. The synthesis method comprises the following steps: reacting cyanuric chloride and N,N-dimethylformamide with 2-acetylthiophene to obtain 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one; reducing 3-(dimethylamino)-1-(2-thienyl)-2-propenyl-1-one through lithium aluminum hydride to obtain a duloxetine hydrochloride intermediate which is (R,S)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. The synthesis method iscapable of synthesizing a target product which is a key intermediate of duloxetine hydrochloride through two-step reaction, is cheap in raw materials, simple in process, simple and convenient to operate, mild in reaction condition, short in reaction period and free of expensive catalysts, is environmentally friendly, and is suitable for industrial production; the prepared products are high in yield and purity.

The invention relates to a purification method for preparing high-purity duloxetine hydrochloride intermediate (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine; (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine is subjected to program-controlled recrystallization in a solvent to obtain a purified product, wherein the solvent is a mixed solvent of methanol and water, and program-controlled recrystallization includes the specific steps of heating and refluxing at 72-74 DEG C for 5-60 min, stirring at a speed of 0.5-15 r/min, cooling for crystallization at a temperature range of 72-80 DEG C for 120-150 min, and stirring at a speed of 6-15 r/min. The purification method is simple to perform, purity of isomer impurity is less than 0.03%, and the purification method is suitable for industrial production.

The invention provides duloxetine hydrochloride enteric-coated tablets. The tablets are prepared from components in parts by weight shown in the specification. The duloxetine hydrochloride enteric-coated tablets are seldom affected by food delivery rhythm of digestive tracts, the distribution area on intestinal tract surfaces is increased, so the drugs are completely absorbed, the bioavailability of the drugs is increased, and the plasma concentration fluctuation is reduced. The method is suitable for industrial production and has higher application value.

The invention encompasses 2-N-methyl-propanamine)-3-(2-naphthol) thiophene, a duloxetine hydrochloride impurity, as well as its use as a reference marker and reference standard.

The invention discloses a method for preparing a noradrenaline reuptake dual inhibitor. On one hand, the invention provides a method for preparing a compound, (+)-(S)-N-methyl-gamma-(1-naphthoxy)-2-thiophene propylamine, as shown in a formula (I) in the specification. The method comprises the step as follows: the compound as shown in a formula (II) in the specification, and (S)-(-)-N-methyl-3-hydroxy-3-(2-thienyl) propylamine and a compound 1-fluoronaphthalene as shown in a formula (III) in the specification are subjected to etherification reaction in a mixed solvent of xylene and dimethyl sulfoxide under presence of potassium hydroxide. On the other hand, the invention provides a high-yield method for obtaining high-purity duloxetine hydrochloride. The method specifically comprises the following steps: (1) dissolving a duloxetine hydrochloride crude product into a mixed solvent of acetone and water, so as to form a solution; and (2) adding acetone and crystallizing.