30 results about "TOFACITINIB CITRATE" patented technology

The present invention discloses a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof, which belongs to the technical field of pharmaceutical preparations. The sustained-release tablet comprises a double-layer core and a coating layer; the double-layer core comprises a drug-containing layer and a push layer; wherein the drug-containing layer comprises: tofacitinib citrate, an adhesive, polyethylene oxide, a glidant and a lubricant; the push layer comprises: mannitol, an adhesive, red iron oxide, polyethylene oxide, a glidant and a lubricant; the coating layer comprises: cellulose acetate, a pore-forming agent, a plasticizer, water and acetone. The sustained-release tablet preparation of the present invention solves the technical problems existing in the prior art by adopting a double-layer osmotic pump prescription design, adopting non-hygroscopic materials such as mannitol, adopting a standard round tablet design, preparing a sustained-release coating layer without using methanol, and adopting a coating machine for coating and curing.

The invention relates to the technical field of animal medicines, and particularly discloses a compound soft chewable tablet as well as a preparation method and application thereof. The compound soft chewable tablet comprises the following raw materials in percentage by weight: 0.4% of tofacitinib, 1% of an echinacea extract, 10-20% of pork liver powder, 10-20% of polyethylene glycol, 3-15% of a release agent, 0.3-1% of lauryl sodium sulfate, 1-3% of magnesium stearate, 2-5% of sucrose, 0.05-0.5% of a preservative, 11% of glycerol, 13-15% of soybean oil and the balance of corn starch. The tofacitinib citrate and the echinacea extract are adopted to prepare the soft chewable tablet, the process has no special requirements on equipment, the process is simple and feasible, and industrial production is utilized; by adopting conventional equipment such as a wet granulator, a mixer and a forming machine, the prepared oral product has the characteristics of stability, palatability, safety and effectiveness.

The invention relates to the field of pharmaceutical preparations, in particular to a tofacitinib citrate tablet and a preparation method thereof.The tofacitinib citrate tablet is prepared from, by mass, 22-23 parts of quick-release layer particles, 67-68 parts of slow-release layer particles, 4-6 parts of coating liquid A and 4-6 parts of coating liquid B. According to the tofacitinib citrate tablet and the preparation method thereof, by constructing a composite structure of a quick-release-slow-release synergistic layer and an enteric-colon-targeted coating, the preparation method has the advantages that the preparation process is simple, and the preparation cost is low; compared with the prior art, the preparation method has the advantages that the blood concentration can be stably maintained for 24 hours under the condition of single-day administration, the gastric acid degradation risk and digestive tract stimulation side effects are remarkably reduced, a safe and convenient solution is provided for long-term administration of patients with chronic diseases such as rheumatoid arthritis, and the preparation method has a wide clinical application prospect.

The invention belongs to the technical field of medicine detection, and particularly relates to a GCMS (Gas Chromatography Mass Spectrometry) detection method for ethyl cyanoacetate in tofacitinib citrate. Respectively injecting the blank solution, the reference solution and the test solution into a GCMS (Gas Chromatography Mass Spectrometer), recording a spectrogram, and calculating the content of ethyl cyanoacetate in tofacitinib citrate by adopting an external standard method; wherein the GCMS conditions comprise a chromatographic column, the column temperature of the chromatographic column is kept at 40 DEG C for 1 min, the temperature is increased to 240 DEG C at the heating rate of 15 DEG C / min, and the temperature is kept for 1 min. The method can accurately and quantitatively detect the content of ethyl cyanoacetate in tofacitinib citrate, and is simple to operate, high in precision, good in stability and good in reproducibility.

The invention discloses a tofacitinib citrate sustained-release tablet composition which is prepared from tofacitinib citrate, raloxifene hydrochloride and pharmaceutically acceptable auxiliary materials, and a preparation method comprises the following steps: preparing a tofacitinib citrate sustained-release tablet; tofacitinib citrate, raloxifene hydrochloride and auxiliary materials are taken, the auxiliary materials are hydroxypropyl methyl cellulose, zein, starch and polyvinylpyrrolidone and sieved through a 30-mesh sieve for standby application, tofacitinib citrate, raloxifene hydrochloride, starch and polyvinylpyrrolidone are subjected to wet granulation and size stabilization to obtain medicine particles, the medicine particles are evenly mixed with hydroxypropyl methyl cellulose, zein and magnesium stearate and tableted, and the tablet is prepared. The tofacitinib citrate and the raloxifene hydrochloride have a synergistic effect in the aspect of improving rheumatoid arthritis accompanied by bone mass loss and bone mineral density of postmenopausal women.

The invention discloses a tofacitinib citrate sustained-release tablet preparation and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations, the sustained-release tablet comprises a double-layer tablet core and a coating layer; the double-layer tablet core comprises a medicine-containing layer and a pushing layer; wherein the medicine-containing layer comprises tofacitinib citrate, an adhesive, polyoxyethylene, a flow aid and a lubricant; the pushing layer comprises mannitol, an adhesive, red iron oxide, polyoxyethylene, a flow aid and a lubricant; the coating layer comprises cellulose acetate, a pore-foaming agent, a plasticizer, water and acetone. According to the sustained-release tablet preparation disclosed by the invention, the technical problems in the prior art are solved by adopting a double-layer osmotic pump prescription design, mannitol and other non-hygroscopic materials, a standard round tablet design, no methanol for preparing a sustained-release coating layer, a coating machine for coating, curing and the like.

The application discloses a preparation method of high-purity tofacitinib citrate, which adopts a two-step method to prepare tofacitinib citrate, and is divided into two steps of tofacitinib preparation and final product preparation. In the preparation of tofacitinib, the reaction liquid is first extracted with an acidic aqueous solution, then the pH value is adjusted with an alkali solution, tofacitinib is extracted with dichloromethane, tofacitinib fine products are obtained by crystallization in an alcohol aqueous solution after concentration, and finally tofacitinib citrate is obtained by salification with citric acid. The total yield of the final product prepared by the method can reach 74.4%, the purity of the prepared tofacitinib citrate is as high as 99.81%, and the maximum single impurity can be as low as below 0.03%. Compared with the prior art, the yield of tofacitinib citrate prepared by the preparation method of the application is increased by about 7.1%, and the purity is effectively improved. The preparation method of the application can not only effectively remove impurities, but also make the color meet the pharmaceutical requirements.

The present invention discloses a method for determining the effective content in tofacitinib citrate tablets by nuclear magnetic resonance hydrogen spectrum. Using the chemical shift of tofacitinib δ at 7.13 as the quantitative peak, 3,5-dimethylpyrazole δ at 5.73 as the internal standard peak, deuterated dimethyl sulfoxide as the solvent, under the conditions of pulse sequence zg30, relaxation delay time of 26 s, and number of scans of 16 times at 298 K, the hydrogen spectrum of the mixture is collected to quantitatively determine the active ingredient in tofacitinib citrate tablets. This method has strong specificity and shows a good linear relationship in the range of 0.793-7.925 mg / mL ( r

The invention relates to a tofacitinib citrate composition. The tofacitinib citrate composition is prepared by mixing active ingredients with a thickening agent, an osmotic pressure regulator, an adhesive and a lubricant, and then tabletting and coating. The tofacitinib citrate composition provided by the invention has the advantages of good stability and suitability for large-scale production.

The invention discloses a tofacitinib citrate controlled release tablet and a preparation method thereof. According to the controlled-release tablet disclosed by the invention, through the unique design of the coating film, the slow and continuous release of the medicine is realized, and meanwhile, the controlled-release tablet is stable in performance, can be stored for a long time, is simple in preparation process, is suitable for industrial production, and is beneficial to reducing the production cost and improving the market competitiveness of the product.

The invention provides a tofacitinib citrate sustained-release tablet, which is composed of a sustained-release tablet core and a coating layer, the sustained-release tablet core is prepared by uniformly mixing a solid dispersion and pharmaceutically acceptable auxiliary materials and then tabletting, the tofacitinib citrate sustained release tablet is characterized in that the solid dispersion is prepared from tofacitinib citrate, acrylic resin E and isomaltitol by utilizing a solvent evaporation method, and the coating layer comprises polyvinylpyrrolidone and tert-butyl p-hydroxyanisole. The prepared tofacitinib citrate tablet core particles are high in density, good in flowability and good in compressibility; the prepared tofacitinib citrate sustained release tablet is stable in quality, simple and feasible in process and suitable for large-scale production.

The invention discloses a method for synthesizing tofacitinib citrate diastereomeric impurities, and relates to the technical field of pharmaceutical organic synthesis. The invention uses 3-amino-4-methylpyridine as a starting raw material, and prepares the tofacitinib diastereomeric impurities through quaternary ammonium salt, reduction, methylation, salification, coupling, reduction and condensation reactions. The raw materials of the entire synthetic route are readily available, the reaction conditions are mild, the post-treatment separation and purification operation is simple and easy, the preparation method has good reproducibility, and the tofacitinib diastereomeric impurities with high yield and high purity can be prepared, thereby being suitable for use as an impurity reference substance for tofacitinib citrate.

The present application provides a kind of tofacitinib citrate sustained-release preparation, which is composed of tablet core, sustained-release layer coating and color layer coating, and the sustained-release layer coating has drug release small holes. By adjusting the composition of osmotic pressure forming agent and its dosage ratio with sustained-release agent, further optimizing the composition and coating weight of sustained-release layer coating, not only the defect of slow dissolution rate after long-term storage when using sorbitol as osmotic pressure forming agent alone is avoided, but also the initial release rate of tofacitinib citrate sustained-release tablet is improved, and slow and sustained release can be maintained for 6 hours, the drug release is more complete, the blood drug concentration is kept at a uniform and stable level for a long time, the fluctuation of blood drug concentration during the interval of administration is reduced, the bioavailability is further improved, the adverse reactions are reduced, and the clinical efficacy and safety are protected.

The application discloses a tofacitinib citrate sustained-release tablet and a preparation method thereof. The tofacitinib citrate sustained-release tablet comprises the following components in parts by weight: tofacitinib citrate 35.54 parts, a filling agent 90-130 parts, a binding agent 20-40 parts, a skeleton material 20-40 parts, a flow aid 0.5-1.5 parts, a lubricant 1-3 parts and a sustained-release coating 25.5-53 parts. The sustained-release coating is a mixture of hydroxypropyl methyl cellulose, a plasticizer and a mineral hydrophobic material. The plasticizer is polyethylene glycol, and the mineral hydrophobic material is any one of kaolin, talcum powder and heavy calcium carbonate. The application can achieve a dissolution curve close to the existing Xeljanz XR through the combination of the skeleton material tablet and the sustained-release coating, has a sustained-release effect in the first one hour, is rapidly dissolved in one to four hours, and can reduce the production cost, improve the production speed and be environment-friendly.

The invention belongs to the technical field of medical preparations and pharmaceutical preparations, and particularly relates to a method for improving the stability of citric acid tofacitinib oral liquid and the citric acid tofacitinib oral liquid. The oral liquid takes water as a solvent, contains citric acid tofacitinib, sodium benzoate and ethylenediamine di-o-phenyl sodium acetate, and the pH is regulated to 3.3-4.3 through a pH regulator. The sodium ethylenediamine diphenylacetate in the tofacitinib citrate oral liquid can synergistically inhibit the generation of impurities, block the degradation path of a main drug, stabilize the content of a preservative, significantly reduce the increase of impurities in acceleration and long-term storage, maintain the stability of the content and pH of the main drug, and effectively guarantee the product quality and efficacy.

The application discloses a tofacitinib citrate sustained-release tablet and a preparation method and application thereof. The tofacitinib citrate sustained-release tablet comprises a tablet core and a coating film, and the tablet core comprises the following components in parts by weight: tofacitinib citrate 18 parts, a skeleton material 10-60 parts, a binder 1-10 parts, a filling agent 10-90 parts and a lubricant 1-3 parts. The coating film comprises the following components in parts by weight: hydroxypropyl methyl cellulose 20-30 parts, a plasticizer 1-5 parts, a solid binding peptide 1-5 parts and L-lactide 1-5 parts. The tofacitinib citrate sustained-release tablet of the application can not only achieve the purpose of delayed release in the body, but also greatly improve the bioavailability of the drug. Due to the improvement of the bioavailability of the drug, the dosage can be reduced, the same therapeutic effect can be achieved, and the incidence of adverse reactions can be reduced in clinical application.

The disclosure relates to a tofacitinib citrate sustained-release tablet and a preparation method thereof. The tofacitinib citrate sustained-release tablet includes the components in parts by weight: 35.54 parts of tofacitinib citrate, 90-130 parts of diluent, 20-40 parts of binder, 20-40 parts of matrix material, 0.5-1.5 parts of glidant, 1-3 parts of lubricant, and 25.5-53 parts of sustained-release coating material. The sustained-release coating is a mixture of hypromellose, plasticizer and mineral hydrophobic material. The plasticizer is polyethylene glycol. The mineral hydrophobic material is any one of kaolin, talc powder, and heavy density calcium carbonate. Through the combination of a matrix core tablet and the sustained-release coating, a dissolution curve close to that of the existing Xeljanz XR can be achieved, with the sustained-released effect when dissolved in the first 1 h, quickly dissolved within 1-4 h, thereby reducing the production cost, improving the production speed and being environmentally friendly.

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for detecting methyl tert-butyl ether and triethylamine in tofacitinib citrate. Respectively detecting the blank solution, the reference solution and the test solution by headspace gas chromatography, recording chromatograms, and quantitatively analyzing methyl tert-butyl ether and triethylamine in the test solution according to an external standard method; wherein a preparation method of the test solution comprises the following steps: precisely weighing 0.1 g of a tofacitinib citrate sample, putting the tofacitinib citrate sample into a 20ml headspace bottle, adding 2ml of N-methyl pyrrolidone and 0.28 ml of a sodium hydroxide solution with the concentration of 100mg / ml, and sealing. The method realizes effective separation and quantitative detection of methyl tert-butyl ether and triethylamine in tofacitinib citrate, is high in sensitivity, good in repeatability and high in accuracy, makes up for the deficiency of research on methyl tert-butyl ether and triethylamine in tofacitinib citrate, and improves clinical medication safety.

The invention discloses a citric acid tofacitinib osmotic pump sustained-release tablet, which comprises a citric acid tofacitinib tablet core and a sustained-release coating layer coated on the surface of the citric acid tofacitinib tablet core, the citric acid tofacitinib tablet core contains a waxy framework material, and the sustained-release coating layer contains a sustained-release membrane material and a pore-foaming agent; the slow-release membrane material is composed of eudragit RL and eudragit RS; the pore-foaming agent is a water-soluble pore-foaming agent. The invention also discloses a preparation method of the tofacitinib citrate osmotic pump sustained release tablet, which comprises the following steps: uniformly mixing the components of the tablet core, and tabletting to obtain the tablet core; coating the tablet core, preserving heat and curing to obtain the tofacitinib citrate osmotic pump sustained release tablet. According to the invention, the corrosion controlled release of the waxy framework material and the controlled release coating layer are hierarchically coupled, so that the drug release stability is obviously improved, the tolerance to the change of the gastrointestinal tract physiological environment is stronger, and the dissolution of the drug is not reduced after long-term storage.

The invention discloses a tofacitinib citrate sustained release tablet as well as a preparation method and application thereof. Comprising a skeleton tablet core and a coating film, and the skeleton tablet core comprises the following components in parts by weight: 18 parts of tofacitinib citrate; 10-60 parts of a framework material; 1-10 parts of an adhesive; 10 to 90 parts of a filling agent; 1-3 parts of a lubricant; the coating film is prepared from the following components in parts by weight: 20 to 30 parts of hydroxypropyl methylcellulose; 1-5 parts of a plasticizer; 1-5 parts of solid binding peptide; 1 to 5 parts of L-lactide; the tofacitinib citrate sustained release tablet disclosed by the invention not only can achieve the purpose of delayed release in vivo, but also greatly improves the bioavailability of the medicine. As the bioavailability of the medicine is improved, not only can the administration dosage be reduced, but also the same treatment effect can be achieved, so that the occurrence rate of untoward effects in clinical application is reduced.

The invention provides a preparation method of a tofacitinib citrate intermediate, and belongs to the technical field of pharmaceutical chemicals. According to the preparation method, 3-halogenated-4-methylpyridine is taken as a raw material, and the (3R, 4R)-1-benzyl-3-methylamino-4-methyl-piperidine dihydrochloride is prepared through nucleophilic substitution, benzyl halide protection, hydroboron reduction, chiral resolution, dissociation and salification. According to the invention, the boron hydride is used as a reducing agent, and a pyridine ring of the 1-benzyl-3-methylamino-4-methylpyridine hydrochloride is reduced into a piperidine ring, so that the production cost is reduced. The synthesis method is mild in reaction condition, simple to operate and suitable for large-scale industrial production.

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a tofacitinib citrate gel as well as a preparation method and application thereof. The invention provides a citric acid tofacitinib gel. The gel comprises the following components in percentage by mass: 0.1-5% of an active component citric acid tofacitinib, 0.5-15% of a gel matrix, 0.1-5% of a surfactant, 5-30% of a transdermal enhancer, 0.01-1% of a preservative and the balance of water, the tofacitinib citrate gel prepared by the preparation method disclosed by the invention is proper in viscosity, good in moisture retention, high in active ingredient content, relatively small in total impurity and single impurity and good in stability; the tofacitinib citrate gel has a remarkable effect of promoting hair follicle growth, has no irritation to skin, and can be used for treating alopecia related diseases.

The invention relates to a preparation method of a spherical crystal of a tofacitinib citrate medicinal crystal form A. The method comprises the following steps: 1) adding tofacitinib citrate into a mixed solvent of water, one or more of n-butyl alcohol, sec-butyl alcohol, isobutyl alcohol and tert-butyl alcohol and one or more of methanol, ethanol, n-propyl alcohol and isopropyl alcohol; heating and dissolving; 2) after stirring and cooling, adding one or a mixture of more of ethyl formate, methyl acetate, ethyl acetate, isopropyl acetate, dichloromethane, n-heptane, n-hexane, isopropyl ether and methyl tert-butyl ether; and 3) continuously cooling and crystallizing to obtain the tofacitinib citrate crystal form A spherical crystal.

The invention provides a preparation method of tofacitinib citrate, and belongs to the technical field of pharmaceutical chemicals. Formic acid and ammonium formate are used as hydrogen donors, transfer hydrogenation is carried out under catalysis of the noble metal catalyst, reaction safety is improved, use of high-pressure hydrogen and high-pressure operation risks are thoroughly avoided, special pressure-resistant equipment is not needed, only a conventional reaction kettle is needed, and equipment investment and safety control cost are greatly reduced.

The invention discloses a tofacitinib citrate new crystal form compound and a preparation method thereof, the crystal form compound has characteristic diffraction peaks at 8 degrees, 9.1 degrees, 10.0 degrees, 10.3 degrees, 11.7 degrees, 12.6 degrees, 14.0 degrees, 16.3 degrees, 16.8 degrees, 19.1 degrees, 20.0 degrees, 20.4 degrees, 21.0 degrees, 22.6 degrees, 24.0 degrees, 27.2 degrees, 27.5 degrees, 28.4 degrees, 29.6 degrees, 34.5 degrees, 35.3 degrees, 36.3 degrees and 39.3 degrees in an X-ray powder diffraction pattern represented by a diffraction angle of 2 theta + / -0.2 degrees, and the crystal form compound is obviously different from the prior art. Compared with the existing citric acid tofacitinib crystal form compound, the citric acid tofacitinib crystal form compound prepared by the invention has the advantages of lower dissolution rate, larger particle size and better flowability, and is expected to have better application prospects in the development of related solid preparation products.

The invention belongs to the technical field of pharmaceutical analysis, and relates to a method for detecting genotoxic impurities in a tofacitinib citrate starting material by gas chromatography-mass spectrometry, the detection method adopts gas chromatography-mass spectrometry, and the detected genotoxic impurities are bromoacetaldehyde and bromoacetaldehyde diethyl acetal. The sample treatment is simple, the specificity is strong, the durability is better, the detection sensitivity is high, and the detection quantity in the sample is far lower than the limit (not greater than 93.75 ppm) requirements of bromoacetaldehyde and bromoacetaldehyde diethyl acetal.

The invention discloses a tofacitinib citrate tablet and a preparation process thereof, and belongs to the technical field of pharmaceutical preparations. According to the tofacitinib citrate tablet, tofacitinib citrate is taken as an effective component and matched with a filling agent, a stable dissolution promoter, a disintegrating agent, an adhesive and a lubricating agent, and a coating material can be selectively added; wherein the stable dissolution promoter is a combination of polyethylene glycol 4000, glycine and ethyl maltol. The preparation process comprises the following steps: pretreatment of the active ingredients, preparation of the stable dissolution promoter, wet granulation, tabletting and optional coating. The tofacitinib citrate tablet effectively solves the technical problems of insufficient stability and poor dissolution performance of the existing tofacitinib citrate tablet by optimizing the component matching, especially the synergistic effect of the specific ternary stable dissolution promoting agent combination, so that the preparation can be quickly and fully dissolved out in different pH environments, can resist the influence of severe storage environments, and can be used for preparing the tofacitinib citrate tablet. The drug degradation is reduced, and the medication safety and the clinical curative effect are guaranteed.

The application discloses a detection method of raw material drug particle size and particle size distribution of tofacitinib citrate, and comprises the following steps: taking tofacitinib citrate raw material drug to be detected, adding Span 80-n-hexane solution as a dispersing agent, ultrasonic stirring until uniform dispersion, and then detecting the prepared sample by using a wet laser diffraction method. Through a large number of experiments, the Span 80-n-hexane solution is specifically selected as the dispersing agent to prepare a stable test suspension, so that the problem that when tofacitinib citrate is detected by using the wet method, the conventional solvent is used as the dispersing agent, the dispersion system is unstable, the light shielding degree rapidly decreases, and the sample particle size cannot be accurately detected is solved, and the method has important significance in the research and production process of tofacitinib citrate related preparations.

The invention discloses a method for detecting cyanoacetate in tofacitinib citrate, impurities in tofacitinib citrate are determined by gas chromatography, the impurities comprise methyl cyanoacetate and ethyl cyanoacetate, and the detection method comprises the following steps: preparing a test solution; preparing an ethyl cyanoacetate and methyl cyanoacetate reference substance solution; performing gas chromatographic analysis on the test solution and the reference solution by using preset chromatographic conditions; through an external standard method, the content of methyl cyanoacetate and ethyl cyanoacetate in tofacitinib citrate is obtained through chromatographic analysis. According to the technical scheme provided by the invention, methyl cyanoacetate and ethyl cyanoacetate impurities in tofacitinib citrate can be simultaneously determined, so that the quality control of a tofacitinib citrate product can be ensured.

Compositions and methods for treating hair loss in a patient are described herein. Injectable compositions including minoxidil, dutasteride, finasteride, tofacitinib citrate, or ruxolitinib phophate, a castor oil derivative, and a pharmaceutically acceptable carrier are described. Methods of treating hair loss in a patient in need thereof by administering the compositions by injection are also described.