41 results about "Ibrutinib" patented technology

Provided are methods of clinical treatment of Diffuse Large B-cell Lymphoma (for example, relapsed and / or refractory Diffuse Large B-cell Lymphoma) in human subjects using a bispecific antibody which binds to CD3 and CD20 in combination with lenalidomide or ibrutinib and lenalidomide.

This application relates to the technical field of pharmaceutical preparations, and specifically discloses a pharmaceutical composition containing ibrutinib and its preparation method. The composition includes the active ingredient ibrutinib, colloidal silicon dioxide, solubilizers, and other excipients such as excipients; its preparation method is: the active ingredient ibrutinib is preferentially mixed with colloidal silicon dioxide and solubilizers, followed by dry granulation, mixing, and capsule filling. The composition of this application can be used for the treatment of diseases such as mantle cell lymphoma (MCL) / chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma, etc. It can effectively break the insoluble complex salt formed by ibrutinib and solubilizers, and has the advantages of fast dissolution rate and significantly improved bioavailability; in addition, the preparation method of this application has the advantages of good process reproducibility, simple process steps, low production cost, and being suitable for large-scale industrial production.

The invention relates to the technical field of medicines, and provides application of ibrutinib as a platinum drug sensitizer in gastric cancer treatment. Furthermore, the invention also provides an application of ibrutinib combined with platinum drugs in preparation of drugs for treating CREB1 high-expression gastric cancer, and further provides a pharmaceutical composition for treating gastric cancer. A mouse in-vivo experiment shows that the size and the growth speed of a stomach tumor overexpressed with CREB1 can be obviously reduced by combined use of ibrutinib and oxaliplatin, so that the platinum drug sensitivity of CREB1 high-expression stomach cancer cells is enhanced; through a gastric cancer organ model and an in-vitro cytology experiment, the ibrutinib can reduce the activity of CREB1 by inhibiting phosphorylation of various proteins of an EGFR-PI3K-AKT-CREB1 pathway, so that proliferation of gastric cancer cells is inhibited, the ferroptosis level of the gastric cancer cells is increased, and IC50 of the ibrutinib can be remarkably reduced by combined use of the ibrutinib and platinum drugs. The invention provides a new basis for the ibrutinib or the derivative thereof to inhibit the growth of CREB1 high-expression gastric cancer cells and enhance the sensitivity of platinum drugs.

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a pharmaceutical composition containing ibrutinib and a preparation method of the pharmaceutical composition. The composition comprises an active component ibrutinib, colloidal silicon dioxide, a solubilizer, an excipient and other auxiliary materials. The preparation method comprises the following steps: preferentially mixing the active component ibrutinib with the colloidal silicon dioxide and the solubilizer, and carrying out dry granulation, mixing and capsule filling. The composition can be used for treating diseases such as mantle cell lymphoma (MCL) / chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma, can effectively break insoluble double salt formed by ibrutinib and a solubilizer, and has the advantages of being high in dissolution rate and remarkably improving bioavailability; in addition, the preparation method has the advantages of being good in process reproducibility, simple in process step, low in production cost and suitable for large-scale industrial production.

Disclosed are formulations / compositions comprising ibrutinib:as well as processes for preparing such formulations / compositions and methods of treatment of a disease or condition that comprises the use of such formulations / compositions.

Described herein are methods for treating and preventing graft versus host disease using ACK inhibitors. The methods include administering to an individual in need thereof an ACK inhibitor such as ibrutinib for treating and preventing graft versus host disease.

The invention discloses an ibrutinib monolaurinol sulfate crystal compound, a preparation method and application, the structural formula of the ibrutinib monolaurinol sulfate crystal compound is shown as a formula II, the ibrutinib monolaurinol sulfate crystal compound is a crystal compound or an amorphous compound, and the crystal compound exists in an anhydrous and solvent-free form. According to the crystal compound, good druggability of the ibrutinib is ensured, the bioavailability of oral absorption is remarkably improved, and meanwhile, the difference between preprandial and postprandial of the ibrutinib is reduced, so that gastrointestinal reaction and potential toxic and side effects can be reduced.

Discussed herein are pharmaceutical compositions containing Ibrutinib and processes for preparing them. The compositions may be utilized in the treatment of a variety of conditions including, without limitation, B-cell proliferative disorders such as non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma, or leukemia. These compositions are designed for oral ingestion. The compositions are contained within a capsule such as a standard or sprinkle or in a liquid formulation such as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water.

The present invention belongs to the technical field of drug synthesis, and in particular to a method for preparing ibrutinib. The present invention uses 3-bromo-1H-pyrazolo[3,4-D]pyrimidine-4-amine as a raw material, and reacts with 4-phenoxyphenylboronic acid under amine catalysis to obtain 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine; 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine is reacted with 1-[(S)-3-hydroxy-1-piperidinyl]-2-propylene-1-one under the catalysis of phosphine oxide to obtain ibrutinib through Mitsunobu reaction. This process uses amine catalysts instead of precious metal palladium to catalyze the Suzuki coupling reaction, which solves the problems of low yield and expensive catalysts in traditional reactions of this type. It uses phosphine oxide as a catalyst to catalyze the Mitsunobu reaction, avoiding the use of equivalent triphenylphosphine in the Mitsunobu reaction, and solves the harsh conditions of the reaction itself that require the acidity of the nucleophilic reagent. The process is simple to operate, and the target product obtained is of high purity, which is suitable for industrial production.

A method of treating cancer includes a combination of a therapeutically effective amount of an illudin or an illudin analog thereof, derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of Bortezomib, Ibrutinib or an analog, derivative, or a pharmaceutically acceptable salt thereof. Compositions and kits of the same are included herein. The cancer may be refractory to Bortezomib and / or Ibrutinib.

A method of treating cancer includes a combination of a therapeutically effective amount of an illudin or an illudin analog thereof, derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of Bortezomib, Ibrutinib or an analog, derivative, or a pharmaceutically acceptable salt thereof. Compositions and kits of the same are included herein. The cancer may be refractory to Bortezomib and / or Ibrutinib.

The present invention relates to a tablet composition comprising Ibrutinib and one ore more pharmaceutically acceptable excipients. The invention further relates to the use of said composition as a medicament, particularly in the treatment of lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinaemia (WM) and chronic graft versus host disease (cGVHD).

This invention provides an ibrutinib capsule formulation. Ibrutinib and a macromolecular polymer are prepared into a solid dispersion via hot melt extrusion. After pulverization, a certain amount of fatty acid glycerides and other excipients are added for granulation. A lubricant is added, the mixture is homogenized, and the granules are then filled into capsules. The ibrutinib capsules prepared by this invention exhibit high dissolution; when water is used as the dissolution medium, they dissolve rapidly without the addition of surfactants. Furthermore, the addition of fatty acid glycerides during granulation further improves bioavailability. The preparation method of the ibrutinib capsules provided by this invention does not require micronization, is simple to operate, does not use organic solvents, and has high safety.

Disclosed in the present invention are a crystalline compound of ibrutinib monododecyl sulfate, and a preparation method therefor and the use thereof. The structural formula of the crystalline compound is as represented by formula II. Ibrutinib monododecyl sulfate is a crystalline compound or an amorphous compound, and the crystalline compound is present in an anhydrous and solvent-free form. The crystalline compound ensures a good druggability of ibrutinib and also significantly improves the bioavailability thereof during oral absorption; moreover, the crystalline compound is also conducive to reducing the difference in the effect of ibrutinib before and after meals, thereby reducing gastrointestinal reactions and potential toxicity and side effects.

The present invention discloses a method for detecting the occupancy rate of BTK receptors, which relates to the technical field of BTK. The method uses the simoa detection method and includes the following steps: S1, connecting the capture antibody to the magnetic beads; S2, preparing the biotinylated detection antibody; S3, the detection method of simoa total BTK. In this method for detecting the occupancy rate of BTK receptors, for the first time, the ibrutinib biotin probe is applied to the simoa platform to replace the biotinylated detection antibody. Based on the principle of the traditional sandwich ELISA method on the simoa platform, small molecule biotin is used as the detection probe to broaden its scope of application. The traditional ELISA reaction takes 6-10 hours, while the present invention using the simoa technology only takes about 2 hours, which can greatly shorten the detection time, improve the detection efficiency, perform automatic analysis, improve the detection throughput, and have more controllable detection precision and accuracy. For the first time, the small molecule biotin probe is used to replace the biotinylated detection antibody and applied to the simoa platform, and this technology is used for the first time to detect the occupancy rate of BTK receptors.

The invention discloses an ibrutinib pharmaceutical composition and preparation as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. In order to solve the problems of low bioavailability, large administration dosage, high side effect risk and the like of ibrutinib, the invention provides an ibrutinib pharmaceutical composition and preparation as well as a preparation method and application thereof, the pharmaceutical composition comprises an active substance ibrutinib monolauryl sulfate, a filler, a release regulator and / or other auxiliary materials, the other auxiliary materials comprise at least one of a lubricant, a disintegrating agent and a flow aid; the preparation is a capsule or a tablet. According to the preparation of the ibrutinib monolaurinol sulfate composition prepared by adopting granulation or direct mixing, the bioavailability is greatly improved, and the dosage is greatly reduced under the condition that the blood exposure is basically unchanged; meanwhile, relatively stable blood concentration can be maintained, and the preparation has the advantages of small toxic and side effects, convenience in taking, high bioavailability and the like.

Described herein are methods for treating and preventing alloantibody driven chronic graft versus host disease (cGVHD). The methods include administering to an individual in need thereof ibrutinib for treating and preventing alloantibody driven graft versus host disease.

Discussed herein are pharmaceutical compositions containing Ibrutinib and processes for preparing them. The compositions may be utilized in the treatment of a variety of conditions including, without limitation, B-cell proliferative disorders such as non-Hodgkin lymphoma (diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma or burkitt lymphoma), Waldenstrom macroglobulinemia, plasma cell myeloma, chronic lymphocytic leukemia, lymphoma, or leukemia. These compositions are designed for oral ingestion. The compositions are contained within a capsule such as a standard or sprinkle or in a liquid formulation such as a suspension. In one embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate. In another embodiment, the pharmaceutical composition contains Ibrutinib, a salt, prodrug, or metabolite thereof, microcrystalline cellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose, citric acid monohydrate, disodium hydrogen phosphate, sucralose, sodium methyl parahydroxybenzoate, sodium ethyl parahydroxybenzoate, concentrated hydrochloric acid, sodium hydroxide, and water.

Disclosed are formulations / compositions comprising ibrutinib:as well as processes for preparing such formulations / compositions and methods of treatment of a disease or condition that comprises the use of such formulations / compositions.

A method of treating cancer includes a combination of a therapeutically effective amount of an illudin or an illudin analog thereof, derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of Bortezomib, Ibrutinib or an analog, derivative, or a pharmaceutically acceptable salt thereof. Compositions and kits of the same are included herein. The cancer may be refractory to Bortezomib and / or Ibrutinib

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for separating, detecting and determining an initial raw material SM3 and impurities thereof of ibrutinib. The impurities comprise one or more of propionyl chloride, 3-chloropropionyl chloride and benzoyl chloride. A mobile phase is a phosphate buffer solution as a mobile phase A, acetonitrile is a mobile phase B, a chromatographic column adopts octadecylsilane chemically bonded silica as a filler, and linear gradient elution of high performance liquid chromatography is carried out after pre-column derivatization. And then, according to a chromatogram, an external standard method is adopted to calculate the impurities according to a peak area. The method has the characteristics of good separation degree, good durability, high sensitivity and good reproducibility.

The present invention discloses ibrutinib and a synthesis method thereof, comprising the following steps: (1) using SM1 (4-phenoxybenzoyl chloride) as a raw material, and carrying out a coupling reaction with SM2 (4,6-dichloropyrimidine) under the condition of a catalyst to obtain an intermediate M1 ((4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methyl ketone); (2) carrying out a cyclization reaction between M1 and SM3 (1-(3R-hydrazino-1-piperidinyl)-2-propylene-1-one) to obtain to the intermediate M2 (1-((R)-3-(4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one); (3) subjecting M2 to a chlorination amination reaction to obtain ibrutinib (1-((R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one). The ibrutinib synthesis method provided by the present invention has a reasonable route design, mild reaction conditions in each step, strong operability, low cost, high yield, simple process operation, is suitable for large-scale industrial production, and is of great significance.

The invention discloses a method for detecting zerbutinib and ibrutinib in human blood. The method comprises the following steps: preparing a mixed stock solution by using zerbutinib and ibrutinib reference substances, diluting step by step to prepare a standard curve working solution, and preparing a standard curve sample by using the standard curve working solution; preparing a mixed internal standard working solution by using a Zebrutini-D5 reference substance and an ibrutini-D5 reference substance, and pretreating the standard curve sample and the sample to be detected by using the mixed internal standard working solution; performing mass spectrum acquisition on the preprocessed to-be-detected sample and the preprocessed standard curve sample by using an electrospray ionization source and a multi-reaction monitoring mode to respectively obtain the signal intensity of the to-be-detected sample and the signal intensity of the standard curve sample; performing linear regression according to the signal intensity of the standard curve sample and the theoretical concentration of the standard curve sample to obtain a regression equation; and according to the regression equation and the signal intensity of the to-be-detected sample, calculating to obtain the concentration of the zebrutinib and the ibrutinib in the to-be-detected sample. The method has the advantages of wide detection linear range and high detection speed.

The invention discloses a purification method of ibrutinib, and belongs to the field of chemical pharmacy. Comprising the following steps: (1) adding ibrutinib capsule contents into purified water, controlling the temperature at 23-27 DEG C, and adding an acid solution to adjust the pH value of a system; (2) stirring until the solution is clear, adding a protective agent and activated carbon, and decolorizing; (3) filtering the decolored solution; (4) adding an organic solvent into the filtrate at 23-27 DEG C, stirring for 15 minutes, dropwise adding alkali liquor to adjust the pH value to 8.0-9.0, crystallizing and growing crystals; (5) dropwise adding the alkali liquor for the second time to adjust the pH value to 9.5-10.5, and growing crystals; (6) filtering and washing after crystal growing; and (7) vacuum drying and discharging. According to the method, the active ingredient ibrutinib raw material medicine which does not meet the quality standard is treated and recycled, the cost is saved, meanwhile, the method can be suitable for preparing a high-content ibrutinib standard product, and the method is simple, energy-saving, environment-friendly and suitable for large-scale industrial production.

The invention discloses a culture method of umbilical cord mesenchymal stem cells for treating cognitive impairment, and belongs to the technical field of cell culture. The culture method specifically comprises the following steps: (1) preparing a special culture medium; (2) umbilical cord pretreatment; and (3) cell culture. The traditional Chinese medicine extract (astragaloside), the B cell depleting agent (rituximab and ibrutinib) and the metabolism regulator (eicosapentaenoic acid) are jointly applied to the UC-MSCs in-vitro culture process, the multiplication capacity, the anti-inflammatory characteristic and the neural restoration function of the UC-MSCs can be synergistically enhanced, and therefore the cognitive disorder treatment efficiency of the UC-MSCs is remarkably improved.

The invention belongs to the technical field of biological medicine and molecular biology, and particularly relates to application of RNF20 in diagnosis and treatment of diffuse large B-cell lymphoma. Specifically, the RNF20 is remarkably and highly expressed in DLBCL cell lines and tissues, and the high expression of the RNF20 is closely related to poor prognosis of a patient; the RNF20 can play a tumor promoting role by promoting DLBCL cell proliferation, regulating and controlling a cell cycle, inhibiting cell apoptosis and positively regulating and controlling FUS protein expression, and the drug sensitivity of DLBCL cells to ibrutinib can be enhanced by knocking down the RNF20. In a word, the research result shows that the RNF20 can serve as a treatment target, a new thought and a new direction are provided for DLBCL prognosis evaluation and targeted therapy, and therefore the RNF20 has good practical application value.

The invention belongs to the technical field of medicines, relates to a composition of mitoxantrone hydrochloride and ibrutinib and application of the composition, and particularly relates to a composition of sialic acid modified mitoxantrone hydrochloride liposome and sialic acid modified ibrutinib phospholipid complex nanoparticles and an effect of the composition in preparation of antitumor drugs. The sialic acid modified mitoxantrone hydrochloride liposome and the sialic acid modified ibrutinib phospholipid compound nanoparticle can be respectively prepared into injections, injections, injections, injections, injections, injections, injections, injections, injections, injections and injections. Or the sialic acid-modified mitoxantrone hydrochloride liposome and the sialic acid-modified ibrutinib phospholipid complex nanoparticles are respectively prepared into injections, the injections are subpackaged in the same medicine box, and the medicine is administered in a sequential manner or is administered at the same time. The sialic acid modified mitoxantrone hydrochloride lipidosome and the sialic acid modified ibrutinib phospholipid compound nanoparticles are combined for use, so that the anti-tumor activity can be obviously improved, immune memory and anti-tumor immune response can be established, and the secondary attack of tumors can be resisted.

A method of treating cancer comprises a combination of: a therapeutically effective amount of pachymutilin or a pachymutilin analogue, a derivative, or a pharmaceutically acceptable salt thereof; and a therapeutically effective amount of bortezomib, ibrutinib, or an analog, derivative, or pharmaceutically acceptable salt thereof. Compositions and kits including such combinations are provided herein. The cancer may be refractory to bortezomib and / or ibrutinib.

The invention discloses a synthesis method of 3-amino-5-(4-phenoxy phenyl)-4-cyano-1H-pyrazole, belongs to the field of organic chemical synthesis, and particularly relates to a synthesis method of an ibrutinib intermediate, which comprises the following steps: (a) dissolving phenol and p-halobenzonitrile in an organic solvent A, adding alkali, and carrying out substitution reaction to obtain an intermediate I-a; (b) dissolving the intermediate I-a in ethanol, dropwise adding acetyl chloride, and carrying out an addition reaction to obtain an intermediate I-b; (c) dissolving the intermediate I-b, malononitrile and alkali in an organic solvent B, and performing condensation reaction to obtain an intermediate I-c; and (d) dissolving the intermediate I-c and hydrazine hydrate in ethanol, and carrying out cyclization reaction to obtain a target product I-d. The synthesis method adopts substitution, addition, condensation, cyclization and other reactions, has the advantages of mild reaction conditions, simple operation, low cost, safety and controllability, avoids the use of high-toxicity and volatile reagents, and is suitable for industrial production.