29 results about "Ibrutinib" patented technology

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.

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.

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.

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.

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 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.

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for separating and determining ibrutinib SM3 and impurities thereof based on gas chromatography. The impurities comprise any one or more of acrylic anhydride, trichlorotoluene, propionyl chloride, 3-chloropropionyl chloride, benzoyl chloride, acrylic acid and benzoic acid; the ibrutinib SM3 and impurities jointly form a composition to be detected. According to the method, (5% phenyl)-diphenylmethylsiloxane is adopted as a chromatographic column of a stationary liquid, or other stationary liquids with the same polarity are adopted; the ibrutinib SM3 and impurities of the ibrutinib SM3 are separated by adopting temperature programming; the temperature programming setting is as follows: the initial temperature is 35 + / -5 DEG C and is maintained for 5 + / -1 minutes, and the temperature is raised to 210 + / -10 DEG C at the rate of 30 + / -5 DEG C / min and is maintained for 8 + / -2 minutes. The method provided by the invention can effectively separate, identify and quantify various related substances in ibrutinib SM3, and has the advantages of short separation time, strong specificity, high sensitivity and good durability.

The present invention relates to a solid oral pharmaceutical for Axitinib, Ibrutinib and / or Palbociclib (API) or any other Kinase Inhibitor API with a novel, well defined method to enhance solubility of active pharmaceutical ingredients (API) with low solubility in aqueous media and use those enhanced API in a new approach of preparing modified and / or sustained release pharmaceutical formulation for API which are regularly not suitable for sustained release formulations because of their low solubility. This invention is applicable for small molecule API (molecular weight < 1000) for which the solubility can be enhanced by formation of a e.g., Cyclodextrin Complex regardless which Cyclodextrin or derivate thereof is employed according to the method described in this invention. Axitinib, Ibrutinib and / or Palbociclib and other Kinase Inhibitors can be found for treatment of malign tumor diseases and others.

The invention belongs to the technical field of analytical chemistry, and particularly relates to a method for separating and determining enantiomer impurities in ibrutinib and related substances thereof. The method is a high performance liquid chromatography, and comprises the following steps: by taking amylose-tris [3, 5-dimethyl phenyl carbamate] derivative bonded silica gel as a chromatographic column filler and a mixed solution of methanol, tetrahydrofuran and normal hexane as a mobile phase, separating enantiomer impurities from ibrutinib and related substances thereof through elution; and then detecting in a detector to obtain a chromatogram. According to the method, enantiomer impurities can be well separated from a main peak of a test sample and other 10 known impurities possibly existing in the test sample within 30 minutes, and the method has the advantages of short analysis time, high sensitivity, strong specificity, good reproducibility and simplicity and feasibility in operation.

The invention discloses a targeting covalent activation prodrug compound and a preparation method and application thereof, the targeting covalent activation prodrug compound is named as Ibt-DOX, and the structural formula of the targeting covalent activation prodrug compound is shown in the specification. According to the invention, high affinity and irreversible inhibition capability of a classical targeting covalent inhibitor to Bruton's tyrosine kinase (BTK) are retained, and in-situ release of potent chemotherapeutic drugs is triggered by a targeting covalent binding process, so that high synergy of targeting covalent inhibition and local chemotherapy is realized; the direct killing capacity of the medicine on BTK high-expression B cell tumor cells is greatly improved, and the treatment effect of the medicine is obviously better than that of the medicine which is independently used or is simply combined with chemotherapy medicine.

The present invention discloses a method for synthesizing 3-amino-5-(4-phenoxyphenyl)-4-cyano-1H-pyrazole, belonging to the field of organic chemical synthesis, and specifically relates to a method for synthesizing an intermediate of ibrutinib, comprising the following steps: (a) dissolving phenol and p-halobenzonitrile in organic solvent A, adding a base, and carrying out a substitution reaction to obtain intermediate I-a; (b) dissolving intermediate I-a in ethanol, dropwise adding acetyl chloride, and carrying out an addition reaction to obtain intermediate I-b; (c) dissolving intermediate I-b, malononitrile and a base in organic solvent B, and carrying out a condensation reaction to obtain intermediate I-c; (d) dissolving intermediate I-c and hydrazine hydrate in ethanol, and carrying out a cyclization reaction to obtain the target product I-d. This synthesis method involves reactions such as substitution, addition, condensation and cyclization, with mild reaction conditions, simple operation, low cost, safe and controllable, avoiding the use of highly toxic and volatile reagents, and is suitable for industrial production.

The present invention relates to a carbonyl reductase mutant and its application in the synthesis of the key intermediate (S)-N-Boc-3-hydroxypiperidine of ibrutinib. It mainly relates to a mutant with significantly improved thermal stability of carbonyl reductase, its coding nucleic acid, recombinant expression vector, recombinant expression transformant, and the application of using the carbonyl reductase mutant or carbonyl reductase catalyst to catalyze the asymmetric reduction of N-Boc-3-piperidone to produce the key intermediate (S)-N-Boc-3-hydroxypiperidine of ibrutinib. Compared with the prior art, the carbonyl reductase mutant of the present invention has advantages such as high catalytic activity and good thermal stability, and has good industrial application prospects in the preparation of drug intermediates such as ibrutinib.

The invention provides a crystal form X of ibrutinib, a composition containing the crystal form X and pharmaceutical application of the crystal form X. An X-ray powder diffraction pattern of the crystal form X has diffraction peaks at the following 2 theta angles: 6.5 degrees + / -0.2 degrees, 9.3 degrees + / -0.2 degrees, 14.9 degrees + / -0.2 degrees, 20.8 degrees + / -0.2 degrees and 21.3 degrees + / -0.2 degrees. Experiments show that the crystal form X is high in solubility and good in chemical stability under a long-term storage condition, and an unexpected technical effect is achieved. Compared with other crystal forms in the prior art, the crystal form X has higher dissolution rate. The present invention also provides compositions of crystalline form X with other compounds.

The present invention relates to a method for expanding peripheral blood lymphocytes (PBL) from peripheral blood, the method being characterized in that it comprises steps d: a. providing a sample of peripheral blood mononuclear cells (PBMCs) from the peripheral blood of a patient with a hematologic malignancy who has been previously treated with ibrutinib or another interleukin-2 inducible T-cell kinase (TKIT) inhibitor and who is refractory to treatment with ibrutinib or any other TKIT inhibitor, wherein the aminothiazole-based TKIT inhibitor, benzimidazole-based TKIT inhibitors, aminopyrimidine-based TKIT inhibitors, 3-aminopyrid-2-one-based TKIT inhibitors, indolindazole-based TKIT inhibitors, pyrazolyl-indole-based TKIT inhibitors, thienopyrazole-based TKIT inhibitors and TKIT inhibitors targeting cysteine-442 in the ATP pocket; b.cultivate said PBMCs in a culture comprising a first culture medium with IL-2 and anti-CD3 / anti-CD28 antibodies, thereby effecting the expansion of peripheral blood lymphocytes (PBLs) from said PBMCs; and c. harvest the PBLs from the culture in step b, wherein the method is carried out for a selected time period from the group consisting of: approximately 9 days, approximately 10 days, approximately 11 days, approximately 12 days, approximately 13 days, and approximately 14 days, and wherein the expanded PBLs comprise higher levels of IFNγ production than those expanded from patients not previously treated with ibrutinib or another KT1 inhibitor.

The invention relates to a method for detecting a genotoxic impurity hydrazine hydrate in ibrutinib in the technical field of pharmaceutical analysis, which comprises the following steps: preparing a derivative of hydrazine hydrate, and quantitatively detecting the derivative by using GC-FID (Gas Chromatography-Flame Ionization Detector), thereby realizing the detection of hydrazine hydrate in ibrutinib. The method is low in detection cost, simple and easy to operate, good in repeatability and high in sensitivity, and has extremely important significance on quality control of ibrutinib bulk drugs and preparations.

A method for treating cancer comprises the combined use of a therapeutically effective amount of elzovtinib or an elzovtinib analog, a derivative thereof, or a pharmaceutically acceptable salt, and a therapeutically effective amount of bortezomib, ibrutinib, or an analog, derivative, or pharmaceutically acceptable salt thereof. The composition and kit are included herein. The cancer may be refractory to bortezomib and / or ibrutinib.