50 results about "Cabozantinib" patented technology

Pharmaceutical compositions are provided, which comprise cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein the inventive compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof. The present invention relates to oral pharmaceutical compositions of cabozantinib, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by cabozantinib.

Pharmaceutical compositions suitable for oral administration (such as a tablet or a capsule) are provided, which comprise a therapeutically effective amount of an amorphous solid dispersion of cabozantinib, e.g., for treating a proliferative disorder. Preferably, the amorphous solid dispersion consists of (a) cabozantinib or a pharmaceutically acceptable salt thereof (such as cabozantinib(S)-malate); (b) at least one pharmaceutically acceptable carrier selected from the group consisting of hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), polyvinyl pyrrolidine and vinyl acetate (PVP / VA) copolymer, hydroxypropyl methylcellulose phthalate (HPMCP), and mixtures thereof; (c) a pore-forming agent; and (d) a plasticizer.

Pharmaceutical compositions are provided, which comprise cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein the inventive compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof. The present invention relates to oral pharmaceutical compositions of cabozantinib, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by cabozantinib.

The invention discloses a kit for simultaneously determining five liver cancer multi-kinase targeted drugs and active metabolites thereof based on LC-MS / MS. The kit comprises an internal standard solution, a standard substance solution, a protein precipitant and a solution used as a mobile phase, the internal standard solution is a gefitinib solution; the standard substance solution is a solution of sorafenib, sorafenib nitric oxide, lenvatinib, lenvatinib nitric oxide, dorafenib, dorafenib nitric oxide, regorafenib, regorafenib nitric oxide, cabozatinib and cabozatinib nitric oxide; the protein precipitant is an ice acetonitrile solution; the mobile phase comprises a mobile phase A and a mobile phase B, the mobile phase A is an aqueous solution containing formic acid, and the mobile phase B is an acetonitrile solution containing formic acid. The invention also discloses a method for determining the liver cancer multi-kinase targeted drug and the active metabolite thereof. The method can be used for monitoring drug concentration and preparing a drug time monitoring curve, and can simultaneously improve the sensitivity and selectivity of the method and shorten the analysis time so as to improve the analysis flux.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associate with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts.

The present invention relates to a process for the purification of Cabozantinib in free base form.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib terephthalic acid as well as a preparation method and application thereof. The novel crystal form provided by the invention contains basic units of two molecules of cabozantinib and one molecule of terephthalic acid crystal form, and the novel crystal form has higher stability and solubility and is more suitable for a cabozantinib preparation.

The present invention provides a new crystalline form of Cabozantinib free base, Formula (I), which is chemically known as N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N'-(4- fluorophenyl)cyclopropane-1,1-dicarboxamide and preparation of its novel crystalline polymorph Form E, Formula (II).

The present invention pertains to stable pharmaceutical compositions comprising cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, which does not contain glidant(s). Preferably, the pharmaceutically acceptable salts of cabozantinib is cabozantinib S-malate. Furthermore, the present invention also covers liquid oral pharmaceutical composition and injectable dosage forms of cabozantinib or pharmaceutically acceptable salts thereof.

The present invention relates to pharmaceutical compositions of cabozantinib suitable for oral administration, and more particularly to solid oral compositions comprising cabozantinib fumarate, wherein such compositions comprise a certain amount of microcrystalline cellulose and at least one sugar alcohol The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associate with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts.

Provided are pharmaceutical compositions which include an amorphous solid dispersion comprising i) a lipophilic active pharmaceutical ingredient such as abiraterone, alectinib, pazopanib, cabozantinib, venetoclax, lurasidone, or vilazodone or a salt thereof, ii) a hydrophilic polymer, iii) optionally a surfactant, iv) optionally an adsorbent, and v) optionally an acid. Also described are methods for preparing such pharmaceutical compositions and treating a subject in need thereof. In one aspect, disclosed herein is an amorphous solid dispersion comprising an active pharmaceutical ingredient.

Disclosed herein are novel polymorphs of Cabozantinib salts and to the process for preparation thereof.

The invention relates to a dual drug loaded, targeted polymer drug nanoconjugate affecting multiple signaling pathways for use as a drug delivery system in the treatment of ovarian cancer. Said nanoconjugate comprises Cabozantinib (CBZ) as a VEGFR (Vascular endothelial growth factor receptor) inhibitor and Ki16425 as a LPAR (Lysophosphatidic acid receptor) 1,2,3 inhibitor. In the nanoconjugate of the invention, synergistic effect is obtained with dual drug use.

The present invention relates to oral compositions comprising a salt of cabozantinib and at least one pharmaceutically acceptable excipient, and methods of using the oral compositions to increase the oral bioavailable rate of cabozantinib and to reduce adverse events associated with oral administration of cabozantinib. The invention also relates to a method for preparing the cabozantinib dodecyl sulfate.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associate with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts.

The present invention provides a pharmaceutical composition that can suppress the crystallization of amorphous active ingredients, improve storage stability, and suppress the formation of related substances. [Solution] A pharmaceutical composition is prepared by combining an amorphous active ingredient with a pharmaceutically acceptable carrier and a pharmaceutically acceptable acidic additive. The carrier comprises at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives. The active ingredient may be cabozantinib or a pharmaceutically acceptable salt thereof. The (meth)acrylic polymer may include a (meth)acrylic polymer having aminoalkyl methacrylate units. The cellulose derivative may include cellulose carboxyalkyl alkyl ethers (in particular carboxymethyl ethyl cellulose). The acidic additive may include an organic acid.

Amorphous solid dispersions of the protein kinase inhibitor cabozantinib. The amorphous solid dispersions exhibit chemical and physical stability under stressed conditions. The amorphous solid dispersions may be suitable for use in pharmaceutical compositions for administration to human subjects or patients.

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a cabozantinib intermediate. The invention provides a novel preparation method of a cabozantinib intermediate 6.7-dimethoxy-4-(4-nitrophenoxy) quinoline, which comprises the following steps: by taking 6.7-dimethoxyquinoline-4-alcohol as a starting material, carrying out hydroxyl protection on the 6.7-dimethoxyquinoline-4-alcohol and tert-butyldimethylsilyl chloride, and then reacting with p-fluoronitrobenzene to obtain 6.7-dimethoxy-4-(4-nitrophenoxy) quinoline; the method avoids the problems of serious environmental pollution and strong corrosion to equipment due to the use of highly toxic reagents such as phosphorus oxychloride, sulfonyl chloride and oxalyl chloride in the traditional hydroxyl chlorination, and is suitable for large-scale process production.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associated with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts. The present invention further relates to polymorphic forms of cabozantinib lauryl sulfate salts, methods for preparing the polymorphic forms and uses thereof.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib as well as a preparation method and application thereof. The novel crystal form provided by the invention is a cabozantinib-isophthalic acid eutectic crystal, the cabozantinib-isophthalic acid eutectic crystal contains basic units of a monomolecular cabozantinib and a monomolecular isophthalic acid crystal form, the stability, the solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing a cabozantinib intermediate. According to the method, 6, 7-dimethoxyquinoline-4-alcohol is taken as a starting material and reacts with tert-butyl 4-hydroxyphenylcarbamate, then deprotection is carried out, and 6, 7-dimethoxy-4-(4-nitrophenoxy) quinoline is obtained, so that the method avoids the problems that reagents such as highly toxic phosphorus oxychloride, sulfonyl chloride and oxalyl chloride are used during traditional hydroxyl chlorination, the environment is seriously polluted, the cost is low, and the like. And the method is suitable for large-scale production.

The present invention refers to an amorphous form of cabozantinib sulphate monohydrate and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The present invention refers to a novel crystalline polymorphic form of cabozantinib hemifumarate sesquihydrate designated as Form A, a novel crystalline polymorphic form of cabozantinib hemifumarate hemipentahydrate designated as Form B and a process for their preparation, a pharmaceutical composition comprising Form A or Form B, and their use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The invention particularly relates to a cabozantinib and osimertinib co-loaded targeting liposome and application thereof in overcoming EGFR-TKI drug resistance, and belongs to the technical field of biological medicine. The co-drug-loaded targeting liposome disclosed by the invention is coated with osimertinib and cabozantinib at the same time, and a GE11 peptide targeting ligand is connected to a membrane material of the co-drug-loaded targeting liposome; wherein the mass ratio of osimertinib to cabozantinib is 1: (0.5-2), preferably 1: 1; the membrane material comprises hydrogenated soybean phosphatidylcholine, cholesterol and DSPE-PEG2000, and the mass ratio of the hydrogenated soybean phosphatidylcholine to the cholesterol to the DSPE-PEG2000 is (2.5-3.5): 1: 1. According to the co-drug-loading targeting liposome disclosed by the invention, a drug can be synergistically delivered to a tumor site through active targeting mediated by GE11 peptide, an EGFR main pathway and key drug-resistant bypasses such as MET are efficiently inhibited, and the co-drug-loading targeting liposome shows a remarkable synergistic interaction effect in the aspect of reversing acquired drug resistance of osimertinib.

The present invention belongs to the technical field of pharmaceutical preparations and provides a cabozantinib malate tablet and a method for preparing the tablet. The tablet comprises the active ingredient cabozantinib malate, trehalose, lecithin, and other pharmaceutically acceptable binders, disintegrants, lubricants, and glidants. By controlling the dosage of trehalose and lecithin, the product achieves rapid dissolution, smooth preparation, stable quality, and safety and effectiveness.

The present invention refers to a crystalline form of cabozantinib hemi-(S)-malate designated as Form A and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.

The invention provides a method for preparing cabozantinib and an intermediate thereof. The preparation method provided by the invention is simple and convenient to operate and more beneficial to industrial production, the yield of each step in the route is high, the purity of the crude product is good, and impurities are easy to remove.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib-saccharin and a preparation method thereof. The cabozantinib-saccharin new crystal form provided by the invention contains basic units of one molecule of cabozantinib and one molecule of saccharin, so that the stability, solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.