# US 12,005,064 B2 · Pharmaceutical composition comprising non-ionic surfactants > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,005,064 B2 - Document ID: US12005064B2 - Status: Granted - Kind: B2 - Application number: 16/773,734 - Filed: 2020-01-27 - Published: 2020-12-24 - Granted: 2024-06-11 - Earliest claimed: 2014-06-18 - Assignees: Hoffmann-La Roche Inc.; Chugai Seiyaku Kabushiki Kaisha - Applicants: Hoffmann-La Roche Inc.; Chugai Seiyaku Kabushiki Kaisha - Inventors: Susanne Meier; Carsten Bruesewitz - Web page: https://patentgrep.com/patent/US12005064B2 ## CPC - A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol - A61K 9/4858: {Organic compounds} - A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters - A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones - A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin - A61P 11/00: Drugs for disorders of the respiratory system - A61P 35/00: Antineoplastic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to a pharmaceutical composition comprising poorly soluble compounds such as BSC class II or IV kinase inhibitors, a process for the preparation thereof and its use in the treatment of diseases, in particular cancer, further particularly in non-small lung cancer. ## Claims ### Claim 1 A pharmaceutical composition comprising: a) 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, b) a non-ionic surfactant A that is a solid at room temperature that is vitamin E polyethylene glycol succinate, and c) a non-ionic surfactant B that is liquid at room temperature that is polysorbate 80, wherein the HLB of surfactants A and B are independently equal or greater than 8 and wherein 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is dispersed in the matrix formed by surfactants A and B. ### Claim 2 (depends on 1) The pharmaceutical composition according to claim 1, comprising 161 mg of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H -benzo[b] carb azole-3-carbonitrile hydrochloride. ### Claim 3 (depends on 1) The pharmaceutical composition according to claim 1, characterized in that the drop point of the pharmaceutical composition is between 32 and 41° C. ### Claim 4 (depends on 1) The pharmaceutical composition according to claim 1, wherein surfactant A is vitamin E polyethylene glycol succinate wherein the chain length of the polyethylene glycol chain is 1000. ### Claim 5 (depends on 1) The pharmaceutical composition according to claim 1, comprising surfactant A and B in a ratio in weight from between 1:1 to 8:2. ### Claim 6 (depends on 1) The pharmaceutical composition according to claim 1, wherein the 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H -benzo[b]carbazole-3-carbonitrile hydrochloride is in a micronized form. ### Claim 7 (depends on 6) The pharmaceutical composition according to claim 6, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo -6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 20 μm. ### Claim 8 (depends on 6) The pharmaceutical composition according to claim 6, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl -piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 15 μm. ### Claim 9 (depends on 6) The pharmaceutical composition according to claim 6, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 8 μm. ### Claim 10 (depends on 1) The pharmaceutical composition according to claim 1, comprising only one active ingredient or pharmaceutically acceptable salt thereof, which is 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 11 (depends on 1) The pharmaceutical composition according to claim 1, comprising from 20 to 250 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl) -11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 12 (depends on 1) The pharmaceutical composition according to claim 1, comprising from 20 to 225 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 13 (depends on 1) The pharmaceutical composition according to claim 1, comprising from 100 to 200 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-SH-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 14 (depends on 1) The pharmaceutical composition according to claim 1, comprising from 125 to 175 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 15 (depends on 1) The pharmaceutical composition according to claim 1, characterized in that the drop point of the pharmaceutical composition is between 35 and 39° C. ### Claim 16 (depends on 1) The pharmaceutical composition according to claim 1, comprising surfactant A and B in a ratio in weight of 7:3. ### Claim 17 (depends on 1) The pharmaceutical composition according to claim 1, comprising; 20 to 225 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl -piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, 150 to 300 mg of vitamin E polyethylene glycol succinate, and 50 to 150 mg of polysorbate 80. ### Claim 18 (depends on 1) The pharmaceutical composition according to claim 1, comprising: 150 mg of free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-rnorpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-caronitrile hydrochloride, 245 mg of vitamin E polyethylene glycol succinate, and 105 mg of polysorbate 80. ### Claim 19 (depends on 1) The pharmaceutical composition according to claim 1, comprising: 161 mg of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro -5H-benzo[b]carbazole-3-carbonitrile hydrochloride, 245 mg of vitamin E polyethylene glycol succinate, and 105 mg of polysorbate 80. ### Claim 20 A pharmaceutical composition comprising: a) 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, b) a non-ionic surfactant A that is a solid at room temperature that is vitamin E polyethylene glycol succinate, and c) a non-ionic surfactant B that is liquid at room temperature that is polysorbate 80, wherein the HLB of surfactants A and B are independently equal or greater than 8, wherein 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l -yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is dispersed in the matrix formed by surfactants A and B, and wherein the pharmaceutical composition is obtainable by: a) melting surfactant A, b) mixing melted surfactant A and liquid surfactant B, and c) suspending 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-l-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride in the obtained mixture. ### Claim 21 A pharmaceutical composition comprising: a) 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6, 1 1-dihydro-5H-benzo[b]carbaxole-3-carbonitrile hydrochloride, b) a non-ionic surfactant A that is a solid at room temperature that is lauroyl polyoxylglyceride, and c) a non-ionic surfactant B that is liquid at room temperature that is polysorbate 80, wherein the HLB of surfactants A and B are independently equal or greater than 8 and wherein 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6, 1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is dispersed in the matrix formed by surfactants A and B. ### Claim 22 (depends on 21) The pharmaceutical composition according to claim 21, comprising 161 mg of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 23 (depends on 21) The pharmaceutical composition according to claim 21, characterized in that the drop point of the pharmaceutical composition is between 32 and 41° C. ### Claim 24 (depends on 21) A pharmaceutical composition according to claim 21, wherein surfactant A is lauroyl polyoxylglyceride that has a hydrophilic balance comprised between 12-15 and a drop point comprised between 40 and 46° C. ### Claim 25 (depends on 21) The pharmaceutical composition according to claim 21, comprising surfactant A and B in a ratio in weight from between 1:1 to 8:2. ### Claim 26 (depends on 21) The pharmaceutical composition according to claim 21, wherein the 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is in a micronized form. ### Claim 27 (depends on 26) The pharmaceutical composition according to claim 26, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 20 μm. ### Claim 28 (depends on 26) The pharmaceutical composition according to claim 26, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 15 μm. ### Claim 29 (depends on 26) The pharmaceutical composition according to claim 26, wherein the particle size of the micronized 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride is between 0.2 μm and 8 μm. ### Claim 30 (depends on 21) The pharmaceutical composition according to claim 21, comprising only one active ingredient or pharmaceutically acceptable salt thereof, which is 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 31 (depends on 21) The pharmaceutical composition according to claim 21, comprising from 20 to 250 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 32 (depends on 21) The pharmaceutical composition according to claim 21, comprising from 20 to 225 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)- 11-oxo-6, 11 -dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 33 (depends on 21) The pharmaceutical composition according to claim 21, comprising from 100 to 200 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 34 (depends on 21) The pharmaceutical composition according to claim 21, comprising from 125 to 175 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride. ### Claim 35 (depends on 21) The pharmaceutical composition according to claim 21, characterized in that the drop point of the pharmaceutical composition is between 35 and 39° C. ### Claim 36 (depends on 21) The pharmaceutical composition according to claim 21, wherein surfactant A is lauroyl polyoxylglyceride with a HLB of 14 and a drop point of 44° C. ### Claim 37 (depends on 21) The pharmaceutical composition according to claim 21, comprising surfactant A and B in a ratio in weight of 7:3. ### Claim 38 (depends on 21) The pharmaceutical composition according to claim 21, comprising; 20 to 225 mg of the free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, 150 to 300 mg of lauroyl polyoxylglyceride, and 50 to 150 mg of polysorbate 80. ### Claim 39 (depends on 21) The pharmaceutical composition according to claim 21, comprising: 150 mg of free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-rnorpholin-4-yl-piperidin-1-yl)-11-oxo-6, 11 -dihydro-5H-benzo[b]carbazole-3-caronitrile hydrochloride, 245 mg of lauroyl polyoxylglyceride, and 105 mg of polysorbate 80. ### Claim 40 (depends on 21) The pharmaceutical composition according to claim 21, comprising: 161 mg of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, 245 mg of lauroyl polyoxylglyceride, and 105 mg of polysorbate 80. ### Claim 41 A pharmaceutical composition comprising: a) 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6, 1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride, b) a non-ionic surfactant A that is a solid at room temperature that is lauroyl polyoxylglyceride, and c) a non-ionic surfactant B that is liquid at room temperature that is polysorbate 80, wherein the HLB of surfactants A and B are independently equal or greater than 8, wherein 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6, 1 1-dihydro-5H-benxo[b]carbazole-3-carbonitrile hydrochloride is dispersed in the matrix formed by surfactants A and B, and wherein the pharmaceutical composition is obtainable by: a) melting surfactant A, b) mixing melted surfactant A and liquid surfactant B, and c) suspending 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-1 1-oxo-6,1 1-dihydro-5H-benzo[b]carbazole-3-carbonitrile hydrochloride in the obtained mixture.