US2017119781A1PendingUtilityA1

Pharmaceutical composition comprising non-ionic surfactants

46
Assignee: HOFFMANN LA ROCHEPriority: Jun 18, 2014Filed: Dec 19, 2016Published: May 4, 2017
Est. expiryJun 18, 2034(~7.9 yrs left)· nominal 20-yr term from priority
Inventors:Susanne MeierCarsten Bruesewitz
A61K 31/00A61K 47/14A61K 47/26A61K 47/22A61K 9/48A61K 9/14A61P 43/00A61P 35/00A61K 9/4858A61P 11/00A61K 31/5377A61K 31/454A61K 31/403A61K 9/10
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Claims

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

exact text as granted — not AI-modified
1 . A pharmaceutical composition comprising
 a) one or more active ingredients or pharmaceutically acceptable salt thereof,   b) a non-ionic surfactant A solid at room temperature, and   c) a non-ionic surfactant B liquid at room temperature,   wherein the HLB of surfactants A and B are independently equal or greater than 8 and wherein the active ingredients or pharmaceutically acceptable salt thereof are dispersed in the matrix formed by the other ingredients.   
     
     
         2 . A pharmaceutical composition according to  claim 1 , wherein one of the active ingredients is a kinase inhibitor or pharmaceutically acceptable salt thereof. 
     
     
         3 . A pharmaceutical composition according to  claim 1 , wherein, one of the active ingredient is 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof. 
     
     
         4 . A pharmaceutical composition according to  claim 1 , comprising 161 mg 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. 
     
     
         5 . A pharmaceutical composition according to  claim 1 , characterized in that the drop point of the pharmaceutical composition is comprised between 32 and 41° C. 
     
     
         6 . A pharmaceutical composition according to  claim 1 , wherein the surfactant A is a tocopherol derivative or polyoxylglyceride. 
     
     
         7 . A pharmaceutical composition according to  claim 1 , wherein the surfactant A is a tocopherol derivative or a lauroyl polyoxylglyceride. 
     
     
         8 . A pharmaceutical composition according to  claim 1 , wherein the lauroyl polyoxylglyceride has a hydrophilic balance comprised between 12-15 and a drop point comprised between 40 and 46° C. 
     
     
         9 . A pharmaceutical composition according to  claim 1 , wherein the tocopherol derivative is vitamin E polyethylene glycol succinate. 
     
     
         10 . A pharmaceutical composition according to  claim 1 , wherein the surfactant A is vitamin E polyethylene glycol succinate wherein the chain length of the polyethylene glycol chain is 1000 or a lauroyl polyoxylglyceride with a HLB of 14 and a drop point of 44° C. 
     
     
         11 . A pharmaceutical composition according to  claim 1 , wherein surfactant B is a polyoxyethylene sorbitan fatty acid ester or propylene glycol monolaurate type II. 
     
     
         12 . A pharmaceutical composition according to  claim 1 , wherein the polyoxyethylene sorbitan fatty acid ester is selected from polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene 20 sorbitan monooleate and polyoxyethylene 20 sorbitan monoisostearate. 
     
     
         13 . A pharmaceutical composition according to  claim 1 , wherein the polyoxyethylene sorbitan fatty acid ester is polyoxyethylene 20 sorbitan monooleate. 
     
     
         14 . A pharmaceutical composition according to  claim 1 , comprising surfactant A and B in a ratio in weight from between 1:1: to 8:2. 
     
     
         15 . A pharmaceutical composition according to  claim 1  comprising
 9-ethyl-6,6dimethyl-8-(4-morpholin-4-yl-piperidin-1yl)-11-oxo-6,11-dihydro-5H-benzo[b]-carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof; 
 vitamin E polyethylene glycol succinate; and 
 polyoxyethylene 20 sorbitan monooleate. 
 
     
     
         16 . A pharmaceutical composition according to  claim 1 , wherein the active ingredients are dispersed in the matrix formed by surfactants A and B. 
     
     
         17 . A pharmaceutical composition according to  claim 1 , wherein the active ingredients are in a micronized form. 
     
     
         18 . A pharmaceutical composition according to  claim 1 , wherein the particle size of the micronized active ingredients is between 0.2 μm and 20 μm. 
     
     
         19 . A pharmaceutical composition according to  claim 1 , wherein the particle size of the micronized active ingredients is between 0.2 μm and 15 μm. 
     
     
         20 . A pharmaceutical composition according to  claim 1 , wherein the particle size of the micronized active ingredients is between 0.2 μm and 8 μm. 
     
     
         21 . A pharmaceutical composition according to  claim 1 , comprising only one active ingredients or pharmaceutically acceptable salt thereof. 
     
     
         22 . A pharmaceutical composition according to  claim 1 , wherein one of the active ingredient or its pharmaceutically acceptable salt thereof is class III or IV drug according to the Biopharmaceutical Classification System. 
     
     
         23 . A pharmaceutical composition according to  claim 1 , wherein one of the active ingredient or its pharmaceutically acceptable salt thereof is class IV drug according to the Biopharmaceutical Classification System. 
     
     
         24 . A pharmaceutical composition according to  claim 1 , wherein one of the active ingredients is an ALK inhibitor or pharmaceutically acceptable salt thereof. 
     
     
         25 . A pharmaceutical composition according to  claim 1 , wherein one of the active ingredient is 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof and is in crystalline form. 
     
     
         26 . A 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-1-yl)-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof. 
     
     
         27 . A 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-1-yl)-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof. 
     
     
         28 . A 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-1-yl)-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof. 
     
     
         29 . A 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-1-yl)-11-oxo-6, 11-dihydro-5H-benzo[b]carbazole-3-carbonitrile or pharmaceutically acceptable salt thereof. 
     
     
         30 . A pharmaceutical composition according to  claim 1  comprising 150 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 or pharmaceutically acceptable salt thereof. 
     
     
         31 . A pharmaceutical composition according to  claim 1 , characterized in that the drop point of the pharmaceutical composition is comprised between 35 and 39° C. 
     
     
         32 . A pharmaceutical composition according to  claim 1 , wherein the surfactant A has a HLB equal or greater than 12. 
     
     
         33 . A pharmaceutical composition according to  claim 1 , wherein wherein the surfactant B has a HLB equal or greater than 12. 
     
     
         34 . A pharmaceutical composition according to  claim 1 , wherein the surfactant A is a tocopherol derivative or a caprylocaproyl polyoxylglyceride, a lauroyl polyoxylglyceride, a linoleoyl polyoxylglyceride, a oleoyl polyoxylglyceride or a stearoyl polyoxylglyceride. 
     
     
         35 . A pharmaceutical composition according to  claim 1 , wherein the polyoxylglyceride has a drop point comprised between 40 and 48° C. 
     
     
         36 . A pharmaceutical composition according to  claim 1 , wherein the polyoxylglyceride has a drop point comprised between 40 and 46° C. 
     
     
         37 . A pharmaceutical composition according to  claim 1 , wherein the tocopherol derivative is a tocopherol polyethylene glycol ester. 
     
     
         38 . A pharmaceutical composition according to  claim 1 , wherein the tocopherol derivative is vitamin E polyethylene glycol succinate wherein the chain length of the polyethylene glycol chain is 1000. 
     
     
         39 . A pharmaceutical composition according to  claim 1 , wherein the lauroyl polyoxylglyceride has a HLB of 14 and a drop point of 44° C. 
     
     
         40 . A pharmaceutical composition according to  claim 1 , wherein the surfactant B is a caprylocaproyl polyoxylglyceride, a polyoxyethylene sorbitan fatty acid ester, propylene glycol monolaurate type I or propylene glycol monolaurate type II. 
     
     
         41 . A pharmaceutical composition according to  claim 1 , wherein the polyoxyethylene sorbitan fatty acid ester is selected from polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene 20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitan tristearate, polyoxyethylene 20 sorbitan monooleate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20 sorbitan trioleate and polyoxyethylene 20 sorbitan monoisostearate. 
     
     
         42 . A pharmaceutical composition according to  claim 1 , comprising surfactant A and B in a ratio in weight of 7:3. 
     
     
         43 . A pharmaceutical composition according to  claim 42  comprising
 4 to 50% in weight 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; 
 35 to 70% of vitamin E polyethylene glycol succinate; and 
 15 to 30% in weight of polyoxyethylene 20 sorbitan monooleate. 
 
     
     
         44 . A pharmaceutical composition according to  claim 1 , comprising
 20 to 225 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 or pharmaceutically acceptable salt thereof;   150 to 300 mg of vitamin E polyethylene glycol succinate; and   50 to 150 mg of polyoxyethylene 20 sorbitan monooleate.   
     
     
         45 . A pharmaceutical composition according to  claim 1 , comprising
 150 mg of free base equivalent of 9-ethyl-6,6-dimethyl-8-(4-morpholin-4-yl-piperidin-1-yl)11)-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile;   245 mg of vitamin E polyethylene glycol succinate; and   105 mg of polyoxyethylene 20 sorbitan monooleate.   
     
     
         46 . A pharmaceutical composition according to  claim 1 , comprising
 161 mg 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;   245 mg of vitamin E polyethylene glycol succinate; and   105 mg of polyoxyethylene 20 sorbitan monooleate.   
     
     
         47 . A pharmaceutical composition according to  claim 1 , comprising an active ingredient or a pharmaceutically acceptable salt thereof obtainable by
 a) melting surfactant A;   b) mixing melted surfactant A and liquid surfactant B; and   c) suspending the active ingredients or pharmaceutically acceptable salts thereof in the obtained mixture.   
     
     
         48 . A capsule comprising a pharmaceutical composition according to  claim 1 . 
     
     
         49 . A method for the treatment or prophylaxis of cancer, the method comprising administering an effective amount of the pharmaceutical composition according to  claim 1 . 
     
     
         50 . The method according to  claim 49 , wherein the cancer is a lung cancer. 
     
     
         51 . The method according to  claim 50 , wherein the cancer is a non-small cells lung cancer. 
     
     
         52 . A pharmaceutical composition according to  claim 51  for the treatment or prophylaxis of cancer. 
     
     
         53 . A pharmaceutical composition according to  claim 52 , wherein the cancer is a lung cancer. 
     
     
         54 . A pharmaceutical composition according to  claim 52 , wherein the cancer is non-small cells lung cancer. 
     
     
         55 - 58 . (canceled)

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