Emulsion formulations of multikinase inhibitors

Abstract

Compositions comprising a therapeutically effective amount of a multikinase inhibitor, such as nintedanib or axitinib or pazopanib, are provided, wherein the composition is an emulsion, such as a nanoemulsion, with lipophilic carrier (e.g., castor oil), a polyoxyl oil (e.g., polyolyl-35 castor oil), optionally with a surfactant (e.g., polysorbate 80), optionally with a cyclic oligosaccharide, such as a cyclodextrin (e.g., 2-hydroxypropyl-beta-cyclodextrin), as a solubilizer. Methods for treating ocular conditions with the compositions are also provided.

1 . An emulsion comprising:
 a therapeutically effective amount of a multikinase inhibitor;   a polyoxyl oil;   a lipophilic carrier;   and   water.   
     
     
         2 . The emulsion of  claim 1 , wherein the multikinase inhibitor is selected from afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, vatalanib, vemurafenib, or combinations thereof. 
     
     
         3 . The emulsion of  claim 2 , wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. 
     
     
         4 . The emulsion of  claim 1 , further comprising a solubilizer. 
     
     
         5 . The emulsion of  claim 1 , wherein the solubilizer is a cyclic polysaccharide. 
     
     
         6 . The emulsion of  claim 1 , wherein the polyoxyl oil is a polyoxyl castor oil. 
     
     
         7 . The emulsion  claim 6 , wherein the polyoxyl castor oil is polyoxyl-40 castor oil, polyoxyl-35 castor oil, or a combination thereof. 
     
     
         8 . The emulsion of  claim 1 , further comprising a surfactant selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polyoxyl-40-stearate, tocopherol, and combinations thereof. 
     
     
         9 . The emulsion of  claim 1 , wherein the multikinase inhibitor is nintedanib, the solubilizer is 2-hydroxypropyl-beta-cyclodextrin, the lipophilic carrier is castor oil, and the polyoxyl oil is polyoxyl-35 castor oil, or a combination thereof. 
     
     
         10 . (canceled) 
     
     
         11 . An emulsion comprising:
 about 0.005% to about 2% w/w of a multikinase inhibitor;   about 0.1% to about 1% w/w of a poloxyl oil;   about 0.05% to about 1% w/w of a lipophilic carrier;   about 5% to about 15% w/w of a solubilizer; and   water.   
     
     
         12 . The emulsion of  claim 11 , wherein the multikinase inhibitor is present in an amount from about 0.1% to about 0.5% w/w. 
     
     
         13 . The emulsion of  claim 11 , wherein the polyoxyl oil is present in an amount from about 0.3% to about 0.7% w/w. 
     
     
         14 . The emulsion of  claim 11 , wherein the lipophilic carrier is present in an amount from about 0.1% to about 0.5% w/w. 
     
     
         15 . The emulsion of  claim 11 , wherein the solubilizer is present in an amount from about 8% to about 12% w/w. 
     
     
         16 . The emulsion of  claim 11 , wherein the multikinase inhibitor is present in an amount of about 0.2% w/w. 
     
     
         17 . The emulsion of  claim 11 , wherein the polyoxyl oil is present in an amount of about 0.5% w/w. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The emulsion of  claim 11 , wherein the multikinase inhibitor is selected from the group consisting of afatinib, amuvatinib, axitinib, cabozantinib, canertinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, foretinib, gefitinib, golvatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, vandetanib, vatalanib, vemurafenib, or combinations thereof. 
     
     
         21 . The emulsion of  claim 11 , wherein the multikinase inhibitor is selected from axitinib, nintedanib, and pazopanib. 
     
     
         22 . The emulsion of  claim 11 , wherein the solubilizer is a cyclic polysaccharide. 
     
     
         23 . The emulsion of  claim 22 , wherein the cyclic polysaccharide is selected from the group consisting of cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, 2-hydroxypropyl-alpha-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin, 2-hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin and combinations thereof. 
     
     
         24 . The emulsion of  claim 11 , wherein the solubilizer comprises 2-hydroxypropyl-beta-cyclodextrin. 
     
     
         25 . An emulsion comprising:
 about 0.2% w/w of nintedanib;   about 0.5% w/w of a polyoxyl castor oil;   about 0.25% w/w of castor oil;   about 10% w/w of 2-hydroxypropyl-beta-cyclodextrin; and   water.   
     
     
         26 . A method of treating an ocular condition, comprising administering the emulsion of  claim 1  to an eye of a subject.