Nanoparticles loaded with chemotherapeutic antitumoral drug

Abstract

The invention relates to new therapeutic approaches for treating cancer, in particular hepatocellular carcinoma, with Nanoparticles loaded with a chemotherapeutic antitumoral agent. In particular, it relates to the treatment of cancer by administration of said Nanoparticles by intravenous infusion for at least 2 hours in order to prevent toxicological side effects and increase the benefit/risk ratio of the treatment.

1 - 15 . (canceled) 
     
     
         16 . A method for reducing, in a cancer patient, the occurrence or severity of macroscopic lung injuries induced by nanoparticles that comprise:
 at least one chemotherapeutic antitumoral agent that is doxorubicin or a pharmaceutically acceptable salt thereof,   at least one poly(alkylcyanoacrylate), and   at least one cyclodextrin,   the method comprising administering the nanoparticles to the cancer patient by intravenous infusion for at least 2 hours; wherein   the macroscopic lung injuries induced by the nanoparticles do not occur at the time of infusion;   the dosage of doxorubicin or pharmaceutically acceptable salt thereof administered by the intravenous infusion is from about 10 to about 30 mg/m 2 ; and   the method treats the cancer of the cancer patient.   
     
     
         17 . The method according to  claim 16 , wherein the nanoparticles are administered by intravenous infusion for between 2 and 24 hours. 
     
     
         18 . The method according to  claim 16 , wherein the nanoparticles are administered by intravenous infusion for between 4 and 12 hours. 
     
     
         19 . The method according to  claim 16 , wherein the nanoparticles are administered by intravenous infusion for about 6 hours. 
     
     
         20 . The method according to  claim 16 , wherein the at least one poly(alkylcyanoacrylate) is a poly(C 6 -C 8  alkylcyanoacrylate). 
     
     
         21 . The method according to  claim 16 , wherein the at least one poly(alkylcyanoacrylate) is a polyisohexylcyanoacrylate. 
     
     
         22 . The method according to  claim 16 , wherein:
 the at least one chemotherapeutic antitumoral agent is at a concentration from 0.01 to 200 mg/g of the nanoparticles,   the at least one cyclodextrin is in an amount of from 0.1% to 70% w/w of the nanoparticles, and   the at least one poly(alkylcyanoacrylate) is in an amount of from 1% to 25% w/w of the nanoparticles.   
     
     
         23 . The method according to  claim 22 , wherein the at least one chemotherapeutic antitumoral agent is at a concentration from about 1 to about 50 mg/g of the nanoparticles. 
     
     
         24 . The method according to  claim 22 , wherein the at least one cyclodextrin is in an amount of from about 1% to about 30% w/w of the nanoparticles. 
     
     
         25 . The method according to  claim 22 , wherein the at least one poly(alkylcyanoacrylate) is in an amount of from about 5% to about 15% w/w of the nanoparticles. 
     
     
         26 . The method according to  claim 16 , wherein the dosage of doxorubicin administered by the intravenous infusion is from about 20 to about 30 mg/m 2 . 
     
     
         27 . The method according to  claim 16 , wherein the dosage of doxorubicin administered by the intravenous infusion is about 30 mg/m 2 . 
     
     
         28 . The method according to  claim 16 , wherein the cancer is a hepatocellular carcinoma. 
     
     
         29 . The method according to  claim 28 , wherein the cancer is an advanced hepatocellular carcinoma after failure or intolerance to sorafenib. 
     
     
         30 . The method according to  claim 16 , wherein the cancer is a solid tumor. 
     
     
         31 . The method according to  claim 16 , wherein the cancer is a hematopoietic tumor. 
     
     
         32 . The method according to  claim 16 , wherein the macroscopic lung injuries induced by the nanoparticles are fatal or life-threatening macroscopic lung injuries. 
     
     
         33 . The method according to  claim 16 , wherein
 the nanoparticles are administered by intravenous infusion for about 6 hours;   the dosage of doxorubicin or pharmaceutically acceptable salt thereof administered by the intravenous infusion is from about 20 to about 30 mg/m 2 ; and   the cancer is an advanced hepatocellular carcinoma after failure or intolerance to sorafenib.   
     
     
         34 . The method according to  claim 16 , wherein the method reduces the occurrence of macroscopic lung injuries such that the macroscopic lung injuries are prevented. 
     
     
         35 . The method according to  claim 16 , wherein the macroscopic lung injuries induced by the nanoparticles occur two or more days after infusion. 
     
     
         36 . A method for reducing, in a cancer patient, the mortality associated with macroscopic lung injuries induced by nanoparticles that comprise:
 at least one chemotherapeutic antitumoral agent that is doxorubicin or a pharmaceutically acceptable salt thereof,   at least one poly(alkylcyanoacrylate), and   at least one cyclodextrin,   the method comprising administering the nanoparticles to the cancer patient by intravenous infusion for at least 2 hours; wherein   the macroscopic lung injuries induced by the nanoparticles do not occur at the time of infusion;   the dosage of doxorubicin or pharmaceutically acceptable salt thereof administered by the intravenous infusion is from about 10 to about 30 mg/m 2 ; and   the method treats the cancer of the cancer patient.   
     
     
         37 . A method for reducing, in a cancer patient, the occurrence of fatal respiratory distress induced by nanoparticles that comprise:
 at least one chemotherapeutic antitumoral agent that is doxorubicin or a pharmaceutically acceptable salt thereof,   at least one poly(alkylcyanoacrylate), and   at least one cyclodextrin,   the method comprising administering the nanoparticles to the cancer patient by intravenous infusion for at least 2 hours; wherein   the fatal respiratory distress induced by the nanoparticles does not occur at the time of infusion;   the dosage of doxorubicin or pharmaceutically acceptable salt thereof administered by the intravenous infusion is from about 10 to about 30 mg/m 2 ; and   the method treats the cancer of the cancer patient.   
     
     
         38 . A liquid pharmaceutical composition comprising a suspension of nanoparticles that comprise:
 at least one chemotherapeutic antitumoral agent that is doxorubicin or a pharmaceutically acceptable salt thereof,   at least one poly(alkylcyanoacrylate), and   at least one cyclodextrin,   wherein the composition is formulated for administering a dosage of about 10 to about 30 mg/m 2  of doxorubicin or a pharmaceutically acceptable salt thereof to a cancer patient by intravenous infusion for an infusion period of at least 2 hours;   wherein administering the dosage for the infusion period reduces, relative to bolus infusion, the occurrence or severity of macroscopic lung injuries induced by the nanoparticles that do not occur at the time of infusion.   
     
     
         39 . A continuous infusion system comprising a liquid pharmaceutical composition that comprises a suspension of nanoparticles that comprise:
 at least one chemotherapeutic antitumoral agent that is doxorubicin or a pharmaceutically acceptable salt thereof,   at least one poly(alkylcyanoacrylate), and   at least one cyclodextrin,   wherein the system is configured for administering a dosage of about 10 to about 30 mg/m 2  of doxorubicin or a pharmaceutically acceptable salt thereof to a cancer patient by intravenous infusion for an infusion period of at least 2 hours;   wherein administering the dosage for the infusion period reduces, relative to bolus infusion, the occurrence or severity of macroscopic lung injuries induced by the nanoparticles that do not occur at the time of infusion.