Particle and pharmaceutical composition comprising an insoluble camptothecin compound with double core-shell structure and method for manufacturing the same

A method for manufacturing a population of freeze-dried particles with particle size of less than 1 μm, said freeze-dried particles comprising

• (a) an inner core comprising
• (a1) a hydrophobic camptothecin compound;
• and
• (a2) a hydrophilic camptothecin compound;
• and
• (b) an outer shell surrounding the inner core, said outer shell being formed of an amphiphilic block copolymer,
• wherein the method comprises steps:
• (i) mixing the hydrophobic camptothecin compound (a1) and the hydrophilic camptothecin compound (a2) in an aqueous solvent;
• (ii) mixing the resulting mixture of step (i) with the amphiphilic block copolymer in an aqueous solvent to form particles comprising the inner core (a) and the outer shell (b);
• and
• (iii) freeze-drying the particles obtained in step (ii) to give the population of freeze-dried particles with particle size less than 1 μm,
• wherein the amphiphilic block copolymer comprises a hydrophobic block and a hydrophilic block in a same chain;
• wherein the hydrophobic camptothecin compound (a1) is selected from the group consisting of 7-ethyl-10-hydroxycamptothecin (SN-38), camptothecin, 10-hydroxycamptothecin, a pharmaceutical acceptable salt thereof, and a combination thereof;
• wherein the hydrophilic camptothecin compound (a2) is selected from irinotecan, topotecan, belotecan, exatecan, lurtotecan, sinotecan, rubitecan, 9-nitrocamptothecin, 9-aminocamptothecin, gimatecan, BNP-1530, DB-67, BN-80915, BN-80927, a pharmaceutically acceptable salt thereof, a glucuronide metabolite thereof, and a glucuronide metabolite of the hydrophobic camptothecin-based compound, and a combination thereof;
• and
• wherein a proportion of the freeze-dried particles with a size more than 200 nm in the population obtained in step (iii) is 11.8% or less as measured by dynamic light scattering (DLS) method.