Liposome composition
The present invention provides a novel liposome composition containing eribulin or its pharmacologically permissible salt, and its method of manufacture.
1. A pharmaceutical composition comprising a liposome:
wherein the internal phase of the liposome comprises (i) eribulin and/or a pharmaceutically acceptable salt thereof, (ii) citric acid and/or a citrate salt and (iii) at least one NH 4 + salt chosen from ammonium sulfate, ammonium citrate, and ammonium tartrate, and wherein the external phase of the liposome comprises no more than 0.4 mM NH 4 + salt.
2. A pharmaceutical composition according to claim 1 , wherein the external phase of the liposome comprises no more than 0.08 mM NH 4 + salt.
3. A method for preparing a pharmaceutical composition comprising eribulin and/or a pharmaceutically acceptable salt thereof comprising:
(a) preparing a liposome, wherein the internal phase of the liposome comprises (i) citric acid and/or a citrate salt and (ii) at least one NH 4 + salt chosen from ammonium sulfate, ammonium citrate, and ammonium tartrate;
(b) preparing a liposome dispersion liquid comprising the liposome prepared in (a) and wherein the liposome dispersion liquid does not substantially contain an ammonium salt in the liquid external to the liposome;
(c) preparing a solution comprising eribulin and/or a pharmaceutically acceptable salt thereof;
(d) combining the liposome dispersion lipid prepared in (b) with the eribulin solution prepared in (c);
(e) adjusting the pH of the liposome external phase to a pH in the range of pH 9.0 to pH 10.5 either before or after the combining of part (d); and
(f) enhancing the membrane permeability of the liposome to obtain a liposome composition comprising eribulin and/or a pharmaceutically acceptable salt thereof entrapped in the internal phase of the liposome;
wherein the external phase of the liposome comprises no more than 0.4 mM NH 4 + salt.
4. The method for preparing a pharmaceutical composition according to claim 3 , further comprising:
(g) adjusting the pH of the liposome external phase of the liposome composition obtained in (f) to a pH in the range pH 6 to 8.
5. A pharmaceutical liposome composition comprising eribulin and/or a pharmaceutically acceptable salt thereof obtained by the method for preparing according to claim 3 or 4 .