Pharmaceutical composition comprising particles comprising a complex of a double-stranded polyribonucleotide and a polyalkyleneimine
The present invention relates to compositions comprising particles, each of said particles comprising a complex of at least one double-stranded polyribonucleotide, such as polyinosinic-polycytidylic acid [poly(I:C)], and at least one linear polyalkyleneimine. The particles are also characterized by their monomodal diameter distribution and z-average diameter within specific ranges. The present invention additionally relates to use of said compositions as medicaments, in particular for the treatment of a cell growth disorder characterized by abnormal growth of human or animal cells, as well as to processes for the preparation of said compositions.
1. An aqueous composition comprising one or more particles, wherein
(a) each particle comprises a complex of at least one double-stranded polyribonucleotide, or a salt or solvate thereof, and at least one polyalkyleneimine, or a salt and/or solvate thereof, wherein
(i) the double-stranded polyribonucleotide is polyinosinic-polycytidylic acid [poly(I:C)], wherein
at least 60% of the double-stranded polyribonucleotides have at least 850 base pairs,
at least 70% of the double-stranded polyribonucleotides have between 400 and 5000 base pairs, and
between 20% and 45% of the double-stranded polyribonucleotides have between 400 and 850 base pairs; and
(ii) the polyalkyleneimine comprises at least 95% linear polyethyleneimines,
wherein the average molecular weight of the linear polyalkyleneimine is between 17 and 23 kDa and the polydispersity index is <1.5, and
wherein the ratio of the number of moles of nitrogen of the polyalkyleneimine to the number of moles of phosphorus of the double-stranded polyribonucleotide is between 2.5 and 5.5; and
(b) the one or more particles each have a z-average diameter measured according to ISO 22412:2008 of between 30 nm and 150 nm.
2. The composition according to claim 1 , wherein at least 99% of the one or more particles have a diameter distribution below 600 nm.
3. The composition according to claim 1 , wherein the composition has a zeta potential of between 35 and 50 mV, measured according to ISO 13099-2:2012.
4. The composition according to claim 1 , wherein the linear polyalkyleneimine is a water-soluble homo-polyalkyleneimine or a hetero-polyalkyleneimine.
5. The composition according to claim 1 , wherein the polyinosinic-polycytidylic acid [poly(I:C)] concentration is at least 0.5 mg/ml.
6. The composition according to claim 1 , wherein the composition further comprises
(a) at least one pharmaceutically acceptable carrier, organic solvent, excipient and/or adjuvant; and/or
(b) at least one compound selected from an organic compound, an inorganic compound, a nucleic acid, an aptamer, a peptide and a protein.
7. The composition according to claim 1 , further comprising glucose or mannitol at a concentration of between 1 and 10% weight/volume of the composition.
8. The composition according to claim 1 , wherein the composition further comprises:
(a) a pH of between 2 and 4; and/or
(b) an osmolarity of between 200 and 600 mOsm/kg.
9. The composition according to claim 1 , wherein the complex contains at least 0.5 mg of polyinosinic-polycytidylic acid [poly(I:C)] per ml of the total volume of the composition.
10. The composition according to claim 1 , wherein the composition further comprises glucose or mannitol in a concentration of between 1 and 10% weight/volume of the composition.
11. The composition according to claim 1 , wherein the one or more particles has a mono-modal diameter distribution.
12. A method for manufacturing the aqueous composition according to claim 1 , comprising:
(a) providing (i) a first aqueous solution of at least one double-stranded polyribonucleotide, or a salt or solvate thereof, and (ii) a second aqueous solution of at least one linear polyalkyleneimine, or a salt or solvate thereof;
(b) filtering each respective first and second aqueous solution of step (a) independently through a filter having a pore diameter of less than or equal to 500 nm to form a respective resulting sterilized solution; and
(c) mixing each respective resulting sterilized solution in a mixing chamber by simultaneous addition of each respective resulting sterilized solution into the mixing chamber, optionally by injection, at a rate of greater than or equal to 1 ml/min, to form the aqueous composition of claim 1 .
13. The method according to claim 12 , further comprising:
(d) filtering the resulting aqueous composition of step (c) through a filter having a pore diameter of less than or equal to 600 nm to form a filtrate, or centrifuging the resulting aqueous composition of step (c) at greater than or equal to 22480 m/s 2 to form a supernatant.
14. The method of claim 13 , further comprising:
(e) lyophilising the filtrate or supernatant of step (d).
15. The method according to claim 12 , wherein each of or both aqueous solutions of step (a) further comprise a pharmaceutically acceptable carrier, organic solvent, excipient and/or adjuvant.