Adenovirus formulations

Patent metadata

Field	Value
Publication number	US-9974737-B2
Application number	US-201414916539-A
Country	US
Kind code	B2
Filing date	Sep 16, 2014
Priority date	Sep 19, 2013
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

This disclosure provides pharmaceutical adenovirus formulations, in particular, liquid pharmaceutical formulations comprising adenoviruses.

First claim

The invention claimed is:

1. A formulation for adenoviruses, the formulation comprising:
a) a recombinant adenovirus;
b) a citrate buffer having a concentration of between about 5 mM and about 30 mM,
c) hydroxypropyl-beta-cyclodextrin (HBCD);
d) a salt; and
e) a non-ionic detergent;
wherein said formulation has a pH of between about 5.5 and about 6.5, and
wherein the formulation is a liquid formulation, and
wherein the formulation is configured for parenteral use.

2. A formulation for adenoviruses, the formulation comprising:
a) a recombinant adenovirus;
b) a citrate buffer having a concentration of between about 5 mM and about 30 mM;
c) hydroxypropyl-beta-cyclodextrin (HBCD), wherein the concentration of HBCD is between about 1% (w/w) to about 10% (w/w);
d) a salt; and
e) a non-ionic detergent;
wherein the formulation has a pH of between about 5.5 and about 6.5, and
wherein the formulation is a liquid formulation.

3. A formulation for adenoviruses, the formulation comprising:
a) a recombinant adenovirus;
b) a citrate buffer having a concentration of between about 5 mM and about 30 mM;
c) hydroxypropyl-beta-cyclodextrin (HBCD);
d) a salt, wherein the salt is sodium chloride; and
e) a non-ionic detergent;
wherein the formulation has a pH of between about 5.5 and about 6.5, and
wherein the formulation is a liquid formulation.

4. The formulation according to claim 3 , wherein the sodium chloride concentration is between about 20 mM and about 200 mM.

5. A formulation for adenoviruses, the formulation comprising:
a) a recombinant adenovirus;
b) a citrate buffer having a concentration of between about 5 mM and about 30 mM;
c) hydroxypropyl-beta-cyclodextrin (HBCD);
d) a salt; and
e) a non-ionic detergent, wherein the non-ionic detergent is Polysorbate-80;
wherein the formulation has a pH of between about 5.5 and about 6.5, and
wherein the formulation is a liquid formulation.

6. The formulation according to claim 5 , wherein the Polysorbate-80 concentration is between 0.005% (w/w) to 0.5% (w/w).

7. A formulation for adenoviruses, wherein said formulation has a pH between about 5.7 and about 6.3, and comprises:
recombinant adenovirus;
citrate at a concentration of between about 5 mM and about 30 mM;
hydroxypropyl-beta-cyclodextrin (HBCD) at a concentration of between about 1% (w/w) and 10% (w/w);
sodium chloride (NaCl) at a concentration of between about 20 mM and about 200 mM; and
Polysorbate-80 at a concentration of between 0.01% (w/w) and 0.05% (w/w),
wherein the formulation is a liquid formulation.

8. A formulation for adenoviruses, wherein the formulation comprises:
a) a recombinant adenovirus;
b) a citrate buffer having a concentration of between about 5 mM and about 30 mM;
c) hydroxypropyl-beta-cyclodextrin (HBCD);
d) a salt;
e) a non-ionic detergent; and
f) a 2-carbon or 4-carbon alcohol,
wherein the formulation has a pH of between about 5.5 and about 6.5,
wherein the formulation is a liquid formulation.

9. The formulation according to claim 8 , wherein the 2-carbon or 4-carbon alcohol is ethanol.

10. The formulation according to claim 9 , wherein the ethanol concentration in the formulation is between 0.1% (w/w) to 1% (w/w).

11. The formulation according to claim 7 , further comprising: ethanol at a concentration of between 0.2% (w/w) and 0.6% (w/w).

12. The formulation according to claim 11 , wherein said formulation has a pH of 6, and comprises
citrate at a concentration of 20 mM;
HBCD at a concentration of 5% (w/w);
NaCl at a concentration of 75 mM;
Polysorbate-80 at a concentration of 0.02% (w/w); and
ethanol at a concentration of 0.4% (w/w).

13. The formulation according to claim 7 , wherein said formulation has a pH of between 5.9 and 6.2, and comprises
citrate at a concentration of between 10 and 25 mM;
HBCD at a concentration of between 4% (w/w) and 6% (w/w);
NaCl at a concentration of between 70 mM and 100 mM; and
Polysorbate-80 at a concentration of between 0.018% (w/w) and 0.035% (w/w); and further comprises
ethanol at a concentration of between 0.3% (w/w) and 0.45% (w/w).

14. A method of using the formulation of claim 1 to preserve a recombinant adenovirus, the method comprising:
utilizing the recombinant adenovirus in the formulation, and
storing said formulation at a temperature of between 2° C. and 8° C.

15. A formulation for adenoviruses, wherein the formulation has a pH of between 5.7 and 6.3, and comprises:
a recombinant adenovirus;
a citrate buffer at a concentration of between about 5 mM and about 30 mM;
hydroxypropyl-beta-cyclodextrin (HBCD) at a concentration of between about 1% (w/w) and about 10% (w/w);
sodium chloride (NaCl) at a concentration of between 20 mM and 200 mM;
Polysorbate-80 at a concentration of between 0.01% (w/w) and 0.05% (w/w); and
ethanol at a concentration of between 0.2% (w/w) and 0.6% (w/w),
wherein the formulation is liquid.

16. The formulation according to claim 15 , wherein the formulation has a pH of 6, and comprises:
citrate at a concentration of 20 mM;
HBCD at a concentration of 5% (w/w);
NaCl at a concentration of 75 mM;
Polysorbate-80 at a concentration of 0.02% (w/w); and
ethanol at a concentration of 0.4% (w/w).

17. The formulation of claim 15 , wherein the formulation is free from magnesium chloride.

18. The formulation of claim 1 , wherein the formulation is free from magnesium chloride.

19. The formulation of claim 15 , wherein the formulation has a pH between 5.8 and 6.2, and comprises:
citrate at a concentration of between 15 and 25 mM;
HBCD at a concentration ranging between 3% (w/w) and 8% (w/w);
NaCl at a concentration between 50 mM and 100 mM;
Polysorbate-80 at a concentration of between 0.01% (w/w) and 0.03% (w/w); and
ethanol at a concentration between 0.2% (w/w) and 0.6% (w/w).

20. The formulation of claim 19 , which comprises:
HBCD at a concentration of 5% (w/w);
NaCl at a concentration of 75 mM, and
ethanol at a concentration of 0.4% (w/w).

21. A formulation for adenoviruses, the formulation comprising:
a recombinant adenovirus;
a citrate buffer having a concentration of between about 5 mM and about 30 mM;
hydroxypropyl-beta-cyclodextrin (HBCD) between about 1% (w/w) to about 10% (w/w);
a salt selected from the group consisting of sodium chloride (NaCl), calcium chloride (CaCl 2 ), and manganese chloride (MnCl 2 ); and
a non-ionic detergent selected from the group consisting of Polysorbate-80, Polysorbate-60, Polysorbate-40, and Polysorbate 20;
wherein the formulation has a pH of between about 5.5 and about 6.5, and
wherein the formulation is a liquid formulation.

22. The formulation of claim 21 , wherein the salt is sodium chloride.

23. The formulation of claim 22 , wherein the sodium chloride concentration is between about 20 mM and about 200 mM.

24. The formulation of claim 21 , wherein the non-ionic detergent is Polysorbate-80.

25. The formulation of claim 24 , wherein the Polysorbate-80 concentration is between 0.005% (w/w) to 0.5% (w/w).

26. A liquid formulation for adenoviruses, the liquid formulation comprising:
a recombinant adenovirus;
citrate at a concentration of between about 5 mM and about 30 mM to buffer the pH of the liquid formulation to between about 5.5 and about 6.5;
hydroxypropyl-beta-cyclodextrin (HBCD);
a salt; and
a polysorbate;
wherein the formula

Assignees

• Crucell Holland Bv
• Janssen Vaccines & Prevention Bv

Inventors

• Adriaansen Janik

Classifications

• A61K2039/5256

  expressing foreign proteins · CPC title

• A61K47/02

  Inorganic compounds · CPC title

• C12N2710/10311

  Mastadenovirus, e.g. human or simian adenoviruses · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K9/08 Primary

  Solutions {(composition of solutions A61K47/00)} · CPC title