METHOD OF REDUCING IMMUNOGENICITY OF DRUG PRODUCTS
The present invention is directed to methods for reducing immunogenicity of a drug product, utilizing filling a container wherein the filled container has no headspace. The present invention is further directed to methods for stabilizing an aqueous drug substance solution by filling a container with the aqueous drug substance solution wherein the filled container has no headspace. The present invention is further directed to formulations of drug substances with reduced immunogenicity.
1 . A method of reducing immunogenicity of an aqueous drug substance solution, the method comprising placing an aqueous drug substance solution in a container with zero headspace, wherein the aqueous drug substance solution has a reduced immunogenicity when administered to a patient in need thereof.
2 . The method of claim 1 , wherein said method comprises the following steps:
a) providing a container with an open end;
b) providing an aqueous drug substance solution;
c) filling the container via the open end with the aqueous drug substance solution;
d) purging the container with at least one soluble gas;
e) inserting a stopper into the open end of the container creating a headspace of soluble gas; and
f) storing the container,
wherein the stopper can move within the container while maintaining an airtight seal; and the storage step results in the container having no visibly detectable headspace, and wherein the aqueous drug substance solution has a reduced immunogenicity when administered to a patient in need thereof.
3 . The method of claim 1 , wherein the aqueous drug substance solution in a container with zero headspace is less immunogenic when administered to a patient in need thereof than the aqueous drug substance solution in a container with a headspace.
4 . The method of claim 1 , wherein the aqueous drug substance solution in the container with zero headspace has fewer subvisible particles than the aqueous drug substance solution in a container with a headspace.
5 . The method of claim 1 , wherein the aqueous drug substance solution in the container with zero headspace has fewer subvisible particles and is less immunogenic when administered to a patient in need thereof, than a composition comprising the aqueous drug substance solution in a container with a headspace.
6 . The method of claim 1 , wherein the aqueous drug substance solution in the container with zero headspace is less immunogenic after the container with zero headspace has been shipped, transported, stored, dropped, handled, or incubated than a composition comprising the aqueous drug substance in a container with headspace subject to the same conditions.
7 . The method of claim 2 , wherein prior to the purging step or prior to inserting the stopper, the container is subjected to a pressure vacuum.
8 . The method of claim 2 , wherein the soluble gas is carbon dioxide.
9 . The method of claim 2 , wherein the container is stored for at least 4 hours.
10 . The method of claim 2 , wherein the storing step is conducted at a temperature below the temperature at which the stoppering step occurred.
11 . The method of claim 2 , comprising the steps:
a) providing a container with an open end;
b) providing an aqueous drug substance solution;
c) filling the container via the open end with the aqueous drug substance solution;
d) degassing the container and aqueous drug substance solution via a pressure vacuum;
e) purging the container with at least one soluble gas;
f) optionally repeating the degassing and purging steps;
g) degassing via a pressure vacuum and while under vacuum, inserting a stopper into the open end of the container creating a headspace of soluble gas; and
h) storing the container.
12 . The method of claim 2 , wherein the container is a syringe or a cartridge.
13 . The method of claim 2 , wherein the aqueous drug substance solution comprises a biologic or non-biologic drug substance.
14 . The method of claim 13 , wherein the biologic drug substance is a protein.
15 . The method of claim 13 , wherein the biologic drug substance is an antibody.
16 . The method of claim 15 , wherein the antibody is adalimumab.
17 . The method of claim 13 , wherein the aqueous drug substance solution is free or substantially free of surfactant, polyol, sugar, buffer, salt, stabilizer, or combinations thereof.
18 . A container closed with a stopper, wherein the container comprises a stable aqueous drug substance solution within the container and zero headspace, wherein the volume of the aqueous drug substance solution is less than 100% of the container volume, and wherein the stable aqueous drug substance solution has a reduced immunogenicity when administered to a patient in need thereof.
19 . The container of claim 18 , wherein the container is prepared as follows:
a) providing a container with an open end;
b) providing an aqueous drug substance solution;
c) filling the container via the open end with the aqueous drug substance solution;
d) purging the container with at least one soluble gas;
e) inserting a stopper into the open end of the container creating a headspace of soluble gas; and
f) storing the container,
wherein the stopper can move within the container while maintaining an airtight seal; and the storage step results in the container having no visibly detectable headspace, and wherein the aqueous drug substance solution has a reduced immunogenicity when administered to a patient in need thereof.
20 . The container of claim 18 , wherein the container is a syringe or a cartridge.
21 . The container of claim 18 , wherein the aqueous drug substance solution is an aqueous non-biologic molecule solution.
22 . The container of claim 18 , wherein the aqueous drug substance solution is a pharmaceutical composition comprising an antibody.
23 . The container of claim 18 , wherein the aqueous drug substance solution is free or substantially free of surfactant, polyol, sugar, buffer, salt, stabilizer, or combinations thereof.
24 . The container of claim 18 , wherein the aqueous drug substance solution comprises an amino acid.
25 . The container of claim 18 , wherein the aqueous drug substance solution comprises a salt.
26 . The container of claim 22 , wherein the antibody is adalimumab.
27 . The container of claim 26 , wherein the aqueous drug substance solution is free or substantially free of surfactant, polyol, sugar, buffer, salt, stabilizer, or combinations thereof.
28 . The container of claim 26 , wherein the aqueous drug substance solution comprises an amino acid.
29 . The container of claim 28 , wherein the amino acid is selected from alanine, lysine, threonine, valine, leucine, isoleucine, histidine, glycine, methionine, serine, proline, and arginine and combinations thereof.
30 . The container of claim 26 , wherein the aqueous drug substance solution comprises a salt.
31 . The container of claim 26 , wherein the aqueous drug substance solution comprises an amino acid and a salt.
32 . The container of claim 18 , wherein the aqueous drug substance solution is stable for at least one week at 40° C. or two weeks at 25° C.
33 . The container of claim 18 , wherein the aqueous drug substance solution is free or substantially free of surfactant; and has stability comparable to, or better than, an aqueous solution of the same drug substance that contains surfactant in a container with a headspace.
34 . The container of claim 18 , wherein the aqueous drug substance solution has fewer subvisible particles than the same aqueous drug substance solution in a container with a headspace.
35 . The container of claim 18 , wherein the aqueous drug substance solution is isotonic.
36 . A machine for performing the method of claim 2 , wherein the machine comprises
a) means for filling a container with an aqueous drug substance solution;
b) means for purging the container with a soluble gas; and
c) means for inserting a stopper into the open end of the container.
37 . The machine of claim 36 , wherein the purging, stoppering, and optionally, filling of the container occurs within a sealed chamber.
38 . The machine of claim 36 , wherein the machine is programmed to perform at least one step of the method.
39 . A machine for performing the method of claim 7 , wherein the machine comprises
a) means for filling a container with an aqueous drug substance solution;
b) means for applying a vacuum to the container and aqueous drug substance solution;
c) means for purging the container with a soluble gas; and
d) means for inserting a stopper into the open end of the container.
40 . The machine of claim 39 , wherein the degassing, purging, stoppering, and optionally, filling of the container occurs within a sealed chamber.
41 . The machine of claim 39 , wherein the machine is programmed to perform at least one step of the method.
42 . An aqueous drug substance solution in a container with zero headspace, wherein the aqueous drug substance solution comprises:
a) adalimumab,
b) stabilizer comprising an amino acid, and
c) salt;
wherein the aqueous drug substance solution is free of buffer, polyol, and surfactant; has a pH of about 5 to about 6; and has a conductivity of greater than 3.0 mS/cm, and wherein the aqueous drug substance solution has a reduced immunogenicity when administered to a patient in need thereof.
43 . The aqueous drug substance solution of claim 42 , wherein the stabilizer comprises two or more amino acids.
44 . The aqueous drug substance solution of claim 43 , wherein the stabilizer comprises glycine and arginine.
45 . The aqueous drug substance solution of claim 43 , wherein the stabilizer comprises glycine, arginine, and threonine.
46 . The aqueous drug substance solution of claim 42 , wherein the salt comprises a divalent cation.
47 . The aqueous drug substance solution of claim 46 , wherein the divalent cation is selected from the group consisting of Ca 2+ , and Mg 2+ .
48 . The aqueous drug substance solution of claim 42 , wherein the pH is about 5.2.
49 . The aqueous drug substance solution of claim 42 , wherein the aqueous drug substance solution has osmolality of about 180 to 420 mOsM; is suitable for administration to a subject as a single dosage; has a concentration of adalimumab in the range of 30 to about 50 mg/ml; and the single dosage contains about 10 to 80 mg of adalimumab.
50 . The aqueous drug substance solution of claim 49 , wherein the concentration of adalimumab is about 50 mg/ml and the single dosage is about 40 mg.
51 . The aqueous drug substance solution of claim 42 , wherein the composition is stable for one or more of:
a) 7 days at −40° C.,
b) 14 days at −40° C.,
c) 30 days at −40° C.,
d) 7 days at 5° C.,
e) 14 days at 5° C.,
f) 30 days at 5° C.,
g) 7 days at 25° C.,
h) 14 days at 25° C.,
i) 30 days at 25° C.,
j) 7 days at 40° C.,
k) 14 days at 40° C., or
l) 30 days at 40° C.
52 . The aqueous drug substance solution of claim 42 , wherein the composition has stability comparable to, or greater than, a Humira® formulation.
53 . The aqueous drug substance solution of claim 42 , wherein the composition has fewer subvisible particles than a Humira® formulation.