High concentration anti-TNFα antibody liquid formulations
The invention provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, which reduces pain associated with injection in a subject by at least about 50% when compared to injecting an otherwise identical formulation comprising at least one salt and/or at least one buffer. The invention also provides a liquid aqueous pharmaceutical formulation comprising a human anti-TNFa antibody, or antigen-binding portion thereof, having increased bioavailability upon subcutaneous administration into a subject. The formulation may comprise a therapeutic protein, such as a human anti-TNF-alpha antibody, or an antigen-binding portion thereof, or a biosimilar thereof.
1. A liquid aqueous formulation comprising:
(1) 100 mg/ml of adalimumab;
(2) 1.0 mg/ml of polysorbate-80; and,
(3) 42 mg/ml of mannitol;
wherein the formulation has a pH of 4.7 to 5.7 and does not contain a buffer or a salt, and wherein injection of the formulation into a human subject results in a Pain Visual Analog Scale (VAS) score of less than 1.0.
2. A liquid aqueous formulation comprising:
(1) 100 mg/ml of adalimumab;
(2) 1.0 mg/ml of polysorbate-80; and,
(3) 42 mg/ml of mannitol;
wherein the formulation has a pH of 4.7 to 5.7 and does not contain a buffer or a salt, and
wherein injection of the formulation reduces pain associated with the injection in a human subject by at least about 50% when compared to injection of an otherwise identical formulation that comprises a salt and/or a buffer.
3. A liquid aqueous formulation consisting essentially of:
(1) 100 mg/ml of adalimumab;
(2) 1.0 mg/ml of polysorbate-80; and
(3) 42 mg/ml of mannitol,
wherein the formulation has a pH of 4.7 to 5.7, and wherein injection of the formulation into a human subject results in a Pain Visual Analog Scale (VAS) score of less than 1.0.
4. The formulation of claim 2 , wherein the pain associated with the injection is assessed using a Pain Visual Analog Scale (VAS).
5. The formulation of claim 2 , wherein the otherwise identical formulation comprises a citrate phosphate buffer and sodium chloride.
6. A liquid aqueous formulation comprising:
(1) 100 mg/ml of adalimumab;
(2) 1.0 mg/ml of polysorbate-80; and,
(3) 42 mg/ml of mannitol;
wherein the formulation has a pH of 4.7 to 5.7, and wherein the formulation is stable up to about 30° C. for at least 6 days.
7. The formulation of claim 6 , wherein the formulation is stable up to about 30° C. for 10 days.
8. A liquid aqueous formulation comprising:
(1) 100 mg/ml of adalimumab;
(2) 1.0 mg/ml of polysorbate-80; and,
(3) 42 mg/ml of mannitol;
wherein the formulation has a pH of 4.7 to 5.7, and wherein the formulation has a characteristic selected from the group consisting of:
a) a conductivity of less than about 2 mS/cm;
b) a hydrodynamic diameter (D h ) which is at least about 50% less than the D h of the protein in a buffered solution at a given concentration; and
c) a hydrodynamic diameter (D h ) of less than about 4 nm.
9. A liquid aqueous formulation consisting essentially of 1.0 mg/ml of polysorbate-80 and 40 mg of adalimumab,
wherein the concentration of adalimumab is 100 mg/ml, and
wherein the formulation has a pH of 4.7 to 5.7, and
wherein the formulation provides increased bioavailability of the adalimumab to a human subject upon subcutaneous injection of the formulation relative to a formulation comprising a citrate phosphate buffer, sodium chloride, and mannitol.
10. A liquid aqueous formulation consisting essentially of 1.0 mg/ml of polysorbate-80 and 40 mg of adalimumab, wherein the formulation has an adalimumab concentration of 100 mg/ml a pH of 4.7-5.7, and
wherein the formulation provides increased bioavailability of adalimumab in a human subject upon subcutaneous injection of the formulation, such that adalimumab has an area under the curve, 0-360 minutes (AUC 0-360 ) greater than 1300 μg/hr/ml.
11. A pre-filled syringe or autoinjector device, comprising the formulation of any one of claims 1 - 7 , 8 , 9 and 10 .