Etanercept formulations exhibiting marked reduction in sub-visible particles
The invention provides stabilized aqueous pharmaceutical etanercept compositions suitable for long-term storage of etanercept, with substantial reduction in sub-visible particles, and methods of manufacture of these compositions, methods of administration, and articles of manufacture.
1. An aqueous pharmaceutical composition stabilized for long term storage comprising:
etanercept at 25 to 75 mg/ml;
a surfactant at 0.01 to 0.05% w/v;
a metal ion selected from the group consisting of calcium, magnesium and zinc, wherein the metal ion is present at 2 mM to 20 mM;
a buffer selected from the group consisting of phosphate, histidine, citrate, maleate, tartrate, succinate, tris-(hydroxymethyl)-aminomethane, and bicarbonate;
wherein the composition has a pH of between 6 and 7, and the composition is free of arginine.
2. The stabilized composition of claim 1 wherein the surfactant is selected from the group consisting of polysorbate 80, polysorbate 60, polysorbate 40 and polysorbate 20.
3. The stabilized composition of claim 1 wherein the surfactant comprises polysorbate 80.
4. The stabilized composition of claim 1 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μm; (ii) less than 3500 particles having size of about 2-5 μm and (iii) less than 700 particles/ml having size of about 1-2 μm.
5. The stabilized composition of claim 1 wherein; etanercept is present at 25 to 50 mg/ml; the metal ion is magnesium; and wherein the composition further comprises sucrose or trehalose at 0.5 to 6 wt %; NaCl at 25 to 150 mM; and the buffer is sodium phosphate at 1 to about 30 mM.
6. The stabilized composition of claim 1 wherein the metal ion is magnesium and wherein the composition further comprises NaCl at 0 to 100 mM; and the buffer is sodium phosphate at 1 to 30 mM.
7. The stabilized composition of claim 1 wherein the composition is characterized by:
(a) an SEC analysis at T 4 of greater than 90 wt % monomer content; and less than 3 wt % aggregate(s) content; and
(b) an HIC analysis at T 2 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and
(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80, wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.
8. A vial or injection device containing the etanercept formulation of claim 1 in final dosage form.
9. A vial or injection device containing the etanercept formulation of claim 5 in final dosage form.
10. A vial or injection device containing the etanercept formulation of claim 6 in final dosage form.
11. The stabilized composition of claim 5 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μm; (ii) less than 3500 particles having size of about 2-5 μm and (iii) less than 700 particles/ml having size of about 1-2 μm.
12. The stabilized composition of claim 6 wherein the composition has (i) less than 2500 particles/ml having a size of 5-10 μm; (ii) less than 3500 particles having size of about 2-5 μm and (iii) less than 700 particles/ml having size of about 1-2 μm.
13. The stabilized composition of claim 5 wherein the composition is characterized by:
(a) an SEC analysis at T 4 of greater than 90 wt % monomer content; and less than 3 wt % aggregate(s) content; and
(b) an HIC analysis at T 2 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and
(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.
14. The stabilized composition of claim 6 wherein the composition is characterized by:
(a) an SEC analysis at T 4 of greater than 90 wt % monomer content; and less than 3 wt % aggregate(s) content; and
(b) an HIC analysis at T 2 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 4 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %; and
(c) an HIC analysis at T4 wherein the amount of the composition represented by peak 1 of the HIC chromatogram is less than 3 wt %; the amount of the composition represented by peak 2 of the HIC chromatogram is greater than 80 wt %; and the amount of the composition represented by peak 3 of the HIC chromatogram is less than 20 wt %.
15. The stabilized composition of claim 1 , wherein a number of sub-visible particles per ml of the formulation having size of 1-10 μm is at least about 50% lower than in the same composition having no surfactant.
16. The composition of claim 1 , wherein said composition has less than about 1 wt % aggregate(s) content as determined by size exclusion chromatography after 4 weeks storage at 25° C.
17. An aqueous pharmaceutical composition comprising:
etanercept at about 50 mg/ml;
up to 0.05% w/v surfactant;
2 mM to 20 mM metal ion;
about 25 mM to about 100 mM NaCl;
10 mM to 200 mM of a phosphate or citrate buffer;
wherein the composition has a pH of between 6 and 7,
wherein the composition is free of arginine,
wherein said composition has less than about 1 wt % aggregate(s) content as determined by size exclusion chromatography after 4 weeks storage at 25° C., and
wherein the formulation has:
(i) less than about 2500 particles/ml having a size of about 5-10 μm;
(ii) less than about 3500 particles having size of about 2-5 μm, and
(iii) less than about 700 particles/ml having size of about 1-2 μm.