Stable Aqueous Formulations of Adalimumab

Abstract

The invention provides aqueous pharmaceutical adalimumab compositions suitable for long-term storage of adalimumab, methods of manufacture of these compositions, methods of administration, and kits containing same.

What is claimed is: 
     
         1 . An aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a buffer combination that comprises both a citrate buffer and a phosphate buffer; and (ii) the composition exhibits long term stability. 
     
     
         2 . The composition of  claim 1  comprising at least one buffer selected from the group consisting of histidine, succinate, phosphate, citrate, acetate, maleate and tartrate buffers, including combinations thereof, provided such combinations do not include a combination of citrate buffer and phosphate buffer. 
     
     
         3 . The composition of  claim 1  wherein the buffer comprises histidine. 
     
     
         4 . The composition of  claim 1  wherein the buffer comprises succinate. 
     
     
         5 . The composition of  claim 1  wherein the buffer comprises a combination of succinate buffer and histidine buffer. 
     
     
         6 . The composition of  claim 2  free or substantially free of citrate buffer. 
     
     
         7 . The composition of  claim 6  in which the sole buffer present therein is either (i) a histidine buffer; (ii) a succinate buffer; or (iii) a buffer combination consisting essentially of histidine buffer and succinate buffer. 
     
     
         8 . The composition of  claim 1  further comprising a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof. 
     
     
         9 . The composition of  claim 8  wherein the stabilizer comprises glycine. 
     
     
         10 . The composition of  claim 8  wherein the stabilizer comprises arginine. 
     
     
         11 . The composition of  claim 8  wherein the stabilizer comprises a combination of glycine and arginine. 
     
     
         12 . The composition of  claim 1  further comprising a polyol selected from the group consisting of mannitol, sorbitol and trehalose. 
     
     
         13 . The composition of  claim 1  further comprising a polysorbate or poloxamer surfactant. 
     
     
         14 . The composition of  claim 1  free or substantially free of polyol. 
     
     
         15 . The composition of  claim 1  free or substantially free of surfactant. 
     
     
         16 . The composition of  claim 1  free or substantially free of both surfactant and polyol. 
     
     
         17 . The composition of  claim 1  comprising (i) a histidine buffer, or a succinate buffer, or combination thereof; (ii) a polysorbate or poloxamer surfactant, or combination thereof; and (iii) one or both of the following:
 (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and 
 (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. 
 
     
     
         18 . The composition of  claim 17  comprising (a) and not (b). 
     
     
         19 . The composition of  claim 17  comprising (b) and not (a). 
     
     
         20 . The composition of  claim 17  comprising (a) and (b). 
     
     
         21 . The composition of  claim 17 , in which (i) histidine buffer, succinate buffer, or combinations of thereof constitute essentially the sole buffers in the composition; (ii); the stabilizer (if present) comprises glycine, arginine or combinations thereof; (iii) the polyol (if present) comprises mannitol; and (iv) the surfactant comprises at least one member of the group consisting of PS 80, PS 40, PS20, Pluronic F-68 and combinations thereof. 
     
     
         22 . The composition of  claim 21  in which the stabilizer further comprises up to about 100 mM sodium chloride. 
     
     
         23 . The composition of  claim 17  wherein the stabilizers may optionally include sucrose. 
     
     
         24 . The composition of  claim 21  wherein the amount of adalimumab is about 50 to about 150 mg/ml; the amount of buffer is up to about 50 mM; the amount of stabilizer (if present) is up to about 300 mM; the amount of polyol (if present) is up to about 300 mM; and the amount of surfactant is in the range of about 0.01 to about 0.1 wt. %. 
     
     
         25 . The composition of  claim 24 , in which the stabilizer is not present. 
     
     
         26 . The composition of  claim 23 , in which the amount of polyol is present in an amount approximately at or greater than about 200 mM. 
     
     
         27 . The composition of  claim 24  in which the polyol is not present. 
     
     
         28 . The composition of  claim 23  in which both the polyol and the stabilizer are present, and wherein the combined amount of the stabilizer and the polyol is about 150 to 300 mM. 
     
     
         29 . An aqueous, buffered pharmaceutical composition exhibiting long term stability, said composition comprising: (i) adalimumab; (ii) a buffer selected from the group consisting of histidine buffer, succinate buffer, and combinations thereof; (iii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iv) one or both of the following:
 (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and   (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof.   
     
     
         30 . The composition of  claim 29  further comprising a buffer selected from the group consisting of phosphate, citrate, acetate, maleate and tartrate buffers, including combinations thereof. 
     
     
         31 . The composition of  claim 29  wherein the composition does not contain a buffer combination comprising a citrate buffer and a phosphate buffer. 
     
     
         32 . The composition of  claim 29  wherein the composition does not contain a citrate buffer and, optionally, wherein histidine buffer, or the combination of histidine and succinate buffer, is/are present as essentially the sole buffer(s) in the composition. 
     
     
         33 . The composition of  claim 29  comprising (a) and not (b). 
     
     
         34 . The composition of  claim 29  comprising (b) and not (a). 
     
     
         35 . The composition of  claim 29  comprising (a) and (b). 
     
     
         36 . The composition of  claim 29 , in which (i); the stabilizer (if present) comprises glycine, arginine or combinations thereof; (ii) the polyol (if present) comprises mannitol; and (iii) the surfactant comprises at least one member of the group consisting of PS 80, PS 40, PS20, Pluronic F-68 and combinations thereof. 
     
     
         37 . The composition of  claim 36  in which the stabilizer further comprises up to about 100 mM sodium chloride. 
     
     
         38 . The composition of  claim 36  wherein the amount of adalimumab is about 50 to about 150 mg/ml; the amount of buffer is up to about 50 mM; the amount of stabilizer (if present) is up to about 300 mM; the amount of polyol (if present) is up to about 300 mM; and the amount of surfactant is in the range of about 0.01 to about 0.1 wt. % 
     
     
         39 . The composition of  claim 38 , in which the stabilizer is not present. 
     
     
         40 . The composition of  claim 39 , in which the polyol is present in an amount approximately at or greater than about 200 mM. 
     
     
         41 . The composition of  claim 38  in which both the polyol and the stabilizer are present, and wherein the combined amount of the stabilizer and the polyol is about 150 to 300 mM. 
     
     
         42 . The composition of  claim 30  free or substantially free of either (i) citrate buffer; or (ii) citrate/phosphate buffer combinations. 
     
     
         43 . The composition of  claim 38  containing the stabilizer but not the polyol. 
     
     
         44 . An aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of a polyol; and (ii) the composition exhibits long term stability. 
     
     
         45 . The composition of  claim 44  comprising at least one buffer selected from the group consisting of histidine, succinate, phosphate, citrate, acetate, maleate and tartrate buffers, including combinations thereof. 
     
     
         46 . The composition of  claim 45  wherein the buffer comprises histidine. 
     
     
         47 . The composition of  claim 45  wherein the buffer comprises succinate. 
     
     
         48 . The composition of  claim 45  wherein the buffer comprises a combination of succinate buffer and histidine buffer. 
     
     
         49 . The composition of  claim 45  in which essentially the sole buffer present therein is either (i) a histidine buffer; (ii) a succinate buffer; or (iii) a buffer combination consisting essentially of histidine buffer and succinate buffer. 
     
     
         50 . The composition of  claim 45  further comprising a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof. 
     
     
         51 . The composition of  claim 50  wherein the stabilizer comprises glycine. 
     
     
         52 . The composition of  claim 50  wherein the stabilizer comprises arginine. 
     
     
         53 . The composition of  claim 50  wherein the stabilizer comprises a combination of glycine and arginine. 
     
     
         54 . The composition of  claim 45  further comprising a polysorbate or poloxamer surfactant. 
     
     
         55 . The composition of  claim 44  comprising (i) a histidine buffer or succinate buffer, or combinations thereof; (ii) a polysorbate or poloxamer surfactant, or combinations thereof; and (iii) a stabilizer selected from glycine, arginine, methionine, EDTA, sodium chloride, and combinations thereof. 
     
     
         56 . The composition of  claim 55 , in which (i) histidine buffer, succinate buffer, or combinations thereof constitute essentially the sole buffers in the composition; (ii); the stabilizer comprises glycine, arginine or combinations thereof; and (iii) the surfactant comprises at least one member of the group consisting of PS 80, PS 40, PS20, Pluronic F-68 and combinations thereof. 
     
     
         57 . The composition of  claim 56  in which the stabilizer further comprises up to about 100 mM sodium chloride. 
     
     
         58 . The composition of  claim 56  wherein the amount of adalimumab is about 50 to about 150 mg/ml; the amount of buffer is up to about 50 mM; the amount of stabilizer is up to about 300 mM; and the amount of surfactant is in the range of about 0.01 to about 0.1 wt. %. 
     
     
         59 . The composition of  claim 45 , free or substantially free of either (i) citrate buffer; or (ii) citrate/phosphate buffer combinations. 
     
     
         60 . The composition of  claim 45  free or substantially free of surfactant. 
     
     
         61 . An aqueous, buffered pharmaceutical composition comprising adalimumab and a buffer, wherein (i) the composition is free or substantially free of surfactant; and (ii) the composition exhibits long term stability. 
     
     
         62 . The composition of  claim 61  comprising at least one buffer selected from the group consisting of histidine, succinate, phosphate, citrate, acetate, maleate and tartrate buffers, including combinations thereof. 
     
     
         63 . The composition of  claim 62  wherein the buffer comprises histidine. 
     
     
         64 . The composition of  claim 62  wherein the buffer comprises succinate. 
     
     
         65 . The composition of  claim 62  wherein the buffer comprises a combination of succinate buffer and histidine buffer. 
     
     
         66 . The composition of  claim 62  in which essentially the sole buffer present therein is either (i) a histidine buffer; (ii) a succinate buffer; or (iii) a buffer combination consisting essentially of histidine buffer and succinate buffer. 
     
     
         67 . The composition of  claim 62  further comprising a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof. 
     
     
         68 . The composition of  claim 67  wherein the stabilizer comprises glycine. 
     
     
         69 . The composition of  claim 67  wherein the stabilizer comprises arginine. 
     
     
         70 . The composition of  claim 67  wherein the stabilizer comprises a combination of glycine and arginine. 
     
     
         71 . The composition of  claim 61  further comprising a polyol. 
     
     
         72 . The composition of  claim 62  comprising (i) a histidine buffer or succinate buffer, or combinations thereof; and one or both of the following:
 (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and/or 
 (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. 
 
     
     
         73 . The composition of  claim 72  comprising (a) and not (b). 
     
     
         74 . The composition of  claim 72  comprising (b) and not (a). 
     
     
         75 . The composition of  claim 72  comprising (a) and (b). 
     
     
         76 . The composition of  claim 72 , in which (i) histidine buffer, succinate buffer, or combinations of thereof constitute essentially the sole buffers in the composition; (ii); the stabilizer (if present) comprises glycine, arginine or combinations thereof; and (iii) the polyol (if present) comprises mannitol. 
     
     
         77 . The composition of  claim 76  in which the stabilizer further comprises up to about 100 mM sodium chloride. 
     
     
         78 . The composition of  claim 76  wherein the amount of adalimumab is about 50 to about 150 mg/ml; the amount of buffer is up to about 50 mM; the amount of stabilizer (if present) is up to about 300 mM; and the amount of polyol (if present) is up to about 300 mM. 
     
     
         79 . The composition of  claim 61  free or substantially free of either (i) citrate buffer; or (ii) citrate/phosphate buffer combinations. 
     
     
         80 . The composition of  claim 62  free or substantially free of polyol. 
     
     
         81 . An aqueous pharmaceutical composition comprising adalimumab wherein: (i) the composition is free or substantially free of buffer; and (ii) the composition exhibits long term stability. 
     
     
         82 . The composition of  claim 81  further comprising one or both of the following:
 (a) a stabilizer selected from the group consisting of glycine, alanine, glutamate, arginine, methionine, EDTA, sodium chloride, sodium sulfate, metal ions, and combinations thereof; and/or 
 (b) a polyol selected from sorbitol, mannitol, and trehalose, or combinations thereof. 
 
     
     
         83 . The composition of  claim 82  comprising (a) and not (b). 
     
     
         84 . The composition of  claim 82  comprising (b) and not (a). 
     
     
         85 . The composition of  claim 82  comprising (a) and (b). 
     
     
         86 . The composition of  claim 82  wherein the stabilizer (if present) comprises glycine, arginine, or a combination thereof. 
     
     
         87 . The composition of  claim 82  wherein the polyol (if present) comprises mannitol. 
     
     
         88 . The composition of  claim 82  wherein the amount of adalimumab is about 50 to about 150 mg/ml; the amount of stabilizer is up to about 300 mM; and the amount of polyol (if present) is up to about 300 mM. 
     
     
         89 . The composition of  claim 82  wherein the combined amount of stabilizer and polyol is in the range of about 150 to 300 mM. 
     
     
         90 . A method for enhancing long term stability in an aqueous, buffered adalimumab formulation, comprising one or more of the steps of:
 (a) incorporating histidine buffer, succinate buffer, or a combination thereof, in the formulation based on empirical data indicating that such buffers contribute to the stability of the formulation to a greater extent than other buffers or buffer combinations; or   (b) incorporating glycine, arginine or a combination thereof as stabilizers in the formulation, based upon empirical data indicating that such stabilizer contribute to the stability of the formulation to a greater extent than other stabilizers; or   (c) substantially excluding the presence of buffer or buffer combinations comprising citrate buffer, based upon empirical data indicating that such buffer or buffer combinations perform poorly in terms of stabilizing the formulation in comparison to other buffers.   
     
     
         91 . The method of  claim 90 , wherein the resulting formulation exhibits long term stability comparable to or better than commercially available adalimumab formulations marketed under the trademark Humira®. 
     
     
         92 . A formulation of adalimumab exhibiting long term stability consisting of, or consisting essentially of: adalimumab, histidine buffer, glycine and polysorbate 80. 
     
     
         93 . A formulation of adalimumab exhibiting long term stability consisting of, or consisting essentially of: adalimumab, histidine buffer, mannitol and polysorbate 80.