Development of a lyophilization formulation that preserves the biological activity of the platelet-inducing cytokine interleukin-11 at low concentrations.
Recombinant human interleukin-11 (rhIL-11) is a licensed biological therapeutic product in at least one country and is used to combat thrombocytopenia during chemotherapeutic regimens, as well as undergoing clinical trials for a range of other disorders. Following attempts to lyophilize IL-11 at low concentrations, it was clear that a significant loss of recoverable biological activity occurred. Investigation of a variety of factors, including the type of container in which the rhIL-11 was lyophilized, revealed that surface adsorption to glass was a major factor resulting in loss of activity of rhIL-11 in solution (> 40% reduction after 3 h at room temperature), in addition to losses of activity post-lyophilization. To overcome this problem, different formulations containing combinations of human serum albumin (HSA), trehalose and Tween-20 have been investigated. Two formulations were successful in entirely preserving the biological activity of rhIL-11 through lyophilization and subsequent reconstitution (potency estimates of formulated relative to original material being > or =0.97). Accelerated degradation studies, performed at intervals over a six-month period, demonstrated the stability of freeze-dried rhIL-11 using these formulations (predicted annual reduction in potency after storage at -20 degrees C < or =1.4%). In conclusion, we have developed a working combination of excipients (0.5% HSA, 0.1% trehalose and 0.02% Tween-20 in potassium phosphate buffer (pH 7.4)) to formulate a stable rhIL-11 freeze-dried product in glass containers, with no loss in potency. These findings should facilitate development of low dose rhIL-11 products and be an indicator of caution to those using this and other material with similar physical properties, without taking appropriate precautions to avoid losses through adsorption.
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Division of Immunobiology, NIBSC, South Mimms, Potters Bar, Hertfordshire.
Dawson
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Woollacott
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Thorpe
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Mire-Sluis
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D000327:Adsorption; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D004797:Enzyme-Linked Immunosorbent Assay; D005079:Excipients; D005612:Freeze Drying / Q000379:methods*; D005898:Glass; D006801:Humans; D017370:Interleukin-11 / Q000737:chemistry* / Q000494:pharmacology; D011136:Polysorbates; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D012709:Serum Albumin; D014199:Trehalose
D000970:Antineoplastic Agents; D005079:Excipients; D017370:Interleukin-11; D011136:Polysorbates; D011994:Recombinant Proteins; D012709:Serum Albumin; D014199:Trehalose; C105308:oprelvekin