Stability of nonaqueous suspension formulations of plasma derived factor IX and recombinant human alpha interferon at elevated temperatures.
OBJECTIVE
To identify a suitable nonaqueous, parenterally acceptable suspending vehicle whereby a therapeutic protein is delivered as a stable flowable powder, making it amenable to delivery from sustained delivery systems maintained at body temperature.


METHODS
Formulations of plasma derived Factor IX (pdFIX) and recombinant human alpha interferon (rhalpha-IFN) were formulated as dry powders, suspended in various vehicles (perfluorodecalin, perfluorotributylamine, methoxyflurane, polyethylene glycol 400, soybean oil, tetradecane or octanol) and stored at 37 degrees C. Stability was assessed by size exclusion chromatography, reverse phase chromatography, ion exchange chromatography, and bioassay, and was compared to the stability of dry powder formulations stored at 37 degrees C and -80 degrees C.


RESULTS
PdFIX was stable when stored at 37 degrees C as a dry powder, or when the dry powder was suspended in the pharmaceutically acceptable vehicles perfluorodecalin or perfluorotributylamine. Suspensions of the powder in other pharmaceutically/parenterally acceptable vehicles such as soybean oil or PEG 400 resulted in aggregation and loss of bioactivity. A dry powder formulation of rhalpha-IFN suspended in perfluorodecalin was also stable at 37 degrees C.


CONCLUSIONS
This study shows the potential utility of perfluorinated hydrocarbons as nonaqueous suspending vehicles for long term in-vivo delivery of therapeutic proteins.
Biopharmaceutical Research and Development, ALZA Corporation, Palo Alto, California 94303-0802, USA. azulyn@worldnet.att.net
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Knepp
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Muchnik
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Oldmark
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Kalashnikova
D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry*; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D004355:Drug Stability; D005164:Factor IX / Q000008:administration & dosage / Q000737:chemistry*; D005466:Fluorocarbons / Q000008:administration & dosage / Q000737:chemistry; D006358:Hot Temperature; D006801:Humans; D007370:Interferon Type I / Q000008:administration & dosage* / Q000737:chemistry*; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage* / Q000737:chemistry*; D011208:Powders; D011994:Recombinant Proteins; D013535:Suspensions
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D005466:Fluorocarbons; D007370:Interferon Type I; D014677:Pharmaceutical Vehicles; D011208:Powders; D011994:Recombinant Proteins; D013535:Suspensions; C008807:perfluorotributylamine; C008805:perfluorodecalin; D005164:Factor IX