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Investigating high-concentration monoclonal antibody powder suspension in nonaqueous suspension vehicles for subcutaneous injection.

Journal of pharmaceutical sciences (2012-09-25)
Mayumi Bowen, Nick Armstrong, Yuh-Fun Maa
ABSTRACT

Developing high-concentration monoclonal antibody (mAb) liquid formulations for subcutaneous (s.c.) administration is challenging because increased viscosity makes injection difficult. To overcome this obstacle, we investigated a nonaqueous powder suspension approach. Three IgG1 mAbs were spray dried and suspended at different concentrations in Miglyol® 840, benzyl benzoate, or ethyl lactate. Suspensions were characterized for viscosity, particle size, and syringeability; physical stability was visually inspected. Suspensions generally outperformed liquid solutions for injectability despite higher viscosity at the same mAb concentrations. Powder formulations and properties had little effect on viscosity or injectability. Ethyl lactate suspensions had lowest viscosity (<20 cP) and lowest syringe injection glide force (<15 N) at mAb concentrations as high as 333 mg/mL (500 mg powder/mL). Inverse gas chromatography analysis indicated that the vehicle was the most important factor impacting suspension performance. Ethyl lactate rendered greater heat of sorption (suggesting strong particle-suspension vehicle interaction may reduce particle-particle self-association, leading to low suspension viscosity and glide force) but lacked the physical suspension stability exhibited by the other vehicles. Specific mixtures of ethyl lactate and Miglyol® 840 improved overall performance in high mAb concentration suspensions. This study demonstrated the viability of high mAb concentration (>300 mg/mL) in suspension formulations for s.c. administration.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzyl benzoate, ReagentPlus®, ≥99.0%
Sigma-Aldrich
Ethyl lactate, natural, ≥98%, FCC, FG
Sigma-Aldrich
Benzyl benzoate, natural, ≥99%, FCC, FG
Sigma-Aldrich
(−)-Ethyl L-lactate, 98%
Sigma-Aldrich
Ethyl lactate, ≥98%, FCC, FG
Supelco
Benzyl benzoate, Pharmaceutical Secondary Standard; Certified Reference Material
Supelco
Benzyl benzoate, analytical standard
Sigma-Aldrich
Benzyl benzoate, ≥99%, FCC, FG
Sigma-Aldrich
(−)-Ethyl L-lactate, photoresist grade, ≥99.0%
Sigma-Aldrich
Benzyl benzoate, meets USP testing specifications
Sigma-Aldrich
(+)-Ethyl D-lactate, ≥99.0% (sum of enantiomers, GC)
Sigma-Aldrich
(−)-Ethyl L-lactate, purum, ≥98.0% (sum of enantiomers, GC)
Sigma-Aldrich
Benzyl benzoate, tested according to Ph. Eur.