Development of a nanosuspension for iv administration: From miniscale screening to a freeze dried formulation

Abstract

The aim was to develop a nanosuspension of the poorly soluble BI XX. The nanosuspension is intended for intravenous (iv) administration in preclinical studies and should not cause any unwanted side effects. Thus, only stabilizers that are accepted for iv application should be used and isotonicity, euhydria and the absence of living microorganisms were targeted. Suspensions were prepared in a ball-mill (mixing mill MM 400 from Retsch). There were various vials used as containers; HPLC-vials were used for the small scale screening of stabilizers and injection vials for preparation of larger quantities of the nanosuspensions. Particle size distribution was analyzed by laser diffraction measurement (Mastersizer 2000). Lyophilization was used for processing of the suspensions (Christ freeze dryer). Stable nanosuspensions (d90 remained <1μm up to 7days) were prepared with several FDA-accepted stabilizers. Freeze drying was evaluated for one formulation containing 2% of the API, 0.5% of arginine and 4% of mannitol. The particle size distribution before freeze drying and after re-dispersion was comparable. After milling for 2h, no living microorganisms were detected in the nanosuspension. Various FDA accepted excipients were identified which resulted in stable nanosuspensions of BI XX. The most stable formulation was successfully freeze dried. It was proven that milling in the ball-mill decreases the presence of living microorganisms.