Stable submicron protein particles : formation, properties, and pulmonary applications

The spray freezing into liquid (SFL) and thin film freezing (TFF) processes were utilized to produce 300 nm protein particles with surface areas on the order of 31 - 73 m²/g and 100% protein activities. Despite a cooling rate of ~10²-10³ K/s in SFL and TFF, the particle sizes and surface areas were similar to those observed in the widely reported process, spray freeze-drying (SFD), where cooling rates reach 10⁶ K/s. In SFL and TFF, the thin liquid channels between the ice domains were sufficiently thin and freezing rates of the thin channels sufficiently fast to achieve the similar particle morphologies. Therefore, the extremely rapid cooling rate in the SFD process was not necessary to form the desired submicron protein particles. In SFL and TFF the surface area/volume ratio of the gas-liquid formed on the liquid protein formulations (46-600 cm⁻¹) was 1-2 orders of magnitude lower than in SFD (6000 cm⁻¹), leading to far less protein adsorption and aggregation. This larger exposure to the gas-liquid interface resulted in lower protein activities in SFD. Although protein stabilities are high in conventional lyophilization, cooling rates are on the order of 1 K/min resulting in large 30 to 100 [mu]m sized particles. Thus, the intermediate cooling rate regime for SFL and TFF, relative to SFD and lyophilization, offers a promising route to form stable submicron protein particles of interest in pulmonary and parenteral delivery applications. The rod-shaped protein particles produced by SFL and TFF are beneficial for forming suspensions stable against settling in hydrofluoroalkanes (HFA) for pressurized metered dose inhaler (pMDI) delivery. The flocculated rods are templated by atomized HFA droplets that evaporate and shrink to form particles with optimal aerodynamic diameters for deep lung delivery. Fine particle fractions of 38-48% were achieved. This novel concept for forming stable suspensions of flocs of rod shaped particles, and templating and shrinking the flocs to produce particles for efficient pMDI deep lung delivery is applicable to a wide variety of drugs.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

The University of Texas at Austin

Year dc:date.issued

2007

Author dc:creator

• Engstrom, Joshua David, 1978-

Advisors dc:contributor.advisor

• Johnston, Keith P., 1955-
• Williams, Robert O., 1956-

• Protein particles

Statement dc:rights

• Copyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/2152/15975

OAI identifier oai:identifier

oai:repositories.lib.utexas.edu:2152/15975