The Development of Thin-Film Freezing and Its Application to Improve Delivery of Biologics as Dry Powder Aerosols

Abstract

While the formulation of pharmaceuticals as liquids is common practice, powders are associated with enhanced stability, avoidance of the cold chain, lower dosing requirements, and more convenient administration. These are particularly critical for proteins, as they are expensive and complicated to manufacture. Powders also have improved aerosol properties for pulmonary delivery. Conventional techniques for formulating powders include spray-drying, shelf freeze-drying, spray freeze-drying, and spray freezing into liquid, but they produce powders with poor aerosol performance and/or activity due to suboptimal powder properties. Thin-film freezing (TFF) is a new cryogenic technique that can engineer highly porous, brittle, powder matrices with excellent aerosol performance properties and stability. Herein, we describe TFF in comparison to other cryogenic techniques. Physical properties of TFF powders such as morphology, moisture sorption, stability, solubility, and dissolution, as well as aerosol properties are discussed. In addition, factors that significantly affect the physical and aerosol properties of dry powders prepared by TFF, such as solids content, drug loading, solvent system, excipient, and dry powder delivery device, are analyzed. Finally, we provide evidence supporting the applicability of using TFF to prepare dry powder formulations of protein-based pharmaceuticals, enabling their cold chain-free storage as well as efficient pulmonary delivery.

Performance Testing for Dry Powder Inhaler Products: Towards Clinical Relevance

“…Particles prepared through thin film formation occur through dropwise deposition of the drug solution or suspension onto a frozen surface to form a thin film, which is then subject to lyophilization for solvent removal. The result is a porous, brittle, interconnected matrix that can be dispersed to small particles upon aerosolization (Hufnagel S. et al, 2022). This process has been used to prepare various aerosol particles containing both small and large molecules, including tacrolimus, lactate dehydrogenase, and lysozyme (Engstrom J.D.…”

Progress on Thin Film Freezing Technology for Dry Powder Inhalation Formulations

“…In the case of biological products and vaccines, the challenges include storage and handling at a lowered temperature [7,8]. TFF technology converts drugs into a more solubilized and stable powder form, which also addresses the major challenges mentioned above [4]. Thin film freezing to produce pharmaceutical powders is an evolution of earlier freezing processes on cold surfaces to form films.…”

“…However, all approaches in the context of biologics result in some extent of the biologics' agglomeration, denaturation, and/or loss of functionality. Additionally, these techniques result in powder particles with limited surface area, low efficiency, and/or a wide size distribution, which are not suitable for pulmonary delivery by inhalation, especially of biologics [4].…”

Accelerated mass transfer from frozen thin films during thin-film freeze-drying

“…Thin-film freeze-dried powders (TFFD powders) are often brittle and highly porous, making them suitable for dry powder aerosolization (Wang et al, 2021). The TFF process and applications have been recently reviewed by Hufnagel et al (Hufnagel et al, 2022). Importantly, the total surface area of the frozen thin films is significantly larger than if the same volume of bulk liquid is frozen in a container/vial on the shelf of a freeze dryer.…”