Formation of Stable Submicron Protein Particles by Thin Film Freezing

Life Sciences : Drug Delivery

Available for licensing

Inventors

  • Keith Johnston, Ph.D. , Chemical Engineering
  • Joshua Engstrom, Ph.D. , Chemical Engineering

Background/unmet need

Therapeutic peptides and proteins such as insulin are difficult to deliver through the digestive tract, so they are usually delivered by injection. Inhalation offers a much simpler, painless and effective alternative. Highly porous micron-sized aggregates of protein nanoparticles have the optimal aerodynamic diameter for delivery deep into the lung where they rapidly dissolve.

The ability to produce high-surface-area stable submicron and micron-sized protein particles creates new opportunities for depot and pulmonary delivery applications. As shown in previous work, the submicron protein particles can be uniformly encapsulated into bioerodable polymers to decrease burst release. The stable submicron protein particles also have many advantages for pulmonary delivery. Although particles need to have an aerodynamic diameter between 1-3 µm for efficient deep lung delivery, the submicron particles can form porous nano-aggregated microparticles that can be effectively delivered to the lung. The highly porous aerosolized particles have advantages over dense micron-sized powders, including more rapid dissolution in the lung leading to decreased long-term immune responses.

Submicron particles may be precipitated from aqueous solution by a variety of processes including spray-drying (SD), spray freeze-drying (SFD) and spray freezing into liquids (SFL). In SFD, an aqueous protein solution is atomized into the cold gas above a cryogenic liquid. The relatively slow rate of freezing allows proteins to adsorb to the large gas-liquid interface where they denature and aggregate. The same problem of protein denaturation at the gas-liquid interface is inherent to SD.

Invention Description

Thin Film Freezing (TFF) is a new process for producing stable submicron protein particles. Droplets of aqueous protein solutions containing the protein and excipients are made to fall on a rotating stainless steel drum. The drum is hollow and filled with a cryogen. Upon impact, the droplets spread out into thin films that freeze in less than a second. The frozen films are removed from the drum by a steel blade mounted on the rotating drum surface and then lyophilized. The submicron protein particles have properties which are advantageous for depot and pulmonary delivery applications. The TFF process is also of interest for preparing protein solids for storage stability.

SFL is a process in which a spray nozzle is immersed under the surface of a cryogenic liquid. The rapid freezing and the elimination of a gas-liquid interface results in less protein denaturation and aggregation. SFL and TFF are highly complementary processes for making stable protein particles.

UT has two continuous units that can produce up to 100 grams per day. The process equipment is relatively simple and based on large-scale processes used in chemical engineering.

Benefits/Advantages

  • Free from the protein denaturation problems of SD or SFD
  • Avoids the costs associated with sterilizing and disposing of the cryogenic liquids used in SFD

Development Stage

Lab/bench prototype

IP Status

  • 1 foreign patent application filed
  • 2 foreign patents issued
  • 1 U.S. patent application filed
  • 1 U.S. patent issued: 8,968,786
  • 1 U.S. patent issued: 9,622,974