Ultrahigh-concentration biologic therapeutics enabled by spray drying with a glassy surfactant excipient

Biopharmaceuticals such as peptides and antibodies have become critical to health care. Despite their exceptional potency and specificity, biopharmaceuticals are prone to aggregation, which can limit efficacy. These therapies therefore often require low-concentration formulations as well as cold storage to maintain stability; however, high doses are required to treat many diseases. Most approved protein drug products are administered intravenously, imposing excessive burdens on patients. New approaches are needed to formulate proteins at high concentrations to enable less burdensome subcutaneous injection, preferably with an autoinjector that can be used directly by patients. To address this challenge, we report a subcutaneously injectable protein delivery platform composed of spray-dried protein microparticles suspended in a nonsolvent liquid carrier. These microparticles contain only biopharmaceuticals and a high-glass transition temperature polyacrylamide-derived copolymer excipient that affords key benefits over traditional excipients. First, the excipient improved stabilization of biopharmaceuticals through the spray-drying process, and second, it improved morphology and properties of the spray-dried particles, enhancing suspension injectability. We demonstrated with albumin, human immunoglobulin G, and an anti-COVID monoclonal antibody (IDBiologics) that this technology enables ultrahigh-concentration protein formulations (exceeding 500 milligrams per milliliter) that are injectable through standard needles with clinically relevant injection forces. In addition, experiments with two clinically relevant antibody drugs show that these ultrahigh-concentration formulations reduce required injection volumes without altering pharmacokinetics or efficacy in mice. This approach could nearly triple the number of commercial protein drugs amenable to subcutaneous administration, improving access to these critical biopharmaceuticals.

Background:

Patients with some cancers, autoimmune diseases, and metabolic disorders often endure time-consuming intravenous (IV) infusions to receive the best protein-based treatments available. Because these protein therapeutics require high doses to be effective and are typically formulated at low concentrations to remain stable, IV infusion has been, until now, the only option. Researchers at Stanford have developed a new delivery platform that allows these drugs to be stored and delivered in much higher concentrations.

Methods:

The researchers developed a polyacrylamide copolymer, abbreviated to MoNi, that has a particularly high glass transition temperature—meaning that it stays solid and glass-like at warmer temperatures, when typical drug additives would become soft and tacky. By mixing MoNi into water with a protein drug, aerosolizing it into tiny droplets, and evaporating the water—a process called spray drying—the researchers were able to create a fine powder made of tiny particles of protein, each encased in a layer of MoNi. The researchers then mixed this powder into a liquid that suspends the drug particles, but won't dissolve them. The MoNi coating prevents the particles from sticking together and keeps the proteins in a dry, stable state until the liquid suspension is injected into the body. The researchers tested their method on three different proteins—albumin, human immunoglobulin, and a monoclonal antibody treatment for COVID.

Results:

They were able to reach concentrations exceeding 500 mg/mL, meaning that fully half of the weight of the solution was a protein drug and it could still be injected smoothly and easily. This is more than double the concentration of typical liquid injections. The formulations also remained stable at a wider array of temperatures than typical liquid formulations, showing no signs of breaking down after 10 freeze-thaw cycles or when stored at elevated temperatures. "The mechanical properties of these dried particles matter a lot more than the chemical structure of the individual drug molecules, which means we can take almost any protein drug and formulate it this way," said Alexander Prossnitz.

Data Summary:

Concentrations exceeded 500 mg/mL, meaning fully half of the weight of the solution was a protein drug, which is more than double the concentration of typical liquid injections. The formulations showed no signs of breaking down after 10 freeze-thaw cycles or when stored at elevated temperatures.

Conclusions:

"This is a platform that potentially works with any biologic drug, so that we can inject it easily," said Eric Appel. "That takes these treatments from a several-hour ordeal at a clinic with an IV infusion to something you can do in seconds with an autoinjector at your house." Spray drying is a fairly common process in the pharmaceutical industry and MoNi has already been evaluated in several preclinical models with no adverse effects, so the researchers are optimistic that it will be able to be approved for clinical use. They have already licensed the technology to a local startup.

Practical Significance:

"If we can take an antibody that used to require an IV and let people inject it at home, that's a big improvement. It totally changes how patients are able to manage their own diseases."