New drug formulation turns intravenous treatments into a quick injection

(Press-News.org) 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. With this new formulation method, published Aug. 20 in Science Translational Medicine, many protein therapeutics could be injected quickly and smoothly with a standard syringe or autoinjector device.

“This is a platform that potentially works with any biologic drug, so that we can inject it easily,” said Eric Appel, an associate professor of materials science and engineering and senior author on the paper. “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.”

A protective polymer coating

When dissolved in high concentrations, many protein therapeutics tend to stick together, which makes them too viscous to inject, prone to forming aggregates that can cause immune responses, and potentially ineffective or even harmful once they get inside the body. Appel and his colleagues needed a way to pack proteins into a liquid at high concentrations but keep them stable and functional.

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.

“We ended up with something that looks like a candy-coated chocolate, where the protein is on the inside and our special polymer forms a solid, glassy coating on the outside,” Appel said.

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.

“Because the microparticles are spherical and have smooth surfaces, they’re able to roll over each other and still be able to go through tiny needles and be injected into a person, but you can hit really, really, high concentrations,” said Carolyn Jons, a doctoral student in Appel’s lab and co-first author on the paper.

The researchers tested their method on three different proteins – albumin, human immunoglobulin, and a monoclonal antibody treatment for COVID. They were able to reach concentrations exceeding 500 mg/mL, meaning that fully half of the weight of the solution was 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, a postdoctoral researcher and co-first author on the paper. “It ends up being a really big improvement over existing technologies.”

Faster, easier treatments

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, which is working to refine the process and eventually use it to develop new drug products.

“There are a lot of molecules that are promising drugs, but that you cannot turn into a drug product because they’re just too unstable given the constraints of currently available technologies,” Appel said. “This platform is really sophisticated in its ability to stabilize proteins and enable new drug products that would not normally be feasible, and which can be administered in a way that is much less burdensome.”

Their hope is that the next generation of protein-based drug treatments will be faster, easier, more effective for patients

“We know patients are willing to do injections themselves, especially if it’s in a simple autoinjector,” Prossnitz said. “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.”

Appel is an associate professor by courtesy of bioengineering and of pediatrics (endocrinology); a senior fellow of the Stanford Woods Institute for the Environment; a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Wu Tsai Human Performance Alliance, the Maternal & Child Health Research Institute, the Stanford Cancer Institute, and the Wu Tsai Neurosciences Institute; and a faculty fellow of Stanford Sarafan ChEM-H.

Additional Stanford co-authors of this research include graduate students Noah Eckman, Changxin Dong, and Ashley Utz.

This work was funded by the Stanford Maternal and Child Health Research Institute, the National Science Foundation, the Stanford University Medical Scientist Training Program, and a Terman Faculty Fellowship.

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