Delivering Life-Saving Drugs to the Children Who Need Them Most

by Donald Gilpin | Photos by David Kelly Crow, Princeton University

Robert Prud’homme, Princeton University professor of chemical and biological engineering, has written more than 200 publications and filed more than 25 patents in a 40-year career that has been distinguished by deep scientific knowledge combined with an affinity for practical problem-solving and a dedication to collaboration.

Those qualities have recently enabled him and his team of six graduate students and postdoctoral students to tackle the challenges of producing thousands of tons of drugs to combat malaria and deadly bacteria afflicting hundreds of thousands of children in the developing world.

To meet the needs of these children and the requirements of the Gates Foundation, one of his collaborators on this project, these drugs have to be inexpensive, between 25 and 50 cents a dose; easy to produce in huge volume; stable for long periods in hot and humid conditions; and both powerful and soluble enough to be administered by mouth in a single dose.

“I’m an engineer,” Prud’homme said, emphasizing his practical approach as a problem-solver. “Engineering is taking science and applying it to solve problems. That’s the way I look at what we’re trying to do. We’re taking the best science, whether it’s polymer science or biology science, and trying to solve these medical problems in global health or delivery of medicines. That’s engineering. That’s what we do.”

15-Year Process

Prud’homme, a professor at Princeton since 1979 and the inaugural director of Princeton’s program in engineering biology, started working in this area of technology, encasing medicine in extremely small particles called nanoparticles, about 15 years ago.

He had been to Germany a few years before that where he was introduced to a process used by the BASF Corporation, the largest chemical producer in the world, to color the flesh of farm salmon. “It was a commercial process,” Prud’homme described. “There wasn’t any scientific interest in polymers, but they asked if we wanted to be involved.”

Over the next few years, Prud’homme and his team at Princeton developed a technology called flash nanoprecipitation, a complex technique to encapsulate drugs in a polymer-based delivery vehicle.

“I’m a polymer person, so my whole career was polymers, how polymers assemble,” Prud’homme said. “I worked in oil recovery, in consumer products like shampoos and things, so that was all my early career. We just accidentally stumbled onto polymers as a solution to the problem of poorly soluble drugs, and that research has bloomed into what most of our lab is working on now, in collaboration with the Gates Foundation.”

Prud’homme’s $2.1M grant in 2016 was one of just three awarded by the Gates Foundation that year for new technologies in the development of global health drugs.

Problem Solving

Noting the value of his perspective from the world of engineering and practical problem-solving, Prud’homme added, “If my career had always been in drug delivery and cell biology, I don’t think we would have come up with this technique. It took my career in polymers and fluid mechanics and flow to know how to run this process and invent this, and because I come from a polymer background, all of our work is collaborative.”

He added, “Using what we have learned over the past 15 years has enabled us in the last three years to do things that no one else can do in this field.”

Over a 12-year period before 2015, the team developed its flash nanoprecipitation technique in working on what Prud’homme calls “high value drugs,” drugs to combat cancer and tuberculosis, “drugs where you can afford expensive components.” Then, in 2015, “the Gates Foundation approached us and said they knew about our technology and wanted us to apply that to low-cost technology to make things cheaply, and also instead of injectable drugs, they asked, ‘Can you use it for oral drugs, for an oral delivery system?'”

Prud’homme continued, “I said, ‘I think I can,’ so Gates funded us and we worked on low-cost coating mateials and it’s worked extremely well.” The Gates program leaders required a manufacturing facility with Good Manufacturing Practices (GMP) certification and low costs and asked Prud’homme to contact the head of formulations at WuXi App Tech in China, “which has a program to translate your lab stuff into large scale manufacturing.”

The head of formulations development at WuXi, it turns out, was Santipharp “Sunny” Panmai, who was Prud’homme’s graduate student 20 years ago, earning his PhD from Princeton in 1998.

“You could not have planned that,” said Prud’homme. “So Sunny and I and our teams have phone calls back and forth, and we’re sending some equipment over to his lab, and we’re collaborating with him to translate our lab results into full-scale manufacturing, translating these drugs into clinical form. It’s still a tough job. We can make the particles, but the tough part is that in global health you have to be able to do this at really low cost, and there are the challenges of making this in very large scales.” It is important that they are able to manufacture these products in a forward-thinking and productive way, so they may look into Toll manufacturing vs contract manufacturing to see which would be the best route to go down that can prove lucrative but not expensive for their output, especially if they have to look into outsourcing their production.

He continued, “Also, the Gates Foundation, with its focus on pediatric health, wants us to make not tablets that an adult would take, but powders that a mother would have like a sugar packet with the drug in it, whether its anti-bacterial or malarial, so she could rip off the top and put it in a small amount of water and give it to an infant. And it also has to remain stable for a long time under harsh conditions.”

Clofazimine, an antibacterial, was the first drug Gates asked Prud’homme and team to work on. It had been effective in killing bacteria and had been used successfully for leprosy by Novartis for about 50 years. Prud’homme had to meet the challenge of adapting this drug for bacterial infections, speeding up dissolution and getting it into the intestinal tract rapidly. “Our technology achieved that, and it worked very well,” Prud’homme said.

In the vicissitudes of public health funding, however, with drinking water improving in Africa and fewer gastrointestinal infections occurring, Gates deprioritized clofazimine, and decided to direct their future grant money elsewhere.

“We had done all the animal tests and gotten this validated, and they just said, ‘It’s not where we want to put our money.’ I understand. They are very quantitatively oriented. It’s not for profit. It’s for public health.”

So now, in partnership with Medicines for Malaria Ventures (MMV) and Gates, Prud’homme’s focus is on two anti-malarial drugs, developing new formulations and taking old drugs and trying to make them more effective. “They’ve given us two of these compounds,’ said Prud’homme, “and we’ve been able to successfully formulate both of them. Most significantly Prud’homme’s process has been able to create formulations that simplify the delivery and the dosing to minimize differences between a child with a full stomach and a child with an empty stomach.

“When you’re talking about pediatrics and a sick child, you can’t tell if they’ve thrown up recently or if their stomach is full, so how you do the dosing is problematic,” he said. “But one of the most important things to come out of our research is a formulation which is less sensitive to whether the child has food in its stomach or not.”

Joanna Zhang, Ellen Dobrijevic ’17, and Robert Prud’homme work to increase medicines’ effectiveness in the developing world.

Teamwork

Prud’homme’s research team at Princeton consists of three graduate students working on their PhDs and three postdocs, who will work at Princeton for a period of one to three years. “It’s been a great experience with this team of postdocs and grad students because often in the academic world people are very competitive. The student or postdoc wants to be the shining star so he or she can get the best faculty position or something, but this group were willing to work together to try to reach our goals, and so they really worked as a team to try to make a difference in world health rather than to be superstars, so the teamwork is excellent – a great group.”

Emphasizing the importance of Princeton University to his career and his unusual accomplishments, Prud’homme pointed out, “Princeton as a university allows you to do what you think is important, and for me that has been engineering, and I’ve had a terrific career.”

He went on to mention his numerous collaborations both within and outside the university. “I’ve made connections to industry and industrial organizations during my career that Princeton has really allowed. Also being here with other terrific faculty members and students has been so valuable. Probably a third of the undergraduates who do a thesis with me end up publishing their work. They’re just amazing students, and it’s a fun place to spend your career.”

Prud’homme’s team’s current work involves finding an effective, low-cost coating for nanoparticles of medication. They are testing three different coatings, seeking to make the drugs more water resistant, and seeking to design systems to make the particles more stable. Prud’homme described the ovens upstairs at the E Quad where the researchers can simulate conditions in Africa, with temperatures of over 100 degrees Fahrenheit and 75 percent relative humidity.

The dissolution rate of the drug has to be fast, but it also has to remain constant over time. It has to be in powder form, because it’s too expensive to send liquids, and it’s also too expensive to individually package the medication, so it has to be delivered in a big bottle.

“For global health drugs, the criteria are really severe,” Prud’homme observed. In addition to working with the Gates Foundation, his team also has collaborations with Merck, Johnson and Johnson, Genentech, the University of Colorado, and Temple University. “Our technology is a platform,” said Prud’homme. “All of these collaborations are with people who will take our nanoparticle forms and will try to solve a medical problem with them.”

He continued, “A lot of pharm companies are talking with us, because we can deliver these drugs that are hard to deliver. And using the same technology, we’ve been able to encapsulate peptides and proteins into nanoparticle form. The biggest growth area in the pharmaceutical world now is peptides and proteins. Using what we have learned over the past 15 years has enabled us to do things that no one else can do in this field.”

About eight years ago, Prud’homme co-founded Optimeos Life Sciences, Inc., a company whose work is based on development of his nanoparticle-enabled technologies. “That’s a capstone to my career,” he said, “something that makes a difference, beyond a research project. That’s an entity that will continue even after I retire.” Prud’homme has served on the executive committees of the American institute of Chemical Engineers Materials Science Division and the U.S. Society of Rheology. He was chair of the Technical Advisory Board for Material Science Research for Dow Chemical Company, a member of BASF’s nanotechnology advisory committee, and a member of Lubrizol’s advisory technology board.

Prud’homme lives in Lawrenceville with his wife Dottie. He has three adult children from a previous marriage, now living across the globe in Kenya, Texas, and California; and three stepchildren living within five miles.

When he’s not teaching, researching, developing new drug formulations, or working with his students and colleagues on future publications and patents, Prud’homme might be found fly fishing or gardening. He spent ten days at a remote lodge in Alaska fishing for salmon this past summer. “When my kids were younger, I put away my fishing rod, but since they grew up and moved out I’ve gone back to fly fishing,” he said.

His collaborations extend into the garden where he plays a supporting role to his wife. “My wife is a Master Gardener of Mercer County, so I’m her set of untrained hands,” he noted. “In all of her gardening, I’m the muscle, on a small scale. She’s the brains. I help her.”