New technology could make critical dose shortages of medicines and vaccines a thing of the past

encapsulated microparticle needle

A sealed microparticle containing a colored dye is shown inside the narrow opening of a standard size hypodermic needle.Credit: Brandon Martin/Rice University

The technology developed by the Rice Lab has the potential to deliver sustained-release drugs and vaccines for months.

Thanks to new technology developed by bioengineers at Rice University, the problem of missing essential doses of medicines and vaccines could be a thing of the past. This state-of-the-art technology enables the production of sustained release drugs.

“This is a big problem in treating chronic diseases,” said Kevin McHugh, corresponding author of a study on the technology published online. advanced materials“It’s estimated that 50% of people aren’t taking their medication correctly. With this, you just give them one shot and they’re all set for the next two months.”

Taking prescription drugs incorrectly can have devastating consequences, resulting in staggering annual costs. In the United States alone, it is estimated to include more than 100,000 deaths, 25% of his hospitalizations, and over $100 billion in medical costs.

Encapsulating drugs into microparticles that dissolve and release the drug over time is not a new idea. But McHugh and his graduate student Tyler Graf have used 21st-century methods to develop next-level encapsulation technology that is far more versatile than the prior art.

Tyler Graff and Kevin McHugh

Tyler Graff (left) and Kevin McHugh.Credit: Brandon Martin/Rice University

Called PULSED (Particles Uniformly Liquified and Sealed to Encapsulate Drugs), the technology uses high-resolution 3D printing and soft lithography to create more than 300 non-toxic, biodegradable drugs that are small enough to be injected with a standard hypodermic needle. Generate an array of cylinders.

The cylinder is made of a polymer called PLGA, which is widely used in clinical medicine. McHugh and Graf demonstrated four methods of loading microcylinders with drugs and fine-tuning the PLGA recipe to vary the rate at which the particles dissolve and release drug, from as little as 10 days to almost 5 weeks. has shown that it can be done. They also developed a quick and easy way to seal the cylinder. This is an important step in demonstrating that the technology is scalable and can address major hurdles of sustained drug delivery.

“What we’re trying to overcome is ‘primary release,'” McHugh said, referring to the uneven dosing characteristic of current drug encapsulation methods. “The general pattern is that many drugs are released early on day one, and he may be ten times less on day one than he was on day one.

Array of packed microparticles

In the lab of Kevin McHugh, a bioengineer at Rice University, an array of hollow microparticles is placed on a microscope slide. The colored, dye-filled particles are designed for sustained drug delivery and are large enough to pass through a standard hypodermic needle.Credit: Brandon Martin/Rice University

“If you have a large therapeutic window, even less than 10-fold release on day 10 might be fine, but it’s rarely the case,” McHugh said. “Most of the time, it’s really a problem because the dose on the first day approaches toxicity, or only 10-fold less, or 4-fold or 5-fold less at later time points. because it is not enough to

In many cases, it is ideal for patients to keep the same amount of drug in their bodies during treatment. McHugh says PULSED can be tailored for that kind of release profile and can be used in other ways as well.

“Our motivation for this particular project actually came from the vaccine space,” he said. “Immunization often requires multiple doses over many months. It’s hard, the idea was, “What if we make a particle that exhibits pulsatile emission?” We then hypothesized that this core-shell structure, which entraps vaccines in pockets within a biodegradable polymer shell, could generate such all-or-nothing release events and provide a reliable method of setting delayed timing. release. “

Tyler Graff and microscope slides

Rice PhD student Tyler Graf has a microscope slide that holds an array of over 300 small biodegradable particles that can be used for sustained drug delivery.Credit: Brandon Martin/Rice University

PULSED has not yet been tested for delayed release over months, but McHugh said previous studies from other labs have shown that PLGA capsules are formulated to release drug as long as six months after injection. It shows what you can do.

Graf and McHugh showed in their work that particles with diameters ranging from 400 microns to 100 microns can be made and loaded. According to McHugh, this size allows the particles to stay where they are injected until they dissolve, allowing him to administer large or continuous doses of one or more drugs to specific locations, such as cancerous tumors. may be useful for

“For toxic cancer chemotherapy, you would want to focus the poison on the tumor and not on other parts of the body,” he said. I injected it into the tumor, but the question is how long it takes for it to spread.

“Our microparticles stay where you put them,” says McHugh. “The idea is to make chemotherapy more effective and reduce its side effects by focusing the drug precisely where it is needed.”

A video explaining the research.Credit: Rice University

The important discovery of the non-contact sealing method happened by chance. McHugh said previous work had explored using his PLGA microparticles for sustained-release drug encapsulation, but sealing large numbers of particles proved to be very difficult, so Manufacturing costs were considered impractical for many applications.

While considering alternative sealing methods, Graf realized that trying to seal the microparticles by dipping them in different molten polymers did not produce the desired results. “Ultimately, I wondered if it was necessary to immerse the microparticles in a liquid polymer,” he said, suspending the PLGA microparticles on top of a hot plate so that the top of the particles could melt and the bottom could self-seal. says Graf. “Those first batches of particles were barely sealed, but it was very exciting to be able to process.” has proven to be one of the easier steps in manufacturing. Time-release drug capsule. Each array of 22 x 14 cylinders was about the size of a postage stamp, and the graphs were made of them on glass microscope slides.

After loading the arrays with drugs, Graf said they briefly hang the arrays about a millimeter above the hotplate. “I flip it over, one on each end, another he puts on two glass slides, and set a timer for how long it takes to seal. It only takes a few seconds.”

Reference: “A scalable platform for manufacturing biodegradable microparticles with pulsatile drug release” Tyler P. Graf, Sherry Yue Qiu, Dhruv Varshney, Mei-Li Laracuente, Erin M. Euliano, Pujita Munnangi, Brett H. Pogostin , Tsvetelina Baryakova, Arnav Garyali and Kevin J. McHugh, 2 March 2023, advanced materials.
DOI: 10.1002/adma.202300228

This study was funded by the Cancer Prevention Institute of Texas. National Institutes of Healthand the National Science Foundation.

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