New tech could deliver time-released drugs, vaccines for months

Date:
April 3, 2023
Source:
Rice University
Summary:
Bioengineers may have the prescription for a $100 billion global
problem: An innovative way to make time-released drugs could allow
patients to receive months-worth of medicines or vaccines in a
single shot.


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FULL STORY ========================================================================== Missing crucial doses of medicines and vaccines could become a thing of
the past thanks to Rice University bioengineers' next-level technology
for making time-released drugs.


========================================================================== "This is a huge problem in the treatment of chronic disease," said Kevin McHugh, corresponding author of a study about the technology published
online inAdvanced Materials. "It's estimated that 50% of people don't
take their medications correctly. With this, you'd give them one shot,
and they'd be all set for the next couple of months." When patients
fail to take prescription medicine or take it incorrectly, the costs
can be staggering. The annual toll in the United States alone has been estimated at more than 100,000 deaths, up to 25% of hospitalizations
and more than $100 billion in healthcare costs.

Encapsulating medicine in microparticles that dissolve and release drugs
over time isn't a new idea. But McHugh and graduate student Tyler Graf
used 21st- century methods to develop next-level encapsulation technology
that is far more versatile than its forerunners.

Dubbed PULSED (short for Particles Uniformly Liquified and Sealed to Encapsulate Drugs), the technology employs high-resolution 3D printing
and soft lithography to produce arrays of more than 300 nontoxic,
biodegradable cylinders that are small enough to be injected with standard hypodermic needles.

The cylinders are made of a polymer called PLGA that's widely used in
clinical medical treatment. McHugh and Graf demonstrated four methods
of loading the microcylinders with drugs, and showed they could tweak
the PLGA recipe to vary how quickly the particles dissolved and released
the drugs -- from as little as 10 days to almost five weeks. They also developed a fast and easy method for sealing the cylinders, a critical
step to demonstrate the technology is both scalable and capable of
addressing a major hurdle in time-release drug delivery.

"The thing we're trying to overcome is 'first-order release,'" McHugh
said, referring to the uneven dosing that's characteristic with current
methods of drug encapsulation. "The common pattern is for a lot of the
drug to be released early, on day one. And then on day 10, you might
get 10 times less than you got on day one.

"If there's a huge therapeutic window, then releasing 10 times less on day
10 might still be OK, but that's rarely the case," McHugh said. "Most of
the time it's really problematic, either because the day-one dose brings
you close to toxicity or because getting 10 times less -- or even four or
five times less - - at later time points isn't enough to be effective."
In many cases, it would be ideal for patients to have the same amount
of a drug in their systems throughout treatment. McHugh said PULSED can
be tailored for that kind of release profile, and it also could be used
in other ways.

"Our motivation for this particular project actually came from the
vaccine space," he said. "In vaccination, you often need multiple doses
spread out over the course of months. That's really difficult to do in
low- and middle-income countries because of health care accessibility
issues. The idea was, 'What if we made particles that exhibit pulsatile release?' And we hypothesized that this core-shell structure -- where
you'd have the vaccine in a pocket inside a biodegradable polymer
shell -- could both produce that kind of all-or-nothing release event
and provide a reliable way to set the delayed timing of the release."
Though PULSED hasn't yet been tested for months-long release delays,
McHugh said previous studies from other labs have shown PLGA capsules
can be formulated to release drugs as much as six months after injection.

In their study, Graf and McHugh showed they could make and load particles
with diameters ranging from 400 microns to 100 microns. McHugh said
this size enables particles to stay where they are injected until they dissolve, which could be useful for delivering large or continuous doses
of one or more drugs at a specific location, like a cancerous tumor.

"For toxic cancer chemotherapies, you'd love to have the poison
concentrated in the tumor and not in the rest of the body," he
said. "People have done that experimentally, injecting soluble drugs
into tumors. But then the question is how long is it going to take for
that to diffuse out.

"Our microparticles will stay where you put them," McHugh said. "The
idea is to make chemotherapy more effective and reduce its side effects
by delivering a prolonged, concentrated dose of the drugs exactly where
they're needed." The crucial discovery of the contactless sealing method happened partly by chance. McHugh said previous studies had explored
the use of PLGA microparticles for time-released drug encapsulation,
but sealing large numbers of particles had proven so difficult that the
cost of production was considered impractical for many applications.

While exploring alternative sealing methods, Graf noticed that trying to
seal the microparticles by dipping them into different melted polymers
was not giving the desired outcome. "Eventually, I questioned whether
dipping the microparticles into a liquid polymer was even necessary,"
said Graf, who proceeded to suspend the PLGA microparticles above a hot
plate, enabling the top of the particles to melt and to self-seal while
the bottom of the particles remained intact, "Those first particle
batches barely sealed, but seeing the process was possible was very exciting."Further optimization and experimentation resulted in consistent
and robust sealing of the cylinders, which eventually proved to be one of
the easier steps in making the time- released drug capsules. Each 22x14
array of cylinders was about the size of a postage stamp, and Graf made
them atop glass microscope slides.

After loading an array with drugs, Graf said he would suspend it about
a millimeter or so above the hot plate for a short time. "I'd just
flip it over and rest it on two other glass slides, one on either end,
and set a timer for however long it would take to seal. It just takes
a few seconds." This work was supported by the Cancer Prevention
and Research Institute of Texas (RR190056), the National Institutes
of Health (EB031495, EB023833) and the National Science Foundation
(1842494, 2236422).

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========================================================================== Story Source: Materials provided by Rice_University. Original written
by Jade Boyd. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tyler P. Graf, Sherry Yue Qiu, Dhruv Varshney, Mei‐Li
Laracuente,
Erin M. Euliano, Pujita Munnangi, Brett H. Pogostin, Tsvetelina
Baryakova, Arnav Garyali, Kevin J. McHugh. A Scalable Platform
for Fabricating Biodegradable Microparticles with Pulsatile Drug
Release.

Advanced Materials, 2023; DOI: 10.1002/adma.202300228 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/04/230403133524.htm

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