Medication compliance refers to the degree to which the patient adheres to the doctor's instructions, including whether the drug is purchased and renewed as prescribed, and whether the medication is used on time and in the right amount. When patient compliance is not high, it can lead to serious consequences. In the United States alone, more than 100,000 people die each year from failing to take prescribed drugs or taking them improperly, hospitalizations are as high as 25 percent, and health care costs exceed $100 billion.
Recently, bioengineers at Rice University have developed a new technology that can release drugs at regular intervals that may make it a thing of the past for patients to miss critical medications or vaccinations. The study, titled "A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release," was published in Advanced Materials on March 2.
Figure 1 Research results (Source: [1])
The technology, called PULSED (Particles Uniformly Liquified and Sealed to Encapsulate Drugs), uses high-resolution three-dimensional printing and soft lithography to produce more than 300 non-toxic, biodegradable tiny cylindrical particles that can be injected with a standard hypodermic needle. The material of the cylindrical particles is a polymer called PLGA that is widely used in clinical practice.
Figure 2 Standard-size hypodermic needles filled with sealing granules (Source: Rice University)
The researchers demonstrated four ways to load drugs into cylindrical pellets and showed that PLGA formulations could be adjusted to alter the rate at which the pellets dissolve and release drugs, with time spans ranging from 10 days to nearly five weeks. They also developed a quick and easy method for cylindrical sealing, demonstrating the technology's ability to mass produce and address critical pain points for time-release drug delivery.
"The problem we're trying to overcome is 'first-degree release,'" said Kevin McHugh, corresponding author of the study. "Primary release" refers to the problem of uneven dosing in current drug encapsulation methods. "It's common for a drug to release too much on the first day. Then on day 10, you may only get less than one-tenth of the amount of the first day. If the treatment window is longer, a 10-fold reduction in the amount of drug released on day 10 may be acceptable, but this is rare. "Most of the time, this leads to very difficult problems, such as the dose on the first day is close to toxicity, or the dose in the later stage is not enough to produce an effective effect." ”
In many cases, patients want the amount of the drug in the body to remain stable throughout treatment. McHugh said the PULSED technology can be tuned for this release pattern while also being used for other purposes, such as vaccination. "Our motivation for this project actually came from the vaccine field," he said. When getting vaccinated, you usually need to get vaccinated multiple times over a period of several months. This is very difficult in low- and middle-income countries due to access to health care. So what if we made particles with pulsed releases? We believe that encapsulating drugs in pockets inside biodegradable polymer shells can both create this all-or-nothing release event and provide a reliable way to set the timing of delayed release. ”
Although the PULSED technology has not been tested for months with a delay in release, McHugh said previous studies from other labs have shown that PLGA capsules can be made in a form that releases the drug within 6 months of injection. In their research, McHugh and graduate student Tyler Graf have achieved the fabrication and loading of particles ranging in diameter from 400 microns to 100 microns. McHugh said the size allows the particles to remain at the place of injection until they dissolve, which could be used to deliver large or continuous doses of one or more drugs at a specific location, such as in the treatment of cancer tumors. During the test, McHugh found that particles made of PLGA materials of different molecular weights produced pulsed releases at different points in time, and the particles did not affect each other.
Figure 3 Tyler Graf and Kevin McHugh (Source: Rice University)
"Cancer chemotherapy is toxic, so it's best for the toxins to be concentrated inside the tumor rather than metastasizing to other parts of the body," he said. "People have done this experimentally, injecting soluble drugs into tumors. But the question is how long it will take for it to spread out. Our particles stay where they started, making chemotherapy more effective by providing an extended, concentrated dose of the drug that reduces the side effects of chemotherapy. ”
Important discoveries about sealing methods occurred in part by chance. McHugh said previous studies have explored how PLGA particles can be used for timed-release drug encapsulation, but sealing large numbers of particles at once is so difficult to engineer that production costs make many applications impractical.
While exploring alternative sealing methods, Graf noticed that immersing the particles in different molten polymers to seal did not work as expected. "I began to wonder if it was necessary to immerse the particulates in a liquid polymer," says Graf, who continues to suspend the PLGA particulates above the hot plate, causing the top to melt and seal itself while the bottom remains intact. "Further optimization and experimentation resulted in a uniform and secure seal of the cylindrical particles, making this step relatively easy. Currently, Graf manufactures particles on glass microscope sheets, takes only a few seconds to heat, and can seal a 22x14 array in a single pass, about the size of a postage stamp.
Figure 4 PLGA particle encapsulation process (Source: [1])
McHugh said: "[Low medication adherence] is a big problem in the treatment of chronic diseases. It is estimated that 50% of people fail to take their medication properly. But with this technology, with just one injection, patients can prepare for the next few months in advance. ”
Responsible editor|Feng Lixiao
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Resources:
[1] Tyler P. Graf, Sherry Yue Qiu, Dhruv Varshney, et al. A Scalable Platform for Fabricating Biodegradable Microparticles with Pulsatile Drug Release. Advanced Materials, 2023; DOI: 10.1002/adma.202300228
[2]https://news.rice.edu/news/2023/21st-century-remedy-missed-meds
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