A Preclinical Study Explores Possibility of Multiple Drug Doses in a Single Injection for Advanced Drug Delivery.

Pharmaceutical medications can save lives, but taking these medications as prescribed—especially among those with chronic illnesses—can be challenging for a variety of different reasons. Improving medication adherence can reduce adverse health outcomes, hospitalizations, and preventable deaths, while simultaneously reducing healthcare costs by up to $300 billion annually In the United States alone.

One potential way to increase adherence is to reduce the number of times a person needs to take their medication. This can be achieved with the controlled release system, in which a single injection contains a drug that is continuously released into the body over a prolonged period of time. Unfortunately, many controlled release systems deliver a significant portion of their payload immediately after injection, Which can lead to inconsistent drug dosing – more drug is released initially (potentially resulting in toxicity) and less drug is released over time (potentially too small a dose to be effective). A system that can release separate doses at specific points in time could revolutionize the way drugs are delivered, from multi-dose vaccines to daily medications.

In response to this challenge, researchers from Rice University developed PULSED (for uniformly liquefied and sealed particles for drug packaging). their way, lately reported in Advanced materialsAnd It creates tiny drug-filled particles that can be engineered to degrade and release their therapeutic charge days or weeks after injection. By combining many microparticles with different disintegration times into a single syringe, researchers can develop a drug formulation that delivers many doses over time.

“As a field, we constantly aim for effective and efficient development Drug delivery systems “With the combination of multiple doses into a single treatment, the controlled release system described here can transform the therapeutic landscape, eliminating the need for Take medication frequently, whether at home or in the clinic.”

PULSED microparticles are made of PLGA, or poly (lactic-co-glycolic acid), a polymer commonly used in a number of FDA-approved devices. PLGA is composed of repeating units of lactic acid and glycolic acid, two molecules found naturally in our bodies. By lengthening the overall length of the polymer, adjusting the ratio of lactic acid to glycolic acid, and “coating” the end of the polymer with different molecules, researchers can determine how long it takes for PLGA to disintegrate (and thus release its healing payload).

“In our case, we can combine groups of microparticles with different PLGA constructs, each releasing their entire contents at one distinct time point,” explains study senior author Kevin McHugh, Ph.D., assistant professor at Rice University. “This allows us to achieve multiple release events at specific, predetermined times.”

Here’s how the drug-laden microparticles are made: Heated semi-liquid PLGA is pressed into a mold and then cooled, solidifying into hollow cylinders with a hole at the top. The core of each microparticle is filled with a medicated charge, then the top of the microparticle is heated, causing the PLGA to melt and flow over the opening to seal the drug inside. The primary particles the researchers developed were 400 micrometers in diameter (for reference, the Dime thickness about 1350 µm).

As a first step, the researchers filled four different shells of PLGA particles with dextran (a type of sugar) tagged with a fluorescent molecule, allowing them to easily visualize and measure the release of the cargo. They incubated the microparticles in a body temperature buffer to mimic real-life conditions and found that the microparticles released their contents at staggered intervals of approximately eight to 31 days, depending on the PLGA composition. Most importantly, the researchers found that each microparticle formulation quickly releases its payload, resulting in 75% of the dextran being excreted over a period of approximately one to three days. They had similar results when they repeated the experiments on mice.

“While we extended the microparticle lysis time to approximately five weeks in this study, we only started to tinker with the PLGA formulations to increase their lysis times and subsequent drug release,” said McHugh. “Based on our previous work with other systems, we are confident that by changing the PLGA’s length and component proportions, we can extend the release to six months and likely a much longer period.”

After the researchers improved the microparticle manufacturing process, they needed to ensure that the pharmaceutical drug was still viable once it was encapsulated inside. Many drugs – in particular biological agentswhich were developed using live, heat-sensitive components, which researchers use to seal their microparticles.

What’s more, the researchers wanted to ensure that long-term storage inside the human body—conditions that heat and acidify the tiny particles—would not adversely affect the drug. They encapsulated bevacizumab (an FDA-approved antibody used to treat several types of cancer) into their microparticles with different types of excipients (inactive drug stabilizers) and evaluated the drug’s activity. With the right combination of excipients, the microparticles released bioactive, viable bevacizumab, even after weeks under simulated body conditions.

Finally, the researchers wanted to push the envelope and shrink their microparticles even further. While the original particles could easily flow through an 18-gauge needle, which is routinely used for things like blood collection, smaller needles are preferred for pediatric vaccines and insulin administration, typically 22- to 31-gauge. Using a smaller mold and the same manufacturing method, the researchers were able to shrink the microparticles down to 100 micrometers in diameter. The loading capacity of these microparticles is 50 times lower than the original microparticles, McHugh said, but they can be used with the smallest needles commonly used. Future work will include evaluation of the dissociation time and cargo release of these microparticles.

“Methods of drug administration in pharmaceutical medicine are often underestimated,” McHugh said. “Our study, while still in an early stage of development, could reshape the way routine vaccines and repeat medications are given, ultimately improving medication adherence and human health.”