Microspheres Provide Precision-Release Drug Delivery

Originally Published MDDI May 2002

R&D DIGEST

The ability to deliver appropriate drug dosages over a prolonged period requires the release rate of encapsulated compounds to be precisely controlled. Such a capability would yield important new tools for treating a range of illnesses. At the University of Illinois (Champaign, IL), Kyekyoon (Kevin) Kim, professor of electrical and computer engineering, and colleagues have developed a method for making drug-filled, biodegradable polymer microspheres that has been shown to provide precise control over sphere size and shell thickness.

The researchers suggest that the microspheres offer the ability to control the drug-delivery kinetics, providing the foundation for creating single-shot vaccines that could improve patient comfort and compliance.

Working with Daniel Pack, professor of chemical engineering, and graduate student Cory Berkland, Kim creates uniform microspheres by spraying a solution of biodegradable polymer, organic solvent, and the drug to be encapsulated through a small nozzle. "Left alone, the resulting stream would naturally break up into droplets, like water spraying from a garden hose," Kim explains, adding that "the droplets would form in random sizes."

To produce uniform droplets, the nozzle is vibrated with a piezoelectric transducer. "This launches a wave of acoustic energy along the thin liquid jet, which develops bulges, resembling sausage links, that snap off as droplets at a controlled rate," Kim explains. "Shaking the nozzle at a defined rate is what makes the spheres all the same size."

To create droplets with a smaller diameter, a coaxial nozzle is used to surround the polymer jet with a faster-moving carrier stream. The researchers explain that the carrier stream pulls on the polymer solution. This stretches the polymer into an even narrower stream, creating smaller droplets. The researchers have found that they can precisely control the size of the resulting spheres by varying the flow rate and vibration frequency.

The group explains that combining the acoustic-activation and carrier-stream techniques creates uniform microspheres with diameters ranging from 5 to 500 µm. They have also used what they describe as a more sophisticated nozzle assembly to fabricate similarly sized microcapsules in which a drug core is surrounded by a biodegradable polymer shell.

According to Pack, "Drug release rates depend very strongly on the size of the spheres or capsules containing the drug. Larger microspheres generally release encapsulated compounds more slowly and over longer time periods." Microcapsules, on the other hand, can be made to release their payload only after the shell has dissolved to the point of rupture. Therefore, by varying the shell size and thickness, the researchers can control the time delay for drug release.

The key to most drug-delivery applications is to achieve drug release at a constant rate. Pack explains, however, that "this is very difficult to achieve with conventional microspheres." He adds that mixing microcapsules of different sizes enables them to generate a constant rate of release over a relatively prolonged period.

The researchers demonstrated their constant-release kinetics with both a model drug compound—rhodamine B— and with piroxicam, a common nonsteroidal anti-inflammatory drug for treating inflammation associated with arthritis. They speculate that the technique would be especially useful for delivering drugs that usually require multiple daily injections and for vaccinations that require additional booster shots at timely intervals. Says Pack, "Single-shot vaccinations could increase both patient comfort and compliance. They would also dramatically reduce the number of injections required when inoculating Third World nations against infectious diseases or inoculating large populations against a bioterror attack."

Photos courtesy of University of Illinois

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