Sustained-release injectable biologics are popular among patients who suffer chronic illnesses. Injectable products that offer
controlled drug release can reduce the frequency of injections, which makes it easier for patients to remain compliant. Sustained-release
injectables also can offer therapeutic advantages and enhance the quality of patients' lives. Demand for these medicines is
increasing, and the desire to extend the patents of branded biologics likely will lead to innovations in controlled-release
(ILLUSTRATION BY DAN WARD. IMAGES: IMAGE SOURCE/GETTY IMAGES)
One controlled-release technique suitable for biopharmaceuticals is based on polymeric microspheres. In this method, manufacturers
use polymers to construct a biodegradable matrix within which a drug can be encapsulated. By choosing polymers with the proper
characteristics, and by modifying the matrix properties, manufacturers can establish the desired release profile for the drug.
Biodegradable microsphere systems can deliver peptides, proteins, nucleic-acid-based drugs, and even small molecules, says
Ramin Darvari, senior principal scientist for novel delivery technologies at Pfizer.
Drugmakers can form the microspheres by creating oil–water emulsions. The process uses an immiscible aqueous–organic solvent
system that formulators can design to accommodate various presentations of the drug compound, including aqueous solutions
and dry particles. "Although traditional emulsion-based processes rely on exerting high shear on the system to generate the
desired particle-size distribution, recent advances in emulsion-based particle-engineering processes have made it possible
to achieve more precise control of the particle-size distribution" without the high shear that could denature a therapeutic
protein, says Darvari.
Manufacturers must extract solvents such as methylene chloride and ethyl acetate from the emulsion to form the particles and
remove the residual solvent through freeze-drying or spray-drying. An alternative approach to avoid solvents is to use hot-melt
encapsulation to create microspheres for heat-tolerant molecules.
Manufacturers can choose among various synthetic and natural biodegradable polymers to create injectable microspheres. Most
often, formulators opt for synthetic polymers, such as polyesters, poly(orthoesters), polyanhydrides, and polyphosphazenes,
In particular, the poly(lactide-co-glycolide) (PLGA) family of polyester copolymers is used extensively in drug delivery.
PLGA might have some undesirable attributes, however. The compound exhibits bulk degradation, rather than surface degradation,
which fosters the formation of the polymer's acidic degradation byproducts, lactic acid and glycolic acid. These byproducts,
in turn, reduce the pH of the microenvironment within the matrix. This effect might cause drug degradation within the matrix,
as well as irritation and discomfort at the site of injection, says Darvari. This problem can be mitigated by adding buffering
or neutralizing agents to the formulation, thus allowing PLGA to be used safely and successfully in controlled-release injectables.