Calling the Shots: Innovation in Controlled-Release Injectables

High demand could lead to innovation in controlled-release injectables.
Jul 01, 2011


(ILLUSTRATION BY DAN WARD. IMAGES: IMAGE SOURCE/GETTY IMAGES)
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 applications.

Polymeric microspheres

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, says Darvari.

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.