Dosage forms that contain more than one active pharmaceutical ingredient (API) can improve patient compliance and facilitate
the treatment of certain diseases. Strategies to control the release of APIs in tablets and inhalable drugs include modifying
the formulation, implementing specific coating technologies, and using techniques in particle-engineering.
ILLUSTRATION BY S. STEWART. IMAGES: DAVID MADISON, MEDICALRF/GETTY IMAGES
The formulation stage offers many opportunities for scientists to impart controlled release to multidrug dosage forms. Hydrogels,
extremely hydrated polymer gels that hold many times their weight in trapped water, are a drug-delivery mechanism that can
be manipulated to change the release profiles of APIs (1).
Rather than using commercially available materials, which is the traditional method, a team of researchers at the Massachusetts
Institute of Technology (MIT) created designer peptides from scratch that had both hydrophobic and hydrophilic parts. When
exposed to water, the peptides' hydrophobic parts assemble into a hydrogel scaffold, explains Shuguang Zhang, associate director
of MIT's Center for Biomedical Engineering. The scaffold, a nanofiber that contains nanopores, can house small- and large-molecule
drugs and carry more than one API at a time.
By modifying the hydrogel scaffold's peptides, scientists could provide different release profiles for separate APIs. The
scaffold could include peptides with physical hooks that are specific to particular receptors in the body. An API associated
with a hook would be released earlier than an API housed in the scaffold's micropores, says Zhang.
The nanopores in the scaffold are components or "harbors" that protect biological drugs from water ingress, Zhang says. Because
the scaffold is stable at high temperatures, it also protects proteins from becoming denatured. The team's recent research
shows that protein drugs are still functional when they emerge from the hydrogel scaffold, which could be used to deliver
erythropoietin by injection, says Zhang (2).
Scientists could modify the hydrogel scaffold to alter the release profile of the drugs it carries. Zhang's team engineered
specific enzymes to cut a particular site on the peptide chain to degrade the scaffold quickly, which increased the release
rate. If the scaffold remained intact longer, it would release drugs slowly. Scientists can engineer the scaffold to resist
enzymatic degradation, but this technique is difficult, says Zhang. Another way to modify the release profile would be to
change the thickness of the nanopore enclosures that house an API.
The hydrogel scaffold is safer for patients than other natural and synthetic materials. In contrast with animal-derived materials,
MIT's hydrogel scaffold is entirely aseptic and has not provoked any immune response, Zhang says. The scaffold is easier for
the body to process and reuse than synthetic polymeric materials, he adds. Innocuous polymers sometimes degrade into toxic
monomers. In contrast, enzymes in the body break down the hydrogel scaffold's peptides into harmless amino acids. The team's
isotope-labeling study found that the hydrogel scaffold breaks down at a rate of 10% every two weeks, an "almost perfect"
rate for many drug-delivery applications, says Zhang. A conventional isotope takes two weeks to degrade by 10%.