Read excerpts from the AAPS PharmSciTech theme editorial.
By Javier Morales, Ph.D.
The field of macromolecule drug development (also known in the literature as biologics, biomacromolecules, and biotechnology drugs) has sharply grown over the past 15 years.1 While most marketed products and clinical trials on macromolecule drugs are injectable dosage forms, there is a drive for more convenient dosage forms evidenced in the body of scientific literature, numerous clinical trials, and a handful of successful products for alternative routes of administration.
Extravascular administration has been widely investigated and shown potential, but there are many difficulties associated with absorption of therapeutic macromolecules into the body. For example, oral delivery of macromolecules for intestinal absorption faces a number of well-known limitations including instability in gastric pH, proteolytic enzyme content in the upper gastrointestinal (GI) tract, and insufficient permeation and bioavailability. With the difficulties of GI tract absorption, alternative routes of delivery have also been investigated, including: buccal/sublingual, transdermal, and nasal/pulmonary. This special AAPS PharmSciTech theme, Formulation and Delivery of Macromolecules, guest edited by Jason McConville and myself, explores specific aspects in the state of the art in macromolecule delivery and showcases innovative research strategies intended to improve absorption and performance of dosage forms containing macromolecular drugs.
In the review article Overview and Future Potential of Buccal Mucoadhesive Films as Drug Delivery Systems for Biologics, Montenegro-Nicolini and Morales describe the major advancements in mucoadhesive films as dosage forms for buccal administration of macromolecule drugs. This review presents the stratified mucosal epithelium as an absorption barrier and introduces strategies to enhance macromolecule permeation. The authors identify solvent casting as the conventional choice for film development; however, recent advancements in hot melt extrusion and inkjet printing, as shown by Montenegro-Nicolini et al in The AAPS Journal article Inkjet Printing of Proteins: an Experimental Approach, could provide new avenues for buccal film product development.
Hot melt extrusion of solid dosage forms for macromolecule drug development has been avoided in the past because of potential drug degradation due to the high temperatures and shear achieved during the process. In their article, Cossé et al focus on systematically investigating all relevant extrusion variables as well as using a low temperature processing polymer. After suitable formulation development, the authors showed that the extruded implants were able to sustain bovine serum albumin (BSA) release for weeks while maintaining very limited conformation changes in the BSA structure.
In an alternative approach for macromolecule drug formulation in nanostructured systems, two articles by Moghassemi et al detail the development and characterization of niosomes as delivery systems. The delivery system presented was successful in controlling drug release and improving cell proliferation even in comparison with the niosomal suspension.
As most macromolecule drug products are injectables, a thorough depiction of structural stability during storage is required during development. In their article, Zheng et al investigate the influence of pH and buffer species in an IgG 1 subtype therapeutic monoclonal antibody A. While this research highlights the need for specificity in monoclonal antibody characterization of degradation, the design used and techniques employed could be useful for investigating similar drugs.
Finally, an approach to study supramolecular inclusion complexes using lab techniques and in silico calculations is included in this theme and could be used in macromolecule drug development. dos Passos Menezes et al investigated the physicochemical properties of inclusion complexes through various spectroscopic techniques and used a molecular modeling approach to contrast their results and show similar tendencies.
The continued growth in the macromolecule drug field will move forward new entities for formulation and thus further push the drive for development of alternative dosage forms. While much is known in formulating and developing injectables, few successful medicines for alternative routes have been approved and are marketed. Research and innovation is expected to continue bringing new molecules to formulate, and the research in alternative routes of administration is likely to result in more availability of macromolecule drug products.
REFERENCES
- Pagels RF, Prud’homme RK. Polymeric nanoparticles and microparticles for the delivery of peptides, biologics, and soluble therapeutics. J Controlled Release. 2015;219:519–535.