Nanotechnology has been used to develop innovative formulations to improve bioavailability of drugs, and have found utility
as carriers for either highly toxic payloads, such as chemotherapeutics, or very fragile payloads, such as proteins or nucleic
acids. Panayiotis P. Constantinides, PhD, founder and principal of Biopharmaceutical and Drug Delivery Consulting, spoke to
Pharmaceutical Technology about the utility of nanotechnology in formulation strategies, both past and future.
Advances in nanoparticles
PharmTech:
Can you identify one or two key technical advances that have enabled the successful development of nanoparticles as drug
delivery vehicles?
Panayiotis P. Constantinides, PhD, founder and principal of Biopharmaceutical and Drug Delivery Consulting, ppconstantinides@bpddc.com.
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Constantinides:
Within the scope of this discussion, both 1–100 nm and submicron particles (100–1000 nm) are considered as nanoparticles
for both oral and non-oral drug delivery applications. The successful development of drug delivery vehicles through advances
in pharmaceutical nanotechnology is certainly reflected in the marketed nanoparticulate drug products which are in the submicron
range (100–1000 nm). These products include Doxil (liposomal doxorubicin, ALZA/1999), Abraxane (albumin-bound paclitaxel,
Abraxis/2005) and NanoCrystal based drug products, Rapamune (Sirolimus, Wyeth/2000), Emend (aprepitant, Merck/2003) TriCor
(fenofibrate, Abbott/2004), Megace ES (megestrol, Par/2004) and Invega (paliperidone palmitate, Ortho-McNeil-Janssen/2009).
Key technical advances which have enabled the successful development and commercialization of the aforementioned nanoparticulate
drug products include advances in biology, materials science and particle engineering, processing, and manufacturing. Top-down
and bottom-up manufacturing methods at small and large scale have been applied and tailored to the specific compound and its
application. During the top-down process, high shearing homogenization or media-milling is used to reduce particle size in
the presence of polymeric and surfactant stabilizers to prevent crystallization and particle growth. In the bottom-up process
of manufacturing nanoparticles, the nanoparticle is created from its individual components, using precipitation, coacervation,
polymerization, and hydrophobic aggregation in an effort to achieve small size by controlling the thermodynamics and kinetics
of nucleation, growth, and chemical reactivity. Layer-by-layer self-assemblies using biopolymers and synthetic polymers create
versatile nanostructures for drug and gene delivery. Nanoformulation is becoming an integral part of life-cycle management
strategies for product line extensions and as enabling drug discovery technology for new molecular entities.
Top-down and bottom-up methods to manufacture nanoparticles have been applied to commercial products, the former for the marketed
parenteral liposomal Doxil and the NanoCrystal drug products, and the latter for the albumin-bound nanoparticle Abraxane.
For these drug products, advances in the characterization of nanoparticles and better understanding of how the ADME properties
of compounds administered as nanoparticles are linked to particle size and surface chemistry have also contributed to their
successful development and commercialization. In the case of the parenteral cancer chemotherapeutic drug products Doxil and
Abraxane, key factors that have also contributed to their successful design and development were advances in nanoparticle
targeting strategies based on the fundamental understanding of tumor biology principles, such as tumor vasculature and permeability,
pH, and surface antigens.
