35th Anniversary Special: Nanoformulations

Published on: 
Pharmaceutical Technology, Pharmaceutical Technology-07-02-2012, Volume 36, Issue 7

A look back at key nanoformulation advances and what lies ahead for nanoparticle-based drug-delivery systems.

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?

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).

Panayiotis P. Constantinides, PhD, founder and principal of Biopharmaceutical and Drug Delivery Consulting, ppconstantinides@bpddc.com.


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.

Gains in selectivity and efficacy

PharmTech: What advances to you expect to see in the future that will improve selectivity or efficacy?

Constantinides: Nanoparticle selectivity and efficacy is particularly important in parenteral drug delivery and targeting for cancer and other diseases. Linked to nanoparticle selectivity and efficacy is their potential toxicity. Further advances in cell and tissue imaging techniques and other in vitro and in vivo characterization methods of nanomaterials and nanoparticles are necessary to better understand and predict toxicity. To this end, further development and clinical application of multifunctional nanoparticles which combine disease diagnosis with therapy (nanotheranostics) could prove to be very useful. These systems consist of a core which can be magnetic for MRI or quantum dot for optical imaging, a lipidic and/or polymeric shell for intracellular targeting and an outer layer incorporating a surfactant or polymeric stabilizer and a targeting moiety (e.g., antibody, aptamer, or ligand). The drug, small molecule or biologic, can be encapsulated in the core and/or the shell of the particle.

Advances in image-guided drug delivery will offer several advantageous features and enable scientists and clinicians to monitor and quantify drug release, noninvasively assess drug site accumulation, visualize biodistribution in real time, analyze drug distribution at the target site, predict drug response and evaluate drug efficacy and toxicity. Ultimately and perhaps not in the distant future, these features could be incorporated into microchips and personalized medicines.

Most nanoparticles accumulate in the liver but depending on their size and charge can also accumulate in the kidney and other tissues. All classes of nanomaterials have extensive tissue retention, particularly carbon nanotubes and quantum dots, and this has toxicological implications. The state of nanomaterials once deposited in the tissue is largely unknown. Furthermore, comparison between and across complex nanoparticles is difficult.

In reference to nanoparticle toxicity, limited number of nanomaterials have been evaluated to date, and mechanisms for nanomaterial toxicity are actively being pursued. Specific properties of nanometerials, particularly their surface characteristics, contribute to their toxicity. There is a need for nanotoxicity guidelines, and no specific regulations are available at the present time. However, assessing nanomaterial risks should be proactively pursued to identify and analyze potential hazards, assess potential exposure scenarios and evaluate toxicity and analyze and communicate potential risks and uncertainties.

From a formulation and process development perspective, we need to critically assess which lessons learned from the marketed nanoparticulate drug products can be applied to 1-100 nm particles and what is truly new science and knowledge. For example, new processing and characterization methods are needed along with the establishment of meaningful controls, specifications, and standards for 1–100 nm particles. Further advances in manufacturing methods are required in order to scale up and reproducibly produce complex multifunctional nanoparticles with an acceptable shelf-life.

Drivers for future growth and commercialization of drug delivery nanoparticles include availability of funding, patent landscape, increased understanding of the pathophysiology of disease, and the need for novel drugs and safe therapies.