Facilitating API Delivery with Nanoscale Solutions

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Pharmaceutical Technology, Pharmaceutical Technology-07-02-2019, Volume 43, Issue 7

Nanotechnology is enabling enhanced bioavailability, improved stability, and targeted delivery of challenging APIs.

Many of the drug substances under development today pose formulation challenges, from poor solubility and bioavailability to limited stability under physiological conditions. The application of nanotechnology in formulation development has the potential to address many of these issues, while also enabling targeted delivery to reduce off-target effects. Nanoparticles have the advantage of allowing chemical modifications, such as addition of ligands to target cell receptors and surface coatings (e.g., PEGylation) to prevent recognition by the body’s immune system, allowing them to carry drug compounds to the site of the disease without being captured and eliminated. The result: rapid development of the emerging field of nanomedicine.

Indeed, the value of the global market for nanopharmaceutical drugs is estimated by market research firm BIS Research to be expanding at a compound annual growth rate of 8.1% and predicted to reach $79.3 billion by 2026 (1). Polymer and liposome drug carrier systems are the two sub-segments driving this growth.

Multiple areas of research

Pharmaceutical companies are always looking for opportunities to improve medicines for patients. Applying the use of nanoformulations to existing drugs based on previous learnings is one avenue for leveraging nanotechnology, but Pfizer is focused on developing nanoformulations and nanotechnology solutions that will ultimately enable the next generation of nanotherapeutics to be brought to cancer and other patients, according to Young-Ho Song, a research fellow at Pfizer Oncology. “We complete this work as early as the discovery phase in collaboration with our medicinal chemistry colleagues,” she notes.

Nanomedicine research is focused in two main areas, agrees Stephan T. Stern, acting deputy director of the Nanotechnology Characterization Lab, which is part of the Frederick National Laboratory for Cancer Research. One area involves reformulation of existing drugs or drug combinations to decrease toxicity and/or increase efficacy, or to develop competing formulations of existing marketed products (e.g., nanosimilars). The second research area involves the formulation of novel drugs, such as difficult-to-formulate new chemical entities, oligonucleotides, and vaccines. “Most pharmaceutical companies have nanotechnology formulation research groups that are involved in resurrecting drugs that are failing due to toxicity/efficacy/formulation issues,” he adds.

Parenteral and oral dosage forms

The most common dosage forms of nanomedicines on the market are intravenous liposomes (e.g., Doxil [Janssen], Onivyde [Ipsen Biopharm], Vyxeos [Jazz Pharmaceuticals]), intravenous polymerics (e.g., Genexol [Samyang Biopharm]), intravenous nanoemulsions (e.g., Diprivan, Intralipid), and oral nanocrystals (e.g., Rapamune [Pfizer], Tricor [AbbVie]), according to Stern. Generally, he observes that the formulation type is first chosen based on API liabilities. “The issue may be solubility, toxicity to off-target tissues, rapid metabolism, or poor distribution to target tissues. Once the liability is recognized, a series of formulations that could overcome the liability are identified and the optimum formulation and preparation method are chosen based on chemical compatibility of the API,” says Stern.

Many preparation methods

Choice of appropriate formulation type is dictated by the properties of the API. “Certain APIs are better suited to certain formulation, due to loading efficiency and stability,” Stern explains. “Amphiphilic weakly basic/acidic drugs, for instance, are suitable for active loading of nanoliposomes, while highly hydrophobic drugs are better suited to nanoemulsions, polymeric nanoparticles, and micelles,” he says. High-temperature techniques, such as microfluidizer homogenizing, are not ideal for thermally labile APIs.

The formulation type will then determine the formulation method. Liposomes and emulsions are produced by solvent evaporation or thin-film hydration followed by extrusion/homogenization (microfluidizer), according to Stern. Polymeric nanoparticles and micelle formulations are generated by solvent evaporation, single/double emulsion, or precipitation techniques. Nanocrystals are generated by top-down techniques, such as milling and homogenization. Stern notes that bottom-up techniques (i.e., precipitation) are not currently used in the manufacture of nanocrystalline APIs.




Pfizer’s nanopolymer approach

Pfizer has been working with biodegradable polymeric nanoparticles for drug delivery. The most widely used processes for the production of these nanoparticles are nanoemulsion, in which the organic phase consists of water-immiscible solvents such as ethyl acetate or dichloromethane, and nanoprecipitation, in which the organic polymer-drug solution contains water-miscible solvents such as dimethyl sulfoxide, tetrahydrofuran, or acetonitrile, according to Song.

The polymeric nanoparticles developed by Pfizer are based on a biodegradable polyester polymer commonly used in dissolving stitches. Loaded nanoparticles are prepared by dissolving the polyester polymer, API, solvents, and excipients in an oil to form an emulsion. Thousands of pounds of pressure are applied to the emulsion, leading to the formation of nanosized droplets. The solvents are removed, and the droplets are hardened into polymeric nanoparticles encasing up to 10,000 API molecules. The surfaces of the nanoparticles are modified with antibodies that will bind to a specific cell type, such as a specific tumor cell. Once bound, the drug will diffuse out from the nanoparticles, slowly releasing and accumulating the API at the desirable target sites.

To date, the Pfizer researchers have investigated the application of their nanopolymeric technology for the development of drugs to treat various cancers and cardiovascular, inflammatory, and infectious diseases. “Our state-of-the-art nanoemulsion process and formulation approach have expanded the chemical space of compounds that can be formulated into our nanoformulations,” Song asserts.

Overcoming challenges

Despite their advantages, nanomedicines do face several challenges, including the lack of predictive preclinical models for safety/efficacy, problems with scale up, and an uncertain regulatory path, according to Stern. Song agrees that there are multiple hurdles that must be overcome before nanomedicines can become commercial products. “An individual’s perspective often determines what is the biggest challenge, and each medicine can present its own set of challenges. It takes a team effort, from discovery through approval, to address each challenge as it is presented,” she observes.

Advances in technology are helping, too. “Recent advances in nanodelivery formulation around oligonucleotides (siRNA, mRNA, and genetic materials) using lipid nanoparticle (LNP) nanosystems are breakthrough technologies,” according to Song. “These new approaches can help to convert a very difficult drug formulation challenge ultimately into a drug product,” she states.

Stern points to a gradual refinement in established platforms regarding improved stability, safety, and delivery as important evolutionary advances in nanomedicine. One example he highlights is the approval of Onpattro, a treatment of transthyretin-mediated amyloidosis and the first gene-delivery nanoliposome, which has been decades in the making. “With market approvals like this one, more venture funding will flow into nanotech, allowing for more research and advancement in the field,” Stern asserts.

Another way these challenges are being overcome, says Stern, is through the participation of contract research, development, and manufacturing organizations that are developing and expanding specialized capabilities at the lab to commercial scale and can assist with the scaleup of complex drug formulations. He also notes that as more nanomedicines reach the clinic and eventually the marketplace, a better understanding of which preclinical studies are useful and important is being realized. In addition, FDA and the European Medicines Agency are in the process of streamlining the regulatory approval process for complex drugs, including their generic/follow-on versions, which should expedite future development.

Shift in focus to next-generation therapies

The future for nanomedicines certainly appears to be exciting. “Complex drug formulation will always have a place in modern drug development for the simple reason that new drugs and drug classes are getting ever more difficult to deliver as a result of poor stability, solubility, and permeability,” Stern observes. There will still be reformulation and repurposing of existing drugs as nanoformulations, but Song agrees that research will move toward a focus on developing new drugs in nanoformulations starting from the early drug discovery phase.

Research in nanomedicine has, according to Stern, already begun shifting toward the use of nanoformulation for immunomodulatory drugs and gene therapies. “Nanotech is well suited to overcoming the lack of selectivity and poor delivery, respectively, of immunotherapies and oligonucleotide-based drugs,” he says. One example is the use of gold nanoparticles rather than an inactivated virus to deliver clustered regularly interspaced short palindromic repeats (CRISPR) gene-editing tools to cells (2).


1. BIS Research, “Global Nanopharmaceutical Drugs Market is Expected to Reach $79.29 Billion by 2026,” Press Release, Dec 11, 2018.
2. Fred Hutchinson Cancer Research Center, “Could Gold Be the Key to Making Gene Therapy for HIV, Blood Disorders More Accessible?” News Release, May 27, 2019. 

Article Details 

Pharmaceutical Technology
Vol. 43, No. 7
July 2019
Pages: 22–23


When referring to this article, please cite it as C. Challener, “Facilitating API Delivery with Nanoscale Solutions,” Pharmaceutical Technology 43 (7) 2019.