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Q&A: Drug delivery

drug delivery

Hans Lennernäs, professor in biopharmaceutics at Uppsala University, has extensive experience in developing drug delivery methods. NLS asked him about his research and ongoing activities in the field. He spoke about the latest progress and challenges in drug delivery, nanotechnology and the importance of multidisciplinary collaborations.

Your research aims to develop novel strategies for tissue targeting and delivery, with the goal to improve the clinical use and efficacy of drugs in various disease states. What are the challenges in this field?

“It is relatively simple to highlight the problems faced in the development of optimized drug delivery systems. For example, this was well-captured in the title by Venditto and Szoka (2012) where the development of cancer products is discussed “so many papers and so few drugs”. It is less easy to define certain routes to success that clearly define the reasons for failures. It is clear that, because of the physical, chemical, pharmaceutical and biological complexity of the challenges, there is a strong need for multidisciplinary innovation and development (such as in integration with diagnostics/imaging for better patient stratification) and to introduce more realism in our expectations for these novel treatment approaches.”

What progress have you and your colleagues made in the field?

“My research group and its multidisciplinary collaborators are working with a tumor-directed delivery project, TargetExact, concerning innovation and the development of novel products for the treatment of liver cancer. Hepatocellular carcinioma (HCC) is a global health problem due to its increasing incidence and high lethality. The rising incidence poses challenges to the clinician since the majority of patients are diagnosed with advanced disease when they are no longer candidates for curative treatment. In addition, the coexistence of cirrhosis and HCC adds two parallel causes of death, each one critical to consider since both influence management. The final product of the TargetExact project is based on a unique and a novel drug delivery formulation, with a strong IP position, which can be used for successful treatments of primarily intermediary and advanced HCC liver cancers. The drug product might be based on a nano-crystalline inorganic powdery product combined with doxorubicin. However, other principles and compositions are also being considered.”

You are the inventor of over 14 patents and you have initiated two start-up companies. Tell me about the company LIDDS, which you co-founded in 2003?

“The company has developed a new proprietary local intelligent drug delivery technology platform. The platform could have many treatment opportunities. The first product, Liproca® Depot, which is currently in clinical Phase II stages for improved tumor-target treatment of localized prostate cancer, is aimed towards satisfying unmet clinical needs in this area. In addition to prostate cancer, there is also a potential for treatment of Benign Prostatic Hyperplasia/Benign Prostatic Obstruction (BPH/BPO). The product comes as a pre-filled sterile drug container/syringe, which also acts as equipment that mixes the paste prior to injection. The dose can be adjusted to the volume of the prostate gland and the paste can be visualized by ultrasound during dosing. The drug carrier (calcium sulfate) will be completely absorbed, leaving no residues or degradation products. The product can therefore be dosed repeatedly. Scalable manufacture has been verified and suitable full-scale equipment and production facilities have been identified. The most rapid road to market for Liproca® Depot for the treatment of localized prostate cancer will be replacement of the current adjuvant systemic antiandrogen therapy prior to radiation therapy. This approach has been endorsed by the Swedish MPA. From now until market launch, total costs are estimated to amount to € 20 million and market launch could be expected in 2019. If desired, the timeline could be compressed by around one year if more resources are made available. It would be possible to develop Liproca® Depot for the treatment of BPH/BPO in parallel to prostate cancer and launch this indication on the market in 2019 as well.”

What is the IMI-project?

“The Innovative Medicines Initiative (IMI) is Europe’s largest public-private initiative in the life science sector between the EU and the European pharmaceutical industry association (EFPIA). The aim is to speed up the development of better and safer medicines for patients and build networks of industrial and academic experts in order to boost pharmaceutical innovation. OrBiTo is a key initiative within IMI, and is designed to streamline and optimize the development of orally administered drug products with a strong focus on developing novel experimental and theoretical models based on increased knowledge of biopharmaceutical factors and their interplay with the dynamic gastrointestinal (GI) physiology. The project started in 2012 and will continue for five years. It will address key gaps in our knowledge of GI drug absorption and deliver a framework for rational application of predictive biopharmaceutics and tools for oral drug delivery. The OrBiTo project is expected to “change the game” in industrial product development from an essentially empirical approach (“trial-and-error”) to a more rational model-based approach.”

What are the latest trends/developments in drug delivery systems and methods?

“Over the past 50 years, a number of innovations have been transformed through extensive research into practical strategies for sophisticated therapies. Many exciting drug delivery technologies are now beginning to realize the concepts of targeted therapies. However, the battle against disease is far from conquered, and the continued pharmaceutical development of these treatment strategies remains an urgent priority to further improve the efficacy and safety of drug therapy. For instance, it has long been considered that spatiotemporal drug presentation is a critical determinant of efficacy. Achieving optimal active drug exposure over time in the target space and within a hostile physiological environment remains a challenge in need of new and innovative solutions. This challenge is unlikely to be conquered without collaboration and integration in multidisciplinary scientific driven projects and teams.”

What impact has new biomaterials and nanotechnology had on the development of drug delivery methods?

“A few exciting pharmaceutical products that are based on nanotechnology have reached the market. These have been especially important for poorly soluble drugs with low dissolution rates that has seriously limited the bioavailability following oral administration. New insights in molecular biology, material sciences and biomedical sciences have produced a wealth of new systems, materials and approaches with the potential to treat disease. The multidisciplinary approach is critical in the search for delivery systems that behave selectively against complex targets at the true target site, delivering optimal concentrations of drug and other actives at the right time and over an optimal period of time. This work must continue but needs to apply established standard system models that are fully, or almost fully characterized. It is crucial to recognize that manufacturing processes are critically important, as are assessments of the physical and chemical stability of nanoparticles (or other constructs) and ligands. The reproducibility of the manufacturing or preparation process and scale-up issues must be addressed.”

Safety is of course of great concern when developing drug delivery systems. What are the safety issues?

“Safety and toxicological issues concerning the chemical or physical properties of these nanosystems may differ from that of micro or macrosystems manufactured from the same material because of differences in organ distribution, surface properties and effects. Even particle shape may be a critical safety factor, with particle asymmetry being associated with greater toxicity

A general feature raised in both the EMEA Reflection Paper (2006) on ‘Nanotechnology-based medicinal products for human use’ and the conclusions of the opinion of the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) reporting to the EM(E)A is the need for new, science-based approaches to be developed to answer regulatory questions regarding efficacy, safety and quality.”