CANADIAN RESEARCH FOCUS
September 2, 2011

Jackson, J., Burt, H. et al.just published a new study
“The use of nanocrystalline cellulose for the binding and controlled release of drugs”, International Journal of Nanomedicine. 6: 321-330, 2011.

Interview with Dr. Helen M. Burt

Dr Burt is the Angiotech Professor of Drug Delivery in the Faculty of Pharmaceutical Sciences at UBC and since September 2011, is the Associate Vice President, Research & International. She was born in Manchester, England and obtained her B. Pharm.(Hons) from the University of Bath and her Ph.D in Pharmaceutics from UBC. Her major research efforts are supported by grants from CIHR and NSERC and involve the development of polymer-based drug delivery systems for controlled and localized drug delivery. She has published over 140 peer-reviewed papers and 8 patents. She has been the recipient of several teaching prizes and research awards, including the UBC Killam Teaching Prize and Killam Faculty Research Prize, NSERC Synergy Award for Innovation, CSPS Award of Leadership in Canadian Pharmaceutical Sciences and YWCA Woman of Distinction Award for Science, Research and Technology. She is a founding scientist in the Centre for Drug Research and Development (CDRD), a member of the Canadian Academy of Health Sciences and has served on the Board of Directors of the Provincial Health Services Authority.

Cellulose and its derivatives have been used in the pharmaceutical industry for many years and is useful as an excipient in orally administered drug-loaded tablets. To date this use of cellulose has not involved a direct molecular level control of drug release by manipulating binding interactions with the drug. However, the large surface area and negative surface charge of nanocrystalline cellulose (NCC) suggests that provided large amount of drugs can be bound to the material's surface, there is great potential for high payloads and optimal control of dosing. The hydroxyl groups on NCC also provide an opportunity for surface modification by a variety of chemical groups for altering the loading and release of drugs. As NCC is a low-cost, readily abundant material it offers a substantial environmental advantage compared with other nanomaterials. In this article Dr. Burt and her research team investigate the binding and release of drugs from NCC with and without surface modification by cetyl trimethylammonium bromide (CTAB).

CC-CRS:
Could you please explain what the key target diseases for your nanocrystalline cellulose (NCC) drug delivery system are and why specifically they will benefit?

Dr. Burt:
This remains to be determined, but we believe there are significant opportunities to explore the pharmaceutical applications of NCC as a drug delivery excipient either alone, or in conjunction with other formulations. For example, it may have applications in topical or mucosal controlled delivery of drugs; such as release of anti-infective agents from hydrocolloid wound dressings. We are also suggesting that NCC may be suitable for implantation into surgical resection voids such as tumor sites, bone or periodontal cavities. Alternatively, it may find application as a component of controlled release oral formulations.

CC-CRS:
Could you please explain further how the surface charge of the NCC assists in the delivery of hydrophobic or hydrophilic drugs? How does this principle assist in the sustained delivery of the therapeutic(s)?

Dr. Burt:
We believe that the two ionized, hydrophilic drugs we studied probably bound by an ionic interaction with the negatively charged surface of NCC and that release occurred via an ion exchange mechanism, with the phosphate buffered saline release medium providing ions for exchange. In the case of the hydrophobic drugs, the NCC was coated with the cationic surfactant CTAB and we believe the hydrophobic drugs partitioned into the hydrophobic domains of the CTAB. The release mechanism was likely due to diffusion of the drugs out of the hydrophobic domains of the CTAB-NCC.

CC-CRS:
In preparing the NCC, does the age (or species) of the tree have an impact on the quality of the cellulose? From 40g of pulp, how much cellulose is obtained? Are there any concerns with using cellulose from softwood in humans (explain what the concerns might be)?

Dr. Burt:
My colleague and co-author, Dr Wadood Hamad (FPInnovations) has expertise in this area and one of his publications reports that NCC with high crystallinity can be produced from commercial softwood pulp with yields of between 21-38%. Studies are ongoing to examine the extraction of NCC and potential environmental and toxicity issues.

CC-CRS:
How does NaCl assist in flocculating NC and why is this a concern in your synthesis of the NCC system? What happens if you add too much NaCl?

Dr. Burt:
NCC samples were provided to us as a stable colloidal dispersion in water and we needed to be able to centrifuge down the NCC particles. However, the NCC dispersion could not be sedimented under high speed centrifugation. The addition of PBS or 5 mM NaCl allowed for flocculation and enabled us to centrifuge the particles. The NaCl is functioning as a flocculating electrolyte by reducing the zeta potential and hence the diffuse layer thickness of the electric double layer associated with NCC particles. The particles then form loosely bound flocculated particles held together by weak Van der Waal's forces of attraction. Theoretically, the addition of excess electrolyte can sometimes result in deflocculation of the particles but this was not a problem in our work.

CC-CRS:
With CTAB the delivery was extended by one day (Figure 9) - are you planning to extend this duration further? What is your goal delivery duration? And, with CTAB the cumulative release is not as high as without it (Figure 8) - can this be similarly improved without harming the delivery duration?

Dr. Burt:
There is a lot of work remaining to be done to optimize the release from this system. At this stage, we don't have a particular release lifetime as our goal. We would like to use different surfactants bound to the surface or conjugate short chain hydrophobic polymers onto the NCC surface to bind drugs.

CC-CRS:
Why does some of the drug bind weakly (and releases quickly initially) and some more strongly bound (and releases more slowly)? Are there sites on the NCC which are more prone to drug binding/interaction?

Dr. Burt:
This is probably explained by the different modes of drug binding to the surface and different release mechanisms between ionized, hydrophilic drugs and hydrophobic drugs..

CC-CRS:
How will the NCC system be administered into the body (systemically/locally)? And, how good is the specificity of this NCC system? Is there any risk of off-target toxicity?

Dr. Burt:
This work is still very early stage. I anticipate that the first drug delivery applications might be topical/mucosal.

CC-CRS:
What major hurdles remain to be overcome in this technology before patients can benefit from its application? What research are you planning to do next in terms of drug delivery with NCC?

Dr. Burt:
There's a lot we still need to learn about this technology and its potential for drug delivery applications. Studies are needed on; biocompatibility, the nature and range of drugs that can be bound to and released from NCC, understanding the factors influencing drug release rates, determining local delivery and disease sites with the best potential for the technology, to name but a few.