Download PharmaMedDevice 2007 Issues in nanodrug delivery and

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PharmaMedDevice 2007
Issues in nanodrug delivery and personalized medicine
24-26 April 2007, New York, NY, USA
Raj Bawa
Addresses
Bawa Biotechnology Consulting LLC
21005 Starflower Way
Ashburn
VA 20147
USA
Rensselaer Polytechnic Institute
110 Eighth Street
Troy
NY 12180
USA
Email: [email protected]
IDrugs 2007 10(7):455-458
© The Thomson Corporation ISSN 1369-7056
Introduction and conference overview
The PharmaMedDevice 2007 conference featured over
50 sessions highlighting the latest issues and trends in the
convergence of the medical device, pharmaceutical and
biological industries. This event, which showcased over 100
exhibitors, addressed the needs of the combination products
market, covering the exciting innovations currently taking
place in drug delivery technology and healthcare.
A combination product consists of at least two regulated
components, such as a drug and device, biological and
device, drug and biological, or drug, device and biological,
and these components are physically, chemically or
otherwise combined or mixed and produced as a single
entity. The global market for drug-device combinations is
rapidly growing by between 10 and 14% per year, and is
dominated by cardiovascular applications, which possess
almost a 90% share. Other potentially active areas of R&D
include steroid-eluting electrodes, closed-loop glucosemonitoring insulin pumps, inhalation devices and
transdermal delivery systems.
Two visionary keynote lectures were presented: Bill Cook
(Cook Group, USA) delivered a presentation entitled 'What's
next: Where devices and medicine go from here', in which he
explored the partnership strategies, innovative approaches to
R&D, investment challenges and regulatory issues needed to
create winning combination products that will transform
healthcare. In the second keynote presentation, Steven Burrill
(Burrill & Co, USA) contemplated the future of the biotech
industry, discussing how scientific advances, technological
convergence and expanding global markets will continue to
transform the lifescience industries and open up new frontiers
for personalization and commercialization.
This report will focus on two specific tracks: (i)
bionanotechnology as applied to drug delivery; and (ii) the
role of genomic biomarkers in personalized medicine.
Rensselaer Polytechnic Institute, USA) emphasized that the
line between medical devices and pharmaceuticals is
blurring as the two technologies continue to increasingly
overlap. Some critical trends and issues pertaining to
nanotechnology and nanomedicine were highlighted.
Dr Bawa stated that one of the major problems facing
nanotechnology is the confusion, hype and disagreement
among experts regarding its definition. Nanotechnology is
an umbrella term used to define the products, processes and
properties at the nano/micro scale that have resulted from
the convergence of the physical, chemical and life sciences.
By manipulating atoms, scientists can create stronger, lighter
and more efficient materials, termed 'nanomaterials', with
tailored properties. In addition to the numerous advantages
provided by this scale of miniaturization over its
conventional 'bulk' counterparts, quantum physical effects at
this scale impart additional novel properties.
One of the most quoted definitions of nanotechnology is
that used by the National Nanotechnology Initiative
(NNI) – 'Nanotechnology is the understanding and control of
matter at dimensions of roughly 1 to 100 nanometers, where
unique phenomena enable novel applications.' Clearly, this
definition excludes numerous devices and materials of
micrometer dimensions, a scale that is included within the
definition of nanotechnology by many leading nanoscientists.
Therefore, experts have cautioned against an overly rigid
definition based on a sub-100-nm size, emphasizing instead
the continuum of scale from the nano to micro.
Dr Bawa discussed how various US federal agencies are also
grappling with the definition of nanotechnology. Agencies
such as the US FDA and the US Patent and Trademark Office
(USPTO) use the NNI definition based on a scale of less than
100 nm. This definition continues to present difficulties, not
only for understanding nanopatent statistics, but also for the
proper assessment of nanotechnology's scientific, legal,
environmental, regulatory and ethical implications. This
problem persists because nanotechnology represents a cluster
of technologies, each possessing different characteristics and
applications. Although the sub-100-nm size range may be
critical for a nanophotonic company, where size-dependent
quantum effects are particularly important, this specific size
range is not important to a drug company from a formulation,
delivery and efficacy perspective, because the desired or
ideal property may be achieved in a size greater than
100 nm. Several examples from the pharmaceutical industry
highlight this critically important point, including the
marketed albumin-bound nanoparticle formulation of
paclitaxel, Abraxane, and anticancer integrin αvβ3-targeted
nanoparticles from Kereos Inc, all of which are larger 100 nm
in size.
Understanding and defining nanotechnology
The opening remarks and presentation by the session chair
Raj Bawa (Bawa Biotechnology Consulting LLC and
Given this confusion, Dr Bawa proposed a more practical
definition of nanotechnology. Unlike the NNI definition, he
456 IDrugs 2007 Vol 10 No 7
proposed a definition that is unconstrained by any arbitrary
size limitation. Thus, he described nanotechnology as, 'The
design, characterization, production and application of
structures, devices and systems by controlled manipulation
of size and shape at the nanometer scale (atomic, molecular,
and macromolecular scale) that produces structures, devices
and systems with at least one novel/superior characteristic
or property.' Dr Bawa proposed that the size limitation
imposed in NNI's definition should be dropped, especially
as applied to nanomedicine. In fact, the phrase 'small
technology' may be more appropriate, as it accurately
encompasses both nanotechnologies and microtechnologies.
Dr Bawa opined that an international nomenclature, as well
as a definition scheme for nanotechnology, should be
promptly developed.
Trends in nanomedicine
The
high-risk,
high-payoff
global
nanotechnology
phenomenon is in full swing as innovations at the intersection
of engineering, biotechnology, medicine, physical sciences
and information technology are spurring new directions in
research, education, commercialization and technology
transfer. In fact, the future of nanotechnology is likely to
continue in this interdisciplinary manner. According to Lux
Research Inc, governments, corporations and venture
capitalists spent US $12.4 billion in 2006 on nanotechnology
R&D globally, up 13% from 2005. One of the greatest impacts
of nanotechnology is taking place in the context of biology,
biotechnology and medicine. This arena of nanotechnology is
generally referred to as nanomedicine.
Dr Bawa discussed how nanomedicine might help improve
the patient's quality of life, reduce societal and economic costs
associated with healthcare, offer early detection of
pathological conditions, reduce the severity of therapy and
result in improved clinical outcomes for the patient. The
nanopharma market is expected to grow significantly in the
coming years. According to a market research company, the
Freedonia Group, the US demand for nanotechnology-related
medical products, such as nanomedicines, nanodiagnostics,
nanodevices and nanotech-based medical supplies, is
predicted to increase by over 17% per year to US $53 billion in
2011 and US $110 billion in 2016. Dr Bawa predicted that the
greatest short-term impact of nanomedicine might be in
therapies and diagnostics for cancer and the CNS disorders.
The speaker explained that, in general, commercial
nanomedicine is at a nascent stage of development and its
full potential remains years or decades away. However,
there are a few bright spots where development is
progressing more rapidly. Drug delivery is one such area of
nanomedicine that is already producing significant results,
accounting for three quarters of all global sales in
nanomedicine and the majority of patent filings worldwide.
For example, site-specific targeted drug-delivery systems
with the potential to address unmet medical needs and
personalized medicine (discussed ahead) are on the horizon.
Other more futuristic targeted drug-delivery approaches
involve 'nanofactories', whereby biological molecules found
in vivo can be converted into active biotherapeutics in
response to a localized medical condition.
There exists enormous excitement and expectation regarding
nanomedicine's potential impact. Although early forecasts
for commercialization are encouraging, there are bottlenecks
as well. Some formidable challenges include legal,
environmental, safety, ethical and regulatory questions, as
well as emerging 'thickets' of overlapping patent claims. In
fact, patent systems are under great scrutiny and strain, with
patent offices around the world continuing to struggle with
the evaluation of a swarm of nanotech-related patent
applications. In fact, this thicket of patent claims has resulted
primarily from patent proliferation, as well as the continued
issuance of surprisingly broad patents by the USPTO.
Added to this confusion is the fact that the NNI's widely
cited definition of nanotechnology is not representative,
especially in reference to nanomedicine. The end result of all
this is quiet predictable – a chaotic, tangled patent landscape
in certain areas of nanomedicine where the competing
players are unsure of the validity and enforceability of
numerous issued patents. If this trend continues, it could
stifle competition and limit access to certain nanomedicine
inventions. Therefore, reforms are urgently needed at the
PTO to address problems ranging from poor patent quality
and questionable examination practices to inadequate search
capabilities, rising attrition, poor employee morale and a
skyrocketing patent application backlog. Clearly, only a
robust patent system can stimulate the development of
commercially viable nanomedicine products that can
positively impact healthcare systems.
Given this backdrop, it is hard to predict whether
nanomedicine will make small, but valuable, contributions
to medicine and healthcare, or whether it will act as a
catalyst for a vast technological and healthcare revolution.
Dr Bawa said that one thing is certain, however –
nanomedicine is here to stay and it is sure to generate both
evolutionary and revolutionary products in the future.
Dr Bawa's presentation also focused on marketed or
commercially promising nanodrugs, medical devices and
drug-delivery technologies. Critical issues, strategies and
challenges relating to patenting such products were
presented,
and
major
factors
that
will
drive
commercialization in the near future were also discussed.
These factors include federal funding, an aging population's
desire for novel drugs and therapies, the high cost and
increasing difficulty of generating novel actives by big
pharma, an ever-increasing understanding of the molecular
basis of disease, and the expiration of blockbuster drug
patents. The inability of the USPTO to check the current
patent proliferation and 'patent land grab' currently
underway, as well as the effect of emerging patent thickets
on commercialization, was carefully analyzed. Quality
control and the important role of regulatory agencies such as
the FDA were also emphasized.
Several examples of potentially innovative products in the
drug-delivery arena that cleverly integrate biological
information and material sciences were presented. Some
products could be available immediately, while others are
on the distant horizon. Nanotech-based drug delivery
advances discussed included: (i) miniaturized nanofluidic
Meeting Report PharmaMedDevice 457
devices and systems that more efficiently transport fluids
to the site of delivery, preventing turbulence and mixing;
(ii) more efficient site-specific or precision targeting via
nanomedicines with reduced systemic side effects and better
patient compliance; (iii) close-looped drug-delivery
nanodevices and implants, also known as 'smart pills',
containing sensors (to monitor biomolecules) and drug
reservoirs (for precise delivery) located on the same chip;
and (iv) microsurgical devices, molecular motors or
nanobots (either man-made or engineered microbes) that are
capable of navigating throughout the body to carry out
targeted healing, such as repairing damaged tissues,
destroying tumors or viruses, and even performing gene
therapy or vaccination.
Application of nanotechnology in oral
inhalation device technology
Ola Nerbrink (Novo Nordisk A/S, Denmark) discussed the
role of pulmonary inhalation devices. Nebulizers, pressurized
metered dose inhalers and liquid devices have all utilized
drug particles and formulation technology in the micron size
range. Dr Nerbrink discussed the possibility of using drug
particle and formulation techniques based on nanotechnology
for drug delivery. He discussed how CFC-free technologies
could improve the lung deposition of nanoparticles. He also
contrasted developments in solution versus suspension
aerosols and compared classic asthma therapy for local
application in the lungs to novel therapy using
nanotechnology.
Nanodrugs are a heterogeneous group of drugs that
generally offer unique properties because of their nanoscale
dimensions or as a result of nanoencapsulation. They are
diverse both in their shape, size and composition. Many of
the properties of nanomaterials are fundamentally different
from those of their macroscopic/bulk analogs. Therefore,
nanodrugs, particularly nanoparticulate drugs, often offer
several advantages over their bulk counterparts, in areas
such as solubility (high surface area/bulk ratio),
bioavailability, half-life, stability/shelf life, ability to
penetrate biological barriers/membranes, toxicity, patient
fasted/fed variability, delivery dose, catalytic properties,
imaging, multifunctionality, site-specific delivery/targeting,
pharmacokinetics, surface structure, drug distribution, and
physical properties.
There are numerous polymeric nanoscale materials of
varying architectures that can act as platforms for active
agents, including pharmaceuticals. It is important to note
that these structures are sometimes loosely classified as
nanoparticles. In other words, there is no universal
convention or nomenclature that classifies nanoparticles as
perfect spherical structures with nanoscale dimensions.
Some of the common shapes include spheres (hollow or
solid), tubules, particles (solid or porous) and tree-like
branched macromolecules (dendrimers). They are
synthesized by various methods, including self-assembly,
vapor
or
electrostatic
deposition,
aggregation,
nanomanipulation or imprinting. Similarly, the polymers that
constitute these structures are diverse. They are selected for
qualities such as biodegradability, biocompatibility,
conjugation, complexation, or encapsulation properties, in
addition to their ability to be functionalized. The specific
protocol for nanoparticle synthesis is dictated by the specific
drug used and the desired delivery route. The critical
characteristics of a nanoparticle that relate to its function are
size, surface charge, encapsulation efficiency and release
properties.
Dr Nerbrink provided a few examples of polymeric nanoscale
materials of varying architectures that can act as platforms
for active agents. These include nanoparticles, colloidal
dispersion and nanocrystals, quantum dots, nanoshells,
dendrimers, liposomes, micelles (polymeric micelles and
cylindrical worm micelles), polymersomes, cyclodextrins,
magnetic nanoparticles, nanosphere hydrogels, fullerenes and
nanocochleate delivery vehicles.
Personalized medicine and genomic
biomarkers
The FDA approved the first race-specific drug, BiDil
(hydralazine + isosorbide dinitrate) in June 2005, for the
treatment of heart failure in African-Americans who are
intolerant of ACE inhibitors. The approval of this drug
highlighted the role of race in medicine. More significant
perhaps, this approval emphasized the fact that drugs have
different effects in different people. In other words, genetics
(or gene variations) influence drug efficacy and toxicity.
Humans have long known that heredity affects health. For
over a century, genetics and the role of human genes in
disease has been slowly reshaping many aspects of medicine
and healthcare delivery. Now, pharmaceutical companies
are exploring genetic testing and genomics as tools to
guide them to improve the drug-development process.
This is particularly pertinent given that the current cost to
bring a new drug to market is estimated to be almost
US $900 million, and usually takes 15 or more years from
discovery to launch. This approach could also eliminate
ineffective or toxic drugs early on in the R&D process, while
highlighting variations in the drug's efficacy and toxicity in
different patient populations. In the near future, as specific
gene variations and their involvement in drug metabolism
are discovered, genetic testing to gauge drug toxicity and
efficacy could become routine in the clinic. Clearly, the
'personalized medicine' revolution is fast approaching a
stage at which drugs could be designed that target different
patient groups, thereby increasing health and safety. In fact,
more than 30 drugs currently on the market have
therapeutic responses dictated by genetic variations. Much
of this revolution in personalized medicine lies in an area of
clinical research known as pharmacogenomics, whereby
analysis of an individual's unique genome can allow for the
development of drugs that are more efficacious and less
toxic. Tailored therapies are on the horizon, where genetic
variations between patient populations can be detected
more precisely and appropriate therapies administered
accordingly.
Dan Levine (Rogosin Institute, USA) explained that the goal
of personalized medicine is to obtain the best medical
outcome (ie, maximizing cure or minimizing adverse effects)
by selecting therapies customized to an individual's genetic
458 IDrugs 2007 Vol 10 No 7
profile. Decreasing adverse effects, while enhancing
therapeutic outcome, could also lower the cost of healthcare.
Personalized medicine represents a significant advance from
most current diagnostic methods and therapies, which were
developed to detect and treat the symptoms and/or
apparent causes of disease broadly across all patients.
Conventional drug-development approaches do not take
into account the fact that, because of genetic variations, a
disease may manifest itself slightly differently in different
types of patients. Although the full potential of personalized
medicine in clinical practice is years away, the completion of
the draft sequence of the human genome, recent advances in
biomarker chemistry and advances in disease biology have
all begun to alter the landscape of medicine. Given this
backdrop, the FDA released guidelines in 2005 on how and
when pharmaceutical companies can submit genomic data.
In fact, the FDA views pharmacogenomics and genetic
profiling for drug development (and subsequent
personalized medicine) as a major opportunity on the critical
path to novel medical products.
In short, Dr Levine predicted that medicine in the future
may be more 'personalized', with patients receiving
treatment based upon the actual underlying biology of their
disease state, not only their symptoms. The speaker stressed
that the pace of this transformation is unknown, but
anticipating and planning for the profound consequences is
vital. He emphasized the fact that new diagnostic tests
making use of nanotechnology to quantify disease-related
biomarkers, including altered genes, a change in protein
production, an altered biochemical pathway or structural
alternations in cells, could offer an earlier and more
personalized risk assessment prior to the appearance of
symptoms. Individuals with increased susceptibility for
certain diseases might benefit from regular personalized
check-ups to monitor changes in their biomarker patterns.
Supported by such an analysis, together with bioinformatic
approaches, healthcare professionals will be able to counsel
high-risk patients to take up a personalized prevention
approach.
Vol 10 No 7 July 2007
IDrugs
The Investigational Drugs Journal
Contents
Meeting Reports
427
463
BIO 2007 Annual International Convention
Angus Dalgleish
Investigational drug activities in Asia: Focus on China,
Taiwan and Japan
Steven Tear
There are many technical challenges involved in even the
most basic decisions in cancer vaccine development, such
as the choice of antigen, formulation, adjuvant, route of
delivery and schedule. However, as discussed in this
feature review, the tumor itself may pose the greatest
technical challenge, particularly with regard to escaping the
immune response. Strategies to overcome this challenge
are discussed.
430 Highlights from the exhibition hall
Steven Tear
433
Digestive Disease Week 2007
Danny Chan
436 Updates from established drugs
Danny Chan
439 Recombinant protein and small-molecule therapeutics
Sarah A De La Rue
443
Drug Evaluations
468
Association for Research in Vision and
Ophthalmology 2007: The Aging Eye
Experimental Biology 2007
Attempts to circumvent resistance to imatinib led to the
discovery of nilotinib, a novel, potent and selective oral Bcr-Abl
kinase inhibitor. Nilotinib is being developed by Novartis AG for
the treatment of chronic myelocytic leukemia and other
disorders.
Today's Research: Tomorrow's Health
Catherine Edwards
450
Neisseria Vaccines 2007 – International
Workshop
Diana Martin
Nilotinib – a novel Bcr-Abl tyrosine kinase
inhibitor for the treatment of chronic
myelocytic leukemia and beyond
Elias Jabbour, Jorge Cortes, Francis Giles, Susan O'Brien &
Hagop Kantarjian
Pascal Deschatelets
447
Overcoming technical challenges in the
development of cancer vaccines
480
Erratum: Deferitrin for iron overload disorders
James C Barton
453
Antiviral Research – 20th International
Conference
Deferitrin, a desferrithiocin-derived hexadentate iron chelator, is
being developed by Genzyme Corp for the treatment of patients
with severe iron overload.
Adekemi Oni
455
PharmaMedDevice 2007
Issues in nanodrug delivery and personalized medicine
Raj Bawa
491
Patent News
Thomson Scientific Current Awareness Analysts
Features
459
The patenting of novel biotech products
495
Licensing Highlights
Jonathan Bright, Jaya Shumoogam & Steven Tear
Philip M Webber
501
Meetings Diary
Patent laws for NCEs require such entities to be novel,
inventive and have some practical use. Patent applications
must describe how to make the entities, and provide data to
support the patent claims. The same criteria are being applied
by Patent Offices to the patenting of the new generation of
biotech products: genes, proteins, microorganisms, transgenic
plants and transgenic animals. This feature review focuses on
the patenting of these novel products.
508
Author Index