659
Drug delivery in biotechnology: present and future
Gorka Orive
, Rosa Maria Hernández
, Alicia Rodrı́guez Gascón
,
Alfonso Domı́nguez-Gily and José Luis Pedraz
z
Drug delivery is becoming a whole interdisciplinary and
independent field of research and is gaining the attention of
pharmaceutical makers, medical doctors and industry. A
targeted and safe drug delivery could improve the performance
of some classical medicines already on the market and,
moreover, will have implications for the development and
success of new therapeutic strategies, such as peptide and
protein delivery, glycoprotein administration, gene therapy and
RNA interference. Many innovative technologies for effective
drug delivery have been developed, including implants,
nanotechnology, cell and peptide encapsulation,
microfabrication, chemical modification and others. On the long
way from the clinic to market, however, several issues will have to
be addressed, including suitable scientific development, specific
financial support as a result of altered scientific policy,
government regulations and market forces.
Addresses


Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of
Pharmacy, University of the Basque Country, Vitoria–Gasteiz, Spain
y This review highlights novel drug delivery systems that
Department of Pharmacy and Pharmaceutical Technology, Faculty of
Pharmacy, University of Salamanca, Salamanca, Spain
z
e-mail: knppemuj@vc.ehu.es
Current Opinion in Biotechnology 2003, 14:659–664
This review comes from a themed issue on
Pharmaceutical biotechnology
Edited by Brian Metcalf and Rino Rappuoli
0958-1669/$ – see front matter
ß 2003 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.copbio.2003.10.007
Abbreviations
RNAi RNA interference
siRNA small interfering RNA
Introduction
The field of drug delivery is developing rapidly and is
gaining the attention of scientists, pharmaceutical makers
and industry. The development of effective drug delivery
systems that can transport and deliver a drug precisely
and safely to its site of action is becoming the ‘holy grail’
of pharmaceutical researchers.
Indeed, a great number of new delivery technologies
surface each year and nearly every part of the body has
been studied as a potential route for administrating both
classical and novel medicines. Consequently, promising
ways of delivering poorly soluble drugs and peptides and
www.current-opinion.com
proteins have been devised. In addition, attractive drug
delivery technologies such as transdermal patches, nano-
devices, bioadhesive systems, implants, microfabricated
systems, cell encapsulation devices and novel nasal drug
delivery systems are currently under intensive study.
As a result of these and other advances, the market for
drug delivery is changing drastically. Benefits from new
formulations that offer a competitive edge after expiry of
patent, market extension, and reduction of the drug
development budget, which have increased demand,
are contributing to creating a new market in the field
of drug delivery. In fact, according to a recent report from
Business Communications Company Inc., the US market
alone for drug delivery systems is estimated at $43.7
billion in 2003 and is expected to rise at an average annual
growth rate of 11.3% to reach $74.5 billion by 2008 [1]
(Table 1).
could improve certain classical medicines already on the
market and discusses new technologies that are being
developed to overcome some of the current obstacles of
drug delivery. In addition, we include our insights on the
research policies of drug delivery and consider how these
issues should be approached to advance the field.
Current obstacles
The final aim of pharmacy and medicine is the delivery of
any drug at the right time in a safe and reproducible
manner to a specific target at the required level. For many
drugs, however, these ideal requirements constitute hype
rather than hope. For example, although the oral route is
one of the preferred methods of drug delivery, owing to its
non-invasive nature, adequate peptide or protein drug
delivery has not yet been attained via this route. This is,
in part, a consequence of the acidic conditions of the
stomach, the first-pass effect of the liver (i.e. the loss of
drug owing to metabolism processes before entering the
systemic circulation) and the resistance exerted by the
intestine, which either alter, destroy or reduce absorption
of nearly all macromolecules, reducing their bioavailabil-
ity. As a result, millions of diabetics worldwide have to
give themselves insulin shots daily, provoking a high
percentage of negligence in this treatment.
Other frequently employed routes for drug administra-
tion are nasal drug delivery and injection. Nasal delivery
shows a poor absorption of polar compounds [2], whereas
injection is associated with pain and the reluctance of
patients to use this method. One alternative to these
Current Opinion in Biotechnology 2003, 14:659–664
660 Pharmaceutical biotechnology

Table 1

Advanced sales of drug delivery systems in the United States 2001–2008 ($ million)].
2001 2002 2003 2008 AAGRy (%)

Sustained release (oral, injectable, topical) 17 710.2 19 482.8 21 475.6 34 102.6 9.7
Implants and intrauterine devices 1000 1185 1387.2 2485.4 12.4
Transdermal drug delivery systems 2010.3 2311.9 2648.1 4485.4 11.1
Targeted drug delivery systems 6271.3 7309.2 8317.7 15 471.9 13.2
Transmucosal drug delivery systems 7358.8 8409.9 9714.8 17 713.6 12.8
Other 107.8 119.5 131 211.1 10
Total 34 458.4 38 818.3 43 674.4 74 470 11.3

y
Provided by [1]. AAGR, average annual growth rate.

routes is the administration of drugs across the skin. To
succeed, drugs must cross the outer membrane, called the
stratum corneum, which offers resistance to the diffusion
of substances. Other major challenges are the intracellular
delivery of macromolecular drugs, the chronic adminis-
tration of drugs into tumours and the targeted delivery of
glycoproteins.
recently when two children administered gene therapy
for severe combined immunodeficiency disease devel-
oped leukaemia [5]. Similarly, if the promise of RNAi
therapies is to be realized, scientists will need to develop
ingenious systems to protect the small interfering RNAs
(siRNAs) in the bloodstream and to target them into the
right cells.

The lack of suitable drug delivery systems not only has
implications for conventional drug administration routes
and dosage forms, but is becoming a drawback for the
advance of novel therapeutic strategies like cell-therapy,
RNA interference (RNAi) [3] and gene therapy. In gene
therapy, a virus is used as a vector to deliver corrective and
active genes into the cells of a patient. But, if the vector
stitches itself into the genes of a cell it can cause uncon-
trolled mutations and induce cancer. This therapy is
clearly not trivial, as evidenced by the tragic death in
1999 of a gene therapy trial volunteer [4] and more
All these drawbacks have stimulated many pharmaceu-
tical companies and start-up biotech companies to
develop drug delivery systems that can exert their func-
tion in an efficient and safe manner (Table 2). Scientific
policies that provide a clear direction on how to advance
the field of drug delivery are still missing, however.
Advances in drug delivery
Oral drug delivery
Many research groups are investigating new ways to
improve the protection and absorption of peptides after

Table 2

Selected pharmaceutical companies working in drug delivery.

Company Technology Product description

NanoSpectra Biosciences (Houston, TX)
Sontra Medical Corporation (Franklin, MA)
MacroMed Inc. (Sandy, UT)
Neurotech SA (Evry, France)
CellMed (Alzenau, Germany)
MicroCHIPS Inc. (Bedford, MA)
Nektar Therapeutics (San Carlos, CA)
Insert Therapeutics (Pasadena, CA)
ALZA (Mountain view, CA)
Advectus Life Science (West Vancouver, CA)
PEG, polyethylene glycol; PLGA, poly(D,L-lactide-co-glycolide).
Nanoshells Nanoparticles with physical properties for optical therapies
Ultrasound technology SonoPrepW: ultrasound skin permeation applications
in transdermal drug delivery
PLGA microspheres Drug delivery systems that facilitate improved
administration of difficult-to-deliver active agents
Encapsulated cells Cell encapsulation technology for the delivery of drugs
to the eye and brain
Encapsulated cells Microencapsulation of allogeneic genetically engineered
human cells for chronic disorders
Microchips Microfabricated devices containing hundreds of
microreservoirs for drug delivery
PEGylation technology Improved performance and dosing of peptides,
proteins, antibodies and oligonucleotides
Cyclodextrins Cyclodextrin-containing polymers for improved systemic
delivery of a wide range of therapeutics
Nanotechnology DoxilW: lipid nanoparticles that incorporate a PEG coating
for the treatment of refractory ovarian cancer and
AIDS-related Kaposi’s sarcoma
Nanotechnology Nanotechnology for the delivery of cancer-fighting drugs
across the blood–brain barrier for the treatment of brain tumors

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oral administration. For instance, the use of bioadhesives
has been studied to promote the penetration of drugs
through and between intestinal cells. Polymers such as
polyanhydrides bind to the gut and cross the intestinal
mucosa, leading to improved bioavailability of the drug.
Lectins have been deemed as a second generation of
bioadhesives, owing to their non-toxicity and special
binding properties, which simulate a ligand–receptor
interaction [6,7]. Other researchers have been working
on the blockade of protease inhibitors and cellular pump
systems, which could prevent effective absorption of
certain drugs and thus reduce their therapeutic effective-
ness. In this regard, Glytech technology, designed to
temporarily inhibit and/or block the p-glycoprotein pump
system, has been developed by Eurand (http://www.
eurand.com). Results obtained with this system in animal
models show improved absorption profiles of several
therapeutically active compounds.
Peptidic drugs can be also conjugated to a macromole-
cular carrier, such as a polymer or protein [8]. At present,
polyethylene glycol is the most widely used polymer for
the modification of proteins with therapeutic potential,
because of its low toxicity and cost and the commercial
availability of many molecular weight variants [9]. Using
a similar approach, Nobex corporation (http://www.
novexcorp.com) attached low molecular weight polymers
to specific sites on drug molecules to create drug–polymer
conjugates [10]. Nobex is using this technology to make a
form of insulin that can be given orally. In fact, according
to a Phase II clinical trial, which involved more than 150
patients, a rapid, dose-dependent absorption of the oral
insulin and a lowering of fasted blood glucose levels (i.e.
morning levels before food) have been achieved with no
safety concerns.
Nasal drug delivery
The use of nasal routes for drug delivery has created much
interest in the pharmaceutical industry in recent years.
Different absorption enhancers have been studied to
improve the absorption of polar drugs. For example, for-
mulations based on chitosan powder have been tested for
the nasal administration of insulin and morphine [11].
Furthermore, the use of cyclodextrins, poly-L-arginine
and lipids as absorption enhancers is also under investiga-
tion [12]. A range of companies working in novel nasal
delivery systems has come to the fore, for example, Ara-
digm (http://www.aradigm.com) has developed a disposa-
ble nozzle-containing element to ensure superior aerosol
performance each and every time the patient inhales
medication. The precision of this technology is currently
being studied in clinical trials for different drugs, including
testosterone, insulin, morphine and interferon a-2b.
Transdermal drug delivery
The transdermal administration of drugs is a relatively
direct route to the bloodstream. As recently reviewed by
www.current-opinion.com
Drug delivery in biotechnology Orive et al. 661
Langer [13], two different physical mechanisms (ionto-
phoresis and ultrasound) are being applied to circumvent
the physical barrier of the skin. Using iontophoresis,
Iomed Inc. (http://www.iomed.com) has developed Phor-
esor1 for the administration of iontocaine for local dermal
anesthesis. Another approach to transdermal drug deliv-
ery is the development of microneedles, which create
microscale pathways across the skin improving its perme-
ability [14,15].
Encapsulation methods
The inclusion of therapeutic active molecules in micro-
particulate delivery systems represents another way to
protect and transport the medication to exactly the right
place. Examples of these systems include polymer-based
microparticules, micelles and liposomes. Liposomes are
formed from concentric spherical phospholipid bilayers
with an inner compartment that can be used for the
encapsulation of different drugs [16,17,18]. Recently,
Saviċ et al. [19] reported the development of tiny
micelles built from two types of polymer. After loading
the molecular ‘globs’ with drugs they showed that these
biocompatible nanocontainers could pass through the
wall of a rat cell. Although they did not reach the cell
nucleus, they were able to access the mitochondria and
Golgi apparatus, which constitute important targets for
drug delivery. Using the technology of microencapsula-
tion, researchers have investigating the possibility of
introducing cells that would work as ‘factories’ secreting
therapeutic molecules [20,21]. To succeed, microcapsules
must be coated with a semipermeable immunobarrier that
would exert a double protective function: immuno-
isolating the transplanted tissue from the host’s immune
response and protecting the host from any biological risk.
Cell encapsulation technology presents several advan-
tages over the encapsulation of peptides, including the
secretion of de novo produced therapeutic proteins and the
possibility to regulate peptide delivery as a function of
physiological requirements [22]. As a result, a wide
range of encapsulated cells have been developed for a
variety of applications and to treat a number of diseases.
These include the development of a bioartificial pancreas
[23–26] and liver [27], the treatment of classical Mende-
lian disorders caused by an enzymatic or gene product
deficiency [28–30], and the treatment of cancer [31–33]
and central nervous system diseases [34]. Recently, cells
secreting ciliary neurotrophic factor have been encapsu-
lated and administered in dogs suffering from retinitis
pigmentosa (a disease characterized by the degeneration
of photoreceptor cells). Results showed that seven weeks
after implantation an increased survival of the photore-
ceptor cells was achieved and the implant showed no
adverse effects [35].
When the size of the particles used for encapsulation is
reduced to less than 100 nm in size, the result is nano-
technology. Although still in its infancy, investment in
Current Opinion in Biotechnology 2003, 14:659–664
662 Pharmaceutical biotechnology

nanotechnology worldwide has increased to almost $3
billion in 2003 [36]. Nanocomposites include nanocap-
sules, micellar systems, conjugates and nanoparticles.
One of the main advantages of these submicron systems
is that they present a higher intracellular uptake than
microsized particles. This has special implications for
gene delivery, as DNA can be easily encapsulated, pro-
tected from lysosomal enzymes and transfected with high
efficiency [37]. Recently, a hybrid nanodevice composed
of oligonucleotide DNA covalently attached to titanium
dioxide nanoparticles with the ability to target, bind and
cleave DNA has open the door to novel strategies for drug
delivery and nanosurgery [38]. Some recent reviews on
nanotechnology provide more useful perspectives for
interested readers [39–42].
Emerging delivery methods
Gene therapy and RNAi technologies are considered the
medical treatments of the future. In fact, RNAi was
announced as the scientific breakthrough of 2002. The
hopes from these technologies have been partially dashed,
however, following safety concerns and the lack of targeted
gene and siRNA delivery. As recently stated by Sharp the
major hurdle right now for these therapies is ‘delivery,
delivery and delivery’ [3]. To overcome this hurdle,
researchers are studying a virus known as adenoassociated
virus, which does not cause disease in animals or humans
[43]. Furthermore, novel, harmless viral vectors [44] and
nonviral gene therapy systems such as the ‘gene gun’ [45]
and liposomes are also under investigation.
Finally, microfabricated systems combine the principles
of microtechnology and biology to provide sophisticated
drug delivery systems that could provide advantages over
existing technologies. Micromachining presents the op-
portunity to create multiple reservoirs of desired size to
contain not just one, but many drugs or biomolecules of
interest. The wide range of possibilities include im-
planted microchips for localized drug delivery [46] and
nanoporous immuno-isolating devices for cell immobili-
zation that are surrounded by microfabricated membranes
with perfectly defined monodisperse pores in the nano-
meter scale [47,48].
Research policies on drug delivery
Drug delivery is a step-by-step process, gaining the
attention of the pharmaceutical industry and specialized
scientific journals alike. Researchers now understand that
successful delivery is a prerequisite to achieve the ther-
apeutic goal of a treatment; however, more efforts are
needed to understand the importance of the field within
pharmaceutical research. The authors believe that, to
succeed, drug delivery should be considered as a whole
multidisciplinary and independent field of research.
To put it simply, it should be evaluated independently
and not as a subfield of pharmacology and, as a conse-
quence, more specific support will be needed from insti-
tutions. This has special implications in Europe, where
EC Framework Programme 6 (2002–2006) supports some
research lines, such as nanotechnology, but does not
consider drug delivery as a whole research field. A com-
mon situation is seen in the scientific policies of many
other countries.
Another challenge is that more specialized scientific
journals are needed to advance and evaluate the field.
Finally, it will be necessary for regulatory agencies to
smooth their regulatory guidelines, making them less
bureaucratic and allowing those drug delivery systems
currently under investigation to evolve into real clinical
products [49].
Conclusions
In the past few years, researchers have studied alternative
ways to improve the efficacy of a wide range of different
medicines (Table 3). These include studies of micropar-
ticles and nanoparticles for peptide and protein admin-
istration, semipermeable membrane-bound capsules for
cell immobilization, nanotechnology, microfabrication
and liposomes, and the development of harmless virus

Table 3

Novel technologies for drug delivery.

Technology Application

PEGylation
Bioadhesive polymers
Chemical modification
Novel transdermal patches
Microparticulation
Nanotechnology
Microfabrication
GI, gastrointestinal; PEG: polyethylene glycol.
The active molecule is coated in PEG to improve the absorption of the drug or to mask it from the immune system
Promote the diffusion of different drugs between intestinal cells
Cobalamin–protein conjugates improve GI drug absorption via the normal vitamin B12 absorption pathway
Using two different physical mechanisms (iontophoresis and ultrasound) the permeability of drugs across the
skin is improved
Inclusion of a peptide within a microparticle has a wide range of applications including long-term secretion of
the therapeutic product, chemical and physical protection, targeted administration of the drug, vaccination,
cell immobilization, gene therapy and so on
By reducing the size of the particle to less than 100 nm, improved uptake by the cells is achieved.
Application for targeted drug delivery and gene therapy
The combination of microtechnology and biology for the controlled administration of one or more drugs

Current Opinion in Biotechnology 2003, 14:659–664 www.current-opinion.com


vectors for gene and siRNA delivery. Although some of
these approaches are at a basic level, and still years away
from the clinic, others such as Gliadel and Nutropin
Depot have recently been approved by the Food and
Drug Administration. Overcoming the current obstacles,
including government regulations, financial support, and
large-scale production and manufacturing, will lead us
to a day where all drugs are delivered in a targeted and
safer manner.
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