Ind. Eng. Chem. Res.

2009, 48, 24752486

2475

REVIEWS
Drug Delivery Technologies: The Way Forward in the New Decade
Eva M. Martn del Valle,*, Miguel A. Galan, and Ruben G. Carbonell

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Department of Chemical Engineering, UniVersity of Salamanca, Pl. de los Cados s/n, 37008 Salamanca,
Spain, and Department of Chemical and Biomolecular Engineering, North Carolina State UniVersity,
Raleigh, North Carolina

The design and development of drug delivery systems involves many different sciences that underpin the
research. It is clear that significant advances will only be made through multidisciplinary teams that utilize
the latest advances in the biological, chemical, physical, and engineering sciences. The underpinning sciences
are also vital to the process of developing successful products. There are three key and interrelated areas of
research. (i) Achieve a greater understanding of the biological fate and the targeting of drugs, particularly
biopharmaceuticals, macromolecules and macromolecular delivery systems, at the molecular, membrane, and
cellular level. (ii) Provide a greater understanding of the physicochemical properties of biopharmaceuticals,
macromolecules, and macromolecular delivery systems and how these are modified within a biological
environment affecting their activity. (iii) Promote the development of novel materials and delivery systems
that will overcome these biological barriers. This article aims to provide a comprehensive review of the key
issues to design an effective drug delivery system.
Introduction
Over the past few decades, the rise of modern pharmaceutical
technology and the amazing growth of the biotechnology
industry have revolutionized the approach to drug delivery
systems development.1 For most of the industrys existence,
pharmaceuticals have primarily consisted of relatively simple,
fast-acting chemical compounds that are dispensed orally (as
solid pills and liquids) or injected. During the past three decades,
however, complex formulations that control the rate and period
of drug delivery (i.e., time-release medications) and that target
specific areas of the body for treatment have become increasingly common.2
Addressing this complexity, coupled with the explosion of
new and potential treatments resulting from discoveries of
bioactive molecules and gene therapies, pharmaceutical research
is facing challenges to, not only the development of new
treatments, but also the mechanisms with which to administer
them.3,4
A controlled release drug delivery system should be able to
achieve the following benefits: (i) maintenance of optimum
therapeutic drug concentration in the blood with minimum
fluctuation; (ii) predictable and reproducible release rates for
extended duration; (iii) enhancement of activity duration for
short half-life drugs; (iv) elimination of side effects, frequent
dosing and wastage of drug; and (v) optimized therapy and
improved patient compliance.5-11
To achieve these benefits, the design of a controlled release
system requires simultaneous considerations of several factors,12-15
such as the chemical and physical properties of the drug,16 the
route of administration,17-19 the nature of the delivery vehicle,
the mechanism of drug release, the potential for targeting,20 and
biocompatibility.
* To whom correspondence should be addressed. E-mail:
emvalle@sal.es.

University of Salamanca.

North Carolina State University.

Due to the extensive interdependency of those factors, it is

not easy to establish a sequential process for designing a
controlled drug delivery system.21
Drug delivery technology can bring both therapeutic and
commercial value to health care products.22 Large pharmaceutical companies are looking to extend the lifetimes of their patents
by forging strategic alliances with usually smaller drug delivery
technology companies aimed at presenting old drugs in new
proprietary forms. Most drug delivery products reach the market
as a result of joint ventures between drug delivery companies
and pharmaceutical companies. For this reason, drug delivery
technology companies enjoy a good return on their investments
in the form of increased revenues and market share and it is a
very fast growing segment of the economy.7-9
However, the design and development of drug delivery
systems involves many different sciences that underpin the
research. It is clear that significant advances will only be made
through multidisciplinary teams that utilize the latest advances
in the biological, chemical, physical, and engineering sciences.
The underpinning sciences are also vital to the process of
developing successful products. There are three key and
interrelated areas of research.23 (i) Achieve a greater understanding of the biological fate and the targeting of drugs,
particularly biopharmaceuticals, macromolecules, and macromolecular delivery systems at the molecular, membrane, and
cellular level. (ii) Provide a greater understanding of the
physicochemical properties of biopharmaceuticals, macromolecules, and macromolecular delivery systems and how these
are modified within a biological environment affecting their
activity. (iii) Promote the development of novel materials and
delivery systems that will overcome these biological barriers.
This article aims to provide a comprehensive review of the key
issues to design an effective drug delivery system.
1. Administration Routes
Drug delivery technologies are classified according to the
route through which a drug is administered into the body. In

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2476 Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009

the oral route, a drug is taken by mouth into the gastrointestinal

(GI) tract to be absorbed. Other important routes include
intravenous injection, intramuscular injection, subcutaneous
injection, pulmonary, ocular, buccal (through the internal wall
of the cheeks), sublingual (under the tongue), nasal, vaginal,
rectal, transdermal, and implanted (inside a body cavity). Drug
delivery research focuses on how a drug is delivered into the
body without much consideration of the fate and effects of the
drug in the body.24 Those aspects are normally the domain of
studies in pharmacokinetics, although obviously, these aspects
are closely linked to the delivery route. Highly sophisticated
drug delivery systems are being developed to exert their effects
after they are administered into the body, in particular, into the
systemic circulation.25 They usually consist of particles in the
size range of nanometers that have unique combinations of
capacities such as controlled release and biological site-specific
targeting. This new group of delivery systems is definitely an
important component of modern drug delivery technology.
A myriad of novel drug delivery technologies are under
development and significant advances are being made in nearly
all branches of drug delivery. This section briefly reviews the
main routes of delivery.
1.1. Oral. The oral route has long been the most convenient
and most widely used drug delivery method worldwide.
However, many drugs including the emerging biotechnology
drugs such as peptides, proteins, and nucleic acids are not
suitable for this route because they are subject to massive
degradation in the GI tract and low permeability through the
intestinal epithelium. As a result, considerable efforts are being
made to develop devices able to protect these drugs in the GI
tract from degradation and enhance drug absorption. Such
advanced oral drug delivery systems include liposomes,24
mucoadhesive patches,25,26 nanoparticles,27 absorption enhancing agents,28 and microfabricated devices.29-31 Oral vaccination
is also attracting significant interest.32
1.2. Pulmonary. Pulmonary drug delivery is an important
research area which impacts the treatment of illnesses including
asthma, chronic obstructive pulmonary disease, and cystic
fibrosis. Inhalation gives the most direct access to drug target.
In the treatment of obstructive respiratory diseases, pulmonary
delivery can minimize systemic side effects, provide rapid
response, and minimize the required dose since the drug is
delivered directly to the conducting zone of the lungs.33
Inhalation is also an attractive option for systemic therapies
because the respiratory region (mainly alveoli) of the lung
provides an enormous surface area (80-100 m2/adult) and a
highly permeable membrane for the absorption of medication
into the blood. It is a needle-free delivery system capable of
administering a variety of therapeutic substances.34 Large protein
molecules which degrade in the harsh gastrointestinal conditions
and are eliminated by the first-pass metabolism in the liver can
be delivered via the pulmonary route if deposited in the
respiratory zone of the lungs.
The dry powder inhaler device-formulation combination has
been shown to be an effective method for delivering drugs to
the lung for treatment of asthma, chronic obstructive pulmonary
disease, and cystic fibrosis. Even with advanced designs,
however, delivery efficiency is still poor mainly due to powder
dispersion problems which cause poor lung deposition and high
dose variability. Drug particles used in current inhalers must
be 1-5 m in diameter for effective deposition in smalldiameter airways and alveoli.35 These powders are very
cohesive, have poor flowability, and are difficult to disperse
into aerosol due to cohesion arising from van der Waals

attraction. These problems are well-known in fluidization

research, much of which is highly relevant to pulmonary drug
delivery.
Processing methods such as spray drying allow control over
critical particle design features, such as particle size and
distribution, surface energy, surface rugosity, particle density,
surface area, porosity, and microviscosity. Control of these
features has enabled new classes of therapeutics to be delivered
by inhalation.33-35 These include therapeutics that have a narrow
therapeutic index, require a high delivered dose, and/or elicit
their action systemically. Engineered particles are also being
utilized for immune modulation, with exciting advances being
made in the delivery of antibodies and inhaled vaccines.
Continued advances are expected to result in smart therapeutics capable of active targeting and intracellular trafficking.36
Considerable effort is currently being focused on the systemic
delivery of therapeutic peptides and proteins via this route
because the lungs have large surface area, a rich supply of blood,
and an alveolar membrane with very high permeability.37
Moreover, pulmonary delivery is noninvasive in contrast to
injection and tends to exhibit less drug degradation than the
oral route. Insulin (for diabetes) is the drug receiving the most
intense interest for this delivery method as a substitute for
injection, because the disease requires long-term management
and frequent administration.38 Some encouraging scientific and
engineering developments, such as large porous particles for
deep lung deposition,37 have been made in this area in recent
years and pulmonary delivery of drugs to the systemic circulation will likely become a reality in the near future.
1.3. Injection. Injection is the gold standard for systemic
drug delivery and the major delivery method for the drugs that
are not suitable for oral delivery. However, this method is
associated with various problems such as pain, burst drug
release, needle phobia, risk of infections, and involvement of
health care workers. For chronic diseases (e.g., insulin-dependent
diabetes) requiring repetitive drug administrations, these problems become more serious.39 Two strategies are being taken to
address these problems. One is to improve the current injection
technology, and the other is to develop alternative delivery
methods. A successful example of improving the current
injection technology is an injectable depot system based on
biodegradable microspheres to lower the injection frequency
and enable constant drug release.3 Many more efforts are being
made to develop alternative delivery methods to injections such
as oral, pulmonary, and transdermal.
1.4. Transdermal. Delivering drugs across the skin is
attractive for several reasons: ease of access, application, and
cessation of delivery; sustained and steady drug release; reduced
systemic side effects; avoidance of drug degradation in the GI
tract and first-pass hepatic metabolism; and absence of pain.40,41
However, the skin functions naturally as a barrier to foreign
substances, preventing the entrance of the majority of drugs.
Therefore, researchers are developing various methods to
enhance the drug permeation across the skin. The more notable
new technologies to meet this goal include electroporation,
ionophoresis, sonophoresis, jet injection, laser irradiation, and
microneedles.41-43 Delivery of many drugs including biological
drugs such as insulin has been successfully demonstrated using
these technologies.44,45
1.5. Implantable. Implantable drug delivery systems (IDDS)
have the advantage of maintaining a steady release of drug to
the specific site of action so that they are safer and more reliable.
IDDS can be classified into three major categories: biodegradable or nonbiodegradable implants, implantable pump systems,

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Figure 1. Concentration profiles for drug delivered by tablet, sustained release device or controlled release device.

and the newest atypical class of implants.46-51 Biodegradable

and nonbiodegradable implants are available as monolithic
systems or reservoir systems. The release kinetics of drugs from
such systems depend on both the solubility and diffusion
coefficient of the drug in the polymer, the drug load, as well as
the in vivo degradation rate of the polymer in the case of the
biodegradable systems.52 Controlled release of drugs from an
implantable pump is generally achieved utilizing the microtechnology of electronic systems and remote-controlled flow
rate manipulation through the maintenance of a constant pressure
difference. The third IDDS system, the atypical class, includes
recently developed systems such as ceramic hydroxyapatite
antibiotic systems used in the treatment of bone infections,
intraocular implants for the treatment of glaucoma, and transurethral implants utilized in the treatment of impotence. The
major advantages of these systems include targeted local
delivery of drugs at a constant rate, less drug required to treat
the disease state, minimization of possible side effects, and
enhanced efficacy of treatment. Also, these forms of delivery
systems are capable of protecting drugs which are unstable in
vivo and that would normally require frequent dosing intervals.53
Due to the development of such sustained release formulations,
it is now possible to administer unstable drugs once a week to
once a year that in the past required frequent daily dosing.
Preliminary studies using these systems have shown superior
effectiveness over conventional methods of treatment.54 However, one limitation of these newly developed drug delivery
systems is the fact that their cost-to-benefit ratio is high which
restricts their use over conventional dosage forms. Hopefully,
in the future, new implantable systems can be developed at a
lower cost, enhancing their use in standard therapeutic practice.
Some of the most recently discovered implants are in the early
developmental stages and more rigorous clinical testing is
required prior to their use in standard practice.52
2. Mechanisms for Drug Delivery
The traditional methods and routes of drug administration
result in a rate of drug uptake that is controlled by the drug
properties (solubility, charge, molecular size, etc.) and the
characteristics of the site of administration (pH, surface area,
presence of enzymes, active transport mechanisms, etc.).52 With
traditional tablets or injections, the drug level in the blood
follows the profile shown in Figure 1, in which the level rises
after each administration of the drug and then decreases until
the next administration. The key point with traditional drug
administration is that the blood level of the agent should remain
between a maximum value, which may represent a toxic level,

and a minimum value, below which the drug is no longer

effective. In controlled drug delivery systems designed for longterm administration, the drug level in the blood follows the
profile also shown in Figure 1, remaining constant, between
the desired maximum and minimum, for an extended period of
time.55
For decades, polymeric systems have been used for pharmaceutical applications, especially to provide controlled release
of drugs. Drug-polymer systems may also be useful in
protecting the drug from biological degradation prior to its
release. The development of these devices starts with the use
of nonbiodegradable polymers, which rely on the diffusion
process, and subsequently progresses to the use of biodegradable
polymers, in which swelling and erosion take place.
On the basis of the physical or chemical characteristics of
polymer, drug release mechanisms from a polymer matrix can
be categorized in accordance to three main processes (systems),
which are the followinf:56
1. Drug diffusion from the nondegraded polymer (diffusioncontrolled system).
2. Enhanced drug diffusion due to polymer swelling (swelling-controlled system).
3. Drug release due to polymer degradation and erosion
(erosion-controlled system). In all three systems, diffusion
is always involved. For a nonbiodegradable polymer
matrix, drug release is due to the concentration gradient
by either diffusion or matrix swelling (enhanced diffusion).
For a biodegradable polymer matrix, release is normally
controlled by the hydrolytic cleavage of polymer chains
that lead to matrix erosion, even though diffusion may be
still dominant when the erosion is slow.
2.1. Diffusion.39,58,.59 Diffusion occurs when a drug or other
active agent passes through the polymer that forms the
controlled-release device. The main devices are classified into
reservoir systems and matrix systems.
2.1.1. Reservoir Systems. One widely used polymeric
system is called the reservoir system. In these systems the drug
is retained in a central compartment and surrounded by a
polymeric membrane through which it must diffuse, thus
controlling the rate of delivery. Figure 2 shows a schematic
diagram of this type of system. Reservoir systems could also
be in the form of microcapsules or hollow fibers.34
The various factors that can affect the diffusion process may
readily be applied to reservoir devices (e.g., the effects of
additives, polymer functionality, and, hence, sink-solution pH,
porosity, film casting conditions, etc.). Also, the choice of

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Figure 2. Reservoir System.

Figure 4. Diffusion from a matrix system.

Figure 3. Matrix devices.

polymer must be an important consideration in the development

of reservoir devices.34,60-62
2.1.2. Matrix Devices. Matrix devices consist of a polymer
throughout which drug is dispersed (Figure 3). Matrix devices
are probably the most common devices for controlling the
release of drugs. This is partly because they are relatively easy
to fabricate, compared to reservoir devices, and there is no the
danger of an accidental high dosage that could result from
rupture of the membrane of a reservoir device. In a matrix device
the active agent is present as a dispersion within the polymer
matrix, and they are typically formed by the compression of a
polymer/drug mixture or by dissolution or melting.39 The dosage
release properties of matrix devices may be dependent upon
the solubility of the drug in the polymer matrix or, in the case
of porous matrixes, the solubility of the drug in the sink solution
within the particles pore network and the tortuosity of the
network.62,63
The diffusion can occur on a macroscopic scalesas through
pores in the polymer matrixsor on a molecular level, by
transport between polymer chains. Examples of diffusion-release
systems are shown in Figures 4 and 5.
In Figure 4, a polymer and active agent have been mixed to
form a homogeneous matrix system. Diffusion occurs when the
drug passes from the polymer matrix into the external environment. As the release continues, the rate normally decreases, since
the active agent has a progressively longer distance to diffuse
and a lower concentration gradient.
For the reservoir systems shown in Figure 5, the drug delivery
rate can remain fairly constant. In this design, a reservoirswhether
solid drug, dilute solution, or highly concentrated drug solution
within a polymer matrixsis surrounded by a film or membrane
of a rate-controlling material. The only structure effectively
limiting the release of the drug is the polymer layer surrounding
the reservoir. Since this polymer coating is essentially uniform
and of a nonchanging thickness, the diffusion rate of the active
agent can be kept fairly constant throughout the lifetime of the
delivery system. The system shown in Figure 5a is representative
of an implantable or oral reservoir delivery system, whereas
the system shown in Figure 5b illustrates a transdermal drug

Figure 5. Diffusion from a reservoir system: (a) implantable or oral

reservoir; (b) transdermal drug delivery system.

delivery system, in which only one side of the device will

actually be delivering the drug.56,60
For the diffusion-controlled systems described thus far, the
drug delivery devices need to be stable in the biological
environment and not change their size either through swelling
or degradation. In these systems, the combinations of polymer
matrices and bioactive agents chosen must allow for the drug
to diffuse through the pores or macromolecular structure of
the polymer upon introduction of the delivery system into the
biological environment without inducing any change in the
polymer itself.39
2.2. Swelling Followed by Diffusion. It is also possible for
a drug delivery system to be designed so that it is incapable of
releasing its agent or agents until it is placed in an appropriate

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Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2479

Figure 6. Drug delivery from (a) reservoir and (b) matrix swelling-controlled
release systems.

biological environment. Swelling-controlled release systems are

initially dry and, when placed in the body, will absorb water or
other body fluids and swell.56,57 The swelling increases the
aqueous solvent content within the formulation as well as the
polymer free volume, enabling the drug to diffuse through
the swollen network into the external environment. Examples
of these types of devices are shown in Figure 6a and b for
reservoir and matrix systems, respectively. Most of the materials
used in swelling-controlled release systems are based on
hydrogels, which are polymers that will swell without dissolving
when placed in water or other biological fluids. The polymer
structure is able to retain the solvents forming a swollen gel
phase. Since these are cross-linked systems, they will not
dissolve regardless of the solvent properties.57 Drug loading by
the swelling method can be performed based on the selection
of the drug for therapeutic efficacy and hydrogel swelling data
in the selected solvent.60,64 The drug loading content is
controlled by the polymer composition and can be estimated
from the swelling level in the loading solvent. The synthesis of
a hydrogel matrix for a specific drug carrier should be tailored
considering the physical properties of drugs, loading level, and
desired release kinetics.60 These hydrogels can absorb a great
deal of fluid and, at equilibrium, typically comprise 60-90%
fluid and only 10-40% polymer.64-66
One of the most remarkable and useful features of a polymers
swelling ability manifests itself when that swelling can be
triggered by a change in the environment surrounding the
delivery system.67 Depending upon the polymer, the environmental change can involve pH, temperature, or ionic strength,
and the system can either shrink or swell upon a change in any
of these environmental factors.68 A number of these environmentally sensitive or intelligent hydrogel materials are listed
in Table 1. For most of these polymers, the structural changes
are reversible and repeatable upon additional changes in the
external environment, and the diagrams in Figure 7 illustrate
the basic changes in structure of these sensitive systems.56,67,69,70
Once again, for this type of system, the drug release is
accomplished only when the polymer swells. Because many of
the potentially most useful pH-sensitive polymers swell at high
pH values and collapse at low pH values, the triggered drug
delivery occurs upon an increase in the pH of the environment.71

Such materials are ideal for systems such as oral delivery, in

which the drug is not released at low pH values in the stomach
but rather at high pH values in the upper small intestine.55
2.3. Polymer Degradation and Erosion. All of the previously described systems are based on polymers that do not
change their chemical structure beyond what occurs during
swelling. However, a great deal of attention and research effort
is being concentrated on biodegradable polymers.59,60,72-74
These materials degrade within the body as a result of natural
biological processes, eliminating the need to remove a drug
delivery system after release of the active agent has been
accomplished.73
With regard to biodegradable polymers, it is essential to
recognize that degradation is a chemical process, whereas
erosion is a physical phenomenon dependent on dissolution and
diffusion processes.75 Depending on the chemical structure of
the polymer backbone, erosion can occur by either surface or
bulk erosion. Surface erosion occurs when the rate of erosion
exceeds the rate of water permeation into the bulk of the polymer
and is desirable because the kinetics of erosion and rate of drug
release (zero order) are highly reproducible. Bulk erosion occurs
when water molecules permeate into the bulk of the matrix at
a faster rate than erosion, thus exhibiting complex degradation/
erosion kinetics. Most of the biodegradable polymers used in
drug delivery undergo bulk erosion.79 Some of the most widely
studied polymers for this purpose are poly lactides and poly
glycolides, which are commonly used as biodegradable sutures
in surgery and have FDA approval, but have the disadvantage
of eroding by bulk erosion. In all cases, care has to be taken to
ensure that the breakdown products of the polymer are nontoxic
and do not interact with the drug46 and affect is efficacy.
Most biodegradable polymers are designed to degrade as a
result of hydrolysis of the polymer chains into biologically
acceptable, and progressively smaller, compounds. In some
casessfor example, in the case of polylactides, polyglycolides,76,77
and their copolymerssthe polymers will eventually break down
to lactic acid and glycolic acid, enter the Krebs cycle, and be
further broken down into carbon dioxide and water and excreted
through normal processes. Degradation may take place through
bulk hydrolysis, in which the polymer degrades in a fairly
uniform manner throughout the matrix, as shown schematically
in Figure 8. For some degradable polymers, most notably the
polyanhydrides and polyorthoesters, the degradation occurs only
at the surface of the polymer, resulting in a release rate that is
proportional to the surface area of the drug delivery system (see
Figure 8b).
The most common formulation for these biodegradable
materials is in the form of microparticles, which have been used
in oral delivery systems and, even more often, in subcutaneously
injected delivery systems. Given appropriate fabrication methods, microparticles of poly(lactide-co-glycolide) (PLGA) can
be prepared in a fairly uniform manner to provide essentially
nonporous microspheres.54 These particles will degrade through
bulk hydrolysis in water or body fluids, yielding polymer
fragments over time.
3. Materials for Drug Delivery
3.1. Polymers. The selection of a polymer for drug delivery
requires a thorough understanding of the surface and bulk
properties of the polymer to provide the desired chemical,
interfacial, mechanical, and biological functions. The choice of
polymer, in addition to its physicochemical properties, is
dependent on the need for extensive biochemical characterization
and specific preclinical tests to prove its safety.

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Table 1. Swelling Stimuli and Mechanisms
stimulus

mechanism

change in pHsswellingsrelease of drug

change in ionic strengthschange in concentration of ions inside
gelschange in swellingsrelease of drug
chemical species
hydrogel containing electron-accepting groups
electron-donating compoundssformation of charge/transfer
complexschange in swellingsrelease of drug
enzyme-substrate
hydrogel containing immobilized enzymes
substrate presentsenzymatic conversionsproduct changes swelling of
gelsrelease of drug
magnetic
magnetic particles dispersed in alginate microshperes
applied magnetic fieldschange in pores in gelschange in
swellingsrelease of drug
thermal
thermoresponsive hrydrogel poly(N-isopro-pylacrylamide) change in temperatureschange in polymer-polymer and
water-polymer interactionsschange in swellingsrelease of drug
electrical
polyelectrolyte hydrogel
applied electric fieldsmembrane chargingselectrophoresis of charged
drugschange in swellingsrelease of drug
ultrasound irradiation ethylene-vinyl alcohol hydrogel
ultrasound irradiationstemperature increasesrelease of drug

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pH
ionic strength

hydrogel
acidic or basic hydrogel
ionic hydrogel

Surface properties such as hydrophilicity, lubricity, smoothness, and surface energy govern the biocompatibility with tissues
and blood, in addition to influencing physical properties such
as durability, permeability, and degradability. The surface
properties also determine the water sorption capacity of the
polymers, which can undergo hydrolytic degradation and
swelling.61
Moreover, bulk properties that need to be considered for
controlled delivery systems include molecular weight, bulk
modulus, and solubility based on the release mechanism
(diffusion- or dissolution-control), and it is the properties of its
potential site of action.78 The structural properties of the matrix,

Figure 7. Drug delivery from environmentally sensitive release systems.

Figure 8. Drug delivery from (a) bulk-eroding and (b) surface-eroding

biodegradable systems.

its micromorphology, and pore size are important with respect

to mass transport (of water) into and (of drug) out of the
polymer.
Several polymers have been investigated for drug-delivery
applications and can be broadly classified into natural and
synthetic, biodegradable, and nonbiodegradable, as shown in
Table 2. However, drug delivery polymer design is highly
dependent on the specific device application. For that reason,
certain basic criteria should be considered for any polymeric
biomaterial used in drug delivery systems. Figure 9 illustrates
some questions and guidelines that could be followed by those
whishing to rationalize material selection. The numbers in Figure
9 refers to the types of polymers that could meet the desired
requirements, as listed in Table 2.
3.1.1. Biodegradable and Nondegradable Polymers. A
variety of biodegradable polymers have been synthesized to
deliver drugs, macromolecules, cells, and enzymes.
The wide acceptability of these polymers can be appreciated
from the fact that the biodegradability can be manipulated by
incorporating a variety of labile groups such as esters, orthoesters, anhydrides, carbonate, amides, ureas, and urethanes in
their backbone.
Biodegradation can be of enzymatic, chemical, or microbial
origin, and these may operate either separately or simultaneously
and are often influenced by many other factors61 as shown in
Table 3.
Polyester-based polymers are one of the most widely investigated for drug delivery. Poly(lactic acid) (PLA), poly(glycolic
acid) (PGA), and their copolymers poly(lactic acid-co-glycolic
acid) (PLGA) are some of the most well-defined biomaterials
with regard to design and performance for drug-delivery
applications.72 Although PLGA is by far the most extensively
studied biodegradable polymers (exemplified by more than 500
patents), increased local acidity because of degradation can lead
to irritation at the site of polymer application.80
Polyorthoesters have been in development since the 1970s,
and most research has focused on the synthesis of polymers by
addition of polyols to diketene acetals. They are unique among
all biodegradable polymers, as mechanical properties can be
readily varied by choosing appropriate diols or mixture of diols
in their synthesis.72 A number of applications have been found
for polyorthoesters and cross-linked polyorthoestes such as
delivery of 5-flurouracil, periodontal delivery of tetracycline,
and pH-sensitive polymer systems for insulin delivery. Polyanhydrides are characterized by their fast degradation followed
by rapid erosion of the material but at the same time can be
designed to release drugs that last from days to weeks by suitable
choice of monomers.80

Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2481

a

Table 2. Classification of Polymers Used in Drug Delivery and Codes for Selection
Natural Polymers
protein-based polymers (2)

polysaccharides (2)

collagen, albumin, gelatin

agarose, alginate (3), carrageenan (8), hyaluronic acid, chitosan (3, 7)

Synthetic Polymers

biodegradable

nonbiodegradable

polyesters (2)
poly (lactic acid), poly (glycolic acid), poly(hydroxy butyrate),
poly(-caprolactone), poly(-malic acid), poly(dioxanones)
polyamides (2)
poly(imino carbonates), polyamino acids
phosphorus-based polymers
polyphosphates, polyphosphonates, polyphosphazenes

cellulose derivatives (7)

carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cellulose
acetate propionate, hydroxypropyl met hyl cellulose
silicones (6)
colloidal silica, polysiloxanes
acrylic polymers (5, 6)
polymethacrylates, poly(methyl methacrylate), poly
hydro(ethylmethacrylate)
others (8)
polyvinyl pyrrolidone, ethyl vinyl acetate, poloxamers, poloxamines

others (1)
poly(cyano acrylates), polyurethanes, polyortho esters,
polydihydropyrans, polyacetals
The parenthesized numbers refer to the selection polymer in Figure 9.

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Figure 9. Guidelines to rationalize material selection.

Polyaminoacids that have good biocompatibility have been

investigated for the delivery of low-molecular-weight compounds. However, their widespread use is limited by their
antigenic potentials and poor control of release because of the

dependence on enzymes for biodegradation. Poly(imino carbonates), which are pseudo polyaminoacids, have been synthesized from tyrosine dipeptide to overcome the abovementioned
limitations.61

2482 Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009

Table 3. Factors Affecting Biodegradation of Polymers
chemical structure and composition

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physicochemical factors (ion exchange, ionic strength, pH)

molecular-weight distribution
route of administration or side
sterilization process
physical factors (shape and size changes, stresses, variation of diffusion
coefficients)
morphology (amorphous/semicrystalline, microstructures)

A variety of nondegradable polymers are used in drug

delivery of which polysaccharide-based and acrylic-based
polymers have found wide application in the fabrication of
peroral dosage forms, transdermal films, and devices.81 Polyethylene oxide (PEO) and polyoxypropylene (POP) copolymers
are one of the most interesting classes used for nanoparticulate
drug delivery systems. They are commercially available in a
wide range of states including liquids, pastes, and solids. Since
their first introduction as nonionic surfactants in the 1950s, they
have found a wide range of applications in the pharmaceutical
and biomedical fields.68 Soluble block copolymers based on
PEO-PLA can self-assemble into novel supramolecular structures and are being investigated for delivery of anticancer agents,
proteins, and plasmid DNA.39 They are advantageous in terms
of drug targeting and safety, and they can mimic biological
transport systems, lipoproteins, or viruses.
Polysiloxanes are a unique class of nondeformable polymer
possessing good low-temperature flexibility, excellent electrical
properties, water repellency, and remarkable biocompatibility,
features that are not common with hydrocarbon polymers.41
Because of ease of fabrication and high permeability, polydimethyl siloxanes (PDMSs) are useful for water-soluble drugs
and steroids for long-acting DDSs such as subdermal implants
and intravagnial systems.46
3.1.2. Natural Polymers.79 Naturally derived polymers are
abundant, usually biodegradable, and offer excellent biocompatibility. Their principal disadvantage lies in the development
of reproducible production methods, because their structural
complexity often renders modification and purification difficult.
Additionally, significant batch-to-batch variations occur because
of their biopreparation in living organisms (plants, crustaceans).
A variety of natural polymers have been used as biomaterials,
including albumin, hyaluronic acid and derivates, alginate, and
chitosan.82
Hyaluronic acid is an interesting biomaterial that is employed
in surgical procedures. Modified hyaluronic acid materials are
available. These have been fabricated into microspheres and
could well have applications in controlled release of drug
injection or nasal administration.83
Of special interest is the natural material chitin; which can
be deacetylated to produce the soluble biopolymer chitosan. The
physical and chemical properties of chitosan, such as inter- and
intramolecular hydrogen bonding and the cationic charge in
acidic medium, makes this polymer attractive for the development of conventional and novel pharmaceutical products.
Chitosan has favorable biological properties, such as nontoxicity,
biocompatibility, biodegradability, and antibacterial characteristics.
Chitosan has unique properties of bioadhesion, absorption
enhancement by increasing the residence time of dosage forms
at mucosal sites, inhibiting proteolytic enzymes, and increasing
the permeability of various drugs across mucosal membranes.
Since chitosan degrades due to the action of microbial flora
present in the colon, it is a good candidate for site-specific drug
delivery. Low toxicity coupled with wide applicability makes

it a promising candidate for drug delivery for a host of drug

moieties (anti-inflammatory, peptides, etc), and as a biologically
active agent.69,79
Polymer science has played a crucial role in the development
of new drug delivery systems for the past few decades. Future
advances will be based on modifying the chemical and physical
properties of the polymer and creating novel combinations of
copolymers with targeting and bioresponsive components that
can deliver a wide variety of bioactive agents. Further, newer
fabrication and manufacturing processes such as molecular
imprinting,84 supercritical fluid technology,85 and nanoscale
engineering are bound to revolutionize the design, development,
and performance of polymer-based drug delivery systems.
3.1.3. Silicon versus Polymer in Drug Delivery. The firstgeneration microfabricated drug delivery devices were mostly
made of silicon-based materials, due to the availability of highly
advanced technology developed for fabricating these devices
by the microelectronics industry. Unfortunately, the physical
and chemical properties of silicon-based materials, including
poor impact strength/toughness, lack of optical clarity, nonbiodegradability, and high manufacturing cost (especially for
relatively small numbers of devices), are not appropriate for
many biomedical applications. On the other hand, polymeric
materials can have a wide variety of properties, including
toughness, optical clarity, good biocompatibility, and biodegradability. Polymers can also be therapeutically active, environment-sensitive, versatile in surface properties, and relatively
inexpensive in materials and processing, making them attractive
for numerous biomedical applications. Moreover, conducting
polymer-based microelectronics are under rapid development
and show great promise to be used in certain low-cost,
biomedical applications that do not require high-speed performance.86
Aside from the materials, conventional microfabrication
techniques for silicon-based processing, such as low-pressure
chemical vapor deposition (LPCVD) of thin films, photolithography, and etching, are also not desirable for many biomedical
uses because ionizing radiation, toxic solvents, corrosive
enchants, and elevated temperatures are commonly employed
in silicon-based processing and they may damage therapeutic
agents such as macrolides, biological macromolecules, or cells.
Polymer-based microfabrication technology is superior to
silicon-based microfabrication in terms of cost and versatility.
Many techniques have been developed or are under development
for polymer microfabrication. Some of them are the microversion of conventional polymer processing techniques such
as solution casting, injection molding, and hot embossing. Some
are developed mainly for polymer microfabrication such as soft
lithography,87 which uses an elastomeric mold with surface relief
features to generate micro- and even nanostructures. All these
techniques rely on the use of a master with microfeatures made
by micromachining or photolithography. Masters can be used
to generate polymer devices directly or to make a silicone mold.
The master and mold can be used repeatedly to create many
polymer devices in a noncleanroom environment, lowering the
cost of these methods significantly.
Although many polymer microfabrication techniques also use
ionizing radiation, organic solvents, and elevated temperature
and pressure, due to the large variety of polymers and processing
techniques, the chance of finding appropriate materials and
techniques for the fabrication of drug delivery devices that are
compatible with the incorporated drugs and clinical applications
is relatively high.88

Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2483

Table 4. Criteria for the Physicochemical Properties of Drug Administrated for Different Routesa
route

MW

HA

HD

PSA

RB

ClogP

oral
transdermal
buccal/sublingual
nasal
vaginal

0 < X < 500

295.9c (188.0-411.7)d
275.1 (163.3-342.3)
391.6 (227.5-575.7)
321.3 (171.8-416.1)

0 < X < 11
3.36 (1-6)
2.93 (1-5)
4.77 (2-8.8)
2.93 (1.6-5)

0<X<6
1.24 (0-2.9)
1.26 (0-2.5)
2.83 (0-4)
1.33 (0-3)

0 < X < 110

45.1 (8.9-75.7)
38.1 (13.0-66.0)
73.6 (23.4-119.5)
43.2 (18.6-69.3)

0 < X < 13
3.86 (0-8)
3.30 (0.5-6)
6.11 (1-12.4)
3.70 (0-7.4)

-2 < X < 5
2.25 (-0.16-4.70)
2.39 (0.58-4.16)
2.05 (-0.61-4.14)
3.04 (0.13-5.81)

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a
MW ) molecular weight, HA ) number of hydrogen bond acceptor sites, HD ) number of hydrogen bond donor sites, PSA ) polar surface area
(2), RB ) number of rotatable bonds, ClogP ) calculated octanol/water partition coefficient. b Criteria for oral absorption. The criteria are based on
the work of Lipinski et al.91 and Palm et al.92 c Average value. d The 10-90% range.

3.2. Toxicological Considerations. The nonclinical toxicology program required for approval of polymers in drug delivery
systems depends on a subjects level of exposure to the polymer
and to the final product. If the polymer is not a new chemical
entity (NCE), a review of the manufacturers and published
scientific literature should be conducted to gather clinical and
nonclinical safety information. If the polymer is not absorbed
or data indicate that blood levels are acceptable based on
historical exposure or existing toxicology data, then it may be
sufficient to conduct toxicology studies with the final drug
delivery formulation with a written review and justification on
the use of the polymer.
If the polymer is an NCE, a series of in vitro and in vivo
(animal) genotoxicity studies should be conducted. These
mutagenicity and clastogenicity studies determine if the polymer
harms the DNA of cells. If the assays reveal a genotoxic result
in multiple assays, development of the polymer is halted. If no
genotoxic activity is present, the next step is to quantify
exposure. If the polymer is absorbed in the GI tract a full
toxicology program consisting of acute, chronic, reproduction,
and cancinogenecity testing is likely to be required. If the
polymer is not absorbed, studies up to 6 months long may be
required with an evaluation of any proliferative change. Whether
the polymer is absorbed or not, additional toxicology studies
need to be conducted with the final formulation at multiple
doses.89
4. Physicochemical Properties Required for Optimal
Systemic Availability of Drugs
The physicochemical properties of drugs are important
variables that determine whether the systemic circulation can
be reached. To reach the systemic circulation, absorption via
different routes will take place through physiologically different
epithelial cells. Absorption is defined as the passage of a drug
from its site of administration into the plasma. Therefore
absorption is important for all routes of administration, except
intravenous injection.
Different studies have been done in order to establish criteria
for the desired physiochemical properties of drugs administrated
by different routes.89
For the different routes of administration drugs are absorbed
by the same mechanisms: transcellular diffusion or paracellular
transport.
In the case of transcellular diffusion the biological membrane
determines whether a drug is absorbed or not. If the barrier is
formed by multiple layered epithelia (transdermal, buccal/
sublingual, vaginal, or nasal administration) the thickness of
the barrier is also of influence.
For paracellular transport of a drug over an epithelial barrier,
the composition of the intercellular matrix is an important
parameter. On the other hand, in the epithelia of the nonoral
routes, hydrophobic as well as hydrophilic domains are present.
For example, in the skin the intercellular matrix contains very

Table 5. Evaluation of Solubility: Equations to Calculate the Dose

and Dissolution Number, Maximum Absorbable Dose, and
Absorption Potentiala
model

application

formula

oral, transdermal, buccal/ Do ) D/(VCs)

sublingual, nasal, vaginal
maximum absorbable
oral, transdermal, buccal/ MAD ) CsVKatres
dose (MAD)
sublingual, nasal, vaginal
Ka ) Cmax/AUC
dissolution number (Dn) oral (buccal/sublingual)
Dn ) tres(6DiffCs/Fd2)
) tres/tdis
absorption potential (AP) oral
AP ) log(mowCsVfu/D)
acid
pH ) pKa + log(fi/fu)
base
pH ) pKa + log(fu/fi)
dose number (Do)

a
Do ) dissolution number, D ) dose, V ) volume available to
dissolve the drug (see Table 6), Cs ) solubility, MAD ) maximum
absorbable dose, Ka ) absorption rate constant ) Cmax/AUC, Cmax )
maximum concentration in time versus the concentration profile, AUC
) area under the curve, Dn ) dissolution number, tres ) residence time,
Diff ) diffusion coefficient, F ) density, d ) particle size diameter, tdis
) time needed for dissolution, AP ) absorption potential, mow )
partition coefficient, fu ) fraction unionized, and fi ) fraction ionized.

hydrophobic ceramides resulting in a very effective barrier for

hydrophilic molecules.
Nevertheless, it has been shown possible to deliver hydrophilic drugs to the systemic circulation via mucosal transport
(buccal/sublingual, nasal, and vaginal), often aided by absorption
enhancers. Examples of these absorption enhancers are C6-C20
fatty acids or salts and fatty acid alkyl esters.90 The physicochemical properties of drugs required to reach the systemic
circulation have been evaluated and they show a large degree
of similarity for the various routes of administration. In all cases,
the physicochemical properties comply with the criteria for good
absorption91,92 as indicated in Table 4.
In addition, an important parameter is the solubility of the
drug in relation to the amount of solvent available. Before a
drug is able to pass through a physiological barrier, it must be
in a dissolved state. Several simple models are available to
characterize the solubility of the drug in the evaluation of
absorption: the dose (Do) and dissolution number (Dn),93 the
maximum absorbable dose (MAD),94 and the absorption potential (AP).95 The equations to calculate the parameters in these
models are given in Table 5.
The dose number evaluates whether the anticipated human
dose (AHD) of the drug can be dissolved in the available
volume.89
The (physiological) volumes to dissolve the drugs are shown
in Table 6 for the different routes of administration. Clearly
the volume of fluid available for dissolving the drug is critical.
For the oral route of administration, a large volume is
available, especially considering the fact that in vivo solubilization by bile can be very large.96-99 If a nonoral route is chosen
it is immediately clear that the solubility is a very restrictive
parameter. Values of the dose number below 0.1 indicate that

2484 Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009

Table 6. Physiological (Aqueous) Volumes Available for Dissolving
Drugs for the Different Routes of Administration
route
oral
transdermal
buccal/sublingual
vaginal
nasal

fluid

volume (mL)

small intestinal water volume or

glass of water
material of the patch containing
the drug
saliva
mucus covering the wall
liquid sprayed into the nasal cavity

250
(0.2a
(0.9
(1.2b
(0.2

a
Volume of patch ) surface area (10 cm2) thickness (0.02 cm).
Volume of vaginal fluid ) surface area vaginal wall (78.5 cm2)
thickness fluid layer (0.015 cm) ) 1.2 mL. It is assumed that the total
surface area contributes to the volume of fluid available for dissolving
the drug
b

Table 7. Criteria for Drugs to Reach the Systemic Circulationa,b

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physicochemical criteria for oral, transdermal, buccal/sublingual, nasal,

and vaginal drug delivery
molecular weight (MW)
number of hydrogen bond
donor sites (HA)
Number of hydrogen bond
acceptor sites (HD)
polar surface area (PSA)
number of rotatable bonds (RB)
ClogP
good absorption
moderate absorption
poor absorption

model

route

dose number (Do)

oral, transdermal
buccal/sublingual
nasal, vaginal
maximum absorbable oral, transdermal
a
dose (MAD)
buccal/sublingual
nasal, vaginal
oral
dissolution
a
number (Dn)
(buccal/sublingual)
absorption
potentiala (AP)
a

oral

0 < MW < 500

0 < HA < 11
0 < HD < 6
0 < PSA < 110
0 < RB < 13
-2 < ClogP < 5
all properties within range
1 or 2 calculated properties
outside indicated range
3 or more properties
outside indicated range

absorption criteria
Do < 0.1
0.1 < Do < 10
Do > 10
MAD < 0.1AHDb

good
moderate
poor
poor

0.1AHD < MAD < AHD moderate

MAD > AHD
good
poor
Dn < 0.1
0.1 < Dn < 10
Dn > 10
AP > 1

moderate
good
good

See Table 5 for equations. b AHD ) anticipated human dose.

solubility is not a problem; while values about 10 show that

the solubility is troublesome.
The maximum absorbable dose (MAD) represents the amount
of drug that can permeate across a barrier. Again the volume
available to dissolve the drug is a critical parameter for the
nonoral routes of administration. However, if the absorption rate
constant is sufficiently high and a longer residence time can be
achieved, a considerable amount of drug can still be absorbed.
The absorption rate constant can be calculated from the
permeability of the epithelium involved or estimated by the ratio
of Cmax to AUC. If the MAD is higher than the AHD, no
problems are to be expected with respect to absorption. The
absorption potential is also suitable for acids and bases as it
takes the degree of ionization of the drug into account. The
criteria presented in Table 7 address the solubility as well as
the permeability of drugs, which are both crucial to obtain a
sufficient systemic exposure.
However, the problem in drug discovery is that the new
compounds tend to be more and more hydrophobic by nature,
as the current high throughput screening (HTS) technologies
are based on binding assays to determine whether a drug binds
to a target.100 One of the major pitfalls of library screening is
that the more hydrophobic compounds appear to bind better to

the targets (the so-called hydrophobic effect).101 The current

analysis emphasizes that the solubility is one of the key
parameters. It becomes immediately clear that in case of
hydrophobic drugs a different route of administration needs to
be used.
The main advantage of the nonoral routes of administration
is found in the circumvention of the first pass effect (FPE) in
comparison to the oral route. Although metabolic enzymes are
present in almost all epithelia, first pass metabolism is clearly
dependent on the expression levels in the involved tissues. Only
a limited number of reports are available in literature where a
first pass effect is reported for the nonoral routes of
administration (e.g., the FPE of nitroglycerin when administered
transdermally40,43,44). Nonetheless, in cases where the administered dose is low, e.g. in the microgram range, presystemic
metabolism might be considerable even when the expression
levels of the metabolic enzymes are low.
It is possible to conclude that, for the different routes of drug
administration, the barriers to the systemic circulation are formed
by multiple layered epithelia, with the exception of the gastrointestinal epithelium which consists of a single layer of
enterocytes.102,103 Strikingly, the ranges of the molecular weight,
number of hydrogen bond donor and acceptor sites, polar
surfaces, number of rotatable bonds, and ClogP are all within
the generally accepted ranges for passive transcellular transport
after oral administration. Evaluating the solubility of drugs in
terms of the physiological volume available for dissolution
showed that this is a very critical parameter. This clearly shows
that the solubility is more critical for the nonoral routes of
administration. It is concluded that, for permeation across
epithelia, the required properties are independent of the route
of administration. If a nonoral route of administration is chosen
the solubility becomes a very critical parameter, as less volume
is available to dissolve the drug. Hence, for the medical chemist
a change in route of administration is not suitable to increase
exposure in the case of hydrophobic drugs.
Outlook
The delivery of drugs to their site of action at the correct
time and concentration is a key requirement, and this presents
a formidable challenge to overcome if the potential postgenomic
benefits to healthcare are to be realized. Although this problem
exists for all types of molecules, it is particularly acute for
biologicals and macromolecules. These are likely to form a
significant proportion of the medicines that will be used in the
future as new approaches to tackling disease become established.
This paper identifies the priority challenges and opportunities
for precompetitive research in drug delivery for the next decade
as follows.
The need to gain greater understanding of the physicochemical properties of biopharmaceuticals, macromolecules, and
macromolecular delivery systems and learn how these properties
are modified within the biological environment will determine
how drug activity will be affected. One of the pivotal challenges
for the future will be the identification of technologies that can
circumvent the complex biological barriers known to limit
bioavailability of small and macromolecular drugs (particularly
proteins, oligonucleotides, and drug-polymer conjugates). With
a fundamental understanding of biological barriers advanced
materials can be developed as carriers and devices for the
delivery of pharmaceuticals. The creation of smart, stimulisensitive systems that respond to subtle changes in the local
cellular environment is likely to yield long-term solutions to
many of the current drug delivery problems.

Ind. Eng. Chem. Res., Vol. 48, No. 5, 2009 2485

Acknowledgment
The authors gratefully acknowledge Prof. Dr. D. Alejandro
Esteller from the Physiology and Pharmacology Department of
the University of Salamanca for the helpful comments suggested
on the paper.

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