Pharmacology: Drug Delivery

Frédéric Chaubet, Université Paris 13, Villetaneuse, France

Violeta Rodriguez-Ruiz and Michel Boissière, Université de Cergy Pontoise, Neuville-sur-Oise, France
Diego Velasquez, Universidad CES, Medellin, Colombia
© 2017 Elsevier Inc. All rights reserved.

Drug Delivery Devices: The Peculiarity of Nanotherapeutics 2

Basic Concepts of Pharmacology 2
ADME 3
Absorption 3
Distribution 3
Metabolism 3
Elimination 3
Pharmacokinetic Parameters 3
Bioavailability (F) 4
Volume of distribution (Vd) 4
Clearance (Cl), elimination constant (K), and half-life (t1/2) 5
Absorption rate constant (ka), peak blood concentration (Cpmax), and related time (tmax) 5
Pharmacokinetic Models 5
Zero-order and first-order kinetics 5
Compartment models 5
Drug Concentration Profiles 5
Classical profiles 5
Controlled-release systems 5
The Obstacles: Illustration with the Oral Route 6
Physicochemical Properties of a Free Drug 7
Nanoparticulate Systems for Drug Delivery 8
Administration of NPS 8
Pharmacokinetics of NPS 8
Clinical Benefits of NPS 9
Further Reading 14

Glossary
Blood plasma The liquid component of blood, holding blood cells, dissolved proteins (6%–8% including clotting factors),
glucose, electrolytes, carbon dioxide, and oxygen. It makes up about 55% of the body’s total blood volume.
Bolus A precise amount of a substance needed to achieve a therapeutic effect. It is a rapid injection, in contrast to a slow and
progressive injection of a product, carried out by venous route.
Endosomes Subcompartments of the cell on which the endocytosis vesicles cling and fuse to release their contents.
First-pass metabolism A set of enzymes (lipases, proteases, glycosidases, etc.) which ensure the degradation of food elements
assimilated by the body in addition to strong acidic conditions in the stomach and bacterial activities in the intestine.
Gastrointestinal tract (GIT) An organ system within humans and other animals which takes in food, digests it to extract and
absorb energy and nutrients, and expels the remaining waste as feces and urine. The mouth, esophagus, stomach, and intestines
are part of the human GIT.
Liposome A bilayer vesicle, with a similar structure as the cellular membrane (units with hydrophilic heads and hydrophobic
tails), with components such as phospholipids.
Lysosomes Cellular organelles of about 0.2–0.5 mm present in the cytosol of eukaryotic cells. Their function is to perform
intracellular digestion with the enzymes they contain in a strong acid environment.
Nanocrystals Structures of nanometric size with a crystalline molecular arrangement.
Nanomedicine Science and technology for the diagnosis, treatment, and prevention of traumatic diseases and injuries, pain
relief, protection, and enhancement of human health through molecular knowledge of the human body, and the use of
material of nanometric dimensions taking advantage of physical properties unique to this scale.
Nanopharmaceutical Nanosystem capable of releasing molecules or macromolecules of therapeutic interest.
PEGylation Covalent or noncovalent binding of poly(ethylene glycol), usually to a structure, in order to enhance its
physicochemical properties, such as stability and solubility.
PK/PD Pharmacokinetics (PK) describes the drug concentration-time courses in body fluids resulting from administration of a
certain drug dose, pharmacodynamics (PD) the observed effect resulting from a certain drug concentration.

Encyclopedia of Biomedical Engineering https://doi.org/10.1016/B978-0-12-801238-3.11007-4 1

2 Pharmacology: Drug Delivery

Portal circulation Circulation of blood to the liver from the small intestine, the right half of the colon, and the spleen through
the portal vein.
Prodrug Compound that, after administration, is converted within the body into a pharmacologically active drug.
P-glycoprotein (P-gP) Also known as multidrug resistance protein 1 (MDR1) is extensively distributed and expressed in the
intestinal epithelium, in liver cells, in the capillary endothelial cells composing the blood–brain barrier, where it pumps
xenobiotics back into the medium they come from.
Systemic circulation The part of the cardiovascular system which carries oxygenated blood away from the heart to the body,
and returns deoxygenated blood back to the heart.
Therapeutic index (TI) For a given substance, TI is the ratio of two characteristic quantities, those of the lethal dose 50 (LD
50), or the amount causing death in 50% of individuals, and the effective dose 50 (DE 50) which is the dose needed to produce
the desired effects in 50% of individuals.

Pharmacology is the science of drugs, which includes, in particular, their therapeutic use, pharmacokinetics (PK), and toxicology.
Delivery of a drug to the systemic circulation, and consequently to the site of action to produce a desired pharmacological effect, is
the ultimate goal of drug delivery; the when, where, and how of drug delivery being the main questions that must be addressed.
Regardless of the route of administration, a drug molecule will undergo a real biological and chemical obstacle course before
reaching the site of action. The metabolic resistance of a drug molecule, its chemical stability, and its ability to cross biological
barriers are major factors in drug delivery. The physicochemical and biochemical characteristics of the molecule strongly influence
the interactions with the obstacles. Pharmacokinetics (PK) and pharmacodynamics (PD) provide an overall approach by allowing
mathematical modeling of the interaction of a drug molecule with the biological system and to predict drug bioavailability and
subsequent pharmacological responses.
A drug delivery system is defined as any system making it possible to improve and/or facilitate the action of drug over time.
Ideally, the release of the correct amount of active ingredient at the site of effect with a rate adapted for the duration of the treatment,
that is, the optimization of the therapeutic response. At the extreme: to each drug would correspond a unique system able to
efficiently deliver its therapeutic payload to the proper area to be treated without unwanted side effects. This concept of “magic
bullet” proposed by the German physician Paul Ehrlich in the late 19th century joins today that of personalized medicine. During
the second part of the 20th century, an integrated approach of physiological, biological, and biochemical phenomena, combined
with the rapid progress of macromolecular chemistry and the emergence of nanotechnology, revolutionized pharmacology and
medicine. Innovative drug delivery nanoscale systems have appeared whose led to the emergence of new therapeutic strategies, as
well as to significant improvements of the effectiveness and tolerability of marketed drugs and to a simplification of their
administration.
After a short contextualization, this article will first outline the basic concepts of pharmacology. Then, the physicochemical
peculiarities of nanoparticulate systems (NPS) will be presented as well as the strategies of optimization leading to a suitable PK,
according to the biological constraints. Finally, a panorama of the main marketed nanosystems will be presented.

Drug Delivery Devices: The Peculiarity of Nanotherapeutics

From the 1950s, controlled drug delivery systems have developed from (macro)medical devices such as oral osmotic pumps,
dermal patches, or anticontraceptive implants of the size of a match, to (nano)medical devices such as bioactive suspensions of
micelles or polymer nanoparticles, namely nanotherapeutics. Nanotherapeutics are generally defined as structures with size below 1
mm that comprise a carrier and a therapeutic agent in order to achieve either improved targeting, reduced toxicity, or otherwise
enhanced efficacy of this agent in vivo. This limitation is closely connected to biological constraints of the vascular environment
(that will be explained below). The size of many systems, especially those administered orally, can reach several microns, but their
physicochemical characteristics can be considered in a first approach as similar to those of objects at the nanoscale. We will include
them in the definition of nanotherapeutics as well.
Whether drug delivery systems are macroscale or nanoscale, the fundamental problem remains the same: to deliver the drug with
a kinetic such that the effective concentration of drug at the site of action is reached as quickly as possible and its therapeutic efficacy
maintained as long as possible with minimal side effects. But the similarities end there. A nanotherapeutic must be truly conceived
as a “magic bullet” that will circulate in the body to its target without losing neither its way nor its payload. Conversely, macroscopic
system is a fixed reservoir that delivers a drug which must still find its way “alone” to the site of action. Nowadays, new
biopharmaceuticals (such as nucleic acids or peptides) cannot be administered without the help of nanoscale carriers. These
technologies can also enhance the screening and evaluation of new compounds and allow sometimes rescuing failed compounds,
such as those with very low solubility or high side toxicity.
 Pharmacology: Drug Delivery 3

Basic Concepts of Pharmacology

ADME
The main concept in pharmacology assumes that the plasma concentration of the drug (Cp) reflects its concentration at the site of
action (Cs) by an equilibrium between the two (Cp $ Cs). After being administered, a drug is absorbed (A), distributed among
different biological compartments (D), metabolized (M), and/or eliminated (E) (Fig. 1).

Absorption
Absorption results in the transfer of the drug to the systemic circulation. This is the primordial phenomenon. Understanding the
mechanisms and pathways of absorption is essential to the implementation of effective therapy.

Distribution
It is the process by which the drug is transferred from the systemic circulation to the therapeutic target. The molecule can then binds
to proteins with, for example, a fall in plasma concentration or an in vivo reservoir phenomenon. The drug may diffuse in tissues
other than the targeted tissue with a risk of side toxicity.

Metabolism
The metabolism of the drug involves altering its chemical structure by one or more enzymes in order to improve its solubility in
aqueous fluids or even to reduce its molecular weight in order to promote rapid urinary excretion. Metabolic activity can lead to
premature degradation of the drug, may generate more active (or even toxic) metabolites with longer lifetimes than the initial
compound. This activity, necessary in the case of a prodrug strategy, can constitute a formidable biochemical barrier to the
absorption of the molecule (e.g., in the gastrointestinal tract, GIT).

Elimination
Molecules with molecular weights <20 kDa are excreted in the urine by glomerular filtration (compounds with molecular weights
>65 kDa are not filtered by the kidneys). There are specific mechanisms of urinary secretion for acidic or basic molecules, amino
acids, sugars, and liposoluble compounds. These mechanisms can be active.

Pharmacokinetic Parameters
PK is concerned with the variation in drug concentration with time within the body. The time course of drug action depends on
(i) drug dose, route of administration, rate and extent of absorption, distribution rate (particularly to the site of action), rate of
elimination, and (ii) the drug minimum effective concentration (MEC) and concentration–effect relationships. The curve linking
the drug plasma concentration versus time after administration allows defining the therapeutic window or drug therapeutic index
(TI) which is the ratio of MEC (or curative dose) to the maximum tolerated or toxic concentration of a drug (TC) (Fig. 2). The

Fig. 1 ADME: the schematic fate of the drug.

4 Pharmacology: Drug Delivery

Fig. 2 Time–course curves of drug concentration in plasma just after administration. (A) Therapeutic window and bioavailability (¼AUC) from a single oral dose.
(B) Curves from different drugs have different shapes (although the bioavailability could be close). (C) Comparison between the administration of a single same dose
by injection and by oral. The latter evidences the absorption phase which corresponds to the crossing of barriers with a lower bioavailability. The maximum of the
curve is identified by Cmax (peak blood concentration) to which corresponds an effect time, tmax.

influence of ADME on the PK of a drug (and ultimately the design of controlled release delivery devices) can be described by eight
PK parameters: bioavailability (F), volume of distribution (Vd), clearance (Cl), elimination constant (K), half-life (t1/2), absorption
rate constant (ka), peak blood concentration (Cpmax), and Cpmax related time (tmax).

Bioavailability (F)
Bioavailability corresponds to the rate and extent of absorption of a drug so that it becomes available at the site of action leading to a
therapeutic response. Since an equilibrium is assumed between the drug concentration in plasma, Cp, and the drug concentration at
the site of action, Cs, the parenteral route (injections) is taken as the reference route. Note that, parenteral route is the only one used
for targeted release systems. All other routes (oral, nasal, pulmonary, vaginal, ocular, cutaneous, etc.) involve specific barriers that
the drug must cross. The absolute bioavailability is measured by the area under the curve (AUC) of the drug concentration in plasma
versus time following the administration (Fig. 2A). The relative bioavailability, defined as the ratio (AUC for a selected mode of
administration) on (AUC for IV injection), allows to assess the effect of the physiological, physical, and/or chemical obstacles
related to the chosen route of administration that limits the access of the drug to the site of action. With this method it is also
possible to compare the rate and extent of absorption of two formulations according to the same mode of administration.

Volume of distribution (Vd)

The volume of distribution Vd is not an actual physiological volume but rather indicates the size of the pool of body fluids that
would be required if the drug was distributed equally throughout the body. It is estimated from measurements of the total
concentration of drug in the blood after a single IV injection by extrapolation of the concentration at t ¼ 0: Vd ¼ (amount of
drug injected)/(blood concentration extrapolated at t ¼ 0). Drug concentrations in body compartments will vary according to the
physicochemical properties of the drug. Thus, Vd is a characteristic property of the drug rather than the patient, although disease
states may influence Vd. If binding to plasma proteins is substantial, most of the drug will be maintained within the intravascular
compartment and Vd will be small. If there is extravascular binding or storage in fat or other tissues, Vd will be large.
 Pharmacology: Drug Delivery 5

Clearance (Cl), elimination constant (K), and half-life (t1/2)

Systemic clearance Cl is defined as the volume of plasma completely cleared of drug per unit time. Cl is calculated by dividing the
amount of drug reaching the systemic circulation by the resulting AUC. Cl and Vd are connected by the first-order elimination rate
constant, K, with the following equation: Cl ¼ VdK. The larger the value of K, the more rapidly elimination occurs. Once K has been
determined, calculating the time it takes to eliminate half of the circulating drug half-life, namely t1/2, is straightforward: t1/2 ¼ ln
(2)/K. Clinically, half-life and clearance are very important when determining patient-specific dosing regimen, Vd helping to get the
size of the dose.

Absorption rate constant (ka), peak blood concentration (Cpmax), and related time (tmax)
Absorption is difficult to model and most drugs experience a mix of zero-order and first-order kinetic absorption. A simplification
assumed that extravascular absorption is a first-order process with a rate constant ka. After the absorption phase, the concentration
reaches a maximum, Cpmax, to which corresponds tmax (Fig. 2C). One considers that the administration of a drug by injection at
intervals shorter than about four elimination half-times will result in accumulation of the drug in the body. The accumulation will
continue until the amount of drug absorbed per unit time equals the amount of drug eliminated per unit time, at which time a
plateau, or steady-state concentration (Css), will be reached. At equilibrium, input ¼ output, that is, ka ¼ ClCss ¼ VdKCss, thus,
Css ¼ ka/(VdK).

Pharmacokinetic Models
Zero-order and first-order kinetics
When Cp is proportional to the dose administered (which is the case for most drugs), its change is proportional to the remaining
quantity and the kinetic law is first order. An exponential decrease of Cp is then observed preceded by an absorption peak in the case
of non-IV administration (Fig. 2C). For most sites of administration, drug absorption follows first-order kinetics and for most routes
of elimination the process also is first order. The PK parameters do not vary with the dose administered, but according to the PK
models used this decrease may correspond to the superposition of several kinetics. When Cp becomes independent of the
administered dose and hence of the remaining quantity, the kinetic law is zero order. In this case, the half-life of the drug increases
with the administered dose, while at the same time the clearance decreases and consequently the time taken to go into the
therapeutic window increases. A drug reservoir is formed in the tissues/compartments not concerned by its therapeutic action
with the risk of undesirable effects, this is the “sink” model. However, a zero-order kinetic makes it possible to maintain Cp constant
in the therapeutic window.

Compartment models
Compartmental modeling is by far the most commonly used PK modeling technique. In compartmental modeling, tissues having
similar kinetic drug concentration profiles are lumped together into a compartment (Fig. 3). Most of the PK concepts describe the
behavior of a simple one-compartment model in which, after a bolus IV injection, drug equilibrates so rapidly in the entire volume
that the dominant factors are the rates of absorption and elimination. When these rates are equal, the amount and concentration in
the compartment are constant. In this model, blood and other tissues are not distinguished (Fig. 3A and B). Multicompartment
models have been developed allowing both distribution and elimination kinetics from different compartments reflecting more
realistic situations (Fig. 3 C-D).

Drug Concentration Profiles

There are several methods to get the desired pharmacological effect (Fig. 4). Since effect usually is proportional to plasma (or tissue)
concentration, the objective of therapy is to attain and maintain the needed plasma concentration for the period needed.

Classical profiles
The most classical is the administration of a single dose with immediate release of drug for acute therapeutic treatment or a
multiple-dose strategy for chronic problems (Fig. 4A–C). When a drug is administered in a single dose, it is possible to have some
idea about the effects of dose. When repeated doses of a drug are given at sufficiently short intervals, the plasma concentration will
increase up to the MEC. The same thing will happen if a drug is administered as a constant rate IV infusion and eliminated by a first-
order process.

Controlled-release systems
Controlled-release nanosystems that maintain Cp constant for the duration of drug efficacy are a major therapeutic advance. They
act as a reservoir while able to limit the adverse effects of the drug and the “sink” model applies with a zero-order kinetic making
possible to maintain Cp constant in the therapeutic window. The whole question of the development of these systems revolves
around their biocompatibility which depends on the control of many parameters related to their design and to the intrinsic
properties of nano-sized objects.
6 Pharmacology: Drug Delivery

Fig. 3 Models of drug distribution and elimination. (A) There is no elimination of the drug, so the graph shows only a steep rise to maximum followed by a plateau.
(B) There is a route of elimination and the graph shows a slow decay after a sharp rise to a maximum. As the drug is eliminated, the overall elimination process also
falls, and the slope of the curve decreases asymptotically to steady state. (C) Drug placed in the first compartment (blood) equilibrates rapidly with the second
compartment (extravascular volume) and the amount of drug declines to a new steady state. (D) This illustrates a more realistic combination of elimination
mechanism and extravascular equilibration. The resulting graph shows an early distribution phase followed by the slower elimination phase.

Fig. 4 Plot of drug concentration versus time for single dose (A), multiple doses (B), and controlled release (C).

The Obstacles: Illustration with the Oral Route

The effectiveness of a drug depends on the crossing of external barriers (skin, mucus, epithelium), “en-route” barriers (blood,
kidney, liver, spleen, blood–brain barrier, extracellular matrix), and cellular barriers (cellular and subcellular membranes). Of all the
possible routes of administration, the oral route is still the most widely used for drug delivery through in-depth studies of a complex
system that degrades nutrients into small molecules and is designed to prevent the passage of macromolecules, as well as other
 Pharmacology: Drug Delivery 7

Fig. 5 Schematic representation of the transcellular and paracellular transport of drugs across the epithelial cells of the GIT into the systemic circulation (small
drug ¼ red triangle; macromolecular drug ¼ red square). Insert depicts the schematic structure of the cell membrane lipid bilayer. (A) Passive diffusion; (B) carrier-
mediated transport of the drug with a specific carrier (blue circle); (C) transcellular endocytosis followed by transcytosis and exocytosis at the basolateral side;
(D) drug diffusion between the cells.

entities such as foreign microbes or antigens which may present hazards to the host. Beside, oral route benefits the patient with good
levels of long-term acceptance and compliance without the pain and discomfort associated with injections.
A drug absorbed orally must cross the first-pass metabolism in the GIT and the hepatic barrier which reduce its bioavailability.
Note that the presence of food in the GIT modifies the rate and extent of absorption. The enzyme activity in GIT is very intense and
widely described. GIT walls are covered with mucus, a lubricating and protective flexible layer of 50–150 mm width, which acts both
at the mechanistic level and physicochemical level. The mucus is a complex medium, rich in glycoproteins, antimicrobial peptides,
immunoglobulins, and many other intestinal proteins, as well as lipids and electrolytes, forming a filter for molecules with a
molecular weight above 600–800 Da. The rate of mucus crossing by a drug to reach underlying cells depends on the thickness of the
layer, its viscosity, and the interactions of the drug with the glycoproteins. The intestine wall is the main area for drug absorption
in GIT.
As soon as the mucus is crossed, two pathways are possible for the crossing of the underlying cells: the paracellular pathway and
the transcellular pathway (Fig. 5). Only very hydrophilic molecules with a hydrodynamic radius <0.1 nm can diffuse between the
cells (paracellular pathway), a size drastically limited by intercellular tight junctions between intestine epithelial cells. Larger
molecules must cross the cell membrane. A small drug molecule with the appropriate physiochemical characteristics can traverse by
passive diffusion through the lipid bilayer that makes up the cell membranes. These membrane barriers are principally comprised of
the phospholipid bilayers that surround cells and also form intracellular barriers around the organelles present in cells (mitochon-
dria, nucleus, etc.). These are formed with the polar-ionized head groups of the phospholipid facing toward the aqueous phases and
the lipid chains providing a hydrophobic inner core. Membranes form the rate-limiting barriers to the passive flow of small
molecules. There are also dedicated systems for recognition and transmembrane active transport which can be used by different
molecules with sufficiently close structures, although with different efficiencies. Macromolecular drugs cannot diffuse across the cell
membranes. Upon arriving at the contact of the membrane, they cause its folding around the macromolecule which forms an
endosome (endocytosis). The small drug molecules as well as macromolecular drug-containing endosomes traverse the cytosol
where various enzymes can also metabolize the drug (by fusion with lysosomes in the case of macromolecules-containing
endosomes) before exiting cell through the basolateral membrane. Effluent systems, such as P-gp, exist that expel drugs outside
the cell. These indispensable protection mechanisms against xenobiotics are implicated in multidrug resistance phenomena.
Beyond the epithelial cells, drug molecules enter the portal circulation which brings them directly in the liver to a targeted
metabolism.

Physicochemical Properties of a Free Drug

The physicochemical properties of the drug are critical in the design of the dosage form. Stability, water solubility, hydrogen
bonding capacity, and the ionization state are the key properties which directly affect the biological fate of the drug. Many of the
processes of drug disposition depend on the ability or inability of the molecule to cross the hydrophobic inner core of the
8 Pharmacology: Drug Delivery

membranes. Indeed, a drug must be both soluble in the lipid membrane to diffuse, and soluble in water to be transported in
biological fluids to its target. For an organic compound, lipophilicity can be described in terms of its partition coefficient P (or log
P as it is generally expressed). This is defined as the ratio of concentrations of the compound at equilibrium between an organic
phase immiscible with water and an aqueous phase: P ¼ Corg/Caq.
Many drug molecules are weak electrolytes, and their degree of ionization depends on both their pKa and the pH of the medium.
The coefficient partition logP must be replaced by the distribution coefficient log D. For a monoprotonic acid, D ¼ [AH]/([AH] þ
[A]) with Ka ¼ [Hþ][A]/[AH], and hence log D ¼ log P  log (1 þ 10pHpKa). The more log P is high, the more soluble the
molecule in the membranes and the faster it passes through passive diffusion. When log P is >6 (i.e., Corg ¼ 106 Caq), the molecule
is then insufficiently soluble in water and remains trapped in the membranes. Conversely, if log P is too low, the molecule is
eliminated early with aqueous fluids. A limited chemical modification of the molecule (e.g., esterification of an acid, replacement of
an OH with chlorine) makes it possible to optimize the capacity of a molecule to cross the membranes with, however, the risk of
reducing its activity and of increasing its toxicity. The formulation is also very important. A poorly soluble drug administered in the
form of a micronized powder will be absorbed faster than a solid tablet.

Nanoparticulate Systems for Drug Delivery

There are two categories of particulate drug delivery systems intended to be injected in the circulation: molecular systems (MS) and
NPS. In MS, the drug is bound to a transporter soluble in an aqueous medium (monoclonal antibody, carbohydrate, lectin,
immunotoxin, etc.) and the size does not exceed a few nanometers. MS are mainly developed for therapeutic targeting. NPS are
subdivided into hard NPS and soft NPS. Hard NPS consist of “inorganic” materials such as metal oxide, gold, silver, or ceramic. Note
that most hard NPS are often used in the biomedical field for their physical properties (magnetism, luminescence, etc.) and have
contributed to the rise of molecular imaging. Soft NPS refer to “organic” materials including liposomes, micelles, virosomes,
dendrimers, polymeric and protein structures. In the following, we will mainly consider soft NPS due to their prevalence for
therapeutic applications. Compared with MS, NPS allow much greater loading capacity without the need for chemical coupling to
the carrier, and they effectively protect the drug inside their structure. However, the use of NPS faces two difficulties: the inability to
cross the intact endothelial barriers and an early filtration from plasma resulting in localization in the liver and spleen. In terms of
pharmacology, the efficacy of NPS depends on clearance kinetics of the carrier as well as a pharmacologically desired free drug
profile.

Administration of NPS
In a general way, the route of administration is a compromise between patient compliance, the potency of the active ingredient, and
the therapeutic efficacy. NPS should be developed keeping this in mind they are mainly administered orally or intravenously and, in
a less extent, via the dermal route. Injected intravenously, NPS can only spread to organs where the endothelium is discontinuous
(liver, spleen, bone marrow, solid tumors, infected foci, or inflamed sites). Within the vascular space, they are eliminated by the
phagocytic cells (macrophages) from the reticuloendothelial system (RES, mainly liver and spleen). Oral NPS must resist the
metabolism of the GIT (pH, enzymes). Enzymes and bile salts acting together destroy most liposomes, but polymeric NPS are more
stable. The passage to the blood flow can proceed by epithelial transcytosis but mostly through the windowed cellular structures of
the Peyer’s patches, or with the aid of absorption promoters which increase para and transcellular transport of the drug by altering
membrane fluidity, mucus viscosity, or opening of tight junctions. Diffusion is also limited by the intestinal transit time which can
be increased by promoting the adhesion of the NPS to the walls using molecules able to interact with mucus (bioadhesion). Other
routes of administration are studied, such as the dermal route. However, differences in the surface area of diffusion (10,000 m2 in
GIT vs. 2 m2 of skin), lack of cutaneous first-pass metabolism, and the nature of cellular barriers (five layers of skin cells against a
single layer covered with mucus for the GIT) require specific responses and the development of specific systems to, for example,
limit catch by lymph nodes or to reduce the lag-time due to the width of the cutaneous cell layer (Table 1).

Pharmacokinetics of NPS
The response of the RES to foreign particles is influenced by particle size, charge, shape, and the nature of the surface.
Particles <5 nm are rapidly cleared from the circulation through extravasation or renal clearance. As particle size increases,
accumulation occurs primarily in the liver, the spleen, and the bone marrow. The first process that occurs when NPS are exposed
to plasma is a quick and massive nonspecific protein adsorption which results in the formation of a protein corona around the
material. Among the adsorbed proteins, opsonins trigger the complement activation and a signaling cascade leading in
phagocytosis via the RES. Eventually, this results in nonideal biodistribution and unpredictable PK of the NPS. This phenom-
enon is considerably attenuated when the average hydrodynamic diameter of the NPS does not exceed 100 nm and when their
surface is coated with low fouling polymers (e.g., polyethylene glycol, PEG) which ensure the formation of a repulsive
hydration shell limiting the protein adsorption. In the majority of cases, NPS achieve their effects through passive targeting,
which relies on nonspecific accumulation in diseased tissue, usually tumors. Within the tumor microenvironment, the
endothelial paving of the vessels is disjoint allowing the paracellular diffusion of NPS whose dimensions do not allow the
 Pharmacology: Drug Delivery 9

Table 1 Comparison of oral, parenteral, and dermal routes of NPS administration: main advantages and disadvantages

Way of Advantages Disadvantages

administration

Parenteral – Excellent bioavailability
– Suitable for all types of
nanosystems
– No metabolism by the liver
– Good reproducibility
Oral – Ease of use
– Good acceptability by patients
Dermal – Ease of use
– Good acceptability by patients
– Good reproducibility
– Invasive and painful (unsuitable for chronic treatment)
– The effect persists as long as the system is not eliminated by the natural routes so no control
possible
– Low bioavailability (first-pass metabolism, high pH effects)
– 6 h maximum effect (without bioadhesive strategy)
– Hepatic toxicity
– Variable reproducibility
– The active ingredients must be powerful (limited area of penetration)
– Lag-time effect
– Essentially limited to micelles and liposomes

passage of a healthy endothelium. This permeability of blood vessels in combination with poor lymphatic drainage or
transport leads to NPS accumulation within the diseased area: this phenomenon is defined as the enhanced permeability
and retention effect.

Clinical Benefits of NPS

Once approved for clinical development, a drug becomes an active pharmaceutical ingredient (API). Nanoencapsulation of API
is an assertive strategy to create drug carriers to enhance API bioavailability by supporting biological barrier crossing and
increasing their solubility. Several types of encapsulations can be made, basically based on the types and structures of carriers:
lipid nanoparticles (liposomes, micelles, and nonliposomes), polymer-based nanoparticles, metal-based nanoparticles, nano-
crystals, or even virosomes. With the possibility to deliver low water soluble API, the main advantage of NPS lies in their ability
to limit the diffusion of their payload to the tissues not concerned by the treatment. However, the living tissues are very
complex and heterogeneous medium. It is therefore difficult to obtain systematic information about the interrelationships
among the physicochemical properties and biological effects of NPS, and in vitro experimental systems mimicking conditions
in vivo are needed. Whatever it may be, most of the NPS-based therapy strategies are encouraging with promising application
potentials with a lack of short-term toxicity both in vitro and in vivo. Table 2 presents the main marketed NPS in 2017. Most
parts are constituted with lipid-based and polymer-based nanosystems. Liposomal drug delivery is nowadays an established
technology platform with a wide clinical acceptance. This success can be attributed in part to the flexibility of lipid-based
delivery systems, which can efficiently encapsulate both high payloads of small molecules as well as macromolecules, can be
biodegradable and are biocompatible, can be manufactured in sizes down to 20 mm in diameter, and can deliver active agents at
optimized rates in a predictable manner. Polymeric NPS covers a wide variety of composition based on polyesters, polyacry-
lates, and carbohydrates, all materials presenting an overall good biocompatibilty. It can be seen that while cancer treatments
remain an important goal in the development of NPS, other pathologies are concerned such as anemia, infections, or
schizophrenia.
In general, nanomedicines and nanomaterial-based formulations are subject to the same stringent rules and regulations as API
and treatments for use in humans. Extensive research is essential to comprehensively understand the effects of nanomaterial-based
drugs, in terms of their safety, toxicity, and efficacy, and for formulating appropriate guidelines and laws for regulating their uses.
The development of a viable commercial NPS poses significant challenges, such as biomaterial and drug compatibility, mass
production and scalability, and long-term stability of the biomaterial and drug. Despite the publication of several prominent
researches and studies, the design of efficient nanomaterial platforms for perfectly controlled drug delivery in human remains a
tremendous task. Safety is likely the most important issue for NPS; consequently, the development of appropriate and well-
validated methods of characterization is imperative for assessing the biodistribution and toxicity profile of the nanosystems,
biodegradability, and sustained release of the loaded drug under physiological conditions. Beside, important commercial and
regulatory challenges need to be tackled with the emerging generation of more advanced nanoparticles due to their multicompo-
nent nature. At last but not least, full consideration must be given to the development of novel PK and PD models that take into
account the physicochemical properties of the nanocarriers.
 10
Table 2 Nanoparticle-based drug delivery systems currently approved by Health agencies (FDA, EMA, etc.)

Trade name Company API Application Carrier Delivery route (administration) Approval Nanosystem

Pharmacology: Drug Delivery

W
Abelcet Teva Pharma Amphotericin B Fungal infections, L-a-Dimyristoylphosphatidylcholine Intravenous FDA, 1995 Lipid nanoparticles
systemic mycosis (DMPC) and L-a- (liposomes)
dimyristoylphosphatidylglycerol
(DMPG)
Abraxane Abraxis Bioscience Albumin-bound Various cancers, Albumin Intravenous FDA, 2005 Protein-based
or Celgene paclitaxel metastatic pancreatic delivery systems
cancer
AmBisome Gilead Sciences Amphotericin B Fungal infections, Hydrogenated soy phosphatidylcholine, Intravenous FDA, 1997 Lipid nanoparticles
cryptococcal cholesterol, (liposomes)
meningitis, visceral distearoylphosphatidylglycerol, alpha
leishmaniasis tocopherol, sucrose
AmphotecW Kadmon Amphotericin B Fungal infections, Cholesteryl sulfate Intravenous FDA, 1996 Lipid nanoparticles
pharmaceuticals cryptococcal (liposomes)
meningitis, visceral
leishmaniasis
CosmoFer/ Pharmacosmos Iron (III) Iron-deficient anemia Dextran Intravenous FDA, 1992 Polymeric
INFeD/ nanoparticles
Ferrisat
DaunoXome Galen Daunorubicin Kaposi’s sarcoma Distearoylphosphatidylcholine and Intravenous FDA, 1996 Lipid nanoparticles
cholesterol (liposomes)
Depocyt Sigma-Tau Cytarabine is Lymphomatous Cholesterol, triolein, Intrathecal administration FDA, 1996 Lipid nanoparticles
Pharmaceuticals 4-amino-1 -b-D- meningitis dioleoylphosphatidylcholine, and (liposomes)
arabinofuranosyl-2 dipalmitoylphosphatidylglycerol
(1H)-pyrimidinone/
cytosine
arabinoside
DepoDur Pacira Morphin sulfate Psychostimulant, 1,2-Dioleoyl-sn- Lumbar epidural administration FDA, 2004 Lipid nanoparticles
Pharmaceuticals treatment of severe glycero-3-phosphocholine, (liposomes)
pain cholesterol, 1,2-dipalmitoyl-sn-
glycero-3-phospho-rac-(1-glycerol),
tricaprylin, and triolein
Dexferrum/ Luitpold Iron (III) Iron-deficient anemia Dextran Intravenous FDA, 1996 Polymeric
Dexiron Pharmaceuticals nanoparticles
Diafer Pharmacosmos Iron (III) Iron-deficient anemia Isomaltoside Intravenous Medical Product Polymeric
Agency, Sweeden, nanoparticles
2013
DiprivanW Fresenius Kabi Propofol Induction and 1,2-Dipalmitoyl-L-a- Intravenous FDA, 1989 Lipid nanoparticles
maintenance of phosphatidylcholine, (liposomes)
sedation or anesthesia 1-palmitoyl-2-oleoyl-L-a-
phosphatidylcholine, and cholesterol
Doxil/Caelyx/ Janssen Doxorubicin Ovarian cancer, PEGylated liposomes: N-(carbonyl- Intravenous FDA, 1995 Lipid (PEGylated)
Lipo-dox hydrochloride AIDS-related Kaposi’s methoxypolyethylene glycol 2000)- nanoparticles
sarcoma, multiple 1,2-distearoyl-sn-glycero3-
myeloma (all as phosphoethanolamine sodium, fully
secondary therapies) hydrogenated soy
phosphatidylcholine, and cholesterol
Durezol Novartis Difluprednate Eye inflammation, Sorbic acid Ocular (eye drops) FDA, 2008 Lipid nanoparticles
endogenous anterior (emulsion)
uveitis
Eligard Tolmar Leuprolide acetate Prostate cancer PLGH copolymer (D,L-lactide/glycolide) Intravenous FDA, 2002 Polymeric
(synthetic GnRH or nanoparticles
LH-RH analog)
Estrasorb™ Novavax Estradiol Menopausal therapy Soybean oil Transdermal FDA, 2003 Lipid nanoparticles
(micelles)
Exparel Pacira Bupivacaine Postsurgical analgesia Dierucoylphosphatidylcholine and Intravenous FDA, 2011 Lipid nanoparticles
Pharmaceuticals dipalmitoylphosphatidylglycerol), (liposomes)
cholesterol, and triglycerides
(e.g., triolein and tricaprylin)
Feraheme™/ AMAG/Takeda Iron (III) Iron deficiency in Polyglucose sorbitol carboxymethyl Intravenous FDA, 2009 Polymeric
Rienso/ patients with chronic ether nanoparticles
Ferumoxytol kidney disease
Ferrlecit Sanofi Iron (III) Iron replacement for Gluconate colloid Intravenous FDA, 1999 Polymeric
anemia treatment in nanoparticles
patients with chronic
kidney disease
Focalin XR Novartis Dexamethyl- Psychostimulant for Methacrylate copolymers, gelatin, Oral FDA, 2005 Polymeric
phenidate HCl attention-deficit titanium dioxide, sugar spheres nanoparticles
hyperactivity disorder
Fungizone Bristol-Myers Amphotericin B Systemic fungal Dimyristoyl phosphatidylcholine and Intravenous FDA, 1997 Lipid nanoparticles
Squibb infections dimyristoyl phosphatidylglycerol (liposomes)
mixture
GendicineW China Shenzhen Recombinant Head and neck Intratumoral injection, China Food and Virosomes
SiBiono Gene adenovirus squamous cell intrapleural and intraperitoneal Drug
Tech Co expressing wildtype carcinoma infusion, intravenous injection, Administration,
p53 hepatic and lung artery 2003
infusion, endotracheal and
intravesical instillation
GenexolW Samyang Biopharm Paclitaxel Metastatic breast Poly(ethylene glycol)-poly(D,L-lactide) Intravenous South Korea, 2001 Polymeric
cancer, pancreatic (PEGyltaed)
cancer nanoparticles
Ikervis Santen Cyclosporine A Keratitis in adult patients Medium-chain triglycerides Ocular (eye drops) EMA, 2014 Lipid nanoparticles

Pharmacology: Drug Delivery

Pharmaceutical with dry eye disease (emulsion)
Co.
Injectafer/ Vifor Iron (III) Iron-deficient anemia Carboxymaltose colloid Intravenous FDA, 2013 Polymeric
Ferinject nanoparticles
Invega/ Janssen Paliperidone palmitate Schizophrenia, Core: Polyethylene oxide 200 K, Oral, intravenous FDA, 2009, 2014 Nanocrystal
Sustenna Pharmaceuticals schizoaffective povidone, stearic acid, butyl
disorder hydroxytoluene, iron oxide,
polyethylene oxide, ferric oxide,
hydroxyethyl cellulose, PEG, cellulose
acetate
Overcoat: Hypromellose, Titanium
dioxide

11
(Continued )
Table 2 (Continued)

12
Trade name Company API Application Carrier Delivery route (administration) Approval Nanosystem

PEG, ferric oxide, carnauba wax

Pharmacology: Drug Delivery

Marqibo Talon Therapeutics Vincristine sulfate Chemotherapy/ Sphingomyelin/cholesterol (60/40, Intravenous FDA, 2012 Lipid nanoparticles
Philadelphia molar) (liposomes)
chromosome-negative
lymphoblastic
leukemia
Megace ES Par Pharmaceutical Megestrol acetate Antianorexic therapy/ Aqueous drug nanosuspension based Oral (suspension) FDA, 2005 Nanocrystals
Companies, Inc. (synthetic derivative anorexia, cachexia, or on nanocrystal dispersion (NCD)
of progesterone) an unexplained technology
significant weight loss
in patients with a
diagnosis of AIDS
Mepact Takeda Oncology Mifamurtide (synthetic Chemotherapy/high- 1-Palmitoyl-2-oleoyl Intravenous EMA, 2009 Lipid nanoparticles
muramyl tripeptide- grade nonmetastatic phosphatidylcholine and 1,2- (liposomes)
phosphatidyl- osteosarcoma dioleoylphosphatidylserine
ethanolamine, an
immunomodulator)
Onivyde Ipsen Group Irinotecan (gelated or Chemotherapy/ 1,2-Distearoyl-sn- Intravenous FDA, 2015 Lipid nanoparticles
MM-398 Merrimack precipitated state as metastatic glycero-3-phosphocholine (DSPC), (liposomes)
Pharmaceuticals the sucrose adenocarcinoma of the cholesterol, and mPEG (2 kDa)
octosulfate salt) pancreas methoxy-terminated PEG-
distearoylphosphatidyl ethanolamine
(MPEG-2000-DSPE)
Monofer Pharmacosmos A/S Iron(III) isomaltoside Iron deficiency anemia Isomaltoside 1000 (oligosaccharide) Intravenous European authorities Polymeric
1000 (IDA) via a decentralized nanoparticles
registration
procedure, 2009
Myocet Teva (Partner) Doxorubicin First-line therapy of Egg phosphatidylcholine (EPC) and intravenous EMA, 2000 FDA fast Lipid nanoparticles
Sopherion hydrochloride HER2- positive cholesterol track designation, (liposomes)
Therapeutics, LLC metastatic breast 2010
cancer
RapamuneW Pfizer Rapamycin (sirolimus) Immunosuppressant Phosphatidylcholine, propylene glycol, Oral FDA, 2002 Lipid nanoparticles
mono- and di-glycerides, ethanol, (liposomes)
soy fatty acids, and ascorbyl
palmitate
RenagelW Sanofi Poly(allylamine Chronic kidney disease, Silica, colloidal anhydrous stearic acid, Oral FDA, 2000 Lipid nanoparticles
(HCl)/CO2-
3) hydrochloride) hyperphosphatemia hypromellose, diacetylated
monoglycerides
Restasis Allergan Cyclosporin Chronic dry eye Glycerin, castor oil, carbomer Ocular (eye drops) FDA, 2003 Lipid nanoparticles
(immunosuppressant) copolymer type A (emulsion)
Rexin-GW Epeius Gene for dominant- Solid tumors Retrovirus derived particle Intravenous Philippines, 2007 Virosomes
Biotechnologies negative mutant
form of human
cyclin G1, which
blocks endogenous
cyclin G1 protein
Ritalin LA Novartis Methylphenidate Psychostimulant Ammonio methacrylate copolymer, Oral FDA, 2002 Polymeric
gelatin, methacrylic acid copolymer, nanoparticles
PEG, red iron oxide, sugar spheres,
 talc, titanium dioxide, triethyl citrate,
and yellow iron oxide
ThermoDox Celsion Corporation Doxorubicin Hepatocellular Dipalmitoylphosphatidylcholine, Intravenous FDA, 2014 Lipid nanoparticles
carcinoma monostearoylphosphatidylcholine, (PEGylated
and PEG 2000- liposomes)
distearoylphosphatidylethanolamine
TricorW Abbott Fenobibrate Hypercholesterolemia, Silicified microcrystalline cellulose, Oral FDA, 2004 Polymeric
hyperglyceridemia crospovidone, and magnesium nanoparticles
stearate
TriglideW Vectura (former Fenofibrate Hypercholesterolemia, PVPP, maltodextrin, carboxymethyl Oral FDA, 2005 Polymeric
Skye Pharma) hyperglyceridemia cellulose sodium, croscarmellose nanoparticles
sodium, colloidal silicon dioxide,
magnesium stearate
Venofer Luitpold Iron (III) Iron deficiency in chronic Sucrose colloid Intravenous FDA, 2000 Polymeric
Pharmaceuticals kidney disease nanoparticles
VisudyneW Bausch and Lomb Verteporfin Macular degeneration, Egg phosphatidylglycerol, dimyristoyl Ocular (eye drops) FDA, 2000 Lipid nanoparticles
wet age-related phosphatidylcholine (liposomes)
myopia, ocular
histoplasmosis
Zanaflex Acorda Tizanidine HCl Short-acting muscle Hypromellose, silicon dioxide, sugar Oral FDA, 2002 Polymeric
relaxant, spasticity spheres, titanium dioxide, gelatin nanoparticles
Zinostatin/ Terumo Corp Neuronal calcium Liver cancer Styrene–maleic acid Intravenous Japan, 1994 Polymeric
stimalamer sensor protein nanoparticles

Modified from Bobo, D., Robinson, K. J., Islam, J., Thurecht, K. J., and Corrie, S. R. (2016). Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date. Pharmaceutical Research, 33(10), 2373–2387; Jiang, W., von
Roemeling, C. A., Chen, Y., Qie, Y., Liu, X., Chen, J. and Kim, B. Y. S. (2017). Designing nanomedicine for immuno-oncology. Nature Biomedical Engineering, 1, 1–11; Sainz, V., Conniot, J., Matos, A., Peres, C., Zupancic, E., Moura, L., Silva, L. C.,
Florindo, H. F., Gaspar, R. S. (2015). Regulatory aspects on nanomedicines. Biochemical and Biophysical Research Communications, 468, 504–510; Weissig, V., Pettinger, T. K., and Murdock, N. (2014). Nanopharmaceuticals (part 1): Products on the
market. International Journal of Nanomedicine, 9, 4357–4373.

Pharmacology: Drug Delivery

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14 Pharmacology: Drug Delivery

Further Reading
Allen TM and Cullis PR (2013) Liposomal drug delivery systems: From concept to clinical applications. Advanced Drug Delivery Reviews 65: 36–48.
Bobo D, Robinson KJ, Islam J, Thurecht KJ, and Corrie SR (2016) Nanoparticle-based medicines: A review of FDA-approved materials and clinical trials to date. Pharmaceutical
Research 33(10): 2373–2387.
Doane TL and Burda C (2012) The unique role of nanoparticles in nanomedicine: Imaging, drug delivery and therapy. Chemical Society Reviews 41: 2885–2911.
Dos Santos, S., Medronho, B., Dos Santos, T., and Antunes F. E. (2013). Amphiphilic molecules in drug delivery systems. In Drug delivery systems: Advanced technologies potentially
applicable in personalized treatment advances in predictive, preventive and personalized medicine, Coelh J, Vol. 4pp. 35–85. Springer.
Etheridge ML, Campbell SA, Erdman AG, Haynes CL, Wolf SM, and McCullough J (2013) The big picture on nanomedicine: The state of investigational and approved nanomedicine
products. Nanomedicine: Nanotechnology, biology, and. Medicine 9: 1–14.
Florence AT (2012) “Targeting” nanoparticles: The constraints of physical laws and physical barriers. Journal of Controlled Release 164: 115–124.
Hoffman A (2008) The origins and evolution of “controlled” drug delivery systems. Journal of Controlled Release 13(3): 153–163.
Illum L, Davis SS, Wilson CG, Thomas NW, Frier M, and Hardy JG (1982) Blood clearance and organ deposition of intravenously administered colloidal particles. The effects of particle
size, nature and shape. International Journal of Pharmaceutics 12: 135–146.
Jain K, Mehra NK, and Jain NK (2014) Potentials and emerging trends in nanopharmacology. Current Opinion in Pharmacology 15: 97–106.
Jiang W, von Roemeling CA, Chen Y, Qie Y, Liu X, Chen J, and Kim BYS (2017) Designing nanomedicine for immuno-oncology. Nature Biomedical Engineering 1: 1–11.
Kamaly N, Xiao Z, Valencia PM, Radovic-Moreno AF, and Farokhzad OC (2012) Targeted polymeric therapeutic nanoparticles: Design, development and clinical translation. Chemical
Society Reviews 41: 2971–3010.
Petros RA and DeSimone JM (2010) Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews Drug Discovery 9: 615–627.
Radomska A, Leszczyszyn J, and Radomski MW (2016) The Nanopharmacology and Nanotoxicology of Nanomaterials: New opportunities and challenges. Advances in Clinical and
Experimental Medicine 25(1): 151–162.
Ranade VV and Cannon JB (2011) Nanoscience and nanotechnology for drug delivery. In: Drug delivery systems, pp. 451–523. CRC Press, Taylor & Francis.
Sainz V, Conniot J, Matos A, Peres C, Zupancic E, Moura L, Silva LC, Florindo HF, and Gaspar RS (2015) Regulatory aspects on nanomedicines. Biochemical and Biophysical Research
Communications 468: 504–510.
Smith, D.A., Allerton, C., Kalgutkar, A.S., van de Waterbeemd, H. and Walker, D.K. (2012) Pharmacokinetics. Pharmacokinetics and metabolism in drug design. pp. 19–41. Wiley.
Weissig V, Pettinger TK, and Murdock N (2014) Nanopharmaceuticals (part 1): Products on the market. International Journal of Nanomedicine 9: 4357–4373.
Wicki A, Witzigmann D, Balasubramanian V, and Huwyler J (2015) Nanomedicine in cancer therapy: Challenges, opportunities, and clinical applications. Journal of Controlled Release
200: 138–157.
Moghimi SM, Hunter AC, and Murray JC (2001) Long-circulating and target-specific nanoparticles: Theory to practice. Pharmacological Reviews 53(2): 283–318.