Dosage Forms II
M. Mehanna, B.Sc. Pharm., M.Sc., Ph.D.
School of Pharmacy
Lebanese American University
Spring 2025
Drug targeting
Lecture-specific student learning outcomes (SLOS)
 Describe the different components, principles and
levels of drug targeting
 Classify the different types of carriers used
 Explain the parameters affecting the drug bioavailability
Targeted drug delivery
 A method of delivering therapeutically active agent in a
pattern that considerably enhances the concentration
of the medication in some parts of the body in
comparison to others.
 Selective and effective localization of an active moiety
at a predetermined target in therapeutic concentration,
while confining its access to non-target cellular linings,
thus minimizing toxic effects and maximizing
therapeutic outcomes.
• Drug targeting can be considered as a form of controlled
release in that it exercises spatial control of drug release
within the body.
1. Recognition of the possibility of patenting successful
drugs by applying TDDSs, coupled with the increasing
expense in bringing new entities to market.
2. New systems are desirable to deliver the novel,
genetically engineered pharmaceuticals i.e., peptides
and proteins, to their sites of action without experiencing
major immunogenicity or biological inactivation.
3. Treating enzyme deficient diseases and cancer
therapies can be enhanced by better targeting.
Drug targeting is achieved by one of two approaches:
a. Chemical variation of the parent compound to a derivative
which is activated only at the intended site.
b. Nanocarriers such as nanospheres, nanoparticles,
liposomes, microsponge, microballoon, carbon nanotubes,
quantum dots, and antibodies to direct the drug to its site
of action
dimitra
Drug Targets
I. Receptors on cell membranes: allow specific
interaction of drug carriers with cells, facilitating their
uptake via receptor-mediated endocytosis. Such as
folate receptors in breast and ovary malignancies.
present in all cells, but heavily expressed on breast cancer cells
adding folic acid to the drug will make it bind to breast cancer cells more than other cells
II. Lipid components of cell membranes: interaction of
synthetic phospholipid complements with cellular
membranes alters:
a.
Lipid composition
b.
Membrane permeability
c.
Flexibility
which affects the signal transduction mechanisms,
inducing apoptotic cell death.
Drug Targets
III. Antigens or proteins on cell surfaces: cells either
express new proteins or exhibit disparate
(under/over) expression of the proteins found on
normal cells. Monoclonal antibodies are used.
The reason for its attractiveness is its ready accessibility,
low expression on normal cells, and a steady delivery
within the tumor.
Levels of Targeting
I. First order targeting (organ level targeting): the target
is tissue or organ as drug-eluting stents.
II. Second order targeting (cell-level targeting); the target
is a definite cell. When an antibody is attached to a
delivery system, it exclusively identifies and couples
to a specific antigen on a cell surface.
III. The third order targeting (intracellular-level targeting)
IV.Fourth level of targeting (molecular-level targeting):
locating a precise molecule inside the cell as in gene
delivery systems
I. Passive targeting
 Inherent route of biodistribution of the vector system,
through which it concentrates in the organ
compartment(s) of the body.
 Body’s natural response to the physicochemical
properties of the drug or the carrier system.
 Colloidal vectors as liposomes are taken up by the
reticuloendothelial framework (RES), particularly in
liver and spleen, has made them extreme vectors for
latent hepatic focusing of medications of these
compartments.
PEGylation
II. Active targeting
 Facilitation of the binding of the carrier to anticipated
cells through the use of ligands to enhance receptormediated localization and target-specific drug delivery.
 Attained by ligand-based targeting and physical
targeting (trigger release). for treatment of hepatic cancer, thermal triggering
 Targeting components are leading molecules
themselves (bioconjugates) or attached as ligands on
delivery system.
 Colloidal carrier systems can be precisely decorated
with polypeptides, antibodies, oligosaccharides, and
viral-mediated proteins.
III. Reverse targeting
• Instead of the drug delivery system seeking its target,
attempts are made to attract the target cells toward the
drug delivery system.
antibody only attracts the immune
reaction and doesn't kill the cancer cell
double
Site-specific delivery
• The main components: receptors, carriers, and
ligands
I.
Receptors
Complex transmembrane proteins, which intervene
highly specific communications between cells and their
extracellular milieu.
II. Ligands
• Ligands are carrier-associated surface groups, which
can selectively direct the carrier to the prespecified
site(s).
memo
Carbohydrate-specific (lectin)
receptors
Normal and malignant cells
Mammalian hepatic lectin,
galactose-specific receptors, or
“galaptins
Hepatocyte-specific receptors
Mannose receptors
Macrophages (alveolar and
peritoneal)
Transferrin receptors
Fibroblasts and blood brain
endothelial cell
Folate receptors
Breast cancer
III. Carriers
• Vectors segregate, carry and hold drugs en route,
while delivering it within a target.
• Characteristics:
a. Capable of crossing the anatomical barriers
b. Identified specifically by the intended cells
c. Conserve the avidity of the surface ligands
d. Non-toxic or immunogenic, easily biodegradable
e. After internalization, it should liberate the drug
molecule inside the target
1. Polymers
a. Dendrimers
• Linear polymers with dendron on each repeating unit
and have a hyper-branched 3D structure.
• contain a variety of peripheral functional groups, which
can be functionally modified with antibody, transferrin,
biotin, folic acid, galactose, or peptide.
• Poly (propylene imine) (PPI) dendrimers,
polyamidoamine (PAMAM) dendrimers, and poly-Llysine (PLL) dendrimers.
gen 4
VivaGel® formulation
• Microbicide gel which uses dendrimers.
• Dendrimer is the active ingredient in its own right rather
than being used as a delivery system.
• The dendrimer has antiviral properties because of its
ability to bind to viruses and thereby block their ability
to infect cells. entraps
• VivaGel® BV has EU market approval for the treatment
and rapid relief of bacterial vaginosis.
b. Chitosan
• Chitosan is one of the most abundant biopolymers
derived from natural chitin that commonly exists in the
exoskeletons of arthropods, and insects.
• Degraded by internal enzymes, which makes chitosan
have good biocompatibility.
• Like other cationic polymers, chitosan is linked to
nucleic acids by electrostatic interaction.
c. Polylactic acid/poly (lactic-co-glycolic acid)
• PLA and PLGA are biodegradable functional polymer
organic compounds with good biocompatibility and
encapsulation properties which can be metabolized in
the body.
byproduct in our body so they are safe
d. Amino acid derived biopolymers
• Abundant source and diverse functional groups.
• Polyamides(PA)s, polyesters(PE)s, and poly(esteramide)s(PEA)s.
like micelles
• Poly(-amino acid)s have the capability of readily selfassemble into stable, structures in solution.
• The positive charge of poly(beta-amino ester)s can
bind to nucleic acids and be internalized into cells
escaping the endolysosomal compartment and release
nucleic acids into the appropriate cell compartment for
gene delivery.
2. Liposomes
• Liposomes are vesicles constituted by an aqueous core
surrounded by one or several phospholipid bilayers.
• Hydrophilic drugs or active components can be
assimilated into the inner aqueous cavity and lipophilic
drugs imbibed into the phospholipid layer.
• Liposomes are spherical vesicles with particle size in
nano to micro range.
• Liposomes can circumvent degradation of the
entrapped moiety, and liberate the therapeutic moieties
at designated targets.
a. Unilamellar vesicles:
vesicle consists of a
single phospholipid
bilayer spheroid
enclosing the
aqueous solution.
b. Multilamellar
vesicles: numerous
unilamellar vesicles
are formed on the
inside of the other.
vesicles of
concentric
phospholipid
globules separated
by layers of water
• Liposomes as carriers have many advantages:
a. low toxicity
b. good biocompatibility
c. improved pharmacokinetics
d. ease of preparation
• Drug can be entrapped either
a. passively (during formation of liposomes)
b. actively (after formation of liposomes).
modify pH of the core which induces
ionization of the drug, which can't
diffuse out anymore
• Interaction of liposomes with cells:
a. Adsorption (electrostatic forces or weak hydrophobic
interactions) or specific adsorption
a. engulfment (phagocytic cells of the RES)
b. Lipid exchange of bilayer component with cell
membrane
c. Fusion
PEGylated liposomes
• Due to their flexible and hydrophilic nature, PEG
polymers on nanoparticles surfaces can form a thick
and dynamic hydration shell, which prevents the
absorption of serum proteins on surfaces.
• Grafted PEG polymers on the surface are able to
reduce opsonization and clearance by the
mononuclear phagocyte system, extending blood
circulation time.
• The risk of cardiotoxicity increases with higher cumulative doses
of doxorubicin. very potent
• Cumulative life time dose of doxorubicin should not exceed 450–
500 mg/m2. (maximum dose per life)
PEGylated liposomes
• Doxil® reduced its cardiotoxicity while preserving its antitumor
efficacy.
• Intravenous liposomes cannot escape the vascular space in
sites that have tight capillary junctions, such as the heart muscle
• The liposomes generally exit the circulation in tissues and
organs lined with cells that are not tightly joined (fenestrated) or
areas where capillaries are disrupted by inflammation or tumor
growth.
EPR diagram
one polymer represents the lipophilic tail and one represents a hydrophilic head
3. Polymeric micelles
• Copolymers with surfactant characteristics are used to
formulate micelles.
• Polymeric micelles have a relatively narrow size
distribution.
• Polymeric micelles have a lower CMC and are more
stable.
• Micelles are sufficiently large (> 50 kDa) to avoid renal
excretion yet small enough (< 200 nm) to avoid
clearance by the liver and spleen, they are able to
specifically accumulate at tumour sites and sites of
inflammation because of passive targeting.
3. Polymeric micelles
• Polymeric micelles are built from copolymers with
hydrophobic components comprising poly(propylene
oxide), poly(D,L-lactic acid), poly(ε-caprolactone),
poly(L-aspartate) and poloxamers. For the hydrophilic
component, which forms the outer hydrophilic shell of
the micelle, PEG is commonly used.
• Can be functionalized
Genexol®-PM
• Polymeric micelle formulation of paclitaxel
• Methoxypolyethylene glycol–poly(D,Llactide) which is approved in South Korea
for treatment of metastatic breast cancer.
• Invivo antitumour efficacy of the micellar
formulation has been shown to be
significantly higher than that of Taxol
4. Solid nanoparticles
• Solid nanoparticles are solid constructs in the
nanometre range.
• Preparation:
a. size reduction of particles (by milling) as nanocrystals
b. Molecular agglomeration (by precipitation) to form
nanoparticles
• Reducing the size of drug particles to within the
nanosize range substantially increases the total
surface area of the system, hence increasing the
solubility, the dissolution ability and bioavailability of
drugs delivered by the oral route.
• NanoCrystals are prepared from drug with no carrier,
and stabilizers (nonionic and anionic surfactants) are
added during the size-reduction process to increase
stability. WHY
Solid nanoparticles
• drug incorporated within the polymer matrix or attached
to the particle surface.
• Allows modified drug biodistribution as the drug
pharmacokinetic profile will be dictated by the
drug
carrier
properties of ……………rather
than those of ………….
PEG
• Stealth nanoparticles, with the hydrated …………..
surface coating prohibiting protein and antibody
binding, thereby reducing recognition and clearance
longer circulation time
from the circulation thus ………….
Solid-lipid nanoparticles
• Nanoparticles made from solid (high mp) lipids
dispersed in an aqueous phase.
• solid triglycerides, saturated phospholipids and fatty
acids, which are well tolerated by the body.
• Parenteral, oral, ocular, dermal and cosmetic
applications.
• lipid nanoparticles loaded with cosmetic components
such as ascorbyl palmitate, β-carotene and coenzyme
Q10.
Protein nanoparticles
• The first commercial product based on protein
nanotechnology was Abraxane®.
• Abraxane® consists of 130 nm particles of albuminbound paclitaxel.
• Before that, paclitaxel was only available as Taxol®
which is paclitaxel solubilized in polyethoxylated castor
oil (Cremophor® EL) and ethanol. However, this
formulation requires special infusion sets and
prolonged infusion times and has toxicity issues
associated with its use.
Inorganic nanoparticles
• Nanoparticles can be fabricated from inorganic
materials, including metal oxides, metal sulfides,
carbon nanotubes, and calcium phosphate.
• Non-biodegradable and so have a limited application.
• Abdoscan® is iron oxide nanoparticle product. Used
during MRI diagnostics of the bowel.
• The particles are suspended in viscosity-increasing
agents, such as starch, to prevent aggregation of the
particles in vivo upon ingestion.
or dextran derivatives