6. When a pharmaceutical agent is encapsulated within, or attached to, a polymer
or lipid, drug safety and efficacy can be greatly improved and new therapies
are possible.
• Drug targeting is concerned with modulation and control of the biodistribution
of a drug based on a suitable delivery system.
• The biodistribution of the drug is not governed by the drug itself but by the
delivery system.
• The biomedical design of the delivery system depends on the properties of the
target in combination with those of the drug and the needs of the patient.
9. Potential advantages of improved drug delivery:
Ability to target specific locations in the body
• Reduction of the quantity of drug needed to attain a particular concentration in the
vicinity of the target;
• Decreased number of dosages and possibly less invasive dosing
• Reduction of harmful side effects due to targeted delivery (reduced concentration of the
drug at non-target sites);
Facilitation of drug administration for pharmaceuticals with short in vivo half-lives (for
example peptides and proteins).
Advantages must be weighed against the following concerns in the development
of each particular drug-delivery system:
1. toxicity of the materials (or their degradation products) from which the drug is
released, or other safety issues such as unwanted rapid release of the drug (dose
dumping);
2. discomfort caused by the system itself or the means of insertion;
3. expense of the system due to the drug encapsulation materials or the manufacturing
process.
10. METHODS OF DRUG DELIVERY
•epicutaneous (application onto the skin). the active substance diffuses through
skin in a transdermal route.
•intradermal, (into the skin itself) is used for skin testing some allergens, and also
for mantoux
•subcutaneous (under the skin), e.g. insulin
•nasal administration (through the nose)
•intravenous (into a vein), e.g. many drugs, total parenteral nutrition
•intraarterial (into an artery),
•intramuscular (into a muscle), e.g. many vaccines, antibiotics, and long-term
psychoactive agents.
•intracardiac (into the heart), e.g. adrenaline during cardiopulmonary resuscitation
(no longer commonly performed)
•intraosseous infusion (into the bone marrow) is, in effect, an indirect intravenous
access because the bone marrow drains directly into the venous system
•intrathecal (into the spinal canal) is most commonly used for spinal anesthesia and
chemotherapy
•intraperitoneal, (infusion or injection into the peritoneum) e.g. peritoneal dialysis
•Intravesical infusion is into the urinary bladder.
•intravitreal, through the eye
11. NP drug delivery systems
Possible mechanisms by which drugs are released:
1. Diffusion of the drug species from or through the system.
2. A chemical or enzymatic reaction leading to degradation of
the system, or cleavage of the drug from the system.
3. Water activation, either through osmosis or swelling of the
system.
Rosen & Abribad, Nature Reviews 2005
14. Ways of controlling drug release locally:
Smart Stimuli-responsive NPs
Stimuli-responsive NPs show a sharp change in properties upon a
small or modest variations of the environmental conditions such
as temperature, light, salt concentration or pH.
Different organs, tissues and cellular compartments may have
large differences in pH, which is considered the most suitable
stimulus.
This behavior can be used for the preparation of so-called ‘smart’
drug delivery systems, which mimic biological response behavior
to a certain extent.
Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006
15. Ways of controlling drug release locally
• pH
• Light
• Thermally
• Ultrasound
• Magnetically
• Enzyme-induced
16. pH in living systems[
Compartment pH
Gastric acid 1
Lysosomes 4.5
Granules of chromaffin cells 5.5
Human skin 5.5
Urine 6.0
Cytosol 7.2
Cerebrospinal fluid (CSF) 7.5
Blood 7.34–7.45
Mitochondrial matrix 7.5
Pancreas secretions 8.1
Solid tumours 6.5
17. HYDROGELS
Polymers or co-polymers (e.g. acrylamide and acrylic acid) create
water-impregnated nanoparticles with pores of well-defined size.
Water flows freely into these particles, carrying proteins and other
small molecules into the polymer matrix.
By controlling the pore size, huge proteins such as albumin and
immunoglobulin are excluded while smaller peptides and other
molecules are allowed.
The polymeric component acts as a negatively
charged "bait" that attracts positively
charged proteins, improving the particles'
performance.
20. pH-responsive POLYMERIC NP in drug delivery
Ionizable polymers with a pKa value between Classical monomers are acrylic acid and
3 and 10 are candidates for pH-responsive derivate
systems. Chitosan has received attention
recently because it maintained its
The change of pH triggers the passage from biocompatibility
ionized to un-ionized form or vice versa
Lactic acid
Poly(ethylene imine) (PEI)
linear or branched
Poly(L-lysine) (PLL)
Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006,
Oh K.T. et al., J. Mater Chem, 17, 2007
21. pH Sensitive Hydrogels
R R
N H3 + N H2
N H3 + N H2
N H y dr o p h o b ic s id e c h a in N H y dr o p h o b ic s id e c h a in
R R
O O
R = p o lym e r b a ckb o n e p H > 6 .5 b u ffe r
p H < 6 .5 b u ffe r
Crosslinking is based on hydrogen bonding, and secondary hydrophobic interactions.
Crosslinking is reversible
Control over the pore sizes
22.
23. Release characteristics are dependent
on the chemical nature of the hydrogel
Hydrogel Requirements:
Controlled or delayed diffusion of molecules
Pore size compatibility with the biological molecule
Solubility of the biological molecule
26. pH-sensitive liposomes for intracellular drug delivery
liposomes can either remain bound at the cell surface, disassociate from the receptor, or accumulate in coated or
non-coated invaginations. Following endocytosis (a), can be delivered to lysosomes (c) where may be degraded by
lysosomal peptidases and hydrolases. Following acidification of the endosomal lumen, pH-sensitive liposomes are
designed to either fuse with the endosomal membrane (e), releasing their contents directly into the cytoplasm, or
become destabilized and subsequently destabilize the endosomal membrane (d) resulting in leakage of the
endosomal contents into the cytosol.
34. Thermo-responsive POLYMERS in drug delivery
Temperature-responsive polymers and hydrogels exhibit a volume phase transition at a
certain temperature, which causes a sudden change in the solvation state.
Upper critical solution Lower critical solution
temperature (UCST) temperature (LCST)
PNIPAM in drug delivery
Poly-N-IsoPropylAcrilAmide (PNIPAM) is the
most prominent candidate as thermo-
responsive polymer.
PNIPAM copolymers have been mainly
studied for the oral delivery of calcitonin and
insulin.
Schmalijohann D., Adv. Drug Deliv. Rev, 58 2006
36. Ultrasound-triggered drug delivery systems
Non-invasively transmitted energy through the skin Elastin-like polypeptide
can be focused on a specific location and employed
for enhanced drug release.
Triggering mechanism: Enhanced cavitation activity
Pluronic
37. O/W Emulsions
The o/w submicron LEs has many appealing properties as drug carriers. They are
biocompatible, biodegradable, physically stable and relatively easy to produce on a
large scale using proven technology.
Tamilvanan S., Prog Lipid Res, 43, 2004
