Download Lecture 22_Drug_Delivery_Systems

Nanochemistry
NAN 601
Instructor:
Dr. Marinella Sandros
Lecture 24: Drug Delivery Systems
1

Oral Delivery
http://www.slimmingpillsreview.com/wpcontent/uploads/2008/08/energy-pill.jpg

Inhalation
http://weblogs.fox61.com/features/family/mommy-minute/Child_using_inhaler.jpg

Transdermal
http://www.wellsprings-health.com/images/articles/transdermal-cream.jpg
Implantation

Injection
http://www.medgadget.com/archives/img/hydron_sm.jpg

http://portfolio.flashwebmaster.com/graphics/graphics_illustrations_medical_injection_3.gif

High initial release (burst)

Loss of bioactivity

Delivery to incorrect sites
The term Nanomedicine refers to the application of
nanotechnology to diagnosis and treatment of
diseases.
 It deals with the intercations of nanomaterials
(surfaces, particles, etc.) or analytical nanodevices with
“living” human material (cells, tissue, body fluids)
It is an extremely large field ranging from in vivo and
in vitro diagnostics to therapy including targeted
delivery and regenerative medicine.
www.certh.gr/dat/E2353434/file.pdf


Up to 50% of existing drugs are
classified as `Poorly-water
soluble` or `in soluble`
Thus, Bioavailability is very poor.
pharm.swu.ac.th/web_npec/content/JOURNAL/j_club.pdf

Safe
◦ Non-toxic, non-immunogenic, non-inflammatory
◦ Biodegradable and/or biocompatible
◦ Degradation products readily eliminated from body or
used by the body.
◦ Ideally , excipients have GRAS designation by the FDA
◦ Compatible with drug
◦ Compatible with cells and tissues
No platelet aggregation, RBC lysis, neutrophil
activation, etc.
Manufacturing: ease and low cost
Stable
*Gras: Generally Regarded as Safe.




Exhibit higher intracellular uptake
Can penetrate the submucosal layers while the
microcarriers are predominantly localized on the
epithelial lining.
Can be administered into systemic circulation
without the problems of particle aggregation or
blockage of fine blood capillaries.
The development of targeted delivery is firmly built
on extensive experience in pharmaco-chemistry,
pharmacology, toxicology, and nowadays is being
pursued as a multi- and interdisciplinary effort.
www.certh.gr/dat/E2353434/file.pdf

Prevention of drug from
biological degradation

Effective Targeting

Patient Compliance

Cost effectiveness

Product life extension
www.photonics.com/Article.aspx?AID=45177
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt
☛Dendrimers
☛Liposomes
☛Micelles
• Tree-like polymers, branching out from a central
core and subdividing into hierarchical branching
units
- Not more that 15 nm in size, Mol. Wt very high
- Very dense surface surrounding a relatively
hollow core (vs. the linear structure in traditional
polymers)
Courtesy of: http://www.uea.ac.uk/cap/wmcc/anc.htm
• Dendrimers consist of series of chemical shells built on a
small core molecule
- Surface may consist of acids or amines  means to attach functional
groups  control/modify properties
- Each shell is called a generation (G0, G1, G2….)
- Branch density increases with each generation
- Contains cavities and channels  can be used to trap guest
molecules for various applications.


Dendrimers have a high degree of molecular uniformity,
narrow molecular weight distribution, specific size and
shape characteristics, and a highly- functionalized
terminal surface.
The manufacturing process is a series of repetitive steps
starting with a central initiator core. Each subsequent
growth step represents a new "generation" of polymer
with a larger molecular diameter, twice the number of
reactive surface sites, and approximately double the
molecular weight of the preceding generation.
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt
www.avidimer.com
◦ Liposomes are microscopic spherical vesicles composed of a
phospholipid bilayer that are capable of encapsulating active
drugs.
Hydrophilic
Hydrophobic
Diagram to show a lipid bilayer and comparison of a liposome and a micelles
Diagram
representing
a liposome
encapsulating an
active drug in its
aqueous core.
Phospholipids are the major structural components of
biological membranes such as the cell membrane

Phospholipids are amiphathic in nature, containing a
hydrophobic tail and hydrophilic head.

When placed in water, the fatty acid tail associates and
excludes the water, hence orientating the hydrophilic heads
towards the water.

This leads to a bilayer configuration
.





Main component of
liposomes are phospholipids
Spontaneously orientate in
water to give a bilayer,
Tails are rearranged away
from the water
Spherical structure reduces
exposure at the edges
Produces a
thermodynamically stable
structure

They were first discovered by Alec D. Bangam in the
early 1960’s while investigating the role of
phospholipids in the clotting cascade.

The phospholipid bilayer enables the liposomes to be
encapsulate active drugs for drug delivery.
Depending on the solubility of
the drug, it can be:
Encapsulated in
aqueous core
Interacting with surface
Of liposome via
Electrostatic interaction
Taken up by bilayer
Figure : Liposomes - (left) A = aqueous soluble drug encapsulated in aqueous
compartment; (centre) B = a hydrophobic drug in the liposome bilayer; (right)
C = hydrophilic polyoxyethylene lipids incorporated into liposome
Drug Targeting
Inactive: Unmodified liposomes gather in specific tissue
reticuloendothelial system
Active: alter liposome surface with ligand (antibodies,
enzymes, protein A, sugars)
Physical: temperature or pH sensitive liposomes
Directly to site
Why Use Liposomes in
Drug Delivery?
Pharmokinetics - efficacy and toxicity
Changes the absorbance and biodistribution
Deliver drug in desired form
Protection
Decrease harmful side effects
Change where drug accumulates in the body
Protects drug
Why Use Liposomes in
Drug Delivery?
Release
Affect the time in which the drug is released
Prolong time -increase duration of action and
decrease administration
Dependent on drug and liposome properties
Liposome composition, pH and osmotic gradient, and
environment




Their exterior lipid bilayer is very chemically reactive, thereby
providing a means to conveniently couple “tags” on a covalent
basis.
Such “tags” can be antibodies, antigens, cell receptors, nucleic
acid probes, etc.
This provides significant versatility in assay formats (i.e.,
immunoassay, receptor-based, nucleic acid probe, etc.)
possible.
With diameters ranging in size from approximately 50 nm to
800 nm, their aqueous core encapsulates up to millions of
molecules of signal generating “markers” that can be detected
in a variety of different way.
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt
•




Micelle is an aggregate of amphipathic
molecules in water, with the nonpolar
portions in the interior and the polar
portions at the exterior surface, exposed to
water.
Amphiphilic molecules form micelle above a particular concentration
which is called as critical micellar concentration (CMC).
Micelles are known to have an anisotropic water distribution within their
structure, means water concentration decreases from the surface
towards the core of the micelle, with a completely hydrophobic (waterexcluded) core.
Hydrophobic drugs can be encapsulated/solubalized, into inner core.
The spatial position of a solubilized drug in a micelle will depend on its
polarity, nonpolar molecules will be solubilized in the micellar core, and
substances with intermediate polarity will be distributed along the
surfactant molecules in certain intermediate positions.
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt
What is Cool Whip?
Whipped toppings are essentially an emulsion of oil
(usually around 35%) and sweetened water (around 60%)
with an emulsifier, like phosphatidyl choline (lecithin), to
maintain the suspension. The oil used for whipped
toppings, like Cool Whip™, is hydrogenated vegetable oil,
and after hydrogenation (saturation with hydrogen), all
vegetable oils are the same (saturated), regardless of
where they come from. So hydrogenated olive oil could
easily be used to make whipped toppings.
What is Cool Whip?
Oils (and fats) are fatty acids—
phospholipids—have two parts (as their
name suggests): a phosphate "head", and a
long hydrocarbon "tail" (the fatty part).
“tail”
O
O
O
ester group
O
O
P
O
O
O N
“head”
hydrogenated
"saturated" fat
What is Cool Whip?
An emulsion of oil and water is really just water with
microscopic oil droplets floating in it (this is called a colloidal
suspension). To get the oil to form these droplets, called
micelles, the molecules of fatty acid have to pack together as
closely as possible to minimize the volume of the micelle. To
form a micelle, the heads of the molecules, which are soluble,
form the outside of the drop, while the tails fill the inside.
micelle
No water
wants to
be here!
Lots of micelles
suspended in water
What is Cool Whip?
The defining
characteristic of
unsaturated fats is that
their tails have kinks in
them. These kinks prevent
the molecules from
packing close together, so
they tend to disrupt the
micelles - the more
unsaturated fats, the
fewer and larger the
micelles. Without good
micelles, the emulsion will
separate into its two
phases (oil and water),
and without a good
emulsion, you can't whip
the suspension into a
dessert topping.
kinks
O
O
O
phospate group
O
O
P
O
O
O N
"unsaturated" fat
What is Cool Whip?
Compare to a
saturated—
hydrogenated— fat
O
O
O
O
ester group
O
O
O
P
O
O
phospate group
O
O-
O
O N+
P
O
hydrogenated
"saturated" fat
OO N+
"unsaturated" fat








Decreasing the non-specific delivery of the drug to nontarget tissues.
Increasing the drug concentration at its site of action (be it
intracellular or extracellular).
Prolonging the residence time of the drug at its site of
action by reducing clearance.
Decreasing toxicity due to high initial doses of the drug.
Improving the stability of the drug in vivo.
Decreasing irritation caused by the drug.
Improving taste of the product.
Improving shelf life of the product.
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt

In recent years, biodegradable polymeric
nanoparticles have attracted considerable
attention as potential drug delivery devices in
view of their applications in drug targeting to
particular organs/tissues, as carriers of DNA in
gene therapy, and in their ability to deliver
proteins, peptides and genes through a per oral
route of administration.
api.ning.com/files/.../NanotechnologyBasedDrugDelivery.ppt
www.certh.gr/dat/E2353434/file.pdf
www.certh.gr/dat/E2353434/file.pdf
Targeted Drug Delivery
•Protected Drug delivery
to target sites:
– Nanoparticles
– Miniature devices
• Higher doses
• Healthy tissue not
affected
• Theranostics



Conventional drug delivery
systems(DDS) such as oral
ingestion or intravascular
injection, the drug is
distributed throughout the
body through the systemic
blood circulation.
For most therapeutic agents,
only a small portion of the
drug reaches the affected
organ.
For example distribution of
aspirin.




AmBisome is an antifungal agent consisting of a
liposomal preparation of amphotericin B that is
administered by intravenous injection.
AmBisome is a true single bilayer liposomal drug
delivery system, consisting of unilamellar bilayer
liposomes with amphotericin B intercalated within
the membrane.
Treatment of cryptococcal meningitis in HIVinfected patients.
Liposomal formulation is preferred because of
decreased side effects and prolonged drug exposure
(due to slow release).
 Poor
scale-up
 Cost
 Short
shelf life
 In some cases toxicity and off
target effects.



The effect of liposome size and charge on the bioactivity of
liposomal bisphosphonates in a wide range of cell types in
vitro including monocyte/macrophage cell lines was recently
investigated.
Liposomes ranged in size from 50 to 800nm in diameter and
were composed of lipids with neutral, positive, or negative
charge.
It was concluded that small (85 nm) negatively charged
liposomes composed of neutral 1,2-distearoylsn-glycero-3phosphocholine (DSPC), anionic distearoylphophatidylglycerol
(DSPG), and cholesterol at a molar ratio 3 : 1 : 2 were
optimum for internalisation by MPS cells while large and
positively charged liposomes induced cytokine activation and
toxicity.
J Drug Deliv. 2011;2011:727241.


Optimal size therefore is likely to be dependent on
multiple factors including the target cell and
specific properties of the liposome formulation, for
example, receptor mediated or nonreceptor
mediated uptake.
Additionally in vitro results often differ from in vivo
findings. Particularly when administered parentally,
liposomes will interact with various circulatory
components and are then cleared by hepatocytes in
vivo.
J Drug Deliv. 2011;2011:727241.
• Molecules have a uniform size and shape
− Globular, true nanoscale dendrimer platform (~ 5nm diameter)
− Ability to move in and out of vascular pores and pass through the filter organs
• Targeted drug delivery
− Ligands on the surface direct the drug to target cells
− Attachment of multiple drug molecules allow increased drug concentration within
the cell
• Improved therapeutic index
− Improved efficacy over traditional therapies
− Lower systemic toxicity to non-targeted cells
• Potential for faster drug development
− Well-known and/or approved drugs
− Well-characterized targeting ligands
www.avidimer.com



Liposomes have demonstrated the tendency to collect in a
specific tissue
◦ There is some evidence that liposomes gather in the tissue
of tumors
Liposomes can take the form of positively charged, negatively
charged and neutral – charge can help direct particles to
specific oppositely charged locations
Liposomes largely consist of Lecithin and cholesterol,
naturally occurring substances in the body, therefore well
tolerated and have some naturally occurring collection sites



Increase absorption into cell membrane
◦
Acting as a wetting agent surfactants, increases the
contact area between the drug and cell wall,
facilitating the absorption of molecules into the cell
membrane
Increase solubility of drug into carrier
◦
Introduction of a surfactant into a solvent lowers the
surface tension thereby increasing solubility limits
Increase stability of vehicle