1. Introduction to Controlled Drug
Delivery
‫محمد صدیق معینی‬
1

2. Classical drug delivery
For most of the pharmaceutical industries existence, drug
delivery induced simple, fast-acting responses via oral or
injection delivery routes
Problems associated with this approach
1. Reduced potencies because of partial degradation
2. Toxic levels of administration
3. Increase costs associated with excess dosing
2

3. Why control drug delivery?
As the cost and complexity of individual drug molecules has
risen the problems with the classical delivery strategies over
took their benefits.
Goal of more sophisticated drug delivery
techniques
1. Deploy to a target site to limit side effects
2. Maintain a therapeutic drug level for
prolonged periods of time
3. Predictable controllable release rates
4. Reduce dosing frequent and increase patient
compliance
Injection
Toxicity level
Therapeutic Level
Controlled release
Time
3

4. Characteristics and Benefits
•
•
•
•
Long delivery
Place of delivery
Delivery at the required time
New patents and exclusive renewals period
production
• Delivery of specific active ingredients
(peptides and proteins)
• Eliminating the peaks and valleys of blood
concentration and reduced side effects
4

5. Drug levels in the blood with (a) traditional drug dosing and (b) controlled-delivery dosing
5

6. Methods of delivery:
•
•
•
•
•
Use Oily solvents
Use sparingly soluble salts drug
Use of pretreatment drugs (Prodrugs)
Use of non-polymeric carriers (liposomes)
Use mechanical drug delivery systems (pumps,
drug delivery)
• Drug molecules bind to specific molecules
(monoclonal antibodies, special proteins, PEG)
• The use of polymeric carriers
6

7. 7

8. Use Fick’s law to design drug release
8

9. Rate control
9

10. Polymers in drug delivery
•
Matrix (Monolithic) devices
-
•
films with the drug in a polymer matrix
Easy to fabricate, typically by simple mixing of polymer and drug
Reservoir devices
-
•
Drug contained by the polymer
Release is usually diffusion controlled (Fickian) i.e. J = -D∇ C where J =flux,
C = component of concentration across membrane of defined area, and ∇ is a
differential vector operator
Polymer drug conjugates
-
Polymer attached to drug by (covalent) sacrificial linker
10

11. Controlled Release Systems
• Controlled release implies controlled release of drugs from
polymer drug delivery systems (DDS)
• Type of polymer
– Non-degradable / Degradable
• Type of Design
Reservoir
Matrix
Release mechanisms
– Diffusion / polymer degradation / combination
11

12. Entrapment or Encapsulation
• During the 1970, scientists first began to encapsulate and
entrap drugs within polymers
• Encapsulation involves surrounding drug molecules with
a solid polymer shell
polymer
drug
• Entrapment involves the suspension of drug molecules
within a polymer matrix.
Drug
Polymer
12

13. Drug release by diffusion
• Early encapsulation and entrapment systems released
the drug from within the polymer via molecular
diffusion
– When the polymer absorbs water it swells in size different
– Swelling created voids throughout the interior polymer
– Smaller molecule drugs can escape via the voids at a known
rate controlled by molecular diffusion (a function of
temperature and drug size)
Add
water
Add
time
13

14. Drug release by erosion
• Modern delivery systems employ biodegradable
polymers
– When the polymer is exposed to water hydrolysis occurs
– Hydrolysis degrades the large polymers into smaller
biocompatible compounds
– Bulk erosion process
Polymer
– Surface erosion process
Water attacks bond
mer mer mer mer mer mer mer mer mer
mer mer mer mer mer mer mer mer mer
mer mer mer mer mer mer mer mer mer
14

15. Bulk erosion:
– These small compound diffuse out of the matrix through the
voids caused by swelling
– Loss of the small compounds accelerates the formation of
voids thus the exit of drug molecules
– Polymers containing ester, ether, and amide groups, such as
poly(lactic acid) (PLA), poly(glycolic acid), poly(εcaprolactone), polyamide, proteins, and cellulose (and its
derivatives), generally exhibit this type of erosion.
Add
water
Add
time
15

16. Surface erosion:
– hydrolysis mainly occurs in the region near the surface,
whereas the bulk material is only slightly or not at all
hydrolyzed. As the surface is eroded and removed.
– Polymers such as poly(ortho ester)s (POEs), PAHs, and
some polycarbonates tend to undergo surface erosion.
Add
water
Add
time
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17. How is entrapment or encapsulation
obtained?
The physical entrapment and encapsulation of drugs
within a polymer is complete via one of five
techniques
1.
2.
3.
4.
5.
Wurster
Coacervation
Spray drying (or precipitation)
Coextrustion
Self-assembly methods
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18. Wurster processing (1949)
• The Wurstur process is essentially a coating process
applied after a drug core is formed.
• The polymer shell is applied via spraying while the drug
cores (liquid or solid) is suspended and recirculated in a
gas stream.
Polymer
Drug
Polymer
Gas
Drug
Gas
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19. • STEP #1:
– Polymer dissolved in a solvent (or oil)
– Drug dissolved in water
• STEP #2:
• STEP # 3:
– Emulsion from step #2 is mixed rapidly with
fresh water
– Oil droplets within the fresh water phase
– Oil droplets contain original dispersed
water/drug phase
– Oil diffuses into the fresh water phase
precipitating the polymer & entrapping the drug
H20
– 2 liquids are rapidly mixed
– water droplets form within the solvent
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Drug/H20
Polymer/Oil
Coacervation Technique

20. Supercritical fluid precipitation
Normal
operating
conditions:
8.5-MPa, 35°C
Solvent-polymer
solution fr om
pump
CO2
from
pump
He a t e xcha nge r
Flow str a ighte ne r
Nozzle
Nozzle
contr a ction
Pr ecipita te
Ba ck pr essur e
r egula tor
Poly(l-lactide) ~1-µm diameter
particles formed by PCA processing
Ga s outle t
0.2µm
filter
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21. Co-extrusion processing
• There are numerous co-extrusion processes but they all
share one feature – the polymer shell is flowed
concentrically around a pipe containing the drug
formulation
Syringe pump
• These concentric
cylinders then breakup
into individual packets
either driven by air
flow, electrostatic or
mechanical vibration
Drug
Neg.
Polymer
HV
supply
21

22. Self-assembling delivery systems
The next advance was to construct materials/polymers
that would self assemble with drugs to create
controlled drug delivery vehicles
• Self assembly is typically approach via one of two
methods:
1. Using a molecule that has a hydrophilic head
and hydrophobic tail to form a shell, or
2. Electrostatic interaction to entrap drug
molecules
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23. Micelles & Bilayers
• Entrapment by micelle or bilayer
formation can be obtained using
lipids, surfactants and block
copolymers
Polar Head
Group
(hydrophilic)
Fatty Tail
(hydrophobic)
monlayer
micelle
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Bilayer

24. Hydrogels
(e.g. polyacrylic acids)
• Cross-linked, hydrophilic, 3-D polymer networks that
are highly permeable
• Do not swell in the presence of water unless activated
• Swelling activate by pH, temperature, electric field
• Drug release happens via void generated & diffusion
(diffusion rate is regulated by cross-linking ratio)
mer mer mer mer
mer mer mer mer
Add water
+
activator
mer
mer
mer
mer
mer mer
mer
mer
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25. Properties and Structures of Hydrogels
Swelling property is influenced by:
•type and composition of monomers
•other environmental factors such as :
temperature, pH, ionic strength
•cross-linking
Rs = (Ws-Wd) / Wd
Rs = swelling ratio
Ws = weight of swollen hydrogels
Wd = weight of dried hydrogels
Cross-linking and/or copolymerization with hydrophobic comonomers
density↑, mechanical strength↑, swelling property ↓
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26. Implantable pumps
The pumps usually use polymer swelling to drive
drug formulations out of a reservoir
Polymer
Drug/H20
Water
Drug/H20
Water
Swell
Drug/H20
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27. Alza – Duros pump
http://www.alza.com/alza/duros
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