Polymeric Drug Delivery

Polymeric Drug Delivery

Time
D
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C
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c
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Therapeutic Window
Overdose
Underdose
Controlled Release vs.
Sustained Release
Sustained release
Complexation, slowly dissolving coatings, use
of derivatives with reduced solubility
Sensitive to environmental conditions to
which they are exposed
Controlled release
Release rate is determined by the device
itself
More accurate, predictable administration
rate
Polymeric Drug Delivery Systems
Incorporate drug into a polymeric matrix
Release drug at a known rate over a
prolonged duration
Release drug directly to the site of action
Constant release - often the goal - difficult
to achieve
Deliver drug such that concentration in
tissue is in appropriate range
Protection of the drug from enzymatic
degradation - particularly applicable to
peptide and protein drugs
Types of Drug Delivery Systems
Matrix systems - monolithic devices
Rate controlling membranes - reservoir
devices
Degradable polymers

Variety of configurations
Release rates generally determined by
solution of Ficks Laws with appropriate
boundary conditions
Membranes
Most important class is nonporous,
homogeneous polymeric films
Transport occurs by dissolution of
permeating species in the polymer at
one interface and diffusion down a
gradient in thermodynamic activity
Measurably permeable to drugs with
MW less than 400
Off the Shelf Polymers Used
in Drug Delivery
EVA
PDMS
pHEMA
PVA


Transport governed by Ficks Law
Steady state version of equation
dx
dC
D J
m
=
Assuming that the permeant on either side of the
membrane is in equilibrium with the respective surface
layer
Concentration just inside the membrane can be related to
the concentration in the adjacent solution
l x at KC C
x at KC C
l l m
o o m
= =
= =
) ( ) (
) ( ) (
0
Assuming that D and K are constant (good
assumption since drugs have low solubility in
polymers)
l
C DK
l
C
D J
m
A
=
A
=
Release rates attainable from
solution diffusion membrane
controlled devices constrained by
physical limitations
Device thickness
Molecular weight of drug is greater
than 500, must expect a substantial
decrease in the achievable release
rate
Release rates between 1 and 200
g/cm
2
h expected
Monolith Devices
Drug dispersed or dissolved in a
suitable polymer
Release
diffusion of drug through the polymer
diffusion through pores in the polymer
structure
Different release profiles result

Dissolved Drug
Consider a matrix system containing drug
This system is placed in a solution containing no
drug and the drug diffuses from the system to
the solution
Release will be a function of time and space



What does the release profile (amount of drug
released from the system per unit time) look
like?
2
2
x
c
D
t
C
c
c
=
c
c
Possible to solve Fickian diffusion
equation analytically for specific
cases and specific device
geometries
Interested in release rate as
function of time
Boundary conditions
( ) ( )

=
|
.
|

\
|
+
|
|
.
|

\
|
+

+
=

0
2
2
2
0
1 2
sin
1 2
exp
1 2
1 4
n
bulk
bulk
L
x n
L
t n D
n c c
c c t t
t
2
0
, 0 0
0 0
L
x t
x
c
L x t c c
L x t c c
bulk
o
= > =
c
c
= > =
< < = =
Solution of Ficks Law with appropriate
boundary conditions
Express desorption of dissolved drug
from the slab by either of the series:
( ) | |
( )
|
.
|

\
|
+
|
.
|

\
|
=
+
+
=

1
5 . 0
2
0
2
2
2 2
2
2
) 1 ( 2
1
4
1 2
/ 1 2 exp 8
1
n
n
t
n
t
Dl
nl
ierfc
l
Dt
M
M
n
l t n D
M
M
t
t
t
Simplifications can be made which apply over
different ranges of the desorption curve -
accurate to 1%
Derived from 2), for the early portion of the
desorption curve
6 . 0 0 4
2
s s
|
|
.
|

\
|
=

M
M
l
Dt
M
M
t t
t
Derived from 1), for the late portion
0 . 1 4 . 0 exp
8
1
2
2
2
s s
|
|
.
|

\
|

=

M
M
l
Dt
M
M
t t
t
t
The drug release rate at any time is also of
interest
Obtained from differentiation of
approximation equations to give:
t l
D
M
dt
dM
t
2
2
t

=
Early time
|
|
.
|

\
|
=

2
2
2
exp
8
l
Dt
l
DM
dt
dM
t
t
Late time
Time to release half of the drug
(half life of the device)
D
l
t
2
5 . 0
0492 . 0 =
Release rate at half time:
2
5 . 0
16
l
DM
dt
dM
t
t

=
|
.
|

\
|
Theory versus Experimental
Early time approximation for cylinder
2 2
2 2
2
/
4
r
D
t r
D
dt
M dM
r
Dt
r
Dt
M
M
t
t
=
=

t
t
Late time approximation for cylinder
|
|
.
|

\
|

=
|
|
.
|

\
|

2
2
2
2
2
2
405 . 2
exp
4 /
405 . 2
exp
405 . 2
4
1
r
Dt
r
D
dt
M dM
r
Dt
M
M
t
t
<0.4
>0.6
Early time approximation for sphere
2 2
2 2
3
3
/
3
6
r
D
t r
D
dt
M dM
r
Dt
r
Dt
M
M
t
t
=
=

t
t
Late time approximation for sphere
|
|
.
|

\
|

=
|
|
.
|

\
|

2
2
2
2
2
2
exp
6 /
exp
6
1
r
Dt
r
D
dt
M dM
r
Dt
M
M
t
t
t
t
t
<0.4
>0.6
Dispersed Drug
Drug dispersed as a solid in the
membrane phase instead of being
dissolved - release kinetics altered
Total concentration of drug C
o
(dissolved
+ dispersed) larger than the solubility of
the drug in the membrane, C
s

Higuchi, J Pharm Sci 50 874 (1961)
Release rate and mass of drug released
at any time are given by:
( ) | |
( )
( )
s
o
s o
o s
s o
s t
s o o s
s o s t
DC
C l
t
C C
t
C DC A
C C
t
DC A
dt
dM
C C C DtC A
C C DtC A M
8
2
2
2
2
2
2
2
5 . 0
5 . 0
5 . 0
5 . 0
=
>>
(

~
(

=
>> ~
=

Reservoir Devices Rate

Controlling Membranes
Reservoir Devices -
Rate Controlling Membranes
Assume that the concentration in the
reservoir is very high (assumed constant),
and the concentration in the sink is very
low (approximate as zero)
After an initial unsteady period, we will
reach steady state
Zero order release (constant rate of drug
release from device)
During the unsteady period
L x t c c
x t c c
L x t c c
x
c
D
t
c
= > =
= > =
< < = =
c
c
=
c
c
0
0 0
0 0
2
1
0
2
2
Can be solved to
give:
( )
( ) ( )

|
|
.
|

\
|
+
|
.
|

\
|
+
+
+
|
|
.
|

\
|

|
.
|

\
|

+ + =
2
2
2
0
2
2 2
1 2
1 2 1
1 2
exp
1 2
sin
1 2
1 4
exp sin
) cos( 2
L
t m D
L
x m
m
c
L
t Dn
L
x n
n
c n c
L
x
c c c c
t t
t
t t t
t
( )
)
`

|
|
.
|

\
|

=

2
2 2
2 2 2
1
exp
1 2
6
1
L
t Dn
n L
Dt
L Ac M
n
t
t
t
For sufficiently large t
|
|
.
|

\
|
=
D
L
t
L
ADc
M
t
6
2
1
Rate Controlling Membrane
0
2
2
=
dx
c d
For sufficiently large t
Which has solution
L
x
c c
c c
o
=

1
Rate Controlling Membranes
The rate of drug delivery is given by:
l
c ADK
dt
dM
L
c c
D
dx
dc
D j
t
o
A
=

= =
1
Assuming a constant activity in the device,
constant release will be achieved
Similar equations derived for both a
cylinder and a sphere
( )
i o
i o t
i o
t
r r
r r
C DK
dt
dM
r r
C hDK
dt
dM

A =
A
=
t
t
4
ln
2
Cylinder
Sphere
Ocusert System
Burst and Lag Effect
Initially exhibit release rates higher or
lower than the steady state value
Immediate use - time required for
establishment of concentration gradient in
the membrane - Lag
Time before use: drug will saturate the
membrane - in solution will result in an
initially higher rate of release - Burst
Solution of Ficks law under unsteady
conditions
Delivery Systems for Water
Soluble Drugs and Proteins
Of considerable interest since protein
drugs are
Of growing importance
Highly unstable in biological media
Mechanism of drug release tends to be
independent of size of the molecule
Generally loaded by dispersing solid
particles throughout the polymer
Release follows t
1/2
kinetics
( )
t
t
t
F
D
D
L
t n D
n
M
M
x
c
D
t
c
o
eff
eff
t
eff
=
(
(

+
=
c
c
=
c
c

2
2 2
2 2
2
2
) 1 2 (
exp
1 2
1 8
1
Degradable Delivery Systems
Release via three different mechanisms
degradation of matrix surrounding the drug
degradation of bonds by which a drug is
joined to polymer matrix
diffusion of drug from the system
Dispersed and dissolved
Dissolved only
Degradation products must be readily
metabolizable and excretable
Degradable Delivery
Systems
Good as surgical leave behind
Suited well to high molecular weight
drugs and drugs which are not soluble
in polymer
Degradable Delivery
Systems
Two mechanisms of polymer
degradation
Surface degradation - more constant
release
Hydrolytic degradation - can result in
dumping
Degradable Delivery
Systems
Models to predict polymer degradation in
vivo
Kinetics of degradation, dissolution, mass
transfer limitations
Models to predict rate of drug release
Diffusion out of matrix with time varying
diffusivity
Surface versus hydrolytic degradation

Effect of 5-FU PGLA Discs
in Glaucoma Filtration Surgery
Days after surgery
0 10 20 30 40 50 60
P
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s
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0
20
40
60
80
100
5-FU
Placebo
Control