Journal of Controlled Release 63 (2000) 6979

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Mathematical modeling of diffusion-mediated release from bulk
degrading matrices
A.R. Tzafriri
Institute of Computer Science and Department of Neurobiology, The Hebrew University, Jerusalem 91904, Israel
Received 1 December 1998; accepted 22 July 1999
Abstract
The release of active agent from a bulk degrading matrix is formulated as a linear reaction diffusion problem. Two pools
of active agent are assumed to contribute to the release: a pool of mobile active agent which readily diffuses out of the
matrix upon immersion in an aqueous medium and a pool of immobilized active agent which can diffuse only after matrix
degradation. Due to the linearity of our model, the dynamics of the two pools of active agent can be considered separately,
for any mode of bulk degradation kinetics. For deniteness, we consider the case of rst order degradation kinetics and a
rectangular parallelepiped shaped matrix. A closed form solution is obtained for the release under perfect sink conditions
which is then used to describe the in vitro release of the PerioChipE. This solution can explain the bi-phasic release prole
characteristic of many hydrolytically degradable matrices. The case of mass transfer boundary conditions is solved
numerically using the nite element method (FEM). This analysis indicates that under ordinary mixing conditions the
diffusion layer is not rate limiting and the release is very well approximated by the analytical result for perfect sink
conditions. 2000 Elsevier Science B.V. All rights reserved.
Keywords: Biodegradable polymers; Finite element method; Mathematical modeling; Reaction diffusion; Release kinetics
1. Introduction which the active agent is either chemically bonded to
the polymer carrier backbone (pendant chain), or is
In chemically controlled release devices the active part of the backbone itself (polyagents). Release
agent is immobilized in a polymeric carrier which is occurs by hydrolytic or enzymatic degradation of the
designed to undergo chemical reactions at the target appropriate bonds. In this context, the term degra-
site, thereby enabling the localized delivery of active dation refers only to the bond cleavage reaction,
agent at the target. Such chemically activated sys- whereas erosion refers to the depletion of material
tems fall into two broad categories [1]: (a) Physical [2,3]. Degradation is a chemical phenomenon; ero-
immobilization systems in which the active agent is sion encompasses physical phenomena, such as
physically trapped within the polymer network, and dissolution and diffusion.
is released by the degradation and erosion of this The hydrolytic degradation (and/ or erosion) of a
network, and (b) chemical immobilization systems in solid polymer matrix can occur by two extreme
mechanisms [4]. In one, referred to as heteroge-
E-mail address: ramit@viola.ls.huji.ac.il (A.R. Tzafriri) neous, degradation is conned to the surface of the
0168-3659/ 00/ $ see front matter 2000 Elsevier Science B.V. All rights reserved.
PI I : S0168- 3659( 99) 00174- 1
70 A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979
device and the undegraded carrier retains its chemi- a covalently bonded active agent from a slab-shaped
cal integrity during the process. In the other, called matrix due to rst order hydrolytic (random) cleav-
homogeneous, hydrolysis involves random cleavage age of the drugpolymer bond. However, we assume
at a uniform rate throughout the bulk of the matrix. that the initial load of active agent is composed of
While the molecular weight of the polymer steadily two pools: a pool of mobile active agent which is
decreases, the carrier can remain essentially intact free to diffuse upon hydration of the matrix, and a
until the polymer has undergone signicant degra- pool of immobilized active agent which can diffuse
dation, and reaches a critical molecular weight at only after hydrolytic degradation of the matrix.
which solubilization commences. As much as 90% Moreover, although swelling is assumed to be much
of the matrix can degrade without signicant mass faster than degradation, its effect on the dynamics of
loss (e.g., erosion) [5]. the pool of mobile active agent are considered in an
In general, the release of active agent from approximate manner. The model equations are
degradable matrix devices is determined by an solved for a rectangular parallelepiped shaped ma-
interplay of the following processes [68]: (a) diffu- trix, and analyzed as a function of the active agent
sion of the external aqueous medium into the device, diffusivity, bulk degradation rate, boundary layer
(b) relaxation of the polymer matrix, including thickness, and initial load of mobile active agent.
swelling or plasticization (c) liberation of the im-
mobilized active agent due to hydrolytic or en-
zymatic degradation of the appropriate bonds, (d) 2. Theory
diffusion of the mobile active agent from the bulk of
the matrix to its surface, (e) phase transfer, and (e) 2.1. Case denition and model assumptions
diffusion across the boundary layer. This complex
interplay is responsible for the diverse release kinet- Consider a matrix system in which part of the
ics exhibited by these devices: diffusion controlled active agent is immobilized by the polymer, whereas
[9], zero-order swelling controlled [8,10] and degra- the rest is free to diffuse upon hydration of the
dation-controlled release ranging from rst order matrix by the environmental uid. The immobiliza-
[11] to sigmoidal kinetics [12]. The systematic tion of the active agent may be due to chemical
realization of this potential for designing new con- conjugation to the polymer backbone or to physical
trolled release devices can only be achieved efcient- entrapment (e.g., steric hindrance). However, we
ly through mathematical modeling (for a recent dene the immobilized active agent, phenom-
example see Ref. [12]). Not surprisingly, the general enologically, as the pool of active agent which is
mathematical modeling of such a problem is a released only upon matrix degradation. In this work
formidable task. However, phenomenologic mathe- we only consider the case of homogeneous matrix
matical modeling which accounts only for the rate degradation and assume that the concentration of
limiting processes may be successfully used in many immobilized active agent is proportional to the
practical cases. A quantitative estimate of the relative substrate concentration. The proportionality constant
importance of the different processes upon the is the immobilizing capacity of the polymer for the
release of active agent may be obtained by evaluat- (given) active agent, which for chemical immobiliza-
ing the ratios of their respective time scales [13,8]. tion, is equal to the number conjugate linkages per
Thus, for example, the degradation processes is more mole of substrate. For physical immobilization, the
or less homogeneous (bulk degradation) whenever maximal immobilization capacity is equal to the
the rate of water penetration into the matrix is fast number of hindering cross-links or entanglements per
compared to the rate of hydrolytic degradation [2]. mole of (fully swollen) substrate. In this work the
This contribution is concerned with the phenom- immobilization capacity is treated as a free parame-
enologic mathematical modeling of the release of a ter. A direct consequence of the assumption of
water soluble active agent from a non-erodible bulk homogeneous matrix degradation is that the degra-
degrading matrix. Our modeling approach is similar dation of the polymeric substrate by the environmen-
to that of Pitt et al. [11] who modeled the release of tal uid is independent of the active agent.
A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979 71
We assume that the diffusion of the mobile active boundary layer we shall adopt mass transfer bound-
agent may be described by a constant diffusion ary conditions for the mobile active agent [15,16].
coefcient, independent of active agent concentration Thus:
and polymer morphology or degradation. This as-
1
sumption is valid for small active agent molecules.
] 2=C(r, t) ? n(r) 5 C(r, t),
d
Note that by using a single diffusion coefcient for
(r, t) [V 3(0, `) (4)
the mobile active agent we implicitly assume that the
degradation liberated active agent is equivalent to the
where V denotes the boundary of the matrix, n(r) is
mobile active agent.
the outward unit normal at the boundary and d is the
Finally, we consider the matrix geometry to be
thickness of the diffusion boundary layer [17]. These
invariant and assume that the active agent is initially
boundary conditions can also be applied to laminated
uniformly distributed in the matrix. In reality, per-
devices, in which case d represents the thickness of
meation of the matrix by the environmental uid
the coating layer [18].
usually leads to some swelling. However, as we are
Finally, we note, that since the amount of im-
only considering bulk degrading matrices, the per-
mobilized active agent is assumed to be proportional
meation and swelling of the matrix by the environ-
to the amount of (undegraded) polymeric substrate,
mental uid is usually signicantly faster than the
its rate of liberation is proportional to the degra-
degradation process so that swelling is not rate
dation rate of the substrate. Thus, in order to model a
limiting and only leads to some extraction of the
specic case we have to specify the matrix geometry,
mobile active agent. Once the swelling phase is over,
the initial distributions of the mobile and immobil-
the system can be modeled as a preswollen matrix by
ized active agent, and the degradation kinetics of the
a judicious choice of non-uniform initial distribution
polymeric substrate.
of mobile active agent [14]. The assumption of an
invariant matrix geometry renders the model invalid
2.2.1. Enzymatic release from swellable devices
once erosion commences. However, we assume a
We now extend the mathematical framework
long induction period for the erosion so that most of
represented by Eqs. (1)(4) to model the release of
the drug is released before signicant matrix erosion.
active agent from enzymatically degrading hydro-
philic matrices. The rst question we have to address
2.2. Mathematical framework
is how to model the degradation kinetics in this case.
Conventionally, enzyme catalyzed hydrolytic degra-
The concentration of the mobile active agent is
dation of polymers in solution is described by the
governed by a diffusion equation with a source term
MichaelisMenten equation [19,20]:
due to the liberation of the immobilized active agent
by matrix degradation. Thus [15]:
V P P
max
] ]]] 5 2 (5)
t K 1P
M
C S
] ] 2D DC 5 2 , (r,t) [V 3(0,`) (1)
t t
where P denotes the concentration of the undegraded
polymer and V and K are constants for a given
max M
S(r,0) 5S (r), r [V (2)
0
enzymesubstrate pair. This equation should still be
a good approximation for a homogeneously hy-
C(r,0) 5C (r), r [V (3)
0
drated, highly swollen polymer matrix, because in
where C and S are the concentrations of the mobile this case the large enzyme molecules can freely
and immobilized active agent, respectively, D is the penetrate the bulk of the matrix as the latter hydrates
diffusion coefcient of the mobile active agent in the and swells. In this case we can substitute the relation
matrix, V denotes the interior of the matrix, and S 5sP into Eq. (5) to obtain:
C (r) and S (r) are the initial distributions of the
0 0
sV S S
max
mobile and immobilized active agent, respectively.
] ]]] 5 2 (6)
t sK 1S
In order to allow for the existence of a diffusion M
72 A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979
where s, is the immobilizing capacity of the poly-
C
1
]] meric substrate, which is assumed to be constant. 2D DC 50, (r, t) [V 3(0, `) (11)
1
t
That is, the enzymatic liberation of immobilized
active agent is also governed by the Michaelis C (r, 0) 5NA f(x/L) ? f( y/W) ? f(z/H),
1 0
Menten equation, but with modied constants.
r [V (12)
Henceforth we shall assume that the initial dis-
tribution of active agent, prior to swelling, is uniform 1
] 2=C (r, t) ? n(r) 5 C (r, t),
1 1
and that the geometry of the swollen matrix is well
d
described as a rectangular parallelepiped
(r, t) [V 3(0, `) (13)
V 5(2L, L) 3(2W, W) 3(2H, H) (7)
and let C satisfy the reaction diffusion problem
2
describing the spatio-temporal dynamics of the pool
Hence, we adopt uniform initial conditions for the
of immobilized active agent:
immobilized active agent
C S
2
]] ] S (r) 5S (8) 2DDC 5 2 , (r, t) [V 3(0, `) (14)
0 0 2
t t
and non-uniform initial conditions for the mobile
sV S S
max
] ]]] 5 2 , (r, t) [V 3(0, `) (15)
active agent, of the form
t sK 1S
M
C (r) 5NA f(x/L) ? f( y/W) ? f(z/H) (9)
0 0 C (r, 0) 50, r [V (16)
2
where A is the load of mobile active agent in the
1 0
] 2=C (r, t) ? n(r) 5 C (r, t),
2 2 matrix, f is an even function representing the
d
extraction of mobile active agent along any of the
(r, t) [V 3(0, `) (17)
axes, and
then
1 23
1
C 5C 1C (18)
] 1 2 N 5 E f(j )dj (10)
1 2 uVu
0
satises the reaction diffusion problem (1)(4), (6)
(10).
is a normalization constant. Lee [14] used non-
The system (11)(13) is a separable diffusion
uniform initial conditions in order to model the drug
problem and can therefore be solved analytically as
concentration prole obtained by freeze drying
the product of the corresponding one dimensional
glassy hydrogel beads following partial swelling and
diffusion problems [21]:
extraction. The initial condition [Eq. (9)] is a simple
generalization of Lees idea to an homogeneously ` ` `
swollen rectangular parallelepiped. As we shall see C 5A NuVu O O O
1 0
l 51 m51 n51
below, the analysis of this problem can be carried
2 2 2
out without specifying the explicit form of f(j ). 3exp[2(a 1a 1a )t]
l m n
2
[1 1(da ) ]cos a x
l l
]]]]] 3
S D 2
[1 1(da ) ]L 1d
l
3. Mathematical methods
2
[1 1(da ) ] cos a y
m m
]]]]]] 3
S D 2
[1 1(da ) ]W 1d 3.1. Analysis
m
2
[1 1(da ) ] cos a z
n n
]]]]]] 3
S D 3.1.1. Linear decomposition 2
[1 1(da ) ]H 1d
n
The system (1)(4), (6)(10) is a linear reaction
1 1
diffusion problem. Therefore, let C satisfy the
1
3E f(j ) cos(a Lj )dj E f(j ) cos(a Wj )dj
diffusion problem describing the spatio-temporal
l m
0 0 dynamics of the pool of mobile active agent:
A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979 73
1 1 / 2
i.e., , 5(D/m) . Thus, the dimensionless length is
3E f(j ) cos(a Hj )dj (19) dened by
n
0
r 5r/, (26)
where a , a and a are the roots of
l m n
As a concentration scale we use S , the initial
0
concentration of immobilized active agent. Thus, L
] aL tan aL 5 , (20)
denoting the dimensionless concentration of mobile
d
drug by u we have
W
] aW tan aW5 (21)
C(r, t)
d
]] u(r, t) 5 (27)
S
0
and
Using these denitions we can rewrite the system of
H
] aH tan aH5 (22) Eqs. (14), (16), (17), (24) in the following dimen-
d
sionless form:
respectively. This solution is not essentially new and
u
2t

is also problem dependent, i.e. must be evaluated
] 2Du 5e , (r,t) [V 3(0,`) (28)
t
separately for each initial distribution of the mobile
active agent, f(j ). Hence, we shall only consider it
u(r, 0) 50, r [V (29)
in the limit of perfect sink conditions.
1 In contrast, the system (14)(17) is problem
] 2=u(r, t) ? n(r ) 5 u(r, t),
independent for a given geometry. Although (15) is
d
decoupled from (14), it can only be integrated

(r, t) [V 3(0, `) (30)

implicitly, e.g., numerically. Henceforth, we shall
only consider the limit S <sK , in which case Eq.
M
where V, V and d are the dimensionless counter-
(15) reduces to:

parts of V, V and d. In the limit d 0, the mass
transfer boundary conditions reduce to perfect sink
S
]5 2mS, m 5V /K (23)
boundary conditions [15,17]: max M
t

and can immediately be integrated to yield the u(r, t) 50, (r, t) [V 3(0, `) (31)
random cleavage limit
2mt
3.2. Numerical methods
S 5S e (24)
0
Even after this simplication the system (14)(17)
The system (28)(30) was solved using FIDAP
can only be solved numerically. However, as we
[22]. FIDAP is a computer simulation package that
shall show, this system can be solved analytically for
employs the nite element method (FEM) [23,24],
the important case of perfect sink conditions.
which is a general method used for numerical
solution of partial differential equations. FIDAP en-
ables handling of any three dimensional geometric
3.1.2. Non-dimensionalization
conguration, however complex. The interested
We shall now introduce dimensionless variables in
reader can nd a concise account of the FEM
order to simplify the algebra and reduce the number
formulation for the problem of simple diffusion in a
of parameters in our model to the bare minimum.
two dimensional region in [25]. For brevity, we only
The reciprocal of the degradation rate constant m is
give an account of our implementation of FIDAP.
chosen as the time scale. Thus, the dimensionless
time t is dened by
3.2.1. Geometric representation of the matrix
t 5mt (25)
The matrix was represented as the parallelepiped

V. As required by FEM, the parallelepiped was As a length scale, ,, we employ the magnitude of the
21
divided into brick elements subject to the constraint distance diffused by the active agent in time m ,
74 A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979
of no overlapping and/ or gaps between the elements. any time, the total amount of active agent in the
The division process yields an ensemble of nodes matrix is proportional to the average drug concen-
and elements that represent the parallelepiped and is tration, which was calculated using the function
called MESH (see Fig. 1). Next, according to the mean provided by FIDAP.
FEM procedure, appropriate shape functions are
constructed. These interpolation functions are used
for constructing approximate solutions of the rel-
4. Results and discussion
evant partial differential equations. We used eight
node brick elements for the interior of the paral-
For deniteness we consider the in vitro release
lelepiped, and four node brick boundary elements for
from the PerioChipE, a commercial enzymatic con-
enforcing the mass transfer boundary conditions at
trolled release device that consists of a biodegradable
the surface of the parallelepiped.
cross-linked hydrolyzed gelatin matrix, containing
2.5 mg of uniformly distributed chlorhexidine gluco-
3.2.2. Solution of the model equations with the aid
nate [26]. When the PerioChipE is placed in a
of FIDAP
buffered enzymatic solution (pH 7.5) at 378C, it
Given any MESH and boundary conditions, the
initially swells at a very fast rate after which it
standard Galerkin FEM on the space variable is used
degrades with an apparent degradation rate of m5
to derive a nite dimensional system of (in our case
21
0.015 h . The transient swelling lasts about 30 min
linear) differential equations. The time derivatives
and the nal shape of the swollen chip is well
were approximated by the standard backward differ-
described by a rectangular parallelepiped (V) with
ence and the system was integrated using implicit
L50.28 cm, W50.22 cm and H50.02 cm. Approxi-
backward Euler scheme, with variable time stepping.
mately 90% of the initial drug load is released during
At each time step the system of linear equations was
the rst 6 days of release without signicant matrix
solved by Gaussian elimination.
erosion. At the end of 7 days the chip disintegrates
abruptly. This behavior is typical of bulk degrading
3.2.3. Obtaining the cumulative release from the
devices.
solution
Below, we adopt these values and consider the
The cumulative release at time t was calculated as
solutions as a function of the diffusion coefcient,
the difference between the initial load and the total
diffusion layer thickness, and initial distributions of
amount of active agent left in the matrix at time t. At
active agent. For simplicity, we assume total release
of the initial load of active agent.
4.1. Numerical solution
Eqs. (28)(30) describe the spatio-temporal dy-
namics of an initially uniform load of immobilized
active agent in a matrix undergoing rst order bulk
degradation. The solution of this system of equations
depends upon two independent length scales: , 5
1 / 2
(D/m) and d. The limit d 0 corresponds to
perfect sink conditions, and has been solved ana-
lytically by Pitt et al. [11] for a slab-shaped matrix.
In solving this system we used the dimensions of
the swollen PerioChip and the corresponding degra-
21
dation rate constant, m50.015 h , and varied , by
Fig. 1. Mesh of a rectangular parallelepiped shaped matrix. Brick
varying D. Fig. 2 shows the calculated fractional
elements numbering1512 were used to model the matrix. Note that
release in the limit of perfect sink conditions, as a
the grading is nest along the z axis since the concentration
gradients are expected to be largest along this direction. function of ,. As can be seen, the fractional release
A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979 75
Fig. 2. The calculated fractional release of immobilized active
Fig. 3. The calculated fractional release of immobilized active
agent under perfect sink conditions. () ,51 cm; (.) ,50.1 cm;
agent. (.) d50.002 cm; () perfect sink conditions (d 0).
(2+ 2) ,50.02 cm. M is the cumulative release up to the
t
dimensionless time t and M is the total release.
`
changes signicantly, both in magnitude and shape, the PerioChip platform are quite insensitive to the
as , is increased from 0.02 to 0.1 cm, but remains possible existence of a thin boundary, and may be
practically the same upon further increase to ,51 adequately described by assuming perfect sink
cm. The relative insensitivity of the fractional release boundary conditions.
to changes in the diffusivity for the range D54.173
28 26 2
10 24.17310 cm / s (corresponding to the
4.2. Perfect sink conditions
range ,50.121 cm) implies that the release of
small immobilized active agent molecules is pre-
Under ordinary mixing conditions a diffusion
24 22
dominantly controlled by the degradation process.
boundary layer of thickness d510 210 cm [17]
1 / 2
The observable decrease of the fractional release,
can evolve, whereas ,5(D/m) can take values on
upon decreasing , from 0.1 to 0.02 cm is not
the order of 0.11 cm for small active agent mole-
surprising if we remember that the half width of the
cules. In this case the dimensionless diffusion layer
matrix, H, was taken to be 0.02 cm and that , is

thickness, d 5d/,, is small, corresponding to perfect
(approximately) equal to the distance diffused by the
sink conditions (see Fig. 3). As we show below, the
21
active agent during time m (t 51). That is, the
system (28)(30) can be solved analytically in the
time scale for diffusion is of the same order of
case of perfect sink conditions using classical meth-
magnitude as the time scale for degradation when
ods [21]. This solution can be used in most practical
,.H. The same qualitative observations were ob-
cases. This is a great advantage when trying to t
tained by Pitt et al. [11] in the purely one dimension-
experimental data, since solving the numerical
al case.
scheme for a given geometry is usually much more
Fig. 3 shows the calculated fractional release
time consuming than evaluating the analytical solu-
assuming a diffusion layer of thickness d50.002 cm.
tion. Moreover, the analytical solution has the advan-
As can be seen, the assumption of a thin boundary
tage of being physically transparent and may be used
layer has practically no effect on the fractional
as the starting point for obtaining simpler approxi-
release for ,50.1 (as compared to the result under
mate forms.
perfect sink conditions), and leads to a slight but
observably decrease in the fractional release for ,5
4.2.1. Derivation of a general analytical solution
0.02 cm. Since the existence of a boundary layer
We begin by effecting the substitution
only affects the diffusive release at the boundary of
2t the matrix, these results are consistent with our
v(r, t) 5u(r, t) 1e 21 (32)
observation that for the system at hand diffusion
becomes important as , approaches H50.02 cm. which transforms the system (28)(30) into a diffu-
These results indicate that the release kinetics from sion problem with zero initial conditions and time
76 A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979
dependent boundary conditions: where we used the notation
1
v

] 2Dv 50 , (r, t) [V 3(0, `) (33) (2l 11)pj

t
]]] I 5E f(j ) cos dj (40)
l
2
0

v(r, 0) 50 , r [V (34)
The rst term on the right-hand side of Eq. (39) is

v(r, t) 5f(t), r [V (35)

proportional to the load of the mobile active agent,
A . This term describes the purely diffusive release
0
where
of the pool of mobile active agent. The second term
2t
is due to pure bulk degradation and the third is due f(t) 5e 21 (36)
to a combination of bulk degradation and diffusion.
The solution of (33)(35) is given in [21]. Substitut-
The cumulative release reduces to a much simpler
ing the form (36) into this solution, and transforming
form in the limit of instantaneous diffusion,
21
back to u we obtain (after performing the necessary
a 0. In this case the rst term reduces to a
lmn
integration and some algebraic manipulations):
constant and the third term vanishes, so that
` ` `
64
2t 21
M(t) 5A 1uVuS (1 2e ), a 0 (41)
] u 5 O O O
0 0 lmn
3
p l 50 m50 n50
l 1m1n 2t 2a t
lmn This result is of relevance to at matrices.
(21) (e 2e )
]]]]]]]]]]
(2l 11)(2m11)(2n 11)(a 21)
lmn
4.2.2. Uniform initial conditions (2l 11)px (2m11)py
]]] ]]]] 3cos cos
We now consider the case when swelling effects
2L 2W
are negligible and the initial distribution of mobile
(2n 11)pz
]]]] active agent may be treated as uniform ( f(j ) 51). 3cos

2H
For deniteness, we used the dimensions of the
21
(37)
swollen PerioChip and m50.015 h . Henceforth all
our results are presented in terms of time (hours or
where
days). A comparison to the results of previous
2 2 2 2
sections is simply carried out by noting t 50.36 p (2l 11) (2m11) (2n 11)
] ]]] ]]] ]]] a 5 1 1 F G
lmn 2 2 2
corresponds to 1 day.
4
L W H
First, a comparison of the analytical solution to the
(38)
numerical one for the case of perfect sink conditions
and A 50 is shown in Fig. 4. Clearly both methods
Finally, using this result and the d 0 limit of result
0
yield essentially the same results.
(19), we obtain the cumulative release under perfect
Next, we consider the effect of increasing the
sink conditions:
initial (uniform) load of mobile active agent in Fig.
` ` `
64uVuN
5. As can be seen, the release kinetics of the
]] M(t) 5A 1 2 O O O
F
0 3
p immobilized active agent (A 50) are quite insensi- l 50 m50 n50
0
l 1m1n
tive to the value of the diffusion coefcient, and the
(21)
2a t
lmn
]]]]]]] 3 I I I e G initial load of mobile active agent is totally depleted
l m n
(2l 11)(2m11)(2n 11)
during a short burst. That is, the limit of instanta-
` ` `
512
2t neous diffusion [result (41)] is an excellent approxi-
] 1uVuS (1 2e ) 2uVuS O O O
26 2 0 0 6
mation for D54.17310 cm / s and remains a p l 50 m50 n50
28 2
2t 2a t good approximation for D54.17310 cm / s, and
lmn
e 2e
]]]]]]]]]]] 3 may be used as a reliable means of estimating the
2 2 2
(2l 11) (2m11) (2n 11) (a 21)
lmn
initial load of mobile active agent, A .
0
(39) This simple picture is no longer true whenever the
A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979 77
Fig. 6. Fractional release under perfect sink conditions for ,5
Fig. 4. Fractional release under perfect sink conditions with A 5
0
21 26 2
0.02 cm and different loads of mobile active agent. Result (39)
0, m50.015 h and D54.17310 cm / s: (.) numerical results;
was evaluated by keeping the rst 50 terms in each of the innite
() analytical solution Eq. (39). The analytical solution was
sums.
evaluated by keeping the rst 50 terms in each of the innite
sums.
4.3. Fit to experimental data
time scale for diffusion is of the same order of
21
magnitude as the time scale for degradation, m . We used the simple form
Fig. 6 shows the fractional release for ,50.02 cm,
2
f(j ) 51 2j , j [[21,1] (42)
as a function of the initial fraction of mobile active
agent. As can be seen, there is no diffusive burst in to model the distribution of mobile drug in the
this case and hence it is no longer possible to PerioChip at the end of the swelling phase. Fig. 7
visually deconvolute the contributions of the differ- shows our theoretical t to the experimental results
26 2
ent pools of active agent. Moreover, it should be assuming D54.17310 cm / s. This t is seen to
noted that when the time scales of diffusion and be very good, and indicates that the pool of mobile
degradation are of the same order of magnitude, the drug is released during a short initial burst which
assumption of a constant diffusion coefcient is probably lasts much less than 24 h. As noted above,
bound to break down. Indeed, in the extreme case for the PerioChip, the diffusivity range D54.173
28 26 2
where the time scale for diffusion is much larger 10 24.17310 cm / s corresponds to the limit of
21
than m the release is diffusion controlled, but with instantaneous diffusion so that Eq. (41) can be used
a time-dependent diffusion coefcient [27]. to describe the in vitro release of the PerioChip.
Fig. 5. Fractional release under perfect sink conditions for differ- Fig. 7. Fractional in vitro release from the PerioChip. ()
ent loads of mobile active agent. (.) ,51 cm; () ,50.1 cm. Experimental results [26]; (.) Result (39) with A 50.37M , m5
0 `
21 26 2
Result (39) was evaluated by keeping the rst 50 terms in each of 0.015 h and D54.17310 cm / s. Result (39) was evaluated
the innite sums. by keeping the rst 50 terms in each of the innite sums.
78 A.R. Tzafriri / Journal of Controlled Release 63 (2000) 6979
However, since the rst experimental point was process. Indeed, many hydrolytically degradable
measured after 24 h of release, we can neither devices exhibit bi-phasic release proles consisting
deduce a more precise value of the diffusivity nor of an initial diffusive burst followed by a rst order
probe the initial distribution of mobile drug, f(j ), (or zero order) phase [2830]. For large active agent
from this data. molecules the rate of diffusion can be comparable to
the degradation rate. In this case, the predicted
release kinetics of the immobilized active agent are
5. Conclusion complex and are neither degradation controlled nor
diffusion controlled. In the extreme case where the
We have presented a phenomenological reaction diffusion rate is slower than the degradation rate the
diffusion model for the diffusive release of active release is diffusion controlled, but with a time
agent from a bulk degrading matrix. In deriving the dependent diffusion coefcient [27]. Strictly speak-
equations we assumed that matrix hydration is ing this case is beyond the scope of our model.
practically instantaneous and that most of the drug is However, this case can be studied numerically by a
released prior to matrix erosion. Thus, the effects of trivial extension of the FEM formulation presented
hydration and swelling are incorporated into the here.
initial conditions and the equations only model the
dynamics of the (mobile and immobilized) active
agent. For deniteness, the model was used for
Acknowledgements
simulating drug release from an enzymatically (bulk)
degrading cross-linked gelatin matrix. However, it is
This work was supported by grant No. 0700 from
important to note that our model assumptions also
the Israeli Ministry of Science, for the development
apply to hydrolytically degradable PLGA matrices,
of scientic and technological infrastructure, and by
in which case bulk degradation follows rst order
a research grant from Perio Products Ltd. I wish to
kinetics and erosion commences only after most of
thank Prof. H. Parnas and Prof. M. Bercovier for
the polymer has degraded [5].
their critical reading of the manuscript and valuable
The model equations were analyzed by treating the
suggestions and Mrs. N. Volfovsky for helping out
dynamics of the mobile and immobilized active
with FIDAP. Special thanks are due to Dr. E. I.
agent separately. Such a decomposition is applicable
Lerner, the head of Perio Products R&D department,
to any matrix geometry and depends only on the
for supplying unpublished data on the PerioChip, and
linearity of the model equations. Moreover, if the
for many stimulating discussions which served as the
initial distribution of the mobile active agent is
impetus to this work.
separable the diffusion problem describing the dy-
namics of the mobile active agent can be solved
analytically for simple geometries such as paral-
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