Journal o/Controlled Release, 5 (1988) 263-270 263

Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands

PHARMACOKINETIC APPROACH TO THE RATIONAL DESIGN OF CONTROLLED

OR SUSTAINED RELEASE FORMULATIONS

Wing K. Cheung, Avraham Yacobi and B. Michael Silber”

Deparrmenf of Pharmacodynamics, Medical Research Division, American Cyanamid Company, Pear/ River, NY 10965
(U.S.A.)

(Received March 3 1, 1987; accepted in revised form August 1 1, 1987)

There is an ever-increasing realization that controlled drug delivery can provide many advan-
tages in drug therapy. Guidelines areprovided to answer three basic questions in the development
of controlled-release (CR) or sustained-release (SR) formulations: (a) is a CR or SR formulation
necessary for a drug product, (b) what should be the release rate for a zero-order product and
rate constant for release for a first-order product, and (c) what dose should the formulation
contain? Although thesepharmacokineticguidelines are simple and straightforward, they assume
ideal conditions for drug release and absorption. Pharmacokinetic simulations are provided for
CR or SR formulations with zero- or first-order release characteristics. Three-dimensional dia-
grams are also provided to illustrate the inter-relationships among the ratio of maximum to min-
imum plasma concentrations, the drug release rate from the CR or SR formulation, the oral
clearance of the drug after an oral solution formulation and the dose. The simulations suggest
that utilization of classical pharmacokinetic principles can lead to a prospective approach to the
rational design of controlled or sustained release formulations.

INTRODUCTION development of CR or SR formulations [ l-81.

However, there have been few instances of a
In the early phases of developing controlled- step-wise and prospective approach to the use
release (CR) or sustained-released (SR) for- of pharmacokinetic principles in the design of
mulations, pharmacokinetic principles can CR or SR formulations. Using computer simu-
provide important guidance as to whether a lations based on pharmacokinetic principles,
specific drug is a good candidate for such a for- these approaches [l-8] provide some guide-
mulation, what release rate and dose the for- lines for the design of CR or SR formulations,
mulation should have, as well as other although they provide little in the area of prac-
important information. Since developing CR or tical applications. Recently, a joint commission
SR formulations can be time consuming and recommended some pharmacokinetic guide-
costly, these guidelines can potentially save sig- lines for the evaluation of CR or SR formula-
nificant time and money that might ordinarily tions [9].
be wasted in the development of unnecessary
formulations. Some workers have advocated the Pharmacokinetic considerations
use of pharmacokinetic concepts as a tool in the
The objective of drug therapy is to maximize
*To whom correspondence should be addressed. the desired pharmacological response while

0168-3659/88/$03.50 0 1988 Elsevier Science Publishers B.V

264
minimizing drug t,oxicity. The goal of CR or SR
formulations is to minimize the ratio of maxi-
mum to minimum plasma drug concentrations
( Cmax/Cmin) at steady-state; this depends on the
dosing interval (5) and the terminal half-life
(t,,,) of the drug [lo].However, this is true
for drugs that decline monoexponentially in
plasma or for drugs that do not distribute ex-
tensively in tissues. For drugs with a distinct
distribution phase (drugs that distribute ex-
tensively in tissues), plasma concentrations
during the terminal phase would be very much
lower than those during the early distribution
phase. The use of the terminal t,12 of these drugs
(those with distinct distribution phase) as a
guide for multiple dosing could result in large
Cmax/Cmin ratios and in unsuccessful drug ther-
apy if the Cmax/Cmin ratio exceeds the therapeu-
tic index (TI) , which is defined as the ratio of
effective and safe plasma concentrations to
concentrations elliciting unwanted toxic effects.
For drugs with narrow TI values and those
that decline multiexponentially in plasma, it is
necessary to identify the tlp2 of a particular
phase of the log concentration-time profile as
a guide for multiple-dosing calculations. The tllz
value that is used as the guide for multiple-dos-
ing therapy should be the multiple-dosing tli2
(t ,/,,m) describedby Benet [II]. This tlp2 value
is the one that most. significantly affects drug
concentrations after multiple dosing. In gen-
eral, the terminal or distribution t1,2 should be
used as the t 1,2,m for drugs with shallow or steep
dist,ribution phases, respectively. However, it
should be emphasized that the use of the distri-
bution tllP as the t,,2, m would result in exten-
sive accumulation of drug in the body. The t,/,,m
should also be chosen based on the site(s) of
action related to the pharmacologic and toxic
effects of the drug. For example, if the site of
action is located in deep tissue compartments
of the body, the terminal tllz used should be the
t,/,,m.
To minimize the C,nax/Cmin ratio, the t,,,,m
has to be longer than r [lo]. For drugs with
tllz,m values less than r, a smaller Cmax/Cmin
ratio can be achieved by controlling the rate of
drug release (and absorption) from the for-
mulation. If a formulation can be developed with
a release rate much slower than the quotient of
In 2/t,,,,m, the t1,2 of a drug after administra-
tion of the SR or CR formulation will reflect the
rate of release of drug from the formulation
(flip-flop) and a smaller Cmax/Cmin ratio can,
therefore, be achieved.
The first step in the development of CR or
SR formulations, therefore, is to determine if a
CR or SR formulation is even necessary. This
can be determined by comparing the Cmax/Cmin
ratio to the therapeutic index of the drug. How-
ever, this criterion requires that a relationship
be known between the effect of the drug (phar-
macologic and toxic) and plasma concentra-
tions. If there is no such relationship, other
considerations can be reviewed. For example,
one can consider whether the pharmacologic or
toxic effects of the drug are a function of drug
input rate or a function of the maximum plasma
concentrations attained.
SIMULATIONS FOR CR OR St3
FORMULATIONS
The development of equations for the sub-
sequent simulations is based on the following
assumptions: (a) the oral clearance ( CL,) of
an oral solution of the drug is known, (b) the
drug, once released from the CR or SR formu-
lation, will have the same absorption and first-
pass metabolism characteristics as the drug ad-
ministered as an oral solution dose, and, there-
fore, have the same CLO, (c) the drug will have
linear pharmacokinetics, (d) drug is released
and absorbed only during the dosing interval,
(e) a flip-flop sit,uation is assumed, where the
release rate of the drug is assumed to be much
slower than the absorption rate and the quo-
tient of In 2/t,,,, m, and (f) a one-compartment
model is assumed.
 265

CL. (Llhr)
DRUG IN
El0 1000
G.I. TRACT DRUG IN ,
3
SR or CR .- PLASM/i
.. E. 1 /’
FORMULATION :
- :,.
(D) k,_ ;‘,.:‘_y::. :; k,_ c k,_
750

3s ,’ ’
5 /’ _- 500
d /’ , -’
k = k, + kd oz 4 i ’ /’

g2 // ,’ __- 250
Scheme 1. ,’ ,”
6 100
5.
B ~_________~~~~---~
p-V e-m
N D
Zero-order release of a drug from an SR or CR 0 1 2 3 4 5 6 7 8 9 10

STEADY.STATE PLASMA CONCENTRATION (ng/mL)

formulation

Fig. 1. Relationship between zero-order release rate from a

Scheme 1 depicts the absorption of drug from
a CR or SR formulation which releases drug at
a constant rate kO, where D, X, and C are the
amount of drug in the CR or SR formulation, in
solution form in the gastrointestinal tract, and
concentration of drug in plasma, respectively,
h, is the rate constant for the gastrointestinal
CR or SR formulation and the steady-state plasma concen-
tration for drugs with different CL, values. Absorption of
drug is assumed to occur only during the dosing interval.
CxFSkO
(l-eeket)
K =& (l-ePkeL) (4)
e 0

absorption of drug from a solution into the cir-

culation, k is the rate constant for the loss of
&IL _e-k,r)e-ke(t-r)
(5)
CL0 (l
drug from the gastrointestinal tract, kd is the
rate constant accounting for the difference be- where F is the ratio of ha/kand CL0 is the prod-
tween k, and k, and k, is the quotient of In uct of V and k, divided by F and is assumed to
2/t,,,,m. C is equal to P divided by V where P is be equal to the CL0 of drug after an oral solu-
the amount of drug in plasma and V is the ap- tion. It can be shown that at steady state, C can
parent volume of distribution. The rate of be related to k, and CL, by a simple relationship,
change in D, X, and P as a function of time can
be described by eqns. (l), (2), and (3),
c,, =& (6)
respectively. 0

dD
L- where C,, is the concentration of drug in plasma
dt - --ho
at steady state. This relationship is shown
graphically in Fig. 1. This figure indicates that
dX
dt=k,, -k-X under the ideal conditions stated previously,
there is a simple relationship between k. and C
dP at steady state. Figure 2 is a simulation of
x=k,.X-k,.P plasma drug concentrations after multiple dos-
ing of SR or CR formulations according to eqn.
By assuming that k, -@k, that drug absorption (5) (by the principle of superposition) with 7
only occurs during the dosing interval (7) and equal to 12 hours. In this example, CL, was set
by solving eqns. (l-3), the concentration of equal to 200 or 600 ml/h and k, was set equal to
drug in plasma during and, after the 7, as a 0.2 or 0.8 h-l. These figures graphically illus-
function of time, can be described by eqns. (4) trate that the time to steady state depends only
and (5)) respectively, on k, and C,, depends only on CLo. It should be
266

DRUG IN
G.I. TRACT DRUG IN
.,,‘,/ PLASMA

‘K=k,

Scheme 2.
t kd
c kd

for a drug, Figs. 1 and 3 can, therefore, be used

30
TIME (hour)
as a guide to determine the release rate of the
drug necessary to attain a desired C,, value.
Fig. 2. Simulated plasma concentrations of four hypothet-
ical drugs after multiple dosing of a CR or SR formulation
which releases the drug at a constant rate of5 mg/h (z = 12 First-order release of drug from SR or CR
hours): (0) with k,=0.2 h-’ and CL,,=200 ml/h, (N)
formulations
with k,=0.8 h-’ and CL,,=200 ml/h, (0) with k,=0.2
h.-.’ and CL,,=600 ml/h, ( q ) with k.zO.8 h- ’ and
CZ,,,= 600 ml/h. Scheme 2 depicts the absorption of a drug
from a CR or SR formulation releasing the drug
noted that. the simuIations will be identical if T with a first-order rate constant k,. The change
is equal to 24 instead of 12 hours. of L), X, and P as a function of time can be de-
Figure 3 is a three-dimensional simulation scribed by eqns. ( 7 ) , (8), and (9 ) , respectively,
based on eqn. (5) to illustrate the inter-rela-
tionships among C,,, ho and CL, with 5 equal to (7)
12 hours. It should be noted that the simula-
tions will be identical if 7 is equal to 24 hours
instead of 12 hours. This and all other three di-
mensional graphs illustrated in this report were
plotted by using the STAT~RAP~ICS~ soft-
ware package (Statistical Graphics Corpora-
tion, Maryland) with the Hewlett-Packard
Vectra@ Computer. By knowing the ho and CL{,, With the assumptions that, k$ k, and k 5>k,, that
drug absorption occurs only during 7 and by
solving eqns. ( ‘i-9)) concentrations of drug in
plasma during and after T can be described by
eqns. (10 ) and (1 I 1, respect,ively,

F*K*D (ep”“t _e-““) (10)

‘=,(kr-k,)
F-k r *D (,-h,,r _e-krT) e-“““-”
‘=V(k,-k,)

(11)

Fig. 3. C,, values after multiple dosing of a CR or SR for- It can be shown that at steady state, C,, can be
mulation (T = 12 hours) as a function of CL,, and k,,. described by eqn. (la),
 267

1
-k,t’(l_e-krr) of one after multiple dosing of an SR or CR for-
c = F-h-D e-krt’ _
e
mulation. To achieve this goal, according to eqn.
” V(k,-k,) 1 -e-her
(16)) the value of k, needs to be infinitely small.
Even if this can be done from a manufacturing
(12) standpoint, because of the limited transit time
where t’ is the time elapsed since the last dose of the formulation in the gastrointestinal tract,
was administered. At the time of the peak there will probably be some problems related to
plasma concentration ( C,,,) [ t,,,] , the change bioavailability. Therefore, there is an inherent
in drug concentration (dC/dt) will be zero. trade-off between k, and F.
Therefore, differentiating eqn. (12) and set- Figure 4 illustrates the relationship between
ting the differentiated equation equal to zero Cmax/Cmin as a function of k, with r=12 or 24
yields eqn. (13 ) , hours. As shown in these figures, the larger the

1/(k-k,)
value of k,, the more pronounced will be the ef-
kr(l-ebke’) fect of changes in k, on the Cmax/Cmin ratio. For
t max = ln (13)
k,(l-eMkr’) a drug with a smaller k, value, improved bioa-
vailability can be achieved by developing a CR
Substitution of eqn. (13) into eqn. (12) yields or SR formulation with a larger k, value, while
the following relationship for C,,,, still maintaining a relatively small Cmax/Cmin
k;F.D ratio. For a drug with a large k, value, a com-
- krtmsx
promise must be made between a decrease in F
cm”“=V(k,-k,)
and the maximum Cmax/Cmin ratio as restricted

1
,-k&ax(]_,-kc?) by the TI of the drug. Figure 5 illustrates the
-
1 _e-ker
(14) relationship between F and k, with r equal to
12 or 24 hours. Therefore, Figs. 4 and 5 provide
At the end of r, the minimum concentration, important guidance to the pharmaceutical sci-
Cmin, can be described by eqn. (15 ) , entist attempting to decide on what k, value is

1 (15)
needed for the CR or SR formulation. They can
also use these figures to reject or accept (ret-
rospectively) the products they have developed.
Since the transit time of a formulation in the
The ratio Cmax/Cmin can be defined by combin-
gastrointestinal tract may range from 9 to 12
ing eqns. (14) and (15))
hours [ 41, to have at least 80% bioavailability
c e-ketmax(l_e-krr) _,-krtmax(~_,-kc.7)
max relative to the immediate release product, the
-=
e-kes _e-kr7 formulation should have a release tllZ of about
Cmin
3 to 4 hours, or a k, value ranging from 0.2 to
(16) 0.17 hh’ [ 41. These k, values may be developed
for the CR or SR product provided that the sub-
Therefore, the ratio of CmJCmin depends only
on k,, k,, and r. Under conditions where k, 4 k,, sequent Cmax/Cmin ratio is acceptable, based on
eqn. (14) further reduces to eqn. (17), the TI of the drug.
The absorption time period for a drug from a
formulation may last as long as 24 hours [ 121
c,,, =!&! [ e-k~r,,,,u _ek”m;!_:rkr7’] and, therefore, smaller k, values may be accept-
c
0
able. Having chosen the k, value for the CR or
SR formulation based on the desired Cmax/Cmin
(17) ratio and acceptable values of F, the next ques-
It is most desirable to have a Cmax/Cmin ratio tion is the total dose in the formulation re-
268

kr (hr 9 k, (hr-I)

Fig. 4. Simulated C ,,,,,, to C ,,,,,, ratio at steady state as a fucntion of first-order release rate (k,) of CR or SR formulations for
h_ypotheticaldrugswithk,.=lh-’ (0),k,=0.9hm’ (m),k,=0.6h-’ (O),k,=0.4h-’ (A),k,=0.3hm1 (A).r=12and
24 hours in the left and right panel, respectively.

CLo, which can be determined from oral solu-

> tion administration. Thus, an advantage of the
k
A 0.80- proposed guidelines is that intravenous data,
: which may not be available in the early stages
$ 0.60- of drug product development, are not required.
d Three-dimensional surface plots are pro-
m
0.40
E vided to illustrate the inter-relationships be-
2
tween C,,,, dose, CL,,, and k, values with z equal
z to 12 or 24 hours. Figure 6 illustrates the de-
a I’ pendency of C,,, values on dose and k, values
OJr / , 7
0.00 0.05 0.10 0.15 0.20 0.25 0.30
with r equal to 12 or 24 hours. For these simu-
k, (hr ‘) lations, the k, value was set equal to 0.6 h-’ and
Fig. 5. Simulated bioavailability (relative to an oral solu- CL, was set equal to 100 l/h. The simulations
tion ) of drug from a CR or SR formulation as a function of
show that C,,, values are more sensitive to dose
first-order release i%te (k,) of drug from the formulation.
Absorption of drug is assumed to occur only during the dos-
at higher k, values and more sensitive to k, at
ing interval of 12 (solid line) or 24 hours (broken line). higher dose values.
Figure 7 illustrates the dependency of C,,,
quired to attain the desired C,,,. C,,, values on CL0 and k, with 7 equal to 12 or 24 hours.
depend on dose, k,, T, CL,, and k,, while CL,, and For these simulations, dose and k, were set equal
k, are known values from the data obtained after to 10 mg and 0.6 h-l, respectively. Figure 8 il-
an oral solution formulation of the drug. After lustrates how C,,, values change as a function
the formulation has been developed, the total of CL0 and dose with 7 equal to 12 or 24 hours.
dose in the formulation that is required to The k, value was set equal to 0.1 hh’. These
achieve the desired C,,, can be predicted by surface plots show that C,,, is most sensitive
solving eqn. (17 ) . Note that eqns. ( 5) and (17 ) to changes in dose or k, when CL, values are
are independent of F and V which are the pa- small.
rameters that must be obtained after intrave- These three-dimensional plots illustrate the
nous administration. By assuming k, $ k,, which usefulness that pharmacokinetic principles can
should be true for CR and SR formulations, k,, provide in the development of CR or SR for-
Vand F combine into one unknown parameter, mulations. These plots illustrate that for drugs
 269

Fig, 6. Simulated values of C,,, at steady state as a function of dose and first-order drug release rate ( k, 1 from a CR or SR
formulation for a h~~t~eti~l drug with k,--0.6 he” and CL,= 100 I/h. r= 12 and 24 hours in the left and right panel,
respectively.

CL, (mLfhr) __ CL* (mUhr)

Fig. 7. S~mula~d values of C,, at steady state as a function of CL,, of h~ot~etical drugs with k, = 0.6 h- ’ and first-order
drug release rate (k,) from CR or SR formulation administered as 10 mg dose every 12 hours (left panel) or 24 hours (right
panel ) .

CL0 {mtlhr)
Fig. 8. Simulated values of C,,, at steady state as a function of dose and CL,, of hypothetical drugs with k, = 0.6 h - ‘. The
drug is administered as a CR or SR formulation with k ~=O.Ol h- ’ every 12 hours (left panel) or 24 hours (right panel ) .

with large CL, values, there is a larger degree of ~~~~LUSl~~

~exibi~~ty in the selection of dose and h, values,
Qn the other band, extreme caution should be In summary, a IogicaI and rational approach
taken for drugs with small Ct;, and narrow TI to the development of CR or SR formulations
values. using pharmacokinetic principles, under con-
270
ditions where specific assumptions are valid,
have been specified. First and most impor-
tantly, the t ,/,,m of the drug must be adequately
estimated using a solution formulation of the
drug. One can then compare the t,,,,m with the
desired r to decide whether CR or SR formu-
lations are really appropriate for the drug prod-
uct. If a CR or SR formulation with zero-order
release characteristics is desired, the total dose
required for the formulation can be estimated
using eqn. (6). If a CR or SR formulation with
a first-order release rate is desired, the required
k, can be estimated by using the simulations
shown in Figs. 4 and 5. Knowing k,, the dose
can also be estimated using eqn. 17.
The simulations shown are based on assump-
tions which may not always be applicable to a
particular drug. Nonetheless, the steps listed
above should provide a general guideline which
should be very helpful in the development of SR
or CR formulations for new drugs, or for drugs
previously administered as immediate release
formulations. Therefore, they should increase
the probabilitiy of developing CR or SR prod-
ucts that achieve the desired end result; in-
creasing the dosing interval for orally
administered products to ideally once-a-day and
reducing the ratio of maximum to minimum
drug concentrations during the dosing interval.
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