Topical Oral Cavity Pharmacokinetic Modeling of a
Stannous Fluoride Dentifrice: An Unusual Two
Compartment Model
DOUGLAS C. SCOTT, JOHN W. COGGAN, CHARLES A. CRUZE, TAO HE, ROBERT D. JOHNSON
The Procter & Gamble Company, Mason Business Center, 8700 Mason Montgomery Road, Mason, Ohio 45040
Received 13 August 2008; revised 25 November 2008; accepted 16 December 2008
Published online 2 February 2009 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21691
ABSTRACT: A pharmacokinetic model was developed describing the pharmacokinetics
of stannous fluoride in human subjects after oral topical application of a stannous
fluoride dentifrice. Twenty subjects participated in an investigation of an experimental
dentifrice. Subjects rinsed their mouths with the experimental dentifrice slurry. Saliva
and plaque samples were obtained from the subjects at various times up to 6 h after
administration. Samples were analyzed for total tin content, used as an analytical
marker for the active stannous fluoride ingredient, using a graphite furnace atomic
absorption spectrometer. The modeling indicates that there is an obvious kinetic
relationship between saliva and plaque compartments and that stannous fluoride is
very well retained in and slowly released from plaque (and oral surfaces) into saliva.
Additionally, both compartments are simultaneously loaded during administration
unlike typical systemic drug behavior, and the elimination rate   constant  from the
central compartment (saliva) changes due to changes in salivary flow. Stannous fluoride
is cleared from saliva rapidly but very well retained in gingival plaque. The model
with simultaneous loading of plaque and saliva describes these observations and may
account for the prolonged antiplaque and antigingivitis benefits of stannous fluoride.
ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci98:3862 3870, 2009
Keywords: adsorption; pharmacokinetic/pharmacodynamic models; population
pharmacokinetics; site-specific delivery; desorption; mathematical model; mucosal
delivery
INTRODUCTION devices such as chewing gums, films, and bioad-
hesive polymers.10 16 Kinetic work has been
Topical oral cavity pharmacokinetics has received performed in the understanding of gingival
relatively little attention in the literature. Most crevicular fluid concentrations, comparing oral
work has focused on fluoride ion delivered via topical administration, and systemic delivery.17
dentifrices (toothpaste) and mouth-rinses,1 6 but, However, for materials with a high level of
fewer published studies exist on other ingredi- substantivity, little to no modeling has been
ents.7 9 Most of these studies focus on generating performed to understand the kinetics of the whole
time course profiles in saliva without supporting mouth and the relationship between multiple
kinetic modeling. Other studies have evaluated fluids and tissues.
the delivery of oral therapeutic agents from Materials introduced into the oral cavity can
be eliminated by the following mechanisms: (1)
salivary washout and swallowing, (2) absorption
Correspondence to: Douglas C. Scott (Telephone: 513-622-
through oral surfaces, or (3) degradation. It is
2434; Fax: [phone]; E-mail: [e-mail])
assumed in most cases that reentry into saliva is
Journal of Pharmaceutical Sciences, Vol. 98, 3862 3870 (2009)
ß 2009 Wiley-Liss, Inc. and the American Pharmacists Association negligible based on the relative concentrations at
3862 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009
PHARMACOKINETIC MODELING OF STANNOUS FLUORIDE 3863
the site of dosing (oral cavity vs. systemic dilution phenomenon will be considered in the develop-
after absorption). ment of a kinetic model for the disposition of tin
Stannous fluoride and other divalent metal following treatment.
salts are a class of materials used in oral care Salivary elimination is a first order process
products which are retained on oral surfaces for a under constant salivary rate and volume condi-
prolonged period of time.18 These oral surfaces can tions. Rates and volumes can vary due to the
be viewed as a unique compartment (depot) into/ degree of stimulation.23 27 It can be shown, based
onto which material is loaded and then released on first principles, that the elimination microrate
into saliva. Therefore, the principles used for constant for salivary flow (k10) is as follows, where
traditional systemic pharmacokinetic modeling Rsal is the salivary flow rate and Vsal is the
are applicable to the mouth cavity. Since oral salivary volume (pooled saliva in oral cavity at any
cavity surfaces are readily accessible, they can be time):
sampled and assayed for material content and
Rsal
used to develop kinetic models to describe the time
k10 ź (1)
Vsal
course of materials in the mouth.
Stannous fluoride is a chemotherapeutic agent
that has been used for many years to improve oral
health. The minimum inhibitory concentrations
(MIC) for the microflora of interest in the treat-
Two Compartment Oral Topical Model for Tin
ment of plaque and gingivitis have been pre-
A two compartment model (Fig. 1) for the oral
viously reported; it was shown that tin, analytical
cavity was developed to describe the time course of
marker for the stannous fluoride, was retained in
tin in saliva (central compartment) and plaque
dental plaque above the MIC for up to 12 h after
administration of a stannous fluoride dentifrice.19 (peripheral compartment). It should be noted that
the central compartment of the entire oral cavity
Breath and gingivitis effects have also been
would include fluids in which drug would readily
reported for stannous fluoride-containing denti-
distribute upon administration in addition to the
frices.20 22 The long-term retention at the site
bulk salivary volume. Estimates of central com-
of action (plaque) is likely responsible for the
partment volumes using kinetic data and mea-
therapeutic efficacy. We herein report a pharma-
sured salivary flow rates have been redundant
cokinetic model for the retention of stannous
observed to be 2 3 mL under nonstimulated
fluoride in the oral cavity which is consistent with
conditions for relatively water soluble compounds
these previous findings.
with little inherent substantivity (unpublished
data); this is additional evidence that the central
compartment volume may not exist as just the
THEORY
salivary pool. However, only saliva and plaque
concentrations were measured in this study and
Salivary Elimination
the kinetic model was confined to these two
spaces. The text, Oral Mucosal Drug Delivery,
Clearance of stannous fluoride from the oral
contains additional information on salivary effects
cavity occurs via the salivary route. As fresh
related to drug deposition and removal from the
saliva is produced, it mixes with and dilutes the
oral cavity.28
drug containing pooled saliva. A fraction of this
The differential equations used to describe the
diluted pooled saliva is then swallowed. At any
disposition of stannous fluoride in saliva and
moment, the pooled salivary volume can vary;
however, on average, it is constant under constant
salivary flow rate conditions. It is known that
salivary flow can vary after administration of an
active in an actual dosage form. Flavors, acids,
salts, sugars, carbohydrates, etc. can stimulate
salivary flow. Additionally, objects in the mouth
during administration can stimulate flow. The
dosage form itself can stimulate flow, such as a
lozenge or chewing gum, as well as a device such
Figure 1. Physiological two-compartment model
as a toothbrush used during administration. This depiction with microrate constants.
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009
3864 SCOTT ET AL.
plaque were: Subjects rinsed with an experimental dentifrice
slurry (10 mL of a 1:3 dentifrice/water mixture)
dS
for 60 s, expectorated, then rinsed with 10 mL
źð k10 k12ÞS þ k21P (2)
dt
water for 5 s, and expectorated again. The neat
dentifrice contained 3400 ppm stannous in the
dP
form of stannous fluoride (0.454% w/w). The stan-
ź k12S k21P (3)
dt
nous concentration in the slurry was 0.086% w/w;
therefore, an 8.6 mg tin dose was introduced
where S is the concentration of tin in saliva, P the
into the oral cavity. Following treatment, saliva
concentration of tin in plaque, k10 the salivary
elimination microrate constant of tin in saliva, k12 samples were collected at 5, 15, 30, 45, 60, 90 min,
2, 3, 4.5, and 6 h post-rinsing. Supergingival
the microrate constant for transfer of tin to plaque
plaque samples were collected using a sterile
(oral surfaces) from the saliva, and k21 the
plastic curette and weighed at 15, 30, 60 min, 2, 3,
microrate constant for movement of tin out of
4.5, and 6 h post-rinsing. The mouth cavity was
plaque into saliva. Since salivary flow is stimu-
divided into four quadrants for plaque sampling
lated following treatment, elimination of tin from
from which only sparse samples were analyzed for
saliva will initially be higher and then return to
tin concentrations (four plaque samples; one per
the normal steady-state salivary flow condition.
Therefore, a nonlinear equation was used for k10 quadrant). Time zero was at the time of expectora-
tion of the water rinse.
as follows:
The study was conducted in accordance with the
k10 źðk10i k10fÞe ðk10atÞ þ k10f (4)
Institutional Review Board (IRB) human study
approval system and according to the Good
where k10i is the initial salivary elimination rate
Clinical Practices (GCPs) and International Con-
constant under stimulated salivary flow conditions,
ference on Harmonization (ICH) guidelines. Sub-
k10f the final salivary elimination rate constant
jects obtained an informed consent prior to study
under nonstimulated or steady-state salivary flow
initiation.
conditions, and k10a the rate constant for the rate
at which the initial stimulated salivary flow
condition decays to the steady-state (nonstimu-
Analytical
lated) condition. Definition of mathematical terms
throughout the remainder of this article can be Whole Saliva Preparation
found in the glossary.
Whole saliva samples were collected in polypropy-
lene centrifuge tubes at time points as described
above and stored in a refrigerator (48C) until the
MATERIALS AND METHODS
day of preparation. The samples were digested at
1008C for 1 h in nitric acid and hydrogen peroxide.
Clinical Study Design
Appropriate dilutions were then made in 5% nitric
This study was conducted in 20 normal healthy acid after cooling samples.
volunteers. Subjects brushed their teeth with
a sodium fluoride containing dentifrice and a Dental Plaque Preparation
manual toothbrush under normal conditions for
Dental plaque samples were collected into tared
1 week prior to study initiation. Subjects did
13 mm 100 mm boroscilicate test tubes and
not brush their teeth or eat after 10:00 p.m. the
accurately weighed to the nearest 0.1 mg. The
evening before treatment to ensure adequate
samples were stored in a refrigerator (48C) until
plaque growth. This enabled adequate sampling
the day of preparation. The samples were digested
the next day since brushing can remove the
in high purity nitric acid at 140 1508C until near
majority of plaque. Subjects were also instructed
dryness followed by addition of hydrogen peroxide
to avoid tin containing foods, vitamins/supple-
and an internal standard.
ments, canned foods, and to drink only water the
evening prior to treatment and during the 6 h
Whole Saliva and Dental Plaque Analysis
duration of the study. Baseline saliva and plaque
samples were collected in the morning on the day Aliquots of sample and matrix modifier were
prior to treatment to ensure that subjects had no injected into a transverse heated graphite atomi-
detectable tin in the oral cavity prior to treatment. zer (THGA) inside a graphite furnace atomic
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009 DOI 10.1002/jps
PHARMACOKINETIC MODELING OF STANNOUS FLUORIDE 3865
absorption (GFAA) spectrometer. Samples were quadrants was evaluated with respect to the
atomized at 24008C and total tin absorption residual variability for plaque concentrations
measured at 286.3 nm following a temperature ð1 þ QD2Q1 þ QD3Q2 þ QD4Q4Þ"ij. Parameters
controlled furnace program. Q1, Q2, and Q3 scale the residual variability to
account for any quadrant differences.
Each covariate was tested individually for
Population Pharmacokinetic Analysis statistical significance ( p < 0.05) to evaluate each
covariate in the absence of other covariates. The
Initial analysis focused on individual subject fits;
final model was selected based upon backwards
however, the sparse sampling scheme used for the
reduction using likelihood ratio tests ( p < 0.001)
plaque compartment prohibited reliable para-
from a full model containing all covariates.
meter estimation. Therefore, data from all sub-
jects were combined for a population analysis.
Pharmacokinetic parameters were estimated by
nonlinear mixed-effect modeling using the NON- RESULTS AND DISCUSSION
MEM (Version V) program. Concentration data in
saliva and plaque were natural logarithmically Pharmacokinetic Analysis
transformed (ln transformed) prior to analysis.
Concentration-time profiles for tin in saliva and
The pharmacokinetic model for tin in the oral
plaque are illustrated in Figure 2 (linear scale
cavity (saliva and plaque) was parameterized in
individual values). Visual inspection of the plots
terms of microconstants and volumes of distri-
shows that stannous is cleared rapidly from saliva
bution. Between-patient variability of pharmaco-
but tends to persist in plaque. Free tin in the
kinetic parameters was modeled using an
central compartment is quickly washed away via
exponential error structure indicative of a log
salivary flow, particularly within the first 5
normal distribution:
15 min due to salivary stimulation. The terminal
PPi ź QiexpðhiÞ (5)
salivary concentrations, while very low, are above
the nondetectable pretreatment levels. Plaque
An additive residual error model was used:
levels indicate that the oral surfaces are readily
charged with tin during administration. It also
lCijÞ ÅºFðQi; hi; tÞ þ "ij (6)
appears there is a small additional accumulation
hi follows a multivariate normal distribution
after administration; however, the plaque levels
½MVNð~ SÞŠ with vector of means 0 and
0;
change very little over the course of 6 h. This is
Pa
covariance matrix , and eij is the independent
consistent with the continual low level appear-
identically normally distributed random residual
ance of tin in saliva at later time points and oral
error [N(0,s2)] with mean 0 and variance s2.
surfaces acting as a slow release depot.
Pharmacokinetic parameters were estimated
Figure 3 shows model fitted and actual con-
using the first order conditional estimation
centration time course profiles for both saliva and
method. A base pharmacostatistical model was
plaque (semilogarithmic scale). The visual model
developed initially. Covariates evaluated in the
fit for the salivary profile is very good; however,
analysis were age and gender. Individual covari- the fit for plaque does not well represent the slight
ates were screened initially to test for statistical
accumulation phase noted above. From a math-
significance. Age was evaluated as follows:
ematical modeling perspective, this is of little
!
practical concern because the general compart-
AGE AGE
mental kinetic relationship between oral surfaces
PPi ź Q1 þ Q2 (7)
AGE
(second compartment) and saliva (central com-
partment) is well demonstrated. It should also be
An indicator variable was used to model the noted that gingival plaque in this model is only
gender effect as follows: representative of the oral surfaces onto which tin
is deposited and released from. Additionally, it is a
PP ź Q1ð1 þ Q2 genderÞ (8)
small fraction of the total oral surfaces. Ideally,
where gender is an indicator variable that takes tongue and buccal scrapings would be analyzed as
numerical values of 1 for males and 0 for females. well as plaque; however, plaque is the sample of
Plaque concentrations were obtained from four interest in the treatment of gum disease. The plots
quadrants of the oral cavity. Variability between show the lack of a terminal phase indicative of a
DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009
3866 SCOTT ET AL.
Figure 2. Salivary and plaque tin concentration time profiles (linear scale).
time-varying salivary elimination rate. The plots and to immediate swallowing after administration
also suggest that the variability of the concentra- (normal incidental ingestion); therefore, the bio-
tions remains constant in the log domain thereby availability term was fixed at 0.05 to produce
justifying logarithmic transformation prior to physiologically realistic volumes in the model
model fitting. (explained below).
The model supported interpatient variability Figure 4 presents the model predicted versus
terms with respect to k21, k10a, and Vsal. The model actual diagnostic plots. Visual inspection of the
included covariance between k21 and Vsal. Corre- diagnostic plots suggests that the model provided
lations between k10a and k21 and between Vsal and a reasonable fit to the data. It appears that the
k21 were low. Hence, these covariance terms were constant variance and independence of residual
0 in the covariance matrix. It was assumed that error assumptions were valid. Figures 5 and 6
95% of the dose applied to the oral cavity was present the residual versus predicted plots, and
lost to expectoration (as intended for dentifrice) normal probability plot of the individual residuals
Figure 3. Model fitted salivary and plaque concentration time profiles (semilog scale).
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009 DOI 10.1002/jps
PHARMACOKINETIC MODELING OF STANNOUS FLUORIDE 3867
Figure 4. Actual versus predicted population kinetics modeling diagnostic plots.
indicating that the ln transformed data was driving force is low due to the fact that saliva
generally normal except for some tailing of the levels are very low relative to oral surfaces.
lowest residuals. Additionally, it may be possible that oral surface
Table 1 presents the pharmacokinetic para- sites are saturable. The k10i and k10f values are
meter estimates from the base model. The half-life smaller than expected based on simple clearance
for the decay of the salivary elimination rate via salivary flow for a compound with no retention
constant (k10a) was 13 min. Therefore, the salivary on oral surfaces using Eq. (1). Stimulated and
elimination rate constant which starts at 0.15 min 1 nonstimulated salivary elimination microrate
(k10i) reaches its final value of 0.029 min 1 (k10f) constants in this case would be 1 and 0.5 min 1,
within about 30 min. This is consistent with the respectively. The model values are an order of
expected physiological response. The numerical magnitude lower indicating that clearance of tin
value of k12 was less than 10 9. This parameter from the central/salivary compartment is not that
was fixed to zero for the analysis. This supports of simple clearance of a simple water soluble ion or
the conceptual model where both compartments molecule. This could be due to a number of factors
are initially loaded with tin and little transfer of including: (1) slower salivary rates due to a less
tin from saliva to plaque exists for hours. The than normal state of hydration during the study
Figure 5. Residual versus predicted population kinetics Figure 6. Population kinetics modeling normal prob-
modeling diagnostic plots. ability plot of individual residuals.
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3868 SCOTT ET AL.
Table 1. Pharmacokinetic Parameter Estimates from the Base Population Model
Population Estimate Between-Patient
Parameter Description (%SEE) Variability (%SEE)
Saliva to plaque rate constant (k12)a 0
Plaque to saliva rate constant (k21)b 0.00425 min 1 (32%) 80% (43%)
Initial salivary elimination rate constant (k10i) 0.151 min 1 (15%)
Final salivary elimination rate constant (k10f) 0.029 min 1 (10%)
Exponential salivary elimination rate constant decay (k10a) 0.052 min 1 (15%) 23% (15%)
Saliva volume (Vsal)b 3.50 mL (20%) 141% (31%)
Plaque volume (Vplq) 1.21 mL (7.9%%)
Residual error (saliva) 43% (14%)
Residual error (plaque) 71% (22%)
a
Parameter estimate very low, fixed to zero.
b
Correlation between k21 and Vsal (0.75).
because patients were restricted from eating and collection of an adequate plaque sample for
may not have consumed liquid as they normally analysis. The act of brushing removes the
would, (2) a more complicated actual physiologic majority of plaque along the gumline; however,
pharmacokinetic model than the mathematical brushing cannot totally eliminate plaque. The
model used, (3) the fact that plaque represents whole oral cavity is covered with a biofilm to which
only a small fraction of the second compartment, tin binds and this biofilm (including gumline
and/or (4) long-term tin is not cleared as an ion in plaque) acts as the second compartment. In spite
solution, rather it may exist as a large complex of brushing removing the outer layers of gumline
with a salivary protein. It is likely due to the latter plaque when the product is used as commercially
two factors. intended, the overall oral surfaces remain rela-
Vsal and Vplq were 3.5 and 1.2 mL, respectively. tively unchanged and some plaque still resides
As stated above, estimates of central compart- along the gumline. It is expected that the non-
ment volumes (nonstimulated) using kinetic data brushing model practically represents the kinetics
and salivary flow rates have been observed to be during actual brushing.
2 3 mL (unpublished data). The estimation of the The subjects were not allowed to eat during
volume of the second compartment is somewhat the study which deviates from their normal daily
speculative. The area of the adult oral cavity activities. That said, eating is a periodic and
accessible to oral care products such as mou- relatively infrequent event and food and mastica-
thrinse and dentifrices has been proposed to be on tion do not significantly disturb or remove plaque
the order of 200 cm2.29 Knowledge of the thickness even when chewing fibrous foods.30 31 As discus-
of the oral surface penetrable by tin would enable sed above, even toothbrushing would not totally
calculation of volume. If we assume the thickness eliminate plaque to which the tin was bound. Our
of the plaque like film that covers the whole oral results demonstrated that tin binds very well to
cavity is about 100 mm (0.01 cm), the volume of the oral surfaces and would not be expected to be
the second compartment would be 2 mL. While easily removed from the oral biofilm by eating or
speculative, it seems reasonable. It should again brushing, thus supporting the oral cavity kinetics
be noted that Vsal and Vplq estimates in this model of tin and the general results of this study.
include fluids and tissues beyond just saliva and
plaque; saliva and plaque are the samples readily
taken to represent compartments. Based on this,
Pharmacological/Therapeutic Relevance
both central and peripheral compartment volume
estimates are well within the realm of physiologic The relevant MIC values associated with a
reason. stannous fluoride dentifrice are 20 ppm (as tin
in stannous fluoride).19 We have demonstrated
that tin is maintained well above that level for at
Clinical Model Relevance
least 6 h after dosing with a stannous fluoride
The clinical model used in this study was a dentifrice. Retention of up to 12 h in dental plaque
nonbrushing model. This was necessary to enable has been demonstrated previously; in that study,
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009 DOI 10.1002/jps
PHARMACOKINETIC MODELING OF STANNOUS FLUORIDE 3869
a single long-term measure was made (12 h post- k10f final (unstimulated) salivary elimina-
treatment). The median tin level was 26.9 ng/mg tion microrate constant
and the mean level was 33.7 ng/mg.19 Our findings k10a rate constant for the decay of the sali-
are consistent with this and provide a deeper vary elimination microrate constant
understanding of the oral cavity kinetics asso- S salivary concentration of tin
ciated with the long-term retention and sustained P plaque (oral surface) concentration
clinical benefits (breath and gingivitis) for a of tin
stannous fluoride containing dentifrice.20 22 The t time
long-term retention in the site of action (plaque) k12 microrate constant for transfer of tin
could be responsible for the long-term efficacy. from saliva to oral surfaces
k21 microrate constant for transfer of tin
from oral surfaces to saliva
CONCLUSIONS
PPi pharmacokinetic parameter of inter-
est for the ith individual
It has been shown that the oral cavity can be
Qi typical value of the pharmacokinetic
modeled using compartmental kinetic approaches
parameter
with the advantage of being able to sample central
hi between-patient variability of phar-
(saliva) and second/other (plaque) compartments.
macokinetic parameters
First order kinetics can reasonably describe the
Cij jth concentration (saliva or plaque)
behavior of salivary elimination and transfer
from the ith individual
between compartments in the case of tin. The
F(Qi,hi,t) jth predicted concentration from the
model used in this paper is a two compartment
ith individual (log domain)
model with two nontraditional differences:
AGE mean age
(1) a varying central compartment elimination
mechanism due to changes in salivary flow after
administration of materials in commercial like
forms (including salivary stimulants in the form of
chemicals or physical stimulation like with a
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JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 10, OCTOBER 2009 DOI 10.1002/jps