American Journal of Therapeutics 0, 1–8 (2015)

Bioequivalence of 2 Formulations of Sildenafil Oral Soluble

Film 100 mg and Sildenafil Citrate (Viagra) 100 mg Oral
Tablets in Healthy Male Volunteers

Eric Dadey, PhD*

Sildenafil citrate tablets (VIAGRA; Pfizer Inc) have been used since 1998 as an oral therapy for the
treatment of erectile dysfunction. However, in some cases, patients may have difficulty in
swallowing tablets, and the need to use water to aid in the oral administration of the tablets has
the potential to interrupt the sexual encounter, reduce spontaneity, and therefore decrease the
quality of the experience. Two oral soluble film (OSF) formulations of sildenafil were developed
using MonoSol Rx’s proprietary PharmFilm technology. Both films were formulated to dissolve
rapidly on the tongue, thereby releasing the drug into the oral cavity, whereupon it is swallowed
without the use of water. From a patient perspective, it is anticipated that the film formulations of
sildenafil citrate will provide a more compliant and discreet dosage form. The purpose of this
clinical study was to compare the bioequivalence of the 2 sildenafil OSF 100 mg formulations
(MonoSol Rx, LLC) with the sildenafil citrate 100 mg tablets. The design was a single-dose,
randomized, open-label, 3-period, 6-sequence, 3-treatment, single-center, crossover study
conducted in 18 healthy, nonsmoking male volunteers under fasting conditions, with each
treatment period separated by a 7-day washout period. Plasma sildenafil concentrations were
measured predose and then periodically to 24 hours after dosing. The 90% confidence intervals
for plasma sildenafil AUC0–t, AUC0–N, and Cmax for both sildenafil OSF formulations as compared
with sildenafil citrate tablets were all within the 80%–125% range, indicating bioequivalence of
both film formulations to sildenafil citrate tablets. Overall, the demonstrated bioequivalence
coupled with the performance advantages of an OSF dosage form (ie, rapid dissolution in the
mouth, can be taken without water, and can be dosed discreetly) suggest that the sildenafil OSF
may provide an attractive alternative to sildenafil citrate oral tablets.

Keywords: sildenafil, oral soluble film, bioequivalence, erectile dysfunction

MonoSol Rx, LLC, Warren, NJ.

Editorial support for this article was provided by Precept Medical Communications (Warren, NJ) and was funded by MonoSol Rx, LLC
(Warren, NJ).
E. Dadey, PhD is an employee of MonoSol Rx, LLC, and receives compensation for employment. MonoSol Rx, LLC provided funding for the
study and manuscript development.
The PharmFilm drug delivery technology was developed by MonoSol Rx, LLC (Warren, New Jersey) and was used to produce 2 sildenafil
oral soluble film formulations for evaluation in a clinical study. The clinical comparisons among the 2 formulations of sildenafil oral soluble
film and sildenafil citrate tablets were conducted at BioPharma Services Inc (Toronto, ON, Canada) under the supervision of Drs. Fathi
Abuzgaya, Ziba Fadavi, Asif Khan, Ola Kassim, and Reza Behjati. The bioanalytical testing was performed at Covance Laboratory Inc
(Indianapolis, IN), and the statistical analyses were performed at BioPharma Services Inc (Toronto, ON, Canada).
*Address for correspondence: Senior Vice President, Scientific and Regulatory Affairs, MonoSol Rx, 30 Technology Drive, Warren, NJ
07059. E-mail: edadey@monosolrx.com

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 2 Dadey
INTRODUCTION
Over the past decade, there has been significant interest
in the clinical management of male sexual dysfunction
resulting from advances in the pharmacological treat-
ment of erectile dysfunction (ED), coupled with the find-
ing that ED is a very common problem.1 For example,
the Men’s Attitudes to Life Events and Sexuality
(MALES) Study found a prevalence of self-reported
ED of 22% among men in the United States.1 Since its
approval in 1998, sildenafil citrate (Viagra; Pfizer Inc,
New York, NY) has shown clinical benefit for the treat-
ment of ED and is known to exert its pharmacological
effect by selectively inhibiting the cyclic guanosine
monophosphate (cGMP)-specific phosphodiesterase
type 5 (PDE5) enzyme.2 However, for some patients,
swallowing the tablets may prove difficult. For example,
patients undergoing chemotherapy and radiation ther-
apy may experience dysphagia or xerostomia (dry
mouth), making swallowing tablets difficult.3,4 Further-
more, the need to use water as an aid in the administra-
tion of conventional solid dosage forms has the potential
to interrupt the sexual encounter, thereby reducing
spontaneity and decreasing the quality of the experience.
Therefore, an easy-to-take oral formulation that
dissolves rapidly in the mouth can be taken without
water and can be discreetly dosed before the sexual
encounter would provide advantages over currently
available oral ED treatments. Advances in drug
delivery systems such as the PharmFilm technology
(MonoSol Rx, LLC, Warren, NJ) have resulted in the
development of an oral soluble film (OSF) formulation
that provides a water-soluble polymer matrix for drug
delivery. When applied to the tongue, the OSF
dissolves rapidly and releases the drug into the saliva.
A randomized single-dose study was conducted in
healthy, nonsmoking male volunteers under fasting
conditions to assess the bioequivalency of 2 sildenafil
OSF 100 mg formulations (MonoSol Rx, LLC) as
compared with sildenafil citrate 100 mg tablets. A
secondary end point was included to evaluate the
relative safety and tolerability of the study drugs.
METHODS
Study design
The clinical study was designed as a pilot, single-dose,
randomized, open-label, 3-period, 6-sequence,
3-treatment, single-center, crossover, comparative
bioavailability study of 2 formulations of sildenafil
OSF 100 mg and sildenafil citrate 100 mg tablets. The
pharmacokinetic performance of each product was
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studied using a crossover design with 18 healthy,
nonsmoking (for at least 6 months before first drug
administration) male volunteers. Each subject was
administered an oral dose of 1 3 sildenafil OSF
100 mg, the alternative sildenafil OSF 100 mg, or
1 3 sildenafil citrate 100 mg tablet under fasting
conditions. The open-label study was conducted at Bio
Pharma Services Inc in Toronto, ON, Canada, and it was
postulated that blinding of the investigator/clinic staff
and subjects was not necessary as the pharmacokinetic
profiles of sildenafil would not be affected by previous
knowledge of which study treatment was administered.
The study was conducted in accordance with current
US Food and Drug Administration guidance
documents,5 Good Clinical Practice, as established by
the International Conference on Harmonization, the
basic principles defined in Division 5 of the Canadian
Food and Drug Regulations, the Belmont Report, and
the principles enunciated in the World Medical
Association Declaration of Helsinki (Fortaleza, Brazil,
October 2013). The protocol and informed consent form
were reviewed and approved by the Institutional Review
Board (Optimum Clinical Research Inc), and all subjects
provided written informed consent before participating.
Materials
The positive control article used in the study, that is,
the reference listed drug, was Viagra (sildenafil citrate)
100 mg tablets and was purchased from a commercial
supplier. The 2-film Test Articles each contained
140 mg of sildenafil citrate (equivalent to 100 mg of
the active moiety) and were manufactured by MonoSol
Rx, LLC (Portage, IN) using a solvent-casting process.
Using this method, the film formulations were prepared
by adding a known quantity of sildenafil citrate to an
aqueous mixture containing the film-forming polymers,
plasticizers, sweeteners, flavors, opacifiers, acidulant,
colorant, and either 0.09% (wt/wt) carboxymethylcellu-
lose (CMC) (ie, the 0.09% CMC film, treatment A)
or 2.98% (wt/wt) CMC (ie, the 3% CMC film, treatment
B). The resulting homogenous viscoelastic matrix was
coated as a film onto an inert substrate using a reverse
roll-coating method. The wet film was then dried to
specified water content in a forced-air, horizontal, custom
drying oven. After drying, the self-supporting film was
removed from the substrate, cut into individual dosage
units, and hermetically sealed between 2 layers of
polyester/foil laminate. Components of the film formu-
lations are provided in Table 1.
Subjects
Inclusion criteria included healthy nonsmoking (for at
least 6 months before first drug administration)
males, $18 years of age with a body mass index
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Bioequivalence of 2 Formulations of Sildenafil 3

Table 1. Composition of the sildenafil citrate film for- clinically significant history or presence of any clinically
mulations.* significant gastrointestinal pathology (eg, chronic diar-
rhea, inflammatory bowel disease), unresolved gastro-
Component(s) Function intestinal symptoms (eg, diarrhea, vomiting), or other
Sildenafil citrate Drug substance conditions known to interfere with the absorption, dis-
Polysaccharide Film-forming polymer tribution metabolism, or excretion of the drug experi-
Polyethylene oxide Film-forming polymer
enced within 7 days before first drug administration, as
determined by the principal investigator/subinstigator;
Fructose, xylitol, and Plasticizer and/or
sucralose sweetener
(5) individuals having undergone any major surgery
within 6 months before the start of the study, unless
Maltodextrin Viscosity enhancer
deemed otherwise by the principal investigator/subin-
Glycerin Plasticizer
vestigator; (6) individuals having tongue piercings
Citric acid Acidulant and/or mouth jewelry or having had a tattoo or body
TiO2 Opacifier piercing within 30 days before first drug administra-
FD&C blue no. 2 Colorant tion; (7) individuals having a positive test result for
Sodium chloride Ionic strength modulator any of the following: HIV, hepatitis B surface antigen,
Sodium CMC* Viscosity enhancer hepatitis C, drugs of abuse, breath alcohol test or coti-
Grapefruit flavor Flavor nine; (8) at screening, individuals with orthostatic hypo-
Taste-masking agents Flavor tension defined as $20 mm Hg reduction in systolic BP,
Water Solvent a $10 mm Hg reduction in diastolic BP, and/or the
development of significant postural symptoms when
*Treatment A contained 0.09% (wt/wt) CMC, and treatment B going from the supine to standing position; (9) at
contained 2.98% (wt/wt) CMC.
screening, individuals with a QTc interval .450 milli-
seconds; (10) individuals with a known history or pres-
between $18.5 and #29.9 kg/m2, systolic blood ence of any of the following: alcohol abuse or
pressure (BP) between $100 and #140 mm Hg, dependence within 1 year before first drug administra-
diastolic BP between $60 and #90 mm Hg, heart rate tion, drug abuse or dependence, hypersensitivity or idi-
(HR) between $50 and #100 beats per minute, and osyncratic reaction to sildenafil citrate, its excipients,
determined to be in good health by medical history, and/or related substances; food allergies and/or pres-
physical examination, vital signs, laboratory results, ence of any dietary restrictions or severe allergic reac-
and electrocardiogram. Individuals were required to tions; (11) individuals with abnormal dietary patterns
have clinical laboratory values within the acceptable (for any reason) during the 4 weeks preceding the
range, unless values were deemed by the principal study, including fasting, high protein diets, etc; (12)
investigator/subinvestigator as not clinically signifi- individuals who were intolerant to and/or had diffi-
cant. Furthermore, individuals needed to fast for .14 culty with blood sampling through venipuncture; (13)
hours and able to consume standard meals. Finally, individuals who donated plasma by plasma pheresis
participants had to agree not to have a tattoo or tongue within 7 days before first drug administration or who
or body piercing until the end of the study and had to donated 50–499 mL of blood 30 days before first drug
agree not to drive or operate heavy machinery if expe- administration, or who donated 500 mL of blood 56
riencing dizziness, drowsiness, or visual abnormalities days before first drug administration; (14) individuals
after drug administration until full mental alertness who had participated in another clinical trial or who
and/or normal vision was regained. Exclusion criteria received an investigational drug within 30 days before
included (1) being unable or unwilling to provide first drug administration; (15) individuals who con-
informed consent; (2) known history or presence of sumed food or beverages containing caffeine/methyl-
any clinically significant hepatic, renal/genitourinary, xanthines, poppy seeds, and/or alcohol within 48 hours
gastrointestinal, cardiovascular, cerebrovascular, before dosing, or containing grapefruit and/or pomelo
pulmonary, musculoskeletal, neurological, psychiatric, within 10 days before first drug administration; or
ophthalmologic, otologic, dermatological, or hemato- (16) individuals having difficulty swallowing whole
logical disease or condition, unless determined as not tablets and/or orally disintegrating film. In addition,
clinically significant by the principal investigator/sub- subjects were ineligible if they had used (1) any pre-
investigator; (3) presence of any clinically significant scription medication within 14 days before the first
illness or presence of any significant physical or organ drug administration; (2) any enzyme-modifying drugs,
abnormality within 30 days before first dosing, as deter- including strong inhibitors of cytochrome P450 (CYP)
mined by the principal investigator/subinvestigator; (4) enzymes and strong inducers of CYP enzymes in the
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 4 Dadey
previous 30 days before first drug administration; (3)
any over-the-counter medications, including oral mul-
tivitamins, herbal and/or dietary supplement, and/or
teas within 14 days before first drug administration; or
(4) any type of nitrate drug therapy, alpha blockers,
other PDE5 inhibitors, or endothelin receptor antago-
nist within 30 days before first drug administration.
Treatment
The dosing regimen involved randomization of each
subject to 1 of 6 dosing sequences: A-B-C, B-C-A,
C-A-B, A-C-B, B-A-C, or C-B-A, where treatments
A, B, and C were identified as follows:
1. Treatment A—Sildenafil OSF 0.09% CMC 100 mg
2. Treatment B—Sildenafil OSF 3% CMC 100 mg
3. Treatment C—Reference product, sildenafil citrate
100 mg tablets.
Subjects received a single dose of the test drug on day
1 of each study period. In accordance with Food and
Drug Administration regulatory requirements, the 100
mg strength was used for this bioequivalence study
because it is the strength of the reference listed drug.6
Subjects were confined to the clinical facility from at
least 10 hours before each drug administration until at
least 24 hours postdose, for a total of at least 34 hours
for each study period. Subjects fasted overnight for at
least 10 hours before each drug administration and
then for at least 4 hours after each drug administration.
Each subject was scheduled to receive a total of 3 treat-
ments by the end of the study. The washout interval
between drug administrations was 7 days.
Assessments
Pharmacokinetics
During each treatment period, blood samples for
pharmacokinetic analysis were collected predose and
at 0.167, 0.333, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6,
8, 10, 12, 18, and 24 hours postdosing. Blood samples
were collected into prechilled 3.0 mL K2EDTA Vacutainer
tubes by direct venipuncture or by indwelling catheter.
Samples were then placed in a refrigerated centrifuge
within 60 minutes from the time of collection and
centrifuged at 3000 revolutions per minute for 10 minutes
under refrigerated (approximately 4°C) conditions. After
centrifugation, the plasma was aspirated and aliquoted
into 2 prechilled clear polypropylene tubes. A minimum
of 1.0 mL plasma was transferred to the first tube, and
remaining plasma (if any) was pipetted into the second
tube. Pending shipment, the samples were stored at
260°C or colder in a freezer within 70 minutes from
the start of centrifugation. Throughout sample collection
and after centrifugation, the samples were maintained in
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an ice bath until stored in the freezer. Plasma samples
were shipped to the bioanalytical facility (Covance
Bioanalytical Services, LLC, Indianapolis, IN) by
overnight courier packed on dry ice.
The sildenafil concentration of each plasma sample
was determined using a validated high performance
liquid chromatography with mass spectrometric detec-
tion (HPLC-MS/MS) analytical method. Specifically,
sildenafil and the added internal standards were ex-
tracted from each sample by liquid–liquid extraction.
After solvent evaporation under nitrogen, the residue
was reconstituted and analyzed using liquid chromatog-
raphy with tandem mass spectrometric detection. At
a minimum, each analytical run included a calibration
curve, a matrix blank, a control zero (matrix blank con-
taining internal standard), a reagent blank, and duplicate
quality control (QC) samples at 3 concentrations within
the calibration range. The samples were interspersed with
calibration standards and QC samples within the analyt-
ical run. Dilution QC samples were also included in ana-
lytical runs where samples were diluted before analysis.
Study samples were reassayed if values exceeded the
curve range or when analytical problems were identified.
Samples were also reassayed to determine incurred
sample reproducibility and were pooled together to
determine incurred sample stability. Based on concentra-
tion levels, the maximum plasma concentration (Cmax),
time at which Cmax observed (Tmax), area under the
plasma concentration–time curve from time 0 to the last
measured concentration (AUC0–t), area under the
plasma concentration–time curve from time 0 to
infinity (AUC0–N), AUC 0–t,/AUC0–N, time required
to reduce the plasma concentration to one-half its ini-
tial value (t1/2), and lambda were estimated for
sildenafil to characterize the pharmacokinetic profile
of each study drug.
Safety
Subject safety was assessed by continuous health mon-
itoring and scheduled recording of safety measure-
ments throughout the study. Medical history, physical
examination, vital signs, laboratory results, and electro-
cardiogram were conducted to screen volunteers before
study starts. The clinical staff monitored vital signs (BP
and HR) at predose (within 12 hours before drug
administration) and at 1 and 24 hours after dosing in
each study period. Subjects were instructed to inform
clinic personnel of any untoward medical symptoms
and/or events that arose during the course of the study.
Before subsequent periods, subjects were questioned
concerning unusual symptoms that may have occurred
after the previous administration of the study drugs.
The principal investigator/subinvestigator evaluated
the relationship of all adverse events (AEs) to the study
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Bioequivalence of 2 Formulations of Sildenafil
drugs. Each AE was assessed as mild, moderate, or
severe as defined in the protocol. The principal investi-
gator/subinvestigator also approved the subjects for
subsequent dosing. At the conclusion of the study, each
subject received a physical examination, including vital
sign measurements (BP, HR, temperature, and respira-
tion rate) and an evaluation of clinical laboratory tests
(hematology, serum chemistry, and urinalysis).
Statistical analysis
Descriptive statistics (minimum, maximum, median,
mean, SD, and coefficient of variability) of all phar-
macokinetic parameters were provided for the test
and reference products. Analysis of variance, includ-
ing sequence, subjects nested within sequenced
period, and treatment, was performed on the natural
log-transformed data for AUC0–t, AUC0–N, and Cmax,
and on the untransformed data for Tmax, lambda, and
t1/2. In addition, Tmax was determined using a nonpara-
metric test. The 90% confidence interval (CI) of the test/
reference ratios of geometric means for AUC0–t,
AUC0–N, and Cmax were calculated based on the least
square means and estimation of the analysis of variance.
RESULTS
A total of 18 subjects were enrolled, and subject
disposition is summarized in Figure 1. One subject
was dismissed after the second dosing sequence due
to noncompliance (prescription medication). All
FIGURE 1. Subject disposition.
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5
plasma sildenafil concentrations and pharmacokinetic
parameters were based on data from all subjects.
The demographics and baseline characteristics of the
study population are summarized in Table 2. The
mean age was 44 years, and the mean body mass index
was 27. About one-half of the study subjects were
white, about one-third were black, and the remaining
subjects were of other races.
Plasma sildenafil pharmacokinetics
The mean plasma sildenafil concentration versus time
profiles of the 2 sildenafil OSF formulations were nearly
identical to that of the sildenafil citrate tablets. Each
profile exhibited a maximum sildenafil concentration at
approximately 1 hour postdose, followed by a decline
over the next 23 hours (Figure 2). Plasma sildenafil
pharmacokinetic parameters were also similar among
all 3 treatment groups (Table 3). The mean AUC0–t
values for treatment A—sildenafil OSF 0.09% CMC
100 mg, treatment B—sildenafil OSF 3% CMC 100
mg, and treatment C—reference product, sildenafil
citrate 100 mg tablets were 1277.616, 1300.832, and
1313.070 ng$h21$mL21, respectively, and the mean
sildenafil Cmax values were 452.500, 442.000, and
470.882 ng/mL, respectively. The median Tmax for all
3 treatment groups was 0.75 hours.
Bioequivalence
The rate and extent of sildenafil absorption parameters
(AUC0–t, AUC0–N, and Cmax) for both OSF formulations
American Journal of Therapeutics (2015) 0(0)
 6 Dadey

Table 2. Demographics and baseline characteristics. Safety

Completed Enrolled Both sildenafil OSF formulations and the reference

Parameter (n 5 17) (n 5 18) product were well tolerated by all subjects. There were
15 AEs involving 9 subjects in the study, all of mild
Age, yrs severity. No serious AEs were reported during the
Mean 6 SD 44 6 12 44 6 11 conduct of the study, and no AEs associated with
Median 47 46 clinical laboratory tests were experienced by any
Min–Max 25–60 25–60 subject after study.
Race, n (%) There were 9 AEs associated with 6 subjects who
White 9 (53) 9 (50) received treatment A—sildenafil OSF 0.09% CMC
Black 5 (29) 6 (33) 100 mg, which consisted of cough (n 5 2), nasal
Asian 1 (6) 1 (6) congestion (n 5 2), catheter site hematoma (n 5 1), cath-
Native 0 (0) 0 (0)
eter site pain (n 5 1), headache (n 5 1), nasopharyngitis
(n 5 1), and somnolence (n 5 1). Of these findings, the
Hispanic/ 2 (12) 2 (11)
Latino
relationship to the study drug was considered unrelated
(n 5 3), unlikely (n 5 3), possible (n 5 2), and probable
Other 0 (0) 0 (0)
(n 5 1). One subject experienced 1 instance of cough
Weight, kg
after drug administration which resolved after pharma-
Mean 6 SD 83.4 6 10.4 83.6 6 10.1 cological actions.
Median 83.8 83.9 There were 4 AEs associated with 3 subjects who
Min–Max 59.9–100.1 59.9–100.1 received treatment B—sildenafil OSF 3% CMC
Height, cm 100 mg, which consisted of somnolence (n 5 1), nasal
Mean 6 SD 175.0 6 7.6 174.9 6 7.4 congestion (n 5 1), pyrexia (n 5 1), and feeling hot
Median 175.9 174.5 (n 5 1). Of these, the relationship to the study drug
Min–Max 162.3–191.9 162.3– was considered unrelated (n 5 2), unlikely (n 5 1), and
191.9 possible (n 5 1). One subject experienced 1 instance of
BMI, kg/m2 pyrexia after drug administration which resolved after
Mean 6 SD 27.2 6 2.4 27.3 6 2.4 pharmacological action.
Median 28.0 28.3 There were 2 AEs associated with 2 subjects who
Min–Max 21.1–29.6 21.1–29.6
received treatment C—reference product, sildenafil
citrate 100 mg tablets, which consisted of somnolence
BMI, body mass index; Max, maximum; Min, minimum. (n 5 1) and laceration (n 5 1). Of these, the relation-
ship to the study drug was considered unrelated
(n 5 1) and unlikely (n 5 1).
of sildenafil and the reference product, sildenafil citrate
tablets, were found to be similar (Table 4).
Both OSF formulations of sildenafil were bioequiva-
lent to sildenafil citrate tablets. The 90% CIs of the DISCUSSION
ratios of treatment A—sildenafil OSF 0.09% CMC
100 mg versus treatment C—reference product, This randomized single-dose study evaluated the
sildenafil citrate 100 mg tablets for the absorption bioequivalence of sildenafil from 2 formulations of
parameters, AUC0–t, AUC0–N, and Cmax were (88.12, sildenafil OSF 100 mg and sildenafil citrate 100 mg tab-
110.64), (87.89, 110.25), and (84.20, 121.36), respec- lets in healthy, nonsmoking male volunteers under fast-
tively, all within the 80%–125% range for bioequiva- ing conditions. Both OSF formulations and the reference
lence. Similarly, the 90% CIs of the ratios of treatment product, sildenafil citrate tablets, demonstrated overall
B—sildenafil OSF 3% CMC 100 mg versus treatment similar plasma sildenafil concentrations postdose. The
C—reference product, sildenafil citrate 100 mg tablets criterion for bioequivalence of plasma sildenafil expo-
for the absorption parameters, AUC0–t, AUC0–N, and sure was met for all parameters (AUC0–t, AUC0–N, and
Cmax were (89.76, 112.70), (89.77, 112.61), and (82.65, Cmax). Both sildenafil OSF formulations and the refer-
119.13), respectively, also all within the 80%–125% ence product, sildenafil citrate tablets, were well toler-
range. Intrasubject variability was calculated to be ated by all subjects. All 15 reported AEs were of mild
approximately 19.36% for AUC0–t, approximately severity, and of these findings, only 3 were considered
19.27% for AUC0–N, and approximately 31.55% for possibly related to the study drug and only 1 was con-
Cmax for sildenafil (Table 4). sidered probably related to the study drug.
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Bioequivalence of 2 Formulations of Sildenafil 7

FIGURE 2. Mean sildenafil plasma concentrations 0–24 hours for all subjects in a linear scale.

In conclusion, the pharmacokinetic results of this to sildenafil citrate 100 mg tablets. The treatments
study demonstrated that a single dose of sildenafil had similar safety profiles and were well tolerated.
OSF 0.09% CMC 100 mg and sildenafil OSF 3% CMC As an easy-to-take oral formulation that dissolves
100 mg under fasting conditions were bioequivalent rapidly in the mouth, can be taken without water,

Table 3. Plasma sildenafil pharmacokinetic parameters.

Pharmacokinetic Treatment A—Sildenafil OSF Treatment B—Sildenafil Treatment C—Reference product,

parameter 0.09% CMC 100 mg OSF 3% CMC 100 mg sildenafil citrate 100 mg tablets

AUC0–t, mean (CV%), 1277.616 (34.61) 1300.832 (32.00) 1313.070 (40.28)

ng$h21$mL21
AUC0–N, mean (CV%), 1294.768 (34.56) 1322.536 (32.23) 1333.095 (40.46)
ng$h21$mL21
Cmax, mean (CV%), 452.500 (42.14) 442.000 (38.54) 470.882 (45.73)
ng/mL
Tmax, median 0.75 (0.33–4.00) 0.75 (0.33–4.00) 0.75 (0.33–3.00)
(min–max), h
l, mean (CV%) (1/h) 0.1754 (26.29) 0.1738 (24.75) 0.1710 (21.36)
t1/2, mean (CV%), h 4.17 (21.32) 4.21 (23.47) 4.21 (19.20)
AUC0–t/AUC0–N Mean 0.9866 (0.80) 0.9840 (1.30) 0.9854 (0.69)
(CV%)

AUC0–N, area under the plasma concentration–time curve from time 0 to infinity; AUC0–t, area under the plasma concentration–time
curve from time 0 to the last measured concentration; Cmax, maximum plasma concentration; CV, coefficient of variation; t1/2, time
required to reduce the plasma concentration to one-half its initial value; Tmax, time at which Cmax observed; l, elimination rate
constant.

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 8 Dadey

Table 4. Bioequivalence results: systemic plasma sildenafil exposure.

Least squares geometric means

Treatment A— Treatment C—Reference

Pharmacokinetic Sildenafil OSF 0.09% product, sildenafil citrate Intrasubject
parameter CMC 100 mg 100 mg Tablets Ratio, % 90% CI CV, %

AUC0–t, ng$h21$mL21 1204.929 1220.301 98.74 88.12–110.64 19.36

AUC0–N, ng$h21$mL21 1221.284 1240.645 98.44 87.89–110.25 19.27
Cmax, ng/mL 416.342 411.867 101.09 4.20–121.36 31.55

Least squares geometric means

Treatment B— Treatment C—Reference

Pharmacokinetic Sildenafil OSF 3% product, sildenafil citrate Intrasubject
parameter CMC 100 mg 100 mg Tablets Ratio, % 90% CI CV, %

AUC0–t, ng$h21$mL21 1227.333 1220.301 100.58 89.76–112.70 19.36

AUC0–N, ng$h21$mL21 1247.421 1240.645 100.55 89.77–112.61 19.27
Cmax, ng/mL 408.692 411.867 99.23 82.65–119.13 31.55

AUC0–N, area under the plasma concentration–time curve from time 0 to infinity; AUC0–t, area under the plasma concentration–time
curve from time 0 to the last measured concentration; Cmax, maximum plasma concentration; CV, coefficient of variation.

and can be discreetly dosed, sildenafil OSF may pro- REFERENCES

vide an attractive alternative to sildenafil citrate oral
tablets.
ACKNOWLEDGMENTS
The PharmFilm drug delivery technology was devel-
oped by and is the property of MonoSol Rx, LLC,
(Warren, NJ). MonoSol Rx, LLC used this proprietary
technology to develop and produce the 2 sildenafil
OSF formulations.
The clinical comparisons between the 2 formulations
of sildenafil OSF and sildenafil citrate tablets were
conducted at BioPharma Services Inc (Toronto, ON,
Canada) under the supervision of Drs. Fathi Abuzgaya,
Ziba Fadavi, Asif Khan, Ola Kassim, and Reza Behjati.
The bioanalytical testing was performed at Covance
Laboratory Inc (Indianapolis, IN), and the statistical
analyses were performed at BioPharma Services Inc
(Toronto, ON, Canada). MonoSol Rx, LLC provided
funding for the study.
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