A Double-blind Placebo-controlled Evaluation of the Effect of Topical Sildenafil on Erectile Dysfunction

Abstract

Several adverse effects have been reported with use of oral sildenafil in the treatment of erectile dysfunction (ED). In this study, a formulation of sildenafil topical gel was compared with sildenafil tablet in a randomized, double-blind, prospective, placebo-controlled clinical trial. A total of 94 patients, with clinically diagnosed ED were recruited. The patients were evaluated by treatment group, nature of ED, and age. The cases received a topical gel containing 1% sildenafil and placebo tablet, and the control group received 100 mg sildenafil tablet and a gel base (without drug) as placebo. The tablets were taken one hour before sexual activity and approximately 0.5 g of the topical gel was applied on the glans of the penis and was massaged for 5 minutes before sexual activity. In the case group, five patients (12.5%) had complete erection, five patients (12.5%) had moderate erection, and 30 patients (75%) had no erection. In the control group, these results were 28 (70%), 6 (15%) and 6 (15%) respectively. The onset of erection in the case group (in patients with complete erection) was 7.4 ± 3.6 minutes, but was 37.8 ± 14.9 minutes in the control group. Four cases of mild headache were observed in the case group. This was pain treated four minutes before receiving any drugs for headache. Two cases of severe headache were observed in the control group. In the control group, one patient developed disturbance in visual function and one patient developed severe dyspepsia. The findings suggest that sildenafil delivery using a transdermal formulation can be enhanced by several synthetic or natural percutaneous absorption enhancers, and appears to be a promising approach for the treatment ED.

Full text

The Journal of Applied Research • Vol. 5, No. 2, 2005 289
A Double-blind Placebo-controlled
Evaluation of the Effect of Topical
Sildenafil on Erectile Dysfunction
Mehdi Yonessi, MD*
Madjid Saeedi, PhD†
*Department of Urology, Faculty of Medicine,Mazandaran University of Medical Sciences,
Sari, Iran
†Department of Pharmaceutics, Faculty of Pharmacy,Mazandaran University of Medical
Sciences, Sari, Iran
onset of erection in the case group (in
patients with complete erection) was 7.4
±3.6 minutes,but was 37.8 ± 14.9 min-
utes in the control group. Four cases of
mild headache were observed in the
case group. This was pain treated four
minutes before receiving any drugs for
headache. Two cases of severe headache
were observed in the control group. In
the control group,one patient devel-
oped disturbance in visual function and
one patient developed severe dyspepsia.
The findings suggest that sildenafil
delivery using a transdermal formula-
tion can be enhanced by several syn-
thetic or natural percutaneous
absorption enhancers,and appears to be
a promising approach for the treatment
ED.
INTRODUCTION
Erectile dysfunction (ED) is a common
problem with a prevalence of approxi-
mately 50% in men aged 40 to 70 years.1
Sildenafil citrate,a selective inhibitor of
cyclic guanosine monophosphate
(cGMP)-specific phosphodiesterase
type 5 (PDE5), is an effective oral treat-
ment of ED.2The physiologic mecha-
nism of erection involves release of
nitric oxide in the corpora during sexual
stimulation. This release activates the
enzyme guanylate cyclase and results in
KEY WO R D S : erectile dysfunction,
s i l d e n a f i l , t o p i c a l , t r a n s d e r m a l , a d v e r s e
e f f e c t
ABSTRACT
Several adverse effects have been
reported with use of oral sildenafil in
the treatment of erectile dysfunction
(ED). In this study,a formulation of
sildenafil topical gel was compared with
sildenafil tablet in a randomized, dou-
ble-blind, prospective,placebo-con-
trolled clinical trial. A total of 94
patients,with clinically diagnosed ED
were recruited. The patients were evalu-
ated by treatment group,nature of ED,
and age. The cases received a topical gel
containing 1% sildenafil and placebo
tablet, and the control group received
100 mg sildenafil tablet and a gel base
(without drug) as placebo. The tablets
were taken one hour before sexual
activity and approximately 0.5 g of the
topical gel was applied on the glans of
the penis and was massaged for 5 min-
utes before sexual activity.In the case
group,five patients (12.5%) had com-
plete erection, five patients (12.5%) had
moderate erection, and 30 patients
(75%) had no erection. In the control
group,these results were 28 (70%), 6
(15%) and 6 (15%) respectively. The
Saedi-vol5no2 6/1/05 8:46 PM Page 289

Vol. 5, No. 2, 2005 •The Journal of Applied Research
290
increased levels of cGMP. This increased
cGMP relaxes the smooth muscle in the
corpus cavernosum and allows greater
inflow of blood, thus increasing the
intracavernosal pressure compressing
the peripheral venules and leading to an
erection. The main action of sildenafil is
the enhancement of the effect of nitric
oxide by inhibiting the cGMP-specific
PDE5 degradation.3
The main adverse effects reported
in clinical trials were headache,dyspep-
sia, visual disturbance (changes in per-
ception of color hue or brightness),
flushing,and rhinitis. These were mild in
severity and the number of discontinua-
tions because of adverse effects was
small (< 1%).
In a prospective study,the adverse
reactions most commonly observed were
flushing (30.8%), headache (25.4%),
nasal congestion (18.7%), and heartburn
(10.5%).3All events were short lived
and mild in nature,with 31.6% of
patients experiencing one or more
adverse events. There was a significant
association between higher doses and
the occurrence of side effects.
In a recent study,no pattern of
errors was evident in any visual function
test following sildenafil administration.5
Sildenafil has been associated with a
mild decrease in systemic arterial pres-
sure as well as a synergistic and often
major decrease in systemic arterial pres-
sure in the presence of organic nitrates.6-
8Priapism (painful or uncomfortable
erection persisting for several hours
after ejaculation) was reported in one
case.9In another study,the number of
deaths associated with sildenafil citrate
and injections of alprostadil, both of
which are used exclusively in the treat-
ment of ED,were compared based on
the number of deaths per filled prescrip-
tion for these agents reported to the
FDA.10 The results showed that the
number of deaths per prescriptions filled
for sildenafil was significantly greater
than that for injections of alprostadil.
Repeated doses of oral sildenafil are
required to sustain plasma levels
because of its short duration of action
(t1/2 = 1 h) with high liver metabolism.11
Thus,topical delivery through local tis-
sue area may be an alternative to oral
administration to reduce the incidence
of adverse effects,increase the time to
onset of response,and sustain effects for
longer periods.Furthermore,transder-
mal delivery of sildenafil can offer sev-
eral advantages over conventional
dosage forms and the multiple dosing
can be eliminated.12 However,transder-
mal permeation of compounds in the
local skin, in general, is slow due to low
permeability resulting from physico-
chemical properties of the compound,
low partition ability,and the tissue barri-
er from the stratum corneum, which cre-
ates a low diffusion coefficient.13 Liaw
showed that after transdermal adminis-
tration of 15.8 µg/mL of sildenafil to
nude mouse skin, it was detected in the
bloodstream as early as 15 minutes.12
The transport amount of sildenafil could
be quantitated and, at pH of 8 to 11, had
the highest permeation rate in nude
mouse skin.
In the present study,sildenafil topi-
cal gel was compared with sildenafil
tablet in a double-blind, placebo-control
clinical trial.
MATERIALS AND METHODS
The following chemicals were used:
Methylparaben and propylparaben,
polyethylene glycol (PEG) 200, PEG
300, PEG 400, isopropyl alcohol, glyc-
erin, ethanol, KH2PO4,NaOH (supplied
by Merck), HPMC K100M (supplied by
Colorcon). The sildenafil powder was
provided by Razak Company, Tehran,
Iran. The sildenafil tablets were pur-
chased from Rouz Daru Company,
Tehran, Iran.
Saedi-vol5no2 6/1/05 8:46 PM Page 290

The Journal of Applied Research • Vol. 5, No. 2, 2005 291
Preparation of the Formulations
Several agents (PEG 200, 300, 400;
ethanol, propylene glycol, glycerin) were
used as cosolvent for sildenafil in water
and a buffer (pH 7.4). The solubility of
sildenafil in several systems was deter-
mined spectrophotometerically at 223
nm. The linearity interval established
was 10-30 µg/mL (r2= 0.9997).14
HPMC K100M was dispersed in
preserved buffer (methylparaben 0.18%
and propylparaben 0.02%) and ethanol
for overnight. The sildenafil powder
(1%)15 was dissolved in solvent system
before the addition of polymer and
stirred with a double bladed mixer (Ika-
werk, Germany) 500 rpm for 30 minutes
and then added to polymer dispersion
and stirred till gel forming. The formula-
tions were kept in 4˚C,25˚C,and 40˚C
for physical stability evaluation during a
two-week period. The drug release from
gel base and percutaneous absorption
was determined in vitro. Final formula-
tions for clinical trial were controlled
microbiologically based on USP XXIV.16
Clinical Trial
The study design was a randomized
(block-random sampling), double blind,
prospective,placebo-controlled trial.
Under the assumption of an overall
mean difference of 0.5 units and a stan-
dard deviation of 0.5 units,78 patients
were required to achieve a power of
95% to reject a null hypothesis of equal-
ity,applying a two-sided test at the 5%
significance level.
All patients with ED (n = 94) who
presented to one urologist from July
2003 to May 2004 were considered for
inclusion in the study.Men with anatom-
ical defects of the penis,other sexual dis-
orders,spinal cord injury,major
psychiatric disorder,poorly controlled
diabetes,stroke,a heart attack within six
months,treatment with organic nitrate,
active peptic ulcer disease,migraine,
vision disorders,and allergic rhinitis,
were excluded. A total of 14 patients
were excluded from the trial based on
these criteria. Thus,80 patients with clin-
ically diagnosed ED were included in
the analysis.
In recognition of the multifactorial
nature of ED,men with a broad variety
of baseline etiologies were enrolled in
the trial, including those with ED of
Figure 1. Comparison of the effect of sildenafil on ED in oral and transdermal administration.
Saedi-vol5no2 6/1/05 8:46 PM Page 291

Vol. 5, No. 2, 2005 •The Journal of Applied Research
292
organic,psychogenic,and mixed causes.
Patients were divided categories by age
(ie, < 50 and ≥50) and by ED etiology.
The case group received a topical
gel containing 1% sildenafil and placebo
tablet, and the control group received
100 mg sildenafil tablet and gel base
(without drug) as placebo. The tablets
were taken one hour before sexual
activity and approximately 0.5 g of the
topical gel was applied to the glans of
penis and was massaged for five minutes
before sexual activity.
The overall clinical response was
assessed by erection (complete,moder-
ate,and none) and the onset of erection.
Headache,dyspepsia, rhinitis,diarrhea,
heartburn, visual dysfunction, and pri-
apism were studied as adverse drug
reactions. The patients were followed for
up to two weeks.
Statistical Analysis
Student ttest, and Chi-square test were
used to determine significant differences
between groups,and a Pvalue of < 0.05
was considered statistically significant.
RESULTS
A total of 24 solvent systems were inves-
tigated and the percent of solubility was
determined. These results showed the
best solubility in media buffer compared
with distilled water.Of these solvents,
ethanol showed the best results.Several
formulations of the topical gel formula-
tions were investigated (data not
shown). Carbopol did not show suitable
results in selected systems and this find-
ing could not be explained by the low
ratio of water in selected systems.
Several kinds of HPMC were tested as
gelling agent and, of these,HPMC
K100M showed the best results.
After evaluation of the physical sta-
bility of formulations,the most stable
gels were chosen for clinical trial. The
release profile of one selected formula-
tion was studied in vitro. These results
showed that ethanol had the most effect
on the release profile of sildenafil.
Patient characteristics are shown in
Table 1. Fourteen patients were exclud-
ed from the efficacy analyses: nine
patients were given another drugs that
stimulated erection and five patients suf-
fered from other disorders during study.
In the case group,five patients
(12.5%) had complete erection, five
patients (12.5%) had moderate erection,
and 30 (75%) had no erection (Figure
1). In the control group,these results
were 28 (70%), six (15%), and six
(15%), respectively.
The onset of erection was 7.4 ± 3.6
minutes in the case group (in patients
with complete erection), and was 37.8 ±
14.9 minutes in the control group.
Four patients experienced mild
headache in the case group. This pain
was treated four minutes before receiv-
ing any drugs.In the control group,two
patients developed severe headache,one
experienced disturbance in visual func-
tion, and one patient experienced severe
dyspepsia.
DISCUSSION
Despite the proven efficacy of oral ther-
apy for ED,some patients are unable to
take these medications because of drug
interactions,side effects,or a lack of
Table 1. Patient Characteristics
Case Control
Age
Mean (year) 47.2 50.8
Range 26-63 37-65
Duration of ED (month)
Mean 17.5 18.1
Range 7-34 7-36
Nature of ED
Organic 17 16
Psychogenic 23 24
Mixed … …
Saedi-vol5no2 6/1/05 8:46 PM Page 292

The Journal of Applied Research • Vol. 5, No. 2, 2005 293
tablet. For example,only 5% of patients
in this study reported headache com-
pared with 25.4% of sildenafil-treated
patients in a study by Baylor et al3and
16.0% in a study by Morales et al4.
Visual disorders was reported in 5.8%
and 3.0% of patients in the Baylor and
Morales studies—an incidence that is
similar to that found in our study.No
cases of heartburn were observed in our
study,however,it seems that our exclu-
sion criteria may explain this subject.
Flushing and nasal congestion were not
observed in our study.
This investigation is the first con-
trolled-randomized trial on sildenafil in
Iran. Thus,further studies are needed for
evaluation of sildenafil tablet side
effects in our country.
CONCLUSION
In conclusion, sildenafil delivery using a
transdermal formulation can be
enhanced by several synthetic or natural
percutaneous absorption enhancers,and
appears to be a promising approach for
the treatment ED.
ACKNOWLEDGMENT
This work was supported by a grant
from the research council of the
Mazandaran University of Medical
Sciences. We would like to thank Dr.
Khorrami (Targolshimi Company) for
her help,Colorcon (UK) for donating
the HPMC,and Razak Company for
supplying sildenafil powder.
REFERENCES
1. Thomas JA. Pharmacological aspects of erec-
tile dysfunction. Jpn J Pharmacol.
2002;89:101-112.
2. Khan MA, Mikhailidis DP,Morgan RJ.
Sildenafil: urologist’s view.Curr Med Res
Opin. 2000;16(suppl 1):S48-S58.
3. Moreira SG,Brannigan RE, Spitz A, Orejuela
FJ, Lipshultz LI, Kim ED.Side-effect profile
of sildenafil citrate (Viagra) in clinical prac-
tice. Urology. 2000;56:474-476.
response. Topical agents represent
another minimally invasive option for
the treatment of ED.17
Therefore,in this study,we evaluat-
ed drug release and kinetic of release of
a topical gel formulation of sildenafil.
More than 90% of the drug was released
at 1.5 hours following application. This
formulation showed percutaneous
absorption as well (data not shown).
The results of our study demon-
strate that oral sildenafil is more effec-
tive than transdermal administration of
the drug (P< 0.01). However,the onset
of erection was faster with transdermal
administration (P< 0.001).
Our study identified a higher inci-
dence of side effects with sildenafil
tablet than with the transdermal gel.
While mild headache was more common
in the transdermal group than in the
oral tablet group (10% vs 5%), severe
dyspepsia and visual disorders were
observed only in the oral tablet group.
No cases of flushing,nasal congestion,
heartburn, or priapism were observed in
this study.
Dyspepsia was related to the route
of administration, and the low blood
concentration resulting from transder-
mal administration cannot produce this
side effect. In addition to the inhibitory
effect of sildenafil on PDE5—the target
enzyme for therapeutic efficacy in
patients with ED—the drug exerts a
minor inhibitory effect on PDE6.
Because PDE6 plays an important role
in retinal phototransduction, its partial
inhibition may account for the infre-
quent occurrence of visual effects
observed in flexible-dose,controlled
clinical trials of sildenafil in men with
ED.5It seems that the low blood con-
centration of sildenafil found in trans-
dermal formulations can not induce this
effect, but more studies are needed to
confirm this potential advantage.
Other studies identified a higher
incidence of side effects with sildenafil
Saedi-vol5no2 6/1/05 8:46 PM Page 293

Vol. 5, No. 2, 2005 •The Journal of Applied Research
294
4. Morales A, Gingell C,Collins M, Wicker PA,
Osterloh IH. Clinical safety of oral sildenafil
citrate in the treatment of erectile dysfunc-
tion. Int J Impot Res.1998;10:69-74.
5. Birch DG, Toler SM, Swanson WH, Fish GE,
Laties AM. A double-blind placebo-con-
trolled evaluation of the acute effects of
sildenafil citrate (Viagra) on visual function
in subjects with early-stage age-related macu-
lar degeneration. Am J Ophtalmol.
2002;133:665-672.
6. Kloner RA, Zusman RM. Cardiovascular
effects of sildenafil citrate and recommenda-
tions for its use.Am J Cardiol. 1999;84:11N-
17N.
7. Kloner RA. Cardiovascular risk and sidenafil.
Am J Cardiol. 2000;86:57F-61F.
8. Shakir SA, Wilton LV, Boshier A, Layton D,
Heeley E. Cardiovascular events in users of
sildenafil: results from first phase of prescrip-
tion event monitoring in England. BMJ.
2001;322:651-652.
9. Shuster J.Priapism with sildenafil citrate.
Hosp Pharm. 2000;35:937.
10. Chen JS.Comparison of FDA reports of
patient deaths associated with sildenafil and
with injectable alprostadil. Ann
Pharmacother. 2001;35:285-288.
11. Flores-Murrieta FJ,Castaneda-Hernandez G,
Granados-Soto V, Herrera JE. Increased
bioavailability of sildenafil in Mexican men.
JAMA. 2000;283:1825-1826.
12. Liaw J,Chang TW. Determination of trans-
dermal sildenafil in nude skin by reversed-
phase high-performance liquid
chromatography. J Chromatogr B.
2001;765:161-166.
13. Mitragotri S.Synergistic effect of enhancers
for transdermal drug delivery.Pharm Res.
2000;17:1354-1359.
14. Altiokka G,Atkosar Z, Sener E,Tuncel M.
FIA of sildenafil citrate using UV-detection. J
Pharm Biomed Anal. 2001;25:339-342.
15. Anon A. Formulations. Indian J Nat Prod.
2001;5:373-383.
16. Saeedi M, Morteza-Semnani K, Ghoreishi
MR. The treatment of atopic dermatitis with
licorice gel. J Dermatolog Treat. 2003;14:153-
157.
17. McVary Y. Topical agents and erecile dysfunc-
tion: is there a place? Curr Urolog Rep.
2002;3:471-476.
Saedi-vol5no2 6/1/05 8:46 PM Page 294