Note: Descriptions are shown in the official language in which they were submitted.
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METHODS OF TREATMENT OF MALE ERECTILE DYSFUNCTION
TECHNICAL FIELD OF THE INVENTION
This invention relates to the methods for treatment of erectile dysfunction in
patients suffering from a co-morbid condition.
S BACKGROUND OF THE INVENTION
The term "impotence" has been used to signify the inability of the male to
attain and maintain erection of the penis sufficient to permit satisfactory
sexual
intercourse. The term "erectile dysfunction" has been suggested as a more
precise
term "to signify an inability of the male to achieve an erect penis as part of
the overall
multifaceted process of male sexual function." Droller, M. J. et al.
Impotence.
Consensus Development Conference Statement, National Institutes of Health
(1993).
Erectile dysfunction may result from psychological causes (psychogenic
erectile dysfunction) or organic causes or a combination of both. Organic
causes
include physiological, nervous, vascular and hormonal pathologies or a
combination
thereof.
The normal physiology of an erection involves nerve impulses that signal
certain muscles to relax. These muscles, when contracted, restrict blood flow
through
arteries in the penis. When relaxed, the muscles permit a significant increase
in blood
flow. The increased blood flow engorges three groups of erectile tissue within
the
penis with blood and the penis becomes less flaccid. The engorged erectile
tissue and
the muscle structure of the penis depress adjacent veins, restricting the flow
of blood
out of the penis. The restriction of blood flow out of the penis increases and
sustains
the erection.
Deficiencies of some hormones, such as testosterone, or elevation of others,
such as prolactin, can cause erectile dysfunction. Many drugs, such diuretics,
antihypertensives, anticonvulsants, narcotics, alcohol, and psychotropic drugs
may
cause erectile dysfunction as a side effect. Murray, F. T. et al. Amer. J.
Medical Sci.
309: 99-109 (1995).
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Damage to nerves and blood vessels may also provide an organic cause for
erectile dysfunction. Disease processes may involve several aspects. For
example,
diabetes, which causes damage to both nerves and blood vessels, can cause
erectile
dysfunction. A significant percent of all diabetic men will suffer from
erectile
dysfunction. While diabetes mellitus is a common risk factor in erectile
dysfiznction
(ED), the pathogenesis of ED in diabetes is not completely understood
(Sullivan,
M.E., et al., Alterations in endothelin B receptor sites in cavernosal tissue
of diabetic
rabbits: potential relevance to the pathogenesis of erectile dysfunction. J
Urol. 1997
158(5):1966-72). ED in diabetes may be one aspect of vascular disease
associated
with diabetes (Sairam, K., et al., Prevalence of undiagnosed diabetes mellitus
in male
erectile dysfunction. BJU Int. 2001 88(1):68-71; Sullivan, M.E., et al. Nitric
oxide
and penile erection: is erectile dysfunction another manifestation of vascular
disease?
Cardiovasc Res. 1999 Aug 15;43(3):658-65)
Microvasculopathy is one of the characteristics of diabetes. Studies have
suggested a link between diabetes, erectile dysfunction and endothelial cell
dysfunction (De Angelis, L., et al., Erectile and endothelial dysfunction in
Type II
diabetes: a possible link. Diabetologia. 2001 44(9):1155-60; Burchardt, T., et
al.,
Reduction of endothelial and smooth muscle density in the corpora cavernosa of
the
streptozotocin induced diabetic rat. J Urol. 2000 164(5):1807-11; Hopfner,
R.L., &
Gopalakrishnan, V., Endothelin: emerging role in diabetic vascular
complications.
Diabetologia. 1999 42(12):1383-94). In other studies, erectile dysfunction has
been
found to be predominant among patients affected by cardiovascular disease or
diabetes mellitus, and the presence of cardiovascular disease increased the
risk of
erectile dysfunction (Sasayama, S., et al. Men's Health Study. Epidemiology of
Erectile Dysfunction and Cardiovascular Disease, Circ. J., 2000; 67:656-659).
Radical retropubic prostatectomy (RPP) has been the standard treatment for
organ/specimen-confined prostate cancer for several decades, yet erectile
dysfunction
in selected series is still reported as high as 90% after this procedure, with
surgical
technique and experience dominant variables influencing outcome (Zippe,
C.D.,et al.,
Management of erectile dysfunction following radical prostatectomy, Current
Urology Reports, 2: 495-503 (2001). Age is also a factor. Although about 50-
70% of
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younger men regain potency after nerve sparing radical prostatectomy, the
potency
recovery rate in patients over 70 years of age is less than 10% (Catalona,
W.J., et al.,
Nerve-sparing radical prostatectomy: evaluation of results after 250 patients.
J. Urol.
1990; 143:538-43; discussion 44; Quinlan, D.M., et al., Sexual function
following
radical prostatectomy: influence of preservation of neurovascular bundles. J.
Urol.
1991; 145:998-1002).
Thus, most men need treatments for erectile dysfunction to be sexually active
following radical prostatectomy. Treatments using vacuum constriction devices,
intracorporeal injections of vasoactive drugs, and transurethral vasodilators,
have
reported response rates of 50% to 70%, but poor long-term compliance, having
discontinuation rates of nearly 50% at one year.
Methods proposed for the treatment of erectile dysfunction have included
external devices, sex therapy, surgical implantation of internal prostheses,
injection of
drugs directly into the penis and topically applied medications. None of these
approaches is entirely effective.
External devices include tourniquets (see U.S. Pat. No. 2,818,855) and
externally applied vacuum erection aids. While some clinicians consider
externally
applied erection aids as a first option for treatment, some patients are
unwilling to use
such devices. O'Keefe, M., et al. Medical Clinics of North America 79: 415-434
(1995).
Symptomatic sex therapy was originally found to be effective by Masters and
Johnson, but later studies have not shown as impressive results. Freudian
therapy
does not appear to patients to be an attractive alternative. Vickers, M. A.,
et al. J.
Urology 149: 1258-1261 (1993).
Surgically implanted mechanical devices, such as hinged or solid rods and
inflatable, spring driven or hydraulic prostheses have been used for some
time.
Several penile prostheses have been described that are pliable plastic
elements with
constant rigidity. However, these prostheses are continuously rigid and can
cause
discomfort for the patient. Other types of penile prostheses include
surgically
positioned pumps for creating high pressure of liquid in the elastic silicon
mantle.
Implantation of these complex devices requires implanting several components
into
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the patient's body, for example, the reservoir with liquid, pump, several
valves,
connecting pipes, and the like, in addition to those components implanted
directly
into the penis. Other penile prostheses use an external source of electricity
and a
source of an alternating magnetic field changing with the frequency of 50 to
1000 Hz
that influences the internal element located in the penis. This element senses
the
magnetic field and causes liquid in the inner reservoir to move from the
reservoir into
the elastic mantles located in the corpora cavernosa, and causes the penis to
erect.
Some disclosures describe prostheses including a permanent magnet that makes
seesaw movements under the influence of this field, which in turn causes
liquid from
the reservoir to pump into the elastic mantles, thus serving as an internal
element
sensing alternating magnetic field of the external source. However, while such
prostheses can provide adequate rigidity for intercourse, patients and the
patients'
partners have been reported to indicate unmet expectations with their penile
prostheses. Case reports have recounted the results of treating a single
patient with
intracavernosal injections of PGE~ (Keogh, E.J. and Earle, C.M., Int. J.
Impotence
Res., 4:113, 1992) or with MUSE~ (Chew, K.K., & Stuckey, B.G.A., Int.
J.Impotence
Res., 12: 195-196, 2000) in an attempt to alleviate dissatisfaction with a
penile
prosthesis.
The administration of erection effecting and enhancing drugs is taught in U.S.
Pat. No.4,127,118 to LaTorre. This patent teaches a method of treating male
impotence by injecting into the penis an appropriate vasodilator, in
particular, an
adrenergic blocking agent or a smooth muscle relaxant to effect and enhance an
erection.
More recently, U.S. Pat. No. 4,801,587 to Voss et al. teaches the application
of an ointment to relieve impotence. The ointment consists of the vasodilators
papaverine, hydralazine, sodium nitroprusside, phenoxybenzamine, or
phentolamine
and a carrier to assist absorption of the primary agent through the skin. U.S.
Pat. No.
5,256,652 to El-Rashidy teaches the use of an aqueous topical composition of a
vasodilator such as papaverine together with hydroxypropyl-(3-cyclodextrin.
The biochemical, physiological, and clinical effects of cyclic guanosine 3',5'-
monophosphate specific phosphodiesterase (cGMP-specific PDE) inhibitors
suggest
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their utility in a variety of disease states in which modulation of smooth
muscle,
renal, hemostatic, inflammatory, and/or endocrine function is desired. One
isozyme in
particular, the type 5 cGMP-specific phosphodiesterase (PDES) is the major
cGMP
hydrolyzing enzyme in vascular smooth muscle, and its expression in penile
corpus
cavernosum has been reported. Thus, PDES is an attractive target in the
treatment of
sexual dysfunction. A selective inhibitor of PDES, sildenafil, has been
available and
marketed in a pharmaceutical product VIAGRA~. While sildenafil has obtained
significant commercial success, it has fallen short due to its significant
adverse side
effects, including facial flushing (10% incidence rate). Adverse side effects
limit the
use of sildenafil in patients suffering from visual abnormalities,
hypertension, and,
most significantly, by individuals who use organic nitrates (Welds et al.,
Amer. J. of
Cardiology, 83 (SA), pp. 21 (C)-28(C) (1999)). The use of sildenafil in
patients taking
organic nitrates is believed to cause a clinically significant drop in blood
pressure
which could place the patient in danger. Accordingly, the package label for
sildenafil
provides strict contraindications against its use in combination with organic
nitrates
(e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, erythrityl
tetranitrate)
and other nitric oxide donors in any form, either regularly or intermittently,
because
sildenafil potentiates the hypotensive effects of nitrates. See C. R. Conti et
al., Amer.
J. of Cardiology, 83(SA), pp. 29C-34C (1999). Thus, even with the availability
of
sildenafil, there remains a need to identify improved pharmaceutical products
that are
useful in treating sexual dysfunction in patients with co-morbid conditions
such as
hypertension.
One approach has been to seek other oral phosphodiesterase-5 inhibitors with
greater selectivity that would hopefully lack the undesirable side effects of
sildenafil.
See U.S. Patent No. 6,451,807. Two such oral phosphodiesterase-5 inhibitors
are
vardenafil (LevitraTM) and tadalafil (CialisTM). Early evidence indicates that
these
other two phosphodiesterase-5 inhibitors are similar to sildenafil in
interactions with
concomitant therapy in angina patients receiving nitrate treatment
(contraindication)
and hypertension patients receiving alpha-blockers. See Gresser, U., &
Gleiter, C.H.,
Erectile dysfunction: Comparison of efficacy and side effects of the PDE-S
inhibitors
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sildenafil, vardenafil and tadalafil. Review of the literature, European J,
Med. Res.,
2002, 7: 435-446.
However, this approach of looking for more specific inhibitors does not
necessarily solve another problem with oral phosphodiesterase-5 inhibitor
treatment,
the lack of response to treatment in a significant fraction of erectile
dysfunction
patients. Alternatively, another class of drugs acting on another therapeutic
target can
be sought for treatment of erectile dysfunction in patients who are
unresponsive to
oral phosphodiesterase-5 inhibitor therapy. It would also be desirable to have
alterative treatments for patients suffering from additional co-morbid
conditions, such
as hypertension treated with alpha blockers, or angina treated with nitrates,
for which
for oral phosphodiesterase-5 inhibitor therapy is contraindicated or subject
to
warnings.
Prostaglandin E1 is a derivative of prostanoic acid, a 20-carbon atom lipid
acid, represented by the formula:
0
COOH
HO OH
and is commercially available, e.g., from Chinoin Pharmaceutical and
Chemical Works Ltd. (Budapest, Hungary) under the designation "Alprostadil
USP,"
and from Pharmacia & Upjohn under the designation "Caverject". Prostaglandin
E1
complexed with alpha-cyclodextrin is available as alprostatil alfadex from Ono
Pharmaceuticals (Japan) and in an injectable form under the designation
"Edex~" or
"Viradex~" from Schwarz Pharma (Germany).
In one commercially available dosage form (MUSE~, Vivus, Menlo Park
CA), alprostadil is administered in a pellet deposited in the urethra using an
applicator with a hollow stem 3.2 cm in length and 3.5 mm in diameter (Padma-
Nathan, H., et al., N. Engl. J. Med., 336: 1-7 (1997), see especially Fig. 1).
In the
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home treatment portion of the Padma-Nathan et al. study, 32.7% of the patients
(10.8% of administrations) receiving MUSE~ complained of penile pain and 5.1%
experienced minor urethral trauma, compared to 3.3% and 1.0%, respectively, of
the
patients receiving placebo. Frequency of report of these side effects has
varied in
subsequent studies: MUSE~ producing penile pain in 17-23.6% of
administrations,
compared to 1.7% with placebo and minor urethral bleeding reported by 4.8% of
patients (Peterson, C.A., et al., J. Urol., 159: 1523-1528 (1998)). In a study
on a
European population, 31% MLJSE~ patients reporting penile pain or burning
sensations, 4.8% reporting urethral bleeding, and 2.9% reporting severe
testicular
pain (Porst, H., Int. J. Impot. Res., 9:187-192 (1997)). The percent of
patients
responding to MUSE~ treatment, defined as having at least one erection
considered
sufficient for intercourse, has been reported to be 43% (Porst, 1997), 65.9%
(Padma-
Nathan et al., 1997) and 70.5% (Peterson et al., 1998), although published
editorial
comment has suggested that the percent of patients responding in the latter
two
studies is more properly reported as 30-40% (Benson, G., J. Urol., 159: 1527-
1528
(1998).
Intraurethral application of a preparation of 1 mg prostaglandin El in
phosphatidylcholine liposomes in 1 ml polyoxyethylene glycol has been reported
to
be less effective than intracavernosal injection of prostaglandin E1
(Englehardt, P.F.,
et al., British J. Urology, 81: 441-444, 1998). No ED patients receiving the
liposomal
preparation achieved complete penile rigidity, and only 6 of 25 patients
achieved an
erection adequate for vaginal penetration. In contrast, intracavernosal
injection of
prostaglandin E~ produced erections adequate for vaginal penetration or
complete
rigidity in 23 of 25 of the same ED patients. The authors suggested that the
transurethral effect of the prostaglandin E, probably arises by diffusion of
prostaglandin E~ first into the corpus spongiosum and then into the corpus
cavernosum.
While the above mechanical and pharmaceutical treatments have focused on
producing adequate penile rigidity, even when the treatments succeed in
producing
adequate rigidity, the satisfaction of the patient and the patient's sexual
partner is
often less than adequate. Patients discontinue medical treatments that produce
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rigidity, such as intracavenosal injections or transurethral suppositories
because of
painful side effects. Penile implants may produce rigidity, but insufficient
tumescence. In particular, lack of tumescence of the glans penis is a
recognized
source of dissatisfaction for both the patient and the sexual partner (See,
e.g., U.S.
Patent No 6,418,934; Chew & Stuckey, 2000).
SUMMARY OF THE INVENTION
The invention provides pharmaceutical methods for the treatment of erectile
dysfunction in a patient suffering from at a co-morbid condition comprising
placing
in the fossa navicularis of a patient in need of such treatment an erection-
inducing
amount of a semi-solid composition comprising a vasoactive prostaglandin and a
penetration enhancer. The co-morbid condition is at least one of diabetes
mellitus,
hypertension, cardiac disease, recovery from prostatectomy, or erectile
dysfunction
unresponsive to oral phosphodiesterase-5 inhibitor therapy.
In one preferred embodiment, the present invention provides methods for the
treatment of erectile dysfunction in an individual suffering from the co-
morbid
condition diabetes mellitus. In another preferred embodiment, the present
invention
provides methods for the treatment of erectile dysfunction in an individual
suffering
from the co-morbid condition hypertension. In yet another preferred
embodiment, the
present invention provides methods for the treatment of erectile dysfunction
in an
individual suffering from the co-morbid condition cardiac disease. In still
another
preferred embodiment, the present invention provides methods for the treatment
of
erectile dysfunction in an individual recovering from prostatectomy In a
further
preferred embodiment, the present invention provides methods for the treatment
of an
individual suffering from erectile dysfunction unresponsive to oral
phosphodiesterase-S inhibitor therapy.
A patient suffering from erectile dysfunction and at least one co-morbid
condition such as diabetes mellitus, hypertension, cardiac disease, recovery
from
prostatectomy or erectile dysfunction unresponsive to oral phosphodiesterase-5
inhibitor therapy can be effectively treated by placing in the fossa
navicularis of the
patient an erection inducing amount of a semi-solid vasoactive prostaglandin
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composition, which contains a dose of about 0.05 mg to about 0.8 mg of a
vasoactive
prostaglandin, a penetration enhancer, a polymeric thickener selected from the
group
consisting of a polysaccharide gum and a polyacrylic acid polymer, a
lipophilic
component that is selected from the group consisting of an aliphatic C~ to Cg
alcohol,
an aliphatic C8 to C3o ester, and a mixture thereof; and an acidic buffer
system. In a
preferred embodiment, the vasoactive prostaglandin is prostaglandin E~.
Preferably
the semi-solid composition is packaged in a unit dose and suitably the dose of
the
prostaglandin E~ is about 0.05 mg to about 0.8 mg per unit dose, preferably
about 0.1
mg to about 0.5 mg per unit dose. In another embodiment, the dose of the
prostaglandin E1 is about 0.1 mg to about 0.3 mg per unit dose.
A preferred penetration enhancer is an alkyl-2-(N-substituted amino)-
alkanoate ester, an (N-substituted amino)-alkanol alkanoate, or a mixture of
these.
The buffer system provides a buffered pH value for the composition in the
range of
about 3 to about 7.4. A preferred pH value is about 3 to about 6.5, most
preferably
from about 3.5 to about 6. If desired, stabilizers, preservatives and
emulsifiers may
be included. In some embodiments; the composition exhibits non-Newtonian
Theological properties, suitably comprising a shear-thinning polysaccharide
gum or a
shear-thinning polyacrylic acid polymer. In one embodiment, the composition is
thixotropic. In another embodiment, the composition is pseudoplastic. In a
preferred
embodiment, the composition has a viscosity of about 5,000 centipoise (cps) to
about
20,000 cps, more preferably from about 7,000 cps to about 13,000 cps.
A preferred pharmaceutical composition suitable for intranavicular
application comprises prostaglandin E1, a penetration enhancer, a modified
polysaccharide gum, a lipophilic compound, and an acidic buffer system. The
penetration enhancer is selected from the group consisting of an alkyl-2-(N-
substituted amino)-alkanoate, an alkyl-2-(N,N-disubstituted amino)-alkanoate,
an (N-
substituted amino)-alkanol alkanoate, an (N, N-disubstituted amino)-alkanol
alkanoate, pharmaceutically acceptable salts thereof and mixtures thereof. The
lipophilic compound may be an aliphatic C~ to Cg alcohol, an aliphatic C8 to
C3o
ester, or a mixture of these. If desired, stabilizers, preservatives and
emulsifiers may
be included.
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In another embodiment, the present invention provides for the use of a
composition comprising prostaglandin EI, a penetration enhancer, a shear-
thinning
polymer selected from the group consisting of a polysaccharide gum and a
polyacrylic
acid polymer, a lipophilic compound, and an acidic buffer system in the
manufacture
of a medicament for the treatment of erectile dysfunction in an individual
suffering
from at least one co-morbid condition such as diabetes mellitus, hypertension,
cardiac
disease, recovery from prostatectomy or erectile dysfunction unresponsive to
oral
phosphodiesterase-5 inhibitor therapy.
Compositions to be administered can take the form of a semi-solid suitable for
intranavicular application. In use as an intranavicular agent, these
compositions
provide effective prostaglandin penetration into the glans penis and produce
bioavailability without requiring a wasteful overloading prostaglandin
concentration
in the tissue. The compositions further exhibit reduced irritation,
sensitivity and
damage of local tissues. These pharmaceutical compositions are packaged
preferably
1 S in a single dose dispenser.
Other and further aims, purposes, features, advantages, embodiments and the
like will be apparent to those skilled in the art from the present
specification and the
appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
In the drawings,
Figure 1 is a diagram of the anatomical structure of the human penis in
longitudinal section view;
Figure 2 is a schematic diagram of the anatomical details of the distal
portion
of the human penis in longitudinal section; and
Figures 3A and 3B are schematic diagrams illustrating the method of
administrating the topical prostaglandin E1 composition. Figure 3A shows the
method of holding the meatus open by applying pressure to the glans on either
side of
the meatus, thereby spreading the meatus. Figure 3B shows the administration
of the
medication dropwise through the open meatus without inserting the tip of
applicator
or dispenser into the meatus.
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DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
It has been found that that a semi-solid prostaglandin E~ composition suitable
for the treatment of erectile dysfunction in the presence of a co-morbid
condition can
be placed advantageously in a natural enlarged space immediately proximal to
the
S penile meatus, the fossa navicularis. As used herein, "co-morbid" refers to
a medical
condition that is present in a patient who also suffers from erectile
dysfunction.
The fossa navicularis provides a restricted site that is ideally suited for
the
application of pharmaceutical compositions. The space is lined by a non-
keratinized
stratified squamous epithelium and is thereby distinguished from the surface
skin
covering the glans and the rest of the penis and from the stratified columnar
epithelium of the lining of the urethra proper. The lining of the fossa
navicularis thus
provides enhanced permeability compared to the keratinized epithelium of the
surface
skin of the outside of the penis. It has been found that the administration of
the
composition of the present invention in the fossa navicularis has high
efficacy and
low incidence of local side effects.
The fossa navicularis is a natural expanded chamber suitably adapted to
receive and retain semisolid medicaments. A semi-solid medicament, such as the
composition of the present invention, when placed in the fossa has higher
impedance
to flow at narrowed exits of this space, the meatus and the urethra. The
impedance to
flow is proportional to the product of the cross sectional area of the path
and the path
length. Thus, a semi-solid medication of suitably chosen viscosity is
naturally
retained within the fossa, facilitating the absorption of active agents such
as
vasodilators and the like. Viscosity of the composition suitably ranges from
about
5,000 cps to about 20,000 cps, preferably from about 7,000 cps to about 13,000
cps.
The fossa navicularis is part of the natural defense system that protects the
body against infection. The fossa navicularis is a more immunologically
protected
site than the adjacent pars spongiosa region of the penile urethra proper.
Depositing a
semisolid medicament within the anatomical limits of the fossa navicularis
thus does
not circumvent the natural barners to disease by artificially transporting
contaminants, e.g., from the surface of the penis, directly into the penile
urethra
proper. The relatively high glycogen content and bacterial flora within the
fossa
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navicularis provides a naturally lower pH within the space, so that relatively
lower
pH compositions in the acidic range that provide for enhanced solubility of
prostaglandin El can be more easily tolerated without excessive irritation of
the
tissues.
Semi-solid compositions and penetration enhancers suitable for the practice of
the present invention are described in detail in U.S. patents 6,046,244,
6,118,020 and
6,323,241, the teachings of which are incorporated herein by reference.
Referring to Figure 1, the basic structure of the human penis is illustrated.
The
fossa navicularis 110 in the glans penis 130 is a natural enlargement of the
lumen of
the male urethra. The fossa navicularis extends distally to the urethral
meatus 128
and proximally to the pendulous region of the urethra 112 (also termed "pars
spongiosa" region of the urethra), the portion of the urethra that passes
through the
corpus spongiosum 134 which is found within the shaft 104 of the penis medial
to the
paired corpora cavernosa 138. The bulbar urethra 114 is proximal to the
pendulous
region of the urethra, and passes through the bulbospongiosus muscle 140. More
proximally, the opening 148 in the wall of the urethra of the bulbourethral
glands
(Cowper's glands) can be seen. More proximally, the urethra passes through the
prostate gland 160, where openings of ejaculatory duct 156 and of the prostate
utricle
158 are visible in the wall of the urethra.
Refernng to Figure 2, the detailed structure of the fossa navicularis 110
within the glans penis 130 is illustrated. The external opening of the
urethral meatus
128 is the distal limit of the fossa navicularis. The external skin of the
glans is
covered by a keratinized stratified squamous epithelium 186 (Pudney, J., and
Anderson, D.J., (1995) Immunobiology of the human penile urethra, Amer. 3.
Path.,
147: 155-165) that is marked by proximally by a sharp transition (dashed line)
to the
nonkeratinized stratified squamous epithelium without glycogen 184 that is
characteristic of the lining of the distal fossa navicularis.
The fossa navicularis widens proximally and the lining changes to a
nonkeratinized stratified squamous epithelium with glycogen 182. The glycogen
in
this region is believed to support a bacterial flora that lowers the pH of the
region and
contributes to a natural defense against infection. Holstein, A.F., et al.,
(1991).
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Different epithelia in the distal human male urethra, Cell Tiss. Res. 264: 23-
32. This
nonkeratinized stratified squamous epithelium with glycogen is under hormonal
control, and increases in extent under increased estrogen levels (Holstein, et
al.,
1991). The proximal fossa navicularis narrows in width, and is lined by a
stratified
columnar epithelium 180.
The semi-solid composition has a suitably chosen viscosity such that the
composition is naturally retained within the fossa navicularis. The semi-solid
composition can exhibit Newtonian or non-Newtonian Theological
characteristics. In
some preferred embodiments, the semi-solid composition of the present
invention
exhibits non-Newtonian Theological characteristics, i.e. in which the apparent
viscosity is dependent on the shear rate applied to the composition.
Preferably the
composition has "shear-thinning" Theological properties. As used herein,
"shear-
thinning" refers to a reduction in apparent viscosity (the ratio of shear
stress to the
shear rate) with increasing shear rate, whether the reduction in apparent
viscosity is
1 S time independent (pseudoplastic), time dependent (thixotropic) or
associated with a
yield stress, defined as a stress that must be exceeded before flow starts,
(Bingham
plastics and generalized Bingham plastics). See, generally, Harris, J., &
Wilkinson,
W.L., "Non-newtonian Fluid," pp.856-858 in Parker, S.P., ed., McGraw-Hill
Encyclopedia of Physics, Second Edition, McGraw-Hill, New York,1993. A
suitable
viscosity range of the composition is from about 5,000 centipoise (cps) to
about
20,000 cps, preferably from about 7,000 cps to about 13,000 cps.
In a preferred embodiment, the pharmaceutical composition comprises at least
one vasoactive prostaglandin, preferably prostaglandin E,, an alkyl (N, N-
disubstituted amino) ester, a polysaccharide gum, a lipophilic component, and
an acid
buffer system. The prostaglandin can be dissolved or substantially uniformly
dispersed in the topical composition, preferably soluble (and dissolved) in
the topical
composition.
Vasoactive prostaglandins are those that act as peripheral vasodilators,
including naturally occurring prostaglandins such as PGE,, PGA~, PGB~, PGF~a,
19-
hydroxy-PGA~, 19-hydroxy-PGB~, PGEz, PGA2, PGB2, 19-hydroxy-PGAz, 19-
hydroxy-PGB2, PGE3, PGF3a; semisynthetic or synthetic derivatives of natural
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prostaglandins, including carboprost tromethamine, dinoprost tromethamine,
dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and tiaprost.
Prostaglandin E~ and prostaglandin EZ are particularly preferred vasoactive
prostaglandins for use in conjunction with the present method.
The quantity of vasoactive prostaglandin, such as prostaglandin E~, in the
pharmaceutical compositions of the present invention is a therapeutically
effective
(i.e., erection inducing) amount and necessarily varies according to the
particular
vasoactive prostaglandin to be delivered, the indication to be treated, the
surface area
of the skin and mucous membrane over which the formulation is to be placed,
the
other components of the composition, the desired dose, the dosage form (e.g.,
suppository or topical), and the particular form of the vasoactive
prostaglandin used.
The term "prostaglandin" as used generically herein refers to the
prostaglandin free
acid and pharmaceutically acceptable derivatives thereof, including e.g.,
prostaglandin E1 (PGE1), pharmaceutically acceptable salts and lower alkyl
esters
thereof (the term "lower alkyl" as used herein means straight chain or
branched chain
alkyl containing one to four carbon atoms). The composition generally contains
about 0.001 weight percent to 1 weight percent prostaglandin El, typically
contains
about 0.05 weight percent to 1 weight percent prostaglandin E~, preferably
about 0.1
weight percent to 0.5 weight percent, based on the total weight of the
composition. In
one embodiment, prostaglandin E1 is present in the composition in an amount of
about 0.07 weight percent of the total composition to about 0.4 weight percent
of the
total composition.
Prostaglandin E1 is well known to those skilled in the art. Accordingly, it is
not practical to enumerate particular preferred amounts but such can be
readily
determined by those skilled in the art with due consideration of the factors
listed
above. Reference may be had to various literature references for its
pharmacological
activities, side effects, and normal dosage ranges. See for example,
Physician's Desk
Reference, 51st Ed. (1997), The Mercklndex, 12th Ed., Merck & Co., N.J.
(1996),
and Martindale The Extra Pharmacopoeia, 28th Ed., London, The Pharmaceutical
Press (1982).
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Additionally, simultaneous administration of one or more non-ecosanoid
vasodilators may be desirable and may in some cases exhibit a synergistic
effect. The
combination of prazosin with prostaglandin E1 has been found to be
particularly
advantageous in this regard; the latter drug appears to act as a potentiator
for
prazosin.
Suitable non-ecosanoid vasodilators include, but are not limited to: nitrates
such as nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl
nitrate, sodium
nitroprusside, molsidomine, linsidomine chlorhydrate ("SIN-1") and S-nitroso-N-
acetyl-d,l-penicillamine ("SNAP"); amino acids such as L-arginine; long and
short
acting a-adrenergic Mockers such as phenoxybenzamine, dibenamine,
phentolamine,
tamsulosin and indoramin, especially quinazoline derivatives such as
alfuzosin,
bunazosin, doxazosin, terazosin, prazosin, and trimazosin; vasodilative
natural herbal
compositions and bioactive extracts thereof, such as gosyajinki-gan, Satureia
obovata,
bai-hua qian-hu, lipotab, saiboku-to, vinpocetine, Gi~ko biloba, bacopa,
Gynostemma~entaphyllum, gypenosides, Evodia rutaecama, rutaecarpine,
dehydroevodiamine, dan-shen, salviae miltiorrhizae radix, shosaikoto, Zizyphi
fructus, ginseng and mixtures thereof (U.S. Patent 6,007,$24); ergot alkaloids
such as
ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline,
bromerguride,
cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine
tartrate,
etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine,
nicergoline, pergolide, propisergide, proterguride and terguride;
antihypertensive
agents such as diazoxide, hydralazine and minoxidil; vasodilators such as
nimodepine, pinacidil, cyclandelate, dipyridamole and isoxsuprine;
chlorpromazine;
haloperidol; yohimbine; trazodone and vasoactive intestinal peptides.
When used in combination with a vasoactive prostaglandin, a piperazinyl
quinazoline antihypertensive, such as prazosin, is present in the amount of
about 0.1
mg to about 2.0 mg per unit dose, depending on the potency of the particular
piperazinyl quinazoline antihypertensive and the type and dose of vasoactive
prostaglandin used. The dose and the proportion of vasoactive prostaglandin
and the
piperazinyl quinazoline antihypertensive can be routinely determined by one of
ordinary skill without undo experimentation.
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The topical composition can contain one or more penetration enhancers.
Among the preferred penetration enhancers for the present invention are
ethanol,
propylene glycol, glycerol, ethyl laurate, isopropyl palmitate, isopropyl
myristate,
laurocapram (AzoneTM ), dioxolanes (described in U.S. Patent No. 4,861,764),
macrocyclic ketones, HP-101, oxazolidones and biodegradable penetration
enhancers
(described in U.S. Patents Nos. 4,980,378 and 5,082,866 to Wong et al. and
U.S.
Patent Number 6,118,020 to Buyuktimkin et al. such as alkyl-2-(N-substituted
amino)
alkanoates, alkyl-2-(N, N-disubstituted amino) alkanoates (e.g., dodecyl N,N-
dimethylamino isoproprionate (DDAIP)), N-substituted amino alkanol
alkanoates),
N, N-disubstituted amino alkanol alkanoates, acid addition salts and mixtures
thereof.
For example, the preparation of crystalline acid addition salts of DDAIP by
cooled
mixing of DDAIP with one of a select group of acids in the presence of a water-
immiscible solvent such as hexane, is disclosed in U.S. Patent Number
6,118,020, the
contents of which are incorporated herein by reference in their entirety. Acid
addition
salts of dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) can be inorganic as
well as organic. Representative inorganic acid addition salts include the
hydrochloric,
hydrobromic, sulfuric, phosphoric, nitric acid addition salts of DDAIP, and
their
solvates. Exemplary organic acid addition salts include acetic, benzoic,
salicylic,
glycolic, succinic, nicotinic, tartaric, malefic, malic, palmoic,
methanesulfonic,
cyclohexanesulfamic, picric, and lactic acid addition salts, as well as their
respective
solvates. Preferred among the inorganic acid addition salts are DDAIP hydrogen
chloride, and DDAIP dihydrogen sulfate.
The penetration enhancer is present in an amount sufficient to enhance the
penetration of the prostaglandin E~. The specific amount varies necessarily
according
to the desired release,rate and the specific form of prostaglandin E~ used.
Generally,
the penetration enhancer is present in an amount ranging from about 0.5 weight
percent to about 20 weight percent, based on the total weight of the
composition.
Preferably, the penetration enhancer is present in an amount ranging from
about 1
weight percent to about 10 weight percent of the composition. More preferably,
the
penetration enhancer is present in an amount ranging from about 1 weight
percent to
about 5 weight percent of the composition.
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In general, suitable penetration enhancers can be chosen from those listed
above as well as sulfoxides, alcohols, fatty acids, fatty acid esters,
polyols, amides,
surfactants, terpenes, alkanones, organic acids and mixtures thereof. See
generally
Chattaraj, S.C. and Walker, R.B., Penetration Enhancer Classification, pp.5-20
in
Maibach, H.L, and Smith, H.E., (eds.), Percutaneous Penetration Enhancers, CRC
Press, Inc., Boca Raton, FL (1995) and Buyuktimkin, N., et al., Chemical Means
of
Transdermal Drug Permeation Enhancement, in Gosh, T.K., et al., (eds.)
Transdermal
and Topical Drug Delivery Systems, Interpharm Press, Inc., Buffalo Grove, IL
(1997). Suitable sulfoxides include dimethylsulfoxide, decylmethylsulfoxide
and
mixtures thereof. Suitable alcohols include ethanol, propanol, butanol,
pentanol,
hexanol, octanol, nonanol, decanol, 2-butanol, 2-pentanol, benzyl alcohol,
caprylic
alcohol, decyl alcohol, lauryl alcohol, 2-lauryl alcohol, myristyl alcohol,
cetyl
alcohol, stearyl alcohol, olcyl alcohol, linolyl alcohol, linolenyl alcohol
and mixtures
thereof. Suitable fatty acids include valeric, heptanoic, pelargonic, caproic,
capric,
lauric, myristic, stearic, oleic, linoleic, linolenic, caprylic, isovaleric,
neopentanoic,
neoheptanoic, neononanoic, trimethyl hexanoic, neodecanoic and isostearic
acids and
mixtures thereof.
Suitable fatty acid esters include isopropyl n-butyrate, isopropyl n-
hexanoate,
isopropyl n-decanoate, isopropyl myristate, isopropyl palmitate, octyldodecyl
myristate, ethyl acetate, butyl acetate, methyl acetate, methylvalerate,
methylpropionate, diethyl sebacate, ethyl oleate, ethyl laurate and mixtures
thereof.
Suitable polyols include propylene glycol, polyethylene glycol, ethylene
glycol,
diethylene glycol, triethylene glycol, dipropylene glycol, glycerol,
propanediol,
sorbitol, dextrans, butanediol, pentanediol, hexanetriol and mixtures thereof.
Suitable amides include urea, dimethylacetamide, diethyltoluamide,
dimethylformamide, dimethyloctamide, dimethyldecamide, 1-alkyl-4-imidazolin-2-
one, pyrrolidone derivatives, cyclic amides, hexamethylenelauramide and its
derivatives, diethanolamine, triethanolamine and mixtures thereof. Suitable
pyrrolidone derivatives include 1-methyl-2-pyrrolidone, 2-pyrrolidone, 1-
lauryl-2-
pyrrolidone, 1-methyl-4-carboxy-2-pyrrolidone, 1-hexyl-4-carboxy-2-
pyrrolidone, 1-
lauryl-4-carboxy-2-pyrrolidone, 1-decyl-thioethyl-2-pyrrolidone (HP-101), 1-
methyl-
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4-methoxycarbonyl-2-pyrrolidone, 1-hexyl-4-methoxycarbonyl-2-pyrrolidone, 1-
lauryl-4-methoxycarbonyl-2-pyrrolidone, N-cyclohexylpyrrolidone, N-
dimethylaminopropylpyrrolidone, N-cocoalkypyrrolidone, N-
tallowalkypyrrolidone,
fatty acid esters of N-(2-hydroxymethyl)-2-pyrrolidone and mixtures thereof.
Suitable cyclic amides include 1-dodecylazacycloheptane-2-one (laurocapram,
AzoneTM), 1-geranylazacycloheptan-2-one, 1-farnesylazacycloheptan-2-one, 1-
geranylgeranylazacycloheptan-2-one, 1-(3,7-dimethyloctyl)azacycloheptan-2-one,
1-
(3,7,11-trimethyloctyl)azacycloheptan-2-one, 1-geranylazacyclohexane-2-one, 1-
geranylazacyclopentan-2,5-dione, 1-farnesylazacyclopentan-2-one and mixtures
thereof.
Suitable surfactants include anionic surfactants, cationic surfactants,
nonionic
surfactants, bile salts and lecithin. Suitable anionic surfactants include
sodium
laurate, sodium lauryl sulfate and mixtures thereof. Suitable cationic
surfactants
include cetyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,
benzalkonium chloride, octadecyltrimethylammonium chloride, cetylpyridinium
chloride, dodecyltrimethylammonium chloride, hexadecyltrimethylammonium
chloride, and mixtures thereof. Suitable nonionic surfactants include a hydro-
c~-
hydroxy- poly(oxyethylene)-poly(oxypropyl) poly(oxyethylene)block copolymers,
polyoxyethylene ethers, polyoxyethylene sorbitan esters, polyethylene glycol
esters of
fatty alcohols and mixtures thereof. Suitable a hydro-W-hydroxy-
poly(oxyethylene)-
poly(oxypropyl) poly(oxyethylene)block copolymers include Poloxamers 231, 182,
and 184 and mixtures thereof. Suitable polyoxyethylene ethers include 4-lauryl
ether
(BRIJ 30TM), (BRIJ 93TM), (BRIJ 96TM), 20-oleyl ether (BRIJ 99TM) and mixtures
thereof. Suitable polyoxyethylene sorbitan esters include the monolaurate
(TWEEN
20TM, SPAN 20TM) the monopalmitate (TWEEN 40TM), the monostearate (TWEEN
60TM), and the monooleate (TWEEN 80TM) and mixtures thereof. Suitable
polyethylene glycol esters of fatty acids include the 8-oxyethylene stearate
ester
(MYRJ 45TM), (MYRJ S 1 TM), the 40-oxyethylene stearate ester (MYRJ 52TM) and
mixtures thereof. Suitable bile salts include sodium cholate, sodium salts of
laurocholic, glycolic and desoxycholic acids and mixtures thereof.
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Suitable terpenes include D-limonene, a-pinene, (3-enrene, a-terpineol,
terpinen-4-ol, carvol, carvone, pulegone, piperitone, menthone, menthol,
geraniol,
cyclohexene oxide, limonene oxide, a-pinene oxide, cyclopentene oxide, 1,8-
cineole,
ylang ylang oil, anise oil, chenopodium oil, eucalyptus oil and mixtures
thereof.
Suitable alkanones include N-heptane, N-octane, N-nonane, N-decane, N-
undecane,
N-dodecane, N-tridecane, N-tetradecane, N-hexadecane and mixtures thereof.
Suitable organic acids include citric acid, succinic acid, salicylic acid,
salicylates
(including the methyl, ethyl and propyl glycol derivatives), tartaric acid and
mixtures
thereof.
Natural and modified polysaccharide gums are also an important ingredient of
the composition. Suitable representative gums are those in the natural and
modified
galactomannan gum category. A galactomannan gum is a carbohydrate polymer
containing D-galactose and D-mannose units, or other derivatives of such a
polymer.
There is a relatively large number of galactomannans, which vary in
composition
depending on their origin. The galactomannan gum is characterized by a linear
structure of (3-D-mannopyranosyl units linked (1~4). Single membered
oc-D-manopyranosyl units, linked (1-~6) with the main chain, are present as
side
branches. Galactomannan gums include guar gum, which is the pulverized
endosperm of the seed of either of two leguminous plants (Cyamposis
tetragonalobus
and psoraloids) and locust bean gum, which is found in the endosperm of the
seeds
of the carobtree (ceratonia siliqua). Suitable modified polysaccharide gums
include
ethers of natural or substituted polysaccharide gums, such as carboxymethyl
ethers,
ethylene glycol ethers and propylene glycol ethers. An exemplary substituted
polysaccharide gum is methylcellulose. A preferred modified galactomannan gum
is
modified guar gum.
Other suitable representative gums include agar gum, carrageenan gum, ghatti
gum, karaya gum, rhamsan gum and xanthan gum. The composition of the present
invention may contain a mixture of various gums, or mixture of gums and acidic
polymers.
Gums, and galactomannan gums in particular, are well-known materials. See
for instance, Industrial Gums: Polysaccharides & Their Derivatives, Whistler
R. L.
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and BeMiller J.N. (eds.), 3rd Ed. Academic Press (1992) and Davidson R. L.,
Handbook of Water-Soluble Gums & Resins, McGraw-Hill, Inc., N.Y. (1980). Most
gums are commercially available in various forms, commonly a powder, and ready
for use in foods and topical compositions. For example, locust bean gum in
powdered form is available from Tic Gums Inc. (Belcam, MD).
When present, the polysaccharide gums are present in the range from about
0.1 percent to about 5 percent, based on the total weight of the composition,
with the
preferred range being from 0.5 percent to 3 percent. In one preferred
embodiment, 2.5
percent by weight of a polysaccharide gum is present. Illustrative
compositions are
given in the examples, below.
An optional alternative to the polysaccharide gum is a polyacrylic acid
polymer. A common variety of polyacrylic acid polymer is known generically as
"carbomer." Carbomer is polyacrylic acid polymers lightly cross-linked with
polyalkenyl polyether. It is commercially available from the B. F. Goodrich
Company (Akron, Ohio) under the designation "CARBOPOLT"~." A particularly
preferred variety of carbomer is that designated as "CARBOPOL 940."
Other polyacrylic acid polymers suitable for use are those commercially
available under the designations "PemulenT""" (B. F. Goodrich Company) and
"POLYCARBOPHIL~~M" (A.H. Robbins, Richmond, VA). The PemulenT~" polymers
are copolymers of C~o to C3o alkyl acrylates and one or more monomers of
acrylic
acid, methacrylic acid or one of their simple esters crosslinked with an allyl
ether of
sucrose or an allyl ether of pentaerythritol. The POLYCARBOPHILTM enhancer is
a
polyacrylic acid cross-linked with divinyl glycol.
Where polyacrylic acid polymers are present, they represent about 0.5 percent
to about S percent of the composition, based on its total weight.
Another important component is a lipophilic component. As used herein
"lipophilic component" refers to an agent that is both lipophilic and
hydrophilic. One
of ordinary skill in the pharmaceutical arts will understand that the
lipophilic nature,
or "lipophilicity" of a given compound is routinely quantified for comparison
to other
compounds by using the partition coefficient. The partition coefficient is
defined by
the International Union of Pure and Applied Chemistry (ICTPAC) as the ratio of
the
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distribution of a substance between two phases when the heterogeneous system
(of
two phases) is in equilibrium; the ratio of concentrations (or, strictly
speaking,
activities) of the same molecular species in the two phases is constant at
constant
temperature.
The Cl to C8 aliphatic alcohols, the C2 to C3o aliphatic esters, and their
mixtures can serve as lipophilic component. Illustrative suitable alcohols are
ethanol,
n-propanol and isopropanol, while suitable esters are ethyl acetate, butyl
acetate, ethyl
laurate, methyl propionate, isopropyl myristate and isopropyl palmitate. As
used
herein, the term "aliphatic alcohol" includes polyols such as glycerol,
propylene
glycol and polyethylene glycols. In one embodiment, a mixture of alcohol and
ester
is preferred, and in particular, a mixture of ethanol and ethyl laurate is
preferred.
In one embodiment, the Cz to C3o aliphatic esters, and their mixtures
comprising the lipophilic component include C$ to C3o aliphatic esters of
glycerol
selected from the group consisting monoglycerides, diglycerides,
triglycerides, and
mixtures thereof. Suitable aliphatic esters include glyceryl esters of
saturated fatty
acids, unsaturated fatty acids and mixtures thereof. Suitable saturated fatty
acids
include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid,
palmitic
acid, stearic acid, arachidic acid, behenic acid and lignoceric acid. Suitable
unsaturated fatty acids include oleic acid, linoleic acid and linolenic acid.
Suitable
glyceryl esters include glyceryl monooleate, triolein, trimyristin and
tristearin,
perferably trimyristin.
The concentration of lipophilic component required necessarily varies
according to other factors such as the desired semi-solid consistency and the
desired
skin penetration promoting effects. Suitably the concentration of lipophilic
component is in the range of 0.5 percent to 40 percent by weight based on the
total
weight of the composition. The preferred topical composition contains
lipophilic
component in the range of 7 percent to 40 percent by weight based on the total
weight
of the composition.
Where a mixture of aliphatic alcohol and aliphatic ester are employed, the
suitable amount of alcohol is in the range of 0.5 percent to 10 percent. In
one
preferred embodiment, the amount of alcohol is in the range of 5 percent to 1
S
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percent, while that of aliphatic ester is in the range from 2 percent to 15
percent
(again based on the total weight of the composition). In another preferred
embodiment, the amount of alcohol is in the range of 0.5 percent to 10
percent, while
that of aliphatic ester is in the range from 0 percent to 10 percent (again
based on the
S total weight of the composition).
The concentration of lipophilic component required necessarily varies
according to other factors such as the desired semi-solid consistency and the
desired
skin penetration promoting effects. The preferred topical composition contains
lipophilic component in the range of 7 percent to 40 percent by weight based
on the
total weight of the composition. Where a lipophilic component that is a
mixture of
aliphatic alcohol and aliphatic ester is used, the preferred amount of alcohol
is in the
range of S percent to 1 S percent, while that of aliphatic ester is in the
range from 2
percent to 15 percent (again based on the total weight of the composition).
An optional, but preferred, component is an emulsifier. Although not a
1 S critical factor, a suitable emulsifier generally will exhibit a
hydrophilic-lipophilic
balance number greater than 10. Sucrose esters, and specifically sucrose
stearate, can
serve as emulsifiers for the composition. Sucrose stearate is a well-known
emulsifier
available from various commercial sources. When an emulsifier is used, sucrose
stearate present up to about 2 percent, based on the total weight of the
composition, is
preferred. The preferred amount of sucrose stearate emulsifier can also be
expressed
as a weight ratio of emulsifier to polysaccharide gum. A ratio of 1 to 6
emulsifier to
gum is preferred, and a ratio of 1 to 4 is most preferred to generate the
desired semi-
solid consistency and separation resistance.
Other emulsifiers are also suitable including polyoxyethylene sorbitan esters,
long chain alcohols, preferably cetostearyl alcohol, and fatty acid
glycerides. Suitable
polyoxyethylene sorbitan esters include the monolaurate (Tween 20TM, Span
20TM)
the monopalmitate (Tween 40TM), the monostearate (Tween 60TM), and the
monooleate (Tween 80TM) and mixtures thereof. Preferred fatty acid glycerides
include glyceryl monooleate, triolein, trimyristin and tristearin.
The composition includes an acid buffer system. Acid buffer systems serve to
maintain or buffer the pH of compositions within a desired range. The term
"buffer
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system" or "buffer" as used herein has reference to a solute agent or agents
which,
when in a water solution, stabilize such solution against a major change in pH
(or
hydrogen ion concentration or activity) when acids or bases are added thereto.
Solute
agent or agents which are thus responsible for a resistance to change in pH
from a
starting buffered pH value in the range indicated above are well known. While
there
are countless suitable buffers, potassium phosphate monohydrate has proven
effective
for compositions of the present invention.
The final pH value of the pharmaceutical composition may vary within the
physiologically compatible range. Necessarily, the final pH value is not
irritating to
human skin. Without violating this constraint, the pH may be selected to
improve
prostaglandin E~ stability and to adjust consistency when required. In one
embodiment, the preferred pH value is about 3 to about 7.4, more preferably
about 3
to about 6.5, most preferably from about 3.5 to about 6.
The remaining component of the composition is water, which is necessarily
purified. The composition contains water in the range of about SO to about 90
percent, based on the total weight of the composition. The specific amount of
water
present is not critical, however, being adjustable to obtain the desired
consistency
and/or concentration of the other components.
Prostaglandin E~ stabilizers, coloring agents, Theological agents, and
preservatives can be added to the extent that they do not overly limit
prostaglandin El
skin penetration or prevent the desired semi-solid consistency.
Contemplated dosage forms of the semi-solid pharmaceutical composition are
creams, gels, ointments, colloidal suspensions and the like, also including
but not
limited to compositions suitable for use with transdermal patches and like
devices.
The ingredients listed above may be combined in any order and manner that
produces a stable composition comprising a prostaglandin E~ evenly dispersed
throughout a semi-solid formulation. One available approach to preparing such
compositions involves evenly dispersing the polysaccharide gum (or polyacrylic
acid
polymer) in a premixed water/buffer solution and then thoroughly homogenizing
(i.e.
mixing) the resulting mixture, which will be referred to as "Part A." When
present,
the emulsifier is added to the water/buffer solution before dispersing the
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polysaccharide gum. Any suitable method of adjusting the pH value of Part A to
the
desired level may be used, for example, by adding concentrated phosphoric acid
or
sodium hydroxide.
Separately, the prostaglandin E~ is dissolved with agitation in the lipophilic
component, which itself may be a mixture of alcohols, esters, or alcohol with
ester.
Next, the penetration enhancer is added. Alternatively, when the lipophilic
component includes both an alcohol and an ester, the prostaglandin E~ can be
dissolved in the alcohol before adding the penetration enhancer followed by
the ester.
In either case, the resulting mixture will be referred to as "Part B." The
final step
involves slow addition (e.g. dropwise) of Part B into Part A under constant
mixing.
The resulting topical composition, when compared to exhibits the
advantageous properties described above, including improved prostaglandin EI
permeation and bioavailability without drug overloading, reduced skin damage
and
related inflammation, and increased flexibility in design of dosage forms.
These
compositions can be used for prolonged treatment of peripheral vascular
disease,
male impotency and other disorders treated by prostaglandin El, while avoiding
the
low bioavailability and rapid chemical decomposition associated with other
delivery
methods. Application of prostaglandin E, in a topical composition to the skin
of a
patient allows a predetermined amount of prostaglandin E1 to be administered
continuously to the patient and avoids undesirable effects present with a
single or
multiple administrations of larger dosages by injection. By maintaining a
sustained
dosage rate, the prostaglandin E~ level in the patient's target tissue can be
better
maintained within the optimal therapeutic range.
In one embodiment, a composition comprises about 0.01 percent to about 5
percent modified polysaccharide gum; about 0.001 percent to about 1 percent of
a
prostaglandin selected from the group consisting of PGE1, pharmaceutically
acceptable salts thereof, lower alkyl esters thereof and mixtures thereof;
about 0.5
percent to about 10 percent DDAIP or salts thereof; about 0.5 percent to about
10
percent of a lower alcohol selected from the group consisting of ethanol,
propanol,
isopropanol and mixtures thereof; about 0.5 percent to about 10 percent on an
ester
selected from the group consisting of ethyl laurate, isopropyl myristate,
isopropyl
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laurate and mixtures thereof; based on the weight of the composition, and an
acid
buffer. Preferably the composition also comprises up to about 2 percent
sucrose
stearate.
Optionally the composition also comprises up to about 5 percent emulsifier.
Preferably, the composition also comprises up to about 2 percent emulsifier.
Suitable
emulsifiers include polysorbates such as Tweens, glyceryl monooleate,
triolein,
trimyristin and tristearin. A preferred emulsifier is trimyristin.
The practice of the present invention is demonstrated in the following
examples. These examples are meant to illustrate the invention rather than to
limit its
scope. Variations in the treating compositions which do not adversely affect
the
effectiveness of prostaglandin El will be evident to one skilled in the art,
and are
within the scope of this invention. For example, additional ingredients such
as
coloring agents, anti-microbial preservatives, emulsifiers, perfumes,
prostaglandin EI
stabilizers, and the like may be included in the compositions as long as the
resulting
composition retains desirable properties, as described above. When present,
preservatives are usually added in amounts of about 0.05 to about 0.30%.
Suitable
preservatives include methylparabens (methyl PABA), propylparabens (propyl
PABA) and butylhydroxy toluene (BHT). Suitable perfumes and fragrances are
known in the art; a suitable fragrance is up to about 5 percent myrtenol,
preferably
about 2 percent myrtenol, based on the total weight of the composition. The
compositions of the present invention can also include a small amount, about
0.01 to
about 4% by weight, of a topical anesthetic, if desired. Typical topical
anesthetics
include lidocaine, dyclonine, dibucaine, pharmaceutically acceptable salts and
mixtures thereof. In one preferred embodiment, the topical anesthetic is about
0.5
percent dyclonine, based on the weight of the composition.
The pharmaceutical preparation is preferably in unit dosage form. In such
form the preparation is subdivided into unit doses containing appropriate
quantities of
the active component. The unit dosage form is a packaged preparation, where
the
package containing the discrete quantities of the pharmaceutical preparation
is, e.g. a
rigid plastic dispenser or flexible packet.
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Another aspect of the invention is an article of manufacture that comprises a
composition for treating erectile dysfunction as described above in a suitable
container, preferably in a container such as the dispenser disclosed in U.S.
Patent No.
6,224,573, in combination with labeling instructions. Alternatively, the
container can
be a tube with a suitable orifice size, such as an extended tip tube, pouch,
packet, or
squeeze bottle and made of any suitable material, for example rigid plastic or
flexible
plastic.
The labeling instructions can come in the form of a pamphlet, a label applied
to or associated with the packaging of the article of manufacture.
The labeling instructions provide for administering a composition of the
invention to the fossa navicularis of the penis of a patient suffering from
erectile
dysfunction, directing the patient to hold the penis upright, hold the meatus
open and
place the composition in the fossa navicularis without introducing the tip of
the
container into the meatus, about 5-30 minutes before sexual intercourse, see
Figures
3A-3B. Printed labeling instructions are functionally related to the
composition of
the invention inasmuch as such labeling instructions describe a method to
treat
erectile dysfunction according to the present invention. The labeling
instructions are
an important aspect of the invention in that before a composition can be
approved for
any particular use, it must be approved for marketing by the responsible
national
regulatory agency, such as the United States Food and Drug Administration.
Part of
that process includes providing a label that will accompany the pharmaceutical
composition which is ultimately sold. While the label will include a
definition of the
composition and such other items such as the clinical pharmacology, mechanism
of
action, drug resistance, pharmacokinetics, absorption, bioavailability,
contraindications and the like, it will also provide the necessary dosage,
administration and usage. Thus, the combination of the composition with the
dispenser with appropriate treatment instructions is important for the proper
usage of
the drug once it is marketed to the patient. Such treatment instructions will
describe
the usage in accordance with the method of treatment set forth herein before.
The quantity of active component in a unit dose preparation may be varied or
adjusted from 0.01 mg to 1 g according to the particular application and the
potency
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of the vasoactive prostaglandin. For example, where the vasoactive
prostaglandin is
prostaglandin E~, about 0.05 mg to about 0.8 mg prostaglandin El is present
per unit
dose, preferably about 0.1 mg to about 0.5 mg per unit dose and in another
embodiment, about 0.1 mg to about 0.3 mg per unit dose. The composition can,
if
desired, also contain other compatible therapeutic agents, such as a
piperazinyl
quinazoline antihypertensive.
For "on demand" treatment, the semi-solid vasoactive prostaglandin
composition should be applied to the fossa navicularis of the penis about 2-30
minutes before sexual intercourse, preferably about 5-15 minutes before sexual
intercourse. In some embodiments, a regular regimen of treatment not
necessarily
linked to anticipated sessions of sexual intercourse can be undertaken. In
such
embodiments, the semi-solid vasoactive prostaglandin composition can be
applied to
the fossa navicularis of the penis at least twice a week, preferably every
other day, or
on a daily basis.
Unless otherwise indicated, each composition is prepared by conventionally
admixing the respective indicated components together.
EXAMPLE 1: Topical Prostaglandin EI Composition A
Composition A was prepared as follows. Part A of the composition was
formed by dissolving 0.4 parts by weight prostaglandin E, (Alprostadil USP) in
S
parts by weight ethyl alcohol. Next, S parts by weight dodecyl 2-(N,N-
dimethylamino)-propionate were mixed into the alcohol-prostaglandin E1
solution,
followed by 5 parts by weight ethyl laurate.
Part B was prepared starting from a pH 5.5 water/buffer solution. The
water/buffer solution was prepared by adding sufficient potassium phosphate
monohydride to purified water to create a 0.1 M solution. The pH of the
water/buffer
solution was adjusted to 5.5 with a strong base solution (1 N sodium
hydroxide) and a
strong acid (1 N phosphoric acid). The buffer solution represented about 80
parts of
the total composition. All parts specified herein are parts by weight.
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Ethyl laurate, 0.5 parts by weight, was added to the buffer solution. Next,
the
locust bean gum (in powder form) was dispersed in the buffer solution and
homogenized using a homogenizer. Table 1, below, contains a list of the
ingredients.
The resulting composition was a spreadable, semi-solid preparation suitable
for application to the skin without the need for supporting devices such as
patches
and adhesive strips. The composition was both homogenous in appearance and
resistant to separation.
Additional exemplary compositions B - H were prepared in the same manner
using the components listed in Table 1. As noted above, in other embodiments,
such
as Composition H, the composition may include a modified polysaccharide gum,
suitably a modified galactomannan gum, such as a guar gum. Alternatively, a
polyacrylic polymer may be used instead of the polysaccharide gum.
Composition A was evaluated for skin penetration using shed snake skin as a
model barrier. Shed snake skin was obtained from the Animal Care Unit of the
1 S University of Kansas. With head and tail sections removed, the skin was
randomly
divided into test sections and then hydrated by soaking.
The samples were then evaluated using Franz-type Diffusion Cells (surface
area 1.8 cmz). Specifically, skin pieces were mounted on top of a receptor
cell of a
vertical diffusion cell assembly in which a small magnetic bar was inserted
and filled
with an isotonic buffer. A seal was placed on top of the skin section followed
by a
donor cell. The two cells were clamped together. Known amounts of the
formulations were applied on the bottom of a small capped vial (weight 0.5
grams)
which fits exactly to the donor cell to ensure uniform distribution. The vials
were
placed on the skin in the donor cell. To reduce the evaporation of the
ingredients, the
donor cell and vial were taped together with a water-resistant adhesive band.
The
cells were transferred to a stirred water bath (32 degrees Celsius). Samples
were
withdrawn from the cells each hour for four hours and analyzed for the
concentration
of prostaglandin E~, with changes in concentration indicating the amount
penetrating.
Tests with multiple skin samples yielded data that were averaged. For a
discussion of
the use of shed snake skin in the evaluation of drug penetration, see U.S.
Patent No.
4,771,004 to Higuchi, which is incorporated here by reference.
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The prostaglandin E~ penetrated quickly at a relatively sustained rate for
four
hours. The results of the penetration study are presented in Table 2, below.
EXAMPLE 2: Topical Prostaglandin E~ Composition B
Composition B was prepared using the ingredients listed in Table 1, below.
Composition B contained more prostaglandin E~ than Composition A. Despite this
increased drug loading, Composition B exhibited a similar semi-solid
consistency and
homogenous appearance. The penetration of prostaglandin E1 was measured
according to the technique described in Example 1. Composition B provided a
relatively fast, sustained delivery of prostaglandin E~ . The results are
presented in
Table 2.
EXAMPLE 3: Topical Prostaglandin E~ Composition C
Composition C was prepared using the ingredients listed in Table l, below.
Composition B contained more prostaglandin E, than either Composition A or B.
The increased drug loading had little or no effect on the consistency or
appearance,
which substantially matched that of Compositions A and B. The penetration of
prostaglandin E~ was again measured according to the technique described in
Example 1. According to this test, Composition C also provided a relatively
fast,
sustained delivery of prostaglandin E~. The results are presented in Table 2,
below.
EXAMPLE 4: Topical Prostaglandin E~ Composition D
Composition D was prepared using the ingredients listed in Table 1, below.
The level of prostaglandin E1 was again increased without substantially
affecting the
favorable consistency and separation resistance. The penetration of
prostaglandin E~
was again measured according to the technique described in Example 1. The
results
are presented in Table 2, below.
EXAMPLE 5: Topical Prostaglandin E~ Composition E
Composition E was prepared using the ingredients listed in Table 1, below.
To assess the repeatability of compositions according to the present
invention, the
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recipe of Composition D was again applied for Composition E. Repeatability was
substantially confirmed by Composition E's favorable, semi-solid consistency
and
separation resistance. The penetration of prostaglandin E~ was again measured
according to the technique described in Example 1. The prostaglandin E~
delivery
from Composition E was again relatively fast and sustained. The results are
presented in Table 2, below.
EXAMPLE 6: Topical Prostaglandin E1 Composition F
The level of prostaglandin EI was again increased for Composition F. The
specific ingredients are listed in Table 1. The favorable consistency and
separation
resistance was undiminished. The results of a penetration analysis are
presented in
Table 2, below.
EXAMPLE 7: Topical Prostaglandin E1 Composition G
Composition G was prepared using the ingredients listed in Table 1. For
Composition G, the recipe of Composition F was repeated except that the ester
component (ethyl laurate) was omitted and the level of ethanol was increased a
corresponding amount. The resulting composition was also a spreadable, semi-
solid
having a homogenous appearance and resistance to separation. The results of a
penetration analysis are presented in Table 2, below. While still favorable,
these
results reflect the relative benefit to compositions of the present invention
from a
lipophilic compound that includes both an ester component and an alcohol
component.
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Table 1: Topical Prostaglandin E~ Compositions
Ingredient (wt%) A B C D E F G H I
prehydrated locust bean gum 3 3 3 3 3 3 3 - -
prehydrated modified guar gum - - - - - - - 3 2.5
water/buffer (pH 5.5) 81 81 81 81 81 81 81 81 86.8
sucrose stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 -
prostaglandin E~ 0.1 0.2 0.3 0.4 0.4 0.5 0.4 0.3 0.2
DDAIP 5 5 5 5 5 5 5 2.5
DDAIP HCI - - - - - - - - 2.5
ethanol 5 5 5 5 5 5 10 5 5
ethyllaurate 5 5 5 5 5 5 - 3 3
EXAMPLE 8: Comparison of Penetration Profiles
Table 2 shows the cumulative amount of prostaglandin E1 penetrating each
hour for 4 hours for each example composition according to the present
invention.
These data demonstrate the ability of the present invention to deliver
prostaglandin E1
drugs transdermally.
Table 2: Cumulative Prostaglandin E~ Penetration (p,glcm2)
Hour A B C D E F G
1 1.96 3.37 5.47 7.20 7.09 10.38 3.03
2 5.49 9.72 18.06 21.26 16.6 25.03 8.17
3 11.25 18.18 30.34 35.53 28.24 42.18 12.93
4 13.98 23.48 38.49 47.98 41.1 52.13 18.71
To further assess the effectiveness of compositions according the present
invention, comparative example compositions were prepared. A first comparative
example (Comparative Example 1) was prepared with the same recipe as
Compositions D and E except that the DDAIP penetration enhancer was omitted.
For
a second comparative example (Comparative Example 2), the DDAIf was again
omitted, but the level of ethanol was increased a corresponding amount. The
specific
ingredients used are listed in Table 3, below.
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Table 3: Comparative Examples
Comparative Comparative
Ingredient (parts by weight) Composition 1 Composition 2
prehydrated locust bean gum 3 3
water/buffer (pH 5.5) 86 81
sucrose stearate 0.5 0.5
prostaglandin E, 0.4 0.4
Ethanol 5 10
ethyllaurate 5 5
The penetration of prostaglandin E~ was evaluated according to the technique
described in Example 1. The results are presented in Table 4, below.
Table 4: Comparative Examples
Cumulative Prostaglandin E, Penetration (p,g/cmz)
Comparative Comparative
Hour Composition Composition
1 2
1 2.64 1.55
2 4.46 3.69
3 6.59 6.63
4 9.67 11.05
EXAMPLE 9: Single Use Double Blind and Open Label Clinical Trials
The safety and efficacy of a 0.4% weight prostaglandin E, (prostaglandin E~
or alprostadil) topical composition (composition D of Example 4 and Table l,
above)
was evaluated in a total of 143 men at three study sites. This study consisted
of a
double-blind, placebo controlled and cross-over portion and an open-label
portion.
The double-blind placebo controlled portion of the study was entered and
completed by 64 men (Table 5, below). Seventy-nine (79) men entered and
completed
the open-label portion of the study (Table S, below). Summarized below are
discussions on the results of the clinical studies.
Inclusion Criteria
1. Males, ages 21-70 years, inclusive.
2. Documented history of erectile dysfunction, defined as the inability to
achieve and maintain an erection of sufficient rigidity for sexual intercourse
due to
psychogenic, neurogenic or vasculogenic causes during the previous 6 months.
This
includes patients who may still have some erections sufficient for intercourse
but not
consistently, which is the typical complaint of the age onset, mild to
moderate
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impotent man. The diagnosis of erectile dysfunction was based on medical
history
and physical examination.
Exclusion Criteria
1. History of urethral stricture or obstruction.
2. Any combination of findings from history, physical examination or
screening studies which indicate pre-existing impairment of heart, liver
and/or kidney
function (such as congestive heart failure, unstable angina or recent acute
myocardial
infarction, uncontrolled diabetes, for erectile dysfunction of hormonal
origin) which
in the investigator's opinion could influence the outcome of the study.
3. History of penile surgery, including penile implant, prostatectomy or
cancer of the prostate, penile trauma including paraplegia or quadriplegia.
4. Any condition which might predispose towards priapism, such as
sickle cell anemia, multiple myeloma, or leukemia.
5. Hypertension, (sitting diastolic pressure >90 or systolic >150)
requiring treatment with other than angiotensin converting enzyme inhibitors
(ACE
inhibitors).
6. Presence of a sexually transmitted disease as determined by physical
examination.
7. Use of a cavernosal injection or external erectile device within 4
weeks prior to entering into this study.
8. Peyronie's Disease or any palpable fibrous scar or plaque on the penis,
evidence of curvature during tumescence and rigidity stimulation or an anomaly
of
the penis skin or mucosa of the glans.
9. Any concomitant medication which are known to interfere with sexual
activity such as antidepressants, some antihypertensives, sedatives hormones
and
some allergy medications.
10. Received any investigational treatment within 30 days of entering into
this study.
11. Inability or unwillingness to give informed consent.
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The patient population in this study consisted of men in the age range of 49 -
70 years old.
Table 5.
Patient Enrollment by Study Sites
Patients Enrolled On Study
Sites
Portion No.1 No.2 No.3 Total
Double-Blind 30 34 0 64
Open Label 32 8 39 79
Clinical efficacy was evaluated from patient history and patient evaluation
questionnaires both before and after medication using a six-point
classification scale
(Table 6). Each patient was given one (1) placebo and one (1) active dose in a
crossover manner with a S to 7 day wash-off period in the double-blind portion
of the
study. In the open-label portion the patients were given only one (1) active
dose. The
clinical supply was packaged in single-dose containers each containing 250 mg
(net
weight) of cream and 1 mg prostaglandin E~.
The efficacy response rate was determined as the number of men that had
erections sufficient for intercourse out of the total number of men. To be
considered
a success, a score of 8 to 10 must be achieved after administration of the
dose or the
patient must have had intercourse.
1 S Statistical analysis compared before and after response scores using a
paired t-
test. A statistically significant difference (P< 0.001) between all before and
after
dosing scores was found for each group of patients receiving active medication
whether in the double-blind portion of the study or the open label portion of
the
study. Also, a statistical significance was seen between the active and
placebo groups
per study site.
Table 6.
Six-Point Classification Scale for Assessing the Severity
of Male Erectile Dysfunction (Impotence)
Classification Definition
0 Severe impotence with no function
2 Severe impotence with very little
function
4 Severe impotence with some function
6 Mild to moderate impotence
8 Not impotent but has some loss
of function
10 Not impotent with full function
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Table 7.
Patient Enrollment by Impotence Classification
Mild to ModerateNot
Severe Impotent Total
Double-Blind 39 25 0 64
Open Label 63 16 0 79
Total Patients 102 41 0 143
The topical prostaglandin E~ composition was found to be safe and effective
in impotent men with the moderate to severe impotence. The efficacy rate was
64.7%
(66/102 patients) in severely impotent men and 100% (41/41 patients) in mild
to
moderately impotent men. The overall clinical efficacy rate for the study is
74.8%
(107/143 patients) as shown in Table 8, below.
Table 8.
Overall Clinical Efficacy Rates
Double-Blind Portion Open-Label Portion Combined Overall Rate
Placebo 4.7% (3/64) - 4.7% (3/64)
Active 87.5% (56/64) 64.6% (51/79) 74.8% (107/143)
P<0.001 P<0.001
The prostaglandin E~ topical composition was extremely effective (100%) in
the mild to moderate impotent patient population. The mild to moderate
impotence
class is the most prevalent class and is estimated to represent 70% of all
erectile
dysfunction complaints. The product was also very effective (64.7%) in the
severely
1 S impotent study population.
A placebo efficacy response was seen in only 3 of 64 (4.7%) patients studied
in the double-blind portion of the study. This is far below the expected rate
of
approximately 10% as reported in other clinical studies. This low rate is
perhaps due
to the fact that the majority (63%) of the patients enrolled in the double-
blind portion
of the study were classified with severe impotence. While 17 of 64 (26.6%)
patients
showed improvement with the placebo, only three (3) of those patients had
sufficient
improvement to be assessed as efficacious (8 or 10 on the classification
scale).
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Table 9.
Clinical Efficacy Rates by Impotence Classification
Study Sites
Portion No.1 No.2 No.3 Combined
Efficacy
SeverelyDouble-Blind85.7% 63.6% No Patients79.5%
Impotent (24/28) (7/11 ) Entered (31 /39)
Open Label 72.2% 33.3% (2/6)51.3% 55.6%
(13/18) (20/39) (35/63)
Mild Double-Blind100% (2/2)100% No Patients100%
to
Moderate (23/23) Entered ( 25/25)
ImpotenceOpen Label 100% 100% (2/2)No Patients100%
((14/14) Entered (16/16)
The open label efficacy rate was lower than the double-blind efficacy rate
(Table 9). This was primarily due to the enrollment of a relatively high
number of
severely impotent men in the open-label portion of the study as compared to
the
double-blind portion. (Table 8) Of the men enrolled in the open label portion
of the
study, 79.7% (63/79) were assessed as severely impotent while only 60.9%
(39/64)
were assessed as severely impotent on entering the double-blind portion. The
efficacy rate among the severely impotent population is expected to be lower
because
by definition these men have little or no function. Practically, it is
expected to be
more difficult to move the impotence classification from 0, 2 or 4 up to 8 or
10.
While most of the severely impotent men showed significant improvement, 36 men
(36/102 or 35.3%) did not have sufficient improvement to be classified as
efficacious.
Adverse events observed in this study were mild transient burning or tingling
at the application site. No systemic toxic side effects were observed. Also,
none of
the spouses involved in the studies reported adverse events. None of the
patients
dropped out of the study or were lost to follow-up
EXAMPLE 10: Multiple Use Open Label Clinical Trial
The safety and efficacy of a 0.4% prostaglandin El topical composition
(composition D of Example 4 and Table l, above) was evaluated in an additional
study of a total of 56 men at three study sites. Fifty-six (56) male patients
with
organic erectile dysfunction entered and completed the study. Patients were
classified
into groups based on their responses to the International Index of Erectile
Dysfunction (IIEF) and the pre dose Sexual Encounter Profile (SEP). Forty-nine
(49)
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patients were classified as having mild to moderate erectile dysfunction and 7
patients
were classified as having severe erectile dysfunction. Each patient was asked
to use
from 3 to 10 doses of medication over a four week period in a multiple use, in-
home
study. The overall efficacy rate for the mild to moderate group was 75%. The
results
of this study were consistent with the combined overall efficacy rate reported
above
in Example 9. None of the patients dropped out of this multiple use study and
no
severe adverse events were noted.
Inclusion Criteria
1 Males, ages 21-70 years, inclusive.
2. Documented history of erectile dysfunction, which is defined as the
inability to achieve and maintain an erection of sufficient rigidity for
sexual
intercourse due to psychogenic, neurogenic or vasculogenic, causes during the
previous 6 months. This includes patients who may still have some erections
sufficient for intercourse but not consistently, which is the typical
complaint of the
age onset, mild to moderate impotent man. The diagnosis of erectile
dysfunction
based on medical history and physical examination.
Exclusion Criteria
1. History of urethral stricture or obstruction.
2. Any combination of findings from history, physical examination or
screening studies which indicate pre-existing impairment of heart, liver
and/or kidney
function (such as congestive heart failure, unstable angina or recent acute
myocardial
infarction, uncontrolled diabetes, for erectile dysfunction of hormonal
origin) which
in the investigator's opinion could influence the outcome of the study.
3. History of penile surgery, including penile implant, prostatectomy or
cancer of the prostate, penile trauma including paraplegia or quadriplegia.
4. Any condition which might predispose towards priapism, such as
sickle cell anemia, multiple myeloma, or leukemia.
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S. Hypertension, (sitting diastolic pressure >90 or systolic >150)
requiring treatment with other than angiotensin converting enzyme inhibitors
(ACE
inhibitors).
6. Presence of a sexually transmitted disease as determined by physical
S examination.
7. Use of a cavernosal injection or external erectile device within 4
weeks prior to entering into this study.
8. Peyronie's Disease or any palpable fibrous scar or plaque on the penis,
evidence of curvature during tumescence and rigidity stimulation or an anomaly
of
the penis skin or mucosa of the glans.
9. Any concomitant medication which are known to interfere with sexual
activity such as antidepressants, some antihypertensives, sedatives hormones
and
some allergy medications.
10. Received any investigational treatment within 30 days of entering into
this study.
11. Inability or unwillingness to give informed consent.
The patient population in this study consisted of men in the age range of 49-
70 years old.
Table 10.
Patient Enrollment by Study Sites
Patients Enrolled On Study Sites
No.1 No.2 No.3 Total
22 13 21 56
Clinical efficacy was evaluated from patient history and patient evaluation
questionnaires both before and after medication using the International Index
of
Erectile Function (Table 11) and the Sexual Encounter Profile (SEP) six-point
classification scale (Table 12). Each patient was given 10 active doses and
asked to
take the medication home and attempt intercourse as many times as possible
over a
4 week period. The medication was packaged in a specially designed single dose
dispenser.
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Table 11.
International Index of Erectile Function
Classification Definition
<12 Severe impotence with no function
12-18 Mild Impotence with very little function
18-24 Moderate Impotence with some function
24+ No dysfunction
The efficacy response rate was determined as the number of intercourse
successes out of the total number of intercourse attempts. To be considered a
success, a SEP score of 8 to 10 must be achieved after administration of the
dose or
the patient must have had satisfactory sexual intercourse. Statistical
analysis
compared before and after response scores using Chi Square statistics. A
statistically significant difference (P< 0.001) between before and after
dosing scores
was found for each group of patients receiving active medication.
Table 12
Sexual Encounter Profile(SEP): Six-Point Classification Scale for
Assessing the Severity of Male Erectile Dysfunction (Impotence)
Classification Definition
0 Severe impotence with no function
2 Moderate Impotence with very little function
4 Moderate Impotence with some function
Mild Impotence
8 Not impotent but has some loss of function
10 Not impotent with full function
The efficacy response rate was determined as the number of intercourse
successes out of the total number of intercourse attempts. To be considered a
success, a SEP score of 8 to 10 must be achieved after administration of the
dose or
the patient must have had satisfactory sexual intercourse. Statistical
analysis
compared before and after response scores using Chi Square statistics. A
statistically
significant difference (P< 0.001 ) between before and after dosing scores was
found.
Table 13.
Patient Enrollment by Impotence Classification
Severe Mild to Moderate Total
Patients 7 49 56
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Table 14.
Efficacy per Patient Group
Efficacy by Patients Efficacy by Attempts
Mild to 36/49 (74%) 178/239 (75%)
Moderate
Severe 4/7 (57%) 16/36 (44%)
As previously discussed, the prostaglandin E~ topical composition was
extremely effective (75%) in the mild to moderate impotent patient population.
The
mild to moderate impotence class is the most prevalent class and is estimated
to
represent 70% of all erectile dysfunction complaints. The product was less
effective
(44%) in the severely impotent study population; however, a statistically
significant
difference was noted between the before and after treatment scores in this
group.
Even though all of the men in the severe group were totally without any
erectile
function before the study, 4 of the 7 men (57%) had successful intercourse
from at
least 3 out of the 10 doses.
Adverse events observed in this study were mild transient burning or tingling
at the application site. No systemic toxic side effects were observed. Also,
none of
the spouses involved in the studies reported adverse events. None of the
patients
dropped out of the study or were lost to follow-up.
The results of this clinical study indicate the use of the prostaglandin E1
0.4%
topical composition of the present invention for the treatment of mild,
moderate to
severe impotence is safe and efficacious.
EXAMPLE 11 Phase 3 Clinical Studies
Phase 3 Clinical Studies were performed using the topical composition I of
Table 1 modified to produce four test compositions having PGE~ doses of 0
micrograms (mcg) (placebo), 100 mcg, 200 mcg or 300 mcg.
The enrolled patients received a four week non-treatment period, then were
randomly assigned one of four treatment groups: placebo, 100 mcg, 200 mcg or
300
mcg for the 12 week take-home portion of the study.
The inclusion criteria were: the patients were at least 21 years of age with
no
upper age limit, a history of erectile dysfunction three months or longer in
duration,
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an ITEF erectile function domain score less than or equal to 25, and at least
4 attempts
of sexual intercourse during the non-treatment period.
Any patient with an erectile dysfunction caused by untreated endocrine
disease, significant penile pathology, a history of orthostatic hypotension,
syncopal
episodes, or pre-syncopal symptoms (previous 6 months), clinically significant
hepatic or renal disease, a history of myocardial infarction (within the
previous 6
months), a significant neurological disease such as stroke or spinal cord
injury,
currently taking prescription or over the counter erectile dysfunction
medication or
therapy, or have a history of allergy to alprostadil was excluded from the
study.
Patients who were not excluded from the studies were patients with a history
of prostatectomy, patients with controlled diabetes, patients taking nitrate
medications and alpha blockers, and patients with a history of efficacy
failure with
oral PDES inhibitor therapy (sildenafil, ViagraTM). The demographic and
baseline
characteristics of the Phase 3 treatment group are summarized in Table 15
below. A
given patient may have had more than one co-morbid condition; the sum of the
percents under "Medical History' is more than 100%.
Phase 3 clinical studies were based on a study design of randomized, placebo
controlled, double-blind, and parallel treatment design involving a take-home
study in
mild to severe erectile dysfunction patient. There were two separate studies
performed in the United States at 85 sites. The patient population consisted
of 1732
men 24 -87 years of age. Of the starting population, 1410 completed the study,
a
18% drop out rate. The patients were randomly assigned to four parallel
treatment
groups: placebo, 100 microgram, 200 microgram, and 300 microgram prostaglandin
E~ dose. An initial 4 week non-treatment period was followed by 12 weeks of
take-
home dosing. Up to 25 doses per patient were self administered over the twelve
week treatment period. The patients in the study were mild to severe erectile
dysfunction patients, having IIEF erectile dysfunction domain scores less than
or
equal to 25. Questions 1, 2, 3, 4, 5, and 15 of the IIEF were entered into the
study.
The demographics of the patient population are summarized in Table 15,
below. Note that a given patient may have more than one co-morbid condition in
his
medical history.
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Table 15
Treatment Group Demographics
Mean Age: 59.6 years (1732 men, 23 - 87
yrs. of age)
Age >65 15%
Baseline Erectile Function Domain Score 13.8
History of ED > 1 yr 93%
Medical History
Diabetes 21
Hypertension 44%
Cardiac Disease 28%
Nitrates and alpha blockers 16%
Prostatectomy 12%
Oral Sildenafil Efficacy Failures 18%
The composition of the four treatment groups is summarized in Table 16,
below. As noted above, a patient may have had more than one co-morbid
condition.
Table 16
Demographic and Baseline Characteristics
Treatment
Group
Placebo 100 mcg 200 mcg 300 mcg All PGE,
(N=434) (N=434) (N=430) (N=434) (N=1732)
Mean age, year61 (31-87)61 (35-86)60 (24-87)61 (23-86)61 (31-87)
(range)
Medical History
Hypertension 191 186 180 198 755
Coronary 118 107 125 135 485
artery disease
Diabetes 85 90 95 86 356
mellitus
Prostatectomy 46 71 45 51 213
Sildenafil 80 83 71 78 312
(Low or no
efficacy)
The measures used a primary efficacy endpoints were: the change in the
International Index of Erectile Function (IIEF) Erectile Function Domain score
from
baseline to final visit compared to placebo; Question 2 of the Sexual
Encounter
Profile (SEP): "Were you able to insert your penis into your partner's
vagina?"; and
Question 3 of the SEP: "Did your erection last long enough for you to complete
intercourse with ejaculation?" For the response to QZ and Q3, mean per patient
scores
were compared to placebo.
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Secondary efficacy end points included a Global Assessment Question
(GAQ): "Did your erections improve while on the study medication?" as well as
the
scores on other domains on the IIEF. Erectile dysfunction severity was
characterized
by LIEF erectile function domain scores as follows: severe (<11), moderate (11-
16),
mild to moderate (17-21), mild (22-25) or normal (>26).
The efficacy of the four treatments as measured by the change in the erectile
function domain of the BEF is shown in Table 17 for the population of patients
who
completed the study. The two highest dosage levels produced the largest
effect. The
differences in scores compared to placebo were significant at the 0.001 level
for all
dosages.
Table 17
Erectile Function Domain
Mean Change Difference Number of
from BaselineSignificancePatients
to Endpoint vs. Placebo
~
Placebo-0.7 N=408
100 1.6 (p<0.001 N=421
mcg )
200 2.5 (p<0.001 N=405
mcg )
300 2.4 (p<0.001 N=417
mcg )
Similarly, the responses to the global assessment question, "When using the
study medication, did you feel your erections improved? (Table 18 below) also
showed differences from placebo at p<0.001 level for all dosage levels of
PGE1.
Table 18
Global Assessment Question
When using the study medication, did you feel your erections improved?
Percent PatientDifference SignificanceNumber of
Improvement vs. Placebo Patients
Placebo 20 N=394
100 mcg 40 (p<0.001 ) N=408
200 mcg 47 (p<0.001 ) N=392
300 mcg 52 (p<0.001 ) N=398
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 19 below)
also showed
differences significant at the p < 0.001 level for all PGE~ doses compared to
placebo.
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Table 19
Sexual Encounter Profile (SEP) Scores
(Ability to insert penis in partner's
vagina)
Percent Patient Difference Number
of
Intercourse Significance vs. Patients
Success Rate Placebo
Placebo 51 N=411
100 mcg 57 (p=0.001 ) N=418
200 mcg 58 (p<0.001 ) N=410
300 mcg 58 (p<0.001 ) N=410
The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 20, below) were significantly different from
control for
the two higher doses (p<0.001), and significant at the 0.003 level for the 100
microgram dose.
Table 20
Sexual Encounter
Profile (SEP)
Scores
(Ability
to
maintain
erection
to
ejaculation)
Percent Patient DifferenceNumber
of
Intercourse SignificancePatients
Success Rate vs. Placebo
Placebo30 N=411
100 39 (p=0.003) N=418
mcg
200 42 (p<0.001 N=410
mcg )
300mcg39 (p<0.001 N=410
)
A summary of the primary and secondary efficacy endpoints is found in Table
21, below. The overall change with PGE~ treatment is significantly different
from
placebo.
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TahlP 21
Summa of Ma'or Efficac
Variables
at
End
oint
Treatment
Grou
s
Placebo 100 200 300 Overall
mcg mcg mcg
(N=416) (N=422) (N=412) (N=419) P
Value
EP than EP than EP than EP than
a a a a
Primary Efficacy
End oints
IIEF, erectile 13.3-0.7 15.31.6 16.1 2.5 16.12.5 <0.001
function,
mean change from
baseline
SEP Scores, mean
success rate per
patient
from baseline
Question 2 51.2-4.5 56.62.9 58.2 5.1 57.57.2 0.002
(Ability to achieve
erections
Question 3 30.20.4 38.97.0 41.9 13.8 38.59.1 <0.001
(Ability to maintain
erections to e'aculation
Secondary Efficacy
End oints
Global Assessment20 40 47 52 <0.001
Question, % of
patients
answering "yes"
(Did the
medication improve
your
erections? Y/N
The percent of patients achieving a normal IIEF score (>26) after treatment
was 6% (placebo), 10% (100 mcg), 14% (200 mcg) and 16% (300 mcg).
EXAMPLE 12: Treatment of Erectile Dysfunction in Diabetic Patients
The measures of efficacy of the treatment in the subset of patients who had a
medical history of diabetes mellitus are summarized in Table 22-23, below. The
efficacy of the four treatments as measured by the change in the erectile
function
domain of the IIEF is shown in Table 22 for the subset of diabetes patients
who
completed the study. The two highest dosage levels produced the largest
effect. The
differences in scores compared to placebo were significant at the p < 0.05
level for all
dosages.
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TABLE 22
Diabetes Patients
Erectile Function Domain
Mean Change Difference SignificanceNumber
of
from Baseline vs. Placebo Patients
to Endpoint
Placebo-1.2 N=81
100 2.1 (p=0.014) N=90
mcg
200 3.7 (p<0.001 ) N=94
mcg
300 2.4 (p=0.003) N=95
mcg
The responses to the global assessment question, "When using the study
medication, did you feel your erections improved? (Table 23 below) showed
differences from placebo at the p<0.001 level for all dosage levels of PGE~.
Table 23
Diabetes Patients
Global Assessment Question
When using
the study
medication,
did you
feel your
erections
improved?
Percent Difference Number of Patients
Patient Significance
Improvement vs. Placebo
Placebo 20 N=76
100 mcg 43 (p=0.001 ) N=69
200 mcg 45 (p=0.001 ) N=92
300 mcg 53 (p<0.001 ) N=79
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 24 below)
did not show
differences significant at the p < 0.05 level for any PGE~ doses compared to
placebo.
Table 24
Diabetes Patients
Sexual Encounter Profile (SEP)
Scores
(Ability to insert penis in
partner's vagina)
Percent Patient Difference Number
Intercourse Significance of
Success Rate vs. Placebo Patients
Placebo44 N=84
100 51 p=0.209 N=90
mcg
200 64 p=0.069 N=95
mcg
300mcg52 p=0.255 N=83
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The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 25, below) were significantly different from
control for
the 200 mcg dose (p<0.005).
Table 25
Diabetes Patients
Sexual Encounter Profile (SEP)
Scores
(Ability to maintain erectionn)
to ejaculatio
Percent Patient Difference Number
of
Intercourse Significance Patients
Success Rate vs. Placebo
Placebo29 N=84
100 36 p=0.123 N=90
mcg
200 46 p=0.002 N=95
mcg
300mcg33 p=0.253 N=83
EXAMPLE 13: Treatment of Erectile Dysfunction in Prostatectomy Patients
The measures of efficacy of the treatment of the subset of patients who had a
medical history of prostatectomy are summarized in Tables 26-29, below. The
efficacy of the four treatments as measured by the change in the erectile
function
domain of the IIEF is shown in Table 27 for this subset of patients who
completed the
study. The two highest dosage levels produced the largest effect. The
differences in
scores compared to placebo were significant at the p < 0.01 level for all
dosages.
Table 26
Prostatectomy Patients
Erectile Function Domain
Mean Difference Number
of
Change SignificancePatients
from vs. Placebo
Baseline
to
Endpoint
Placebo -2.2 N=46
100 mcg 2.2 p=0.004 N=71
200 mcg 2.4 p=0.006 N=44
300 mcg 2.5 p=0.003 N=51
The responses to the global assessment question, "When using the study
medication, did you feel your erections improved? (Table 27 below) showed
differences from placebo at the p<0.001 level for all dosage levels of PGE~.
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Table 27
Prostatectomy Patients
Global Assessment Question
When using
the study
medication,
did you
feel
your
erections
improved?
Percent Difference Number of
Patient Significance Patients
Improvement
vs. Placebo
Placebo 11 N=44
100 mcg 47 p<0.001 N=70
200 mcg 57 p<0.001 N=42
300 mcg 55 p<0.001 N=51
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 28 below)
only showed
differences significant at the p < 0.01 level for 300 mcg PGE~ dose compared
to
placebo.
Table 28
Prostatectomy Patients
Sexual Encounter Profile (SEP)
Scores
(Ability to insert penis in
partner's vagina)
Percent Patient Difference Number
of
Intercourse Significance Patients
Success Rate vs. Placebo
Placebo21 N=45
100 41 p=0.129 N=71
mcg
200 35 p=0.155 N=45
mcg
300mcg36 p=0.006 N=51
The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 29, below) were significantly different from
control at
the p = 0.056 level for the 300 mcg dose.
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Table 29
Prostatectomy Patients
Sexual Encounter Profile (SEP)
Scores
(Ability to maintain erectionn)
to ejaculatio
Percent Patient Difference Number
of
Intercourse Significance Patients
Success Rate vs. Placebo
Placebo13 N=45
100 22 p=0.541 N=71
mcg
200 24 p=0.511 N=45
mcg
300 24 p=0.056 N=51
mcg
EXAMPLE 14: Regimen of Treatment of Erectile Dysfunction in Prostatectomy
Patients
Patients needing treatment for erectile dysfunction following radical
prostatectomy or nerve-sparing prostatectomy are treated with the semisolid
prostaglandin composition of Example 11. While treatment can be started at any
time
after prostatectomy surgery, it is preferred that treatment start about one to
about six
months after surgery. Depending on the severity of erectile dysfunction as
assessed
using the IIEF, a regular regimen of treatment not necessarily linked to
anticipated
sessions of sexual intercourse is administered. A semi-solid vasoactive
prostaglandin
composition delivering a dose of about 100 mcg to about 400 mcg prostaglandin
EI
is applied to the fossa navicularis of the penis at least twice a week, every
other day,
or on a daily basis. For "on demand" treatment, the semi-solid vasoactive
prostaglandin composition is applied to the fossa navicularis of the penis
about 2-30
minutes before sexual intercourse, preferably about 5-15 minutes before sexual
intercourse. About 40 to about 60 percent of the treated patients report that
they feel
that their erections have improved while taking the medication after about
three
months of treatment.
EXAMPLE 15: Treatment of Erectile Dysfunction in Erectile Dysfunction Patients
for Whom Oral Phosphodiesterase-5 Inhibitor Therapy Was Ineffective
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The measures of efficacy of the treatment in the treatment in the subset of
erectile dysfunction patients for whom oral phosphodiesterase-5 inhibitor
therapy was
ineffective are summarized in Tables 30-33, below. The efficacy of the four
treatments as measured by the change in the erectile function domain of the
1ZEF is
shown in Table 31 for this subset of patients who completed the study. The two
highest dosage levels produced the largest effect. The differences in scores
compared
to placebo were not significant at the p < 0.05 level for all dosages.
Table 30
Erectile Dysfunction Patients For Whom Oral Sildenafil
Treatment was Ineffective
Erectile Function Domain
Mean Change from Difference Number of
Baseline to Endpoint Significance vs. Patients
Placebo
Placebo -0.4 N=80
100 mcg 1.2 p=0.134 N=83
200 mcg 1.7 p<0.061 N=70
300 mcg 1.4 p<0.097 N=78
The responses to the global assessment question, "When using the study
medication, did you feel your erections improved? (Table 31 below) showed
differences from placebo at the p<0.05 level for the 200 mcg and 300 mcg
dosage
levels of PGE~.
Table 31
Erectile Dysfunction Patients For
Whom Oral Sildenafil
Treatment was Ineffective
Global Assessment Question
When
using
the
study
medication,
did
you
feel
your
erections
improved?
Percent Difference Number of
Patient Significance Patients
Improvement vs. Placebo
Placebo21 N=77
100 29 p=0.158 N=82
mcg
200 37 p=0.025 N=68
mcg
300 45 p=0.001 N=73
mcg
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 32 below)
showed
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differences significant at the p < 0.0$ level for the 200 mcg and 300 mcg PGE,
doses
compared to placebo.
Table 32
Erectile Dysfunction Patients For Whom Oral Sildenafil
Treatment was Ineffective
Sexual Encounter Profile (SEP) Scores
(Ability to insert penis in partner's vagina)
Percent Patient Difference Number of
Intercourse Significance Patients
Success Rate vs. Placebo
Placebo 43 N=80
100 mcg 45 p=0.181 N=83
200 mcg 45 p=0.046 N=70
300mcg 49 p=0.004 N=78
The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 33, below) were not significantly different
from control.
Table 33
Erectile Dysfunction Patients For Whom Oral Sildenafil
Treatment was Ineffective
Sexual Encounter Profile (SEP) Scores
(Ability to maintain erection to ejaculation)
Percent Patient Difference Number of
Intercourse Success Significance vs. Patients
Rate Placebo
Placebo23 N=80
100 29 p=0.809 N=83
mcg
200 32 p=0.112 N=70
mcg
300mcg 30 p=0.820 N=78
EXAMPLE 16: Treatment of Erectile Dysfunction in Hypertensive Patients
The measures of efficacy of the treatment in the subset of patients who had a
medical history of hypertension are summarized in Tables 34-37, below. The
efficacy of the four treatments as measured by the change in the erectile
function
domain of the >ZEF is shown in Table 3$ for this subset of patients who
completed the
study. The two highest dosage levels produced the largest effect. The
differences in
1$ scores compared to placebo were significant at the p < 0.0$ level for all
dosages, and
significant at the p < 0.001 level for the 200 mcg and 300 mcg doses.
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Table 34
Erectile Function Domain
Mean Change from Difference Number of
Baseline to Significance Patients
Endpoint vs. Placebo
Placebo -0.6 N=187
100 mcg 1 p=0.022 N=185
200 mcg 2.9 p<0.001 N=175
300 mcg 2.0 p<0.001 N=198
The responses to the global assessment question, "When using the study
medication, did you feel your erections improved? (Table 35 below) showed
differences from placebo at the p<0.001 level for all dosage levels of PGE1.
Table 35
Global Assessment
Question
When
using
the
study
medication,
did
you
feel
your
erections
improved?
Percent PatientDifference SignificanceNumber
of
Improvement vs. Placebo Patients
Placebo20 N=178
100 37 p<0.001 N=178
mcg
200 47 p<0.001 N=173
mcg
300 49 p<0.001 N=187
mcg
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 36 below)
also showed
differences significant at the p < 0.05 level compared to placebo for all PGE,
doses.
Table 36
Sexual Encounter Profile (SEP) Scores
(Ability to insert penis in partner's
vagina)
Percent Patient Intercourse Difference Number
Sign. vs.
Success Rate Placebo
Placebo47 N=189
100 53 p=0.038 N=182
mcg
200 59 p<0.001 N=179
mcg
300mcg 54 p=0.006 N=195
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The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 37, below) were significantly different from
control
only for the 200 mcg dose (p = 0.001).
Table 37
Sexual Encounter Profile (SEP) Scores
(Ability to maintain erection to ejaculation)
Percent Patient Difference Number
of
Intercourse Success Significance vs. Patients
Rate Placebo
Placebo26 N=189
100 35 p=0.329 N=182
mcg
200 41 p=0.001 N=179
mcg
300mcg 35 p=0.34 N=195
EXAMPLE 17: Treatment of Erectile Dysfunction in Cardiac Patients
The measures of efficacy of the treatment in the subset of patients who had a
medical history of cardiac disease are summarized in Tables 38-41, below. The
efficacy of the four treatments as measured by the change in the erectile
function
domain of the IIEF is shown in Table 38 for this subset of patients who
completed the
study. The two highest dosage levels produced the largest effect. The
differences in
scores compared to placebo were significant at the p < 0.005 level for all
dosages.
Table 38
Erectile Function Domain
Mean Change from Difference Number
of
Baseline to Significance Patients
vs.
Endpoint Placebo
Placebo -1.7 N=115
100 mcg 1.4 p=0.002 N=107
200 mcg 1.5 p=0.001 N=122
300 mcg 1.9 p<0.001 N=135
The responses to the global assessment question, "When using the study
1 S medication, did you feel your erections improved? (Table 39 below) showed
differences from placebo at the p<0.005 level for all dosage levels of PGE1.
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Table 39
Global Assessment Question
When using
the study
medication,
did you
feel
your
erections
improved?
Percent Difference Number of
Patient Significance Patients
Improvement
vs. Placebo
Placebo 17 N=111
100 mcg 35 p<0.003 N=104
200 mcg 48 p<0.001 N=116
300 mcg 50 p<0.001 N=126
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 40 below)
also showed
differences significant at the p < 0.05 level compared to placebo only at the
200 mcg
dose, although the difference compared to control was significant at the p =
0.054
level for the 300 mcg PGE1.
Table 40
Sexual Encounter Profile (SEP) Scores
(Ability to insert penis in partner's vagina)
Percent Patient Difference Number of
Intercourse Significance Patients
Success Rate vs. Placebo
Placebo 44 N=117
100 mcg 54 p=0.109 N=105
200 mcg 54 p=0.018 N=125
300mcg 51 p=0.054 N=130
The responses to question 3 of the SEP regarding the ability to maintain an
erection to ejaculation (Table 41, below) were significantly different from
control for
the two higher doses (p<0.05).
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Table 41
Sexual Encounter Profile (SEP) Scores
(Ability to maintain erection to ejaculation)
Percent Patient Difference Number
of
Intercourse Success Significance vs. Patients
Rate Placebo
Placebo23 N=117
100 33 p=0.260 N=105
mcg
200 36 p=0.003 N=125
mcg
300 31 p=0.022 N=130
mcg
EXAMPLE 18: Efficacy of Treatment Measures by Baseline Severity of Erectile
Dysfunction
S The efficacy of treatment compared to the initial baseline severity was
analyzed separately for the two studies comprising the Phase 3 study. Baseline
severity was defined by IIEF Erectile Function domain scores as follows:
severe (1-
10), Moderate (11-18), Mild to Moderate (17-21), Mild (23-25). The results are
summarized in Tables 42-46, below.
Table 42
Change
from
Baseline
in IIEF
EF Domain
Scores
at Endpoint
by
Baseline Severity (Study
1)
Mild Mild to Moderate Severe
Moderate
Placebo -4 -1.9 -0.4 2.5
100 mcg -0.5 -0.7 2.3 4.1
200 mcg 1 1.1 2.9 4.9
300 mcg -0.2 1.6 3.8 5.1
Table 43
Change
from
Baseline
in IIEF
EF Domain
Scores
at Endpoint
by
Baseline Severity (Study
2)
Mild Mild to Moderate Severe
Moderate
Placebo -4.8 -0.7 -0.1 0.6
100 mcg -1.6 0.3 1.5 4.6
200 mcg -3.1 2.9 2.7 2.5
300 mcg -0.4 1.2 1.5 3.4
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Table 44
Treatment on Vaginal Penetration
Success
Rates Baseline ED ED Severity
SEPQ21SEPQ1 (Percent Penetration Successes/Attempts)
(Study 2)
Mild Mild to Moderate Severe
Moderate
Placebo77.7 68.3 51.2 23.1
100 90.5 72.8 60.4 25.9
mcg
200 83.9 82.5 62.6 25.4
mcg
300 88.4 78.9 63.8 33.2
mcg
Table 45
Treatment on Successful Intercourse Completion Rates by Baseline
ED Severity
SEPQ3/SEPQ1 (Number of completions to ejaculation/Attempts)
Percent of Patients with Success (Study 2)
Mild Mild to Moderate Severe
Moderate
Placebo 62.6 47.6 27.4 10.3
100 mcg 73.5 48.6 38.2 17.3
200 mcg 71.9 63.7 41.4 23.9
300 mcg 75.7 61.9 37.7 15.4
EXAMPLE 19: Integrated Safety Analysis
The results of the integrated safety analysis are presented in Tables 46-47,
below.
Table 46
Summary of Treatment Related Adverse Events
Treatment
Group
Placebo100 mcg 200 mcg 300 mcg Overall
N=434 N=434 N=434 N=434 N=1732
Patients with 61 (14)156 (36)187 (20) 188 (42)592
a least orie (34)
drug related adverse
event, n (%)
Drug related serious0 0 0 0 0
adverse events
Patients withdrawn1 (1 10 (2) 14 (3) 26 (6) 51 (3)
due )
to drug related
adverse
events, n (%)
Drug related adverse
events occurring
in >3%
of all patients
Penile Burning 26 (6) 76 (18) 106 (25) 101 (23)309
(18)
Penile Erythema 9 (2) 33 (8) 39 (9) 49 (11 121
) (7)
Genital Pain 2 (0,5)48 (11 67 (16) 76 (18) 193
) (11
)
Vaginal Burning 7 (2) 15 (3) 30 (7) 18 (4) 70 (4)
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Table 47
Summary of
Patients
Discontinued
Due to Drug
Related
Adverse Events
Adverse Event
Number of
Patients
Discontinued (%)
Genital Pain 15 (0.9)
Penile Burning21 (1.2)
Penile Erythema4 (0.2)
Vaginal Burning3 (0.3)
Other 8 (0.5)
Total, n(%) 51 (3)
In general, the treatment produced no serious side effects. Most adverse
events were localized to the site of application but were mild, short in
duration and
well tolerated. Overall, the treatment demonstrated efficacy across a broad
range of
erectile dysfunction severity and co-morbid conditions.
EXAMPLE 20: Treatment of Hypertension Patients Also Receiving Alphas Blockers
The measures of efficacy of the treatment in the subset of patients who had a
medical history of hypertension and who were also being treated with alphas
blockers
are summarized in Tables 48-51, below. The small sample size limits the
calculation
of the p values for comparison of differences.
The efficacy of the four treatments as measured by the change in the erectile
function domain of the IIEF is shown in Table 48 for this subset of patients
who
completed the study. The 300 mcg dosage level produced the largest effect. The
differences in scores compared to placebo were not significant at the p < 0.05
level
for any dosages.
Table 48
Erectile Function Domain
Mean Change from Difference SignificanceNumber
of
Baseline to Endpointvs. Placebo Patients
Placebo-1.2 N=27
100 0.0 p<0.619 N=24
mcg
200 -0.2 p<0.543 N=26
mcg
300 2.2 p<0.112 N=25
mcg
In spite of the small sample size, the responses to the global assessment
question, "When using the study medication, did you feel your erections
improved?
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(Table 49 below) showed differences from placebo at the p < 0.05 level for the
300
mcg dosage level.
Table 49
Global Assessment Question
When using the study medication, did you feel your erections improved?
Percent PatientDifference SignificanceNumber of
vs.
Improvement Placebo Patients
Placebo11.5 N=26
100 25 p<0.474 N=24
mcg
200 28 p<0.103 N=25
mcg
300 44 p<0.033 N=25
mcg
The responses to question 2 of the Sexual Encounter Profile (SEP) regarding
the ability to insert the penis into the partner's vagina, (Table 50 below)
did not show
differences compared to placebo that were not at the p < 0.05 level for any
dose
levels. The 200 and 300 mcg dose levels produced the largest effects.
Table 50
Sexual Encounter Profile (SEP) Scores
(Ability to insert penis in partner's vagina)
Percent Patient Mean Change Difference Number
Intercourse Success Compared to Significance of
Rate Baseline vs. Placebo Patients
Placebo 52.8 -5.6 N=28
100 mcg 39.8 2.4 p<0.266 N=24
200 mcg 47.3 4.8 p<0.327 N=26
300mcg 59.5 6.7 p<0.151 N=26
The responses to question 3 of the SEP regarding
the ability to maintain an
erection to ejaculation (Table 51, below) were not significantly different
from
placebo.
Table 51
Sexual Encounter Profile (SEP) Scores
(Ability to maintain erection to ejaculation)
Percent Patient Mean Change Difference Number
Intercourse Compared to Significanceof
Success Rate Baseline vs. PlaceboPatients
Placebo 29.0 2.8 N=28
100 mcg 30.8 12.0 p<0.140 N=24
200 mcg 34.3 14.0 p<0.317 N=26
300mcg 40.1 1.5 p<0.559 N=26
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A similar analysis on a smaller subset of patients who had a medical history
of
hypertension and who were also being treated with nitrates provided no useful
information due to small sample size (a total of 22 patients in all four
treatment
groups).
The claims should not be read as limited to the described order or elements
unless stated to that effect. Therefore, all embodiments that come within the
scope
and spirit of the following claims and equivalents thereto are claimed as the
invention.
