Note: Descriptions are shown in the official language in which they were submitted.
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LOCAL ADMINISTRATION OF PHOSPHODIESTERASE
INHIBITORS FOR THE TREATMENT OF ERECTILE DYSFUNCTION
TECHNICAL FIELD
This invention relates generally to methods and pharmaceutical compositions
for treating erectile dysfunction; more particularly, the invention relates to
local
administration of phosphodiesterase inhibitors to treat erectile dysfunction.
BACKGROUND ART
Impotence is the consistent inability to achieve or sustain an erection of
sufficient rigidity for sexual intercourse. It has recently been estimated
that approximately
10 million American men are impotent (R. Shabsigh et al., "Evaluation of
Erectile
Impotence," Urology x:83-90 (1988); W.L. Furlow, "Prevalence of Impotence in
the
United States," Med. Aspects Hum. Sex. x:13-6 (1985)). Impotence is recognized
to be an
age-dependent disorder, with an incidence of 1.9 percent at 40 years of age
and 25 percent at
65 years of age (A.C. Kinsey et al., "Age and Sexual Outlet," in Sexual
Behavior in the
Human Male; A.C. Kinsey et al., eds., Philadelphia, PA: W.B. Saunders, 218-262
(1948)).
In 1985 in the United States, impotence accounted for more than several
hundred thousand
outpatient visits to physicians (National Center for Health Statistics,
National Hospital
Discharge Survey, 1985, Bethesda, MD, Department of Health and Human Services,
1989
DHHS publication no. 87-1751 ). Depending on the nature and cause of the
problem,
treatments include psychosexual therapy, hormonal therapy, administration of
vasodilators
such as nitroglycerin and a-adrenergic blocking agents ("a-blockers"), oral
administration
of other pharmaceutical agents, vascular surgery, implanted penile prostheses,
vacuum
constriction devices and external aids such as penile splints to support the
penis or penile
constricting rings to alter the flow of blood through the penis.
A number of causes of impotence have been identified, including
vasculogenic, neurogenic, endocrinologic and psychogenic. Vasculogenic
impotence,
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which is caused by alterations in the flow of blood to and from the penis, is
thought to be
the most frequent organic cause of impotence. Common risk factors for
vasculogenic
impotence include hypertension, diabetes, cigarette smoking, pelvic trauma,
and the like.
Newogenic impotence is associated with spinal-cord injury, multiple sclerosis,
peripheral
newopathy caused by diabetes or alcoholism and severance of the autonomic
nerve supply
to the penis consequent to prostate surgery. Erectile dysfunction is also
associated with
distwbances in endocrine function resulting in low circulating testosterone
levels and
elevated prolactin levels.
Impotence can also be a side effect of various classes of drugs, in
particular,
those that interfere with central newoendocrine control or local newovascular
control of
penile smooth muscle. Krane et al., New England Journal of Medicine x:1648 (
I989).
Penile erection requires ( 1 ) dilation of the arteries that regulate blood
flow to the lacunae of
the corpora cavernoswn, (2) relaxation of trabecular smooth muscle, which
facilitates
engorgement of the penis with blood, and (3) compression of the venules by the
expanding
trabecular walls to decrease venous outflow.
Trabecular smooth muscle tone is controlled locally by adrenergic
(constrictor), cholinergic (dilator) and nonadrenergic, noncholinergic
(dilator) innervation,
and by endothelium-derived vasoactive substances such as vasoactive intestinal
polypeptide
(VIP), prostanoids, endothelin and nitric oxide. High sympathetic tone
{noradrenergic) is
implicated in erectile dysfunction, and, in some patients, the disorder can be
successfully
treated with noradrenergic receptor antagonists. See, e.g., Krane et al.,
supra.
There is also evidence that dopaminergic mechanisms are involved in erectile
function. For example, pharmacologic agents that elevate the level of brain
dopamine or
stimulate brain dopamine receptors increase sexual activity in animals (see,
e.g., Gessa &
Tagliamonte, Life Sciences 14:425 (1974); Da Prada et al., Brain Research
X7:383 (1973)).
Administration of L-DOPA, a dopamine precwsor, enhances sexual activity
in male rats. L-DOPA has been used in the treatment of Parkinsonism and is
known to act
as an aphrodisiac in some patients (Gessa & Tagliamonte, supra; Hyppa et al.,
Acta
Neurologic Scand. x,ø:223 (Supp. 43, 1970)). Specific dopamine agonists have
been studied
for their effects on erectile function. Apomorphine, (n-propyl)norapo-
morphine,
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bromocryptine, amantidine, fenfluramine, L-DOPA and various other
pharmacological
activators of central dopaminergic receptors have been found to increase
episodes of penile
erection in male rats {Benassi-Benelli et al., Arch. int. Pharmacodyn. 2:241 (
1979);
Poggioli et al., Riv. di Farm. & Terap. x:213 (1978); Falaschi et al.,
Apomorphine and
Other Dopaminomimetics, x:117-121 (Gessa & Corsini, Eds., Raven Press, N.Y.)).
In
addition, U.S. Patent No. 4,521,421 to Foreman relates to the oral or
intravenous
administration of quinoline compounds to treat sexual dysfunction in mammals.
The currently available dopamine agonists, with few exceptions, have found
limited use in the treatment of erectile dysfunction because of their
peripheral side effects.
These effects include nausea and vomiting, postural hypotension; arrhythmias,
tachycardia,
dysphoria, psychosis, hallucinations, drowsiness and dyskinesias (See, e.g.,
Martindale The
Extra Pharmacopoeia, 31st Ed., pages 1151-1168).
Other pharmaceutical methods for treating erectile dysfunction have also
proved to be problematic. For example, with Viagra~, the most recently
introduced oral
drug therapy, not only have significant side effects been encountered, but
interaction with
other systemically administered medications has posed enormous risks and
numerous
fatalities have in fact been reported.
The invention described herein provides a means to avoid the above-
mentioned problems encountered with the systemic administration of
pharmacologically
active agents to treat erectile dysfunction. Specifically, the invention
relates to methods and
formulations for effectively treating erectile dysfunction by locally
administering a selected
active agent, wherein the active agent is an inhibitor of a phosphodiesterase.
Phosphodiesterases are a class of intracellular enzymes involved in the
metabolism of the second messenger nucleotides, cyclic adenosine monophosphate
(cAMP),
and cyclic guanosine monophosphate (cGMP) (see, e.g., Doherty, "Oral,
Transdermal, and
Transurethral Therapies for Erectile Dysfunction" in ]~~j~~e Infertility and
Dysfunction,
Hellstrom, ed., Chapter 34 (New York, New York: Springer-VerlagHellstrom,
1997)).
Numerous phosphodiesterase inhibitors have previously been described in the
literature for
a variety of therapeutic uses, including treatment of obstructive lung
disease, allergies,
hypertension, angina, congestive heart failure and depression (see, e.g.,
Goodman and
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Gilman's The Pharmacological Basis of Therapeutic Ninth Edition, Chapter 34).
Oral and
parenteral administration of phosphodiesterase inhibitors, as alluded to
above, have also
been suggested for the treatment of erectile dysfunction (Doherty, supra; see
also PCT
Publication Nos. WO 96/16644, and WO 94/28902). The phosphodiesterases have
been
classified into seven major families, Types I-VII, based on amino acid or DNA
sequences.
The members of the family vary in their tissue, cellular and subcellular
distribution, as well
as their links to cAMP and cGMP pathways. For example, the corpora cavernosa
contains:
type III phosphodiesterases, which are cAMP-specific cGMP inhibitable; type IV
phosphodiesterases, the high affinity, high-specificity cAMP-specific form;
and type V
phosphodiesterases, one of the cGMP-specific forms.
Various compounds are known as inhibitors of phosphodiesterases are
known, including vinpocetine, milrinone, amrinone, pimobendan, cilostamide,
enoximone,
peroximone, vesnarinone, rolipram, 8020-1724, zaprinast, dipyridamole,
pentoxifylline,
sildenafil citrate (Viagra~), doxazosin, papaverine, prazosin, terazosin,
trimazosin, and
hydralazine. PCT Publication No. WO 94/28902 discloses a series of pyrazole
[4,3-
d]pyrimidin-7-ones cGMP phosphodiesterase inhibitors. PCT Publication No. WO
96/16644 also discloses a variety of cGMP phosphodiesterase inhibitors,
including griseolic
acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives,
fused and
condensed pyrimidines, a pyrimdopyrimidine derivative, a purine compound, a
quinazoline
compound, a phenylpyrimidone derivative, an imidazoquinoxalinone derivative or
aza
analogues thereof, a phenylpyridone derivative, and others.
The following documents are of interest insofar as they relate to the
treatment of erectile dysfunction by delivering pharmacologically active
agents locally to
the penis:
U.S. Patent No. 4,127,118 to Latorre describes the injection of vasodilator
drugs into the corpora cavernosa of the penis to dilate the arteries that
supply blood to the
erectile tissues, thereby inducing an erection;
U.S. Patent No. 5,439,938 to Snyder et al. describes the administration of
nitric oxide (NO) synthase inhibitors by direct injection of a drug into the
corpora
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cavernosa, by topical drug administration or transurethral drug
administration, for inhibiting
penile erection due to priapism and for treating urinary incontinence;
Virag et al., Angiology-Journal of Vascular Diseases (February 1984), pp.
79-87, Brindley, Brit. J. Psychiat. ,3:332-337 (1983) and Stief et al.,
Urology ~X :483-
S 485 (1988) respectively describe the intracavernosal injection of papaverine
(a smooth
muscle relaxant), phenoxybenzamine or phentolamine (a-receptor blockers) and a
phentolamine-papaverine mixture to treat erectile dysfunction; and
PCT Publication No. WO 91/16021, U.S. Patent No. 4,801,587 to Voss et
al., and U.S. Patent Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020 to
Place et al.
relate to the treatment of erectile dysfunction by delivery of a vasoactive
agent into the male
urethra.
The invention, as noted above, is directed to local administration of
pharmacologically active agents to treat erectile dysfunction. The agents are
preferably,
although not necessarily, Type V phosphodiesterase inhibitors. Surprisingly,
it has now
been found by the inventors herein that local administration of these
phosphodiesterase
inhibitors as disclosed herein is highly effective in treating erectile
dysfunction, particularly
vasculogenic impotence. Local administration of phosphodiesterase inhibitors,
and
transurethral drug administration in particular, generally enables use of a
lower drug dosage,
avoids many of the side effects encountered with other modes of
administration, and avoids
interaction with other systemically administered medications an individual may
be taking.
The Iocal administration of phosphodiesterase inhibitors, particularly Type V
phosphodiesterase inhibitors, to treat erectile dysfunction, accordingly
represents an
important advance in the treatment of impotence and other erectile disorders.
DISCLOSURE OF INVENTION
It is a primary object of the invention to address the above-described need in
the art by providing a novel method for treating erectile dysfunction by
locally
administering an effective amount of a selected phosphodiesterase inhibitor to
an individual
in need of such therapy.
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It is another object of the invention to provide such a method wherein the
phosphodiesterase inhibitor is administered transurethrally.
It is still another object of the invention to provide such a method wherein
the phosphodiesterase inhibitor is administered via intracavernosal injection.
It is yet another object of the invention to provide such a method wherein the
phosphodiesterase inhibitor is administered topically.
It is a further object of the invention to provide such a method wherein the
phasphodiesterase inhibitor is administered transdenmally.
It is yet a further object of the invention to provide pharmaceutical
formulations for carrying out the aforementioned methods.
It is an additional object of the invention to provide a kit capable of use by
an
individual for self administration of a phosphodiesterase inhibitor as
provided herein.
Additional objects, advantages and novel features of the invention will be set
forth in part in the description that follows, and in part will become
apparent to those skilled
in the art upon examination of the following, or may be learned by practice of
the invention.
In a first aspect of the invention, a method is provided for treating an
individual prone to erectile dysfunction, particularly vasculogenic erectile
dysfunction, the
method comprising locally administering to the individual a pharmaceutical
formulation
containing a phosphodiesterase inhibitor. Administration of the pharmaceutical
formulation
is carned out within the context of a predetermined dosing regimen such that
the agent is
effective in the treatment of erectile dysfunction. The method is especially
useful in the
treatment of vasculogenic impotence, although other types of erectile
dysfunction may also
be treated using the present formulations. Drug delivery is preferably
effected
transurethrally, but the drug may also be administered via intracavernosal
injection or using
topical or transdermal administration.
In another aspect of the invention, a pharmaceutical formulation is provided
for carrying out the present method for treating erectile dysfunction. The
pharmaceutical
formulation comprises an effective amount of a phosphodiesterase inhibitor, a
Garner or
vehicle preferably suitable for the selected mode of administration, and,
optionally, a
permeation enhancer. The formulation may contain one or more additional active
agents,
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e.g., dopaminergic drugs, smooth muscle relaxants, vasoactive drugs, and
additives, e.g., excipients, surfactants, preservatives (e.g., antioxidants),
stabilizers, chelating agents, enzyme inhibitors, antibacterial agents and the
like,
as will be appreciated by those skilled in the art of drug formulation
preparation
and delivery.
In another aspect, a kit is provided to assist an individual in drug
administration to carry out the method of the invention. Generally, the kit
will
include the following components: a pharmaceutical formulation comprising the
phosphodiesterase inhibitor to be administered; a device for effecting
delivery of
the pharmaceuti6al formulation; a container housing the pharmaceutical
formulation during storage and prior to use; and instructions for carrying out
drug
administration in a manner effective to treat erectile dysfunction.
According to a first aspect of the invention, there is provided the use of an
effective amount of a phosphodiesterase inhibitor or a pharmaceutically
acceptable salt, ester, amide or prodrug thereof for treating erectile
dysfunction in
a male individual, wherein the phosphodiesterase inhibitor is formulated for
local
administration and further wherein the phosphodiesterase inhibitor is selected
from
the group consisting of Type IV phosphodiesterase inhibitors, Type V
phosphodiesterase inhibitors, and combinations thereof.
According to a second aspect of the invention, there is provided the use of
an effective amount of a Type III phosphodiesterase inhibitor or a
pharmaceutically
acceptable salt, ester, amide or prodrug thereof for treating erectile
dysfunction in
a male individual, wherein the Type III phosphodiesterase inhibitor is
formulated
for local administration.
According to a third aspect of the invention, there is provided a
pharmaceutical formulation for treating erectile dysfunction in an individual,
comprising a urethral dosage form of a phosphodiesterase inhibitor, and a
carrier
suitable for transurethral drug administration, wherein the pharmaceutical
formulation is formulated for local administration.
According to a fourth aspect of the invention, there is provided a kit for
treating erectile dysfunction in an individual, comprising: a pharmaceutical
formulation containing a phosphodiesterase inhibitor; a means for
administering
the agent; a container for housing the formulation and drug delivery means;
and
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instructions for using the drug delivery means to administer the drug within
the
context of a dosing regimen effective to treat erectile dysfunction, wherein
the
pharmaceutical formulation is formulated for local administration.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is an exploded view of one embodiment of a transurethral
therapeutic device which may be used in conjunction with the present method.
MODES FOR CARRYING OUT THE INVENTION
Definitions:
Before describing the present invention in detail, it is to be understood that
this invention is not limited to particular drugs or drug delivery systems, as
such
may vary. It is also to be understood that the terminology used herein is for
the
purpose of describing particular embodiments only, and is not intended to be
limiting.
It must be noted that, as used in this specification and the appended claims,
the singular forms "a," "an" and "the°' include plural referents unless
the context
clearly dictates otherwise. Thus, for example, reference to "a
phosphodiesterase
inhibitor" includes a mixture of two or more such compounds, reference to "a
permeation enhancer" includes mixtures of two or more enhancers, and the like.
In describing and claiming the present invention, the following terminology
will be used in accordance with the definitions set out below.
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The term "erectile dysfunction" is intended to include any and all types of
erectile dysfunction, including: vasculogenic, neurogenic, endocrinologic and
psychogenic
impotence ("impotence" is used here in its broadest sense to indicate an
inability a periodic
or consistent inability to achieve or sustain an erection of sufficient
rigidity for sexual
intercourse; see U.S. Patent No. 5,242,391 to Place et al., cited supra);
Peyronie's
syndrome; priapism; premature ejaculation; and any other condition, disease or
disorder,
regardless of cause or origin, which interferes with at least one of the three
phases of human
sexual response, i.e., desire, excitement and orgasm (see Kaplan, Disorders of
Sexual Desire
(New York, New York: Brunner Mazel Book Inc., 1979)).
The terms "treating" and "treatment" as used herein refer to reduction in
severity and/or frequency of symptoms, elimination of symptoms and/or
underlying cause,
prevention of the occurrence of symptoms and/or their underlying cause, and
improvement
or remediaton of damage. The present method of "treating" erectile
dysfunction, as the term
is used herein, thus encompasses both prevention of the disorder in a
predisposed individual
and treatment of the disorder in a clinically symptomatic individual.
The term "phosphodiesterase inhibitor" as used herein is intended to mean an
agent that is capable of inhibiting or selectively reducing the activity of
any one or more
phosphodiesterases.
The terms "active agent," "drug" and "pharmacologically active agent" are
used interchangeably herein to refer to a chemical material or compound that
induces a
desired effect. In the preferred embodiment herein, the terms refer to a
phosphodiesterase
inhibitor which is capable of being delivered locally, preferably
transurethrally. Included
are derivatives and analogs of those compounds or classes of compounds
specifically
mentioned which also induce the desired effect.
The terms "transurethral," "intraurethral" and "urethral" to specify the
preferred mode of administration herein are used interchangeably to refer to
the delivery of
the drug into the urethra such that drug contacts and passes through the wall
of the urethra.
As noted elsewhere herein, the present method preferably involves delivery of
the drug at
least about 3 cm and preferably at least about 7 cm into the urethra.
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The term "intracavernosal" as used herein refers to an alternative mode of
drug administration and involves injection into one or both corpora of the
corpora
cavernosal tissues of the penis.
The term "transdermal" delivery, applicants intend to include both
transdermal (or "percutaneous") and transmucosal administration, i.e.,
delivery by passage
of a drug through the skin or mucosal tissue and into the bloodstream. The
term "body
surface" will sometimes be used herein to refer to either the skin or the
mucosal tissue.
"Transdermal" delivery is also intended to encompass delivery of a drug by
passage across
scrotal tissue.
The term "topical administration" is used in its conventional sense to mean
delivery of a topical drug or pharmacologically active agent to the skin or
mucosa.
"Penetration enhancement" or "permeation enhancement" as used herein
relates to an increase in the permeability of the urethral wall to the
selected
pharmacologically active agent, i.e., so that the rate at which the drug
permeates through the
urethral wall is increased.
"Garners" or "vehicles" as used herein refer to carrier materials suitable for
local drug administration. Carriers and vehicles useful herein include any
such materials
known in the art which is nontoxic and does not interact with other components
of the
composition in a deleterious manner.
By an "effective" amount of a drug or pharmacologically active agent is
meant a nontoxic but sufficient amount of the drug or agent to provide the
desired effect,
i.e., treatment of erectile dysfunction.
Active Agents for Treatment of Erectile Dysfunction:
In order to carry out the method of the invention, a selected
phosphodiesterase inhibitor is locally administered to an individual prone to
erectile
dysfunction.
The active agent herein may be any agent which is effective to inhibit the
activity of a phosphodiesterase. Suitable phosphodiesterase inhibitors
include, but are not
limited to, inhibitors of the type III phosphodiesterases (CAMP-specific-cGMP
inhibitable
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form), the type IV phospodiesterase (high affinity-high specificity cAMP form)
and the type
V phosphodiesterases (the cGMP specific form). Additional inhibitors that may
be used in
conjunction with the present invention are cGMP-specific phosphodiesterase
inhibitors
other than Type V inhibitors.
Examples of type III phospodiesterase inhibitors that may be administered
include, but are not limited to, bypyridines such as milrinone and amirinone,
imidazolones
such as piroximone and enoximone, dihydropyridazinones such as imazodan, 5-
methyl-
imazodan, indolidan and ICI118233, quinolinone compounds such as cilostamide,
cilostazol
and vesnarinone, and other molecules such as bemoradan, anergrelide,
siguazodan,
trequinsin, pimobendan, SKF-94120, SKF-95654, lixazinone and isomazole.
Examples of type IV phosphodiesterase inhibitors suitable herein include,
but are not limited to, rolipram and rolipram derivatives such as 8020-1724,
nitraquazone
and nitraquazone derivatives such as CP-77059 and RS-25344-00, xanthine
derivatives such
as denbufylline and ICI63197, and other compounds such as EMD54622, LAS-31025
and
etazolate.
Examples of type V phosphodiesterase inhibitors include, but are .not limited
to, zaprinast, MY5445, dipyridamole, and sildenafil. Other type V
phosphodiesterase
inhibitors are disclosed in PCT Publication Nos. WO 94/28902 and WO 96/16644.
The compounds described in PCT Publication No. WO 94/28902 are
pyrazolopyrimidinones. Examples of the inhibitor compounds include 5-(2-ethoxy-
5-
morpholinoacetylphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-
d]pyrimidin-7-
one, 5-(5-morpholinoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-
7H-
pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)-
phenyl]-1-
methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-allyloxy-
5-(4-
methyl-1-piperazinylsulfonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-
pyrazolo[4,3-
d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-propyl)-1-piperazinylsulfonyl)-phenyl]-
1-methyl-3-
n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-[4-(2-
hydroxyethyl)-1-piperazinyl sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-
7H-
pyrazolo[4,3-d]pyrimidin-7-one, 5-[5-[4-(2-hydroxyethyl}-1-
piperazinylsulfonyl]-2-n-
propoxyphenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-
one, 5-
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[2-ethoxy-5-(4-methyl-1-piperazinylcarbonyl)phenyl]-1-methyl-3-n-propyl-1,6-
dihydro-7H-
pyrazolo[4,3-d]pyrimidin-7-one, and 5-[2-ethoxy-S-(1-methyl-2-
imidazolyl)phenyl]-1-
methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
The phosphodiesterase inhibitors described in PCT Publication No. WO
96/16644 include griseolic acid derivatives, 2-phenylpurinone derivatives,
phenylpyridone
derivatives, fused and condensed pyrimidines, pyrimidopyrimidine derivatives,
purine
compounds, quinazoline compounds, phenylpyrimidinone derivative,
imidawquinoxalinone
derivatives or aza analogues thereof, phenylpyridone derivatives, and others.
Specific
examples of the phosphodiesterase inhibitors disclosed in WO 96/16644 include
1,3-
dimethyl-5-benzylpyrazolo[4,3-d]pyrimidine-7-one, 2-(2-propoxyphenyl)-6-
purinone, 6-(2-
propoxyphenyl)-1,2-dihydro-2-oxypyridine-3-carboxamide, 2-(2-propoxyphenyl)-
pyrido[2,3-d]pyrimid-4(3H)-one, 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-
dihydro-
pyrimido[4,5-d]pyrimidine, 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-
carboxamide, 1-
ethyl-3-methylimidazo[l,Sa]quinoxalin-4(SH)-one, 4-phenylmethylamino-6-chloro-
2-(1-
imidazoloyl)quinazoline, 5-ethyl-8-[3-(N-cyclohexyl-N-methylcarbamoyl)-
propyloxy]-4,5-
dihydro-4-oxo-pyrido[3,2-a]-pyrrolo[1,2-a]pyrazine, 5.'rmethyl-3'-
(phenylmethyl)-
spiro[cyclopentane-1,T(8'H)-(3'H)-imidazo[2,1-b]purin]4'(5'H)-one, 1-[6-chloro-
4-(3,4-
methylenedioxybenzyl)-aminoquinazolin-2-yl)piperidine-4-carboxylic acid, (6R,
9S)-2-(4-
trifluoromethylphenyl)methyl-S-methyl-3,4,5,6a,7,8,9,9a-
octahydrocyclopent[4,5]-
imidazo[2,1-b]-purin-4-one, 1-t-butyl-3-phenylmethyl-6-(4-pyridyl)pyrazolo[3,4-
d]-
pyrimid-4-one, 1-cyclopentyl-3-methyl-6-(4-pyridyl)-4,5-dihydro-1H-
pyrazolo[3,4-
d]pyrimid-4-one, 2-butyl-1-(2-chlorobenzyl)6-ethoxy-carbonylbenzimidazole, and
2-(4-
carboxypiperidino)-4-(3,4-methylenedioxybenzyl)amino-6-nitroquinazoline, and 2-
phenyl-
8-ethoxycycloheptimidazole.
Still other type V phosphodiesterase inhibitors useful in conjunction with the
present invention include: IC-351 (ICOS); 4-bromo-5-(pyridylmethylamino)-6-[3-
(4-
chlorophenyl)propoxy]-3(2H)pyridazinone; 1-[4-[(1,3-benzodioxol-5-
ylmethyl)amiono]-6-
chloro-2-quinazolinyl]-4-piperidine-carboxylic acid, monosodium salt; (+)-cis-
5,6a,7,9,9,9a-hexahydro-2-[4-(trifluoromethyl)-phenylmethyl-5-methyl-cyclopent
4,5]imidazo[2,1-b]purin-4(3H)one; furazlocillin; cis-2-hexyl-5-methyl-
3,4,5,6a,7,8,9,9a
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octahydrocyclopent[4,5]imidazo[2,1-b]purin-4-one; 3-acetyl-1-(2-chlorobenzyl)-
2-
propylindole-6-carboxylate; 4-bromo-5-(3-pyridylmethylamino)-6-(3-(4-
chlorophenyl)
propoxy)-3-(2H)pyridazinone; 1-methyl-5-(5-morpholinoacetyl-2-n-propoxyphenyl)-
3-n-
propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one; 1-[4-[(1,3-benzodioxol-5-
ylmethyl)aminoJ-6-chloro-2-quinazolinyl]-4-piperidinecarboxylic acid,
monosodium salt;
Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer);
Phaimaprojects No. 5064 (Kyowa Hakko; see WO 96/26940); Pharmaprojects No.
5069
(Schering Plough); GF-196960 (Glaxo Wellcome); and Sch-51866.
Other phosphodiesterase inhibitors that may be used in the method of this
invention include nonspecific phosphodiesterase inhibitors such as
theophylline, IBMX,
pentoxifylline and papaverine, and direct vasodilators such as hydralazine.
The active agents may be administered, if desired, in the form of salts,
esters,
amides, prodrugs, derivatives, and the like, provided the salt, ester, amide,
prodrug or
derivative is suitable pharmacologically, i.e., effective in the present
method. Salts, esters,
amides, prodrugs and other derivatives of the active agents may be prepared
using standard
procedures known to those skilled in the art of synthetic organic chemistry
and described,
for example, by J. March, ~4dva_n_ced Organic Chemistry: Reactions_ Mechanisms
and
Structure, 4th Ed. (New York: Wiley-Interscience, 1992). For example, acid
addition salts
are prepared from the free base using conventional methodology, and involves
reaction with
a suitable acid. Generally, the base form of the drug is dissolved in a polar
organic solvent
such as methanol or ethanol and the acid is added thereto. The resulting salt
either
precipitates or may be brought out of solution by addition of a less polar
solvent. Suitable
acids for preparing acid addition salts include both organic acids, e.g.,
acetic acid, propionic
acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid,
succinic acid, malefic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,
mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic
acid, and the
like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid,
sulfuric acid,
nitric acid, phosphoric acid, and the like. An acid addition salt may be
reconverted to the
free base by treatment with a suitable base. Particularly preferred acid
addition salts of the
active agents herein are halide salts, such as may be prepared using
hydrochloric or
hydrobromic acids. Conversely, preparation of basic salts of acid moieties
which may be
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present on a phosphodiesterase inhibitor molecule are prepared in a similar
manner using a
pharmaceutically acceptable base such as sodium hydroxide, potassium
hydroxide,
ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
Particularly
preferred basic salts herein are alkali metal salts, e.g., the sodium salt,
and copper salts.
Preparation of esters involves functionalization of hydroxyl and/or carboxyl
groups which
may be present within the molecular structure of the drug. The esters are
typically acyl-
substituted derivatives of free alcohol groups, i.e., moieties which are
derived from
carboxylic acids of the formula RCOOH where R is alkyl, and preferably is
lower alkyl.
Esters can be reconverted to the free acids, if desired, by using conventional
hydrogenolysis
or hydrolysis procedures. Amides and prodrugs may also be prepared using
techniques
known to those skilled in the art or described in the pertinent literature.
For example,
amides may be prepared from esters, using suitable amine reactants, or they
may be
prepared from an anhydride or an acid chloride by reaction with ammonia or a
lower alkyl
amine. Prodrugs are typically prepared by covalent attachment of a moiety
which results in
a compound that is therapeutically inactive until modified by an individual's
metabolic
system.
Pharmaceutical Formulations and Modes of Administration:
The active agent is administered locally to treat erectile dysfunction, and is
accordingly administered in a pharmaceutical formulation suitable for local
administration.
Depending on the specific, "local" mode of administration, the
pharmaceutical compositions may be in the form of solid, semi-solid or liquid
dosage forms,
such as, for example, suppositories, powders, liquids, suspensions, creams,
ointments,
lotions or the like, preferably in unit dosage form suitable for single
administration of a
precise dosage. The compositions comprise an effective amount of the
phosphodiesterase
inhibitor in combination with a pharmaceutically acceptable Garner and, in
addition, may
include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
Fvr solid compositions, conventional nontoxic solid carriers include, for
example, pharmaceutical grades of mannitol, lactose, starch, magnesium
stearate, sodium
saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the
like. Liquid
pharmaceutically administrable compositions can, for example, be prepared by
dissolving,
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dispersing, etc., an active compound as described herein and optional
pharmaceutical
adjuvants in an excipient, such as, for example, water, saline, aqueous
dextrose, glycerol,
ethanol, and the like, to thereby form a solution or suspension. If desired,
the
pharmaceutical composition to be administered may also contain minor amounts
of non-
toxic auxiliary substances such as wetting or emulsifying agents, pH buffering
agents and
the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine
sodium acetate,
triethanolamine oleate, etc. Actual methods of preparing such dosage forms are
known, or
will be apparent, to those skilled in this art; for example, see Remington's
Pharmaceutical_
Science, referenced above.
The formulation may, for example, be administered transurethrally. For
transurethral administration, the formulation comprises a urethral dosage form
containing
the active agent and one or more selected carriers or excipients, such as
water, silicone,
waxes, petroleum jelly, polyethylene glycol ("PEG"), propylene glycol ("PG"),
liposomes,
sugars such as mannitol and lactose, and/or a variety of other materials, with
polyethylene
glycol and derivatives thereof particularly preferred.
Depending on the particular phosphodiesterase inhibitor administered, it may
be desirable to incorporate a transurethral permeation enhancer in the
urethral dosage form.
Examples of suitable transurethral permeation enhancers include
dimethylsulfoxide
("DMSO"), dimethyl formamide ("DMF"), N,N-dimethylacetamide ("DMA"),
decylmethylsulfoxide ("ClpMSO"), polyethylene glycol monolaurate ("PEGML"),
glycerol
monolaurate, lecithin, the 1-substituted azacycloheptan-2-ones, particularly 1-
n-
dodecylcyclazacycloheptan-2-one (available under the trademark Azone~ from
Nelson
Research & Development Co., Irvine, CA), SEPA~ (available from Macrochem Co.,
Lexington, MA), alcohols (e.g., ethanol), surfactants as discussed above,
including, for
example, Tergitol~, Nonoxynol-9~ and TWEEN-80~, and lower alkanols such as
ethanol.
Transurethral formulations may additionally include one or more enzyme
inhibitors effective to inhibit drug-degrading enzymes which may be present in
the urethra.
Such enzyme inhibiting compounds may be determined by those skilled in the art
by
reference to the pertinent literature and/or using routine experimental
methods. Additional
optional components include excipients, preservatives (e.g., antioxidants),
chelating agents,
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solubilizing agents (e.g., surfactants), and the like, as will be appreciated
by those skilled in
the art of drug formulation preparation and delivery.
Transurethral drug administration, as explained in U.S. Patent Nos.
5,242,391, 5,474,535, 5,686,093 and 5,773,020 to Place et al., can be carried
out in a
number of different ways using a variety of urethral dosage forms. For
example, the drug
can be introduced into the urethra from a flexible tube, squeeze bottle, pump
or aerosol
spray. The drug may also be contained in coatings, pellets or suppositories
which are
absorbed, melted or bioeroded in the urethra. In certain embodiments, the drug
is included
in a coating on the exterior surface of a penile insert. A preferred drug
delivery device for
administering a drug transurethrally is shown in Figure 1. It is preferred,
although not
essential, that the drug be delivered at least about 3 cm into the urethra,
and preferably at
least about 7 cm into the urethra. Generally, delivery at about 3 cm to about
8 cm into the
urethra will provide ei~ective results in conjunction with the present method.
Urethral suppository formulations containing PEG or a PEG derivative are
particularly preferred urethral dosage forms herein, and may be conveniently
formulated
using conventional techniques, e.g., compression molding, heat molding or the
like, as will
be appreciated by those skilled in the art and as described in the pertinent
literature and
pharmaceutical texts. See, for example, ltemington: The Science and Practice
of
ph~~~y, 19th Ed. {Easton, PA: Mack Publishing Co., 1995), which discloses
typical
methods of preparing pharmaceutical compositions in the form of urethral
suppositories.
The PEG or PEG derivative preferably has a molecular weight MW in the range of
about 200
to 2500, more preferably in the range of about 1000 to 2000. Suitable
polyethylene glycol
derivatives include polyethylene glycol fatty acid esters, for example,
polyethylene glycol
monostearate, polyethylene glycol sorbitan esters, e.g., polysorbates, and the
like. It is also
preferred that urethral suppositories contain one or more solubilizing agents
effective to
increase the solubility of the active agent in the PEG or other transurethral
vehicle.
The solubilizing agent may be a nonionic, anionic, cationic or amphoteric
surfactant. Nonionic surfactants include: long-chain fatty acids, i.e., acids
having the
structural formula CH3(CH2)mCOOH where m is an integer in the range of 8 to
16; fatty
alcohols, that is, alcohols having the structural formula CH3(CH2)mC(H)OH,
such as lauryl,
cetyl and stearyl alcohols; glyceryl esters such as the naturally occurring
mono-, di- and
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triglycerides; and esters of fatty alcohols or other alcohols such as
propylene glycol,
polyethylene glycol, sorbitan, sucrose, and cholesterol. Examples of water-
soluble nonionic
surfactant derivatives include sorbitan fatty acid esters (such as those sold
under the
tradename Span~), polyoxyethylene sorbitan fatty acid esters (such as those
sold under the
tradename TWEEN~), polyoxyethylene fatty acid esters (such as those sold under
the
tradename Myrj~), polyoxyethylene steroidal esters, polyoxypropylene sorbitan
fatty acid
esters, polyoxypropylene fatty acid esters, polyoxypropylene steroidal esters,
polyoxyethylene ethers (such as those sold under the tradename Brij~),
polyglycol ethers
(such as those sold under the tradename Tergitolc~), and the like. Preferred
nonionic
surfactants for use as the solubilizing agent herein are polyglycol ether,
polyoxyethylene
sorbitan trioleate, sorbitan monopalmitate, polysorbate 80, polyoxyethylene 4-
lauryl ether,
propylene glycol, and mixtwes thereof. Anionic surfactants which may be used
as the
solubilizing agent herein include long-chain alkyl suIfonates, carboxylates,
and sulfates, as
well as alkyl aryl sulfonates, and the like. Preferred anionic surfactants are
sodium dodecyl
sulfate, dialkyl sodium sulfosuccinate (e.g., sodium bis-(2-ethylhexyl)-
sulfosuccinate),
sodium 7-ethyl-2-methyl-4-dodecyl sulfate and sodium dodecylbenzene sulfonate.
Cationic
surfactants which may be used to solubilize the active agent are generally
long-chain amine
salts or quaternary ammonium salts, e.g., decyltrimethyl-ammonium bromide,
dodecyltrimethylammonium bromide, tetradecyltrimethylammonium bromide,
tetradecyltrimethylammonium chloride, and the like. Amphoteric swfactants are
generally,
although not necessarily, compounds which include a carboxylate or phosphate
group as the
anion and an amino or quaternary ammonium moiety as the cation. These include,
for
example, various polypeptides, proteins, alkyl betaines, and natwal
phospholipids such as
lecithins and cephalins. Other suitable solubilizing agents (e.g., glycerin)
may also be used,
as will be appreciated by those skilled in the art. The solubilizing agent
will be present in
the range of approximately 0.01 wt.% to 40 wt.%, more preferably in the range
of
approximately 5.0 wt.% to 40 wt.%, and most preferably in the range of
approximately
10.0 wt.% to 40 wt.%.
It may be desirable to deliver the active agent in a wethral dosage form
which provides for controlled or sustained release of the agent. In such a
case, the dosage
form typically comprises a biocompatible, biodegradable material, typically a
biodegradable
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polymer. Examples of such polymers include polyester, polyalkylcyanoacrylate,
polyorthoester, polyanhydride, albumin, gelatin and starch. As explained, for
example, in
PCT Publication No. W096/40054, these and other polymers can be used to
provide
biodegradable microparticles which enable controlled and sustained drug
release, in turn
minimizing the required dosing frequency.
The urethral dosage form will preferably comprise a suppository that is on
the order of 2 to 20 mm, preferably 5 to 10 mm, in length and less than about
5 mm,
preferably less than about 2 mm in width. The weight of the suppository will
typically be in
the range of approximately 1 mg to 100 mg, preferably in the range of
approximately 1 mg
to 50 mg. However, it will be appreciated by those skilled in the art that the
size of the
suppository can and will vary, depending on the potency of the drug, the
nature of the
formulation, and other factors.
In Figure 1, a suitable transurethral drug delivery device is shown generally
at 10. The device comprises a transurethral inserter I1 having an easily
graspable segment
12 that has opposing symmetrically concave surfaces 13 and 14 adapted to be
held by two
fingers. Drug is contained within a urethral suppository (not shown) within
shaft 15, which
is sized to fit within the urethra. A longitudinal plunger, the tip of which
is seen at 16, is
slidably insertable into the longitudinal bore contained within shaft 15. To
extrude drug
into the urethra, shaft I5 is inserted into the urethra, and plunger tip 16 is
pushed into
segment 12. The inserter I1 is then removed. Prior to use, and during storage,
the device is
capped with elongate cap 17 which fits snugly over flange 18 at the proximal
end of shaft
15. The cap 17 is provided with a series of parallel ridges 19 to facilitate
gripping of the cap
and removal from inserter 11.
Although the transurethral drug delivery device shown in Figure 1 represents
a preferred device for use herein, again, it should be emphasized that a wide
variety of
device configurations and urethral dosage forms can be used. Examples of other
devices
suited to deliver a drug transurethrally are those described and illustrated
in PCT
Publication No. WO 91/16021 and in U.S. Patent Nos. 5,242,391, 5,474,535,
5,686,093
and 5,773,020 to Place et al.
~ The devices can either be manufactured under sterile conditions, thereby
eliminating the need for post-manufacturing sterilization, or they can be
manufactured under
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non-sterile conditions and then subsequently sterilized by any suitable
technique, e.g.,
radiation sterilization. The devices can be manufactured by typical plastic
forming and
coating processes known in the art, including molding extrusion, heat forming,
dip coating,
and the like.
Transurethral drug delivery may involve an "active" delivery mechanism
such as iontophoresis, electroporation or phonophoresis. Devices and methods
for
delivering drugs in this way are well known in the art. Iontophoretically
assisted drug
delivery is, for example, described in PCT Publication No. W096/40054, cited
above.
Briefly, the active agent is driven through the urethral wall by means of an
electric current
passed from an external electrode to a second electrode contained within or
affixed to a
urethral probe.
Other modes of "local" drug administration can also be employed. For
example, the selected active agent may be administered by way of
intracavernosal injection,
or it may be administered topically, in an ointment, gel or the like, or
transdermally,
including transscrotally, using a conventional transdermal drug delivery
system.
Intracavernosal injection can be carried out by use of a syringe any other
suitable device. An example of a hypodermic syringe useful herein, that can be
used for
simultaneous injection into both corpora, is described in U.S. Patent No.
4,127,118 to
Latorre. The injection is made on the dorsum of the penis by placement of the
needle to the
side of each dorsal vein and inserting it deep into the corpora.
For intracavernosal injection, the active agent to be administered is
incorporated into a sterile liquid preparation, typically a solution or
suspension in an
aqueous or oleaginous medium. This solution or suspension may be formulated
according
to techniques known in the art using suitable carriers, dispersants, wetting
agents, diluents,
suspending agents or the like. Among the acceptable vehicles and solvents that
may be
employed are water, isotonic saline, vegetable oil, fatty esters and polyols.
The phosphodiesterase inhibitors useful herein may also be delivered through
the skin using conventional transdermal drug delivery systems, i.e.,
transdermal "patches"
wherein the agent is typically contained within a laminated structure that
serves as a drug
delivery device to be affixed to the skin. In such a structure, the drug
composition is
typically contained in a layer, or "reservoir," underlying an upper backing
layer. The
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laminated device may contain a single reservoir, or it may contain multiple
reservoirs. In
one embodiment, the reservoir comprises a polymeric niatrix of a
pharmaceutically
acceptable contact adhesive material that serves to affix the system to the
skin during drug
delivery. Examples of suitable skin contact adhesive materials include, but
are not limited
to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates,
polyurethanes, and the
like. Alternatively, the drug-containing reservoir and skin contact adhesive
are present as
separate and distinct layers, with the adhesive underlying the reservoir
which, in this case,
may be either a polymeric matrix as described above, or it may be a liquid or
hydrogel
reservoir, or may take some other form. The backing layer in these laminates,
which serves
as the upper surface of the device, functions as the primary structural
element of the
laminated structure and provides the device with much of its flexibility. The
material
selected for the backing layer should be substantially impermeable to the
active agent and
any other materials that are present.
Preferred formulations for topical drug delivery herein are ointments and
creams. Ointments are semisolid preparations which are typically based on
petrolatum or
other petroleum derivatives. Creams containing the selected active agent, are,
as known in
the art, viscous liquid or semisolid emulsions, either oil-in-water or water-
in-oil. Cream
bases are water-washable, and contain an oil phase, an emulsifier and an
aqueous phase.
The oil phase, also sometimes called the "internal" phase, is generally
comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous
phase usually,
although not necessarily, exceeds the oil phase in volume, and generally
contains a
humectant. The emulsifier in a cream formulation is generally a nonionic,
anionic, cationic
or amphoteric surfactant. The specific ointment or cream base to be used, as
will be
appreciated by those skilled in the art, is one that will provide for optimum
drug delivery.
As with other carriers or vehicles, an ointment base should be inert, stable,
nonirritating and
nonsensitizing.
Additional pharmacologically active agents may be delivered along with the
primary active agent, i.e., the phosphodiesterase inhibitor. Vasoactive
agents, particularly
vasodilators, are preferred additional agents. Suitable vasoactive agents
include, but are not
limited to: nitrates and like compounds such as nitroglycerin, isosorbide
dinitrate, erythrityl
tetranitrate, amyl nitrate, sodium nitroprusside, molsidomine, linsidomine
chlorhydrate
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("SIN-1 "), S-nitroso-N-acetyl-d,l-penicillamine ("SNAP"), S-nitroso-N-
cysteine, S-nitroso-
N-glutathione ("SNO-GLU") and diazenium diolates ("NONOates"); long and short
acting
a-blockers such as phenoxybenzamine, dibenamine, doxazosin, terazosin,
phentolamine,
tolazoline, prazosin, trimazosin, alfuzosin, tamsulosin and indoramin; 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 and
isoxsuprine; chlorpromazine; haloperidol; yohimbine; ReclS/2739; trazodone;
naturally
occurring prostaglandins such as PGEo, PGE1, PGA1, PGB1, PGF~«, 19-hydroxy-
PGAI,
19-hydroxy-PGB1, PGE2, PGA2, PGB2, 19-hydroxy-PGA2, 19-hydroxy-PGB2, PGE3,
PGF3a; semisynthetic or synthetic derivatives of natural prostaglandins,
including
carboprost tromethamine, dinoprost tromethamine, dinoprostone, lipoprost,
gemeprost,
metenoprost, sulprostone and tiaprost; and vasoactive intestinal peptides.
Prazosin,
prostaglandin Eo, prostaglandin E1 and prostaglandin E2 are particularly
preferred
vasoactive agents to be co-administered with the active agent.
The amount of active agent administered, and the dosing regimen used, will,
of course, be dependent on the particular drug selected, the age and general
condition of the
subject being treated, the severity of the subject's condition, and the
judgment of the
prescribing physician. Generally, the daily dosage when administered locally
will be less
than the dosage normally given in conjunction with systemic modes of
administration, and
typically, the drug will be administered one to four times daily or, with some
active agents,
just prior to intercourse. Alternatively, a large initial loading dose can be
used to achieve
effective levels of the agent and can be followed by smaller doses to maintain
those levels.
A typical daily dose of an active agent as administered locally is generally
in the range of
approximately 0.1 to 500 mg. Depending on the half life of the drug and the
availability via
the chosen route of administration, the dosing regimen can be modulated in
order to achieve
satisfactory control of the onset of ejaculation. By administering the drug
locally, the side
effects, drug interactions and disease considerations of systemic (e.g., oral)
drug
administration are avoided, as is the stigma associated with psychotherapeutic
drug therapy.
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Kits:
The invention also encompasses a kit for patients to carry out the present
method of treating premature ejaculation using local drug therapy. The kit
contains the
pharmaceutical formulation to be administered, a device for administering the
formulation
(e.g., a transurethral drug delivery device such as shown in Figure 1), a
container, preferably
sealed, for housing the drug and device during storage and prior to use, and
instructions for
carrying out drug administration in an effective manner. The formulation may
consist of the
drug in unit dosage form. The kit may contain multiple formulations of
different dosages of
the same agent. The kit may also contain multiple formulations of different
active agents.
The instructions may be in written or pictograph form, or can be on recorded
media
including audio tape, video tape, or the like.
Use in Conjunction with Venous Flow Control ("VFC") Device:
In an alternative embodiment of the invention, a pharmaceutical formulation
containing the selected phosphodiesterase inhibitor is administered in
combination with a
venous flow control device such as that described in PCT Publication No. WO
97/47260,
entitled "Venous Flow Control Element for Maintaining Penile Erection."
Preferred devices
are formed from a length of flexible tubing having an integral fastening
means, so as to
provide for readily adjustable venous flow control when applied to the penis.
The device is
applied to the base of the penis prior to and during sexual intercourse, such
that it
effectively enhances retention of blood within the penis without substantially
obstructing
arterial inflow or becoming too constrictive during the erectile process. Use
of the VFC
device also enables enhanced effectiveness of local drug therapy, in that the
active agent is
retained within the penis, allowing movement into the corpus cavernosa. This
produces
smooth muscle response and a consistent erectile response. In this embodiment,
a kit will
include the venous flow control device in addition to the components noted
above, along
with instructions for using the device.
It is to be understood that while the invention has been described in
conjunction with the preferred specific embodiments thereof, that the
foregoing description
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as well as the examples which follow are intended to illustrate and not limit
the scope of the
invention. Other aspects, advantages and modifications within the scope of the
invention
will be apparent to those skilled in the art to which the invention pertains.
EXAMPLE 1
Preparation of urethral dosage form: A transurethral pharmaceutical
formulation containing zaprinast, a type V phosphodiesterase inhibitor, is
prepared by
mixing 0.2 to 1.5 g of zaprinast with a suitable amount of polyethylene
glycol, typically 1-5
g, molecular weight (MW) approximately 2000, and heating the mixture to a
temperature just
high enough to produce a drug-polymer melt. The mixture can then be poured
into a mold
suitable to provide a suppository, and allowed to cool. The suppository so
provided is a unit
dosage form suitable for transurethral administration. This procedure can be
used with
various phosphodiesterase inhibitors, PEGS, and additional components, e.g.,
enhancers or
the like.
The aforementioned method may also be used to prepare urethral
suppositories containing other phosphodiesterase inhibitors as the active
agent.
EXAMPLE 2
A penile insert coated with zaprinast is prepared as follows. An ethylene
vinyl acetate rod is formed into an insert having a shaft approximately 10 cm
long with a
spherical, blunted tip. A dipping bath comprising a 50-50 weight blend of PEG
1450 and
PEG 4000 and sufficient zaprinast to attain the desired concentration in the
coating is
prepared and heated to 70°C. The insert is suspended by its head,
dipped into the dipping
bath and removed. A penile insert suitable for transurethral administration is
thus provided.
The aforementioned procedure may be used to prepare penile inserts coated
with any number of other phosphodiesterase inhibitors as well.
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EXAMPLE 3
An effective phosphodiesterase-inhibiting dose may be determined using the
following procedures.
Transurethral administration: Patients with penile vascular insufficiency are
given a single dose of 0.5 g of a phosphodiesterase inhibitor (e.g.,
zaprinast) transurethrally
in a PEG-based urethral suppository. Prior to and approximately 3 hours after
administering the inhibitor, blood samples are taken and assayed for plasma
phosphodiesterase activity using, for example, high-performance liquid
chromatography
with fluorimetric detection as described by Lee et al, J. Chromatography x:237-
244
(1987). This procedure is repeated at 24 hour intervals with dosage adjusted
as necessary.
EXAMPLE 4
The pharmaceutical preparations of Examples 1 and 2 can be used to treat
erectile dysfunction in individuals in which the dysfunction is associated,
for example,
vascular insufficiency. Dosage may be adjusted using the methodology of
Example 3. In
all instances the individuals are expected to respond positively, although
variations in the
intensity and duration of erection may be observed depending on dose,
formulation and
environment. Generally, between approximately 20 and 90 minutes following drug
administration, it is expected that an erection may be achieved.
EXAMPLE 5
In this experiment, zaprinast, a Type V phosphodiesterase inhibitor, was
evaluated for its capability to induce erections in the anesthetized male cat.
Adult male cats
(3.5 to 5.0 kg) were initially sedated with ketamine and then anesthetized and
maintained
with supplemental doses of pentobarbital administered through a polyethylene
catheter
inserted into the left external jugular vein. After exposure of the pubic
area, a 25-gauge
needle was placed into the left corpus cavernosum for measurement of
intracavernous
pressure. Vehicle and various doses of zaprinast (5, 10, S0, 100 and 200 ~.g)
were
administered by direct injection into the right corpus cavernosum using a 30-
gauge needle.
All injections were made using a total volume of 200 pl. At the end of the
experiment, each
CA 02305394 2000-04-07
WO 99/21558 PCT/US98/22928
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animal received a control drug solution containing 1.65 mg papaverine, 25 p,g
phentolamine, and 0.5 p.g of prostaglandin E, to establish maximal response in
each subject.
Zaprinast caused dose-related increases in intracavernosal pressure and penile
length.
Maximal effects were observed at the 100 ~g dose at which intracorporal
pressure (70.5 mm
of Hg) and penile length (25.75 mm) were 80.5% and 97.5% of the responses seen
after
injection of the control drug solution (87.6 mm of Hg and 26.40 mm,
respectively). These
results suggest that a selective Type V phosphodiesterase inhibitor, when
administered
locally, can induce significant increases in erectile response in a mammalian
male. The
same or greater effects are expected upon administration of a urethral
suppository.
Substantially the same results are expected with other Type V
phosphodiesterase inhibitors, and with Type III and Type IV phosphodiesterase
inhibitors as
well.
