Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS FOR TREATMENT OF ERECTILE DYSFUNCTION
FIELD OF THE INVENTION
The present invention relates to a novel carrier for use with vaso-active
therapeutic
compositions for the treatment of erectile dysfunction, or impotence, within
human
males, for delivery by catheter into the male urethra. In particular, the
invention
relates to an emulsified gel for carrying the vasodilator impotence treatment
compounds such as alprostadil, with the gel existing as a semi-solid at room
temperatures while being substantially liquid at refrigerated temperatures.
BACKGROUND OF THE INVENTION
Compositions for the treatment of impotence within human males include various
compounds and compositions injected by catheter into the urethra. Typically,
such
1 S compounds require injection prior to intercourse, and remain effective for
a period of
time.
Prior to the introduction of the compound alprostadil (commonly sold under the
trademark "Caverject") and other like vasodilators, the primary treatment
erectile
dysfi~nction was the implantation of a penile prosthesis. Over the past
decade,
however, the introduction of intracavernous-injection therapy using vasoactive
agents
such as alprostadil have dramatically changed the treatment of impotence.
With several specific medical exceptions, alprostadil introduced by injection
can
result in high-quality erections in men whose impotence is caused by vascular,
hormonal, neurologic, and psychogenic factors.
It has been found that interaction between the central nervous system and
autonomic
receptors in the arterial and corporeal (trabecular) smooth-muscle cells of
the penis
are the main cause of natural erections. Relaxation of arterial and trabecular
smooth
muscle tissue permits a increased inflow of blood into the sinusoidal spaces
of the
cavernous bodies and compression of the trabecular smooth muscle against the
emissary veins. Alprostadil and other like compounds are vasoactive substances
that
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2
compression of the trabecular smooth muscle against the emissary veins.
Alpro~tadil and
other like compounds are vasoactive substances that inhibit sympathetic tone
and directly
relax the corporeal smooth muscle tissue, thus stimulating erectile
functioning.
Specifically, alprostadil relaxes the smooth muscle of the corpus cavernosa.
Alprostadil is
rapidly metabolized, thus minimizing its systemic effects.'
The use of a vasodilator compound to treat erectile dysfunction by penile
injection of the
compound is disclosed in U.S. patent no. 4,127,118 (Latorre).
Intracavernous injection of alprostadil by application into the urethra is a
well-accepted and
e~cacious treatment for erectile dysfunction. Conveniently, such application
is by way of
a single-use syringe or other like delivery device. Other ways of
administering alprostadil,
such as by a medicated urethral system and in a topical gel; have not yet been
demonstrated
to have similar results. Although this formulation of alprostadil is now
approved by the
FDA and is easy to reconstitute in a single-use syringe, prescription of this
medication is
best left to urologists, who can offer the most comprehensive diagnostic
evaluation and are
best equipped to treat complications such as priapism. Simply prescribing an
injection
without conducting an appropriate 'evaluation does not constitute an
appropriate standard of
care. In the coming years, as the baby-boomer generation ages and looks for a
quick fix for
the diseases associated with aging, public awareness and its ease of
administration will
doubtless further popularize the use of intracavernous-injection therapy for
erectile
dysfunction.
Vasodilators such as alprostadil can be effectively delivered by way of direct
urethral
injection when they are emulsified within a gel. It has been found that an
effective
emulsion can be formed by formulating a composition from pluroruc and a
lecithin-organo
gel. This carrier preparation has the singular quality of being generally
liquid at
refrigerated temperatures and semi-solid at room temperatures. This permits
the active
'The New England Journal of Medicine -- April 4, 1996 -- Volume 334, Number
14;
Larry I. Lipshultz, M.D.
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3
ingredient to be mixed into the carrier at reduced temperatures to prevent
denaturing, and
further permits the resulting therapeutic compound to be easily introduced
into a syringe or
other like delivery device. The preparation may then be easily transported and
stored at
room temperatures as a semi-solid within the delivery device with minimal risk
of leakage.
The resulting preparation may then be delivered by injection with a catheter-
tipped syringe
into the urethra, typically by insertion of the catheter about one inch into
the urethra.
The use of a pluronic/lecithin type gel has been previously disclosed for use
in treatment of
blood vessel disorders of the skin and subcutaneous tissues (U.S. Patent
5,510,391 -
Elson). However, it has not been previously suggested to deliver vasoactive
'substances for
the treatment of male impotence in a gel of this type.
It is desirable to provide a preparation comprising an active impotence
treatment
compound with a carrier, whereby the preparation may be stored in a semi-solid
gel form.
This permits the preparation to be stored in single-use syringes, without risk
of leakage or
spillage. This aspect is particularly important in this type of preparation,
since typically
users will carry with them a single-use syringe applicators on their person,
or have the
applicators conveniently stored in a bedroom or the like. It is particularly
important to
avoid inadvertent spillage or leakage in such circumstances. Accordingly, it
is useful to
provide the pharmaceutically active compound in a delivery system that
includes a gel-type
carrier that is semi-solid at room temperatures.
It is a further requirement that such a carrier be sufficiently fluid to
permit delivery through
a generally conventional syringe and catheter combination. Further, the
carrier must be
sufl-iciently fluid to permit the preparation of a mixture of the active
ingredient and the
carrier, without the necessity of heating the carrier, which may deactivate
the active
ingredient. Accordingly, it is desirable to provide a carrier that may be
liquefied or partly
liquefied at a decreased temperature.
Alprostadil and similar compounds are in their normal state relatively
hydrophilic.
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Accordingly, passage across liposoluble cell membranes may be hindered and
this can
delay the activity of the compound. The use of a lecithin-based gel Garner as
in the
present invention renders the mixture relatively lipid soluble and assists
passage of
the compound across cell membranes.
In a further aspect, it is desirable to provide a local anaesthetic such as
lidocain within
the carrier to facilitate use of the medicament.
SUMMARY OF THE INVENTION
It is an object of the invention to provide an improved delivery means for
vasoactive
compounds for treatment of erectile dysfunction. It is a further specific
object to
provide a semi-solid gel-type combination of a carrier and a therapeutically
active
substance of the group that includes alprostadil and other vasoactive
compounds, for
delivery by way of a catheter-tipped syringe into the human male urethra. It
is a
further object to provide a delivery system for delivery of a vasodilator for
treatment
of impotence, comprising a syringe containing a single dose of a vasoactive
compound carried within an emulsion that permits an effective delivery of the
medication. It is a further object to provide a carrier/active ingredient
combination
that may be retained at room temperature (i. e. 16 - 28 ° C
approximately) within a
syringe or other like holder as a semi-solid gel without substantial risk of
spillage or
leakage, but which is sufficiently liquid at refrigerated temperatures (i.e.
about 0 -
10°C) to permit a pharmacist to fil individual syringes with the
mixture.
In light of the foregoing objects, the present invention comprises in one
aspect a
composition comprising a carrier for a pharmaceutically active vasoactive
preparation
for the treatment of male erectile dysfunction. The carrier comprises a
mixture of a
lecithin compound, isopropyl palmitate, sorbic acid and Pluronic ~ gel
comprised of
Pluronic and potassium sorbate in an aqueous base, in a proportion such that
the
Garner has the quality of existing in a semi-solid gel state at room
temperature and in
a relatively liquid state at temperatures of between about 0 and 10° C.
The term
"Pluronic" is a proprietary name for difucntional block polymers terminating
in
primary hydroxyl groups. In particular, such compounds are polyoxyalkylene
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derivatives of propylene glycol (The Condensed Chemical Dictionary, 7°'
ed. 1966).
Preferably, the vasoactive compound comprises alprostadil.
The lecithin organic gel preferably comprises a mixture of lecithin soya
granules;
isopropyl palmitate and sorbic acid.
In a further aspect, the carrier includes a suitable local anaesthetic, such
as a 2%
lidocain solution.
In a further aspect, the invention comprises a method of preparing a Garner
for a
vasoactive pharmaceutical preparation such as alprostadil, comprising the
steps of
preparing a stock pluronic solution by combining and dissolving pluronic and
potassium sorbate within water chilled to approximately between about 0 and
10° C;
mixing together a lecithin compound, isopropyl palmitate, sorbic acid and
permitting said mixture to stand until a syrupy consistency is achieved;
combining the mixture with said stock solution at a temperature of between
about 0 and 10° C;
the ratio of the compounds within the Garner being selected to achieve a
carrier having a semi-solid gel consistency at room temperature and a
relatively liquid
consistence at temperatures between about 0 and 10° C.
The invention comprises in another aspect the use of a therapeutically
effective
concentration of a vasoactive medicament such as alprostadil carned within a
gel of
the type described above for the treatment of male erectile dysfunction.
In another aspect, the invention comprises a delivery means for delivering a
dose of a
preparation as described above. The delivery means comprises a single-use
applicator, comprising a syringe-type dispenser, the barrel of which contains
a
pharmaceutically active dose of a vasoactive compound pre-mixed within a
carrier as
described above.
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Having thus characterised and summarized the invention, the invention will now
be
described in detail by way of a description of a preferred embodiment thereof.
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6
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
' The preferred present invention comprises a single dosage application of an
active
ingredient, namely alprostadil or other like vasoactive compound for treatment
of male
erectile dysfunction, suspended within a pluronic.gel. The dosage is contained
within a
catheter-tipped syringe. A typical dosage is about 0.1-0.2 cc.
The pluronic gel carrier according to the present invention comprises a
mixture of lecithin
soya granules, isopropyl palmitate SF, sorbic acid and pluronic gel in an
aqueous base.
The mixture is prepared with ratios of the ingredients sufficient to provide a
semi-solid gel
at room temperatures, while being substantially liquid at refrigerated
temperatures.
In one example, the mixture is prepared by combining these compounds in the
following
amounts:
Lecithin soya granules 10 gm
Isopropyl Palmitate SF 10 gm (11.7 ml.)
Sorbic acid NF-FCC powder 0.3 gm
Pluronic gel 20% q.s. 100 ml
The stock solution of pluronic gel 20% comprises the following mixture:
Pluronic F127 NF 20 gm
Potassium Sorbate NF 0.3 gm
Purified Water q.s.
Potassium sorbate and pluronic is combined and chilled (0-10° C) and
purified water is
added to bring the volume to 100 ml, following which the mixture is stirred or
mixed for
12-24 hours, with additional water added as required to bring the final volume
to 100 ml.
The resulting gel is refrigerated, and dissolution into a relatively liquid
form occurs upon
chilling. To compensate for volume reduction upon chilling, additional water
is added as
required to bring the volume back to 100 ml. The stock solution of pluronic
gel is
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maintained at a refrigerated temperature (i.e. 0-10° C) until used, to
prevent solidification.
The lecithin/pluronic mixture is prepared by dispersing the lecithin granules
and the sorbic
acid in isopropyl palmitate, and permitting this mixture to stand about 8-16
hours. A
mixture of syrupy consistency will result. The chilled pluronic gel stock
solution is mixed
into to the resulting mixture to bring the total volume to 100 ml.
The resulting gel comprises a carrier for an active ingredient, preferably
alprostadil, which
is added in therapeutic amounts. Conveniently, a single dosage is 0.1-0.2 ml.
of the
carrier/active ingredient combination. Typically, a therapeutic dosage of
alprostadil gel is
about 500-1000 mcg. Accordingly, either sufficient active ingredient may be
added to the
entire carrier batch to achieve the desired carrier/pharmaceutical mixture, or
individual
dosages of the therapeutically active preparation may as desired be prepared.
A pharmaceutically active dosage of a local anaesthetic may be added to the
mixture. For
example, sufficient lidocain may be added such that the final mixture
comprises a 2%
lidocain solution.
Upon preparation of the therapeutically active carrier/active ingredient
preparation, one or
more single use syringes are filled with a selected single dose amount of the
preparation.
Typically, the filled syringes will be prepared by a pharmacist and the exact
dosage will be
determined by the patient's physician. The syringes may be easily filled while
the mixture
is chilled, since at these temperatures the mixture remains in a generally
liquid state. The
preparation solidifies into a semi-solid gel upon reaching room temperature,
and may be
stored in this form without substantial risk of leakage or spillage.
The resulting compound will gel into a semi-solid upon reaching room
temperature:
Within this state, the compound will in normal circumstances not leak or spill
from a
syringe or other like delivery device. However, the mixture will remain
sufficiently fluid
to permit the user to, discharge the mixture through the catheter tip of the
syringe.
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The invention further comprises the combination of a syringe or other like
delivery
apparatus, with the above-described mixture contained within the syringe
barrel. It will be
seen that any known delivery apparatus may be adapted for use with the present
invention,
the apparatus being provided with a barrel or other chamber for holding a
therapeutic dose
of the mixture, in communication with a catheter or like delivery tube for
insertion into the
urethra.
It will also be seen that the carrier described above may be used in
association with other
pharmaceutical preparations having similar requirements as described above.
However,
the Garner is particularly suited for use with vasoactive impotence treatment
preparations.
It will be seen that although the present invention has been described by way
of a preferred
embodiment thereof, numerous variations of and departures from this version
may be made
without departing from the spirit and scope of the invention, as described in
the appended
claims. In a further aspect, it may be noted that while precise amounts and
concentrations
of various components of the invention are described in this specification,
persons skilled
in the art will recognize that the present invention may be still achieved
even if at least
some of these quantities and ratios are varied.
