Note: Descriptions are shown in the official language in which they were submitted.
CA 02214418 2004-12-07
WATER-BASED TOPICAL CREAM CONTAINING NITROGLYCERIN; METHOD
OF PREPARATION AND USE THEREOF
DESCRIPTION
Technical Field
The present invention is concerned with stable, uniform, water-based topical
creams
of nitroglycerin. The topical creams of the present invention are especially
useful for
treating erectile dysfunction and female anorgasmia. Topical creams of the
present
invention are also useful in stimulating blood flow to peripheral nerves in
patients suffering
from diabetic neuropathy andlor other microvascular diseases. Creams of the
present
invention also find use in stimulating hemodynamic blood flow into injured
tissue.
The present invention relates to topical creams that facilitate the
transdermal
delivery of nitroglycerin through the dermal and epidermal layers of the penis
and clitoris
for treating male erectile dysfunction and female anorgasmia, respectively.
The creams of the present invention provide fast penetration of vasoactive
agents
into the penis and clitoris with less discomfort and transference among sexual
partners.
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The present invention also relates to the use of the creams for treating
male erectiIe dysfunction and female anorgasmia. Moreover, the present
invention relates to a method for preparing the topical creams of the present
invention.
Bac3cground of the Invention
The term sexual impotence, or inhibited sexual excitement, refers to the
inability of a man to achieve a quality of erection sufficient to enable him
to
successfully experience coitus. The cause of this impotence may be either
primary
or secondary. In primary impotence, the man has never been able to achieve a
satisfactory erection for coitus. In secondary impotence, the man has
previously
been potent and usually has been able to reach coitus but has subsequently
developed his impotence.
The Kinsey study (Kinsey, A. C., Pomeroy, W. B., and Martin, C. E.,
I5 SezuaI Behavior in the Human Male W. B. Saunders, Philadelphia, 1948.)
declared impotence to be a relatively rare occurrence in men up to age 35.
However, with the advent of the so-called "sexual revolution" mare men under
this
age group appear to be seeidng treatment for this condition. The Kinsey
statistics
do reveal a gradual rise in the incidence of erectlqe dysfunction with age,
ZO particularly after 45, with a more rapid increase after 55. By age 75,
nearly 55
percent of males reported problems, and by 80, 75 percent However, research
has shown (The Sexual Experience (Sadock, KapIan, and Freeman, eds.),
WiIIiams and WOlans, Baltimore, 1976, Chapt 15.4.) that aging is not an
inevitable cause of impotence, even into the seventh and eighth decades of
life.
ZS ErectiIe dysfunction is almost always due to physical factors. Physical
factors include systemic diseases (e.g. diabetes mellitus (the most commonJ,
syphilis, alcoholism, drug dependency, hvpopituitarism, and hypothyroidism);
local
disorders (e.g. congenital abnormalities and inflammatory diseases of the
genitalia); vascular disturbances such as aortic aneurysm and atheroxlerosis
(e.g.
30 Leriche's syndrome): neurogenic disorders (e.g. multiple xlerosis, spinal
cord
Z
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VGO 96127372 PCT/USy6102989
lesions, pituitary microadenoma with hyperprolactinemia, and cardiovascular
accident); drugs such as antihypertensives, sedatives, tranquilizers, and
amphetamines; and surgical procedures such as sympathectomy. Prostatectomy
and castration produce varying effects. Impotence is usually not induced by
S transurethral prostatectomy, whereas it almost always occurs after perineal
prostatectomy. The Merck Manual, I6th edition, (Berkow, R., ed.), Merck
Research Laboratories, Rahway, NJ, 1992, Chapt 139.
Psychological factors, which include an abnormal fear of the vagina, sexual
guilt, fear of intimacy, or depression, are the cause in about 20% of the
cases of
erectile dysfunction.
To date the pharmacological management of erectile dysfunction has been
based mainly on the intracavernous injection of various smooth muxie relaxant
drugs. Self injection of smooth muxle relaxant drugs such as papaverine and/or
prostaglandin El alone or in combination with.phentoIamine has been used
successfully for a number of year in the treatment of impotence. However,
numerous side effects have been reported and many patients have stopped using
the self injection procedure for various reasons mainly because of the lack of
spontaneity and because of the unpleasant and sometimes pathological side
effects
caused by this technique. Consequently, a non-invasive therapeutic alternative
seems attractive.
To this end, a number of investigators have begun to utilize preparations
consisting of nitroglycerin in either ointment or patch form. In a study by
Meyhoff, et aI. (Meyhof~, H., RosenkiIde, P., and Bodker, Al., Brit J. Urol..
Vol.
68, pp. 89-90, (1992)) a nitroglycerin ointment was evaluated with good
results
and in a previous study by CIaes and Baert (Oven, J. A., et aL, J. Urol.. VoL
141,
pp. 54b548, (1989)) a nitroglycerin ointment was used with positave results.
Both
types of preparations suffer from one or more of the following disadvantages.
The time necessary to achieve an erection varied widely with latent periods
ranging from 1 to 2 hours. Consequently, any notion of spontaneity is
invalidated.
Both preparations primarily use IipophiIic agents, such as petroleum jelly
and/or
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lanolin as the matrix for the nitroglycerin. These agents lead to not only a
very
slow release of nitroglycerin into the penile tissue but also leave an oily
residue on
the penile shaft such that the nitroglycerin contained in this residue is
easily
transferred to the partner via the vaginal mucosa. A further drawback to the
use
S of these preparations is the production of an intense burning sensation when
the
material is applied to the penis.
Concerning a different problem, no medications and/or viable treatment
methods are currently available for the female who suffers from inhibited
sexual
excitement (i.e., anorgasmia or sexual arousal disorder), even though there
are
certain physiological and anatomical similarities between male and female
external
genitalia.
In the normal man or woman, a sequence of physiological sexual responses
exists that has been dexribed by Sadock et al., in Sadock, Kaplan, and
Freeman,
Eds., The Sexual E~erience. Wl'Iliams and Wl'Ildns, Baltimore, (I976), Chapter
3.
These levels of sexual. arousal consist of four discrete phases, each
accompanied
by unique physiological changes. These phases can be understood
physiologically
as increasing levels of vasocongestion and myotonia (tumescence) and the
subsequent rapid release of this vascular activity and muxie tone as a result
of
orgasm (detumexence).
If the clitoris does not become engorged with blood, for any number of
reasons, orgasm is not attainable. Women who present this complaint are
diagnosed as having a sexual arousal disorder. This condition is more
precisely
defined as the persistent or recurrent failure to attain or maintain the
lubrication-swelling response of sexual excitement until completion of sexual
activity. This inhibition occurs despite adequate sexual stimulation in focus,
intensity, and duration. The disorder may be primary or, more frequently,
secondary and restricted to the partner. Psychologically acquired factors
cause
most of the cases of secondary dysfunction; e.g., marital discord (about 80%
of
the cases), depression, and stressful life situations. Ignorance of genital
anatomy
and function is common, particularly of clitoral function and of effective
arousal
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patterns and techniques. Association of sex with sinfulness, and sexual
pleasure
with guilt, may be lifelong. Fear of intimacy may also play a part
The physical causes include localized disease (e.g., endomen-iosis, cystitis,
vaginitis); systemic diseases (e.g., hypothyroidism, diabetes mellitus -
though its
impact is greater on men); peripheral of CNS disorders (e.g., multiple
sclerosis);
muscular disorders (e.g., muscular dystrophy); drugs (e.g. oral
contraceptives,
antihypertensives, tranquilizers have variable effects); and ablative surgery
(e.g.,
hysterectomy, mastectomy, which may have a negative impact on the woman's
sexual self-image).
Besides those women in the general population, recent publications have
emphasized these problems in older female populations (Osburn, M., Brit Med.
J..
Vol. 296, pp. 959-962, (1988)), in post-menopausal women, and in those who
have
undergone a hysterectomy ('Ihe American College of Obstetricians.
Gynecologists
Office Practice and Practice Management: Sexuality and Sexual Dysfunction
American College of Obstetricians and Gynecologists, Chapter 1Q (1986)). In
addition, those women afflicted with Type II diabetes appear to suffer from an
increased frequency of sexual problems, including anorgasmia (Schreiner, et
al.,
"Diagnosing and Treating the Sexual Problems of Diabetic Women," in Clinical
Diabetes. Vol 6, pp. 12I-136 (1988)).
Although there are many reasons given for the inability of a woman to
reach orgasm, one aspect of the present invention is directed toward the first
phase of the sexual response cycle, the excitement phase. Since the female
clitoris
and its associated structures are both anatomically and embryologically
simzZar to
the male penis, it is medically correct to assume that the clitoris should
(and does)
respond in land during the excitement phase of the response cycle.
Both the clitoris and the penis have corpora cavernosa, an anatomical
shaft, and both are erectile. Consequently, since a satisfactory erection can
be
produced in impotent males by the introduction of vasoactive agents into the
male
members, either by injection or by transdermal methods, it follows that the
same
procedures) will be equally valid in treating women why complain of inhibited
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sezuaI excitement However, the introduction of vasodilators or other
vasoactive
agents by hypodermic injection would be both impractical and dangerous.
Further, since the clitoris is much smaller than its male counterpart, has a
much thinner striatum cornuium, and is more sensitive to tactile stimulation,
any
S topical transdermal preparations containing a vasodilator must address these
characteristics.
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wb 96127372 PCT/US96/02989
Summary of Invention
The present invention provides a stable, uniform, water-based cream
containing nitroglycerin. The present invention overcomes the problem of the
nitroglycerin precipitating out of water-based compositions.
The compositions of the present invention are especially useful for treating
individuals suffering from erectde dysfunction or female anorgasmia. The
compositions exhibit an improved safety profile resulting in significantly
less
burning, headache and transference to a partner. Moreover, the compositions of
the present invention result in reduced mess and residual material after
application, thereby improving "feel" Furthermore, the compositions are faster
acting when compared to previously disclosed topical preparations.
Compositions of the present invention are also useful in stimulating blood
flow to peripheral nerves in patients suffering from microvascuIar diseases,
such as
IS diabetic neuropathy. Moreover, compositions of the present invention are
useful
in stimulating hemodynamic blood flow into injured tissue, such as a wound or
surgical incision.
The results and properties achieved by the present invention are due to the
judicious selection of the ingredients and their relative amounts. More
particularly, the topical cream of the present invention contains:
A) about 0.1 to about 3% by weight of nitroglycerin;
B) about 5 to about 24% by weight of a penetration enhancer;
C) about 60 to about 90% by weight of water,
D) about 0.5 to about 3% by weight of a thic3cener; and
ZS E) about 0.4 to about 2% by weight of an emulsifier
In addition, the present invention is concerned with a method for treating
an individual suffering from erecti7e dysfunction or female anorgasmia. The
method comprises topically applying to the genital area of the individual, an
effective amount of the above disclosed topical cream.
Another aspect of the present invention relates to treating patients
suffering from a microvascular disease by topically applying to the afflicted
areas
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W O 96127372
of the patient an effective amount of the above disclosed topical cream. A
further
aspect of the present invention relates to treating patients suffering from a
wound
or having a surgical incision by topically applying to the area near or within
the
vicinity of the wound or surgical incision of the patient an effective amount
of the
above disclosed topical cream.
A srill further aspect of the present invention relates to preparing the
above disclosed topical cream. The method involves admixing the thickener and
about 80 to about 90% of the water and heating to provide a first solution.
Admixing the emulsifier, about 15 to about 85% of the penetration enhancer,
the
remaining portion of the water with heating results in a second solution.
Next,
admndng the first solution and second solution provides a cream base. Admixing
the nitroglycerin, remaining portion of the penetration enhancer and the cream
base results in the desired topical cream.
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VlfO 96!27372 PCT/US96/0298~
Best and Various Modes for Canvin~ out the Present Invention
The stable, uniform, water-based topical cream of the present invention
contains nitroglycerin as a vasodilator. The nitroglycerin is present in the
cream
in an amount of about 0.1 to about 3% and preferably about 0.1 to about 1% by
weight
In addition, the cream contains a penetration enhancer in an amount of
about 5 to about 24%, and preferably about 8 to 13% by weight
The preferred penetration enhancers employed, according to the present
invention, are propylene glycol, glycerine, isopropyl palmitate, isopropyl
myriatate,
and laurocapram.
The topical creams of the present invention must contain water in an
amount of about 60 to about 90%, and preferably about 75 to about 88% by
weight
The creams of the present invention also contains a thickener in an amount
of about 0.5 to about 3%, and preferably about 1.1 to about 2% by weight
Preferred thickeners employed in the present invention are methyIcelluIose,
polyethylene glycol, and acrylic acid polymers. Carbopol 934P and Carbopol
940,
commercially available from B.F. Goodrich Co., when neutralized, are suitable
acrylic acid polymers. A preferred polyethylene glycol is polyethylene glycol
8000.
A preferred methylcellulose is methylcelluiose 4000.
The creams also contain an emulsifier in an amount of about 0.4 to about
2%, and preferably about 0.4 to about I% by weight The emulsifier is
prezerably
a non-ionic surface active agent Typical non-ionic surfactants include the
polysorbates, which are mixtures of partial esters of sorbitoI and its mono-
and
dianhydrides, typically condensed with approximately 20 mot of ethylene nude;
polyethyoxylated alkyl ethers and esters, in which the alkyl chain can be
either
saturated, unsaturated, branched or linear, poIyeihoxylated alkyl phenols, in
which
the hydrophobic group normally octyi or nonylphenol; and poloxamers,
polyozyethylene-polyoxypropyiene block copoImyers, in which the
polyvxypropyiene chain acts as the hydrophobic moiety.
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Some commercially available non-ionic surfactants are Brij 99, Brij 78,
poIyozyl 40 stearate and polysorbate 80. Brij 99 and Brij 78 are polyethylene
glycol fatty alcohol ethers. PolyoxyI 40 stearate is a mixture of mono and
distearate esters of polyoxyethylene and of free polyoxyethylene. Polysorbate
80 is
poIyozyethylene (20) sorbitan mono-oIeate.
The compositions of the present invention preferably have a pH value of
about 6.5 to about 9Ø When desired, the pH value can be adjusted by adding
alkyl ethanolamines and/or a suitable buffer system, such as phosphate or
citrate
based buffers.
The compositions of the present invention can optionally contain auxiliary
ingredients, such as flavorings, fragrances, preservatives and/or coloring
agents.
When present, such are usually added in amounts of about 0.05 to about 0.30%.
Suitable preservatives include methylparabens (methyl PABA), propyIparabens
(propyl PABA) and butyIhydroxy toluene (BHT).
IS 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
anesthetics include lidocaine and dibucaine.
The topical creams of the present invention are preferably prepared by
admiung the thickener and about 80 to about 90% of the water and heating to a
temperature of about 45°C to about 75°C to provide a first
solution. Admixing
the emulsifier, about 15 to about 85% of the penetration enhancer, the
remaining
portion of the water with heating to a temperature of about 35°C to
about 70°C
results in a second solution. Next, admixing the first solution and second
solution
at a lowered temperature, preferably below about 50°C provides a cream
base.
Admiung the nitroglycerin, remaining portion of the penetration enhancer and
any auJdliary ingredients and the cream base, resuILs in the desired topical
cream.
To treat impotence or anorgasmia, the cream is applied to the shaft and
glans of the penis or to the clitoris and massaged until absorption is
complete.
Amounts of the invention ranging between about 0.I and about 10 grams and
preferably about 0.1 to about 3 are sufficient for vasod~lation and the
erectfle
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VSO 96127372 PCTIUS96/02989'
process to occur. The most preferred amount for treating erecrile dysfunction
is
about 0.2 to about 3 grams, and for treating female anorgasmia is about 0.1 to
about 1 gram. The present invention can be used with or without benefit of
erotic
stimuli. The determination of an ideal dose of the composition should be
determined with each individual by one sloped in the art, such as a physician
or
sez therapist
Use of the present invention in treating the problem of impotence and
anorgasmia is far superior to other methods thus far proposed. It is non-
invasive
and offers a treatment that the sexual partner need not be aware of. It uses
only .
ingredients that have been approved for human use by those regulatory agencies
charged with such matters. It does not use penetration enhancers, such as
dimeihyl sulfoude, which have not been approved for such uses. The creams of
the present invention act in a relatively short time (about 5-15 minutes). In
addition, in view of the long lasting ability of the compositions of the
present
IS invention, such do not require a vasoconstrictor, as required in certain
prior art
formulations. This invention causes vasodllation in and around the penis or
clitoris, and produces an erection lasting from 15 minutes to 2 hours.
The present invention is formulated with a rapidly absorbed aqueous base
so that little, if any, of the active ingredient is transferred to the sexual
partner.
Compositions of the present invention, in addition to promoting the
vasoactive agents to penetrate into the striatum cornium and its associated
structures are also useful in stimulating blood flow to peripheral nerves in
patients
suffering from microvascular diseases, such as diabetic neuropathy. The
abnormalities, which patients with such diseases in their platelet function
exhibit
including the increased blood and plasma vixosity, and the increased
erythrocyte
ago egabiIity and adhesiveness lead to a reduction in capillary erythrocyte
velocity.
Episodes of sludging and stasis in the microcapl7laries that consequently
develop
eventually lead to local hypoxia. Therefore, these patients will benefit from
the
vasorlilation effect following topical application of the present invention to
the
sIdn of their afflicted area. For such uses, topical astringent. antioxidant,
anti-
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fungal and/or moisturiang ingredients may be incorporated into select
formulations. The preferred amount for treating microvascular diseases is
about I
to about 3 grams of the composition.
Furthermore, the present invention is useful in stimulating hemodynamic
blood flow into injured tissue. An increase in blood flow (or the maintenance
of
normal flow) into such tissue ensures the presence of natural healing factors.
This
property of the present invention is of considerable benefit to patients who
have
incurred traumatic cuts, abrasions and/or surgical incisions. Fur such uses,
antibiotic and/or topical anesthetics may be incorporated into selected
IO formulations. The preferred amount used for stimulating hemodvnamic blood
flow into injured tissue is about 0.2 to about 1 gram of the composition.
The following non-limiting examples further dIustrate compositions and
dosage forms of the present invention. The compositions were prepared by the
process disclosed above, unless stated otherwise.
IS
Example I Example 2
Water 82.60% Water 70.75%
Nitroglycerin LSO Nitroglycerin 1,00
Propylene Glycol 3.00 Propylene Glycol 15.00
20 Glycerine 5.00 Glycerine 5.00
Isopropyl Palmitate 1.00 Laurocapram 1.50
Polyethylene Glycol 8000 OSO Isopropyl Pahnitate L00
Carbopo1940 1S0 Methylcellulose 1.80
Polyoxyl 40 Steatite 0.50 Carbomer 934P 1.05
25 Brij 78 1.00 Brij 78 1S0
Triethanolamine 2.00 Triethanolamine L00
Sodium Borate 030 Sodium Borate 0.2$
Butylated HydroxytoIuene 0.02 Butylated HydrozytoIuene0.05
Methyl Parabens 0.02 Methyl Parabens 0.05
30 Flavoring Agents 0.04 Propyl Parabens 0.05
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VVO 96/27372 PCT/US95/02989
Exam~Ie 3 Example 4
Water 83.00% Water 83.00%
Nitroglycerin 0.50 Nitroglycerin 1S0
Propylene Glycol 5.00 Propylene Glycol 5.00
Glycerine 3.00 Glycerine 3.00
Isopropyl Myristate 1.00 Laurocapram 1.00
CarbopoI 934P - 1.I0 Carbomer 934P 0.80
Grape Seed 0~1 0.50 Light Mineral Oil OSO
Cocoa Butter L00 MethyIcellulose L00
Brij 99 2.00 Brij 99 1.50
TriethanoIamine 2.00 Triethanolamine 1S0
Potassium Phosphate 0.83 Disodium Phosphate 1.00
Methyl Parabens 0.02 Methyl Parabens 0.02
IS Propyl Parabens 0.02 PropyI Parabens 0.02
Flavoring 0.02 Fragrance 0.02
Flavorings 0.14
Example 5 Example 6 _
Water 86.00% Water 84.46%
Nitroglycerin 0.75 Nitroglycerin 1.00
Propylene Glycol 6.75 Propylene Glycol 9.00
ZS Isopropyl Palmitate Z.QO Isopropyl Palmitate 2.00
MethylcelluIose, 4000 0.40 Carbopol 934P 0.70
Carbopo1934P 0.70 Methylcellulose 0.40
Polyethylene Glycol 0.50 Polyethylene Glycol 0S0
8000 8000
Brij 99 1.00 Brij 99 OSO
PoIyozyI 40 Stearate 0.50 Triethanolamine I20
Triethanolamine L00 Sodium Borate 0.20
Sodium Borate 0.20 Methyl Parabens 0.02
Methyl Parabens 0.02 Propyl Parabens 0.02
PropyI Parabens 0.02 Butylated Hydroacytoluene0.02
Fragrance 0.14 Fragrance 0.15
Coloring 0.02 Coloring 0.02
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Example 7 Example 8
Water 84.46% Water 81.47
Nitroglycerin 0.20 Nitroglycerin 0.75%
Propylene Glycol 9.80 Dibucaine 2.00%
Isopropyl Paimitate 2.00 Propylene Glycol 9.25
Carbopol 934P 0.?0 Isopropyl Myristate 3.00
Methylcellulose, 4000 0.40 Carbopol 930P OS0
Polyethylene Glycol 8000 0.50 Methylcellulose, 4000 0.40
Brij 99 OS0 Polyethylene Glycol OSO
8000
TriethanoIamine 1.20 Brij 99 OSO
Sodium Borate 0.20 TriethanoIamine 120
Methyl Parabens 0.02 Sodium Borate 0.20
Propyl Parabens 0.02 Methyl Parabens 0.02
Butylated Hydroxytoluene 0.02 PropyI Parabens 0.02
'
Fragrance 0.15 Butylated Hydroxytoluene0.02
Coloring 0.03 Fragrance O.IS
Coloring 0.02
E.~c-ampIe 9
Water $0.27
Nitroglycerin L00%
Lidocaine 4.00%
Propylene Glycol 9.00
Isopropyl Palmitate 2.00
Carbopol 934P 0.70
Methylcellulose, 4000 0.40
Polyethylene Glycol 8000 OS0
Brij 99 050
Triethanolamine 1.20
Sodium Borate 0.20
Methyl Parabens 0.02
Propyl Parabens 0.02
Butylated Hydroxytoluene 0.02
Fragrance 0.15
Coloring 0.02
14
