Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF TREATMENT
Field of the Invention
The present invention is related to the method and composition for treating a
patient suffering from irritations and inflammation of a cutaneous or mucosal
surface of a
mammal. More particularly, there is provided a method of treatment of
inflammation in
the vaginal cavity while maintaining normal vaginal floral activity and to
treat cutaneous
and anal/vaginal irritation and inflammation with magnesium and alkali metal
salts.
Background of the Invention
The most common anorectal irritation or inflammation is caused by hemorrhoids.
This condition can be caused by poor sanitary conditions, constipation,
bacterial
infection, etc. Common treatment is with sanitary wipes, suppositories and
gels.
Other anal inflammations are involved with anal fissures, anorectal fistula
and
proctitis.
One of the main disciplines of medicine is the treatment of the female
reproductive system for the prevention, treatment, mitigation, diagnosis, and
cure of
diseases, and the prevention of conception. Usually, this involves the
delivery of active
agents to the vaginal cavity and its environs. Systems to affect the delivery
of such
agents are usually in the form of gels, foams, creams, or suppositories and
quick
dissolving tablets.
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The vaginal cavity is subject to conditions which render it as a target for
disease
and infection; however, it is extremely difficult to deliver an active agent
to this area for
an extended period of time. The vaginal cavity exhibits an aqueous environment
containing secreting glands whose fluids create an acidic pH in the range of
3.5 to 5.5.
The environment of the vagina is conducive to the growth of bacteria, fungi,
yeast and
other microorganisms since it is warm, moist, and dark. It is also the
vestibule for
menstrual debris and residual seminal fluid from sexual intercourse. The
crevices of the
vaginal cavity facilitate the retention of undesirable bacteria, fungi, yeast,
and other
microorganisms as well as the debris from menstruation and sexual intercourse.
The
vaginal cavity is also subject to considerable physical deformation, such as
during sexual
intercourse or the insertion of tampons.
Infectious diseases and other inflammatory conditions affecting the vaginal
mucosa and often secondarily involving the vulva are commonly referred to as
vulvovaginitis. Physicians and investigators often believe that the normal
vaginal flora
has a nice role in protecting the vagina and contiguous tissues from various
microorganisms that are causes of vulvovaginitis.
Most vulvovaginitis and symptomatic vaginal discharges are caused by bacteria,
usually Gardnerella vaginalis in combination with various anaerobes. Protozoa
(Trichomonas vaginalis) cause one third of all cases. Candida is a frequent
cause in
pregnant women and diabetics, and occasionally oral contraceptives increase
susceptibility. Candida also causes symptoms in women who do not have the risk
factors
of diabetes, pregnancy, and hormonal therapy.
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Other less common causes of vulvovaginitis are other bacteria (e.g. Neisseria
gonorrhoeae, members of the Chlamydia and Mycoplsma groups, streptococci,
Escherichiacoli, and staphylococci), foreign bodies, viral infections (herpes
simplex and
HIV infections), pinworms (Enterobius vermicularis), fituals, radiation, and
tumors of the
genital tract. Frequent douching, especially with chemicals, may disturb
normal vaginal
milieu. Deodorant sprays, laundry soaps and fabric softeners, and bath water
additives
may cause vulvar irritation and inflammation. Tight, nonporous, nonabsorbent
underclothing, as well as poor hygiene, may foster fungal and bacterial
growth.
Occasionally, sensitivity to spermicides, coital lubricants, or latex in a
diaphragm or
condom causes irritation and inflammation.
The pH of a healthy vaginal is mildly acidic (pH 3.5-4.5) and this acidity is
thought to be generated by the production of lactic acid by lactobacilli,
which form a
major component of the healthy vaginal flora. Together with other factors,
this acid pH
is widely recognized to prevent overgrowth of undesirable endogenous microbes
(Candida, harmful anaerobes, and bacteria that may cause urinary tract
infections) and
encourages the continued dominance of lactobacilli which, in addition to mild
acidity,
provides other protective mechanisms such as production of hydrogen peroxide
which
aids in modulating cell growth of other microbial species.
It is also known that sperms are inactivated by the mild acidity of the
healthy
vagina, and acid substances have been used as home made vaginal contraceptives
for
centuries. More recently, it has been recognized that many sexually
transmitted disease
pathogens and most or all enveloped STD (sexually transmitted disease) viruses
(Kempf
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1001, Martin 1985) including herpes simplex virus, cytomegalovirus, and human
immunodeficiency virus, are also inhibited or inactivated by mild acidic pH.
However,
semen contains a potent alkaline buffering capacity that neutralizes the
vaginal acidity for
a period of many hours after intercourse. The alkaline buffering capacity
enables sperm
to swim from the vagina into the cervix and upper reproductive tract.
Unfortunately, STD pathogens in genital secretions can also exploit this
period of
neutral vaginal pH, since it allows time for them to reach and infect their
target cells. If
this semen-induced neutralization of vaginal acidity could be promptly and
reliably
overcome, both contraception and STD prevention could be achieved by a method
that
closely mimics the normal physiological state of the vagina.
In addition, the elevated pH also allows certain strains of Staphylococcus
aureus
to produce shock toxin I, whereas production of this toxin is completely
inhibited at
acidic pH 5.0 (Schlievert 1983). Thus, loss of protective acidity may result
in
staphylococcal toxic shock syndrome, candida vaginitis, bacterial vaginosis,
or urinary
tract infection.
Summary of the Invention
The present invention relates to method for treating a patient suffering from
cutaneous or mucosal surface irritations and inflammations with the proviso
that oral
mucosal surfaces are excluded. More particularly, there is provided a method
comprising
administering an effective amount of a composition composed of:
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a) about 0.5 to 20% by weight, preferably about 0.6 to 10% by weight of
salts comprising
1) about 45 to 60% by weight of magnesium salts selected from the group
consisting of magnesium bromide, magnesium chloride, magnesium
citrate and magnesium sulfate, preferably about 55 to 88% by weight of
magnesium bromide is used,
2) about 29 to 41% by weight of potassium chloride, preferably about 39 to
40% by weight,
3) about 0 to 2% by weight of calcium salts, and
4) a buffer,
b) the remainder being a suitable pharmaceutically acceptable vehicle.
The composition can be buffered to a pH between about 3.5 to 6.5, preferably
between
3.5 and 5.5 when used vaginally or 5-8 when use is cutaneously.
The composition can be in the form of a douche, gel, suppository, cream or
foam.
It is therefore a general object of the invention to treat anal and/or vaginal
and
other mucosal irritations and inflammations while maintaining a proper pH.
It is another object of the invention to treat cutaneous irritations.
It is still another object of the invention to provide a vaginal douche or
urinary
bladder wash to maintain an acid environment in the vaginal cavity.
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Description of the Preferred Embodiments
The present invention relates to a method for treatment of a patient suffering
from
cutaneous and mucosal surfaces for inflammation and irritations, excluding
oral cavities.
More particularly, there is provided a composition for use in the method which
comprises:
a) about 0.5 to 20% by weight, preferably about 0.6 to 10% by weight of salts
comprising
1) about 45 to 60% by weight of salts selected from the group consisting of
magnesium bromide, magnesium chloride and magnesium sulfate, preferably
with magnesium bromide being the majority;
2) about 29 to 41% by weight of potassium chloride, preferably about 39 to 41%
by weight,
3) about 0 to 2% by weight of calcium salts, and
4) a buffer,
b) the remainder being a suitable pharmaceutically acceptable vehicle.
The composition is buffered to a pH between about 3.5 to 5.5 when used
vaginally or for treating the urinary bladder. .
The presence of chloride salts aids in cell membrane lysis. Also, chloride
ions
augment the antimicrobial activity of endogenous that contribute to protection
against
bacterial pathogens.
Magnesium salts have been found to inhibit the activation of arachadonic acid
and
5-lipoxygenase enzyme which are associated with pain.
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Magnesium bromide inhibits the activation of white blood cells and
particularly
activate kinase activity. White blood cells are pro-inflammatory so that their
inhibition
reduces further irritation.
By inhibiting white blood cell activation there is also inhibiting
neutrophils,
lymphocites, eosinophils and basophils which are related to pro-inflammatory
activity.
Non-limiting examples of wounds of a mucosal surface or cutaneous surface of a
mammal include bums, surgical wounds, wounds of bleeding hemorrhoids,
vaginitis,
radiation burns and non-surgical traumatic wounds. The mucosal surface
includes
urethral mucosa, especially radiation urethritis, and urinary bladder mucosa
can be
treated.
The acidic or non-acidic composition, according to the invention, may be
presented in liquid and forms normally used for topical application, in
particular in the
form of aqueous, aqueous-alcoholic or, oil solutions, or lipophilic gels, or
emulsions of
liquid or semi-solid consistency of the milk type, obtained by dispersing a
fatty phase in
an aqueous phase (O/W) or vice versa (W/O), or of suspensions or emulsions of
soft,
semi-solid consistency of the gel types. These compositions are prepared
according to
standard methods.
They are preferably used in the form of aqueous solutions, or in the form of
gels,
foams, or suppositories.
The amounts of the different constituents of the compositions according to the
invention are those traditionally used in the pharmaceutical field.
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In a known manner, the composition of the invention may also contain adjuvants
which are customary in the pharmaceutical field, such as hydrophilic or
lipophilic gelling
agents, hydrophilic or lipophilic active agents, preservatives, antioxidants,
solvents,
perfumes and fillers. The amounts of these different adjuvants are those
traditionally
used in the pharmaceutical or dermatological field, and are, for example from
0.01% to
10% of the total weight of the composition. Those adjuvants, depending on
their nature
may be introduced into the fatty phase or into the aqueous phase.
As hydrophilic gelling agents, carboxyvinyl polymers (carbomer), acrylic
copolymers such as acrylate/alkylacrylate copolymers, polyacrylamides,
polysaccharides
such as hydroxypropylcellulose, clays and natural gums may be mentioned.
Natural gums which may be used includes carageenan gum, xantham gum,
alginates and gelation. As hydrophilic active agents, proteins or protein
hydrolysates,
amino acids, polyols, urea, allantonin, sugars and sugar derivatives, water-
soluble
vitamins, starch and plant extracts, in particular those of the Aloe vera may
be used.
As lipophilic active agents, retinol (vitamin A) and its derivatives,
tocopherol
(vitamin E) and its derivatives, essential fatty acids, ceramides and
essential oils may be
used. These agents add extra moisturizing or skin softening features when
utilized.
The compositions of the invention may include plant or herbal extracts that
reduce
irritation. For example, there may be utilized extracts of Paraguay tea, Kola
and
Guarana, which provide a source of methylxanthines, saponius, tannins, and
glycosides
that have been shown to be anti-inflammatory and can be used to treat
irritations. The
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extract of Paraguay tea is known as "Mate extract" and is described in the
"International
Cosmetic Ingredient Dictionary", 5t' Edition. Mate extract is commercially
available in
combination with extracts of Koa and Guarana, which is sold by Cosmetic
Ingredient
Resources of Stamford, CT under the trademark "QUENCHT".
A surfactant can be included in the composition so as to provide deeper
penetration of the ingredients. Many surfactants are also antimicrobial
agents, for
example, nonoxynol-9 and octoxynol-p are used to prevent HIV. Generally, about
0.05
to 2.0% by weight surfactant can be used.
An example of a lubricating base which can be used is HISPAGEL a glycol-free
glycerine clarthrate which is generally described as glycerin polyacrylate
which is sold by
Centerchem Inc. of Stamford, Ct. Generally, up to about 20% by weight of the
composition comprises HISPAGEL. It can be used in combination with other
gellants
such as Cabopols, cellulose derivatives, clays and the like.
The preferred natural gums that can be used in amounts up to about 5% by
weight
include carageenan gum, xantham gum, alginates, and gelatin.
The preferred synthetic polymers that can be used include Carbopol,
polyacrylic
acid, polymethacrylic acid, hydroxyalkyl cellulose, methacrylate, and
polyacrylamide.
The compositions may contain an additional therapeutic active agent as well as
a
spermicide. The additional active agent may be any of those which are approved
for or
used for the treatment, propylaxis, cure or mitigation of any disease of the
vulva, vagina,
urinary tract, cervix or other female reproductive organ or preventant of
conception; for
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aesthetic or cosmetic usage, for diagnostic purposes; for systemic drug
therapy. The
agent must have utility when administered by delivery to all or a portion of
the vaginal
surfaces. Therapeutic active agents are normally well-known. Without being
limited
thereto, exemplary agents include:
Antibacterial agents such as C31 G, trimethoprim, sulfamethoxazole, and
chloromycetin;
antiseptic agents such as chlorhexidine gluconate;
antibiotic agents such as erythromycin, penicillins, cephalosporins and their
derivatives, ampicillin, methicillin, and doxycycline;
antiparasitic agents such as thiabendazole;
antiprotozoal agents such as metronidazole, and chloroquine hydrochloride;
antiviral agents such as dextran sulfate and other sulfated polysaccharides, n-
Docosanol (Lidak Pharmaceuticals), squalamine, and vidarabine;
and antifungal agents such as ketoconazole, flucytosine, itraconazole,
amphotericin B, nystatin, butoconazole nitrate, and clotrimazole.
The preparations of this invention must possess a pH between 3.5 to about 5.5
and
preferably between about 4 and 5.5 for vaginal use. pH's above 6.5 are not
preferred
since they promote vaginal infections and inflammation. When necessary,
buffers are
used to adjust the pH of the system. Acceptable buffers include commonly used
mixtures
of a weak acid and its conjugate base, such as acetic acid and sodium acetate.
Acceptable
buffers may be based on inorganic salts such as phosphate and carbonate, and
organic
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acid sodium and potassium salts such as acetate, citrate, succinate, formate,
glycine,
maleate, phosphates and barbiturates, with sodium citrate being preferred.
It has also been unexpectedly found that the microbial kill rate for
undesirable
microbes is 20 to 50 times more effective at pH's about 4.0 for vaginal use. A
pH of 5-8
can be used for cutaneous irritations.
The gelled compositions of this invention are formed by preparing a
translucent
gel of the polymer in a suitable carrier. One procedure would involve mixing
the acrylic
acid polymer with glycerine until the polymer is completely absorbed by the
glycerine.
Acceptable amounts of polymer to glycerine for this purpose may range from a
ratio of
1:5 to 20 w/w. It should be recognized that other processes may be used to
prepare the
composition of this invention depending on the vehicle being used to prepare
the gel
composition and excipients employed.
As discussed above, the compositions may contain an additional therapeutic
active agent as well as a spermicide. The additional active agent may be any
of those
which are approved for or used for the treatment, prophylaxis, cure or
mitigation of any
disease of the vulva, vagina, urinary tract, cervix or other female
reproductive organ.
A preferred 100 ml composition of the present invention comprises:
In edient Wt.
Magnesium Bromide 1.0 - 2.00 g
Magnesium Chloride 0.01 - 0.05 g
Magnesium Sulfate 0.01 - 0.05 g
Potassium Chloride 0.08 - 1.00 g
Calcium Chloride 0 - 0.05 g
Sodium Carbonate 0 - 0.05 g
Water q.s.
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The pharmaceutical compositions may be prepared for a vaginal douche or a
urinary bladder wash according to standard formulating procedures.
The salts may be dissolved in sterile water, and buffered to a pH of 3.5 to
5.5
which is advantageously ionically balanced. A preferred buffering agent is
sodium
hydrogen phosphate.
It is preferred to include a preservative, for example, Thimerosal or
benzalkonium
chloride and/or an antioxidant, for example, vitamin E. Other filler materials
which can
be included are commonly found in douche or enema compositions.
Osmolality
Osmotic pressure is a main cause for the movement of water across cell
membranes and is defined as the hydrostatic pressure needed to stop the net
flow of water
across a membrane, e.g., a cell membrane. The osmotic process occurs because
there is a
physical and chemical tendency for solutions on different sides of a semi-
permeable
membrane to try to have the same concentrations of solutes in them.
In the most general sense, the osmolality of the compositions of the present
invention can be regulated by changing the amounts of any of all components.
In a specific sense, the most practical method of regulating the osmolality is
to
change the amount of single or multiple chemical components (normally present
in a
large enough amount to allow varying the osmolality over a sufficient range)
whose
alterations will not significantly affect either the stability, the efficacy,
or the other
physical-chemical properties (pH, viscosity) of the composition.
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Based on these criteria, it is preferred to regulate the osmolality by varying
the
amount of the source of anions and/or source of cations. It is present in
adequate
amounts to allow varying the osmotic pressure over a sufficient range for
various
compositions. Varying amounts of, for example, magnesium chloride over the
necessary
range does not significantly affect the stability, the efficacy, the pH, or
the viscosity of
the composition. Any of the other chemical components can be varied to adjust
the
osmolality.
In performing an adjustment of the osmolality, a theoretical calculation may
be
performed to predict the osmolality based on the amounts of the chemical
components in
the composition. This is useful for an initial estimate, however, using an
osmometer to
measure osmolality is the method of choice. Osmometers are standard, reliable,
and
relatively easy to operate instruments, which give actual measurements that
allow
determination of the osmolality of the formulation of compositions with high
precision.
The following examples illustrate the invention.
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Example 1
A 100 ml solution which is effective as a vaginal douche or urinary bladder
wash is
prepared as follows:
Ingredient
Magnesium Bromide 3.0 mg
Magnesium Chloride 0.5 mg
Magnesium Sulfate 0.5 mg
Potassium Chloride 3.4 mg
Potassium sorbate solution 100 mg
Calcium Chloride 0.1 mg
Purified Water q.s.
The composition is buffered to pH 4Ø
Optionally, the composition contains about 0.5% of nonoxynol-9.
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Example 2
Preparation of a gel.
Ingredients % W/W
Magnesium bromide 1.60
Phytosphingosine 0.05
Magnesium Chloride 0.05
Magnesium sulfate 0.03
Carbopol 940 0.4
Potassium Chloride 1.0
Butylene glycol 6.5
Quench T 3.0
Chamomile glycolic extract 3.0
Sodium hydrogenphosphate 0.5
Preservative 0.1
Fragrance 0.1
Deionized Water g.s.
100%
To 20 ml of water with stirring, is added the Carbopol 940. The mixture is
stirred
until hydration is complete and then butylenes glycol is added. The remaining
ingredients are mixed together and added to the first mixture. The mixing is
continued
until uniform. Optionally, 0.2% clotrimazole is added.
The composition may be used to treat vaginal or cutaneous irritations.
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Example 3
A lubricant is prepared by admixing the following ingredients.
Ingredients % W/W
Hispagel 20.0
Magnesium bromide 1.2
Magnesium Chloride 0.05
Flax Oil 1.0
Carbopol 940 0.4
Butylene Glycol 6.0
Potassium hydrogen phosphate 0.1
Citric Acid 0.5
Saffron 0.2
Potassium Chloride 0.8
Deionized Water g s.
100%
The pH of the composition is adjusted to 4Ø
The composition can be used to treat hemorrhoids or cutaneous irritations.
