Note: Descriptions are shown in the official language in which they were submitted.
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Treatment of vaginal atrophy as novel indication for myrrh
Specification
The instant invention relates to a novel indication for myrrh according to
claim 1, a
pharmaceutical preparation in vaginal dosage form according to claim 10, and a
method for
preparing a pharmaceutical preparation against menopausal symptoms according
to the
preamble of claim 13.
Myrrh Resin
Myrrh is the oleo-gum resin obtained from stems and branches of Commiphora
molmol
Engler and other related species of Commiphora other than Commiphora mukul.
Commiphora mukul ¨ although sharing the genus name ¨ cannot be used for
obtaining
myrrh. Commiphora molmol Engler is sometimes also referred to as Commiphora
myrrha or
Commiphora myrrha (Nees) Engler. Suited related species of Commiphora molmol
for
obtaining myrrh are Commiphora abyssinica Engler and Commiphora schimperi
Engler.
Pharmacopoeia myrrh is generally obtained from Commiphora molmol Engler, but
the other
related species, in particular those referred to above, are also well suited.
For medical purposes, myrrh is used as powdered resin, capsules, myrrh
tincture and other
galenical preparations for topical use.
Myrrh can be separated into three components: volatile oil (ca. 2 to 10%),
alcohol-soluble
resin (ca. 25 to 40 %) and water-soluble gum.
The main constituents of myrrh essential oil are furanosesquiterpenes of
various structural
types together with sesquiterpenes. Furanosesquiterpenes are the source of its
characteristic
balsamic odour; a mixture of furanoeudesma-1,3-diene and lindestrene has the
typical aroma
of myrrh.
Myrrh essential oil is generally obtained by hydrodistillation, steam
distillation, and solvent
extraction. Extraction by carbon dioxide in the supercritical state is the
state-of-the-art
process that offers many advantages in obtaining volatile extracts. The mild
extraction
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conditions give assurance against chemical reactions not taking place during
the process;
i.e. no hydrolysis, oxidation, or isomerisation taking place. Other possible
extraction agents
include nitrogen, hexane, methane, and ethane.
Marongiu et al.: "Chemical Composition of the Essential Oil and Supercritical
CO2 Extract of
Commiphora myrrha (Nees) Engl. and of Acorus calamus L.", J. Agric. Food Chem.
53
(2005), 7939-7943 discloses the composition of myrrh extract obtained by
different methods.
The authors demonstrated that hydrodistillation (HD), steam distillation (SD)
and supercritical
extraction with carbon dioxide (SFE) yield similar results as far as main
components and
quantities extracted are concerned.
Myrrh is known for its wound healing effect. Dolara, P. et al.: "Local
Anaesthetic, Antibacterial
and Antifungal Properties of Sesquiterpenes from Myrrh", Planta Medica 66
(2000), 356-358
describe the anaesthetic, antibacterial and antifungal properties of certain
sesquiterpenes of
myrrh.
US 4,719,111 A discloses the external use of myrrh gum for treating decubitus
ulcers.
US 4,592,912 A discloses the topical use for the relief of or for the
prevention of muscular
aches, pains, cramps and muscular spasms such as are found, for example, in
overexerted
muscles, misused muscles, headaches and back aches.
US 5,350,774 A describes the topical treatment of skin disorders with myrrh.
US 5,248,503 A discloses the utilization of myrrh as food or dietary
supplement.
US 6,077,513 A discloses a pharmaceutical composition containing myrrh oil and
myrrh resin
as the active ingredients therein for treating schistosomiasis.
CN 1 679 687 A describes the use of a composition comprising seven substances
of the
traditional Chinese medicine against several diseases, namely vaginitis,
cervical erosion,
endometritis, hysteromyoma and adnexitis. However, this document does not
teach or
suggest the use of myrrh against other diseases or impaired states of a
patient, like, e.g.
vaginal atrophy.
Physiology of Menopausal Vaginal Symptoms
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The menopause is defined as the permanent cessation of cyclical menstruation
due to loss
of ovarian follicular activity. The decline in estrogen concentration is
associated with both
acute and long-term effects. Established acute symptoms are vasomotor
instability,
manifesting as hot flushes and night sweats, and vaginal atrophy, manifesting
as vaginal
dryness, itching, burning, and discomfort.
Menopausal symptoms may be managed by using hormone replacement therapy (HRT)
with
estrogens, with or without progestogens. Adverse effects of HRT include an
increased risk of
breast cancer, ovarian and endometrial cancer, an increased risk of venous
thromboembolism, stroke, dementia, gallstone formation and cholecystectomy. It
is now
generally recommended that menopausal HRT used to relieve vasomotor and
vaginal
symptoms should be given at the lowest effective dose for no longer than
necessary. But to
withdraw HRT means recurrence of menopausal symptoms.
Density of estrogen receptors is highest in endometrium and vagina. A drop in
estrogen
levels results in
- a decrease in mitotic activity, so the vaginal lining becomes thinner and
more fragile;
- a drop in collagen content in the connective tissue;
- decreased blood flow and decreased vaginal lubrication;
leading to vaginal symptoms and findings of pallor, dryness and decreased
rugosity of the
vaginal mucosa.
US 2003/0170325 Al discloses compositions in gel or suppository form for the
treatment of
vaginal dryness. The compositions comprise herbal compounds with or without
vitamin.
However, this patent application does not suggest using extracts of myrrh for
the treatment of
vaginal dryness.
A non-hormonal effective treatment of vaginal atrophy as menopausal symptom is
needed,
as an alternative to HRT. It is an objective of the instant invention to
provide an active
ingredient for a pharmaceutical preparation or a medicinal product for such a
treatment, a
pharmaceutical preparation in a suitable dosage form as well as a method for
preparing a
pharmaceutical preparation against menopausal symptoms.
This objective is achieved by using myrrh in vaginal dosage form for the
treatment of vaginal
atrophy as menopausal symptom according to claim 1. In the patent and non-
patent literature
known to the inventor, no teaching or suggestion for such an indication of
myrrh could be
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found. This novel indication is surprising since vaginal atrophy as menopausal
symptom is
not related to bacteria and fungi against which myrrh has been used hitherto.
In other words, the myrrh is intended to be used for the treatment of vaginal
atrophy and
symptoms related therewith occurring (not exclusively but also) during
menopause.
In an embodiment, the myrrh is the sole active ingredient within the claimed
novel indication
of myrrh. This means that pharmaceutical preparations or medicinal products
comprise only
myrrh as active pharmaceutical ingredient, but no other pharmaceutically
active substances.
The term "myrrh" is to be understood as the oleo-gum resin originating from
Commiphora
species with the exception of Commiphora mukul. The myrrh used in connection
to this
invention is preferably pharmacopeia myrrh.
The term "menopausal symptoms" relates to all symptoms occurring in the
menopause.
Established acute symptoms are vasomotor instability, manifesting as hot
flushes, and
vaginal atrophy, manifesting as vaginal dryness, itching, burning, and
discomfort.
In an embodiment, the myrrh is present in the form of a powdered resin, a
myrrh tincture or
an extract of myrrh. In doing so, the resin, tincture or extract are provided
in vaginal dosage
form, i.e. in a form suited for the topical application to the vagina of a
patient to be treated.
The resin tincture or extract can, e.g., be used to impregnate a tampon or
another carrier
suited for vaginal application.
In another embodiment, the extract of myrrh is a dry extract (preferably
obtained by
extraction of myrrh with an organic solvent) or an aqueous extract. In a
further embodiment,
the myrrh is used in pastry form. To obtain a pastry, myrrh resin is subjected
to extraction
with an organic solvent, for example ethanol, petroleum ether or ethyl
acetate. The extract
thus obtained is filtered and vacuum-concentrated to a pastry form. Thus,
myrrh pastry is a
filtered and concentrated form of a myrrh extract. The residue is again
dissolved in alcohol
(e.g., ethanol) or a mixture of alcohol and water, filtered and vacuum-
concentrated.
In a further embodiment, the myrrh is used as lipophilic extract of myrrh, in
particular
obtained by extraction with liquid carbon dioxide in the supercritical state.
Other standard
extraction methods as explained above are also applicable.
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In a further embodiment, the extract contains furanoeudesma-1,3-diene,
lindestrene and
curzerene as main ingredients. The according chemical structures of these
compounds are
displayed below:
CH3 CH3 CH3
0
/
05/ H2
H2C
/
CH31:1
2
CH1:1 1:1
CH3 CH3 CH3 0 CH3
furanoeudesma-1,3-diene lindestrene curzerene
5 Preferably, furanoeudesma-1,3-diene is present in the extract in an
amount of more than 20
A), in particular more than 25 A), in particular more than 30 A, and very
particular more than
35 %. All percentages given in the present application are to be understood as
percent by
weight if not explicitly indicated otherwise.
In a further embodiment, the extract contains more than 10 A), in particular
more than 15 A),
in particular more than 20 A, and in particular more than 25 A, of
curzerene.
In a further embodiment, the extract contains more than 5 A), in particular
more than 10 A), in
particular more than 15 A, of lindestrene.
In a further embodiment, the extract has a refractive index at 20 C (measured
with an Abbe
refractometer) of 1.5 to 1.6, in particular of 1.51 to 1.55, in particular of
1.515 to 1.54, in
particular of 1.517 to 1.537.
In a further embodiment, the extract has a density at 20 C (measured with a
pycnometer) of
1.0 to 2.0 g/cm3, in particular of 1.02 to 1.08 g/cm3, in particular of 1.025
to 1.075 g/cm3.
In a further embodiment, the myrrh is present in a semisolid dosage form for
vaginal
application, in particular as vaginal ointment, vaginal cream, or vaginal gel.
In such semisolid
preparations, oleaginous bases or water-soluble bases can be used. The
semisolid
preparations might be water-in-oil emulsions or oil-in-water emulsions.
In yet another embodiment, the myrrh is present in a liquid dosage form for
vaginal
application, in particular as vaginal liquid, vaginal emulsion, or vaginal
suspension.
In another embodiment, the myrrh is present as vaginal foam or vaginal tampon.
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In still another embodiment, the myrrh is present in a solid dosage form for
vaginal
application, in particular as vaginal tablet, vaginal capsule, or vaginal
suppository.
Any of the afore-mentioned vaginal dosage forms enables a user to apply the
myrrh at the
location at which it can develop its activity against menopausal symptoms in a
very well
suited manner.
In a further embodiment, the solid dosage form, in particular the vaginal
tablet, vaginal
capsule, or vaginal suppository essentially consists of a fatty, oleaginous,
or oil-type base
and the myrrh. Cocoa butter and hard fat are members of this group of
substances. Cocoa
butter is an oleaginous base that softens at 30 C and melts at about 34 C,
just below body
temperature, thus representing an ideal suppository base. Other bases in this
category
include commercial products such as Fattibase (triglycerides from palm, palm
kernel, and
coconut oils with self-emulsifying glyceryl monostearate and polyoxyl
stearate), Wecobee
bases (triglycerides derived from coconut oil), Witepsol bases (triglycerides
of saturated C12-
C15 fatty acids with varying portions of the corresponding partial
glycerides), Suppocire and
Ovucire bases)
The inventor could already establish a synergistic effect of the combination
of cocoa butter
and myrrh. In particular, experiments indicate that constituents of cocoa
butter and
ingredients of myrrh essential oil show synergistic effects on mitotic
activity, collagen
metabolism, blood flow or lubrication when applied vaginally for treatment of
vaginal atrophy.
Thus, using cocoa butter as basic material even enhances the effectiveness of
the myrrh.
It was found that a very well suited dosage for using the myrrh, in particular
in form of a
suppository, is daily, in particular once a day, in particular once a day at
bed time. Such a
dosage regime is sufficient to alleviate the menopausal symptoms, in
particular vaginal
atrophy.
The invention also relates to a pharmaceutical preparation or medicinal
product in vaginal
dosage form which is suited for the treatment of vaginal atrophy (in
particular of vaginal
atrophy as menopausal symptom), in particular a vaginal ointment, a vaginal
cream, a
vaginal gel, a vaginal liquid, a vaginal emulsion, a vaginal suspension, a
vaginal foam, a
vaginal tampon, a vaginal tablet, a vaginal capsule, or a vaginal suppository
containing myrrh
as the only pharmaceutical active ingredient. It is not known from prior art
that myrrh alone
(without any other pharmaceutically active substance) can have a positive
effect on the
symptoms related with vaginal atrophy.
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In an embodiment, the pharmaceutical preparation is present in form of a
vaginal tablet,
vaginal capsule or vaginal suppository essentially consisting of a fatty, an
oleaginous or an
oil-type base material and myrrh according to the preceding explanations. Such
a vaginal
tablet, capsule or suppository is suitable for the treatment of menopausal
symptoms, in
particular for the treatment of vaginal atrophy and vaginal symptoms of
dryness, itching,
burning, and discomfort.
In an embodiment, the tablet, capsule or suppository has a weight of 0.5 to 5
g, in particular
of 1 to 4 g, in particular of 2 to 3 g, in particular of 1.5 to 2.5 g, in
particular of 1.7 to 1.9 g. 1.8
g is a particular well suited weight. Thereby, the myrrh is preferably present
in the tablet,
capsule or suppository in an amount of 0.1 to 10 %, in particular of 0.25 to 9
%, in particular
of 0.5 to 8 %, in particular of 0.75 to 7 %, in particular of 1 to 6 %, in
particular of 1.5 to 5 %,
in particular of 2 to 4 %, in particular of 2.5 to 3 % based on the total
weight of the tablet,
capsule or suppository. An amount around 1 % of myrrh is particularly well
suited.
The objective is also solved by a method for preparing a pharmaceutical
preparation or
medicinal product, respectively, against vaginal atrophy as menopausal
symptom, having the
following steps:
- melting a fatty, an oleaginous or an oil-type base at an elevated
temperature above
the melting temperature of this base material to obtain a melt,
- adding myrrh as the only pharmaceutically active ingredient to the melt
in an amount
of 0.1 to 10 % with respect to the sum of the base material and the myrrh so
as to
obtain a mixture of the base and the myrrh,
- stirring the mixture,
- pouring the mixture into at least one mould,
- cooling the mixture to room temperature,
- removing the solidified mixture from the mould.
By such a method, differently shaped pharmaceutical preparations or medicinal
products
against menopausal symptoms can be obtained. It should be noted that besides
myrrh no
other pharmaceutically active ingredient is used within the claimed method.
In an embodiment, the mould has a shape to form the mixture such that at least
one vaginal
tablet, capsule or suppository is obtained. Preferably, the mould forms the
mixture in such a
way that a plurality of tablets, capsules or suppositories is obtained. These
tablets, capsules
or suppositories can have the same size and/or shape or different shapes
and/or sizes.
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Thus, differently sized and/or shaped tablets, capsules or suppositories can
be provided to
address the individual needs of the users of this medical product.
Explained embodiments of the claimed use of myrrh are also applicable with
respect to the
claimed pharmaceutical preparation and the claimed method, and vice versa.
Furthermore, a method for treating the (female) human or animal body with
myrrh to relieve
menopausal symptoms, in particular to relieve vaginal atrophy, is hereby
disclosed.
Explained embodiments of the claimed use of myrrh or the claimed
pharmaceutical
preparation are also applicable with respect to this method.
Further details of the instant invention are explained in connection to the
following examples
which are, however, not to be construed in a limiting way.
A lipophilic extract of Commiphora myrrha, produced by supercritical CO2
extraction, was
used.
Vaginal suppositories were prepared using either hard fat or cocoa butter as
suppository
base.
Cocoa butter was melted at 50 C. Under stirring, myrrh extract was added to a
final
concentration of 1 % by weight of the total weight of the formula (mixture).
Stirring was
continued for several hours to obtain a stable crystalline form. The mixture
was then poured
into molds and cooled.
Hard fat was melted at 50 C. Myrrh extract was added to a final concentration
of 1% of the
total weight of the formula to obtain a mixture. The mixture was poured into
molds and
cooled.
The suppositories weighed 2 grams each, containing 20 mg of myrrh extract
each.
Both preparations (hard fat/cocoa butter) were tested in postmenopausal women
(more than
2 years past last menstrual period) with vaginal symptoms of dryness,
discomfort and itching.
The vaginal suppositories were applied over a period of 14 consecutive days
once a day,
namely at bedtime each night.
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Both preparations provided subjective and objective relief of menopausal
symptoms, in
particular vaginal symptoms due to vaginal atrophy. Colposcopy revealed an
improved status
of the vaginal mucosa.
Improvement of genital symptoms was more pronounced with the cocoa butter
suppositories.
Theobroma cocoa seeds contain polyphenols and flavonoids ¨ substances with
high
antioxidation potential ¨ and procyanidins which exhibit vascular effects. It
appeared that in
connection to the myrrh extract synergistic effects on mitotic activity,
collagen metabolism,
blood flow or lubrication occur when both substances are applied concomitantly
for the
treatment of vaginal atrophy.
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