Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TOPICAL PHENYLEPHRINE PREPARATION
FIELD OF THE INVENTION
This invention relates to a topical preparation containing
phenylephrine for application to the skin in the vicinity of
a wound to substantially reduce bleeding from the wound.
BACKGROUND OF THE INVENTION
Human skin is a multilayer structure containing a complex
network of blood vessels. The upper layer of the skin, the
epidermis, comprises sheets of cells and provides a protective
outer layer over the entire body. Beneath the epidermis is the
dermis which contains nutritive arteries, veins and capillaries
which supply nutrients to the skin. Located below the dermis
is a subcutaneous layer containing the venous plexus, which
holds large quantities of blood to heat the surface of the
skin.
In order to regulate skin temperature, arteriovenous (AV)
anastomoses are provided in the dermis, comprising large
vascular communications directly between the arteries in the
dermis and the subcutaneous venous plexus. The AV anastomoses
have strong muscular walls innervated by sympathetic
vasoconstricting nerve fibres and when constricted, reduce or
stop the flow of blood between the arteries of the dermis and
the venous plexus.
Although this vasoconstricting effect is most powerful in
parts of the body containing AV anastomoses, such as the hands,
feet, lips, nose and ears, the skin throughout the body
contains sympathetic vasoconstrictor nerve fibres which provide
vasoconstrictive control of the nutritive vessels in the
dermis.
These sympathetic vasoconstrictor nerve fibres are
provided with adrenergic receptors, the two main types of which
are classified as alpha receptors and beta receptors.
Stimulation of alpha receptors causes vasoconstriction of blood
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vessels, whereas beta receptor stimulation causes dilation of
blood vessels. Drugs which can stimulate either alpha or beta
receptors can be used to increase or decrease blood circulation
in the dermis.
Phenylephrine is a known sympathomimetic agent and is
believed to stimulate alpha receptors of sympathetic
vasoconstrictor nerve fibres and thereby cause
vasoconstriction. Phenylephrine is commonly found in over-the-
counter preparations for temporary relief of nasal congestion.
Its decongesting effect is produced by constriction of the
smaller arterioles of the nasal passages. Phenylephrine and
other sympathomimetics have also been used in epistaxis
(nosebleed) control, and in dentistry and surgery to minimize
blood loss during surgical procedures.
Phenylephrine is also known to produce vasoconstriction
in the AV anastomoses and nutritive vessels of the skin.
However, the disadvantage exists that, to date, phenylephrine
has not been used in a topically applied form as a treatment
to stop or reduce bleeding from skin wounds, particularly
cutaneous bleeding from minor skin wounds.
SUMMARY OF THE INVENTION
To overcome the above disadvantage, the inventors have
found that topical application of phenylephrine or one of its
physiologically active salts, in the vicinity of a bleeding
skin wound, can substantially reduce or eliminate the flow of
blood from the wound.
Accordingly, the inventors have developed a topical
preparation containing phenylephrine as a treatment to
substantially reduce or stop bleeding from skin wounds.
Preferably, phenylephrine is present in the topical preparation
as phenylephrine hydrochloride. Preferably the concentration
of phenylephrine in the topical preparation is from about 0.5%
to about 50% by weight.
Preferably, the topical preparation of the present
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invention is in the form of an ointment, cream, or liquid,
comprising an effective amount of phenylephrine and a base, the
type of base depending on the site of application and reason
for use. For example, bases for an ointment or cream maybe
selected from organogels, hydrogels, and emulsion-type
semisolids.
It is one object of the present invention to provide a
topical preparation containing phenylephrine in an amount
effective to constrict blood vessels in and below the skin.
It is another object of the present invention to provide
a topical preparation containing phenylephrine in an amount
effective to substantially reduce or stop cutaneous bleeding
from a skin wound.
In one aspect, the present invention provides a topical
preparation comprising: phenylephrine; and an inert carrier,
wherein said phenylephrine is present in said topical
preparation in an amount effective to substantially reduce flow
of blood from a bleeding skin wound when said topical
preparation is applied to said skin wound.
In another aspect, the present invention provides a
topical composition for stemming the flow of blood from a skin
wound, comprising: phenylephrine; and an inert carrier.
Preferably, phenylephrine is present in the above topical
preparation and composition in an amount effective to
substantially stop cutaneous bleeding from minor skin wounds.
In yet another aspect, the present invention provides a
method for treatment of skin wound to substantially reduce
bleeding therefrom, said method comprising: applying a topical
preparation comprising phenylephrine in an inert carrier to the
skin wound.
Preferably, the topical preparation and composition of the
present invention is further applied directly to the wound and
to an area of skin surrounding the wound.
Use of the topical preparation and composition of the
present invention preferably causes cutaneous bleeding from a
skin wound to be substantially stopped.
In topical preparations and compositions of the present
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invention, the inert carrier is preferably selected from a
group comprising organogels, hydrogels and emulsion-type
semisolids.
In topical preparations and compositions of the present
invention, phenylephrine comprises from about 0.5% to 50% by
weight of the preparation, preferably in the form of
phenylephrine hydrochloride.
BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects and advantages of the present invention
will become apparent from the following description, taken
together with the accompanying drawing, in which:
Figure 1 is a sectional, schematic diagram illustrating
the structure of human skin and blood circulation therein.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preferred embodiments of the invention are now described
with reference to Figure 1.
Figure 1 is a schematic diagram showing a sectional view
of the structure of human skin. As shown in Figure 1, skin
comprises an upper epidermis 10 which contains layers of skin
c~lls and provides the body with an outer protective barrier.
Under the epidermis 10 is the dermis 12, which contains
the nutritive blood vessels of the skin. Figure 1 illustrates
these nutritive vessels as comprising arteries 14, veins 16 and
capillaries 18.
Under the dermis 12 is the subcutaneous layer 20 which
contains the venous plexus 22, shown in Figure 1 as an
intricate network of blood vessels.
The arteries 14 of the dermis 12 communicate with the
venous plexus 22 of the subcutaneous tissue 20 by means of AV
anastomoses 24.
As discussed above, the blood vessels 14, 16 and 18 of the
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dermis 12 and the AV anastomoses 24 have alpha-adrenergic
receptors which may be caused to constrict by sympathomimetic
agents, thereby restricting or cutting off blood flow to and/or
in the blood vessels 14, 16 and 18 of the dermis 12 and between
the arteries 14 and the venous plexus 22.
In the topical preparation of the present invention,
phenylephrine, or (R)-3-hydroxy-alpha-[(methylamino)methyl]
benzenemethanol, is applied to the skin and is believed to
stimulate adrenergic alpha receptors in the AV anastomoses 22
and the nutritive vessels 14, 16 and 18, thereby causing
vasoconstriction of the AV anastomoses 22, and the blood
vessels 14, 16 and 18 in the dermis 12.
When applied to the skin in the vicinity of a skin wound,
the topical preparation of the present invention substantially
reduces, and preferably completely stops, bleeding from the
wound.
The term "skin wound" as used herein refers to wounds
which penetrate the upper epidermis 10 and cause damage to
blood vessels 14, 16 and 18 in the dermis, resulting in the
flow of blood from the wound. A skin wound may also damage the
AV anastomoses 24 and the venous plexus 22 of the subcutaneous
layer 20. Types of skin wounds include cuts, punctures and
scrapes. Preferably, the topical preparation of the present
invention is used on skin wounds of a minor nature.
Preferably, the topical preparation according to the
present invention may be used to substantially reduce or
completely stop cutaneous bleeding from a minor skin wound.
The term "cutaneous bleeding" refers to blood flow from the
blood vessels 14, 16 and 18 of the dermis 12.
Preferably, the topical preparation of the present
invention is used of skin wounds of humans, although it may be
used on other mammals such as dogs.
To stop or substantially reduce bleeding, the topical
preparation of the present invention is applied in the vicinity
of the wound, meaning the wound itself and the skin immediately
surrounding the wound.
Phenylephrine is the active ingredient of the topical
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preparation of the present invention, causing vasoconstriction
of the blood vessels in the vicinity of the wound, thereby
substantially reducing or completely stopping bleeding from the
wound.
s The stoppage of blood flow by the topical preparation of
the present invention can be of great value in preventing
substantial loss of blood from a wound.
The topical preparation according to the present invention
comprises a vasoconstricting effective amount of phenylephrine
dispersed in an inert carrier. Preferably, phenylephrine is
present in the topical preparation in an amount of 0.5 to 50%
by weight of the preparation. Preferably, the amount of
phenylephrine in the preparation is effective to reduce or stop
blood flow in less than about five minutes. More preferably,
phenylephrine is present in the preparation in an amount of
about 2 to about 6% w/w, with about 5% w/w being most
preferred.
It is to be appreciated that preparations containing
smaller concentrations of phenylephrine may preferably be used
to reduce or stop cutaneous bleeding from minor skin wounds and
may require a longer time to reduce or stop bleeding, whereas
preparations containing higher concentrations of phenylephrine
may preferably be used to stop or reduce bleeding from more
serious wounds and result in faster reduction or stoppage of
bleeding.
Phenylephrine is preferably present in the topical
preparation in the form of a physiologically active salt, the
hydrochloride being most preferred. However, it is to be
understood that other forms of phenylephrine may also be
suitable, such as other physiologically active salts.
Preferred forms of topical preparations include creams,
ointments, lotions, shampoos, aerosols, gels and liquids.
Topical preparations according to the present invention may
also be incorporated into pads or wound dressings.
The topical preparation according to the present invention
is more preferably in the form of a cream or ointment. The
inert carrier is preferably a base which may comprise one or
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more compounds selected from a number of groups of substances,
including organogels, hydrogels, emulsion-type semisolids and
emulsified bases. A particularly preferred base comprises
about 45 to 50% DermobaseTM, about 45 to 50% AquadermTM, and
about 0 to 5% distilled water, the amounts being expressed in
terms of percent by volume of the base.
Preferred organogels include hydrocarbon type organogels
such as those selected from the group comprising petrolatum and
mineral oil-polyethylene gels; animal and vegetable fats such
as those selected from the group comprising lard, hydrogenated
vegetable oils and theobroma oil; soap base greases such as
those selected from the group comprising aluminum stearate and
mineral oil gels; and hydrophilic organogels such as those
selected from the group comprising carbowax bases and
polyethylene glycol ointment.
Preferred hydrogels include organic hydrogels such as
those selected from the group comprising pectin paste and
tragacanth jelly, and inorganic hydrogels such as those
selected from the group comprising bentonite gels and colloidal
magnesium aluminum silicate gels.
Preferred emulsion-type semisolids include water-in-oil
emulsifiable bases and oil-in-water emulsifiable bases selected
from the group comprising hydrophillic petrolatum, wool fat,
and anhydrous Tween base (white petrolatum, stearyl alcohol,
glycerine and tween 60). Preferred emulsion-type semisolids
also include emulsified bases such as water-in oil emulsified
bases and oil-in water emulsified bases, such as those selected
from the group comprising hydrous wool fat, rose water
ointment, hydrophillic ointment and vanishing cream.
A preferred method of preparing a topical phenylephrine
preparation according to the present invention comprises
reducing phenylephrine to an impalpable powder by levigating
it with an equal amount of water. The base in then added
incrementally using geometric dilution using a spatula on a
hard surface (such as an ointment pad).
A number of trials were conducted to test the efficacy of
topical preparations of the present invention in humans and
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other mammals. The results of some of these trials are
presented in the following examples, in which the subjects are
human unless otherwise indicated.
Example 1
Subject: Male
Age Range: 36-50
Location(s) of Laceration(s): Neck, chin.
Type(s) of Laceration(s): Cuts from shaving.
Number of Applications: 8
Form of Topical Preparation: Cream containing 5% w/w
phenylephrine
hydrochloride.
Time Required to Stop Bleeding: Stopped immediately
after application.
Side Effects: None.
Example 2
Subject: Male
Age Range: 36-50
Location(s) of Laceration(s): Hands and face.
Type(s) of Laceration(s): Cuts from shaving and
skinned knuckles
resulting in detachment
of a flap of skin.
Number of Applications: 5
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: 10-20 seconds.
Side Effects: None.
Example 3
Subject: Male
Age Range: 26-35
Location(s) of Laceration(s): Face.
Type(s) of Laceration(s): Cuts, close to surface.
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Number of Applications: 10-15
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: 5-10 seconds.
Side Effects: None.
Example 4
Subject: Female
Age Range: 26-35
Location(s) of Laceration(s): Leg.
Type(s) of Laceration(s): Cut, close to surface.
Number of Applications:
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: 30-60 seconds.
Side Effects: None.
Example 5
Subject: Male
Age Range: 51-65
Location(s) of Laceration(s): Face and neck.
Type(s) of Laceration(s): Shaving lacerations.
Number of Applications: 10
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: 1 minute.
Side Effects: None.
Comments: Subject takes aspirin daily as a blood thinner.
Example 6
Subject: Male
Age Range: 36-50
Location(s) of Laceration(s): Face and hands.
Type(s) of Laceration(s): Cuts from shaving,
lacerations to hand.
Number of Applications: 50
Form of Topical Preparation: As in Example 1.
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Time Required to Stop Bleeding: 1 minute for facial
cuts; 3-5 minutes
for deeper hand
cuts.
Side Effects: Moisturization of skin.
Example 7
Subject: Male
Age Range: 36-50
Location(s) of Laceration(s): Face.
Type(s) of Laceration(s): Scrapes.
Number of Applications: 3
Form of Topical Preparation: Ointment containing 5%
w/w phenylephrine
hydrochloride.
Time Required to Stop Bleeding: Short time.
Side Effects: None.
Example 8
Subject: Male
Age Range: Under 25
Location(s) of Laceration(s): Face and scalp.
Type(s) of Laceration(s): Puncture wounds,
lacerations up to 1 cm
long, shaving cuts,
bleeding pimples.
Number of Applications: 12
Form of Topical Preparation: As in Example 7.
Time Required to Stop Bleeding: Less than 1 minute.
Side Effects: Temporary whitening of skin in area around
a pimple to which preparation was applied.
Example 9
Subject: Male dog
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Age Range: --
Location(s) of Laceration(s): Scrotum.
Type(s) of Laceration(s): Surface abrasion with
slow seepage of blood.
Number of Applications: 3
Form of Topical Preparation: Liquid containing 3% w/w
phenylephrine
hydrochloride.
Time Required to Stop Bleeding: 3 minutes.
Side Effects: Nothing obvious.
Example 10
Subject: Dogs
Age Range: --
Location(s) of Laceration(s): Feet, ear flap.
Type(s) of Laceration(s): Toenails cut too short,
blood vessel exposed
"end-on"; puncture and
cut in ear flap.
Number of Applications: 4-5
Form of Topical Preparation: Ointment and liquid
containing 4-5~ w/w
phenylephrine
hydrochloride.
Time Required to Stop Bleeding: Bleeding not
stopped.
Side Effects: None.
Example 11
Subject: Male
Age Range: Under 25
Location(s) of Laceration(s): Neck.
Type(s) of Laceration(s): Cut, close to surface.
Number of Applications: 5
Form of Topical Preparation: As in Example 1.
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Time Required to Stop Bleeding: 1-2 minutes.
Side Effects: None.
Example 12
Subject: Male
Age Range: 26-35
Location(s) of Laceration(s): Legs.
Type(s) of Laceration(s): Scrapes, abrasions.
Number of Applications: 10
Form of Topical Preparation: As in Example 7.
Time Required to Stop Bleeding: 30-40 seconds.
Side Effects: None.
Example 13
Subject: Female
Age Range: 26-35
Location(s) of Laceration(s): Hand.
Type(s) of Laceration(s): Cut, close to surface.
Number of Applications:
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: Few minutes.
Side Effects: Burning.
Example 14
Subject: Male
Age Range: 26-35
Location(s) of Laceration(s): Legs.
Type(s) of Laceration(s): Scrapes, abrasions
Number of Applications: 10
Form of Topical Preparation: As in Example 7.
Time Required to Stop Bleeding: 30-40 seconds.
Side Effects: None.
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Example 15
Subject: Male
Age Range: 36-50
Location(s) of Laceration(s): Neck.
Type(s) of Laceration(s): Shaving cut.
Number of Applications:
Form of Topical Preparation: As in Example 1.
Time Required to Stop Bleeding: Less than 1 minute.
Side Effects: N/A.
The results of the above examples are generally
favourable, with bleeding generally being stopped within a few
minutes and few side effects being reported. All human
subjects reported that they would use the product again, and
most reported that the topical preparation of the present
invention is superior to other products on the market to stop
bleeding.
Although the invention has been described with reference
to certain preferred embodiments, it is to be understood the
invention includes all embodiments which are within the scope
of the following claims.
