COMPOSITIONS FOR THE TREATMENT OF EPISTAXIS

COMPOSITIONS POUR LE TRAITEMENT DE L'EPISTAXIS

English Abstract

A topical composition includes at least one film forming agent; at least one surfactant; at least one non-polar volatile siloxane solvent; and a therapeutically effective concentration of at least one pharmaceutical agent selected from the groups comprising vasoconstrictors and antifibrinolytics, wherein the composition is sufficiently designed to dry within 60 seconds after application to a body surface to form a dried composition, and wherein the dried composition forms: (i) a flexible film, wherein the flexible film closely follows irregularities of the nostril surface as well as movement of the nostril surface, and (ii) a durable film, wherein the durable film does not crack or flake off and remains intact for more than 12 hours giving release of the pharmaceutical agent for an extended period of time.

French Abstract

La présente invention concerne une composition topique comprenant au moins un agent surfactant ; au moins un tensioactif ; au moins un solvant siloxane volatil non polaire; et une concentration thérapeutiquement efficace d'au moins un agent pharmaceutique sélectionné dans le groupe comprenant des vasoconstricteurs et des antifibrinolytiques, la composition étant conçue pour sécher dans les 60 secondes qui suivent son application sur une surface corporelle pour former une composition sèche, et la composition sèche formant : (i) un film souple, le film souple suivant étroitement les irrégularités de la surface des narines ainsi que le mouvement de la surface des narines, et (ii) un film durable, le film durable ne se fissurant pas ou ne formant pas de paillettes et restant intact pendant plus de 12 heures pour permettre une libération de l'agent pharmaceutique pendant une période prolongée.

Claims

WHAT IS CLAIMED IS:

1. A topical composition, comprising:
(i) from 15.0% to 30% of at least one silicon resin film forming agent
selected from the
group consisting of siloxysilicates, silicone acrylates and combinations
thereof;
(ii) from 30% to 75% of at least one volatile solvent selected from the group
consisting of
non-polar volatile siloxanes, volatile aliphatic hydrocarbons, volatile
hydrofluoroalkanes
and combinations thereof; and
(iii) from 0.05% (w/w) to 20% of at least one vasoconstrictor active agent
selected from
the group consisting of phenylephrine, epinephrine, tetrahydrozoline, an
amphetamine,
an antihistamine, methylphenidate, mephedrone, oxymetazoline, pseudoephedrine,

psilocybin, ephedrine, their salts and combinations thereof.
2. The composition of claim 1 further comprising from 0.05% to 20% of at
least one
additional active agent,
wherein the at least one additional active agent is an antifibrinolytic active
agent selected
from the group consisting of tranexamic acid, aprotinin, .epsilon.-
aminocaproic acid,
aminomethylbenzoic acid, their salts and combinations thereof.
3. The composition of claim 1, wherein the siloxysilicate is
trimethylsiloxysilicate.
4. The composition of claim 1, wherein the at least one vasoconstrictor is
phenylephrine, its hydrochloride or combinations thereof.
5. The composition of claim 2, wherein the antifibrinolytic is tranexamic
acid.
6. The composition of claim 2, further comprising from 0.05% to 2% of
phenylephrine or its hydrochloride and from 3% to 10% tranexamic acid or its
salt.
7. The composition of claim 2, further comprising 0.25% w/w of
phenylephrine or
its hydrochloride and about 5 w/w tranexamic acid or its salt.


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8. The composition of claim 1, wherein the non-polar volatile siloxanes are
selected
from the group consisting of hexamethyldisiloxane,
heptamethyloctyltrisiloxane,
octamethylcyclotetrasiloxane, octamethyltrisiloxane,
decamethylcyclopentasiloxane,
decamethyltetrasiloxane, dodecamethylpentasiloxane,
dodecamethylcyclohexasiloxane,
and any combination thereof.
9. The composition of claim 1, wherein the volatile aliphatic hydrocarbons
are
selected from the group consisting of pentane, isooctane, isododecane,
isohexadecane and
combinations thereof.
10. The composition of claim 1, wherein the volatile hydrofluoroalkanes are
selected
from the group consisting of 1,1,1,2-tetrafluoroethane (HFA 134a),
1,1,1,2,3,3,3-
heptafluoro-n-propane (HFA 227) and combinations thereof.
11. The compositions of claim 1, further comprising from 15% (w/w) to 40%
(w/w)
of water or a buffer.
12. A composition comprising:
(i) from 10.0% (w/w) to 30.0% (w/w) of a silicone acrylate;
(ii) from 1.0% (w/w) to 5.0% (w/w) of at least one surfactant selected from
the group
consisting of siliconic surfactants, anionic surfactants, nonionic
surfactants, and
combinations thereof;
(iii) from 30.0% (w/w) to 75.0% (w/w) of a volatile solvent selected from the
group
consisting of a polydimethylsiloxane, an aliphatic hydrocarbon, and
combinations
thereof;
(iv) from 15% (w/w) to 40% (w/w) of water; and
(v) from 0.005% (w/w) to about 25.0% (w/w) of a vasoconstrictor selected
from the
group consisting of phenylephrine, phenylephrine, epinephrine, epinephrine,
tetrahydrozoline, an amphetamine, an antihistamine, methylphenidate,
mephedrone,

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oxymetazoline, pseudoephedrine, psilocybin, ephedrine their salts and
combinations
thereof.
13. A composition comprising:
(0 from10-40% w/w of trimethylsiloxysilicate;
(ii) from 0.5-7% w/w of a surfactant selected from the group consisting of
sodium
lauryl sulfate, alkyl- and alkoxy- dimethicone copolyol, polysorbate and a
combination
thereof;
(iii) from 30-80% w/w of a volatile solvent selected from the group
consisting of
hexamethyldisiloxane, isooctane and combinations thereof;
(iv) from 20% (w/w) to 40% (w/w) of water; and
(v) from 0.005% w/w to 25% w/w of a vasoconstrictor selected from the group

consisting of phenylephrine, phenylephrine hydrochloride, epinephrine,
epinephrine
hydrochloride, tetrahydrozoline hydrochloride, an amphetamine, an
antihistamine,
methylphenidate, mephedrone, oxymetazoline, pseudoephedrine, psilocybin,
ephedrine
sulfate, and combinations thereof
14. The composition of claim 13, comprising:
(0 from 15% w/w to 20% w/w trimethylsiloxysilicate;
(ii) from 1.5% w/w to 3.0% w/w sodium lauryl sulfate;
(iii) from 22% w/w to 30% w/w hexamethyldisiloxane and from 20-25% w/w
isooctane;
(iv) from 25% w/w to 30% w/w water;
(v) from 10% w/w tol5% of a silicone acrylate; and
(vi) from 0.05% w/w to 0.25% w/w phenylephrine hydrochloride.
15. The composition of claim 14, further comprising from 3% w/w to 10% w/w
of
tranexamic acid.
16. The composition of claim 1, wherein the topical composition is
administered to a
subject in need thereof in the form of nasal swab, a single use wipe, a gel, a
nasal spray, a

55
foam, a towelette, a syringe, a dropper, a spray dispenser, a compressible
bottle or tube, a
spatula, a suppository insertion tube, an extrusion tube, and an inflatable
member.
17. A method of treatment or prevention of any type of nose bleeding,
including an
Epistaxis disorder, the method comprising the step of topically applying to
the mucosal
surface of the affected nostril of a subject in need of such treatment a
therapeutically
effective amount of the composition according to claim1.
18. A kit comprising a pharmaceutical liquid adhesive composition according
to
claim 1 and a container-applicator device suitable for storage and application
of the
composition to the nose, into the affected nostril.
19. The kit according to claim 18, wherein the container-applicator device
comprises
at least one of a single use wipe, a towelette, a syringe, a dropper, a spray
dispenser, a
compressible bottle or tube, a spatula, a suppository insertion tube, an
extrusion tube, and
an inflatable member.
20. A pharmaceutical liquid adhesive composition of claim 1, for use in
preventing or
treating any type of nose bleeding, including an Epistaxis disorder.

Description

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COMPOSITIONS FOR THE TREATMENT OF EPISTAXIS
RELATED APPLICATIONS
This application hereby incorporates United States Non-Provisional Application

No. 14/203,246, filed March 10, 2014, and United States Provisional
Application No.
61/775,598, filed March 10, 2013, by reference in their entirety.
BACKGROUND OF THE INVENTION
Topical disorders are widespread and include a number of different conditions
of
the body surfaces such as the skin, nails and mucous membranes. Topical
disorders
include but are not limited to various kinds of dermatitis, acne, rosacea,
onychomycosis,
pityriasis, actinic keratosis, eczema, erythema, urticaria, hemorrhoids, anal
fissures, anal
pruritus, common warts, genital warts, anal warts, herpes and epistaxis.
Currently, there
are a number of topically applied formulations for the treatment of topical
conditions,
including ointments, creams, gels, lotions, jellies and pastes, foams, sprays
and medicated
pads.
Epistaxis or nosebleed, the term used to describe hemorrhage from the nose, is
relatively common, usually noticed when the blood drains out through the
nostrils. There
are two types: anterior (the most common), and posterior (less common, more
likely to
require medical attention). Sometimes in more severe cases, the blood can come
up the
nasolacrimal duct and out from the eye. Fresh blood and clotted blood can also
flow
down into the stomach and cause nausea and vomiting.
While usually not life threatening, Epistaxis is a topical disorder for which
there is
no arsenal of effective and safe treatments.
SUMMARY OF THE INVENTION
Topical compositions and methods of topical treatment of Epistaxis are
disclosed
herein.
According to aspects illustrated herein, there is provided a topical
composition that
includes at least one film forming agent; at least one surfactant; at least
one non-polar
volatile siloxane solvent; and a therapeutically effective concentration of at
least one
pharmaceutical agent, wherein the composition is sufficiently designed to dry
within 60
seconds after application to a body surface such as the inner part of the
nostril, to form a

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dried composition, and wherein the dried composition forms: a flexible film,
wherein the
flexible film closely follows irregularities of the nostril inner surface as
well as
movement of said surface, and (ii) a durable film, wherein the durable film
does not crack
or flake off and remains intact for more than 12 hours giving release of the
pharmaceutical agent(s) for an extended period of time.
According to aspects illustrated herein, there is provided a topical
composition that
includes a silicone resin film forming agent; at least one surfactant selected
from the
group consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone
copoiyoi,
polysorbate and a combination thereof; a non-polar volatile siloxane solvent;
at least one
vasoconstrictor selected from the group consisting of phenylephrine,
epinephrine,
tetrahydrozoline hydrochloride, an amphetamine, an antihistamine,
methylphenidate
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine and plant
extracts
and at least one antifibrinolytic agent selected from the group consisting of
tranexamic
acid, aprotinin, 8-aminocaproic acid, aminomethylbenzoic acid or their salts
and
combinations thereof, wherein the composition is sufficiently designed to dry
within 60
seconds after application to a skin or a mucosal surface to form a dried
composition, and
wherein the dried composition forms: a flexible film, wherein the flexible
film closely
follows irregularities of the surface as well as movement of the surface, and
(ii) a durable
film, wherein the durable film does not crack or flake off and remains intact
for more
than 12 hours giving release of the pharmaceutical agent for an extended
period of time.
According to aspects illustrated herein, there is provided a topical
composition that
includes from about 10.0% (w/w) to about 30.0% (w/w) of
trimethylsiloxysilicate; from
about 1.0% (w/w) to about 5.0% (w/w) of at least one surfactant selected from
the group
consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone cope**,
polysorbate
and a combination thereof; from about 30.0% (w/w) to about 75.0% (w/w) of a
non-
polar volatile siloxane solvent; from about 0.005% (w/w) to about 25.0% (w/w)
of a
vasoconstrictor selected from the group consisting of phenylephrine,
epinephrine,
tetrahydrozoline hydrochloride, an amphetamine, an antihistamine,
methylphenidate
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine and plant
extracts
and about 0.005%-to about 25.0% of an antifibrinolytic agent selected from the
group
consisting of tranexamic acid, aprotinin, 8-aminocaproic acid,
aminomethylbenzoic acid

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or their salts and combinations thereof wherein the composition is
sufficiently designed
to dry within 60 seconds after application to a body surface to form a dried
composition,
and wherein the dried composition forms: a flexible film, wherein the flexible
film
closely follows irregularities of the surface as well as movement of the
surface, and (ii) a
durable film, wherein the durable film does not crack or flake off and remains
intact for
more than 12 hours giving release of the pharmaceutical agent for an extended
period of
time.
According to aspects illustrated herein, there are provided topical Epistaxis
compositions that include at least one flexible film forming ingredient, at
least one
surfactant, at least one non-polar volatile solvent, and a therapeutically
effective
concentration of at least one pharmaceutical agent, wherein the composition is

sufficiently designed to dry within 60 seconds after application to a topical
surface to
form a dried composition, and wherein the dried composition forms: (i) a
flexible film,
wherein the flexible film closely follows irregularities of the surface as
well as movement
of the surface, and (ii) a durable film, wherein the durable film does not
crack or flake off
and remains intact for more than 12 hours giving release of the pharmaceutical
agent for
an extended period of time.
According to aspects illustrated herein, there is provided a method of
preventing or
treating Epistaxis that includes topically applying when need arises or
several times daily,
once daily, once every other day or twice weekly to the Epistaxis affected
nostril of a
subject in need of such treatment a therapeutically effective concentration of
a topical
Epistaxis composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides topical compositions and methods of treatment
of
Epistaxis disorders.
The topical compositions of the present invention are applied to the Epistaxis

affected nostril of a subject in need thereof Topical formulations typically
comprise
polar solvents which enable the incorporation of the medicaments into the
formulation.
The major disadvantage of these topical formulations comprising polar
solvents, e.g.
ethanol, is their stinging effect when applied to the mucosal surface (mucous
membrane).

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In contrast to currently available topical formulations, the topical
compositions of
the present invention comprise an aqueous phase which allows dissolution and
substantially homogeneous distribution of the pharmaceutical agents. In an
embodiment,
addition of water to the topical composition reduces the use of stinging polar
solvents and
hence improves the compliancy of the subject to be treated. It is further
disclosed that the
topical compositions of the present invention, upon drying, form a film on the
nasal
mucosa surface and thus provide a protective coating
In addition, the topical compositions of the present invention, when dried,
form a
durable film which does not crack or flake off and remains intact for more
than 12 hours
giving release of the pharmaceutical agent for an extended period of time,
thus leading to
enhanced healing of the affected areas.
The sustained or extended release of the pharmaceutical agent(s) from the
compositions of the present invention enables methods of treatment including
less
frequent administration (such as once daily, once every other day or twice
weekly) than
existing commercially available products, while achieving similar or better
therapeutic
results.
Further, the topical compositions of the present invention, when dried, form a

flexible film, closely following irregularities of the body surface as well as
movement of
the body surface.
According to an aspect, the present invention provides a topical composition
that
includes:
from about 10.0% (w/w) to about 30.0% (w/w) of a silicone film forming agent
like
trimethylsiloxysilicate;
from about 1.0% (w/w) to about 5.0% (w/w) of at least one surfactant selected
from
the group consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone
copo iyo polysorbate and a combination thereof;
from about 30.0% (w/w) to about 75.0% (w/w) of a non-polar volatile siloxane
solvent;
from about 0.005% (w/w) to about 25.0% (w/w) of a vasoconstrictor selected
from
the group consisting of phenylephrine, epinephrine, tetrahydrozoline
hydrochloride,

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an amphetamine, an antihistamine, methylphenidate mephedrone, oxymetazoline,
pseudoephedrine, psilocybin, ephedrine and plant extracts and about 0.005% to
about
25.0% of an antifibrinolytic agent selected from the group consisting of
tranexamic
acid, aprotinin, 8-aminocaproic acid, aminomethylbenzoic acid or their salts
and
5
combinations thereof wherein the composition is sufficiently designed to dry
within
60 seconds after application to a skin surface or a mucosal surface to form a
dried
composition, and wherein the dried composition forms:
(0 a
flexible film, wherein the flexible film closely follows irregularities of
the surface as well as movement of the surface, and
(ii) a durable
film, wherein the durable film does not crack or flake off and
remains intact for more than 12 hours giving release of the pharmaceutical
agent
for an extended period of time.
According to an aspect, the present invention provides a topical composition
that
includes:
(0 at least one
flexible film forming ingredient, (ii) at least one surfactant, (iii)
at least one non-polar volatile solvent (iv) at least 15% w/w water, and (v) a

therapeutically effective concentration of at least one pharmaceutical agent,
wherein the composition is sufficiently designed to dry within 60 seconds
after application to a mucosal surface to form a dried composition, wherein
the dried composition forms: (i) a flexible film, wherein the flexible film
closely follows irregularities of the mucosal surface as well as movement of
the mucosal surface, and (ii) a durable film, wherein the durable film does
not crack or flake off and remains intact for more than 12 hours giving
release of the pharmaceutical agent for an extended period of time.
According to an embodiment, a topical composition of the present invention is
in
the form of an emulsion. In an embodiment, the emulsion is an oil-in-water
emulsion.
The emulsion may be in the form of a viscous gel (25000-45000 cP) or a liquid
whose
viscosity ranges from 1-1.2 cP, close to the viscosity of water. While the gel
is applied
to the mucosal surface as such, the liquid emulsion is mainly used for the
preparation of
the nasal swabs/wipes.

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The topical compositions of the present invention can be administered as a
gel, a
nasal swab, a wipe, a towellete, a water-based solution, a spray or a foam.
According to one embodiment, the at least one film forming ingredient is
selected
from the silicone resin group consisting of siloxysilicate, silsesquioxane or
other silicone
polymers. According to one embodiment, the siloxysilicate is
trimethylsiloxysilicate.
According to an additional embodiment, the silsesquioxane is
polymethylsilsesquioxane.
According to some embodiments, the at least one surfactant is an anionic
surfactant. The anionic surfactant can be selected from the group consisting
of sodium
alkyl sulfate, sodium alkyl sulfonate, sodium alkyl aryl sulfonate, sodium
stearate, dioctyl
sodium sulfosuccinate, sodium cholate, and any combination thereof According
to a
certain embodiment, the sodium alkyl sulfate is sodium lauryl sulfate.
According to further embodiments, the at least one surfactant is a nonionic
surfactant. The nonionic surfactant can be selected from the group consisting
of
organosilicon surfactants, nonionic organic surfactants and a combination
thereof
According to some embodiments, the organosilicon surfactant comprises alkyl-
and
alkoxy- dimethicone copolyol. According to further embodiments, the alkyl- and
alkoxy-
dimethicone copolyol is cetyl dimethicone copolyol. According to a certain
embodiment,
the cetyl dimethicone copolyol is Cetyl PEG/PPG-10/1 Dimethicone.
According to further embodiments, the nonionic organic surfactant is selected
from
the group consisting of polysorbate, glyceryl stearate, polyoxyethylene (POE)
fatty acid
ester, poly(oxyethylene) alkylyl ether, polyethoxylene castor oil derivative,
PEG-6
octanoic/decanoic glycerides, polyoxyethylene glycerol trioleate, decaglycerol

mono/dioleate, and any combination thereof The polysorbate can be selected
from the
group consisting of polyoxyethylene sorbitan monolaurate (Tween 20),
polyoxyethylene
sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate
(Tween 60)
and polyoxyethylene sorbitan monooleate (Tween 80).
According to still further embodiments, the at least one surfactant is a
cationic
surfactant, an amphoteric surfactant, or a combination thereof
According to additional embodiments, the volatile solvent is a non-polar
volatile
siloxane, such as methylsiloxane or a polydimethylsiloxane. According to some
embodiments, the volatile polydimethylsiloxane is a linear
polydimethylsiloxane or a

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cyclic polydimethylsiloxane. According to further embodiments, the volatile
polydimethylsiloxane is selected from the group consisting of
hexamethyldisiloxane,
heptamethylo ctyltrisiloxane octamethylcyclotetrasiloxane,
octamethyltrisiloxane,
decamethylcyclop entasiloxane, decamethyltetrasiloxane, do decamethylp
entasilox ane,
dodecamethylcyclohexasiloxane, and a combination thereof. According to a
certain
embodiment, the volatile polydimethylsiloxane is hexamethyldisiloxane.
According to further embodiments, the volatile solvent is a volatile aliphatic

hydrocarbon selected from the group consisting of alkanes, alkenes, alkynes,
and
mixtures thereof. According to yet further embodiments, the alkane is selected
from the
group consisting of pentane, isooctane, isododecane, isohexadecane and a
combination
thereof According to a certain embodiment, the volatile aliphatic hydrocarbon
is
isooctane. According to another embodiment, the volatile solvent is a
combination of a
siloxane and isooctane.
According to further embodiments, the vasoconstrictor is selected from the
group
consisting of phenylephrine, phenylephrine hydrochloride, epinephrine,
epinephrine
hydrochloride, tetrahydrozoline hydrochloride, an amphetamine, an
antihistamine,
methylphenidate, mephedrone, oxymetazoline, pseudoephedrine, psilocybin,
ephedrine
sulfate, and a combination thereof According to an exemplary embodiment, the
vasoconstrictor is phenylephrine or its hydrochloride. According to some
embodiments,
the vasoconstrictor is present in the topical composition in an amount ranging
from about
0.005% to about 2% w/w.
According to an embodiment, the antifibrinolytic agent is selected from the
group
consisting of tranexamic acid, aprotinin, 8-aminocaproic acid,
aminomethylbenzoic acid
or their salts and combinations thereof.
According to a certain embodiment, the pharmaceutical topical Epistaxis
composition comprises a combination of tranexamic acid and phenylephrine
hydrochloride.
According to some embodiments, pharmaceutical topical composition of the
present invention can further comprise an additive/excipient selected from the
group
consisting of a dimethicone/vinyl dimethicone crosspolymer, a silicone gum
blend, a
gelling agent and a combination thereof. Each possibility is a separate
embodiment of the

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invention.
According to a certain embodiment, the dimethicone/vinyl dimethicone
crosspolymer comprises bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone.
According to additional embodiments, the silicone gum blend comprises a blend
of
high and low molecular weight silicones. According to a certain embodiment,
the silicone
gum blend comprises cyclopentasiloxane and dimethiconol.
According to additional embodiments, the gelling agent is a cellulose
derivative.
According to a certain embodiment, the cellulose derivative is hydroxypropyl
methyl
cellulose. According to other embodiments, the gelling agent is selected from
the group
consisting of carbomer, carbomer copolymers, gelatin, aluminum monostearate,
dextrin,
sodium alginate, alginic acid, pectin, acacia, alginic acid, carrageenan,
xanthan,
tragacanth, magnesium aluminum silicate, bentonite, poloxamers, polyvinyl
alcohol, and
a combination thereof.
According to some embodiments, a topical composition comprises: (i)
trimethylsiloxysilicate; (ii) a surfactant selected from the group consisting
of an anionic
surfactant, a nonionic surfactant and a combination thereof; (iii) a volatile
solvent
selected from the group consisting of a siloxane such as methylsiloxane or a
polydimethylsiloxane, an aliphatic hydrocarbon, and a combination thereof,
(iv) water;
and (v) at least one pharmaceutical agent selected from the group consisting
of an a
vasoconstrictor, an antifibrinolytic, an anti-inflammatory agent, and
combinations
thereof According to a certain embodiment, the surfactant is an anionic
surfactant.
According to some embodiments, the topical composition further comprises an
additive
selected from the group consisting of a dimethicone/vinyl dimethicone
crosspolymer, a
silicone gum blend, a gelling agent and a combination thereof.
According to some embodiments, a topical composition comprises: (i) about 10-
40% w/w of trimethylsiloxysilicate; (ii) about 0.5-7% w/w of a surfactant
selected from
the group consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone
copolyol,
polysorbate, and a combination thereof (iii) about 30-80% w/w of a volatile
solvent,
selected from the group consisting of a siloxane such as methylsiloxane or a
polydimethylsiloxane, volatile aliphatic hydrocarbon and a combination
thereof; (iv)

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about 20-40% w/w of water; and (v) from about 0.005% (w/w) to about 25.0%
(w/w) of a
vasoconstrictor selected from the group consisting of phenylephrine,
epinephrine,
tetrahydrozoline hydrochloride, an amphetamine, an antihistamine,
methylphenidate
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine and plant
extracts
and about 0.005% to about 25.0% of an antifibrinolytic agent selected from the
group
consisting of tranexamic acid, aprotinin, 8-aminocaproic acid,
aminomethylbenzoic acid
or their salts and combinations thereof. According to a certain embodiment,
the at least
one surfactant is sodium lauryl sulfate. According to another embodiment, the
surfactant
is a combination of sodium lauryl sulfate and cetyl dimethicone copolyol.
According to
additional embodiments, the surfactant is a combination of polysorbate and
cetyl
dimethicone copolyol. According to some embodiments, cetyl dimethicone
copolyol is
Cetyl PEG/PPG- 10/1 D
imethi con e . According to some embodiments,
polydimethylsiloxane is hexamethyldisiloxane. According to additional
embodiments,
volatile aliphatic hydrocarbon is isooctane. According to some embodiments,
the topical
composition further comprises about 0.2-15% w/w of an additive selected from
the group
consisting of bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone;

cyclopentasiloxane and dimethiconol; hydroxypropyl methyl cellulose; and a
combination thereof. According to some embodiments, bis-vinyldimethicone,
vinyldimethicone and hydrogen dimethicone can be present in the topical
composition in
an amount ranging from about 5 to 15% w/w. According to further embodiments,
cyclopentasiloxane and dimethiconol can be present in the topical composition
in an
amount ranging from about 0.5 to 2.5% w/w. According to still further
embodiments,
hydroxypropyl methyl cellulose can be present in the topical composition in an
amount
ranging from about 0.05 to 5% w/w.
According to some embodiments, a topical composition comprises: (i) about 20%
w/w trimethylsiloxysilicate; (ii) about 3% w/w sodium lauryl sulfate; (iii)
about 267%
w/w hexamethyldisiloxane and 20% w/w isooctane; (iv) about 30% w/w water; and
(v)
about 0.1%-0.25% w/w phenylephrine or its hydrochloride as the pharmaceutical
agent.
Alternatively, the pharmaceutical agent is a combination of about 0.1-0.25%
w/w
phenylephrine or its hydrochloride and about 3.0-10.0% w/w tranexamic acid.
According to a certain embodiment, a topical composition comprises: (i) about
20%

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w/w trimethylsiloxysilicate; (ii) about 3% w/w sodium lauryl sulfate; (iii)
about 26% w/w
hexamethyldisiloxane and 20% w/w isooctane; (iv) about 30% w/w water; (v)
about 5%
w/w tranexamic acid; and (vi) about 0.05% w/w phenylephrine.
According to further embodiments, a topical composition comprises: (i) about
20%
5 w/w trimethylsiloxysilicate; (ii) about 1.5% w/w sodium lauryl sulfate;
(iii) about 4%
w/w Cetyl PEG/PPG-1011 Dimethicone (iv) about 24% w/w hexamethyldisiloxane and

20% w/w isooctane; (v) about 30% w/w water; and (vi) about 3-10% w/w
tranexamic
acid as the pharmaceutical agent. Alternatively, the pharmaceutical agent is
phenylephrine or its hydrochloride in an amount of about 0.25% w/w. Further
10 alternatively, the pharmaceutical agent is a combination of about 5% w/w
tranexamic
acid and about 0.25% w/w phenylephrine or its hydrochloride.
According to still further embodiments, a topical composition comprises: (i)
about
20% w/w trimethylsiloxysilicate; (ii) about 1.5% w/w Tween 80; (iii) about 4%
w/w
Cetyl PEO/PPG40/1 Dimethicone (iv) about 24% w/w hexamethyldisiloxane and 20%
w/w isooctane; (v) about 30% w/w water; and (vi) about 10% w/w tranexamic acid
as the
pharmaceutical agent. Alternatively, the pharmaceutical agent is phenylephrine
or its
hydrochloride in an amount of about 0.25% w/w. Further alternatively, the
pharmaceutical agent is a combination of about 3% w/w tranexamic acid and
about
0.25% w/w phenylephrine.
According to some embodiments, the pH of a topical composition of the present
invention is from about 3.5 to about 5. According to other embodiments, the pH
of a
topical composition of the present invention is from about 4.0 to about 4.6.
According to
additional embodiments, the pH of a topical composition of the present
invention is from
about 4.2 to about 4.4. According to some embodiments, the pH is maintained
using
citrate buffer.
According to another aspect, the present invention provides a method of
treating or
preventing an Epistaxis disorder, the method comprising the step of topically
applying to
the nostril of a subject in need of such treatment a therapeutically effective
amount of a
topical composition of the present invention.
According to one embodiment, the subject to be treated is a human being.

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According to another embodiment, the subject to be treated is an animal.
According to yet another aspect, the present invention provides a kit
comprising a
topical composition of the present invention, a container-applicator device
suitable for
storage and application of the composition to a body surface, and instructions
for
administering the topical composition to a subject in need thereof
According to some embodiments, the container-applicator device is selected
from
the group consisting of a single use wipe, a nasal swab, a syringe, a dropper,
a spray
dispenser, a swab, a compressible bottle or tube, a spatula, a suppository
insertion tube,
an extrusion tube, a pump dispenser, a pressurized dispenser and an inflatable
member.
According to another aspect, the present invention provides a topical
composition
for use in treating or preventing an Epistaxis disorder.
Other objects, features and advantages of the present invention will become
clear
from the following description and claims.
A topical composition of the present invention comprises at least one film
forming
agent, at least one surfactant, at least one non-polar volatile solvent, water
and at least
one pharmaceutically active agent. One such film forming agent may be a
silicone resin.
The topical composition can further comprise additives, such as
dimethicone/vinyl
dimethicone crosspolymers, silicone gum blends and gelling agents.
The term "film forming agent" or "film forming ingredient" or "film former",
as
used herein, means an inactive ingredient such as a silicone resin that after
dissolution in
at least one solvent and application on a substrate leaves a film on the
substrate to which
it is applied, for example once the at least one solvent evaporates, absorbs
and/or
dissipates on the substrate.
Silicone resins, such as polydimethylsiloxane and polymethylsilsesquioxane
have
an unique semi-organic structure and are flexible.
While using film forming agents in the instant invention, it is desirable to
use such
flexible film forming agents and formulate them in such compositions which
produce
flexible and durable films. In an embodiment, there are provided flexible and
durable
film forming compositions, providing beneficial therapeutic effects like
reduced
bleeding, pain and itching.
The film formed on the skin or mucosal surface allows the tissues to
"breathe",

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which is beneficial because of the extended period of time the film stays on
the tissues.
The compositions of the instant invention dry relatively fast after
application on the
mucosal surface between 5 seconds and 1 minute to form a durable and elastic
film.
The film formed on the substrate is substantially dry, which means it contains
less
than 10% volatiles, typically less than 5% and less than 2% volatiles. The
important
aspect of the substantially dry films of this invention, whatever the
percentage of volatiles
left, is that they feel dry to touch. Without wishing to be bound by theory,
the inclusion of
the active pharmaceutical in the flexible film seems to have a long-acting or
sustained
release effect, achieving comparable or superior results compared to similar
commercial
products, while exposing the patient to smaller amounts of the active
pharmaceutical
ingredient(s).
In an embodiment, there are provided once daily Epistaxis topical compositions

comprising:
(0 at least one flexible film forming ingredient
(ii) at least one surfactant;
(iii) at least one non-polar volatile solvent;
(iv) at least 15% w/w water; and
(v) a therapeutically effective concentration of at least one
pharmaceutical
agent,
wherein the composition is sufficiently designed to dry within 60 seconds
after
application to a mucosal surface of an Epistaxis affected nostril to form a
dried
composition, wherein the dried composition forms: (i) a flexible film, wherein
the
flexible film closely follows irregularities of the mucosal surface as well as

movement of the mucosal surface, and (ii) a durable film, wherein the durable
film
does not crack or flake off and remains intact for more than 12 hours giving
release
of the pharmaceutical agent for an extended period of time. The dried film in
non-
soiling.
The above compositions may be topically administered even less often than once

daily, such as once every other day or twice weekly.
In an embodiment, there are provided once daily Epistaxis topical compositions
comprising:

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(0 at least one flexible film forming ingredient;
(ii) at least one surfactant;
(iii) at least one non-polar volatile solvent;
(iv) at least 15% w/w water;
(v) at least one viscosity modifier; and
(vi) a
therapeutically effective concentration of at least one pharmaceutical
agent,
wherein the composition is sufficiently designed to dry within 60 seconds
after
application to a mucosal surface of a nostril to form a dried composition,
wherein
the dried composition forms: (i) a flexible film, wherein the flexible film
closely
follows irregularities of the mucosal surface as well as movement of the
mucosal
surface, and (ii) a durable film, wherein the durable film does not crack or
flake off
and remains intact for more than 12 hours giving release of the pharmaceutical

agent for an extended period of time. The dried film in non-soiling.
The selection of the inactive pharmaceutical ingredients and their
concentration has
an impact on the therapeutic effect of the compositions, so that extensive
experimentation
was needed until the optimal compositions were developed. Thus, for example,
low
concentrations of water result in incomplete solubilization of the active(s)
and high water
concentrations lead to slow rate of drying.
It has been surprisingly found that when a topical composition of the present
invention is formulated for use as a nasal swab or a wipe, the addition of
inactive
ingredients like Pemulen0, have a profound effect on the viscosity of the
compositions,
lowering the viscosity even at concentrations below 0.1% w/w. Therefore,
Pemulen0
may be included in the composition for the nasal swabs or wipes, which
requires a lower
viscosity.
In an embodiment, the film forming agents used in the compositions of the
present
invention are non-polymerizable and therefore, unlike the polymerizable agents
are less
sensitive to moisture, more stable and more suitable for repeated use.
The term "volatile solvent", as used herein, means that the solvent has a
measurable
vapor pressure. The volatile solvents used in this invention are non-polar
solvents.

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Some of the film forming agents according to the present invention are
silicone
resins. The non-limiting examples of silicone resins useful in the
compositions of the
invention are siloxysilicates, silsesquioxanes (usually denoted as T-resins)
and a
combination thereof One non-limiting example of a siloxysilicate in accordance
with the
present invention is trimethylsiloxysilicate, which may be represented by the
following
formula:
[(CH3)3-Si-O]x-(5iO4/2)y
wherein x and y may, for example, range from 50 to 80. Such siloxysilicates
are
commercially available from General Electric and Dow Corning under the trade
name
Resin MOO. One non-limiting example of silsesquioxane is
polymethylsilsesquioxane.
Trimethylsiloxysilicate and polymethylsilsesquioxane are widely used in
cosmetic
industry due to their film forming properties. The present invention discloses
for the first
time the use of trimethylsiloxysilicate for therapeutic applications, inter
alia, for
treatment of Epistaxis disorders. Trimethylsiloxysilicate is soluble in the
volatile solvent
of a topical composition of the present invention. The amount of the silicone
resin film
forming agent in the composition is determined based on the desired adhesion
properties
of the dried film to the target surface. The amount depends, inter alia, on
the target
surface, the condition to be treated, and the amount of composition
ingredients. The
amount of the silicone resin film forming agent further defines the viscosity
of the topical
composition. The amount of the silicone resin film forming agent in the
composition
typically ranges from about 10% to 40% w/w. The term "about" as used herein
denotes
10 % of the value indicated.
The volatile solvent useful for dissolving the silicone resin is chosen from
volatile
silicone or volatile aliphatic hydrocarbon. Water solubility of the volatile
solvent is less
than about 0.1%. According to some embodiments, the volatile silicone solvent
is a linear
or cyclic polydimethylsiloxane, having from 2 to 9 silicon atoms, these
silicones being
optionally substituted with alkyl or alkoxy groups of 1 to 10 carbon atoms.
The non-
limiting examples of a siloxane such as methylsiloxane or a
polydimethylsiloxanes in
accordance with the present invention are hexamethyldisiloxane,
heptamethylo ctyltrisiloxane octamethylcyclotetrasiloxane,
octamethyltrisiloxane,
decamethylcyclop entasiloxane, decamethyltetrasiloxane, do decamethylp
entasilox ane,

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dodecamethylcyclohexasiloxane, and mixtures thereof The polydimethylsiloxane
used in
the compositions is hexamethyldisiloxane.
The volatile solvent can further comprise a volatile aliphatic hydrocarbon.
The
aliphatic hydrocarbon in accordance with the present invention may be any
aliphatic
5 hydrocarbon, including an alkane, a mixture of alkanes, an alkene, a
mixture of alkenes,
an alkyne, a mixture of alkynes, an ester or a mixture thereof. The aliphatic
hydrocarbon
is an alkane such as pentane, isooctane, isododecane, isohexadecane or a
mixture thereof
According to a certain embodiment, the aliphatic hydrocarbon is isooctane. The
volatile
ester useful for dissolving the film former may be a branched ester, such as
isohexyl or
10 isodecyl neopentanoate and mixture thereof
The volatile solvent may comprise a volatile silicone, a volatile aliphatic
hydrocarbon or a mixture thereof According to a certain embodiment, the
volatile
solvent comprises methylsiloxane or a hexamethyldisiloxane and isooctane.
According to some embodiments, the presence of water in a topical composition
of
15 the present invention allows dissolution of the pharmaceutically active
agents, which are
not soluble in the non-polar volatile solvents used for dissolving the film-
former, thus
avoiding the need to use polar solvents. As the pharmaceutically active agents
are
completely dissolved in the compositions of the present invention and do not
precipitate
or crystallize on drying, the resulting essentially dry films comprising the
active(s) are
clear, transparent and not "white films".
The emulsion can be a water-in-oil or oil-in-water emulsion. According to
exemplary embodiments, a topical composition of the present invention is an
oil-in-water
emulsion, wherein the aqueous phase includes the pharmaceutical agents
dissolved
therein and the oil phase includes the film forming agent dissolved in the
volatile solvent.
The oil-in-water emulsion allows the film former and the pharmaceutical active
agents to
be homogeneously dispersed in the topical composition. The stable emulsion
provides
fine dispersion of the emulsion ingredients in the topical composition, in the
container-
applicator device and upon the application to the target surface, such that
once the
volatile solvent and water evaporate both the film former and the
pharmaceutical active
ingredients remain finely dispersed on the target surface. The stable emulsion
prevents
clamping, floating and/or precipitation of the polar active ingredients in the
non-polar

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volatile solvents. The presence of the aqueous phase in the topical
composition further
obviates the use of polar solvents, formerly required to dissolve and disperse

pharmaceutical active ingredients in silicone based liquid bandages.
The amount of the volatile solvent and water affects the viscosity and
evaporation
time of the topical composition when applied to a target surface. The amount
of the
volatile solvent and water is determined so as to adjust the viscosity and
evaporation time
to desired values. The amount of volatile solvent and water further affects
the
morphology of the silicone/water emulsion. The amount of the volatile solvent
can be
adjusted to obtain the desired emulsion type. The amount of the volatile
solvent in the
composition typically ranges from about 30% to about 80% w/w. The amount of
water
can be adjusted to obtain the desired emulsion type. The amount of water in
the
composition typically ranges from about 20% to about 40% w/w.
The topical compositions of the present invention further comprise at least
one
surfactant. Addition of the surfactant allows mixing of the silicone and the
aqueous
phases, producing a silicone/water emulsion. Addition of the surfactant
further allows the
emulsion stabilization. As described hereinabove, the obtained emulsion may be
an oil-
in-water emulsion, wherein the aqueous phase includes dissolved pharmaceutical

ingredients and finely dispersed volatile solvent phase, containing the
dissolved film
former.
The surfactant is selected from the group consisting of an anionic surfactant,
a non-
ionic surfactant, selected from organosilicon surfactant or nonionic organic
surfactant, a
cationic surfactant, an amphoteric surfactant and a combination thereof. Each
possibility
is a separate embodiment of the invention.
The anionic surfactants usable in the compositions of the present invention
include
sodium alkyl sulfates, such as, but not limited to sodium lauryl sulfate;
sodium alkyl
sulfonates; sodium alkyl aryl sulfonates, such as sodium dodecyl benzene
sulfonate and
the like; sodium stearate; dioctyl sodium sulfosuccinate; sodium cholate; and
a
combination thereof.
Examples of suitable organosilicon surfactants include, but are not limited to

dimethicone copolyols such as: alkoxy dimethicone copolyols, alkyl and alkoxy-
dimethicone copolyols, silicones having pendant hydrophilic moieties such as
linear

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silicones having pendant polyether groups, branched polyether and alkyl
modified
silicones, branched polyglycerin and alkyl modified silicones. Dimethicone
copolyol is
cetyl dimethicone copolyol, such as Cetyl. PEG/PPG-10/1 Dimethicone sold under
the
name Abil EM-90. Other suitable dimethicone copolyols include branched
polyether and
alkyl modified silicones such as Lautyl PEG-9 Pcilydimethylsiloxyeth.y1
Dim.ethicone
sold under the name KF-6038, and branched polyglycerin and alkyl modified
silicones
such as Lauryl Polyglyceryl-3 Polyclimethylsiloxyethyl Dimethicone sold under
the name
KF-6105. Additional dimethicone copolyols useful in the compositions of the
present
invention include bis-PEGIPPG-141dimethicone copolyol sold under the name Abil
EM-
97 and the polyglycery1-4 isostearate/cetyl dimethicone copolyol/hexyl laurate
mixture
sold. under the name Abil WE 09, Another suitable dimethicone copolyol is PEG-
9
Polydimethylsiloxyethyl Dimethicone sold under the name KF-6028. Abil EM-90,
Abil
EM-97 and Abil WE 09 are available from Evonik Goldschmidt GmbH of Essen,
Germany. KF-6038 are KF-6105 are available from Shin-Etsu Silicones of Akron,
Ohio.
Non-limiting examples of possible non-ionic organic surfactants include
polysorbates, such as polyoxyethylene sorbitan monolaurate (Tween 20),
polyoxyethylene
sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate
(Tween 60)
and polyoxyethylene sorbitan monooleate (Tween 80); glyceryl stearate;
polyoxyethylene
(POE) fatty acid esters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59;
poly(oxyethylene)
alkylyl ethers, such as poly(oxyethylene) cetyl ether (Brij 52, Brij 56, Brij
58),
poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether,
polyethylene glycol
cetyl ether, and the like; polyethoxylene castor oil derivatives, such as
Cremophor EL, ELP
and RH 40; PEG-6 octanoic/decanoic glycerides, such as Softigen 767 and the
like;
polyoxyethylene glycerol trioleate, such as but not limited to Tagat TO;
decaglycerol
mono/dioleate, such as Caprol PGE860 and the like; and a combination thereof.
The nonionic organic surfactants may further comprise sorbitan fatty acid
esters, such
as sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan
monooleate
(Span 80), sorbitan monostearate (Span 60); mono/diglycerides of
octanoic/dectanoic
acids, such as but not limited to Imwitor-742, Imwitor-308, and a combination
thereof
Non-limiting examples of possible cationic surfactants include phosphatides,
such
as phosphatidyl choline and the like; quaternary ammonium cationic
surfactants, such as

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hexadecyltrimethyl ammonium bromide and the like; pyrimidinium cationic
surfactants,
such as, but not limited to dodecyl pyridinium chloride; and a combination
thereof.
The amphoteric surfactant may include lecithine, N-dodecyl alanine,
cocamidopropyl amino betaine or a combination thereof
The type and the amount of surfactant may be determined by a person skilled in
art
so as to obtain the Hydrophile-Liphophile Balance (HLB) of the surfactant or
the
surfactant mixture suitable for the oil-in-water systems.
According to some embodiments, the surfactant used in the compositions of the
present invention is an anionic surfactant. According to additional
embodiments, the
surfactant may further comprise nonionic surfactant. The nonionic surfactant
may be
selected from the group consisting of nonionic organic surfactant,
organosilicone
surfactant and a combination thereof. According to other embodiments, the
surfactant in
the compositions of the present invention is a nonionic surfactant.
According to an embodiment, the surfactant is sodium alkyl sulfate, such as
sodium
lauryl sulfate. According to other embodiments, the surfactant is a
combination of sodium
alkyl sulfate and alkyl and alkoxy- dirnethicone copolyol, for example, sodium
lauryl
sulfate and Cetyl PEG/PPG-10/1 Dimethicone. According to other embodiments,
the
surfactant is selected from polyoxyethylene sorbitan monolaurate (Tween 20),
polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene sorbitan
monostearate (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80) or any
mixture thereof According to further embodiments, the silicone surfactant is a

combination of polysorbate alkyl and alkoxy- dimethieone eopolyol, for
example,
polyoxyethylene sorbitan monooleate (Tween 80) and Cetyl PEG/PPG-10/1
Dimethieone.
A topical composition of the present invention may further comprise an
additive
selected from the group consisting of dimethicone/vinyldimethicone
crosspolymers,
silicone gum blends, gelling agents, and a combination thereof
The dimethicone/vinyldimethicone crosspolymer is available, for example, from
Dow Corning as Dow Corning 9506 Cosmetic Powder. According to other
embodiments, the dimethicone/vinyldimethicone crosspolymer can be present in
the
compositions of the present invention in a form of two-part silicone
elastomer. Without

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being bound to any mechanism of action, the addition of two-part silicone
elastomers to
the topical composition can provide enhanced film adhesion onto the target
surface and
can allow reduction of skin strain, which may be caused by the silicone resin.
The two-
part silicone elastomers form a crosspolymer network by addition reaction,
upon mixing
the two parts, enhancing the composition adhesive properties. One part of the
two-part
silicone elastomer usually contains vinyl endblocked silicone polymer and a
catalyst
suitable for promoting the addition reaction and another part contains vinyl
endblocked
silicone polymer and silicone polymer carrying SiH groups. These two parts are
stored
separately before use and the crosslinking reaction starts upon mixing the two
parts in a
defined ratio. The ratio of the two parts is usually 50:50 and the
crosslinking reaction
may proceed at room temperature (25 5 C). The two-part silicone elastomers may

comprise dimethicone, hydrogen dimethicone, vinyldimethicone, bis-
vinyldimethicon
and phenyltrimethicone. According to a certain embodiment, the topical
composition of
the present invention comprises bis-vinyldimethicone as the first part of the
two-part
silicone elastomers and vinyldimethicone and hydrogen dimethicone as the
second part.
The first part can further contain a platinum catalyst. The bis-
vinyldimethicone,
vinyldimethicone and hydrogen dimethicone are available, for example, from KCC
as
SM9010Tm or SM9020Tm. The amount of the dimethicone/vinyldimethicone in the
composition may be in a range from about 5% to 15% w/w.
The topical compositions of the present invention may further comprise a
silicone
gum blend. Without being bound to any mechanism of action, the addition of the
silicone
gum blend provides enhancement of silkiness of the film. Silicone gum blend
may be a
blend of a high molecular weight and a low molecular weight silicone. The
average
molecular weight of the high molecular weight silicone is 100,000 or greater.
The
average molecular weight of the low molecular weight silicone is 10,000 or
less. High
molecular and low molecular weight silicones may comprise dimethicone and/or
dimethiconol. The non-limiting examples of a silicone gum blend are
cyclopentasiloxane
and dimethiconol, and cyclotetrasiloxane and cyclopentasiloxane and
dimethiconol. The
cyclopentasiloxane and dimethiconol blends are available, for example, from
KCC as
5F9902ETM or from Momentive as Silsoft 1215 dimethiconeTM. The amount of the
silicone gum blend in the composition may be in a range from about 0.5% to
2.5% w/w.

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The gelling agent increases the aqueous phase viscosity when introduced in
said
aqueous phase. Without being bound to any mechanism of action, the topical
composition
in form of a gel comprises pharmaceutical agents primordially dissolved in the
aqueous
phase of the emulsion, finely dispersed in the continuous jelly phase and the
silicone
5 resin, primordially dissolved in the volatile solvent and finely
dispersed in the aqueous
phase of the emulsion, dispersed in the continuous jelly phase of the topical
composition.
The gelling agent useful in a topical composition of the present invention may

comprise hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl

cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose,
carbomer,
10 carbomer copolymers, gelatin, aluminum monostearate, dextrin, sodium
alginate, alginic
acid, pectin, acacia, alginic acid, carrageenan, xanthan, tragacanth,
magnesium aluminum
silicate (Veegum0), bentonite, poloxamers (Pluronics0), polyvinyl alcohol, or
mixtures
thereof Each possibility is a separate embodiment of the invention. The
gelling agents
are cellulose derivatives. According to one embodiment, the gelling agent is
15 hydroxypropyl methylcellulose. According to some embodiments, the
gelling agent is not
soluble is the volatile solvent and/or in the silicone oil phase of the
emulsion. The amount
of the gelling agent in the composition may be in a range from about 0.05% to
5% w/w.
According to some embodiments, the pH is maintained in the range from about
3.5
to about 5, or from about 4.0 to about 4.6, or from about 4.2 to about 4.4
using an
20 appropriate buffering system. The non-limiting examples of the weak
acids suitable for
buffering the compositions of the present invention include citric acid,
citric acid
monohydrate, boric acid, and phosphoric acid. Examples of some acid salts
which can be
used in the buffering systems of the compositions of the present invention
include, but
are not limited to, sodium citrate, sodium citrate dihydrate, monopotassium
phosphate,
and disodium phosphate.
Upon application of a topical composition to a mucosal surface, the volatile
solvent
and water evaporate, leaving an adhered, dry film which includes at least one
pharmaceutically active agent. The dried film is elastic and durable. It is to
be appreciated
that the compositions of the present invention are devoid of polar solvents
required for
dissolving active ingredients, thus providing non-stinging topical
compositions that have
a comfortable feel when applying on the mucosal nostril surface.

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The emulsions of the instant invention possess the advantage of reduced
stinging
effect in comparison with non-aqueous or polar compositions.
In an embodiment, the compositions of the instant invention are essentially
non-
stinging.
It is further appreciated that the compositions of the present invention are
devoid of
acrylates. The adhesiveness of the compositions does not require acrylates.
Pharmaceutical agents
The compositions of the present invention further comprise at least one
pharmaceutically active agent, such as a vasoconstrictor, an antifibrinolytic,
an anti-
inflammatory, an anesthetic, an astringent, an antibiotic, an antiseptic, or a
combination
thereof Each possibility is a separate embodiment of the invention. Additional

pharmaceutical active agents include for example, analgesics, antimicrobial
agents and
botanical products or extracts. The compositions of the present invention may
further
comprise antioxidants. The compositions may further contain one or more
protectant
active ingredients, excipients and carriers. Pharmaceutically and
dermatologically
acceptable excipients and carriers as are known in the art may be included in
the
composition, in particular for maintaining the stability and sterility of the
composition,
and for promoting delivery, release and/or application of the active agent(s)
to the
mucosal surface to which the composition is applied.
It is to be understood that the compositions may contain more than one active
agent, and/or may be suitable for use in treating different nosebleed
disorders. The
pharmaceutically active agent and the dosage thereof is dependent upon the
particular
condition to be treated, the age of the subject and other factors evident to
those skilled in
the art. In an exemplified embodiment, the composition comprises a
vasoconstrictor and
an antifibrinolytic. Pharmaceutically acceptable salts of the aforementioned
active agents
may also be included in the composition of the invention. Suitable amounts of
such active
agents in the composition may be readily ascertained by one of ordinary skill
in the art,
and may range, for example, between 0.15% and 25% by weight.
Vasoconstrictors which are suitable for use in the invention include
amphetamines,
antihistamines, methylphenidate, mephedrone, oxymetazoline, phenylephrine,
pseudoephedrine, psilocybin, phenylephrine hydrochloride, ephedrine sulfate,

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epinephrine, epinephrine hydrochloride, tetrahydrozoline hydrochloride, and
combinations thereof. Suitable amounts of such vasoconstrictor agents in the
composition
may be readily ascertained by one of ordinary skill in the art, and may range,
for
example, between 0.005% and 2% w/w. Exemplary vasoconstrictor agent is
phenylephrine HC1. In a particular embodiment, the composition of the
invention
comprises phenylephrine HC1 at a concentration of about 0.25% w/w based on the
total
weight of the composition.
Anti-inflammatory agents include salicylic acid, indomethacin, sodium
indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen,
sulindac,
diflunisal, diclofenac, indoprofen and sodium salicylamide.
A topical composition of the present invention may further include an
astringent.
As used herein, an "astringent" refers to a substance that causes tissue
(e.g., nostril) to
contract and can optionally arrest secretion or control bleeding from tissue.
Astringents
which are suitable for use in the invention include, e.g., alum, tannic acid,
calamine,
witch hazel, zinc oxide, or a combination thereof. Suitable amounts of such
astringents in
the composition may be readily ascertained by one of ordinary skill in the
art, and may
range, for example, between 2% and 50% w/w.
Antibiotics for use in the invention are those suitable for topical
application. The
antibiotic(s) may be classified in one or more of the following groups:
penicillins,
cephalosporins, carbepenems, beta-lactam antibiotics, aminoglycosides,
amphenicols,
ansamycins, macrolides, lincosamides, glycopeptides, polyp eptides,
tetracylines,
chloramphenicol, quinolones, fucidins, sulfonamides, sulfones, nitrofurans,
diaminopyrimidines, trimethoprim, rifamycins, oxalines, streptogramins,
lipopeptides,
ketolides, polyenes, azoles, and echinocandins.
Specific examples of antibiotics which are suitable for use in the invention
include:
amikacin, aminosidine, paromomycin, chloramphenicol, ciprofloxacin,
clindamycin,
colistimethate-sodium, colistin, enfuvirtid, enoxacin, erythromycin,
flucloxacillin,
fosfomycin, fusafungin, gentamicin, levofloxacin, linezolid, mefloquin,
metronidazol,
mezlocillin, moxifloxacin, mupirocin, norfloxacin, ofloxacin, oxacillin,
penicillin G,
penicillin V, phenoxymethylpenicillin, phenoxymethylpenicillin-benzathin,
pipemidinic
acid, piperacillin, piperacillin+tazobactam, proguanil, propicillin,
pyrimethamine,

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retapamulin, rifaximin, roxithromycin, sodium sulfacetamide, sulbactam,
sulbactam+ampicillin, sulfadiazine, spiramycin, sultamicillin,
tazobactam+piperacillin,
teicoplanin, telithromycin, tigecyclin, vancomycin and combinations thereof.
Antiseptics which are suitable for use in the invention include, e.g.,
triclosan,
phenoxy isopropanol, chlorhexidine gluconate, povidone iodine, and any
combination
thereof
Antioxidative compounds may also be included in the composition, in particular

the antioxidative compounds collectively termed catechins. These include for
example,
epicatechin, epicatechin gallate, epigallocatechin gallate, and gallocatechin,
as well as
stereoisomers and enantiomers of these compounds and combinations thereof Such
compounds may be provided as synthetic compounds or in the forms of mixtures
as
components of plant extracts, in particular green tea extracts. Botanical
products and
extracts include those derived from peppermint, ginger horseradish, yarrow,
chamomile,
rosemary, capsicum, aloe vera, tea tree oil (melaleuca oil), among many
others.
A topical composition of the present invention may further include protectant
active ingredients. The protectant active ingredients can be selected from the
group
consisting of aluminum hydroxide gel, cocoa butter, aqueous solution of
glycerin, hard
fat, kaolin, lanolin, mineral oil, petrolatum, topical starch, white
petrolatum, cod liver,
shark liver oil, and a combination thereof. The protectant active ingredient
and the dosage
thereof is dependent upon the particular condition to be treated, the
pharmaceutical active
agents present in the composition and other factors evident to those skilled
in the art.
According to some embodiments, the pharmaceutical liquid adhesive
compositions of this disclosure may be administered as gel, nasal swabs/wipes
and nasal
aerosols.
A topical composition of the present invention may include one or more of the
following additional ingredients: emulsifiers (e.g. anionic, cationic or
nonionic),
chelating agents, colorants, emollients, fragrances, humectants, lubricants,
moisturizers,
preservatives, skin penetration enhancers, stabilizers, thickeners, and
viscosity modifiers.
Formulations
According to an embodiment, a topical composition of the present invention

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comprises: (i) trimethylsiloxysilicate; (ii) at least one surfactant selected
from the group
consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone copolyol,
polysorbate
and a combination thereof; (iii) a non-polar volatile siloxane solvent, and
(iv) a
pharmaceutical agent selected from the group consisting of pramoxine,
phenylephrine,
hydrocortisone, salicylic acid, nitroglycerine, sildenafil, or their salts and
combinations
thereof In an embodiment, the composition further comprises from about 15%
(w/w) to
about 40% (w/w) of water. In an embodiment, the composition further comprises
a
buffer to adjust the pH of the composition to a pH of about 4.2-4.4. In an
embodiment,
the composition further comprises a viscosity modifier.
According to an embodiment, a topical composition of the present invention
comprises: (i) from about 10.0% (w/w) to about 30.0% (w/w) of
trimethylsiloxysilicate;
(ii) from about 1.0% (w/w) to about 5.0% (w/w) of at least one surfactant
selected from
the group consisting of sodium lauryl sulfate, alkyl- and alkoxy- dimethicone
copolyol,
polysorbate and a combination thereof; (iii) from about 30.0% (w/w) to about
75.0%
(w/w) of a non-polar volatile siloxane solvent, and (iv) from about 0.005%
(w/w) to
about 25.0% (w/w) of a pharmaceutical agent selected from the group consisting

ofphenylephrine, epinephrine, tetrahydrozoline hydrochloride, an amphetamine,
an
antihistamine, methylphenidate mephedrone, oxymetazoline, pseudoephedrine,
psilocybin, ephedrine and plant extracts and about 0.005% to about 25.0% of an
antifibrinolytic agent selected from the group consisting of tranexamic acid,
aprotinin, 8-
aminocaproic acid, aminomethylbenzoic acid or their salts and combinations
thereof. In
an embodiment, the composition further comprises from about 15% (w/w) to about
40%
(w/w) of water. In an embodiment, the composition further comprises a buffer
to adjust
the pH of the composition to a pH of about 4.2-4.4. In an embodiment, the
composition
further comprises a viscosity modifier.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) an anionic
surfactant; (iii) a
volatile solvent, (iv) water; and (v) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,

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silsesquioxane, or a derivative or a combination thereof; (ii) an anionic
surfactant; (iii) a
nonionic surfactant, (iv) a volatile solvent, (v) water; and (vi) at least one
pharmaceutical
agent.
According to an embodiment, a topical composition of the present invention
5 comprises: (i) a silicone resin film forming agent comprising
siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) a nonionic
surfactant; (iii) a
volatile solvent, (iv) water; and (v) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
10 silsesquioxane, or a derivative or a combination thereof; (ii) an
anionic surfactant; (iii) a
volatile solvent, (iv) water; (v) gelling agent; and (vi) at least one
pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) an anionic
surfactant; (iii) a
15 nonionic surfactant, (iv) a volatile solvent, (v) water; (vi) gelling
agent; and (vii) at least
one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) a nonionic
surfactant; (iii) a
20 volatile solvent, (iv) water; (v) gelling agent; and (vi) at least one
pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic
hydrocarbon and a combination thereof; (iv) water; and (v) at least one
pharmaceutical
25 agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, hexamethyldisiloxane,
isooctane
and a combination thereof; (iv) water; and (v) at least one pharmaceutical
agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) alkyl-
and alkoxy-

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dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) water; and (vi) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii)
Cetyl PEGIPPG-10/1
Dimethicone; (iv) a volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination thereof; (v)
water;
and (vi) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) polysorbate; (iii) alkyl- and
alkoxy-
dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of
polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof; (v)
water; and
(vi) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii) Cetyl PEG/PPG-
10/1
Dimethicone; (iv) a volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination thereof; (v)
water;
and (vi) at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic
hydrocarbon and a combination thereof; (iv) water; (v) cellulose derivatives
at least one
pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, hexamethyldisiloxane,
isooctane
and a combination thereof; (iv) water; (v) hydroxypropyl methyl cellulose; and
(vi) at
least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) a surfactant;
(iii) a volatile

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solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) a surfactant;
(iii) a volatile
solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum blend; and
(ix) a
gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) anionic
surfactant; (iii) a
volatile solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) anionic
surfactant; (iii) a
volatile solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum blend; and
(ix) a
gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent; (ii) anionic surfactant;
(iii) nonionic
surfactant; (iv) a volatile solvent, (v) water; (vi) at least one
pharmaceutical agent; (vii) a
dimethicone/vinyldimethicone crosspolymer; and (viii) a silicone gum blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) anionic
surfactant; (Iii)
nonionic surfactant; (iv) a volatile solvent, (v) water; (vi) at least one
pharmaceutical
agent; (vii) a dimethicone/vinyldimethicone crosspolymer; (viii) a silicone
gum blend;
and (ix) a gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,

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silsesquioxane, or a derivative or a combination thereof; (ii) nonionic
surfactant; (iii) a
volatile solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; and (vii) a silicone gum blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) a silicone resin film forming agent comprising siloxysilicate,
silsesquioxane, or a derivative or a combination thereof; (ii) nonionic
surfactant; (iii) a
volatile solvent, (iv) water; (v) at least one pharmaceutical agent; (vi) a
dimethicone/vinyldimethicone crosspolymer; (vii) a silicone gum blend; and
(ix) a
gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic
hydrocarbon and a combination thereof; (iv) water; (v) at least one
pharmaceutical agent;
(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and
(vii)
dimethiconol and silicone oil blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, a polydimethylsiloxane,
aliphatic
hydrocarbon and a combination thereof; (iv) water; (v) at least one
pharmaceutical agent;
(vi) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (vii)
dimethiconol and silicone oil blend; and (iv) cellulose derivative.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) alkyl-
and alkoxy-
dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) water; (vi) at least one pharmaceutical agent; (vii) bis-
vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; and (viii) dimethiconol and
silicone oil
blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium alkyl sulfate; (iii) alkyl-
and alkoxy-
dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of

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methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) water; (vi) at least one pharmaceutical agent; (vii) bis-
vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; (viii) dimethiconol and silicone
oil blend;
and (ix) cellulose derivative.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) polysorbate; (iii) alkyl- and
alkoxy-
dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) water; (vi) at least one pharmaceutical agent; (vii) bis-
vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; and (viii) dimethiconol and
silicone oil
blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) polysorbate; (iii) alkyl- and
alkoxy-
dimethicone copolyol; (iv) a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) water; (vi) at least one pharmaceutical agent; (vii) bis-
vinyldimethicone,
vinyldimethicone and hydrogen dimethicone; (viii) dimethiconol and silicone
oil blend;
and (ix) cellulose derivative.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, hexamethyldisiloxane,
isooctane
and a combination thereof; (iv) water; (v) at least one pharmaceutical agent,
selected
from the group consisting of an antifibrinolytic, a vasoconstrictor, an anti-
inflammatory
agent, and a combination thereof; (vi) bis-vinyldimethicone, vinyldimethicone
and
hydrogen dimethicone; and (vii) cyclopentasiloxane and dimethiconol.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii) a
volatile solvent,
selected from the group consisting of methylsiloxane, hexamethyldisiloxane,
isooctane
and a combination thereof; (iv) water; (v) at least one pharmaceutical agent,
selected
from the group consisting of at least one pharmaceutical agent, selected from
the group
consisting of an antifibrinolytic, a vasoconstrictor, an anti-inflammatory
agent, and a

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combination thereof; (vi) bis-vinyldimethicone, vinyldimethicone and hydrogen
dimethicone; (vii) cyclopentasiloxane and dimethiconol; and (iv) hydroxypropyl
methyl
cellulose.
According to an embodiment, a topical composition of the present invention
5 comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii)
Cetyl PEG/PPG-10/1
Dimethicone; (iv) a volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination thereof; (v)
water;
(vi) at least one pharmaceutical agent selected from the group consisting of
at least one
pharmaceutical agent, selected from the group consisting of an
antifibrinolytic, a
10 vasoconstrictor, an anti-inflammatory agent, and a combination thereof;
(vii) bis-
vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and (viii)
cyclopentasiloxane and dimethiconol.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) sodium lauryl sulfate; (iii)
Cetyl PEG/PPG-10/1
15 Dimethicone; (iv) a volatile solvent, selected from the group consisting of

hexamethyldisiloxane, isooctane and a combination thereof; (v) water; (vi) at
least one
pharmaceutical agent selected from the group consisting of at least one
pharmaceutical
agent, selected from the group consisting of an antifibrinolytic, a
vasoconstrictor, an anti-
inflammatory agent, and a combination thereof; (vii) bis-vinyldimethicone,
20 vinyldimethicone and hydrogen dimethicone; (viii) cyclopentasiloxane and
dimethiconol;
and (ix) hydroxypropyl methyl cellulose.
According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii) Cetyl PEG/PPG-
10/1
Dimethicone; (iv) a volatile solvent, selected from the group consisting of
25 methylsiloxane, hexamethyldisiloxane, isooctane and a combination
thereof; (v) water;
(vi) at least one pharmaceutical agent selected from the group consisting of
at least one pharmaceutical agent, selected from the group consisting of an
antifibrinolytic, a vasoconstrictor, an anti-inflammatory agent, and a
combination thereof;
(vii) bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and
(viii)
30 cyclopentasiloxane and dimethiconol.

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According to an embodiment, a topical composition of the present invention
comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii) Cetyl PEG/PPG-
10/1
Dimethicone; (iv) a volatile solvent, selected from the group consisting of
methylsiloxane, hexamethyldisiloxane, isooctane and a combination thereof; (v)
water;
(vi) at least one pharmaceutical agent selected from the group consisting of
at least one
pharmaceutical agent, selected from the group consisting of an
antifibrinolytic, a
vasoconstrictor, an anti-inflammatory agent, and a combination thereof; (vii)
bis-
vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (viii)
cyclopentasiloxane
and dimethiconol; and (ix) hydroxypropyl methyl cellulose.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-7%
w/w of a surfactant; (iii) about 30-80% w/w of a volatile solvent; (iv) about
20-40% w/w
of water; and (v) about 0.005-25% w/w of at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-
2.5% w/w of an anionic surfactant; (iii) about 30-80% w/w of a volatile
solvent; (iv)
about 15-40% w/w of water; and (v) about 0.005-25% w/w of at least one
pharmaceutical
agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-
2.5% w/w of an anionic surfactant; (iii) about 30-80%w/w of a volatile
solvent; (iv)
about 20-40%w/w of water; (v) about 0.005-25% w/w of at least one
pharmaceutical
agent; and (vi) about 0.05 -5% w/w gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-
2.5% w/w of an anionic surfactant; (iii) about 2-7% w/w of a nonionic
surfactant; (iv)
about 30-50% w/w of a volatile solvent; (v) about 25-40% w/w of water; and
(vi) about

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0.005-25% w/w of at least one pharmaceutical agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-
2.5% w/w of an anionic surfactant; (iii) about 2-7% w/w of a nonionic
surfactant; (iv)
about 30-80% w/w of a volatile solvent; (v) about 20-40% w/w of water; (vi)
about
0.005-25% w/w of at least one pharmaceutical agent and (vii) about 0.05- 5%
w/w
gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-7%
w/w of a nonionic surfactant; (iii) about 30-80% w/w of a volatile solvent;
(iv) about 20-
40% w/w of water; and (v) about 0.005-25% w/w of at least one pharmaceutical
agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of a silicone resin film forming agent
comprising
siloxysilicate, silsesquioxane, or a derivative or a combination thereof; (ii)
about 0.5-7%
w/w of a nonionic surfactant; (iii) about 30-80% w/w of a volatile solvent;
(iv) about 20-
40% w/w of water; (v) about 0.005-25% w/w of at least one pharmaceutical
agent; and
(vi) about 0.05-5% w/w gelling agent.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-
2.5% w/w of
sodium alkyl sulfate; (iii) about 30-80% w/w of a volatile solvent, selected
from the
group consisting of methylsiloxane, a polydimethylsiloxane, aliphatic
hydrocarbon and a
combination thereof; (iv) about 15-40% w/w of water; (v) about 0.005-25% w/w
of at
least one pharmaceutical agent, selected from the group consisting of an
antifibrinolytic,
a vasoconstrictor, an anti-inflammatory agent, and a combination thereof; (vi)
about 5-
15% w/w bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and
(vii)
about 0.5-2.5% w/w dimethiconol and silicone oil blend.
According to an embodiment, a topical composition of the present invention
comprises:
(i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-2.5% w/w of
sodium alkyl
sulfate; (iii) about 30-80% w/w of a volatile solvent, selected from the group
consisting

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of methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (iv) about 15-40% w/w of water; (v) about 0.005-25% w/w of at least
one
pharmaceutical agent, selected from the group consisting of an at least one
pharmaceutical agent, selected from the group consisting of an
antifibrinolytic, a
vasoconstrictor, an anti-inflammatory agent, and a combination thereof; (vi)
about 5-15%
w/w bis-vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (vii)
about 0.5-
2.5% w/w dimethiconol and silicone oil blend; and (viii) about 0.05-5% w/w
cellulose
derivative.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-
2.5% w/w of
sodium alkyl sulfate; (iii) about 2-7% w/w of alkyl- and alkoxy- dimethicone
copolyol;
(iv) about 30-80% w/w of a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) about 15-40% w/w of water; (vi) about 0.005-25% w/w of at least
one
pharmaceutical agent, selected from the group consisting of at least one
pharmaceutical
agent, selected from the group consisting of an antifibrinolytic, a
vasoconstrictor, an anti-
inflammatory agent, and a combination thereof; (vii) about 5-15% w/w bis-
vinyldimethicone, vinyldimethicone and hydrogen dimethicone; and (viii) about
0.5-
2.5% w/w dimethiconol and silicone oil blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-
2.5% w/w of
sodium alkyl sulfate; (iii) about 2-7% w/w of alkyl- and alkoxy- dimethicone
copolyol;
(iv) about 30-80% w/w of a volatile solvent, selected from the group
consisting of
methylsiloxane, a polydimethylsiloxane, aliphatic hydrocarbon and a
combination
thereof; (v) about 15-40% w/w of water; (vi) about 0.005-25% w/w of at least
one
pharmaceutical agent, selected from the group consisting of at least one
pharmaceutical
agent, selected from the group consisting of an antifibrinolytic, a
vasoconstrictor, an anti-
inflammatory agent, and a combination thereof;
(vii) about 5-15% w/w bis-
vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (viii) about 0.5-
2.5%
w/w dimethiconol and silicone oil blend and (viii) about 0.05-5% cellulose
derivative.

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According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-
2.5% w/w of
polysorbate; (iii) about 2-7% w/w of alkyl- and alkoxy- dimethicone copolyol;
(iv) about
30-80% w/w of a volatile solvent, selected from the group consisting of
methylsiloxane,
a polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof; (v)
about 15-
40% w/w of water; (vi) about 0.005-25% w/w of at least one pharmaceutical
agent,
selected from the group consisting of at least one pharmaceutical agent,
selected from the
group consisting of an antifibrinolytic, a vasoconstrictor, an anti-
inflammatory agent, and
a combination thereof; (vii) about 5-15% w/w bis-vinyldimethicone,
vinyldimethicone
and hydrogen dimethicone; and (viii) about 0.5-2.5% w/w dimethiconol and
silicone oil
blend.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 10-40% w/w of trimethylsiloxysilicate; (ii) about 0.5-
2.5% w/w of
polysorbate; (iii) about 2-7% w/w of alkyl- and alkoxy- dimethicone copolyol;
(iv) about
30-80% w/w of a volatile solvent, selected from the group consisting of
methylsiloxane,
a polydimethylsiloxane, aliphatic hydrocarbon and a combination thereof; (v)
about 15-
40% w/w of water; (vi) about 0.005-25% w/w of at least one pharmaceutical
agent,
selected from the group consisting of an antifibrinolytic, a vasoconstrictor,
an anti-
inflammatory agent, and a combination thereof; (vii) about 5-15% w/w bis-
vinyldimethicone, vinyldimethicone and hydrogen dimethicone; (viii) about 0.5-
2.5%
w/w dimethiconol and silicone oil blend and (viii) about 0.05-5% cellulose
derivative.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 3% w/w sodium
lauryl
sulfate; (iii) about 22% w/w hexamethyldisiloxane and 21% w/w isooctane; (iv)
about
27% w/w water or citrate buffer or a combination thereof; (v) about 7% w/w
tranexamic
acid; (vi) about 0.25% w/w phenylephrine; (vii) about 5% w/w bis-
vinyldimethicone and
5% w/w vinyldimethicone and hydrogen dimethicone; and (viii) about 1% w/w
cyclopentasiloxane and dimethiconol.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 3% w/w sodium
lauryl
sulfate; (iii) about 22% w/w hexamethyldisiloxane and 21% w/w isooctane; (iv)
about

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27% w/w water or citrate buffer or a combination thereof; (v) about 10% w/w
tranexamic
acid; (vi) about 0.25% w/w phenylephrine; (vii) about 5% w/w bis-
vinyldimethicone and
5% w/w vinyldimethicone and hydrogen dimethicone; (viii) about 1% w/w
cyclopentasiloxane and dimethiconol; and (ix) about 0.5% w/w hydroxypropyl
methyl
5 cellulose
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 1.5% w/w
sodium lauryl
sulfate; (iii) about 4% w/w Cetyl PEG/PPG-1011 Dimethicone; (iv) about 22% w/w

hexamethyldisiloxane and 21% w/w isooctane; (v) about 25% w/w water; (vi)
about 5%
10 w/w tranexamic acid; (vii) about 0.25% w/w phenylephrine; (viii) about
5% w/w bis-
vinyldimethicone and 5% w/w vinyldimethicone and hydrogen dimethicone; and
(ix)
about 1% w/w cyclopentasiloxane and dimethiconol.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 1.5% w/w
sodium lauryl
15 sulfate; (iii) about 4% w/w Cetyl PEG/PPG-10/1 Dimethicone; (iv) about
18% w/w
hexamethyldisiloxane and 19% w/w isooctane; (v) about 30% w/w water; (vi)
about 5%
w/w tranexamic acid; (vii) about 0.25% w/w phenylephrine; (viii) about 5% w/w
bis-
vinyldimethicone and 5% w/w vinyldimethicone and hydrogen dimethicone; (ix)
about
1% w/w cyclopentasiloxane and dimethiconol; and (x) about 0.5% w/w
hydroxypropyl
20 methyl cellulose.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 1.5% w/w
Tween 80;
(iii) about 4% w/w Cetyl PEG/PPG40/1 Dimethicone; (iv) about 22% w/w
hexamethyldisiloxane and 21% w/w isooctane; (v) about 25% w/w water; (vi)
about 10%
25 w/w tranexamic acid; (vii) about 0.25% w/w phenylephrine; (viii) about
5% w/w bis-
vinyldimethicone and 5% w/w vinyldimethicone and hydrogen dimethicone; and
(ix)
about 1% w/w cyclopentasiloxane and dimethiconol.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate; (ii) about 1.5% w/w
Tween 80;
30 (iii) about 4% w/w Cetyl Pk:Cl/PPG-10/1 Dirnethicone; (iv) about 18% w/w
hexamethyldisiloxane and 19% w/w isooctane; (v) about 30% w/w water; (vi)
about 7%

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w/w tranexamic acid; (vii) about 0.25% w/w phenylephrine; (viii) about 5% w/w
bis-
vinyldimethicone and 5% w/w vinyldimethicone and hydrogen dimethicone; (ix)
about
1% w/w cyclopentasiloxane and dimethiconol; and (x) about 0.5% w/w
hydroxypropyl
methyl cellulose.
According to an embodiment, a topical composition of the present invention in
the
form of a gel, comprises: (i) about 25% w/w trimethylsiloxysilicate (ii) about
43%
methylsiloxane (iii) about 4% Cetyl PEG/PPG-10/1 Dimethicone (iv) about 1.5%
Tween
80 (v) about 25% water, (vi) about 10% tranexamic acid (vii) about 0.25%
phenylephrine
hydrochloride and (viii) about 0.6% Hydroxyethylcellulose (Natrosol HHX).
According to an embodiment, a topical composition of the present invention
comprises: (i) about 25% w/w trimethylsiloxysilicate (ii) about 38%
methylsiloxane (0.54
cP) (iii) about 4% Cetyl PEG/PPG-10/1 Dimethicone (iv) about 3% Tween 80 (v)
about
30% acetate buffer pH 4.4 (vi) about 5% tranexamic acid and (vii) about 0.25%
phenylephrine HC1.
According to an embodiment, a topical composition of the present invention
comprises: (i) about 15% w/w trimethylsiloxysilicate (ii) about 47%
methylsiloxane (0.54
cP) (iii) about 4% Cetyl PEG/PPG-10/1 Dimethicone (iv) about 3% Tween 80 (v)
about
20% acetate buffer pH 4.4 (vi) about 5% tranexamic acid and (vii) about 0.25%
phenylephrine HC1 and (viii) about 0.01-0.1% Pemulen TR-1.
According to an embodiment, there is provided a topical composition for the
treatment and prevention of all types of nosebleed (Epistaxis) comprising
(i) from 15.0% to 30% of at least one silicon resin film forming agent
selected from the group consisting of siloxysilicates, silicone acrylates
and combinations thereof
(ii) from 30% to 75% of at least one volatile solvent selected from the
group consisting of non-polar volatile siloxanes, volatile aliphatic
hydrocarbons, volatile hydrofluoroalkanes and combinations thereof;
(iii) from 0.05% (w/w) to 20% of at least one vasoconstrictor active
agent selected from the group consisting of phenylephrine, epinephrine,
tetrahydrozoline, an amphetamine, an antihistamine, methylphenidate,
mephedrone, oxymetazoline, pseudoephedrine, psilocybin, ephedrine,

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their salts and combinations thereof.
According to another embodiment, there is provided a composition as detailed
above, wherein further comprising from 0.05% to 20% of at least one more
active agent,
wherein the at least one more active agent is an antifibrinolytic active agent
selected from
tranexamic acid, aprotinin, 8-aminocaproic acid, aminomethylbenzoic acid or
their salts
and combinations thereof
The aforementioned compositions may optionally further comprise from 15%
(w/w) to 40% (w/w) of water or a buffer and from 1% (w/w) to 5% of at least
one
surfactant selected from the group consisting of sodium lauryl sulfate, alkyl-
and alkoxy-
dimethicone copolyol, polysorbate and a combination thereof Such compositions
may be
administered in the form of a gel or nasal swab/wipe.
The aforementioned at least one siloxysilicate may be trimethylsiloxysilicate.
The above at least one vasoconstrictor may be phenylephrine, its hydrochloride
or
combinations thereof
The aforementioned at least one antifibrinolytic may be tranexamic acid, its
salt
or combinations thereof
In an embodiment, there is provided a composition comprising from 0.05% to 2%
of phenylephrine or its hydrochloride and from 3% to 10% tranexamic acid or
its
salt.
In another embodiment, there is provided a composition comprising about 0.25%
w/w of phenylephrine or its hydrochloride and about 5 % w/w tranexamic acid or

its salt.
The aforementioned non-polar volatile siloxanes are selected from the group
consisting of hexamethyldisiloxane,
heptamethyloctyltrisiloxane,
octamethylcyclotetrasiloxane,
octamethyltrisiloxane,
decamethylcyclopentasiloxane,
decamethyltetrasiloxane,
dodecamethylpentasiloxane, dodecamethylcyclohexasiloxane, and combinations
thereof.

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The aforementioned volatile aliphatic hydrocarbons are selected from the group

consisting of pentane, isooctane, isododecane, isohexadecane and combinations
thereof.
The aforementioned volatile hydrofluoroalkanes are selected from the group
consisting of 1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,1,2,3,3,3-heptafluoro-
n-
propane (HFA 227) and combinations thereof.
The aforementioned at least one surfactant is a siliconic surfactant and
optionally
an additional surfactant is anionic.
The optional additional anionic surfactant is selected from the group
consisting of
sodium alkyl sulfate, sodium alkyl sulfonate, sodium alkyl aryl sulfonate,
sodium
stearate, dioctyl sodium sulfosuccinate, sodium cholate, and any combination
thereof
The sodium alkyl sulfate may be sodium lauryl sulfate. The at least one
surfactant
may be a nonionic surfactant.
The aforementioned nonionic surfactant is selected from the group consisting
of
organo silicon surfactants, nonionic organic surfactants, and combinations
thereof.
The aforementioned organosilicon surfactant is selected from the group
comprising alkyl- and alkoxy- dimethicone copolyol.
A typical alkyl- and alkoxy- dimethicone copolyol is cetyl dimethicone
copolyol.
A typical cetyl dimethicone copolyol is Cetyl PEG/PPG-10/1 Dimethicone.
The aforementioned nonionic organic surfactant is selected from the group
consisting of polysorbate, glyceryl stearate, polyoxyethylene (POE) fatty acid
ester,
poly(oxyethylene) alkylyl ether, polyethoxylene castor oil derivative, PEG-6
octanoic/decanoic glycerides, polyoxyethylene glycerol trioleate, decaglycerol

mono/dioleate, and any combination thereof
The aforementioned polysorbate is selected from the group consisting of
polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan
monopalmitate (Tween 40), polyoxyethylene sorbitan monostearate (Tween 60) and

polyoxyethylene sorbitan monooleate (Tween 80).
The aforementioned at least one surfactant is selected from the group
consisting
of a cationic surfactant, an amphoteric surfactant, and a combination thereof.
In an embodiment, there is provided a composition comprising

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(i) from 10.0% (w/w) to 30.0% (w/w) of a silicone
acrylate;
(ii) from 1.0% (w/w) to 5.0% (w/w) of at least one
surfactant selected from the group consisting of
siliconic surfactants, anionic surfactants, nonionic
surfactants, and combinations thereof;
(iii) from 30.0% (w/w) to 75.0% (w/w) of a volatile
solvent selected from the group consisting of a
polydimethylsiloxane, an aliphatic hydrocarbon,
and combinations thereof;
(iv) from 15% (w/w) to 40% (w/w) of water; and
(v) from 0.005% (w/w) to about 25.0% (w/w) of a
vasoconstrictor selected from the group
consisting of phenylephrine, phenylephrine,
epinephrine, epinephrine, tetrahydrozoline, an
amphetamine, an antihistamine, methylphenidate,
mephedrone, oxymetazo line, pseudo ephedrine,
psilocybin, ephedrine their salts and
combinations thereof.
In another embodiment, there is provided a composition comprising
(i) about 10-40% w/w of trimethylsiloxysilicate;
(ii) about 0.5-7% w/w of a surfactant selected from the group consisting of
sodium lauryl sulfate, alkyl- and alkoxy- dimethicone copolyol, polysorbate
and a combination thereof:
(iii) about 30-80% w/w of a volatile solvent selected from the group
consisting of hexamethyldisiloxane, isooctane and combinations thereof;
(iv) from 20% (w/w) to 40% (w/w) of water; and
(v) from 0.005% w/w to 25% w/w of a vasoconstrictor selected from the
group consisting of phenylephrine, phenylephrine hydrochloride, epinephrine,
epinephrine hydrochloride, tetrahydrozoline hydrochloride, an amphetamine,

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an antihistamine, methylphenidate, mephedrone, oxymetazoline,
pseudoephedrine, psilocybin, ephedrine sulfate, and combinations thereof.
In another embodiment, there is provided a composition comprising
(i) from 15% w/w to 20% w/w trimethylsiloxysilicate;
5 (ii) from 1.5% w/w to 3.0% w/w sodium lauryl sulfate;
(iii) from 22% w/w to 30% w/w hexamethyldisiloxane and from 20-
25% w/w isooctane;
(iv) from 25% w/w to 30% w/w water;
(v) from 10% w/w to15% of a silicone acrylate; and
10 (vi) from 0.05% w/w to 0.25% w/w phenylephrine hydrochloride.
In yet another embodiment, there is provided a composition comprising
(i) from 15% w/w to 20% w/w trimethylsiloxysilicate;
(ii) from 1.5% w/w to 3.0% w/w sodium lauryl sulfate;
(iii) from 22% w/w to 30% w/w hexamethyldisiloxane and from 20-
15 25% w/w isooctane;
(iv) from 25% w/w to 30% w/w water;
(v) from 10% w/w to 15% of a silicone acrylate;
(vi) 0.05% w/w to 0.25% w/w of phenylephrine hydrochloride; and
(vii) from 3% w/w to 10% w/w of tranexamic acid.
20 The
composition of the instant disclosure may be administered to a subject in
need thereof in the form of nasal swab, a single use wipe, a gel, a nasal
spray, a foam,
a towelette, a syringe, a dropper, a spray dispenser, a compressible bottle or
tube, a
spatula, a suppository insertion tube, an extrusion tube, and an inflatable
member.
In an embodiment, there is provided a method of treatment or prevention of any
25 type
of nose bleeding, including an Epistaxis disorder, the method comprising the
step
of topically applying to the mucosal surface of the affected nostril of a
subject in need
of such treatment a therapeutically effective amount of the composition of the
instant

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disclosure.
There is provided a kit comprising a pharmaceutical liquid adhesive
composition
and a container-applicator device suitable for storage and application of the
composition to the nose, into the affected nostril.
The container-applicator device the aforementioned kit comprises at least one
of a
single use wipe, a towelette, a syringe, a dropper, a spray dispenser, a
compressible
bottle or tube, a spatula, a suppository insertion tube, an extrusion tube,
and an
inflatable member.
In an embodiment, there is provided a pharmaceutical liquid adhesive
composition of the instant disclosure for use in preventing or treating any
type of nose
bleeding, including an Epistaxis disorder.
In an embodiment, there is provided a composition in the form of a HFA nasal
spray/aerosol with a metering valve comprising:
(i) from 0.025% w/w to 2% w/w micronised phenylephrine hydrochloride;
(ii) from 3% w/w to 10% w/w micronised tranexamic acid;
(iii) from 15% w/w to 30% w/w trimethylsiloxysilicate powder; and
(iv) from 50% w/w to 75% w/w 1,1,1,2-tetrafluoroethane.
Mode of administration, containers and applicators
The compositions for use in the present invention are generally stored in a
container-applicator device for use in a single dose application (e.g., a wipe
or a nasal
swab in a disposable packing) or for use in repeated applications to the anus
and rectum.
Single dose applicators include those having breakable or removable seals that
prevent
moisture, including atmospheric moisture, from contacting the formulation.
The compositions may be administered to an Epistaxis affected subject in need
thereof in the form of gel, nasal swab/wipe or nasal spray/aerosol.
In an embodiment of this disclosure, a topical water-based composition is in
the
form of a pre-packaged nasal swab/towelette/wipe. The nasal swab or wipe
substrate is
typically uniformly impregnated with the topical water-based composition.
According to
an embodiment, the topical water-based composition is in a liquid form, when
applied to
the wipe. According to an embodiment, the topical water-based composition is
in a gel

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form, when applied to a nasal swab or wipe. The wipe provides the user with a
single
dose of sterile medication. The topical composition is transferred to the body
surface
upon contacting the wipe with the target surface.
The design of nasal swabs or wipes is well known to those of skill in the art.
Each
nasal swab or wipe is generally packaged as a single-use sealed unit. The
nasal
swab/wipe is formed of woven or non-woven fabric, cloth or tissue substrate
and the
impregnated nasal swab/wipe issealed into an enveloping sachet or pocket. The
sachet or
pocket is formed by sandwiching a folded and impregnated nasal swab or wipe
between
two sheets of an aluminum foil/polyethylene film laminate. The sheets of
laminate may
comprise folded over portions of a single sheet of such material.
A container-applicator may further comprise two parts: (1) a storage area or
reservoir which holds the composition and protects it from air, water and
contaminants;
and (2) the applicator which generally comprises a specially shaped tip
designed to aid in
application of the composition to the nasal mucosa. In particular embodiments,
the
applicator is an element integral to the container, for example, an elongated
insertion tube
extending from a reservoir. Alternately, the storage area and the applicator
may be
separate components, such as a tube reservoir and a separately supplied
dropper. In yet
other embodiments, the container and the applicator may be supplied as
separate
elements which are connected during use, for example via compatible male and
female
connectors respectively provided on the container and the applicator or vice
versa.
For repeated and intermittent usage, minimal exposure to atmospheric moisture
is
required. This can be achieved by devices having very narrow applicator
outlets and low
initial dead space. One applicator for such repeated intermittent use
dispenses the
composition in a controlled drop wise manner, as described for example in U.S.
Pat. No.
4,958,748.
Still another container-applicator device comprises a brush or solid paddle
applicator wherein the topical composition is "painted" onto the nostril
requiring
treatment.
The container-applicator device for repeated and intermittent usage may
comprise a
container suitable for non-sterile storage of the composition, and an
applicator suitable
for metered dispensing of the composition after opening of the applicator. In
particular

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embodiments, the applicator is characterized as having a resealable opening of
no more
than about 0.05 square inch (0.323 square centimeters) so as to permit the
metered
dispensement of the composition from the applicator and which is capable of
multiple
administrations of the composition, and is further characterized as having
resealing
means such as a cap which either tightly mates with the applicator or which
screws onto
the applicator. The opening may be at the terminus of an elongated and tapered
tube-like
member suitable for insertion into the nostril. The opening of the applicator
is about
0.001 to about 0.01 square inch (about 0.00645 to about 0.0645 square
centimeters).
In an embodiment, the walls of the container-applicator device are made of a
pliable material, so that upon application of pressure onto the walls, the
walls depress
sufficiently to force the composition in the container into the applicator and
through the
opening. In another embodiment, the composition is released from the
applicator by
gravity feed methods well known in the art. Such methods do not require
application of
pressure to the walls of the container.
In an embodiment, the applicator is manufactured with its opening covered by a
metal foil or other similar construction which closes this opening until the
device is ready
for use. The opening is then reinstated by use of a pin or similar device
which punctures
the covering.
Such devices for intermittent use enable multiple uses of the topical
composition at
different points in time by the same individual.
In container-applicator devices suitable for repeated intermittent uses, the
topical
composition is stored at ambient conditions and is selected to be
bacteriostatic (see, for
example, U.S. Pat. No. 3,527,224). When the selected composition is
bacteriostatic,
prolonged storage at ambient conditions can be achieved without regard to the
sterility of
the formulation because there is no adverse buildup of bacteria during
storage.
The reservoir of the container-applicator device may be both air-tight and
water-
tight, and keeps the media within free from contaminants. The reservoir may
contain a
desiccant material to keep the media free of water. Reservoirs may be of any
shape,
although shapes which provide for a smooth internal flow of media, such as
cylindrical or
conical shapes. The size of the reservoir may vary within a wide range, but is
slightly
larger than the volume of composition which will be placed inside the
reservoir to

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minimize the amount of gas within the reservoir. The reservoir may be made
from any of
a variety of medical grade materials, such as plastics, excluding glass.
Pharmaceutical
agents of the topical composition suffer from caking when stored in glass
reservoir. The
reservoir may be rigid, collapsible, or compressible. Use of a compressible or
collapsible
reservoir allows the user to have greater control over the rate at which the
composition is
expressed, as exertion of pressure on a compressible or collapsible reservoir
would place
a force on the on the composition causing it to flow at a faster rate than it
would in the
absence of such pressure. The compressible or collapsible reservoir design is
especially
for the topical composition in the form of gel, for which the force of gravity
may not be
strong enough to cause a flow through an applicator sufficient to treat
Epistaxis.
Collapsible reservoirs which retain their collapsed shape have the additional
advantage of
reducing the amount of air which enters the reservoir following use. This
advantage of
collapsible containers is of greater importance in multiple-use (reusable)
devices, wherein
media is kept relatively free of potential contaminants between uses.
Applicator tips can be of any of a number of shapes, sizes, and
configurations. They
may be fairly rigid and may be made out of any material which is compatible
with the
media formulation, e.g., plastic, excluding glass. The choice of a proper
applicator tip for
a given application will depend on factors such as the viscosity of the
composition, the
desired application rate of the composition, the nature of the Epistaxis
disorder, and its
severity.
The container-applicators of the present invention may be either single-use or

multiple-use devices. A container or reservoir containing enough topical
composition for
multiple applications may be configured to accommodate replaceable tips. In
such an
embodiment, at the place whereon the replaceable tips connect with the
reservoir, the
reservoir would have a means such as a valve, septum or sealing gasket which
allows the
reservoir to be sealed in the absence of an applicator tip. Placing an
applicator tip on the
reservoir would cause the valve to open, allowing composition to flow out from
the
reservoir. In this manner, one reservoir containing enough composition for
several
applications could be used over a period of hours, days or weeks. This
embodiment
would also allow the user to use one reservoir with applicator tips of varying
shapes and
sizes chosen to best accommodate the Epistaxis disorder during the healing
process.

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In an embodiment, there are provided nasal sprays/aerosols for the treatment
and
prevention of Epistaxis (see Examples 8-11).
The nasal sprays/aerosols of this disclosure are suspensions of the
pharmaceutical
active agents selected from the group consisting of vasoconstrictors,
antifibrinolytics and
5 optionally anti-inflammatory agents in at least one HFA
(hydrofluoroalkane) containing a
film forming agent. As the aerosol is intended for local topical use in the
nostril and not
for inhalation to the lungs, the nozzle is best designed for delivering a wide
plume of
aerosol, to be deposited laterally on the nostril walls.
The nasal sprays of this disclosure may be metered dose nasal spray aerosols
10 formulated with HFAs, aqueous nasal sprays or dry powder nasal sprays.
The compositions in the nasal sprays may be delivered in metered doses, also
named actuations or "puffs'. A number of actuations (puffs) per day from a
metered dose
aerosol may be needed for the treatment and prevention of Epistaxis, according
to
doctor's instructions
15 After evaporation of the HFA(s), the compositions leave on the nostril's
surface a
flexible and durable film which contains therapeutically effective doses of
the active
pharmaceutical ingredient(s). These active ingredients are delivered slowly
over a period
of time, affording an extended release effect and protection against
nosebleeds. The film
obtained affords in addition to the therapeutic effect of the active
ingredients, also a
20 physical occlusive effect.
The HFAs are selected from the group of FDA-approved hydrofluoroalkanes,
including 1,1,1,2-tetrafluoro ethane (HFA 134a), 1,1,1,2,3 ,3 ,3 -heptafluoro-
n-prop ane
(HFA 227) and combinations thereof
In some embodiments, the composition of the present invention is a HFA nasal
25 spray/aerosol with a metering valve comprising:
(0 from 0.025% w/w to 2% w/w micronised phenylephrine
hydrochloride;
(ii) from 3% w/w to 10% w/w micronised tranexamic acid;
(iii) from 15% w/w to 30% w/w trimethylsiloxysilicate powder; and
(iv) 50% w/w to 75% w/w 1,1,1,2-tetrafluoroethane.
Uses

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The present invention provides compositions which are useful for effectively
treating a variety of Epistaxis disorders caused by injury to the nose,
hemophilia, upper
respiratory infection, hypertension, antiplatelet medication, foreign body,
insufflated
drugs, barotrauma, nasal surgery, nasal sprays, allergic reactions or
combinations thereof.
The composition is applied to the Epistaxis affected nostril under conditions
suitable for film formation of the composition so as to form a protective
coating and
typically under non-sterile conditions. In general, sufficient amounts of
topical
composition are employed to cover the entire affected mucosal surface area.
The coating
is extended by at least about 1 centimeter and by at least about 5 centimeters
beyond the
affected surface area.
The term "therapeutically effective amount" as used herein means an amount of
the
pharmaceutical agent which is sufficient to provide a beneficial effect to the
subject to
which the pharmaceutical agent is administered. More specifically, a
therapeutically
effective amount means an amount of the pharmaceutical agent effective to
alleviate or
ameliorate the symptoms of an Epistaxis disorder of the subject being treated.
As the topical disorders are treated with topical compositions of certain
fixed
concentrations, reference is made herein to "therapeutically effective
concentration".
After an initial layer of topical composition has been applied and the solvent
has
evaporated, providing an initial dried film coating, a second layer may be
applied over
the initial film. Additional amounts of topical composition can be applied as
needed.
In an embodiment, a topical composition is employed to form a coating of less
than
about 0.5 mm thick and more of at least about 0.1 mm thick. Such coatings can
be formed
by applying, for example, about 0.02 ml of topical composition per square
centimeter of
affected surface area.
In general, the particular length of time required for film formation will
vary
depending on factors such as the amount of composition applied, the
temperature of the
mucosal area, the moisture content of the surface area for composition
application, and
the like. However, in an embodiment, film formation is generally complete
within about
10 to about 60 seconds. During this period, the person to whom application of
the topical
composition has been made minimizes actions and body movements thus allowing
the
composition to form a dried film coating.

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The topical compositions of the present invention typically act at
temperatures
between room temperature (20 C) and body temperature (37 C). The dried films
are
conformable and comfortable and may be elastic and flexible, and do not
irritate the skin
and mucous membrane during the application and in use after drying. The dried
films are
substantially painless and easily removable substantially without pain. The
dried films
formed from the topical compositions are also substantially non-water
sensitive and
waterproof The dried films formed from the topical compositions comprise
finely-
dispersed pharmaceutical ingredients, which can be gradually released to the
adhesion
area.
The compositions of the present invention are applicable to both human
patients
and to non-human mammalian subjects such as in veterinary use, for example for

treatment of canine, feline, equine, bovine, porcine and primate species.
The foregoing description of the specific embodiments will so fully reveal the

general nature of the invention that others can, by applying current
knowledge, readily
modify and/or adapt for various applications such specific embodiments without
undue
experimentation and without departing from the generic concept, and,
therefore, such
adaptations and modifications should and are intended to be comprehended
within the
meaning and range of equivalents of the disclosed embodiments. It is to be
understood
that the phraseology or terminology employed herein is for the purpose of
description and
not of limitation. The means, materials, and steps for carrying out various
disclosed
functions may take a variety of alternative forms without departing from the
invention.
The following examples illustrate certain embodiments of the invention but are

not meant to limit the scope of the claims in any way. The following examples
are put
forth so as to provide those of ordinary skill in the art with a complete
disclosure and
description of how to make and use the described invention, and are not
intended to limit
the scope of what the inventors regard as their invention nor are they
intended to represent
that the experiments below are all or the only experiments performed. Efforts
have been
made to ensure accuracy with respect to numbers used (e.g. amounts,
temperature, etc.)
but some experimental errors and deviations should be accounted for. Unless
indicated
otherwise, parts are parts by weight, molecular weight is weight average
molecular
weight, temperature is in degrees Centigrade, and pressure is at or near
atmospheric.

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EXAMPLES
The following examples further illustrate the invention as it may be carried
out
but, of course, should not be construed as in any way limiting its scope.
EXAMPLE 1 - Liquid composition for the preparation of nasal swabs/wipes
25 g (25% w/w) trimethylsiloxysilicate powder is dissolved in 38.25 g (38.25%
w/w) methylsiloxane at room temperature. 4 g (4% w/w) Cetyl PEG/PPG-10/1
Dimethicone is added to the trimethylsiloxysilicate solution. 00.25 g (0.25%)
phenylephrine hydrochloride is dissolved in water. The pH of the aqueous
solution is
adjusted to 4.2-4.4 with acetate buffer (30% w/w). 1.5 g (1.5% w/w) Tween 80
is added
to the aqueous solution. The trimethylsiloxysilicate solution is combined with
the
aqueous solution and mix by means of a homogenizer at room temperature.
The obtained topical liquid solution is applied to a wipe substrate and is
sealed to provide
a sealed package of single-use wipe impregnated with the topical liquid
composition. The
composition is configured to be applied to the Epistaxis affected nostril
using single use
wipe(s).
EXAMPLE 2 - Liquid composition with Pemulen TR-1 for the preparation of
nasal swabs/wipes
This composition is prepared similarly to composition of Example 1, with added

Pemulen TR-1:
25 g (25%) trimethylsiloxysilicate powder is dissolved in 38.25 g (38.25% w/w)
methylsiloxane at room temperature. 4 g (4% w/w) Cetyl PEG/PPG-10/1
Dimethicone is
added to the trimethylsiloxysilicate solution. 0.25 g (0.25% w/w)
phenylephrine
hydrochloride is dissolved in water. The pH of the aqueous solution is
adjusted to 4.2-4.4
using acetate buffer (30% w/w). 1.5 g (1.5% w/w) Tween 80 is added to the
aqueous
solution. The trimethylsiloxysilicate solution is combined with the aqueous
solution and
mixed by means of a homogenizer at room temperature. 0.1 g (0.1% w/w) Pemulen
TR-1
is added and mixed by means of a homogenizer at room temperature.
A topical liquid composition is obtained, with a viscosity ranging from 1-1.2
cP,
close to the viscosity of water.
The obtained topical liquid composition is applied to a wipe substrate and
sealed to
provide a sealed package of single-use wipe impregnated with the topical
liquid

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composition. The composition is configured to be applied to the Epistaxis
affected nostril
using single use nasal swabs(s)/wipe(s).
EXAMPLE 3 - Gel composition
25 g (25% w/w) trimethylsiloxysilicate powder is dissolved in 47.25 g (47.25%
w/w) methylsiloxane at RT. 4 g (4% w/w) Silicon Surfactant Cetyl PEG/PPG-10/1
Dimethicone is added to the solution of trimethylsiloxysilicate. 0.25% g
(0.25% w/w)
phenylephrine hydrochloride is dissolved in water. The pH of the aqueous
solution is
adjusted to 4.2-4.4 using an acetate buffer 25 g (25% w/w). 1.5 g (1.5% w/w)
Tween 80
is added to the aqueous solution with slow mixing to avoid bubbling. 0.6 g
(0.6% w/w)
Hydroxyethylcellulose (Natrosol HHX) is dispersed in the aqueous phase under
intensive
mixing and heated up to 70 deg C. The mixing continues after the mixture is
obtained and
is further continued until the mixture cools to room temperature. The
trimethylsiloxysilicate solution is combined with the aqueous solution and
mixed in a
homogenizer at room temperature. Upon dissolution of hydroxypropyl
methylcellulose
in the aqueous phase, a viscous gel with a viscosity ranging from 25000-45000
cP is
formed.
EXAMPLE 4
2.5 g (2.5% w/w) of sodium alkyl sulfate; 50 g (50% w/w) of the volatile
solvent
polydimethylsiloxane, 30 g (30% w/w) of water; (vi) 0.25 g (0.25% w/w) of
phenylephrine hydrochloride, 12 g (12% w/w) of silicone acrylate (FA 4001-Dow)
5.4 g
(5.4% w/w) of silicone surfactant (ES 5612-Dow) is mixed together in low shear
mixer
at room temperature and stored in a closed container protected from light.
EXAMPLE 5
1 g (1% w/w) of sodium alkyl sulfate; 50 g (50% w/w) of the volatile solvent
polydimethylsiloxane, 30 g (30% w/w) of water; (vi) 0.1 g (0.1% w/w) of
oxymethazoline, 12 g (12% w/w) of silicone acrylate (FA 4001-Dow), 6.9 g (6.9%
w/w)
of silicone surfactant (ES 5612-Dow) is mixed together in low shear mixer at
room
temperature and stored in a closed container protected from light.
EXAMPLE 6

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50g of the volatile solvent polydimethylsiloxane, 32.5 g (32.5% w/w) of water;

(vi) 0.1 g (0.1% w/w) of phenylephrine hydrochloride, 12 g (12% w/w) of
silicone
acrylate (FA 4002-Dow), 5.4 g (5.4% w/w) of silicone surfactant (ES 5612-Dow)
is
mixed together in low shear mixer at room temperature and stored in a closed
container
5 protected from light.
EXAMPLE 7
70 g (70% w/w) of the volatile solvent polydimethylsiloxane, 10 g (10% w/w) of

water; (vi) 0.1 g (0.1% w/w) of phenylephrine hydrochloride, 12 g (12% w/w) of
silicone
acrylate (FA 4001-Dow), 5.4 g (5.4% w/w) of silicone surfactant (ES 5612-Dow)
is
10 mixed together in low shear mixer at room temperature and stored in a
closed container
protected from light.
EXAMPLE 8 Metered Aerosol Epistaxis compositions with
propellant 134a, tranexamic acid and phenylephrine
Micronised tranexamic acid (5.0g, 5% w/w), micronised phenylephrine (0.25g.
15 0.25% w/w), tranexamic acid (5 g, 5% w/w), trimethylsiloxysilicate
powder (25.0g, 25%
w/w) and 1,1,1,2-tetrafluoroethane (69.75g, 69.75% w/w) is weighed into a
pressure
vessel and mixed with a high shear mixer for 20 minutes to obtain a
suspension. Aliquots
(20 g) of the suspension are filled into aluminum cans closed with a metering
valve,
filling under pressure through the valve using conventional filling equipment.
The
20 resulting inhalers contain 1 g tranexamic acid and 0.05 g phenylephrine
and deliver 100
puffs of 10 mg tranexamic acid and 0.5 mg phenylephrine per actuation.
EXAMPLE 9 Metered Aerosol Epistaxis compositions with
propellant 134a, tranexamic acid and phenylephrine hydrochloride
Micronised phenylephrine hydrochloride (0.25g, 0.25% w/w), tranexamic acid (5
25 g, 5% w/w) trimethylsiloxysilicate powder (25.0g, 25% w/w) and 1,1,1,2-
tetrafluoroethane (74.75g, 74.75% w/w) is weighed into a pressure vessel and
mixed with
a high shear mixer for 20 minutes to obtain a suspension. Aliquots (20 g) of
the
suspension are filled into aluminum cans closed with a metering valve, filling
under
pressure through the valve using conventional filling equipment. The resulting
inhalers

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contain 0.05 g phenylephrine and deliver 100 puffs of 0.5 mg phenylephrine
hydrochloride per actuation.
EXAMPLE 10 Metered Aerosol Epistaxis compositions with
propellant 134a and phenylephrine
Micronised phenylephrine (0.25g. 0.25% w/w), trimethylsiloxysilicate powder
(25.0g, 25% w/w) and 1,1,1,2-tetrafluoro ethane (74.75g, 74.75% w/w) are
weighed into a
pressure vessel and mixed with a high shear mixer for 20 minutes to obtain a
suspension.
Aliquots (20 g) of the suspension are filled into aluminum cans closed with a
metering
valve, filling under pressure through the valve using conventional filling
equipment. The
resulting inhalers contain 0.05 g phenylephrine and deliver 100 puffs of 0.5
mg
phenylephrine per actuation.
EXAMPLE 11 Metered Aerosol Epistaxis compositions with
propellant 134a and phenylephrine hydrochloride
Micronised phenylephrine hydrochloride (0.25g, 0.25% w/w),
trimethylsiloxysilicate powder (25.0g, 25% w/w) and 1,1,1,2-tetrafluoro ethane
(74.75g,
74.75% w/w) are weighed into a pressure vessel and mixed with a high shear
mixer for
minutes to obtain a suspension. Aliquots (20 g) of the suspension are filled
into
aluminum cans closed with a metering valve, filling under pressure through the
valve
using conventional filling equipment. The resulting inhalers contain 0.05 g
phenylephrine
20 and deliver 100 puffs of 0.5 mg phenylephrine hydrochloride per
actuation.
30