CA2952818A1 - Compositions for the treatment of epistaxis - Google Patents

Compositions for the treatment of epistaxis Download PDF

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Publication number
CA2952818A1
CA2952818A1 CA2952818A CA2952818A CA2952818A1 CA 2952818 A1 CA2952818 A1 CA 2952818A1 CA 2952818 A CA2952818 A CA 2952818A CA 2952818 A CA2952818 A CA 2952818A CA 2952818 A1 CA2952818 A1 CA 2952818A1
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Prior art keywords
composition
group
phenylephrine
combinations
water
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CA2952818A
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French (fr)
Inventor
Eran Eilat
Evgenia LOZINSKY
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Topitech Pharma Israel Ltd
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Topitech Pharma Israel Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0043—Nose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants

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.

Description

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
2 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
3 PCT/1B2015/001451 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).
4 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, 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.
6 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, 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
7 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
8 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)
9 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%

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.
11 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",
12 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:
13 (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.
14 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, 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
16 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
17 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-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
18 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
19 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.

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.
21 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,
22 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,
23 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
24 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, 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-
26 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-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
27 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,
28 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
29 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 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-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.
31 According to an embodiment, a topical composition of the present invention comprises: (i) trimethylsiloxysilicate; (ii) Tween 80; (iii) Cetyl PEG/PPG-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
32 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
33 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.
34 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 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%

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, 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.

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 (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, 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 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 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 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 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.

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 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.

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.

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 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 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.

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.

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.

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.

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 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.

Claims (20)

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.
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, 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 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.
CA2952818A 2015-05-01 2015-05-01 Compositions for the treatment of epistaxis Abandoned CA2952818A1 (en)

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EP3288636A1 (en) 2018-03-07

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