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WO2024261708A1 - Topical compositions for treating cold sores - Google Patents

Topical compositions for treating cold sores Download PDF

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Publication number
WO2024261708A1
WO2024261708A1 PCT/IB2024/056070 IB2024056070W WO2024261708A1 WO 2024261708 A1 WO2024261708 A1 WO 2024261708A1 IB 2024056070 W IB2024056070 W IB 2024056070W WO 2024261708 A1 WO2024261708 A1 WO 2024261708A1
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WO
WIPO (PCT)
Prior art keywords
topical composition
composition according
topical
cold
amount
Prior art date
Application number
PCT/IB2024/056070
Other languages
French (fr)
Inventor
Sudha GUNDUGOLA
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Haleon UK IP Limited
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Publication date
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Publication of WO2024261708A1 publication Critical patent/WO2024261708A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention is directed to topical pharmaceutical compositions comprising the combination of a topical anesthetic and glycerin in therapeutically active amounts, and their use for treating cold sores (fever blisters).
  • BACKGROUND OF THE INVENTION According to recent estimates of the World Health Organization, approximately 3.7 billion people under age 50 are afflicted with herpes simplex virus type 1 (HSV-1) infection.
  • HSV-1 (as well as, albeit far less commonly, the herpes simplex virus primarily causing genital herpes, HSV-2) manifest as painful and unsightly fluid-filled blisters or open sores, often grouped together in patches, that appear on the outside of the mouth generally around the border of the lips, typically preceded by a sensation of tingling, itching or burning; and persisting for about two to three weeks until complete healing.
  • the virus establishes latency in the sensory nerve cells for the life of the patient and can be repeatedly reactivated in response to various stimuli, such as changes in body temperature, stress, ultraviolet radiation, and exposure to chemicals.
  • the virus Upon reactivation, the virus is transported through the nerves to the skin resulting in formation of one or more orofacial lesions, with accompanying symptoms of inflammation and itching, swelling and pain around the area of the lesion.
  • Outbreaks of the herpes virus generally follow a staged progression.
  • the stages are easily identifiable and include prodrome, erythema/papule, blister/vesicles, ulceration, crust and healing. Some of the stages can last less than 24 hours.
  • Prodrome is generally a short period of tingling, itching, numbness or burning with no visible sign of an outbreak. Erythema/papule is characterized by a raised reddened area.
  • Vesicles are the formation of one or more fluid-filled blisters, often in a cluster and usually surrounded by sore, red skin.
  • the ulceration stage is when the blisters open to form painful ulcers or open sores. At the edge of the sore, a soft or hard yellow crust begins to appear. Ulcers and painful, sore, red skin persist through this stage.
  • weeping sores or ulcers become completely covered by a crust or scab. No open ulcers or blisters are present at this stage.
  • the healing process is manifested by disappearance of the crust or scab, swelling, pain and itching. A typical outbreak will generally regress within 7-10 days, with complete healing in 12-14 days, although a scar or erythema may persist.
  • Herpes virus infections are characterized by a high frequency of recurrence and are extremely contagious. Herpes labialis causes physical pain and discomfort and can also be disfiguring, especially in those patients with a high frequency of recurrence.
  • Orally administered antivirals such as acyclovir, famciclovir and valacyclovir, are commonly prescribed for oral herpes infection. However, due to viral resistance and side- effects associated with systemic administration, topical treatment is often preferred; and acyclovir and penciclovir creams or ointments are available by prescription in the U.S.
  • Abreva® Cream (Haleon) comprises 10% docosanol, an anti-viral, which is currently the only OTC ingredient approved by the U.S. Food and Drug Administration (FDA) to shorten cold sore healing time, having a median healing time of 4.1 days, down to 2.5 days in 25 percent of users if used as directed at the first sign of a “tingle.”
  • the product is a smooth, white cream that dries clear and has no smell or taste.
  • symptomatic OTC treatments relying on the numbing effect of topical anesthetics to relieve pain and itching associated with cold sores include, for example, Herpecin L® Pain Relief Triple Action Lidocaine Cold Sore Gel (containing 4% lidocaine hydrochloride together with allantoin and benzethonium chloride as active ingredients); and OrajelTM Cold Sore (containing 5% benzocaine and benzalkonium chloride as active ingredients).
  • Other topical treatments include drying agents (e.g., Domeboro® (aluminum acetate) astringent solution; calamine (zinc oxide/iron oxide) lotion; witch hazel; and anti-inflammatory agents such as hydrocortisone.
  • the present invention comprises compositions for treating cold sores comprising the combination of a topical anesthetic and glycerin, each in a therapeutically effective amount, in a topically administrable vehicle; and the use of said compositions for treating cold sores.
  • compositions and methods of the invention may be used for self-treatment by the U.S. consumer without a prescription, giving the cold sore sufferer direct access to safe and effective treatment as soon as prodromal symptoms are first experienced. This is an important advantage, since as is well known in the art, early intervention is often critical to achieving rapid cold sore clearance.
  • the compositions of the invention may be free of antiseptic. This is a distinct advantage over products on the market which rely on benzalkonium chloride or other quaternary ammonium compounds (known as “quats” or “QACs”) to eliminate environmental pathogens from the skin or membrane surface.
  • Quats as skin irritants, can interfere with the cold sore healing process in susceptible individuals, and deter the user from adhering to a recommended treatment regimen. Additionally, from a public health standpoint, the continuous use of such antiseptics and their release to the environment in subinhibitory concentrations can lead to the emergence of tolerant, resistant, and cross-resistant microbial strains.
  • the present invention provides a safe and effective cold sore treatment composition and method which is preferably free of quats and is preferably free of any antiseptic.
  • the compositions of the invention are suitable for topical application and include, without limitation, creams, lotions, gels, ointments, pastes, and the like.
  • compositions comprise the actives dissolved or dispersed in a topically administrable aqueous gel, such as described, e.g., in U.S.6,565,850 (2003), incorporated by reference.
  • aqueous gel herein refers to an aqueous dispersion comprising water and one or more gelling agents.
  • administer as used herein with respect to the compositions and methods of the invention refers to topical administration.
  • Cold sore and “fever blister,” are used interchangeably in the present application to mean an orofacial lesion (defined below) that occurs at the junction of the mucous membrane and skin on the lips or nose that is caused by the herpes virus (esp. HSV- 1).
  • Cold Sore Affected Skin Area means the area on the face on which a Prodromal Cold Sore Symptom (defined below) is perceived (i.e., by feel or observation) and/or on which fever blister forms.
  • Cold Sore Event means the period starting from the visible emergence of the first fever blister(s), continuing through the bursting of blisters, formation of shallow open sores, scabbing, shrinking of the scabs and ending with Cold Sore Healing.
  • Cold Sore Healing is the resolution of a cold sore event and means re- epithelialization —sloughing/ peeling off of scabs, which may be accompanied flaking and/or erythema. A cold sore is considered “healed” when scabs slough or peel off.
  • Orofacial lesion means an eruption (i.e.
  • "Prodromal Cold Sore Symptom” means tingling, redness, inflammation, burning, itching, numbness, tenderness and/or swelling on an area of the face-especially the lips or perioral skin-that occurs about 6 to 48 hours before an orofacial lesion erupts.
  • Treat” or “treating” or “treatment” as used herein has the meaning of providing relief from cold sore symptoms, especially Prodromal Cold Sore Symptoms.
  • “Reduction in Cold Sore Severity” can be measured based on (a) reduced orofacial lesion count, (b) shortened duration of a Cold Sore Event, and/or (c) lesser degree of pain, burning, itching and/or erythema during a Cold Sore Event.
  • a suitable topical anesthetic is preferably a “caine alcohol” selected from the group consisting of lidocaine, procaine, ropivacaine, bupivacaine, prilocaine, dibucaine and pharmaceutically acceptable salts and mixtures thereof, and is more preferably lidocaine or a pharmaceutically acceptable salt of lidocaine, e.g., lidocaine hydrochloride.
  • a therapeutically effective amount of lidocaine or its pharmaceutically acceptable salt shall be understood to be in the range from about 0.5% to 4% by weight, preferably from about 1 to 4 wt.%, and most preferably, 4 wt.%, of the total composition (which is the maximum strength allowed pursuant to FDA monograph). All percentages are based on the weight of the lidocaine free base or its pharmaceutically acceptable salt, whichever is employed as the active pharmaceutical ingredient.
  • Examples of other “caine” anesthetics and suitable concentration ranges are as follows: (a) benzocaine, at a concentration of from 5 to 20 wt.%; (b) dibucaine, or its hydrochloride salt, at a concentration of from 0.25 to 1 wt.%; (c) pramocaine hydrochloride, at a concentration of from 0.5 to 1 wt.%; and (d) tetracaine, or its hydrochloride salt, at a concentration of from 0.5 to 2.0 wt.% , e.g., from 1 to 2 wt.%.
  • compositions of the invention may include: benzyl alcohol, 1 to 4 wt.%; dyclonine hydrochloride, 0.5 to 1 wt.%; and pramoxine hydrochloride, 1 wt.%.
  • Glycerin By “therapeutically effective amount of glycerin” is meant an amount or concentration of glycerin which is generally recognized as safe and effective for topical use as a skin protectant active ingredient pursuant to FDA monograph M016.10(h).
  • glycerin (alternately referred to as glycerine or glycerol) is employed in the compositions of the invention in a range of from 20 to 45 wt.% based on the total composition, and preferably in the range of from 20 to about 35 wt. %, more preferably, from 20 to about 25 wt.%, even more preferably 20 wt.%.
  • glycerin when applied to the Cold Sore Affected Skin Area, especially at the beginning stages of a Cold Sore Event when Prodromal Cold Sore Symptoms first appear, has been found, unexpectedly, to potentiate absorption of the anesthetic agent into the skin layers, affording a significant Reduction in Cold Sore Severity and creating conditions favorable for Cold Sore Healing.
  • Hydration of the skin with glycerin at a concentration of 20 wt.% or greater has also, advantageously, been found to maintain the integrity of the skin as a protective barrier against bacteria, viruses or other invasive environmental factors, promoting Cold Sore Healing without resort to antiseptics.
  • glycerin e.g., comprising 99.9% glycerin and essentially no water
  • other grades e.g., 96% glycerin
  • any water contained in the glycerin should be included in the determination of total water in the composition, and likewise, glycerin concentration in the formulation is based on the actual amount of the chemical entity, glycerin, i.e. free of water.
  • the amount of water in the composition is generally from about 40 to about 75 wt.%, preferably from about 50 to about 70 wt.% more preferably from about 50 to about 60 wt.%, based on the total composition.
  • the amount of water should be at least sufficient to fully solubilize the anesthetic agent. Full solubilization presents the active ingredients as molecular species in the water medium.
  • Both the amounts of glycerin and water, as well as their relative proportions, are important to optimize the hydration benefit of the glycerin. The hydration process in itself provides some relief from itching, discomfort and pain.
  • the ratio of the glycerin amount by weight to the sum of the glycerin amount and water amount by weight is about 20 wt.% to about 30 wt.%, especially about 25 wt.%.
  • the sum of the glycerin amount and the water present in the composition is at least about 65 wt.% (e.g., 65-80 wt.%), more preferably at least about 70 wt.%, e.g., about 75 wt.%, of the composition.
  • the amount of water in the composition can be adjusted relative to the amounts of the other ingredients, especially the gelling agent, to give a satisfactory viscosity to the gel.
  • the viscosity is high enough so that the gel is not too mobile so that after application it is retained on the Cold Sore Affected Skin Area for a period of time sufficient to achieve maximum numbing, yet low enough so that the gel can be dispensed satisfactorily from a tube or other dispenser.
  • Glycol co-solvent [0038]
  • the compositions also preferably comprise a water-miscible glycol co-solvent.
  • Preferred glycol solvents include propylene glycol and polyethylene glycols having an average molecular weight of about 200 to 800.
  • the glycol co-solvent preferably comprises propylene glycol.
  • the glycol co-solvent may be present in an amount from about 10 wt.% to about 30 wt.
  • the gelling agent is adapted to make a gel out of an aqueous medium.
  • the gelling agent comprises a polymer which contains free carboxylic groups that are all or partly neutralized in a form of carboxylate through the use of a base.
  • Such gelling agents include vinyl polymers with hydrodispersible carboxylate groups, such as a polyacrylic acid gel, that is neutralized by a base, e.g., sodium hydroxide. Also preferred are polymers with a molecular weight of about 1,250,000 to 4,000,000.
  • Crosslinked polyacrylic acids such as polyacrylic acid reticulated with polyalkenyl polyethers are also encompassed.
  • water-soluble derivatives of cellulose i.e. non-ionic celluloses of ether, including hydroxyethylcellulose, hydroxypropylmethylcellulose, methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, and carboxymethylcellulose, and combinations thereof.
  • a preferred gelling agent is a non-ionic cellulose ether, preferably hydroxyethyl- cellulose, e.g., the product marketed as NatrosolTM.
  • Preferred hydroxyethylcelluloses have a viscosity from about 6,400 cps to about 11,900 cps per USP ⁇ 912>.
  • the amount required is chosen having regard to the desired consistency of the gel.
  • the composition will comprise from about 0.5 to about 5% by total weight of water-soluble cellulose derivative, preferably from about 1 wt.% to about 4 wt.%, most preferably about 2 wt.% based on the composition.
  • the ratio of the gelling agent and the glycol co-solvent to water are such that the gel has a viscosity from about 90,000 cps to about 150,000 cps at 20° C. (Brookfield heliopath T-D, 1 rpm, 1 min., 25 ⁇ C.).
  • the compositions of the invention may comprise additional ingredients including surfactants, antioxidants, preservatives as required, and chelating agents, as well as sensates and/or fragrance.
  • a cooling sensate such as menthol
  • menthol typically in an amount of from about 0.01 wt.% to about 1.0% wt.% based on the composition.
  • Suitable antioxidants may be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, carotenoids, kojic acid, thioglycolic acid, tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, tocophereth-80, and mixtures thereof.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • ascorbyl linoleate ascorbyl dipalmitate
  • ascorbyl tocopherol maleate calcium ascorbate
  • carotenoids kojic acid
  • thioglycolic acid tocopherol
  • tocopherol acetate tocophereth-5, tocophereth
  • Preferred antioxidants are sodium citrate (0.3 to 20 wt.%), sodium metabisulphite (0.01-1 wt.%) and disodium edetate (0.005 to 0.1 wt.%).
  • Preservatives suitable for use in the present invention include, but are not limited to, methyl paraben, propyl paraben, butyl paraben, benzyl paraben, methylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene monostearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate and combinations thereof.
  • the preservative comprises methyl and/or propyl paraben.
  • the total preservative may be in an amount of from about 0.0 wt.% to about 1 wt.%.
  • Chelating agent may further comprise a chelating agent to chelate metal cations that may be present as impurities, which makes it possible to avoid side effects in certain patients, and to inhibit browning during storage.
  • the chelating agent is advantageously selected from among ethylenediamine tetraacetic acid (EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, hydroxyethyl EDTA (HEDTA), triethanolamine salt of EDATA (TEA-EDTA), tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric acid, galacturonic acid, gluconic acid, glucuronic acid, humic acid, cyclodextrin, potassium citrate, potassium ethylenediaminetetramethylenephosphonic acid (EDTMP), sodium citrate, sodium EDTMP, and mixtures thereof.
  • EDTA ethylenediamine tetraacetic acid
  • diammonium EDTA diammonium EDTA
  • dipotassium EDTA calcium disodium EDTA
  • HEDTA hydroxyethyl EDTA
  • the chelating agent is ethylene diamine tetraacetic acid (EDTA) or one of its salts, such as EDTA disodium and/or sodium citrate, preferably in a total amount of 0.05 to 0.5 wt.%, typically about 0.1 wt.%.
  • the surfactant may be any surfactant suitable for use in a pharmaceutical formulation, e.g., a non-ionic surfactant, a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a mixture thereof.
  • the surfactant is a non- ionic surfactant.
  • surfactants examples include: Labrasol® (which is a mixture of acylglycerols and PEG esters); LauroglycolTM FCC (which comprises propylene glycol monolaurate); TweenTM 80 (polysorbate 80); TweenTM 20 (polysorbate 20); and ArlamolTM PS11E (polyoxypropylene stearyl ether).
  • the surfactant is a polysorbate, preferably polysorbate 80.
  • the surfactant is present in an amount of from 0 % to 5 % by weight of the total composition, preferably from 0.2 % to 2 % by weight of the total composition, more preferably from 0.5 % to 1.5 % by weight of the total composition. pH.
  • the pH of the composition is between about 5 and about 6.5, preferably between about 5.2 and about 6.2. The pH may be adjusted as necessary.
  • Other active pharmaceutical ingredients and inactive ingredients may also be incorporated in the gel compositions of this invention to provide symptomatic relief.
  • such active ingredients are water soluble (e.g., ionic) and colorless.
  • compositions are preferably free of oils, fats or glycerides in amounts sufficient to form an emulsion, and are also preferably free of silicones.
  • the compositions are preferably free of monohydric alcohols such as methanol, ethanol, propanol, butanol or mixtures thereof, which can have a drying effect on the skin.
  • the compositions are preferably free of antiseptics in general, and in particular, are free of quarternary ammonium compounds, e.g., benzalkonium chloride, such as benzethonium chloride.
  • the compositions are preferably free of artificial dyes or fragrances.
  • the aqueous gel compositions of the invention are non-greasy, non-staining, and clear on application; and can easily be washed from the user’s hands.
  • the compositions provide excellent water retaining properties upon application.
  • the large water content has a cooling and soothing effect, giving symptomatic relief to the user, and can be adjusted relative to the amounts of the other ingredients, especially the gelling agent, to give a satisfactory viscosity to the gel. It is preferred that the viscosity is high enough so that the gel is not too mobile and so is retained on the topography of the Cold Sore Skin Affected Area, yet low enough so that the gel can be dispensed satisfactorily from a tube or other dispenser.
  • a further advantage of a water-based gel is that dispensers may be cold-filled unlike grease-based ointments which are generally hot filled to achieve a lower viscosity so that the tubes may be filled prior to cooling.
  • An even further advantage is that the viscous properties of the gel minimize physical risk of active ingredient loss due to run off from the site of application.
  • the clear formulations provided by embodiments of the invention are also preferred because they give a more natural appearance than creams or ointments.
  • the compositions comprise lidocaine hydrochloride in an amount of from about 1 to 4 wt.% and glycerin in an amount of from 20 to 45 wt.%, in an aqueous gel vehicle.
  • compositions comprise lidocaine hydrochloride in an amount of 4 wt.% and glycerin in an amount of 20 wt.%, in an aqueous gel vehicle.
  • compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a gelling agent comprising a water-soluble derivative of cellulose; a glycol co-solvent; and water.
  • compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a non-ionic cellulose ether gelling agent in an amount of from about 1 wt.% to about 2 wt.%, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, and water to make up 100 wt.%.
  • compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, hydroxyethylcellulose in an amount of from about 1 wt.% to about 2 wt.%, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, and water in an amount from about 45 to about 60 wt.%.
  • the compositions comprise, consist essentially of, or consist of, lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a non-ionic cellulose ether gelling agent, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, water in an amount from about 45 to about 60 wt.%, and optionally, an effective amount of one or more of a preservative, surfactant, antioxidant, and sensate agent.
  • the invention comprises any of the foregoing compositions comprising an effective amount of menthol.
  • compositions comprise: and optionally, an effective amount of one or more of a preservative, surfactant, antioxidant, and sensate agent.
  • All weight percentages recited herein are based on the total composition unless otherwise indicated.
  • Methods of the invention also provides a method for treating cold sores of a subject in need of said treatment comprising topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject.
  • This invention also provides a method for relieving the symptoms associated with cold sores in a subject so-afflicted which comprises topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject.
  • the invention further provides a method for achieving a Reduction in Cold Sore Severity in a subject in need thereof, comprising topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject.
  • Other methods are disclosed in co-pending application, Docket No.70200US01P, which is incorporated herein by reference.
  • the subject is mammalian, especially, human, and includes human adults and children age 12 and over.
  • the compositions of the invention are intended for topical application to the involved skin and optionally the surrounding area.
  • kits for administering the compositions of the invention for treatment of cold sores comprising an outer container comprising one or more primary packages together with written instructions to facilitate compliance with the treatment, each of said one or more primary packages containing a topical composition according to the invention.
  • the instruction for administering the treatment may be printed on the outer container or on a sheet inserted therein. It is also contemplated that the kit may optionally include other products suitable for treating cold sores, such as, e.g., a cleanser for use in cleaning the afflicted area prior to the application of the one or more compositions comprising the active ingredients and/or one or more applicators.
  • a cleanser for use in cleaning the afflicted area prior to the application of the one or more compositions comprising the active ingredients and/or one or more applicators.
  • All weight percentages recited herein are based on the total composition.
  • Method of Preparation [0082] The compositions of the invention may be prepared by mixing the ingredients in any convenient order according to techniques known to workers in the art. [0083] All weight percentages recited herein are based on the total composition.
  • Example 1 The following example describes an aqueous gel composition for treating cold sores which is exemplary of the invention: [0085] Water was added to the main reaction vessel. The salts to be incorporated (lidocaine hydrochloride, sodium citrate, disodium edetate) were added sequentially, with mixing, to give a clear solution. [0086] Methyl and propyl p-hydroxybenzoates, menthol, and Polysorbate 80 were added sequentially to the propylene glycol at 40 ⁇ C., with mixing, to form a pre-mix, which was added to the main reaction vessel.
  • the salts to be incorporated (lidocaine hydrochloride, sodium citrate, disodium edetate) were added sequentially, with mixing, to give a clear solution.
  • Methyl and propyl p-hydroxybenzoates, menthol, and Polysorbate 80 were added sequentially to the propylene glycol at 40 ⁇ C., with mixing, to form a pre-mix, which

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Abstract

Topical compositions and methods for treating cold sores (fever blisters) associated with herpes infection, and kits therefor.

Description

TOPICAL COMPOSITIONS FOR TREATING COLD SORES [0001] The present invention is directed to topical pharmaceutical compositions comprising the combination of a topical anesthetic and glycerin in therapeutically active amounts, and their use for treating cold sores (fever blisters). BACKGROUND OF THE INVENTION [0002] According to recent estimates of the World Health Organization, approximately 3.7 billion people under age 50 are afflicted with herpes simplex virus type 1 (HSV-1) infection. HSV-1 (as well as, albeit far less commonly, the herpes simplex virus primarily causing genital herpes, HSV-2) manifest as painful and unsightly fluid-filled blisters or open sores, often grouped together in patches, that appear on the outside of the mouth generally around the border of the lips, typically preceded by a sensation of tingling, itching or burning; and persisting for about two to three weeks until complete healing. After the initial infection, the virus establishes latency in the sensory nerve cells for the life of the patient and can be repeatedly reactivated in response to various stimuli, such as changes in body temperature, stress, ultraviolet radiation, and exposure to chemicals. Upon reactivation, the virus is transported through the nerves to the skin resulting in formation of one or more orofacial lesions, with accompanying symptoms of inflammation and itching, swelling and pain around the area of the lesion. [0003] Outbreaks of the herpes virus generally follow a staged progression. The stages are easily identifiable and include prodrome, erythema/papule, blister/vesicles, ulceration, crust and healing. Some of the stages can last less than 24 hours. Prodrome is generally a short period of tingling, itching, numbness or burning with no visible sign of an outbreak. Erythema/papule is characterized by a raised reddened area. Vesicles are the formation of one or more fluid-filled blisters, often in a cluster and usually surrounded by sore, red skin. The ulceration stage is when the blisters open to form painful ulcers or open sores. At the edge of the sore, a soft or hard yellow crust begins to appear. Ulcers and painful, sore, red skin persist through this stage. At the crust stage, weeping sores or ulcers become completely covered by a crust or scab. No open ulcers or blisters are present at this stage. The healing process is manifested by disappearance of the crust or scab, swelling, pain and itching. A typical outbreak will generally regress within 7-10 days, with complete healing in 12-14 days, although a scar or erythema may persist. [0004] Herpes virus infections are characterized by a high frequency of recurrence and are extremely contagious. Herpes labialis causes physical pain and discomfort and can also be disfiguring, especially in those patients with a high frequency of recurrence. [0005] Orally administered antivirals such as acyclovir, famciclovir and valacyclovir, are commonly prescribed for oral herpes infection. However, due to viral resistance and side- effects associated with systemic administration, topical treatment is often preferred; and acyclovir and penciclovir creams or ointments are available by prescription in the U.S. [0006] Additionally, certain anti-viral as well as non-anti-viral, symptomatic treatments have achieved wide availability due to their non-prescription, “over-the-counter” (OTC) status. [0007] For example, Abreva® Cream (Haleon) comprises 10% docosanol, an anti-viral, which is currently the only OTC ingredient approved by the U.S. Food and Drug Administration (FDA) to shorten cold sore healing time, having a median healing time of 4.1 days, down to 2.5 days in 25 percent of users if used as directed at the first sign of a “tingle.” The product is a smooth, white cream that dries clear and has no smell or taste. Additionally, symptomatic OTC treatments relying on the numbing effect of topical anesthetics to relieve pain and itching associated with cold sores include, for example, Herpecin L® Pain Relief Triple Action Lidocaine Cold Sore Gel (containing 4% lidocaine hydrochloride together with allantoin and benzethonium chloride as active ingredients); and Orajel™ Cold Sore (containing 5% benzocaine and benzalkonium chloride as active ingredients). Other topical treatments include drying agents (e.g., Domeboro® (aluminum acetate) astringent solution; calamine (zinc oxide/iron oxide) lotion; witch hazel; and anti-inflammatory agents such as hydrocortisone. [0008] There is a need for new improved products and therapies for treating cold sores (fever blisters) that are directly accessible to consumers without a prescription. Summary of the Invention [0009] It has been discovered that glycerin, typically employed as a humectant in topical pharmaceutical and cosmetic products, can be employed at higher concentrations to improve the effectiveness of a topical anesthetic agent in relieving debilitating cold sore symptoms, such as, e.g., pain and itching. [0010] In particular, glycerin in an amount sufficient to act as a skin protectant active ingredient (referred to herein as a “therapeutically effective amount” of glycerin) has been found to potentiate skin absorption of the topical anesthetic when the active ingredients are co-administered to the cold sore-affected skin or membrane, resulting in more rapid numbing and thus more immediate and effective relief from cold sore symptoms. [0011] Accordingly, the present invention comprises compositions for treating cold sores comprising the combination of a topical anesthetic and glycerin, each in a therapeutically effective amount, in a topically administrable vehicle; and the use of said compositions for treating cold sores. [0012] The compositions and methods of the invention may be used for self-treatment by the U.S. consumer without a prescription, giving the cold sore sufferer direct access to safe and effective treatment as soon as prodromal symptoms are first experienced. This is an important advantage, since as is well known in the art, early intervention is often critical to achieving rapid cold sore clearance. [0013] Also advantageously, the compositions of the invention may be free of antiseptic. This is a distinct advantage over products on the market which rely on benzalkonium chloride or other quaternary ammonium compounds (known as “quats” or “QACs”) to eliminate environmental pathogens from the skin or membrane surface. Quats, as skin irritants, can interfere with the cold sore healing process in susceptible individuals, and deter the user from adhering to a recommended treatment regimen. Additionally, from a public health standpoint, the continuous use of such antiseptics and their release to the environment in subinhibitory concentrations can lead to the emergence of tolerant, resistant, and cross-resistant microbial strains. The present invention provides a safe and effective cold sore treatment composition and method which is preferably free of quats and is preferably free of any antiseptic. [0014] The compositions of the invention are suitable for topical application and include, without limitation, creams, lotions, gels, ointments, pastes, and the like. Another suitable vehicle is an occlusive film, as described in US Patent Publication No.2010/0063004, incorporated by reference. [0015] Preferably, the compositions comprise the actives dissolved or dispersed in a topically administrable aqueous gel, such as described, e.g., in U.S.6,565,850 (2003), incorporated by reference. The term, "aqueous gel" herein refers to an aqueous dispersion comprising water and one or more gelling agents. Detailed Description of the Invention [0016] The term “administer” as used herein with respect to the compositions and methods of the invention refers to topical administration. [0017] The terms, "cold sore” and “fever blister," are used interchangeably in the present application to mean an orofacial lesion (defined below) that occurs at the junction of the mucous membrane and skin on the lips or nose that is caused by the herpes virus (esp. HSV- 1). [0018] "Cold Sore Affected Skin Area" means the area on the face on which a Prodromal Cold Sore Symptom (defined below) is perceived (i.e., by feel or observation) and/or on which fever blister forms. [0019] "Cold Sore Event" means the period starting from the visible emergence of the first fever blister(s), continuing through the bursting of blisters, formation of shallow open sores, scabbing, shrinking of the scabs and ending with Cold Sore Healing. [0020] "Cold Sore Healing" is the resolution of a cold sore event and means re- epithelialization —sloughing/ peeling off of scabs, which may be accompanied flaking and/or erythema. A cold sore is considered "healed" when scabs slough or peel off. [0021] "Orofacial lesion" means an eruption (i.e. breaking out and becoming visible) of one or more of a macule, papule, pustule, vesicle on (i) the lips or perioral skin area, (ii) gingiva, oral palate, or tongue, or, less commonly, (iii) cheek, chin or nose. [0022] "Prodromal Cold Sore Symptom" means tingling, redness, inflammation, burning, itching, numbness, tenderness and/or swelling on an area of the face-especially the lips or perioral skin-that occurs about 6 to 48 hours before an orofacial lesion erupts. [0023] The term “treat” or “treating” or “treatment” as used herein has the meaning of providing relief from cold sore symptoms, especially Prodromal Cold Sore Symptoms. [0024] “Reduction in Cold Sore Severity" can be measured based on (a) reduced orofacial lesion count, (b) shortened duration of a Cold Sore Event, and/or (c) lesser degree of pain, burning, itching and/or erythema during a Cold Sore Event. Topical anesthetic [0025] In the compositions of the invention, a suitable topical anesthetic is preferably a “caine alcohol” selected from the group consisting of lidocaine, procaine, ropivacaine, bupivacaine, prilocaine, dibucaine and pharmaceutically acceptable salts and mixtures thereof, and is more preferably lidocaine or a pharmaceutically acceptable salt of lidocaine, e.g., lidocaine hydrochloride. [0026] A therapeutically effective amount of lidocaine or its pharmaceutically acceptable salt, shall be understood to be in the range from about 0.5% to 4% by weight, preferably from about 1 to 4 wt.%, and most preferably, 4 wt.%, of the total composition (which is the maximum strength allowed pursuant to FDA monograph). All percentages are based on the weight of the lidocaine free base or its pharmaceutically acceptable salt, whichever is employed as the active pharmaceutical ingredient. [0027] Examples of other “caine” anesthetics and suitable concentration ranges are as follows: (a) benzocaine, at a concentration of from 5 to 20 wt.%; (b) dibucaine, or its hydrochloride salt, at a concentration of from 0.25 to 1 wt.%; (c) pramocaine hydrochloride, at a concentration of from 0.5 to 1 wt.%; and (d) tetracaine, or its hydrochloride salt, at a concentration of from 0.5 to 2.0 wt.% , e.g., from 1 to 2 wt.%. [0028] Other topical anesthetics for use in the compositions of the invention may include: benzyl alcohol, 1 to 4 wt.%; dyclonine hydrochloride, 0.5 to 1 wt.%; and pramoxine hydrochloride, 1 wt.%. Glycerin [0029] By “therapeutically effective amount of glycerin” is meant an amount or concentration of glycerin which is generally recognized as safe and effective for topical use as a skin protectant active ingredient pursuant to FDA monograph M016.10(h). [0030] Thus glycerin (alternately referred to as glycerine or glycerol) is employed in the compositions of the invention in a range of from 20 to 45 wt.% based on the total composition, and preferably in the range of from 20 to about 35 wt. %, more preferably, from 20 to about 25 wt.%, even more preferably 20 wt.%. In such amounts, as well as when present in certain ratios to water in the composition, glycerin when applied to the Cold Sore Affected Skin Area, especially at the beginning stages of a Cold Sore Event when Prodromal Cold Sore Symptoms first appear, has been found, unexpectedly, to potentiate absorption of the anesthetic agent into the skin layers, affording a significant Reduction in Cold Sore Severity and creating conditions favorable for Cold Sore Healing. [0031] Hydration of the skin with glycerin at a concentration of 20 wt.% or greater has also, advantageously, been found to maintain the integrity of the skin as a protective barrier against bacteria, viruses or other invasive environmental factors, promoting Cold Sore Healing without resort to antiseptics. [0032] Pharmaceutical grade glycerin, e.g., comprising 99.9% glycerin and essentially no water, is preferred for use in the practice of the invention, although other grades (e.g., 96% glycerin) may be used, in which case any water contained in the glycerin should be included in the determination of total water in the composition, and likewise, glycerin concentration in the formulation is based on the actual amount of the chemical entity, glycerin, i.e. free of water. Water [0033] The amount of water in the composition is generally from about 40 to about 75 wt.%, preferably from about 50 to about 70 wt.% more preferably from about 50 to about 60 wt.%, based on the total composition. The amount of water should be at least sufficient to fully solubilize the anesthetic agent. Full solubilization presents the active ingredients as molecular species in the water medium. [0034] Both the amounts of glycerin and water, as well as their relative proportions, are important to optimize the hydration benefit of the glycerin. The hydration process in itself provides some relief from itching, discomfort and pain. As previously indicated, it has been discovered that hydration resulting from the higher amounts of glycerin used in the inventive compositions also facilitates skin penetration of the topical anesthetic, and thus more effective numbing of the Cold Sore Affected Skin Area. [0035] In one embodiment, the ratio of the glycerin amount by weight to the sum of the glycerin amount and water amount by weight is about 20 wt.% to about 30 wt.%, especially about 25 wt.%. [0036] The sum of the glycerin amount and the water present in the composition is at least about 65 wt.% (e.g., 65-80 wt.%), more preferably at least about 70 wt.%, e.g., about 75 wt.%, of the composition. [0037] The amount of water in the composition can be adjusted relative to the amounts of the other ingredients, especially the gelling agent, to give a satisfactory viscosity to the gel. It is preferred that the viscosity is high enough so that the gel is not too mobile so that after application it is retained on the Cold Sore Affected Skin Area for a period of time sufficient to achieve maximum numbing, yet low enough so that the gel can be dispensed satisfactorily from a tube or other dispenser. Glycol co-solvent [0038] The compositions also preferably comprise a water-miscible glycol co-solvent. Preferred glycol solvents include propylene glycol and polyethylene glycols having an average molecular weight of about 200 to 800. The glycol co-solvent preferably comprises propylene glycol. [0039] The glycol co-solvent may be present in an amount from about 10 wt.% to about 30 wt. %, preferably about 12 wt.% to about 20 wt.%, more preferably about 15 wt.% based on the total composition. Gelling agent [0040] The gelling agent is adapted to make a gel out of an aqueous medium. In one embodiment, the gelling agent comprises a polymer which contains free carboxylic groups that are all or partly neutralized in a form of carboxylate through the use of a base. Such gelling agents include vinyl polymers with hydrodispersible carboxylate groups, such as a polyacrylic acid gel, that is neutralized by a base, e.g., sodium hydroxide. Also preferred are polymers with a molecular weight of about 1,250,000 to 4,000,000. Crosslinked polyacrylic acids such as polyacrylic acid reticulated with polyalkenyl polyethers are also encompassed. [0041] Also suitable are water-soluble derivatives of cellulose, i.e. non-ionic celluloses of ether, including hydroxyethylcellulose, hydroxypropylmethylcellulose, methyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, and carboxymethylcellulose, and combinations thereof. [0042] A preferred gelling agent is a non-ionic cellulose ether, preferably hydroxyethyl- cellulose, e.g., the product marketed as Natrosol™. Preferred hydroxyethylcelluloses have a viscosity from about 6,400 cps to about 11,900 cps per USP <912>. [0043] The amount required is chosen having regard to the desired consistency of the gel. Typically, the composition will comprise from about 0.5 to about 5% by total weight of water-soluble cellulose derivative, preferably from about 1 wt.% to about 4 wt.%, most preferably about 2 wt.% based on the composition. [0044] To provide optimum skin softening and dispensing properties, it is preferred that the ratio of the gelling agent and the glycol co-solvent to water are such that the gel has a viscosity from about 90,000 cps to about 150,000 cps at 20° C. (Brookfield heliopath T-D, 1 rpm, 1 min., 25˚C.). [0045] The compositions of the invention may comprise additional ingredients including surfactants, antioxidants, preservatives as required, and chelating agents, as well as sensates and/or fragrance. Sensate [0046] While the water in the composition beneficially provides a cooling effect upon application, it is desirable to also include a cooling sensate such as menthol, typically in an amount of from about 0.01 wt.% to about 1.0% wt.% based on the composition. Antioxidant [0047] Suitable antioxidants may be selected from the group consisting of butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, carotenoids, kojic acid, thioglycolic acid, tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, tocophereth-80, and mixtures thereof. [0048] Preferred antioxidants are sodium citrate (0.3 to 20 wt.%), sodium metabisulphite (0.01-1 wt.%) and disodium edetate (0.005 to 0.1 wt.%). Preservative [0049] Preservatives suitable for use in the present invention include, but are not limited to, methyl paraben, propyl paraben, butyl paraben, benzyl paraben, methylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene monostearate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate and combinations thereof. [0050] Preferably, the preservative comprises methyl and/or propyl paraben. The total preservative may be in an amount of from about 0.0 wt.% to about 1 wt.%. Chelating agent. [0051] The compositions may further comprise a chelating agent to chelate metal cations that may be present as impurities, which makes it possible to avoid side effects in certain patients, and to inhibit browning during storage. The chelating agent is advantageously selected from among ethylenediamine tetraacetic acid (EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, hydroxyethyl EDTA (HEDTA), triethanolamine salt of EDATA (TEA-EDTA), tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric acid, galacturonic acid, gluconic acid, glucuronic acid, humic acid, cyclodextrin, potassium citrate, potassium ethylenediaminetetramethylenephosphonic acid (EDTMP), sodium citrate, sodium EDTMP, and mixtures thereof. [0052] Preferably, the chelating agent is ethylene diamine tetraacetic acid (EDTA) or one of its salts, such as EDTA disodium and/or sodium citrate, preferably in a total amount of 0.05 to 0.5 wt.%, typically about 0.1 wt.%. Surfactant [0053] The surfactant (or emulsifier) may be any surfactant suitable for use in a pharmaceutical formulation, e.g., a non-ionic surfactant, a cationic surfactant, an anionic surfactant, a zwitterionic surfactant, or a mixture thereof. Typically, the surfactant is a non- ionic surfactant. [0054] Examples of commercially available surfactants that may be used in the present invention include: Labrasol® (which is a mixture of acylglycerols and PEG esters); Lauroglycol™ FCC (which comprises propylene glycol monolaurate); Tween™ 80 (polysorbate 80); Tween™ 20 (polysorbate 20); and Arlamol™ PS11E (polyoxypropylene stearyl ether). [0055] Preferably, the surfactant is a polysorbate, preferably polysorbate 80. [0056] When present in the topical gel compositions of the invention, typically, the surfactant is present in an amount of from 0 % to 5 % by weight of the total composition, preferably from 0.2 % to 2 % by weight of the total composition, more preferably from 0.5 % to 1.5 % by weight of the total composition. pH. [0057] Preferably, the pH of the composition is between about 5 and about 6.5, preferably between about 5.2 and about 6.2. The pH may be adjusted as necessary. [0058] Other active pharmaceutical ingredients and inactive ingredients may also be incorporated in the gel compositions of this invention to provide symptomatic relief. Preferably such active ingredients are water soluble (e.g., ionic) and colorless. [0059] The compositions are preferably free of oils, fats or glycerides in amounts sufficient to form an emulsion, and are also preferably free of silicones. [0060] The compositions are preferably free of monohydric alcohols such as methanol, ethanol, propanol, butanol or mixtures thereof, which can have a drying effect on the skin. [0061] The compositions are preferably free of antiseptics in general, and in particular, are free of quarternary ammonium compounds, e.g., benzalkonium chloride, such as benzethonium chloride. [0062] The compositions are preferably free of artificial dyes or fragrances. [0063] The aqueous gel compositions of the invention are non-greasy, non-staining, and clear on application; and can easily be washed from the user’s hands. The compositions provide excellent water retaining properties upon application. The large water content has a cooling and soothing effect, giving symptomatic relief to the user, and can be adjusted relative to the amounts of the other ingredients, especially the gelling agent, to give a satisfactory viscosity to the gel. It is preferred that the viscosity is high enough so that the gel is not too mobile and so is retained on the topography of the Cold Sore Skin Affected Area, yet low enough so that the gel can be dispensed satisfactorily from a tube or other dispenser. A further advantage of a water-based gel is that dispensers may be cold-filled unlike grease-based ointments which are generally hot filled to achieve a lower viscosity so that the tubes may be filled prior to cooling. An even further advantage is that the viscous properties of the gel minimize physical risk of active ingredient loss due to run off from the site of application. The clear formulations provided by embodiments of the invention are also preferred because they give a more natural appearance than creams or ointments. Specific Embodiments of the Invention [0064] In one non-limiting embodiment, the compositions comprise lidocaine hydrochloride in an amount of from about 1 to 4 wt.% and glycerin in an amount of from 20 to 45 wt.%, in an aqueous gel vehicle. [0065] In another non-limiting embodiment, the compositions comprise lidocaine hydrochloride in an amount of 4 wt.% and glycerin in an amount of 20 wt.%, in an aqueous gel vehicle. [0066] In another non-limiting embodiment, the compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a gelling agent comprising a water-soluble derivative of cellulose; a glycol co-solvent; and water. [0067] In another non-limiting embodiment, the compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a non-ionic cellulose ether gelling agent in an amount of from about 1 wt.% to about 2 wt.%, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, and water to make up 100 wt.%. [0068] In another non-limiting embodiment, the compositions comprise lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, hydroxyethylcellulose in an amount of from about 1 wt.% to about 2 wt.%, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, and water in an amount from about 45 to about 60 wt.%. [0069] In another non-limiting embodiment, the compositions comprise, consist essentially of, or consist of, lidocaine hydrochloride in an amount of 4 wt.%, glycerin in an amount of 20 wt.%, a non-ionic cellulose ether gelling agent, propylene glycol in an amount of from about 10 wt.% to about 20 wt.%, water in an amount from about 45 to about 60 wt.%, and optionally, an effective amount of one or more of a preservative, surfactant, antioxidant, and sensate agent. [0070] In another non-limiting embodiment, the invention comprises any of the foregoing compositions comprising an effective amount of menthol. [0071] In another non-limiting embodiment, the compositions comprise:
Figure imgf000014_0001
and optionally, an effective amount of one or more of a preservative, surfactant, antioxidant, and sensate agent. [0072] All weight percentages recited herein are based on the total composition unless otherwise indicated. Methods of the invention [0073] The invention also provides a method for treating cold sores of a subject in need of said treatment comprising topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject. [0074] This invention also provides a method for relieving the symptoms associated with cold sores in a subject so-afflicted which comprises topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject. [0075] The invention further provides a method for achieving a Reduction in Cold Sore Severity in a subject in need thereof, comprising topically administering a composition of the invention to the Cold Sore Affected Skin Area of the subject. [0076] Other methods are disclosed in co-pending application, Docket No.70200US01P, which is incorporated herein by reference. [0077] The subject is mammalian, especially, human, and includes human adults and children age 12 and over. [0078] The compositions of the invention are intended for topical application to the involved skin and optionally the surrounding area. It is contemplated that an aliquot of the composition sufficient to completely cover the Cold Sore Affected Skin Area may be applied by adults and children 12 years or over, up to, e.g., 3 to 4 times per day, until a Reduction in Cold Sore Severity is achieved. Advantageously, the compositions, being free of antiseptics and/or drying agents, may be applied repeatedly as needed without irritating or dehydrating the affected area. Kit [0079] Also within the scope of the invention is a kit for administering the compositions of the invention for treatment of cold sores, said kit comprising an outer container comprising one or more primary packages together with written instructions to facilitate compliance with the treatment, each of said one or more primary packages containing a topical composition according to the invention. [0080] The instruction for administering the treatment may be printed on the outer container or on a sheet inserted therein. It is also contemplated that the kit may optionally include other products suitable for treating cold sores, such as, e.g., a cleanser for use in cleaning the afflicted area prior to the application of the one or more compositions comprising the active ingredients and/or one or more applicators. [0081] All weight percentages recited herein are based on the total composition. Method of Preparation [0082] The compositions of the invention may be prepared by mixing the ingredients in any convenient order according to techniques known to workers in the art. [0083] All weight percentages recited herein are based on the total composition. Example 1 [0084] The following example describes an aqueous gel composition for treating cold sores which is exemplary of the invention:
Figure imgf000015_0001
Figure imgf000016_0001
[0085] Water was added to the main reaction vessel. The salts to be incorporated (lidocaine hydrochloride, sodium citrate, disodium edetate) were added sequentially, with mixing, to give a clear solution. [0086] Methyl and propyl p-hydroxybenzoates, menthol, and Polysorbate 80 were added sequentially to the propylene glycol at 40˚C., with mixing, to form a pre-mix, which was added to the main reaction vessel. [0087] Separately, glycerin and hydroxyethyl cellulose were combined with mixing to make a lump free slurry, which was then added to the main vessel with mixing for approximately 20 minutes, until the resulting gel was clear and homogeneous.

Claims

What is claimed is: 1. A topical composition for treating cold sores comprising the combination of therapeutically effective amounts of a topical anesthetic and glycerin in a topically administrable vehicle.
2. A topical composition according to claim 1, wherein the topical anesthetic comprises lidocaine or a pharmaceutically acceptable salt thereof.
3. A topical composition according to claim 1, wherein the topical anesthetic comprises lidocaine hydrochloride.
4. A topical composition according to claim 1, wherein the topical anesthetic comprises lidocaine hydrochloride in an amount of 4 wt.%.
5. A topical composition according to any of the preceding claims which comprises glycerin in an amount of from 20 to 45 wt.%.
6. A topical composition according to any of the preceding claims which comprises glycerin in an amount of 20 wt.%.
7. A topical composition according to any of the preceding claims wherein the topically administrable vehicle comprises an aqueous gel.
8. A topical composition according to claim 7, wherein the aqueous gel comprises a water-soluble derivative of cellulose; a glycol co-solvent; and water.
9. A topical composition according to any of the preceding claims which is free of antiseptics.
10. A topical composition according to claim 8, which is free of quarternary ammonium compounds.
11. A topical composition according to claim 1 comprising:
Figure imgf000018_0001
and optionally, one or more of a preservative, surfactant, antioxidant, and sensate agent.
12. A topical composition according to claim 1, comprising:
Figure imgf000018_0002
13. A method for treating cold sores of a subject in need of said treatment comprising administering a topical composition according to claim 1 to the cold sore-affected skin area of the subject.
14. A method according to claim 13, wherein the cold sore is caused by herpes virus infection.
15. A method for relieving symptoms associated with cold sores in a subject in need thereof which comprises administering a topical composition according to claim 1 to the cold sore affected skin area of the subject.
16. A method for achieving a reduction in cold sore severity in a subject in need thereof, comprising administering a topical composition according to claim 1 to the cold sore affected skin area of the subject.
17. A kit for administering the compositions according to claim 1 for treatment of cold sores, said kit comprising an outer container comprising one or more primary packages together with written instructions to facilitate compliance with the treatment, each of said one or more primary packages containing a topical composition.
PCT/IB2024/056070 2023-06-23 2024-06-21 Topical compositions for treating cold sores WO2024261708A1 (en)

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Citations (4)

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US6565850B2 (en) 1994-11-09 2003-05-20 Amparo Blanco Hemorrhoidal compositions and method of use
US20090048296A1 (en) * 2007-08-17 2009-02-19 Arcion Therapeutics, Inc. High concentration local anesthetic formulations
US20100063004A1 (en) 2006-12-04 2010-03-11 Ranjan Ray Chaudhuri Topical pharmaceutical composition
US20160015731A1 (en) * 2013-03-13 2016-01-21 Nal Pharmaceuticals, Ltd. A topical antiviral composition containing a local anesthetic and method of making the same

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Publication number Priority date Publication date Assignee Title
US6565850B2 (en) 1994-11-09 2003-05-20 Amparo Blanco Hemorrhoidal compositions and method of use
US20100063004A1 (en) 2006-12-04 2010-03-11 Ranjan Ray Chaudhuri Topical pharmaceutical composition
US20090048296A1 (en) * 2007-08-17 2009-02-19 Arcion Therapeutics, Inc. High concentration local anesthetic formulations
US20160015731A1 (en) * 2013-03-13 2016-01-21 Nal Pharmaceuticals, Ltd. A topical antiviral composition containing a local anesthetic and method of making the same

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ANONYMOUS: "Herpecin Pain Relief", 1 April 2021 (2021-04-01), XP093204703, Retrieved from the Internet <URL:https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=beeb6043-6547-4fe9-e053-2995a90a5d74&type=display> [retrieved on 20240916] *

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