Topical regimen for treating cold sores

Abstract

Therapeutic regimens for treating cold sores (fever blisters) associated with herpes infection, and kits therefor.

Description

TOPICAL REGIMEN FOR TREATING COLD SORES

[0001] The present invention is directed to a topical therapeutic regimen for treating cold sores (fever blisters), and kits therefor. 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 (and, 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 ismanifested 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 used to treat herpes. 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 to dry up the blister and its fluid (e.g., Domeboro® (aluminum acetate) astringent solution; calamine (zinc oxide / iron oxide) lotion; witch hazel; and anti-inflammatory agents such as hydrocortisone.

[0008] The present invention provides improvements in the treatment of cold sores by combining docosanol anti-viral treatment with certain symptomatic treatments. The inventive combination has been found to give immediate relief from debilitating cold sore symptoms as well as more rapid progression to cold sore healing.

[0009] The regimen 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. Summary of the Invention

[0010] The invention is directed to a combination therapy for treating cold sores comprising co- administering to a subject in need thereof a therapeutically effective amount of each of the active pharmaceutical ingredients, (a) docosanol (b) a topical anesthetic; and (c) optionally, glycerin, in the same topically administrable vehicle or divided between two or more topically administrable vehicles.

[0011] In a preferred aspect, the invention is directed to a “triple” combination therapy comprising co-administration of the three active ingredients (a), (b) and (c).

[0012] The invention also relates to a kit for administering the treatment regimen to a subject in need thereof, the kit comprising an outer container which comprises one or more primary packages together with written instructions for treatment, each of said one or more primary packages containing a topical product which comprises one or more of active ingredients (a), (b), and optionally (c) in a topically administrable vehicle, said one or more primary packages collectively comprising a therapeutically effective amount of the active ingredients for carrying out the treatment regimen according to the written instructions.

[0013] In one embodiment, the kit comprises a first primary package containing a product comprising the active ingredient, docosanol (a), and a second primary package containing a product comprising, as active ingredients, topical analgesic (b) and glycerin (c).Detailed Description of the Invention

[0014] Unless otherwise indicated, the term “administer” or “co-administer” as used herein with respect to the compositions and methods of the invention refers to topical administration.

[0015] 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).

[0016] "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.

[0017] “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.

[0018] "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.

[0019] / "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.

[0020] "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.

[0021] “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.

[0022] The terms “treat,” “treating” or “treatment” as used herein with reference to active ingredients (b) and (c), have the meaning of providing relief from cold sore symptoms, especially Prodromal Cold Sore Symptoms; and the same terms when used with reference to active ingredient (a) (docosonal) also refer to anti-viral activity against herpes virus.

[0023] By “co-administer“ (or “co-administration”) is meant that the active ingredients are administered either essentially simultaneously to the Cold Sore Affected Skin Area (for example, by being formulated for administration in the same topically administrable vehicle), or sequentially (for example, by being formulated in separate topically administrable vehicles), provided the sequential administration is carried out within a temporal proximity that facilitates the combined therapeutic effect of the actives on the Cold Sore Affected Skin Area.

[0024] In principle, the sequential administration of (a), (b) and optionally (c) to the Cold Sore Affected Skin Area according to the treatment regimens of the invention may be in any order, e.g.: (a) then (b); (b) then (a); (a) then (b) then (c); (a) then (c) then (b); (b) then (a) then (c); (b) then (c) then (a); (c) then (a) then (b); and (c) then (b) then (a).

[0025] In certain embodiments of the treatment regimen of the invention, active ingredients (a) and (b) are co-administered simultaneously to the Cold Sore Affected Skin Area (e.g., by being formulated for administration in the same topically administrable vehicle), preceded or followed by co-administration of active ingredient (c) if present (via separate vehicle); or alternatively, active ingredients (a) and (c) are co-administered essentially simultaneously (e.g., in the same topically administrable vehicle), preceded or followed by co-administration of active ingredient (b) in a separate vehicle; or active ingredients (b) and (c) are administered essentially simultaneously, preceded or followed by co-administration of active ingredient (a) in a separate vehicle.

[0026] In a preferred embodiment, the treatment regimen of the invention comprises essentially simultaneous co-administration of active ingredients (b) and (c) to the Cold Sore Affected Skin Area, preceded or followed by co-administration of active ingredient (a).

[0027] In an even more preferred embodiment, the treatment regimen comprises essentially simultaneous co-administration of active ingredients (b) and (c), followed by co-administration of active ingredient (a).

[0028] The subject is mammalian, especially, human, and includes human adults and children age 12 and over.Docosanol.

[0029] n-Docosanol, also known as 1-docosanol or behenyl alcohol, is a straight chain 22- carbon saturated alcohol, which occurs naturally and has broad activity in cell cultures against lipid enveloped viruses such as herpes HSV-1 and HSV-2, cytomegalovirus, and varicella zoster virus. Data suggest that after cellular incorporation and metabolic conversion, docosanol inhibits viral entry by inhibiting viral fusion with the host cell, blocking nuclear localization and subsequent replication of the virus, see Pope et al., "Anti-herpes simplex virus activity of n- docosanol correlates with intracellular metabolic conversion of the drug," J. Lipid Res.77:2167- 78 (1996). This mechanism of action is different from that of other available treatment options for herpes infections, where antiviral activity results from inhibition of DNA synthesis, see Elion, "Acyclovir: discovery, mechanism of action, and selectivity," J. Med. Virol.1:2-6 (1992).

[0030] By “therapeutically effective amount” of docosanol is an amount sufficient to exert anti- viral activity, especially against herpes virus.

[0031] Docosanol, 10 wt.%, is approved by FDA for the anti-viral treatment of cold sores, and is available without prescription under the tradename Abreva®Cream. Abreva® Cream has been shown to shorten healing by 17.5 hours on average (95% confidence interval: 2 to 22 hours) in a placebo-controlled trial, see Sacks et al. (2001) "Clinical efficacy of topical docosanol 10% cream for herpes simplex labialis: A multicenter, randomized, placebo-controlled trial". J Am Acad Dermatol.45 (2): 222–230. Docosanol also helps to shorten the duration of cold sore symptoms, such as tingling, pain, burning and itching.

[0032] n-Docosanol is a crystalline waxy solid which is insoluble in water, and has typically been formulated as a cream such as Abreva®. See further, U.S. Patent No.5,534,554, which describes formulations comprising a non-ionic surfactant and a carrier to facilitate dermal penetration and interaction at the target cell level); and US Patent Publication No. 2004 / 0033982, both incorporated by reference. For example, a suitable cream may comprise 10 weight percent n-docosanol; about 5 weight percent of a stearate selected from the group consisting of sucrose monostearate, sucrose distearate, and mixtures thereof; about 8 weight percent light mineral oil; about 5 weight percent propylene glycol; about 2.7 weight percent benzyl alcohol; and about 69.3 weight percent water. Alternatively, an overnight topicalcomposition for treating cold sores comprising a film-forming polymer is described in US Patent Publication No.2010 / 0063004, incorporated by reference.

[0033] Abreva® Cream is approved for topical application up to five times a day, for a sufficient number of days until the cold sore is healed, up to 10 days maximum. Abreva Cream is packaged in a tube or pump. According to the instructions, the subject rubs an aliquot of the cream into the Cold Sore Affected Skin Area up to 5 times per day for a maximum of 10 days. A unit dose amount of the product is that amount which is sufficient to completely cover the Cold Sore Affected Skin Area. Topical anesthetic

[0034] A suitable topical anesthetic may be a “caine anesthetic” selected from the group consisting of lidocaine, procaine, ropivacaine, bupivacaine, prilocaine, dibucaine and pharmaceutically acceptable salts and mixtures thereof.

[0035] Examples of “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) lidocaine, or its hydrochloride salt, at a concentration of from 0.5 to 4 wt.%; (d) pramocaine hydrochloride, at a concentration of from 0.5 to 1 wt.%; and (e) tetracaine, or its hydrochloride salt, at a concentration of from 0.5 to 2.0 wt.% , e.g., from 1 to 2 wt.%.

[0036] 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.%.

[0037] Most preferably, the topical anesthetic is lidocaine or lidocaine hydrochloride.

[0038] A therapeutically effective amount of lidocaine or its pharmaceutically acceptable salt, shall be understood to be in the range from 0.5% to 4% by weight, and preferably from about 1 to 4 wt.%, and most preferably, 4 wt.%, of the composition, which is the maximum strength allowed by FDA monograph for skin applications. (All percentages are based on the weight ofthe lidocaine free base or its pharmaceutically acceptable salt, whichever is employed as the active pharmaceutical ingredient.) Glycerin

[0039] By “therapeutically effective amount of glycerin” is meant an amount of glycerin which is generally recognized as safe and effective for topical use as a skin protectant active ingredient according to FDA’s “Over-the-Counter (OTC) Monograph M016: Skin Protectant Drug Products for Over-the-Counter Human Use,” September 24, 2021, M016.10(h).

[0040] Thus glycerin (alternately referred to in the art 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, as provided in the Monograph, 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.%.

[0041] The use of glycerin in an amount sufficient to act as a skin protectant active ingredient (referred to herein as a “therapeutically effective amount” of glycerin) has unexpectedly been found to potentiate skin absorption of the topical anesthetic agent when the active ingredients are solubilized in an aqueous gel vehicle and topically applied to the Cold Sore Affected Skin Area, resulting not only in more rapid Reduction in Cold Sore Severity but also in accelerated Cold Sore Healing.

[0042] Hydration of the skin with glycerin at a concentration of 20 wt.% or greater has also 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.

[0043] 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.Topically Administrable Vehicle

[0044] The topically administrable vehicles of the compositions utilized in the invention include, without limitation, creams, lotions, gels, ointments or pastes, and the like.

[0045] The topical vehicles are preferably free of antiseptics in general, and especially free of quarternary ammonium compounds, e.g., benzalkonium chloride, especially, benzethonium chloride.

[0046] A suitable vehicle for administering active ingredient (a) according to the methods of the invention is a cream, exemplified by Abreva® cream, which comprises the inactive ingredients: benzyl alcohol, light mineral oil, propylene glycol, purified water, sucrose distearate, and sucrose stearate.

[0047] A suitable vehicle for simultaneously administering active ingredients (b) and (c) according to the methods of the invention is an aqueous gel comprising water, a glycol co- solvent, and a gelling agent, as described in co-pending application Docket No.70188US01P, which is incorporated herein by reference. Methods for Carrying out Combination Therapy

[0048] This invention contemplates administering the combination of docosanol and the topical anesthetic, and optionally glycerin, in therapeutically effective amounts, for the treatment of cold sores. The co-administration of a topical anesthetic such as lidocaine hydrochloride with docosanol to a cold-sore afflicted individual has been found to provide synergies in achieving rapid Cold Sore Healing. The addition to this combination of glycerin in a therapeutically effective amount has been found to potentiate not only the symptomatic relief provided by lidocaine, as disclosed in co-pending application Docket No.70188US01P, but also the anti-viral activity of docosanol, as a consequence of increased permeation into the Cold Sore Affected Skin Area. The benefit to the treated individual is immediate relief from often debilitating cold sore symptoms accompanied by reductions in overall healing time.

[0049] A suitable treatment regimen may comprise applying the active ingredients in one or more topically administrable vehicles to the Cold Sore Affected Skin Area at the first sign of lesion formation, typically described as a tingling sensation, and thereafter repeating theadministration over the course of at least about 4 days, and up to about 10 days, depending on speed to healing of the lesion.

[0050] In a triple therapy according to the invention, where active ingredients (b) and (c) are co-administered in an aqueous gel vehicle, and active ingredient (a) is independently administered in a cream, it is preferred that the composition comprising (b) and (c) be applied to the Cold Sore Affected Skin Area and allowed to dry, followed by administration of the composition comprising (a). The composition comprising (a) should be applied within a temporal proximity to administration of (b) and (c) such that the therapeutic effect exerted by all three actives overlaps to at least some extent. For example, active ingredient (a) (docosanol) is best applied within about one hour, and more preferably within about 30 minutes (e.g., within about 10 minutes or within no more than 5 minutes) after the composition comprising (b) and (c) has been applied and allowed to dry on the Cold Sore Affected Skin Area.

[0051] It is contemplated that an aliquot of an aqueous gel composition comprising active ingredients (b) and (c) may be applied by adults and children 12 years or over, on an as needed basis, up to 3 to 4 times per day. Thus a suitable treatment regimen consists of applying active ingredients (b) and (c) in an aqueous gel composition to the Cold Sore Affected Skin Area; allowing the composition to dry; and within a reasonable period thereafter (e.g., within about 10 and preferably within about 5 minutes after drying), applying active ingredient (a) (dosanol) in a cream composition to the Cold Sore Affected Skin Area. Such a regimen may be carried out, for example, up to 4x a day, for up to 10 days. Abreva® Cream (docosanol, 10%) is approved for administration up to 5 times per day up to 10 days; thus the inventive regimen may also optionally include a fifth daily application of active ingredient (a) (docosanol), as needed, for up to 10 days.

[0052] For best results, the treatment regimen should be initiated as soon as the subject experiences Prodromal Cold Sore Symptoms, although in principle the therapy may be initiated at any point during the Cold Sore Event. The compositions may be applied using a finger, cotton swab, or applicator, preferably completely covering the entirety of the Cold Sore Affected Skin Area.Kit

[0053] This invention also relates to a kit for administering the treatment regimens of the invention to a cold-sore afflicted subject, said kit comprising an outer container containing one or more primary packages together with written instructions to facilitate compliance with the regimen, each of said one or more primary packages containing a topical composition which comprises one or more of active ingredients (a), (b), and optionally (c) in a topically administrable carrier, said one or more primary packages collectively containing therapeutically effective amounts of the respective active ingredients for carrying out the regimen.

[0054] The instruction for administering the therapeutic regimen of the invention 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 treatment, and / or one or more applicators.

[0055] All weight percentages recited herein are based on the total composition.

Claims

What is claimed is:

1. A method for treating cold sores comprising co-administering to a subject in need thereof therapeutically effective amounts of the active pharmaceutical ingredients, (a) docosanol; (b) a topical anesthetic; and (c) optionally, glycerin, in one or more topically administrable vehicles.

2. A method according to claim 1, wherein the topical anesthetic comprises a caine anesthetic.

3. A method according to claim 2, wherein the topical anesthetic comprises lidocaine or a pharmaceutically acceptable salt thereof.

3. A method according to claim 1, wherein the topical anesthetic comprises lidocaine hydrochloride.

4. A method according to claim 1, wherein the topical anesthetic comprises lidocaine hydrochloride in the amount of 4 wt.%.

5. A method according to claim 1, which includes glycerin (c) in the amount of 20 wt.%.

6. A method according to any of the preceding claims wherein the topical anesthetic and optional glycerin are co-administered prior to administration of docosanol.

7. A method according to claim 6, wherein the topical anesthetic and optional glycerin are co-administered in a topically administrable vehicle comprising an aqueous gel.

8. A method according to claim 7, wherein the topical anesthetic is co-administered in a topically administrable gel comprising a cream.

9. A kit for administering a regimen for treating cold sores in a subject so afflicted, the kit comprising an outer container containing one or more primary packages together with written instructions to facilitate compliance with the regimen, each of said one or more primary packages containing a topical composition which comprises one or more of active ingredients (a), (b), and optionally (c) in a topically administrable vehicle, said one or more primary packages collectively containing therapeutically effective amounts of the respective active ingredients for carrying out the regimen.

10. A kit according to claim 9, comprising a first primary package containing a topical composition which comprises docosanol in an amount of 10% wt.%, and a second primary package containing a topical composition comprising lidocaine or a pharmaceutically acceptable salt thereof and glycerin in therapeutically effective amounts.

11. A kit according to claim 10, which comprises a first primary package containing a topical composition which comprises docosanol in an amount of 10% wt.%, and a second primary package containing a topical composition comprising lidocaine or lidocaine hydrochloride in an amount of 4 wt.% and glycerin in an amount of 20 wt.%.

12. A kit according to claim 11, wherein the composition comprising docosanol is a cream and the composition comprising lidocaine or a pharmaceutically acceptable salt thereof and glycerin is an aqueous gel.