Composition comprising hinokitiol and zinc salt for use in the treatment of herpes labialis

Abstract

The invention relates to a composition for use in the treatment of symptoms of herpes labialis in a human subject, wherein the treatment comprises topical administration to the skin of said human subject of a composition containing hinokitiol and 0.1-3 wt.% of water-soluble zinc salt. The invention also provides a topical formulation in the form of an emulsion, said formulation comprising: 15-70 wt.% of water; 10-50 wt.% of hydrophobic carrier selected from wax, petroleum jelly, paraffin, triglycerides and combinations thereof; 0.01-1 wt.% of hinokitiol; and 0.1-3 wt.% of water-soluble zinc salt.

Description

[0001] COMPOSITION COMPRISING HINOKITIOL AND ZINC SALT FOR USE IN THE TREATMENT OF HERPES LABIALIS

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to a method of treating symptoms of herpes labialis in a human subject, the treatment comprising topical administration to the skin of said human subject of a composition containing hinokitiol and water-soluble zinc salt

[0004] The invention also relates to a topical formulation in the form of an emulsion comprising hinokitiol and a water-soluble zinc salt.

[0005] BACKGROUND OF THE INVENTION

[0006] Herpes labialis, commonly known as cold sores, is a type of infection by the herpes simplex virus that affects primarily the lip. Symptoms typically include a burning pain followed by small blisters or sores. The first attack may also be accompanied by fever, sore throat, and enlarged lymph nodes. The rash usually heals within ten days, but the virus remains dormant in the trigeminal ganglion. The virus may periodically reactivate to create another outbreak of sores in the mouth or lip. The cause is usually herpes simplex virus type 1 (HSV-1) and occasionally herpes simplex virus type 2 (HSV-2). Attacks can be triggered by sunlight, fever, psychological stress, or a menstrual period.

[0007] Once infected with herpes simplex virus, there is no cure. Antiviral medications may, however, prevent outbreaks or shorten outbreaks if they occur. The long-term use of antivirals may also decrease the risk of further spread.

[0008] A zinc oxide, anesthetic, or antiviral cream can decrease the duration of symptoms of herpes simplex. Antiviral medications may also decrease the frequency of outbreaks.

[0009] Hinokitiol is a natural monoterpenoid found in the wood of trees in the family Cupressaceae. Hinokitiol is a zinc ionophore that aids zinc ions transport into cells. Ionophores are chemical compounds that reversibly bind and transport ions through biological membranes in the absence of a protein pore. Read et al. (The Role of Zinc in Antiviral Immunity, Adv Nutr 2019; 10: 696-710) provide a review that summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. According to the authors, an abundance of evidence has accumulated over the past 50 years to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings.

[0010] WO 2021 / 184070 describes a composition for use in oral care comprising at least one water soluble zinc salt and a zinc ionophore selected from one or more of hinokitiol, quecertin, epigallocatechin, and zincophorin or a salt thereof.

[0011] EP-A 3 169 433 describes a composition for the preventive treatment of fever blisters, including recurring fever blisters, wherein a composition, which comprises a physical UV filter, a zinc salt with antiviral action and an additive suitable for topical application, is preventively applied topically to parts of the face which can be affected by fever blisters.

[0012] Hoang et al. (A possible application of hinokitiol as a natural zinc inophore and anti-infective agent for the prevention and treatment of CO VID-19 and viral infections, Medical Hypotheses, 145 (2020) 110333) is concerned with finding an anti-infective agent for the prevention and treatment of COVID-19 and other viral infections.

[0013] US 10,463,664 relates to inhibitors of HSC nucleotidyl transferases and the use thereof in the treatment and prevention of herpesvirus diseases.

[0014] Ranjbar et al. (Comparative study of serum zinc concentration in recurrent herpes labialis patients and healthy individuals, BMC Oral Health (2020) 20:296) describe a study of serum zinc concentration in recurrent herpes labialis (RHL) patients.

[0015] SUMMARY OF THE INVENTION

[0016] The inventors have unexpectedly discovered that symptoms of herpes labialis may be treated successfully by topical administration of a combination of hinokitiol and water-soluble zinc salt to the skin.

[0017] Accordingly, one aspect of the invention relates to a composition for use in the treatment of symptoms of herpes labialis in a human subject, wherein the treatment comprises topical administration to the skin of said human subject of a composition containing hinokitiol and 0.1-3 wt.% of water-soluble zinc salt.

[0018] Although the inventors do not wish to be bound by theory, it is believed that hinokitiol, when topically applied to the skin, acts as a zinc ionophore, enabling transport into epithelial cells of the zinc ions that are simultaneously provided by the same composition. Zinc is considered to have both a preventive and therapeutic effect on symptoms of herpes labialis.

[0019] The invention also provides a topical formulation in the form of an emulsion, said formulation comprising:

[0020] • 15-70 wt.% of water;

[0021] • 10-50 wt.% of hydrophobic carrier selected from wax, petroleum jelly, paraffin, triglycerides and combinations thereof;

[0022] • 0.01-1 wt.% of hinokitiol; and

[0023] • 0.1-3 wt.% of water-soluble zinc salt.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The invention provides a composition for use in the treatment of symptoms of herpes labialis in a human subject, wherein the treatment comprises topical administration to the skin of said human subject of a composition containing hinokitiol and 0.1-3 wt.% of water-soluble zinc salt.

[0026] The term “skin” as used herein refers to the outer covering of the human body, including hairy and glabrous skin. Mucous membranes, such as oral mucosa, are not encompassed by the term “skin”.

[0027] The term “treatment” as used herein encompasses both therapeutic and prophylactic treatment.

[0028] The term “hinokitiol” as used herein refers to the substance with IUPAC name 2-Hydroxy-6- (propan-2-yl)cyclohepta-2,4,6-trien-1-one, as well as pharmaceutically acceptable salts or hydrates thereof.

[0029] The term “water-soluble zinc salt” as used herein refers to a zinc salt having a solubility in demineralized water at a pH in the range of 4 to 8 of at least 5 g / L, pH of the demineralized water being adjusted using HCI or NaOH. The term “petroleum jelly” as used herein encompasses Vaseline.

[0030] The term “a” or “an” as used herein is defined as “at least one” unless specified otherwise.

[0031] The term “or” as used herein is defined as “and / or” unless specified otherwise.

[0032] Unless indicated otherwise, all percentages mentioned herein should be construed as percentages by weight.

[0033] In a preferred embodiment of the invention, the herpes labialis that is treated in accordance with the present invention is caused by herpes simplex virus type 1.

[0034] The present treatment preferably comprises at least once daily topical administration of the composition to the skin during a period of at least 2 days, more preferably during a period of at least 3 days.

[0035] In one embodiment, the present treatment comprises acute treatment of recurrent herpes labialis during a period of 2 to 20 days, preferably during a period of 3-15 days. According to a particularly preferred embodiment, the treatment comprises acute treatment of recurrent herpes labialis during a period of 2 to 20 days, preferably during a period of 3-15 days.

[0036] The aforementioned acute treatment preferably comprises at least one, more preferably at least two and most preferably three to ten topical administrations to the skin of the composition per day.

[0037] In another embodiment, the present treatment comprises prophylactic treatment of symptoms of herpes labialis during a period of at least 30 days, more preferably of at least 60 days and most preferably of at least 100 days.

[0038] The prophylactic treatment preferably comprises at least once daily topical administration of the composition to the skin. More preferably, the prophylactic treatment comprise one to three topical administrations to the skin per day.

[0039] The composition that is used in the treatment according to the present invention preferably contains 0.01-1 wt.%, more preferably 0.03-0.5 wt.% and most preferably 0.05-0.2 wt.% of hinokitiol. According to a particularly preferred embodiment, the composition of the present invention contains 0.5-2 wt.% of water-soluble zinc salt and most preferably 0.7-1.5 wt.% of water- soluble zinc salt.

[0040] The water-soluble zinc salt, if present in the composition of the present invention, is preferably present in fully dissolved form at a temperature of 20°C.

[0041] The water-soluble zinc salt is preferably selected from zinc sulphate, zinc chloride, zinc acetate, zinc citrate, zinc nitrate, zinc tartrate, zinc maleate, zinc lactate, zinc amino acetate, zinc aspartate, zinc glutamate, zinc propionate, zinc gluconate, zinc butyrate, zinc formate, zinc glyceride, zinc glycolate, zinc ascorbate and combinations thereof.

[0042] According to one particularly preferred embodiment, the water-soluble zinc salt is selected from zinc ascorbate, zinc sulphate and combinations thereof. Most preferably, the water- soluble zinc salt is zinc sulphate.

[0043] The zinc content of the composition of the present invention preferably is at least 0.03 wt.%, more preferably 0.1-1 wt.%, most preferably 0.2-0.6 wt.%.

[0044] In a preferred embodiment, the composition used in the present treatment comprises at least 10 wt.%, more preferably 12-40 wt.% and most preferably 15-32 wt.% of a transdermal penetration enhancer. The transdermal penetration enhancer is preferably selected from mono-alcohols, glycols, fatty acids, esters, sulphoxides and combinations thereof. More preferably, the transdermal penetration enhancer is selected from glycols, fatty acid esters of mono alcohols and combinations thereof.

[0045] In a preferred embodiment, the transdermal penetration enhancer comprises a glycol selected from propylene glycol, dipropylene glycol and combinations thereof. Even more preferably, the transdermal penetration enhancer comprises propylene glycol. According to a particularly preferred embodiment the composition for use in the present treatment contains 2-20 wt.%, more preferably 6-15 wt.% and most preferably 8-12 wt.% of propylene glycol.

[0046] In another preferred embodiment, the transdermal penetration enhancer comprises a fatty acid isopropyl ester. According to a particularly preferred embodiment the composition for use in the present treatment contains 2-25 wt.%, more preferably 6-22 wt.% and most preferably 10-20 wt.% of fatty acid isopropyl ester. Isopropyl myristate is an example of a fatty acid isopropyl ester that may suitably be used in the present composition.

[0047] According to a particularly preferred embodiment, the present composition contains a combination of two transdermal penetration enhancers, i.e. propylene glycol and fatty acid isopropyl ester.

[0048] In yet another preferred embodiment, the transdermal penetration enhancer comprises a fatty alcohol. Preferably, the composition contains 1-15 wt.%, preferably 2-10 wt.% of fatty alcohol. The fatty alcohol preferably is an aliphatic unbranched primary alcohol comprising 10-20 carbon atoms. More preferably, the fatty alcohol is selected from lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and combinations thereof.

[0049] In another advantageous embodiment, the composition of the present invention contains 0.1- 5 wt.% of a tocopherol component selected from tocopherol, tocopherol ester and combinations thereof. Even more preferably, the composition contains 0.1-5 wt.%, more preferably 0.2-3 wt.% and most preferably 0.3-2 wt.% of a tocopherol component selected from alpha-tocopherol, alpha-tocopherol ester and combinations thereof. Examples of tocopherol esters that may be applied in accordance with the present invention include tocopherol acetate.

[0050] The composition for use in the present treatment preferably contains 2-20 wt.%, more preferably 5-15 wt.% and most preferably 7-12 wt.% of nanoparticles of inorganic UV filter. Examples of inorganic UV filters that may be employed include inorganic oxides. Preferably, the nanoparticles of inorganic UV filter contain at least 50 wt.%, more preferably at least 80 wt.% and most preferably at least 90 wt.% of inorganic oxide selected from titanium dioxide, zinc oxide and combinations thereof.

[0051] The composition for use in the present treatment preferably is a cream, a gel, an ointment or a lotion.

[0052] According to a particularly preferred embodiment, the composition used in the present treatment contains 10-70 wt.% water, more preferably 20-60 wt.% water and most preferably 25-50 wt.% water.

[0053] According to a particularly preferred embodiment, the composition used in the treatment is an emulsion comprising an aqueous phase and an oil phase. Preferably, the aqueous phase constitutes 25 to 75 wt.% of the composition and the oil phase constitutes 75 to 25 wt.% of the composition. More preferably, the aqueous phase constitutes 30 to 70 wt.% of the composition and the oil phase constitutes 70 to 30 wt.% of the composition. The combination of aqueous phase and oil phase preferably constitutes at least 90 wt.%, more preferably at least 95 wt.% of the composition.

[0054] The composition used in the present treatment, especially in the treatment of herpes labialis, preferably has a sun protection factor (SPF) of at least 5, more preferably of at least 10 and most preferably of 15 to 50.

[0055] In the present treatment, hinokitiol is preferably topically applied to the skin in a dosage of 0.1 to 50 g / cm2, more preferably in a dosage of 0.5 to 20 pg / cm2and most preferably in a dosage of 1 to 10 pg / cm2. Here the dosage equals the total amount of hinokitiol that is topically applied to the skin, divided by the by surface area across which it is applied.

[0056] In a preferred embodiment of the present invention the treatment comprises topical administration of the composition onto the face or onto the genitals of the human subject. In a particularly preferred embodiment the composition is topically administered onto the upper and / or lower lip of the human subject.

[0057] In another embodiment of the present invention, the herpes infection that is treated is herpes keratitis and the composition is administered into an eye of the human subject.

[0058] In the treatment of herpes keratitis, the composition that is applied preferably is an aqueous liquid.

[0059] The composition that is applied in the treatment of herpes keratitis preferably has a water content of at least 80 wt.%, more preferably of at least 90 wt.% and most preferably of at least 92 wt.%.

[0060] Another aspect of the invention relates to a topical formulation in the form of an emulsion, said formulation comprising:

[0061] • 15-70 wt.% of water;

[0062] • 10-50 wt.% of hydrophobic carrier selected from wax, petroleum jelly, paraffin, triglycerides and combinations thereof;

[0063] • 0.01-1 wt.% of hinokitiol; and

[0064] • 0.1-3 wt.% of water-soluble zinc salt. The topical formulation typically contains 20-60 wt.% more preferably 25-50 wt.% water.

[0065] The hydrophobic carrier is preferably contained in the topical formulation in a concentration of 12-35 wt.%, more preferably of 13-25 wt.%.

[0066] The combination of water and hydrophobic carried preferably constitutes 40-80 wt.%, more preferably 45-65 wt.% of the topical formulation.

[0067] The topical formulation of the present invention preferably comprises a continuous aqueous phase and a dispersed hydrophobic phase.

[0068] Preferably, the topical formulation of the present invention comprises 0.03-0.5 wt.%, most preferably 0.05-0.2 wt.% of hinokitiol.

[0069] The topical formulation preferably contains 0.5-2 wt.% of water-soluble zinc salt and most preferably 0.7-1.5 wt.% of water-soluble zinc salt.

[0070] The water-soluble zinc salt is preferably present in the formulation in fully dissolved form at a temperature of 20°C.

[0071] The water-soluble zinc salt is preferably selected from zinc sulphate, zinc chloride, zinc acetate, zinc citrate, zinc nitrate, zinc tartrate, zinc maleate, zinc lactate, zinc amino acetate, zinc aspartate, zinc glutamate, zinc propionate, zinc gluconate, zinc butyrate, zinc formate, zinc glyceride, zinc glycolate, zinc ascorbate and combinations thereof.

[0072] According to one particularly preferred embodiment, the water-soluble zinc salt is selected from zinc ascorbate, zinc sulphate and combinations thereof. Most preferably, the water- soluble zinc salt is zinc sulphate.

[0073] The zinc content of the topical formulation preferably is at least 0.03 wt.%, more preferably 0.1-1 wt.%, most preferably 0.2-0.6 wt.%.

[0074] In a preferred embodiment, the topical formulation contains a transdermal penetration enhancer. The transdermal penetration enhancer is preferably selected from mono-alcohols, glycols, fatty acids, esters, sulphoxides and combinations thereof. More preferably, the transdermal penetration enhancer is selected from glycols, fatty acid esters of mono alcohols and combinations thereof.

[0075] In a preferred embodiment, the transdermal penetration enhancer comprises a glycol selected from propylene glycol, dipropylene glycol and combinations thereof. Even more preferably, the transdermal penetration enhancer comprises propylene glycol. According to a particularly preferred embodiment the topical formulation contains 2-20 wt.%, more preferably 6-15 wt.% and most preferably 8-12 wt.% of propylene glycol.

[0076] In another preferred embodiment, the transdermal penetration enhancer comprises a fatty acid isopropyl ester. According to a particularly preferred embodiment the topical formulation contains 2-25 wt.%, more preferably 6-22 wt.% and most preferably 10-20 wt.% of fatty acid isopropyl ester. Isopropyl myristate is an example of a fatty acid isopropyl ester that may suitably be used in the present composition.

[0077] According to a particularly preferred embodiment, the present composition contains a combination of two transdermal penetration enhancers, i.e. propylene glycol and fatty acid isopropyl ester.

[0078] In yet another preferred embodiment, the transdermal penetration enhancer comprises a fatty alcohol. Preferably, the topical formulation contains 1-15 wt.%, preferably 2-10 wt.% of fatty alcohol. The fatty alcohol preferably is an aliphatic unbranched primary alcohol comprising 10-20 carbon atoms. More preferably, the fatty alcohol is selected from lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol and combinations thereof.

[0079] The topical formulation preferably contains 0.1-5 wt.% of a tocopherol component selected from tocopherol, tocopherol ester and combinations thereof. Even more preferably, the formulation contains 0.1-5 wt.%, more preferably 0.2-3 wt.% and most preferably 0.3-2 wt.% of a tocopherol component selected from alpha-tocopherol, alpha-tocopherol ester and combinations thereof. Examples of tocopherol esters that may be applied in accordance with the present invention include tocopherol acetate.

[0080] The topical formulation preferably contains 2-20 wt.%, more preferably 5-15 wt.% and most preferably 7-12 wt.% of nanoparticles of inorganic UV filter. Examples of inorganic UV filters that may be employed include inorganic oxides. Preferably, the nanoparticles of inorganic UV filter contain at least 50 wt.%, more preferably at least 80 wt.% and most preferably at least 90 wt.% of inorganic oxide selected from titanium dioxide, zinc oxide and combinations thereof.

[0081] Preferably, the topical formulation contains a UV absorber, more preferably a UV absorber selected from triazine, a benzotriazole, a vinyl group-containing amide, a cinnamic acid amide, a sulfonated benzimidazole or a combination thereof. Most preferably, the UV absorber is a triazine.

[0082] The topical formulation of the present invention may suitably contain additional ingredients, such as preservatives, anti-oxidants, emulsifiers, co-solvents, skin conditioners, colourants and fragrance.

[0083] The topical formulation of the present invention preferably is a cream or an ointment.

[0084] The topical formulation of the present invention preferably has a sun protection factor (SPF) of at least 5, more preferably of at least 10 and most preferably of 15 to 50.

[0085] The invention is further illustrated by the following non-limiting examples.

[0086] EXAMPLES

[0087] Example 1

[0088] A cream formulation for the treatment of herpes labialis was compounded on the basis of the recipe that is shown in Table 1.

[0089] Table 1

[0090] 1UV filter containing bis-ethylhexyloxyphenol methoxyphenyl triazine, ex BASF

[0091] The oil phase and the water phase were prepared separately and stirred until homogeneity. After heating both phases to 80 °C, they were combined under high-shear mixing (Ultraturrax, 10,000 rpm). Subsequently the composition was cooled to below 30 °C and the cream so obtained was filled into tubes.

[0092] Example 2

[0093] A blind cross-over study was performed with 6 subjects who had a history of recurrent herpes labialis.

[0094] During the study, the subjects were provided with 3 different creams which they administered once daily onto the upper and lower lip.

[0095] The compositions of the three 3 creams are shown in Table 2. Table 2

[0096] The treatment schedule of the cross-over study is shown in Table 3. Table 3

[0097] During the treatment periods, the recurrence of herpes labialis was monitored and each recurring episode was recorded. In Table 4 the number of recurrences during each of the three different treatment periods are listed.

[0098] Table 4 Example 3

[0099] A study is performed to determine effect on herpes labialis relapses during six months of prophylactic and acute treatment, using the cream of Example 1.

[0100] Subject selection

[0101] A total of 20 patients are recruited (Visit 1). Male and female adult patients with a history of recurrent herpes labialis are recruited for the study. Patients are enrolled in the study if they fulfilled the following inclusion criteria:

[0102] • 18 to 50 years of age;

[0103] • Medical history of herpes labialis with lesions on the lips or in the perioral area (<1 cm from the border of the lips);

[0104] • At least eight recurrences of herpes labialis during the previous year before being enrolled in the study;

[0105] Patients who fulfilled any one of the following criteria are excluded from the study:

[0106] • Females with child bearing potential who are not using a reliable, medically accepted method of birth control (e.g., surgical, intra-uterine contraceptive device, birth control pill, double barrier, hormone delivery systems such as implants or injectibles, condoms or diaphragm (each in combination with contraceptive creams, foams, etc.);

[0107] • Pregnant or breast feeding females, or women planning a pregnancy during the trial;

[0108] • Medical history of immunosuppression by radiotherapy, chemo therapy, immunomodulatory drugs, or HIV;

[0109] • Participation in another clinical study within 30 days prior to beginning of this study;

[0110] • Medical history of any severe diseases like hepatitis, renal or liver dysfunction, cardiovascular, gastrointestinal, malignant tumor(s), or psychiatric disorders etc., which might influence the assessments or conduct of the trial;

[0111] • Intake or application of antivirals or other prohibited concomitant medication within 30 days prior to the beginning of this study, or intention to take such drugs during the trial;

[0112] • Use of anti-inflammatory medications and steroids during the course of the study;

[0113] • Eczema herpeticatum or any history of other skin disease that would predispose to eczema herpeticatum;

[0114] • Any abnormal perioral skin condition;

[0115] • Medical history of alcohol and / or drug abuse within the previous 12 months before enrolment in the study. Study Design

[0116] Patients are not informed of the chemical content of the cream used in the study.

[0117] The study covers a period of 12 months, including 6 months of continuous treatment with the cream of Example 1 and 6 months of no treatment. Ten patients start with 6 months of treatment followed by 6 months of no treatment. The other ten patients start with 6 months of no treatment followed by 6 months of treatment.

[0118] The first application of cream is performed by the patient at the study site on the second visit (Visit 2), under the supervision of an investigator.

[0119] If a patient has an acute relapse of recurrent herpes labialis at Visit 2, cream is then administered 5 times a day for 14 days (acute dosing) over the whole lips. Each time cream is applied on the upper lip and on the lower lip (both together ca. 0.2 g). After these 14 days, the cream is applied twice daily, for 6 months (the 14 days of acute treatment are included in these 6 months) over the whole lips (prophylaxis dosing). In case of no current relapse at Visit 2, cream is applied twice daily, for 6 months, over the whole lips.

[0120] To check the compliance and any herpes symptoms during the whole study, the patient is asked to record all applications and any symptoms into a diary. In addition, the patient is asked to fill in a visual analogue scale (VAS) to record pain levels at the end of each day of the acute herpes relapse episode.

[0121] During the treatment period, all relapses are treated as soon as the first symptoms (prodromal symptoms such as: feeling of tension, hypersensitivity of the skin, tingling, burning, and itching) occur for 14 days with cream 5 times a day.

[0122] During an acute phase (relapse), patients are asked to come to the study site for visits on day 1 (within 24 hours after first symptoms), day 5, day 10 and day 14. During the visit on day 1 , an examination is conducted by the investigator, which included: recording the location of the lesion, measurement of the lesion, judgement of the state of lesion (erythema, papule, vesicle, ulcerated, eroded, hard crusted, dry flaking, residual swelling, healed and associated with pain). On day 15, the prophylaxis period starts again with two applications daily until the next relapse or the end of the study (6 months). During the prophylaxis period, the patients are required to visit the study site every 60 days (Visits 3 to 5) for control examination and to receive study medication. Visit 5 is the final examination visit (end of the study). The final examination includes a physical examination of the skin (especially perioral region)..

[0123] For each individual patient the following data are documented for both the treatment period and the no treatment period:

[0124] • Number of herpes relapses

[0125] • Maximal Lesion Area. The lesion area is defined as the product of the length and the width. For measuring this, a caliper is used. The results are noted in mm2along with the observed stage. The maximal lesion area is determined at every visit during a herpes relapse episode.

[0126] • Determination of the Duration. For determining the duration of an episode, the days from the first prodromal signs of cold sore until complete healing are counted. Healing is defined as the loss of crust (residual erythema may be present) and / or the cessation of all symptoms. The last remaining effect (either normal skin or cessation of all symptoms) is recorded and used as the endpoint of lesion duration.

[0127] • Determination of the Degree of Pain / Discomfort. For determining the degree of pain during a relapse, a 100 mm visual analogue scale (VAS) is used (where 0 indicated no pain and 10 indicated unbearable pain). During the whole relapse time (14 days) patients mark on the VAS at the end of every day, the level of pain that they have experienced within the past 24 hours (only regarding their cold sore).

[0128] Results

[0129] The data obtained from the investigation show that treatment with the cream of Example 1 significantly reduced the number of relapses of herpes labialis per year.

[0130] The data also show that treatment with the cream reduced the duration of the relapse, the maximal lesion area and the degree of pain / discomfort experienced during the relapse.

Claims

CLAIMS1. A composition for use in the treatment of symptoms of herpes labialis in a human subject, wherein the treatment comprises topical administration to the skin of said human subject of a composition containing hinokitiol and 0.1-3 wt.% of water-soluble zinc salt.

2. Composition for use in the treatment according to claim 1 , wherein the herpes labialis is caused by herpes simplex virus type 1.

3. Composition for use in the treatment according to claim 1 or 2, wherein the composition is topically administered onto the upper and / or lower lip of the human subject.

4. Composition for use in the treatment according to any one of the preceding claims, wherein the wherein the composition contains 0.01-1 wt.% of hinokitiol.

5. Composition for use in the treatment according to any one of the preceding claims, wherein the composition contains 0.5-2 wt.% of water-soluble zinc salt.

6. Composition for use in the treatment according to any one of the preceding claims, wherein the water-soluble zinc salt is selected from zinc sulphate, zinc chloride, zinc acetate, zinc citrate, zinc nitrate, zinc tartrate, zinc maleate, zinc lactate, zinc amino acetate, zinc aspartate, zinc glutamate, zinc propionate, zinc gluconate, zinc butyrate, zinc formate, zinc glyceride, zinc glycolate, zinc ascorbate and combinations thereof.

7. Composition for use in the treatment according to any one of the preceding claims, wherein the composition contains 10-70 wt.% water.

8. Composition for use in the treatment according to any one of the preceding claims, wherein the composition comprises 10-50 wt.% of hydrophobic carrier selected from wax, petroleum jelly, paraffin, triglycerides and combinations thereof.

9. A topical formulation in the form of an emulsion, said formulation comprising:• 15-70 wt.% of water;• 10-50 wt.% of hydrophobic carrier selected from wax, petroleum jelly, paraffin, triglycerides and combinations thereof;• 0.01-1 wt.% of hinokitiol; and• 0.1-3 wt.% of water-soluble zinc salt.

10. Topical formulation according to claim 9, wherein the water-soluble zinc salt is selected from zinc sulphate, zinc chloride, zinc acetate, zinc citrate, zinc nitrate, zinc tartrate, zinc maleate, zinc lactate, zinc amino acetate, zinc aspartate, zinc glutamate, zinc propionate, zinc gluconate, zinc butyrate, zinc formate, zinc glyceride, zinc glycolate, zinc ascorbate and combinations thereof.

11. Topical formulation according to claim 9 or 10, wherein the formulation contains 2-20 wt.% of propylene glycol.

12. Topical formulation according to any one of claims 9-11 , wherein the formulation contains 2-25 wt.% of fatty acid isopropyl ester.

13. Topical formulation according to any one of claims 9-12, wherein the formulation contains propylene glycol and fatty acid isopropyl ester.

14. Topical formulation according to any one of claims 9-13, wherein the formulation contains 0.1-5 wt.% of a tocopherol component selected from tocopherol, tocopherol ester and combinations thereof.

15. Topical formulation according to any one of claims 9-14, wherein the formulation contains 2-20 wt.% of nanoparticles of inorganic UV filter.

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