Composition comprising terbinafine and a polymer for use in the treatment of onychomycosis

Abstract

The present invention relates to a composition for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand in the range of about 100µg to about 1mg of terbinafine. The invention also relates to a combination of the composition and a liquid dispensing device for dispensing a pre-defined quantity of the composition to a user's toes and / or inter-digital spaces and / or the foot or hand.

Description

[0001] COMPOSITION COMPRISING TERBINAFINE AND A POLYMER FOR USE IN THE TREATMENT OF ONYCHOMYCOSIS

[0002] Technical Field of the Invention

[0003] The invention relates to compositions (and methods of producing such compositions) comprising nanoparticles formed of a polymer and terbinafine. Such compositions are particularly suited, but not limited, to the treatment of fungal nail and / or skin infections.

[0004] Background to the Invention

[0005] Fungal infections are increasingly common in both human and animals, yet the treatment of such infections remains problematic due to toxicity of the antifungal compositions, poor solubility of these compositions and the remote location of some infections which can prove difficult to reach using traditional medicinal formulations.

[0006] A broad spectrum of antifungals such as amphotericin B, hamycin, filipin and nystatin were discovered in 1960s. But due to toxicity only hamycin and nystatin are used topically and amphotericin B systemically. A breakthrough in antifungal therapy was the introduction of azoles especially ketoconazole. The major classes of antifungals currently used are polyenes, azoles allyl amines, lipopeptides, and pyrimidines. However, polyenes are toxic to mammalian cells. Azoles are well tolerated topically but have side effects when given systemically and there have been several reports of resistance to azoles. Flucytosine is the most common pyrimidine used. Whilst it has excellent tissue penetration, resistance against flucytosine can develop rapidly and produce gastro intestinal side effects. Lipopetides display low toxicity and several trials are still on going to test efficacy.

[0007] The development of new antifungals is constrained because fungi are eukaryotic and cellular targets, if disrupted, can also damage host cells. The increase in fungal infections and increase in use of antifungals has resulted in emergence of resistance among fungi. Anti- fungal resistance has high clinical impact as fungal diseases are causing an increase in morbidity and mortality of immunocompromised patients.

[0008] It is estimated that around 40% of newly discovered drugs fail due to lack of proper delivery because of aqueous solubility problems. In the case of topical delivery of drugs, the barrier properties of skin often require permeation enhancers to achieve the required dose of drugs.

[0009] Onychomycosis (more commonly known as fungal nail infection) causes nails to thicken, discolor, disfigure, and split. Without treatment, the nails can become so thick that they press against the inside of shoes, causing pressure, irritation, and pain. There are risks for further complications especially in patients with diabetes, those with peripheral vascular disease and the immunocompromised patient. Fungal nail infection may cause psychological and social problems. The incidence of fungal nail infection increases with age and has a prevalence of -30% of the over 60s with significant incidence in Europe with even higher levels in Asia. Fungal nail infection may affect one or more toenails and / or fingernails and can completely destroy the nail if left untreated.

[0010] The current treatment for fungal nail infection is as topical nail lacquer / paint (such as amorolfine) 1-2 times per week for 6-12 months and / or oral antifungals (such as terbinafine or itraconazole). Oral antifungals can have severe side effects such as gastro-intestinal upset and can even result in liver failure. Relapse is commonly reported and many patients will not commit to the treatment course due to predicted side effects and length of treatment time and often only when disease becomes more aggressive will treatment begin. Current oral or topical treatments can take 6-12 months to work. Oral treatments have to saturate the systemic circulation to reach the toes and the increased doses increases the risk to the gastro-intestinal and liver complications. Topical treatments are ineffective at penetrating the thickened nail and again require high dosing. WO2019 / 002862 discloses a composition for use in the treatment of onychomycosis, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an infected area in the range of about 5pg to about 50pg of terbinafine.

[0011] An object of the present invention is to address one or more of the above problems associated with current anti-fungal treatments. One object of the present invention is to provide a topical anti-fungal treatment. Another object of the present invention is to provide a treatment which allows for better penetration of an anti-fungal agent through the nail and / or dermis. A further objective is to provide an effective dose of active ingredient in a topical anti-fungal treatment to treat onychomycosis. It is desirable if the present invention could be used as a treatment for addressing onychomycosis and also be easily applied resulting in a high treatment adherence and have a low re-occurrence rate.

[0012] Summary of the Invention

[0013] In accordance with the present invention, there is provided a composition for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of each foot and / or hand and / or digit and / or the inter-digital spaces in the range of about 100pg to about 1mg of terbinafine.

[0014] In accordance with a further alternative first aspect of the present invention, there is provided a composition for use as a medicament, for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand in the range of about 100pg to about 1 mg of terbinafine.

[0015] In accordance with a yet further alternative first aspect of the present invention, there is provided use of a composition for the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of the digits and / or the interdigital spaces and / or each foot and / or hand in the range of about 100pg to about 1 mg of terbinafine.

[0016] In accordance with yet another further alternative first aspect of the present invention, there is provided use of a composition for the manufacture of a medicament for the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand in the range of about 100pg to about 1 mg of terbinafine.

[0017] In accordance with yet another further alternative first aspect of the present invention, there is provided a method of treating onychomycosis in a foot and / or hand of a patient, by topically administering to a patient in need thereof, a composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered in a daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand in the range of about 100pg to about 1mg of terbinafine.

[0018] Alternatively, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 50 pg to 1 mg. Preferably, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 75 pg to about 1 mg. Preferably, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 300pg to about 1mg. Most preferably, the daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is about 1 mg. Alternatively, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 50 pg to about 300 pg. Alternatively, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 75 pg to about 300 pg. Alternatively, the daily dose to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand of terbinafine is in the range of about 100 pg to about 300 pg.

[0019] The term “daily dose” is intended to mean the quantity of terbinafine which is topically applied to an affected area of the digits and / or the inter-digital spaces and / or foot and / or hand, of an individual or animal suffering from onychomycosis. It is envisaged that more than one area of the individual or animal may be affected with onychomycosis and therefore require separate doses of the composition. Typically, both feet and / or hands will be treated at the same time. When both feet and / or hands are treated at the same time the daily dose is intended to be the daily dose applied to each foot or hand. The daily dose will preferably consist of a topical application twice daily (such as once in the morning and once in the evening).

[0020] The daily dose may comprise up to about 10 spray applications (i.e. about 5 spray applications in the morning and about 5 spray applications in the evening).

[0021] In accordance with another aspect of the present invention, there is provided a composition for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof, and wherein the composition is administered topically by means of a spray application using one or more spray applications to provide a daily spray dose of up to about 1 mg of terbinafine to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand.

[0022] Preferably, the daily spray dose comprises up to about 10 spray applications, with up to about 5 spray applications administered twice a day. It is preferred that both feet and / or hands are treated at the same time.

[0023] The spray will preferably be effective to cover the digits and / or the inter-digital spaces and / or the foot and / or hand.

[0024] Each spray application may dispense up to about 100 mg of liquid.

[0025] The composition may be atomised during each spray application. The spray application may be administered by means of a pump-action spray device or a metered aerosol spray device. The pump-action spray device may be a metered pump-action spray device. The metered pump-action or metered aerosol spray device may be set to dispense 100 pL of liquid in each pump or spray of the device. Both the pump-action and aerosol spray devices are those that dispense the correct metered volume of liquid whether the device is used upright or in any other orientation including upside down.

[0026] There are many examples of metered pump-action and metered aerosol spray devices suitable for use with the composition of the invention and that are available to the skilled person.

[0027] The daily dose may be for administration for up to about 48 weeks, up to about 36 weeks, up to about 12 weeks, or up to about 4 weeks.

[0028] In accordance with a further aspect of the present invention, there is provided a combination of a composition for use in the treatment of onychomycosis in a foot and / or hand of an individual and a composition dispensing device for dispensing a pre-defined quantity of composition to the digits and / or the inter-digital spaces and / or foot and / or hand of an individual, the device comprising a vessel containing the composition, an atomising nozzle, and an actuation arrangement operable by the user to dispense the predefined quantity of composition from the vessel via the nozzle, thereby atomizing the composition, wherein the composition comprises a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof, and wherein the pre-defined quantity of the composition contains terbinafine in the range of about 1Opg to about 100pg per actuation of the dispensing device.

[0029] The pre-defined quantity of the composition may comprise about 10OpI of liquid.

[0030] The actuation arrangement may be a pump-action spray device or a metered aerosol spray device.

[0031] The spray should be effective to cover the entire affected area, digits and / or the interdigital spaces and / or front of the foot and / or hand so as to be able to treat onychomycosis and surrounding area. The composition as herein above described, and the composition of the combination may comprise: a) terbinafine, or derivative or salt thereof, tin an amount in the range of 0.01 % w / v to about 0.1 % w / v; and b) a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the polymer is present in an amount of about 0.03% w / v to about 0.3%

[0032] The composition may further comprise up to about 30% (w / v) alcohol. Alternatively, the composition may further comprise alcohol at between about 20% (w / v) and about 30% (w / v). Alternatively, the composition may further comprise alcohol at up to about 20% (w / v). Preferably the alcohol is present in the composition at about 20% (w / v).

[0033] The polymer may comprise one or more of polyhexamethylene biguanide (PHMB), polyhexamethylene monoguanide (PHMG), polyethylene biguanide (PEB), polytetramethylene biguanide (PTMB) or polyethylene hexamethylene biguanide (PEHMB).

[0034] Thus, the polymer may comprise homogeneous or heterogeneous mixtures of one or more of polyhexamethylene biguanide (PHMB), polyhexamethylene monoguanide (PHMG), polyethylene biguanide (PEB), polytetramethylene biguanide (PTMB), polyethylene hexamethylene biguanide (PEHMB), polymethylene biguanides (PMB), poly(allylbiguanidnio- co-allylamine), poly(N-vinylbiguanide), polyallybiguanide.

[0035] The most preferred polymer comprises polyhexamethylene biguanide (PHMB).

[0036] The term “terbinafine, or derivative or salt thereof” is intended to mean the pharmaceutically active substance related to terbinafine hydrochloride, which is a synthetic allylamine antifungal originally marketed under the trade name Lamisil®. The term is also intended to include pharmaceutical variations, derivatives, alternative salts, of terbinafine hydrochloride such as non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable form.

[0037] The alcohol will preferably comprise ethanol, although it may comprise (whether alone or in combination with) other alcohols such as methanol or propanol.

[0038] The composition may also comprise water. The water will preferably be purified, for example the water may be distilled water. The water may be present in an amount in a formulation in the range of about 70% to about 95% (v / v). Preferably, the water will be in a formulation in an amount in the range of about 70% to about 90% (v / v). More preferably, the water will be in a formulation in an amount in the range of about 70% to about 80% (v / v). Yet more preferably, the water will be in a formulation in an amount over about 77% (v / v). Most preferably, the water is in a formulation in an amount up to about 90% (v / v), up to about 80% (v / v) or up to about 79.6% (v / v).

[0039] Preferably, the water may be present in an amount in a formulation in the range of about 70% to about 95% (w / v). Preferably, the water will be in a formulation in an amount in the range of about 70% to about 90% (w / v). More preferably, the water will be in a formulation in an amount in the range of about 70% to about 80% (w / v). Yet more preferably, the water will be in a formulation in an amount over about 77% (w / v). Most preferably, the water is in a formulation in an amount up to about 90% (w / v), up to about 80% (w / v) or up to about 79.6% (w / v).

[0040] It will be apparent to the skilled addressee that the composition may further comprise one or more of the following components: buffers, excipients, binders, oils, solvents, water, emulsifiers, glycerin, antioxidants, preservatives and fragrances or any additional components usually found in medicaments.

[0041] A number of techniques may be employed to further process the mixture so as to select the nanoparticles in the required size ranges, such as centrifugation, electrophoretic, chromatographic or filtration methods. The measurement of the size / diameter of the nanoparticles is preferably conducted using dynamic light scattering analysis.

[0042] The composition dispensing device may further comprise a metering valve, through which the pre-defined quantity of composition is dispensed. It is preferred that the pre-defined quantity of composition comprises up to about 100 pl.

[0043] The composition dispensing device may further comprise and / or be associated with a distance indicator or measurement device to indicate the correct distance the user should place the nozzle of the device relative to the infected area (such as their digits and / or inter-digital spaces and / or front of the foot or hand or limb).

[0044] The composition according to the invention may be formulated into a number of different formulations with differing concentrations of each component. Example formulations are included below:

[0045] Example formulation A:

[0046] Example formulation B:

[0047]

[0048] Example formulation C:

[0049] Example formulation D: Example formulation E:

[0050] Detailed Description of the Invention

[0051] Embodiments of the present invention will now be described, by way of example only, with reference to the following experiments and accompanying figures, in which:

[0052] Figure 1 is a bar graph showing the data from a clinical trial in which the nails of patients with confirmed fungal nail infections were sprayed daily for 12 weeks with compositions comprising either BB2603 (terbinafine and PHMB nanoparticles, i.e. nanoparticles that comprise both terbinafine and PHMB and are a complex of terbinafine and PHMB) or with a negative control (PHMB without terbinafine) (Vehicle). Patients treated with BB2603 were given one of three different compositions containing different concentrations of terbinafine. These different concentrations were equivalent to a daily dose per foot of 100 pg, (BB2603 - 1), 300 pg (BB2603-3), or 1 mg (BB2603-10) terbinafine. As is common with infections affecting the foot and / or hands, patients were instructed to treat both feet with the same daily dosage. The left-hand bar of each treatment group represents the percentage of patients with fungal negative cultures after completing 12 weeks of treatment (End of treatment). The right- hand bar of each treatment group represents the percentage of patients with fungal negative cultures sixteen weeks after the start of treatment. The results show that the percentage of patients with negative cultures increased when treated with an increased daily dose of terbinafine at both 12 and 16 weeks .

[0053] Figure 2 is a swim lane analysis table showing the results of a clinical trial in which the nails of patients with confirmed fungal nail infections were sprayed daily for 12 weeks with compositions comprising either BB2603-10 (terbinafine and PHMB nanoparticles providing a daily dose of 1 mg terbinafine) or with a negative control (PHMB without terbinafine) (Vehicle). Each box of the table represents the recorded mycological effects of treatment on an individual patient at a given time point. Each row of each table represents a different patient. Each column of each table represents a different time point before or after treatment, with the second column being the end of treatment and the far-right column representing 9 months after treatment.

[0054] Figure 3 is a line graph showing the results of a clinical trial in which the nails of patients with confirmed fungal nail infections were sprayed daily for 12 weeks with compositions comprising BB2603-10 (terbinafine and PHMB nanoparticles) to provide a daily dose to each foot of 1 mg terbinafine. The results show that over 85% of patients exhibited fungal negative cultures immediately after treatment (12 weeks) which decreased to about 64% after 52 weeks. The results also show a 20-30% increase in the percentage of patients that were confirmed as KOH negative from 12 to 52 weeks, and a 15-20% increase in the percentage of patients that were confirmed as mycologically cured in the same period.

[0055] Figure 4 is a line graph showing the results of a clinical trial in which the nails of patients with confirmed fungal nail infections were sprayed daily for 12 weeks with compositions comprising PHMB without terbinafine (vehicle). The results show no significant difference between the percentage of patients that exhibited fungal negative cultures immediately after treatment (12 weeks) or at any point up to week 52. Additionally, there was no significant difference between the percentage of patients that were confirmed as KOH negative or mycologically cured immediately after treatment, or at any point up to 52 weeks.

[0056] Examples

[0057] Human Trials

[0058] A human volunteer study was conducted to establish the efficacy, safety, and systemic exposure, elicited by topically administering compositions comprising nanoparticles of PHMB and terbinafine in amounts of up to 1 mg / day of terbinafine per foot.

[0059] The study was carried out as a randomised, double-blinded trial comprising a four-arm parallel assignment intervention model. Each group was topically administered twice daily with one of the following compositions: Vehicle, BB2603-1. BB2603-3 and BB2603-10. All four compositions comprised a polyhexanide / 20% ethanol / water formulation. BB2603-1 , BB2603- 3 and BB2603-10 further comprised 0.01% w / v, 0.03% w / v, and 0.1 % w / v of terbinafine respectively.

[0060] The treatments under study were as follows:

[0061] Per Pump / Actuation:

[0062] BB2603-10: 0.1 % w / v terbinafine - 100 pL pump = 100 pg terbinafine per pump. BB2603-3: 0.03% w / v terbinafine - 100 pL pump = 30 pg terbinafine per pump. BB2603-1 : 0.01% w / v terbinafine - 100 pL pump = 10 pg terbinafine per pump.

[0063] • Each composition had 300 pg, 90 pg or 30 pg polyhexanide respectively per pump actuation (0.3% w / v, 0.09% w / v, 0.03% w / v).

[0064] • Compositions were administered twice daily, once in the morning, once in the evening, as a 5-pump dose on each foot.

[0065] Daily Dose to Each Foot: BB2603-10: 0.1 % w / v terbinafine - 5x100 pL dose = 500 ug per dose twice a day = 1mg / day.

[0066] BB2603-3: 0.03% w / v terbinafine - 5x100 pL dose = 150 ug per dose twice a day = 300 pg / day.

[0067] BB2603-1 : 0.01 % w / v terbinafine - 5x100 pL dose = 50 ug per dose twice a day = 100pg / day.

[0068] • This equates to 1 mL a day total sprayed / applied to each foot.

[0069] • Each treatment provided either 0.3 mg, 0.09 mg, or 0.03 mg respectively of polyhexanide per day.

[0070] • All four compositions (including the Vehicle negative control) comprise a polyhexanide / 20% ethanol / water formulation.

[0071] Participants were male or female, recruited in Germany, Poland or the Czech Republic, aged 18-99 years (>95% of participants 75 years or younger) with confirmed onychomycosis (fungal nail infection) affecting >25% to <60% of the target toenail as determined through clinimetric measurement. The age distribution of participants was representative of the expected population with onychomycosis in those countries.

[0072] Participants were excluded from entering the trial if they had previously had topical treatment with antifungal medication within 12 weeks before the beginning of trial treatment, had systemic use of an anti-fungal treatment within 12 months before the start of trial treatment, or had past use of laser therapy, photodynamic therapy, chemical, surgical, or relevant mechanical removal for OM within 6 months of the start of trial treatment.

[0073] Baseline analyses examined the OM disease characteristics of each participant at the start of treatment. The results of these analyses are shown in tables 1 and 2. Table 1 shows the percentage area of each nail infected with OM. Table 2 shows the profile of dermatophyte species detected in target toenails prior to the beginning of treatment. The percentage of affected nail prior to treatment was balanced across all groups. Additionally, it was determined that the most prevalent dermatophyte species was T rubrum, with over 70% of subjects being infected.

[0074] Table 1 : Percentage Disease in Target Toenail at the start of treatment for each of the 4 treatment groups (eligibility for inclusion into the study, ^25- <60% was established at V1 screening).

[0075] Compositions were provided to participants in 30 mL plastic bottles comprising a handpump spray attachment. Each participant was given instructions to self-administer treatment by spraying five pumps of the provided composition on to each foot; once in the morning, once in the evening, for a period 12 weeks. Participants were asked to record the time of each topical application and to provide reasons for any missed or incorrect applications.

[0076] Treatment effects were determined during regular participant visits. Participants were asked to visit the trial sites at weeks 12, 16, 28, 40 and 52. During visits after the treatment period, samples were taken of the infected area and used to determine the mycological effects of each treatment. Clinimetric data, such as clear nail growth and percentage of nail area infected measured by a grid were also determined, in addition to any relevant safety and tolerability data including any adverse effects.

[0077] The number of participants in each group, and their status at each stage of the study is presented in table 3 below:

[0078] Table 3: Status of participants. There were no withdrawals due to adverse effects. Notably, a higher proportion of participants from the Vehicle group withdrew from the study when compared to the proportion of those in the BB2603-10 group.

[0079] Efficacy

[0080] The differences in efficacy were assessed using three different statistical analyses; modified Intention to Treat with Last observation carried forward (mITT+LOCF), Per Protocol Analysis, and modified Intention to Treat without Last observation carried forward (mITT no LOCF). The mITT+LOCF was the main analysis.

[0081] The study met the primary endpoints; statistically significantly more participants in the BB2603-10 group had negative dermatophyte culture and / or clear nail growth at Week 16 (early response assessment) compared to vehicle-treated participants (83.3% vs 51.4%, p=0.004).

[0082] Mycological Effects of Treatment

[0083] A summary of the recorded mycological effects for participants treated with either BB2603-10 or the Vehicle negative control are presented in Figure 2 and Table 4 below. Mycological effects shown are from fungal culture tests performed at 16 weeks and 52 weeks from the start of treatment. Mycological effects at Week 52 further assessed using potassium hydroxide (KOH) microscopy are also shown.

[0084] Statistically significant differences in the mycological effects between treatments with BB2603-10 and the Vehicle were found at both Week 16 and Week 52, demonstrating that

[0085] BB2603-10 is an excellent candidate for the effective treatment of OM.

[0086]

[0087] Table 4: Recorded mycological effects for participants ^Statistically Significant).

[0088] As shown in Figure 1 , a higher percentage of participants in the Per Protocol Population treated with BB2603-10 returned negative fungal culture tests when compared to participants treated with BB2603-1 or BB2603-3 at the end of treatment (Week 12), and at the early response assessment (Week 16), demonstrating that the BB2603-10 novel dosage regime disclosed herein provides an more efficacious option for the treatment of OM than any previously disclosed dose.

[0089] As illustrated in Table 4, of the 36 patients treated with BB2603-10, 23 patients exhibited fungal negative cultures at 9 months post treatment, whereas, of the 37 patients treated with the Vehicle, only 18 patients exhibited fungal negative cultures at 9 months post treatment. Furthermore, 11 patients treated with BB2603-10 were confirmed to be mycologically cured, whereas only 2 patients treated with the vehicle were confirmed as mycologically cured.

[0090] As shown in Figure 3, over 85% of samples taken from participants treated with BB2603-10 returned negative fungal culture tests at the end of treatment (12 Weeks). Fungal culture results from samples of participants treated with BB2603-10 after 52 weeks showed an approximately 20% reduction in negative fungal culture tests, which is consistent with expected mycological recurrence rate and less than reported for other anti-fungals, possibly because of an advantageous slow release of terbinafine. . Without wishing to be bound by theory the inventors determine that this is depot effect.

[0091] Figure 3 also shows that there was a significant increase from Week 12 to Week 52 in the percentage of negative KOH microscopy tests and the percentage of participants that were mycologically cured from Week 12 to Week 52. These results are consistent with nails that grow out clear of infection. By contrast, Figure 4 shows that there was no difference in the percentage of culture negative, KOH microscopy negative or mycologically cured participants over the study duration when treated with the Vehicle. Safety and Pharmacokinetics

[0092] Experiments were conducted in order to determine the level of systemic exposure to terbinafine. Pharmacokinetic (PK) blood plasma samples of 109 participants evaluable for PK were taken from (Visit 3- to Visit 9), and all samples taken from evaluable patients were below the limit of quantification, determined as 0.5 ng / mL terbinafine in human plasma. These results show that the topical use of BB2603-10 produces undetectable levels of terbinafine and, therefore, this treatment carries none of the drug liabilities associated with systemic exposure of terbinafine. This is in direct contrast to a single dose of oral terbinafine, which produces peak plasma concentrations of 2 pg / mL terbinafine. Furthermore, there were no treatment related adverse effects, no serious adverse events and no adverse events leading to treatment discontinuation, confirming that the topical treatment of BB2603 has an excellent safety and tolerability profile.

[0093] Conclusions

[0094] The foregoing clinical trial experiments were performed to determine the onychomycosis treatment effects of a composition comprising a polymer capable of forming nanoparticles and terbinafine, when topically administered using three different topical dosage regimes. The results from these clinical trials demonstrate that a daily spray dose (to each foot) of 1 mg terbinafine to an area affected with onychomycosis provides a significantly improved treatment effect, when compared to 0 pg terbinafine (vehicle), and that effects with 1 mg terbinafine were greater than with 300 pg or 100 pg of terbinafine. This improved treatment effect was observed through both KOH microscopy and fungal culture testing. Advantageously, about 87% of participants who followed the protocol closely and who that receivedtreatment with a daily dose of 1 mg terbinafine presented fungal culture negative results 16 weeks after the start of treatment. By contrast, only about 75%, 77% and 42% of participants presented fungal culture negative tests after 16 weeks in groups treated with a daily dose of 300 pg and 100 g and 0 pg of terbinafine respectively. No treatment related adverse effects were recorded during the trial, and pharmacokinetic data collected from participants in every treatment group failed to show quantifiable amounts of systemic terbinafine. This finding confirms that the topical treatment outlined above has an excellent safety and tolerability profile.

[0095] The forgoing embodiments are not intended to limit the scope of the protection afforded by the claims, but rather to describe examples of how the invention may be put into practice.

Claims

Claims1. A composition for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the composition is administered topically to provide a daily dose to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand in the range of about 100pg to about 1mg of terbinafine.

2. The composition as claimed in claim 1 , wherein the daily dose of terbinafine administered to an affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand is in the range of about 300pg to about 1mg.3 The composition as claimed in claim 2, wherein the daily dose of terbinafine administered to an infected area of the digits and / or the inter-digital spaces and / or foot and / or hand is about 1mg.

4. A composition for use in the treatment of onychomycosis in a foot and / or hand of an individual, the composition comprising a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof, and wherein the composition is administered topically by means of a spray application using one or more spray applications to provide a daily spray dose of up to about 1 mg of terbinafine to the affected area of the digits and / or the inter-digital spaces and / or each foot and / or hand.

5. The composition as claimed in claim 4, wherein the daily spray dose to the digits and / or the inter-digital spaces and / or each foot and / or hand comprises up to about 10 spray applications.

6. The composition as claimed in claim 4, wherein the daily spray dose to the digits and / or the inter-digital spaces and / or each foot and / or hand comprises up to about 5 spray applications administered twice a day.

7. The composition as claimed in any of claims 4 to 6, wherein the spray is effective to cover the digits and / or the inter-digital spaces and / or the front of the foot and / or hand.

8. The composition as claimed in any one of claims 4 to 7, wherein each spray actuation application dispenses up to about 100 pg of liquid.

9. The composition as claimed in any one of claims 4 to 8, wherein the composition is atomised during each spray actuation application.

10. The composition as claimed in any one of claims 4 to 9, wherein the spray application is administered by means of a pump-action spray device or a metered aerosol spray device.

11. The composition as claimed in any preceding claim, wherein the daily dose is for administration for up to about 48 weeks.

12. The composition as claimed in any one of claims 1 to 11 , wherein the daily dose is for administration for up to about 36 weeks.

13. The composition as claimed in any one of claims 1 to 11 , wherein the daily dose is for administration for up to about 12 weeks.

14. The composition as claimed in any one of claims 1 to 11 , wherein the daily dose is for administration for up to about 4 weeks.

15. A combination of a composition for use in the treatment if onychomycosis in a foot and / or hand of an individual and a composition dispensing device for dispensing a predefined quantity of composition to the digits and / or the inter-digital spaces and / or each foot and / or hand of an individual, the device comprising a vessel containing thecomposition, an atomising nozzle, and an actuation arrangement operable by the user to dispense the predefined quantity of composition from the vessel via the nozzle, thereby atomizing the composition, wherein the composition comprises a polymer capable of forming nanoparticles and terbinafine, or derivative salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof, and wherein the pre-defined quantity of the composition contains terbinafine in the range of about 10 pg to about 100 pg.

16. The combination of claim 15, wherein pre-defined quantity of the composition comprises about 10OpI of liquid.

17. The combination of either claim 15 or 16, wherein the actuation arrangement is a pumpaction spray device or a metered aerosol spray device.

18. The composition as claimed in any of claims 1 to 14, or the composition of the combination of any of claims 15 to 17, comprising;(a) terbinafine, or derivative or salt thereof, in an amount in the range of about 0.01 % w / v to about 0.1 % w / v; and(b) a polymer capable of forming nanoparticles and terbinafine, or derivative or salt thereof, wherein the nanoparticles are formed with and / or in the presence of terbinafine, or derivative or salt thereof and wherein the polymer is present in an amount of about 0.03% w / v to about 0.3% w / v.

19. The composition as claimed in claim 18, wherein the composition comprises terbinafine, or derivative or salt thereof, in an amount of about 0.1% w / v.

20. The composition as claimed in any preceding claim, wherein the polymer comprises a linear and / or branched or cyclic polymonoguanide / polyguanidine, polybiguanide, analogue or derivative thereof.

21. The composition as claimed in any preceding claim, wherein the polymer comprises polyhexamethylene biguanide (PHMB).

22. The composition as claimed in any preceding claim, further comprising alcohol, and optionally the alcohol comprises ethanol.

23. The composition as claimed in any preceding claim, wherein the composition further comprises one or more of the following components: buffers, excipients, binders, oils, water, emulsifiers, glycerine, antioxidants, preservatives and fragrances and urea.

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