COMPOSITION FOR THE TREATMENT OF A FUNGAL INFECTION

Abstract

A packaged treatment composition comprising a polymerisable and/or curable composition comprising (1) a packaged first flowable component comprising a source of hydrogen peroxide and (2) a separately packaged second flowable component; the composition comprising a polymerisable monomer or oligomer, a polymer and/or a curing agent, wherein the composition comprises a photoinitiator and wherein the first flowable component is substantially free of photoinitiator, the composition capable of forming a solid composition by UV-initiated polymerisation and/or curing following mixing of the first and second flowable components.

Claims

1. A packaged treatment composition comprising a polymerisable and/or curable composition comprising (1) a packaged first flowable component comprising a source of hydrogen peroxide and (2) a separately packaged second flowable component; the composition comprising a polymerisable monomer or oligomer, a polymer and/or a curing agent, wherein the composition comprises a photoinitiator and wherein the first flowable component is substantially free of photoinitiator, the composition capable of forming a solid composition by UV-initiated polymerisation and/or curing following mixing of the first and second flowable components.

2. The packaged treatment composition according to claim 1, wherein the composition comprises a polymerisable composition comprising a polymerisable monomer or oligomer.

3. The packaged treatment composition according to claim 1, wherein the first flowable component is substantially free of polymerisable monomer or oligomer.

4. The packaged treatment composition according to claim 1, wherein the second flowable component is substantially free of polymerisable monomer or oligomer.

5. The packaged treatment composition according to claim 1, comprising a curable composition comprising a polymer and a curing agent.

6. The packaged treatment composition according to claim 5, wherein the curing agent is a cross-linking agent.

7. The packaged treatment composition according to claim 5, wherein the first flowable composition is substantially free of curing agent.

8. The packaged treatment composition according to claim 1, which is accompanied by a UV source.

9. The packaged treatment composition according to claim 1, wherein the first and second flowable components are arranged to produce a hydrated hydrogel upon polymerisation and optionally curing.

10. The packaged treatment composition according to claim 9, wherein the polymerisable monomer is an AMPS monomer, forming a poly-AMPS hydrogel upon polymerisation.

11. The packaged treatment composition according to claim 1, wherein the first and second flowable components have substantially the same viscosity.

12. The packaged treatment composition according to claim 1, wherein one or both of the flowable components comprises a thickener.

13. The packaged treatment composition according to claim 1, wherein the first and second compositions are both aqueous solutions.

14. The packaged treatment composition according to any one of claim 1, wherein the first and second components are in gel form.

15. The packaged treatment composition according to claim 1, wherein the source of hydrogen peroxide comprises pre-formed hydrogen peroxide.

16. The packaged treatment composition according to claim 1, wherein the first and second components are packaged to dispense a predefined amount of each of the first and second flowable components.

17. The packaged treatment composition according to claim 15, wherein the pre-formed hydrogen peroxide is present at a concentration of from 0.2 to 1.5 wt % of the total of the predefined amount of the first and second flowable components.

18. The packaged treatment composition according to claim 1, wherein the pH of the first flowable component is less than 5.0.

19. The packaged treatment composition according to claim 16, configured to provide for mixing of the predefined amount of the first and second flowable components prior to dispensing.

20. The packaged treatment composition according to claim 1, wherein the first and second components are contained in syringes, either each in their own syringe or together in a dual syringe.

21. The packaging treatment composition according to claim 1, wherein the first and second components are stored in respective first and second flexible compartments joined together by a breakable seal.

Description

[0044] The invention will be illustrated by way of example and with reference to the following figures, in which:

[0045] FIG. 1 shows a suitable primary container. Single-Use Dual-syringes, which would be pre-loaded with Hydrogen Peroxide Active Gel and photoinitiator gels. Mixing is obtained by fitting a mixing tip to the end of the syringe.

[0046] FIG. 2 is a chart showing the release of hydrogen peroxide beneath the nail, as evidenced by colour changes in starch iodide plates.

[0047] FIG. 3 is a table showing the outcome of starch iodide agar sensing of through-the-nail diffusion of hydrogen peroxide after three applications of 25 L and 125 L of 0.5% w/w of a gel according to the invention.

[0048] FIG. 4 is a diagrammatic representation of the experimental technique of Example 5 (not drawn to scale). In this set-up the T. rubrum is held in a much reduced volume only 0.25 ml (or 0.25 gram by weight). This means that the hydrogen peroxide released by the 0.05 g of gel can only be diluted by a factor of 5 while it is attacking the target T. rubrum contained in the agar. The killing efficiency can then be determined by removing the 0.25 g seeded agar target and placing it onto sterile nutrient agar, so allowing any surviving T. rubrum to grow and become detectable.

[0049] FIG. 5 is a table showing the fungicidal activity of hydrogen peroxide released from a dual gel (0.05 g) applied to intact nail pieces. In this experiment the target T. rubrum was held in a small quantity (0.25 g) of nutrient agar, separated from the gel by an intact nail piece. Hydrogen peroxide could only reach the target by passing through the nail

EXAMPLES

[0050] Users of the dual syringe format as shown in FIGS. 1 a to 1c, are able to mix the contents of one Active Gel and one Photo-initiator gel by depressing the plunger on the provided dual syringe, to administer the final formulation onto the nail, based on delivering a dose of e.g. 0.15 mL per cm.sup.2 of mixed product. This will provide for a gel thickness of approximately 1.5 mm thick. The applied gel is subsequently exposed to UV light for 1-2 mins using a standardised UV light source. This action polymerises (cures) the active polymer onto the nail and allows it to firmly adhere to the surface of the nail, thereby allowing it to remain in place overnight (i.e. for a period of 8-10 hours). Although cured to the nail, the polymerized gel (due to the presence of glycerol) remains soft and rubbery and is designed to allow the patient to peel the gel off the nail after the appropriate time. This process can be repeated daily over several weeks if required to obtain a complete of the nail infection.

Example Formulation

[0051] A formulation of the two component solutions according to the invention is as follows:

TABLE-US-00001 TABLE 1 An example of a formulation for the first component containing the active ingredient, hydrogen peroxide, but lacking the photoinitiator. Ingredient Function Quantity Hydrogen Peroxide Ph Eur * Active 1.0% w/w 2-Acrylamido-2-methyl-1-propanesulfonic Monomer 30.0% w/w acid sodium salt solution (50% solution) (HSE) Poly(ethylene glycol) diacrylate (Avergage Cross-linker 0.2% w/w Mn 700) (HSE) Hydroxyethyl cellulose PH Eur Thickener 1.5% w/w Glycerol Ph Eur Humectant 10.0% w/w

[0052] The balance of the formulation is de-ionised water.

TABLE-US-00002 TABLE 2 An example of a formulation for the second component containing photoinitiator, but lacking the hydrogen peroxide. Ingredient Function Quantity 2-Hydroxy-2-methylpropiophenone (HSE) Photoinitator 1.0% w/w 2-Acrylamido-2-methyl-1-propanesulfonic Monomer 30.0% w/w acid sodium salt solution (50% solution) (HSE) Poly(ethylene glycol) diacrylate (Avergage Cross-linker 0.2% w/w Mn 700) (HSE) Hydroxyethyl cellulose PH Eur Thickener 1.5% w/w Glycerol Ph Eur Humectant 10.0% w/w

[0053] The balance of the formulation is de-ionised water.

[0054] In this embodiment of the invention hydrogen peroxide is employed at a nominal concentration of 0.5 w/w but, because it is present as a chemotherapeutic agent, in most jurisdictions it is necessary to use only material proved to be of pharmaceutical grade. A suitable commercially available preparation of hydrogen peroxide is known as PERSYNT (Evonik GmbH), in the form of high purity hydrogen peroxide, which is understood to have been optimised for food treatment, fine chemical synthesis as well as for use in the cosmetic and pharmaceutical industries; this material complies with the requirements of the European Pharmacopoeia 7 (except for concentration) and EN DIN 902.

[0055] Information supplied by Evonik indicates that PERSYNT is manufactured according to the anthraquinone-autoxidation (AO) process. In this AO process, hydrogen peroxide is produced from hydrogen and atmospheric oxygen, and utilises an anthraquinone derivative, which is circulated, as a reaction carrier. The crude hydrogen peroxide derived through the AO process is then purified and concentrated. After appropriate stabilization, it is marketed as an aqueous solution at concentrations ranging between 20-35 percent by weight.

[0056] Another formulation of the two component solutions according to the invention is as follows:

TABLE-US-00003 TABLE 3 An example of a formulation for the first component containing the active ingredient, hydrogen peroxide and thickener. Ingredient Function Quantity Hydrogen Peroxide Ph Eur * Active 1.0% w/w Hydroxyethyl cellulose PH Eur Thickener 1.5% w/w

[0057] The balance of the formulation is de-ionised water.

TABLE-US-00004 TABLE 4 An example of a formulation for the second component containing photoinitiator, monomer and cross-linker. Ingredient Function Quantity 2-Hydroxy-2-methylpropiophenone (HSE) Photoinitator 1.0% w/w 2-Acrylamido-2-methyl-1-propanesulfonic Monomer 60.0% w/w acid sodium salt solution (50% solution) (HSE) Poly(ethylene glycol) diacrylate (Avergage Cross-linker 0.4% w/w Mn 700) (HSE) Hydroxyethyl cellulose PH Eur Thickener 1.5% w/w Glycerol Ph Eur Humectant 20.0% w/w

[0058] The balance of the formulation is de-ionised water.

Example 1: In-Vitro Hydrogen Peroxide Release Characteristics

[0059] Three formulations were prepared at levels of 0.5, 1.0 and 2.0 wt % active like the formulation in Table 1.

[0060] The ability of dual phase formulations to release hydrogen peroxide has been studied in-vitro. In an initial study, samples of the 2% w/w active and photoinitiator gels were mixed and then applied to flat sheet receiver gel and polymerised in-situ using a standardised UV lamp. Samples were then incubated overnight and for 3 days before removing the test gel. The receiver gel was then tested for the presence of hydrogen peroxide using a gel extraction assay, yielding the following results. [0061] Overnight, more than 70% of the hydrogen peroxide content of the polymerised gel was detected in the receiver gel [0062] After 3 days' incubation, the receiver gel contained 50-60% of the hydrogen peroxide content of the polymerised gel, suggestive of an equilibrium being established during longer exposure times.

Example 2: In-Vitro Hydrogen Peroxide Transmission from the Gel, Through-the-Nail

[0063] A variation of the example 1 experiment was set up to explore the ability of hydrogen peroxide to penetrate through the nail at concentrations expected to be effective in killing dermatophyte fungal cells. Intact pieces of human nails were glued to the outside of holes (3.2 mm diameter) drilled in the centre of petri dishes which were then loaded with starch/iodide agar, taking care to see that the starch iodide gel was in direct contact with the nail piece. The dual phase formulations were mixed in a 1:1 ratio for 20-30 seconds before a single topical application of 0.05-0.06 g onto the outer surface of the healthy nail pieces fixed over the hole in each petri dish. The mixed gel was then cured to the nail surface using UV light for 30 seconds. The plates were monitored for colour development, indicative of a reaction between the released hydrogen peroxide and the starch/iodide indicator over a period of 9 hours.

[0064] The results, summarised in FIG. 2, indicate that colour development, (i.e. release and penetration of hydrogen peroxide through the nail) was fastest and most intense when 2% w/w hydrogen peroxide was applied to healthy nails in the range of 0.1-0.3 mm thick. Lower concentrations, 0.5% w/w and 1.0% w/w hydrogen peroxide also showed evidence of significant colour changes, albeit with less intense staining. Consistent with the in-vitro efficacy however, no colour changes were observed when the thickest healthy nails (>0.5 mm) were used in the assay, irrespective of hydrogen peroxide concentration, indicating that the availability of hydrogen peroxide from single application at the nail bed is likely dependent on the thickness (and therefore permeability) of the healthy nail.

Example 3: In-Vitro Hydrogen Peroxide Transmission from Repeat Applications

[0065] The aim of this invention is to have sufficient hydrogen peroxide at the nail bed to provide anti-fungal action, whilst avoiding significant collection of oxygen gas underneath the nail, as the pressure of the gas could cause separation of the nail from the nail bed, resulting in pain to the patient. The ideal product therefore provides slow release of hydrogen peroxide, into the nail over several applications, although nail thickness will affect transmission.

[0066] In this example repeated applications of the lowest dose of hydrogen peroxide (0.5% w/v gel) were employed in an iodine starch test, using healthy intact nails ranging in thickness from 0.1-0.5 mm. Either 25 L (equivalent to 0.03 mL/cm2) or 125 L (equivalent to 0.15 mL/cm2) of the final 0.5% w/v formulation was cured onto the top of the nail pieces and samples were incubated at 25 C. overnight. Following incubation, the starch iodide agar was examined for evidence of colour change. Where no colour was observed after the first application, gels were removed from the nail and a fresh gel was reapplied. Samples were then again incubated at 25 C. and kept hydrated while monitoring the starch iodide agar for a further 48 hours.

[0067] Results after three applications indicate that in the thinnest nails (0.1-0.3 mm thick) colour changes are observed after a single application of either 25 or 125 L of 0.5% w/w gel. Additionally, some colour change was observed after a single application in the thickest nail (0.5 mm) when 125 L (0.15 mL/cm2) was added to the nail. Second applications of the 0.5% w/w gel further enhanced the colour changes observed when 125 L was used and, in addition, colour changes in the 0.4 mm thick nails were observed after a second application of only 25 L. Minimal changes were observed after three applications of 25 L of 0.5% w/w gel in the thickest (0.5 mm) nails (Table 5).

Example 4: In-Vitro Fungicidal Action of Hydrogen Peroxide Transmitted Through-the-Nail, from Gels According to the Invention

[0068] To confirm that hydrogen peroxide delivered through-the-nail has relevant fungicidal activity, a similar experiment was conducted with fungal killing as the outcome, rather than simply detection of hydrogen peroxide. In this experiment the agar was seeded with T. rubrum. A 2% w/w concentration of hydrogen peroxide was used in the final gel applied to the nail pieces, which was polymerised in-situ using a standardised UV lamp. In order to compare the efficiency of hydrogen peroxide release from the gel, positive controls were included in the form of simple aqueous solutions of hydrogen peroxide at 0.35%, 3.5% and 35%, which were applied as liquids to the nail surface. Negative controls in the form of water and gels lacking hydrogen peroxide were also included.

[0069] The results are summarised in Table 4 below. In overview, these data indicate that the dual phase formulation of this invention, comprising 2% w/w hydrogen peroxide, was capable of penetrating through healthy intact nail pieces and resulted in zones of fungal killing in the underlying agar, although with variable responses. Further investigations indicated that the size of the zones of inhibition was, in large part, related to the thickness of the healthy nail piece used; thicker nail pieces resulted in smaller zones of inhibition, presumably due to slower diffusion and/or impeded penetration through the nail.

[0070] By way of confirmation, when the test was repeated without the nail piece, the formulation achieved zones of inhibition comparable with 3.5% hydrogen peroxide solution, indicating that the polymerised gel in itself did not prevent release of the hydrogen peroxide.

TABLE-US-00005 TABLE 4 Outcome of fungicidal activity of through-the-nail diffusion of hydrogen peroxide from 2% w/w Gel Healthy Nail Barrier No Nail Barrier Zone of inhibition (mm) Zone of inhibition (mm) Treatment Plate 1 Plate 2 Plate 3 Plate 1 Plate 2 Plate 3 No Treatment 0 Water (Neg 0 0 control) 0.35% H.sub.2O.sub.2 6 0 10 27 25 25 Solution 3.5% H.sub.2O.sub.2 0 30 49 70 72 66 Solution 35% H.sub.2O.sub.2 35 No No No No No Solution Growth Growth Growth Growth Growth Placebo Gel 0 0 0.5 0.5 Dual Gel 16 25 2 72 66 80 (2% w/w)

Example 5: In-Vitro Fungicidal Action of Hydrogen Peroxide Transmitted Through-the-Nail, from Gels According to the Invention in a Model More Closely Resembling the In-Vivo Situation

[0071] The test model of example suffers from a significant drawback, in that the hydrogen peroxide becomes substantially diluted as it diffuses through the agar gel seeded with T. rubrum. Any zone of clearance is limited by this dilution effect. In the in-vivo situation, the fungicidal action is not limited by dilution into a large volume of fungally infected fluid or tissue. In onychomycosis the fungus is largely confined to the nail plate and, possibly, the interface between the nail plate and the nail bed.

[0072] To better simulate the clinical condition of onychomycosis, the test model of Example 4 was modified as shown in FIG. 4.

[0073] Small quantities (0.05-0.06 g) of dual phase gels of varying concentration (0.5%, 1.0% and 2.0% w/w) were cured to the top of a nail clipping using UV light as per the standard model; the primary difference compared to the standard R-SNIPP model was that the 0.25 mL of molten YEPD agar (104 spores of T. rubrum) droplets were allowed to directly contact the underlying side of the nail, rather than relying on diffusion through the agar. The plate was incubated overnight at 25 C.; 1 mL of sterile water was also added to a petri dish to prevent the agar from drying out. To develop the plates, the agar droplets were transferred to fresh YEPD agar plates and incubated for 4 days at 25 C.

[0074] The results from this experiment are shown in FIG. 5, in which each result is recorded in words as well as in a photograph of the 0.25 g target gel after incubation following exposure to through-the-nail hydrogen peroxide.

[0075] In this experiment, no growth of T. rubrum underlying the nail was observed when dual phase OnyxMyco gels containing hydrogen peroxide from 0.5-2.0% w/v were used on nail clippings of depth 0.1-0.2 mm thick. (Table 4). Growth was however recorded with healthy nail clippings in excess of 0.4 mm thick, indicating that permeation of hydrogen peroxide through thicker intact healthy nails after a single application may be insufficient to achieve a full fungicidal concentration. Even so, in the 0.4 mm thick nail pieces the extent of growth when hydrogen peroxide was included in the formulation was noticeably less than in the zero hydrogen peroxide control.

[0076] It is important to recognise that this model assesses only a single application of the invention to a nail piece. In clinical practice, it is intended that applications of this invention are to be repeated daily over the course of several weeks to achieve complete fungal kill. In Example 3, it was clear that repeat applications enhanced the penetration of detectable hydrogen peroxide, even through thicker nails.

[0077] A further formulation of the two component solutions according to the invention is as follows:

TABLE-US-00006 TABLE 5 An example of a formulation for the first component containing the active ingredient, hydrogen peroxide, but lacking the photoinitiator. Ingredient Function Quantity Persynt 300 GMP Evonik (Hydrogen Active 1.0% w/w Peroxide) 2-Acrylamido-2-methyl-1-propanesulfonic Monomer 60.0% w/w acid sodium salt solution (50% solution) (AMPS) Poly(ethylene glycol) diacrylate (Avergage Cross-linker 0.4% w/w Mn 700) Natrosol 250M (Hydroxyethyl cellulose) Thickener 1.25% w/w Glycerol Humectant 10.0% w/w Disodium EDTA Peroxide 0.1 stabiliser pH 4 citric acid/sodium citrate buffer, Diluent 27.25 w/w 0.1M

[0078] If desired, water may be eliminated by increasing the amount of glycerol pro-rata the removed water and [0079] substituting the acid version of AMPS for the sodium salt of AMPS, [0080] eliminating EDTA, [0081] eliminating Natrosol [0082] replacing Persynt with an equivalent amount of urea-hydrogen peroxide complex

[0083] Disodium EDTA may be omitted if desired.

[0084] Guar gum may be used as a substitute thickener.

TABLE-US-00007 TABLE 6 An example of a formulation for the second component containing photoinitiator, monomer and cross-linker. Ingredient Function Quantity 2-Hydroxy-2-methylpropiophenone Photoinitiator 1.0% w/w 8-Hydroxyquinoline Preservative 0.4% w/w Natrosol 250M (Hydroxyethyl Thickener 1.25% w/w cellulose) Glycerol Ph Eur Humectant 10.0% w/w pH 4 citric acid/sodium citrate buffer, Diluent 87.35 w/w 0.1M

[0085] If desired the following preservatives may be used instead: [0086] Boric acid/sodium borate buffer [0087] Bronopol 0.02% [0088] Hexetidine 0.2% [0089] Potassium sorbate 0.2%

[0090] If desired, HMPP may be used at inclusion levels ranging from 0.2% to 0.8% depending on the intensity of UV irradiation available.