WO2016189529A1

WO2016189529A1 - Iodine-based topical compositions

Info

Publication number: WO2016189529A1
Application number: PCT/IL2016/050540
Authority: WO
Inventors: Perry ABRAMOV
Original assignee: Abramov Perry
Priority date: 2015-05-28
Filing date: 2016-05-24
Publication date: 2016-12-01

Abstract

The disclosure provides a composition for topical application, comprising iodine, hydroiodic acid, at least one organic add and at least one emollient. The disclosure further provides methods of preparing such compositions, uses thereof as topically- applied compositions for treating fungal-associated skin disorders, and kits comprising the compositions.

Description

IODINE-BASED TOPICAL COMPOSITIONS

TECHNOLOGICAL FIELD

The present disclosure provides iodine-based compositions for topical applications, such as drops, liquid-containing capsules or creams for treating fungal- associated skin disorders.

BACKGROUND ART

References considered to be relevant as background to the presently disclosed subject matter are listed below:

[1] WO 2004/010952

[2] US 6,921,529

[3] Strickler A., Arch Derm Syphiloi 1946, 53(5), 454-457

[4] Strickler A., JAMA 1946, 132(2), 65-66

Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject-matter.

BACKGROUND

Being constantly exposed to the environment, dermal structures of humans and animals (such as skin, hair, hair follicles, cornea, sclera, dura, toenails, fingernails, hooves, horns, and oilier cellular stmctures made from epithelial cells or keratinized structures) are often the site of infections caused by other living organisms. In particular, many of the common dermal infections are caused by organisms that live in or on the dermis, such as yeasts, fungi, and mycoplasma.

The presence of these organisms in and on dermal structures often cause a range of changes to the dermis and dermal stmctures, from merely unsightly to pathological conditions, and can interfere with the functions of the dermis as well as cause great discomfort to the patient. Such infections often cause visible changes to the infected tissue, resulting also in various cosmetic problems and/or secretion of unpleasant odors due to prosperity of organisms which decompose bodily fluids (such as sweat). 11ms, there is a need to prevent infection and treat the affected sites, as well as prevent the reinfection and re -attachment of such organisms to the skin or surrounding tissue.

It is of note that infections of the nail structure are one of the most common and problematic conditions requiring attention, as the anatomy of the nail and its supporting structures profoundly influence the effectiveness of treating the tissues. The nail structure and anatomy are complex and, to some degree, are isolated from systemic circulation. Furthermore the heavily keratinized nail plate is relatively impermeable to penetration of topical agents.

There are several known iodine-based topical treatment products for the skin and nails. One of the common disinfectants used is tincture of iodine, which is an antiseptic, typically containing 2-7% elemental iodine and a potassium- or sodium-iodide salt, dissolved in a mixture of water and ethanol. Another commercial product is Lugol's iodine, typically comprising about 5% iodine, potassium-iodide salt and water. A different product based on iodine and known as disinfectant is povidone, in which iodine is cornpiexed with polyvinylpyrrolidone and contains 9-12% available iodine. Although widely used as disinfectants, these compositions have not been proven to have significant effect in treating and preventing fungal-associated conditions of the skin and nails.

GENERAL DESCRIPTION

The inventor of the present invention has developed a unique composition for the treatment of fungal and mycotic infections, specifically for treating fungal infections in areas such as hand palms and feet. The composition is based on a combination of active ingredients, carried in an emollient carrier, and is intended for topical application onto fungal-infected skin areas. Without wishing to be bound by theory, the combination of components in a composition of the invention have a synergistic effect for treating fungal-associated skin conditions, compared to the anti-fungal activity of each of the compositions' components taken alone. In an aspect, the invention provides a composition for topical application, comprising iodine, hydroiodic acid, at least one organic acid and at least one emollient.

The term iodine refers to molecular iodine, i.e. the diatomic molecule h. Iodine is typically provided in solid crystalline form, and in the composition of the invention iodine is present in a dissolved form within the organic acid.

According to some embodiments, the composition comprises between about 0.5 and about 5 wt% iodine. Namely, the concentration of iodine in the composition may range between 1 and 5 wt%, 1.5 and 5wt%, 2 and 5 wt%, 2.5 and 5 wt% or even between 3 and 5 wt%. In other embodiments, the concentration of iodine may range between 0.5 and 4.5 wt%, 0,5 and 4 wt%, 0,5 and 3.5% or even 0.5 and 3 wt%. According to some other embodiments, the iodine may be present in the composition in a concentration of between 1 and 4 wt%, 1 and 3 wt% or 2 and 3 wt%.

Hydroiodic acid (HI) refers to the diatomic molecule hydrogen iodide in an aqueous solution form.

In some embodiments, the composition comprises between about 0.5 and about 5 wt% hydroiodic acid. Namely, the concentration of hydroiodic acid in the composition may range between 1 and 5 wt%, 1 ,5 and 5wt%, 2 and 5 wt%, 2.5 and 5 wt% or even between 3 and 5 wt%. In other embodiments, the concentration of hydroiodic acid may range between 0.5 and 4.5 wt%, 0.5 and 4 wt%, 0.5 and 3.5% or even 0.5 and 3 wt%. According to some other embodiments, the hydroiodic acid may be present in the composition in a concentration of between 1 and 4 wt%, 1 and 3 wt% or 2 and 3 wt%. According to certain embodiments, the hydroiodic acid is in a concentration of between 1 and 2 wt%.

According to some embodiments, the ratio between the iodine and the hydroiodic acid is between about 2: 1 and 1:2. In other embodiments, the ratio between the iodine and the hydroiodic acid may be between about 1 : 1 and 1:2.

In a composition the invention, both the iodine and the hydroiodic acid are mixed with an organic acid, to form a solution. The term organic acid is mean to encompass any suitable organic compound, typically in liquid form or in an aqueous solution, having acidic properties. Namely, the organic acid (or an aqueous solution thereof) will have a pH of below 7. Suitable organic acids are such that have a pKa value of >2. In some embodiments, the organic acid may be selected from acetic acid, propionic acid, propanoic acid, citric acid, butyric acid, sorbic acid, ascorbic acid, salicylic acid, tannic acid, succinic acid, lactic acid, pyruvic acid, alpha ketoglutaric acid, glutamic acid, undecylenic acid, and combinations thereof.

In other embodiments, the organic acid has a pKa value of >3.

In further embodiments, the organic acid is acetic acid.

According to some embodiments, the composition of the invention may- comprise between about 10 and about 25 wt% of organic acid. In other embodiments, the composition may comprise between 12 and 25 wt%, 15 and 25 wt%, 17 and 25 wt% or even 20 and 25 wt% organic acid. . In some other embodiments, the composition may comprise between 10 and 23 wt%, 10 and 20 wt%, or even 10 and 18 wt% organic acid. In certain embodiments, the composition comprises between about 12 and about 18 wt% of organic acid.

The composition of the invention further comprises at least one emollient. The term emollient refers to a chemical agent (or a mixture of compounds) which increase skm hydration, thereby softening the external layers of the skin. Emollients may be active, i.e. delivering water molecules into the skin, or passive, namely reducing and preventing water evaporation from the skin. In the present context, the term also refers to chemical agents that can form a water-impermeable layer once applied onto the infected skin or nail area. In compositions of the invention, any suitable emollient may be used. As a person of skill in the art would appreciate, the emollient should be chemically compatible with the other components of the composition (i.e. with the iodine, hydroiodic acid and organic acid), as well as medically or cosmetically approved.

In some embodiments, the emollient may be selected from optionally hydroxy- substituted Cs-Cso unsaturated fatty acids and esters thereof, C 1-C24 esters of

saturated fatty acids, beeswax, petroleum jelly, saturated and unsaturated fatty alcohols, hydrocarbons such as mineral oils, petrolatum, squalane, fatty sorbitan esters, lanolin and lanolin derivatives, cholesterol and derivatives thereof, animal and vegetable triglycerides, C1-C24 esters of dimer and trimer acids, natural or synthetic oils selected from mineral, vegetable, and animal oils, alkylene glycol and polyalkylene glycol ethers, and mixtures thereof. In other embodiments, the emollient may be selected from isopropyl myristate, cetyl palmitate, octykiodecyimyristate, behenyl alcohol, cetyl alcohol, lanolin alcohol ethoxylated lanolin, hydroxylated lanolin, acetylated lanolin, diisopropyl dimerate, diisostearylrnalate, diisostearyldimerate, triisosteaiyltrimerate, isocetyl alcohol, octyl palmitate, isostearyi neopentanoate and isocetyl stearyl stearate, polyethylene glycol and polypropylene glycol and mixtures thereof.

In some other embodiments, the emollient may be a natural oil, selected from almond oil, peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts, pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach pit oil, poppy seed oil, pine oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape seed oil, and sunflower seed oil and mixtures thereof.

According to further embodiments, the emollients may be a polyol, at times a C3-6polyol. The term polyol refers to a compound having at least 2 hydroxy! groups.

According to yet further embodiments, the emollient may be glycerol.

In some embodiments, the composition may comprise between about 15 and about 25 wt% emollients. In other embodiments the concentration of emollients in the compositions is between about 18 and 22 wt%.

As some of the components of the compositions may be provided in solution forms, the composition may further comprise a suitable solvent. In some embodiments, however non-limiting, said solvent is water, i.e. distilled or de-ionized water.

Compositions of the invention are suitable and mainly intended for topical application. The tenn topical (or any lingual variation thereof), as used herein, refers to the application of a composition according to the invention directly onto at least a portion of a subject's skin (human's or non-human's skin) or nails, so as to achieve a desired effect, e.g., cosmetic or therapeutic effect, at the site of application. In some embodiments, the desired effect is achieved at the site of application without inducing one or more systemic effects.

The compositions (and/or formulations comprising the compositions), according to some embodiments, may be in the form of a solution, an emulsion, a gel, a cream, an ointment, or any other form suitable for topical application.

To obtain the desired form, compositions of the invention may further comprise at least one additive. The additives may render the composition with a desired physical property, such as viscosity, color, scent, stabilization, etc. In some embodiments, said at least one additive may be selected from a coloring agent, a perfume, a emulsifier, a thickener, a filler, a preservative and a gelling agent.

Non-limiting suitable emulsifiers include glyceryl stearate and laureth 23, PEG 20 stearate, and mink-amidopropyl dimethyl 2-hydroxyetliylammonium chloride. The use of emulsifiers typically affords obtaining an emulsion of the aqueous phase (containing the iodine, hydroiodic acid and acetic acid) with the fatty emollient phase.

The use of gelling agents, typically hydrophilic gelling agents, may render the composition with gel-like properties, by gelling the aqueous phase. Non -limiting examples of gelling agents may be water-soluble or colloidal water-soluble polymers, such as cellulose ethers (e.g., hydroxyethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose), polyvinylalcohol, polyquateraium-10, guar gum, hydroxy-propyl guar gum, xanthan gum, Aloe vera gel, amia, carrageenan, oat flour, starch (from com rice or other plants), gelatin (porcine skin), ghatty gum, gum Arabic, inulin (from chicory), Konjac gum, locust bean gum, marshmallow root, pectin, quinoa extract, red alga, soiagum, tragacanth gum (TG), acrylic acid/ethyl aciylate copolymers and the carboxyvinyl polymers sold by the B.F. Goodrich Company under the trademark of Carbopol resins, oleogels such as triliydroxystearin and aluminum magnesium hydroxy stearate.

Thickeners may impart the composition with a higher viscosity, and may be selected in a non-limiting manner from crosslinked maleic anhydride-alkyl methylvinylethers, copolymers, carbomers, natural gums, highly crosslinked polymethacrylate copolymer, etc.

As noted above, the compositions of the invention are suitable for treatment of fungal-associated skin and nail diseases. Thus, in another aspect, the invention provides a composition as described herein for use in treating fungal-associated skin disorders.

Another aspect provides a composition as herein described for use in balancing skin flora.

A further aspect provides the use of a composition as herein described for the preparation of a topically-applied formulation for treating fungal-associated skin condition.

Another aspect provides a method of preventing, treating or ameliorating a fungal-associated skin condition by topically applying the composition as herein described onto a skin or nail area of a subject infected with said fungal-associated skin condition.

The composition of the present invention may be selected to treat or prevent a fungal-associated skin condition The term treatment or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of the composition of the present invention to a subject which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.

Administration of the composition of the inv ention may, by some embodiments, be daily (i.e. once, twice, three, four, etc. application per day), once or twice every other day, once or twice every two days, once or twice every three das, weekly, bi-weekly or even monthly. According to other embodiments, the composition of the invention is applied one daily, twice daily, or once or twice every other day.

The term subject may be human or non-human.

In some embodiments, the fungal-associated skin condition is caused by dermatophytes, and may be selected from Tinea pedis (athlete's foot), Tinea unguium (onychomycosis). Tinea corporis. Tinea cruris (jock itch). Tinea manuum, and Tinea capitis.

In other embodiments, the fungal-associated skin condition is Tinea pedis. Tinea manuum or Tinea unguium.

In another aspect, the invention provides a kit (or a commercial package) comprising a container containing a composition of the invention as herein described, and instructions for use.

In some embodiments, the kit may comprise at least one container comprising a dose of composition for a single application. Namely, the kit may comprise a plurality of single-dose units. The single dose units may be in any form known in the art, for example, as single-dose ampoules, single-dose capsules, single-dose sachets, etc. In some embodiments, the kit may further comprise means for topically applying the composition. Non limiting examples of such means are drip bottles, pipettes, smear sticks, smearing applicators, adsorbing pads, etc.

In a further aspect, the invention provides a patch for applying onto skin, the patch comprising a composition of the invention as herein described.

The patch may be made of an adsorbing substrate, onto which the composition of the invention is pre-adsorbed. In another example, the composition of the invention may be encapsulated within a suitable gel formulation that enables release of the composition when in contact with the skin.

The patch may further include an adhesive layer or area, enabling a user to adhere the patch onto the infected area of the skin, thereby ensuring delivery of the composition for a prolonged period of time. The patch may also be made of a biodegradable material, such that the patch may be degraded upon expiration of a given period of use.

In anotlier one of its aspects, the invention provides a method of preparing a composition as herein described, the method comprising: dissolving iodine in at least one organic acid to obtain a solution; adding hydroiodie acid to the solution and mixing to obtain a homogenous mixture: and mixing the mixture with at least one emollient to obtain the composition.

As used herein, the term "about" is meant to encompass deviation of ±10% from the specifically mentioned value of a parameter, such as temperature, pressure, concentration, etc.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging/ranges between" a first indicate number and a second indicate number and "ranging/ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween. BRIEF DESCRI PTION OF THE DRAWINGS

In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non -limiting example only, with reference to the accompanying drawings, in which:

Figs. 1A-1D show photographs of a patient's feet prior to treatment (1A-1B) and a day after application of a composition of the invention ( 1 C- 1 D) .

Figs. 2A-2E show photographs of a patient's tow-nails to treatment (2A-2B), after 2 months of treatment (2C-2D), and after 3 months of treatment with a composition of the invention (2E).

DETAILED DESCRIPTION OF EMBODIMENTS

Compositions of the invention were prepared by dissolving solid iodine (b.) in an aqueous solution of acetic acid, and heated for about 2-7 minutes at between 30- 45°C. Once full dissolution of the iodine was obtained, an aqueous solution of hydrogen iodide (HI) was added. Glycerol

was then added and mixed thoroughly for obtaining a homogenous liquid composition . Concentrations of the components in the compositions are provided in Table 1.

Table 1: Tested compositions

* solution in distilled water

Compositions of the invention were topically applied to patients' skin areas on feet and hands, infected with various fungal infections. The composition was left on the infected are for between 10 minutes and 24 hours, and then washed or wiped off. In some cases, the infected skin or nail area can be treated with the composition twice daily, i.e. the composition may be applied every 12 hours. In the present example, treatment was repeated once daily; prior to application the skin was gently scrapped or scrubbed to remove dead tissue. The treatment was continued until complete elimination of the infection.

Treatment results for 9 patients are provided in Table 2. In general, the higher the concentration of hydroiodic acid in the composition, the faster a visible improvement is obtained.

Table 2: Test results for various patients

Fig. 1 shows photographs of patient's feet infected by a fungal infection in the tows area. Figs. 1A-1B show the left and right feet, respectively, prior to treatment, while Figs. 1C-1D show the feet after 1 day of treatment. It is clearly evident that application of the composition reduced significantly the size of the infected area.

Treatment results for 4 patients suffering from, fungal infection of the tow-nails that were unsuccessfully treated by various anti-fungal treatments prior to treatment with the composition of the invention (according to Table 1) are provided in Table 3.

Table 3: Additional test results for various patients

f ^, refers to time since last treatment

Fig, 2 shows photographs of patient (A) right foot tow-nails infected by a fungal infection. Figs. 2A-2B show the extent of the infection prior to treatment. Figures 2C-2D show the nails after 2 months of treatment (once daily). Figure 2E shows full recovery obtained after a total of 3 months of treatment.

Claims

CLAIMS:

1. A composition for topical application, comprising iodine, hydroiodic acid, at least one organic acid and at least one emollient.

2. The composition of claim 1, wherein said organic acid is selected from acetic acid, propionic acid, citric acid, butaric acid, sorbic acid, ascorbic acid, salicylic acid, tannic acid, succinic acid, lactic acid, pyruvic acid, alpha ketoglutaric acid, glutamic acid, undecylenic acid, and combinations thereof.

3. The composition of claim 2, wherein said organic acid is acetic acid.

4. The composition of any one of claims 1 to 3, wherein said emollient is selected from optionally hydroxy-substituted Cg-Cso unsaturated fatty acids and esters thereof, Ci-C^'24 esters of Cs-Cso saturated fatty acids, beeswax, petroleum jelly, saturated and unsaturated fatty alcohols, hydrocarbons such as mineral oils, petrolatum, squaiane, fatty sorbitan esters, lanolin and lanolin derivatives, cholesterol and derivatives thereof, animal and vegetable triglycerides, C 1-C24 esters of dimer and trimer acids, natural or synthetic oils selected from mineral, vegetable, and animal oils, alkylene glycol and polyalkylene glycol ethers, and mixtures thereof.

5. The composition of claim 4, wherein said emollient is selected from isopropyl myristate, cetyl palmitate, octyldodecylmyristate, behenyl alcohol, cetyl alcohol, lanolin alcohol ethoxylated lanolin, hydroxylated lanolin, acetylated lanolin, diisopropyl dimerate, diisostearylmalate, diisostearyldimerate, triisostearyltrimerate, isocetyl alcohol, octyl palmitate, isostearyl neopentanoate and isocetyl stearyl stearate, polyethylene glycol and polypropylene glycol and mixtures thereof.

6. The composition of claim 4, wherein said emollient is selected from almond oii, peanut oil, wheat germ oil, linseed oil, jojoba oil, oil of apricot pits, walnuts, palm nuts, pistachio nuts, sesame seeds, rapeseed, cade oil, corn oil, peach pit oil, poppy seed oil, pine oil, castor oil, soybean oil, avocado oil, safflower oil, coconut oil, hazelnut oil, olive oil, grape seed oil, and sunflower seed oil and mixtures thereof.

7. The composition of claim 4, wherein said emollients is a C 3-0 polyol.

8. The composition of claim 7, wherein said emollient is glycerol.

9. The composition of any one of claims 1 to 8, further comprising at least one additive.

10. The composition of claim 9, wherein said at least one additive is selected from a coloring agent, a perfume, an emuisifier, a thickener, a filler, a preservative and a gelling agent,

11. The composition of any one of claims 1 to 10, comprising between about 0.5 and about 5 wt% iodine.

12. The composition of claim 1 , comprising between about 1 and about 3 wt% iodine.

13. The composition of any one of claims 1 to 12, comprising between about 0.5 and about 5 wt% hydrogen iodide.

14. The composition of claim 13, comprising between about 1 and about 2 wt% hydroiodic acid.

15. The composition of any one of claims 1 to 14, comprising between about 10 and about 25 wt% organic acid.

16. The composition of any one of claims 1 to 15, comprising between about 12 and about 18 wt% emollients.

17. The composition of any one of claims 1 to 16, wherein the ratio between the iodine and the hydroiodic acid is between about 2: 1 and 1 :2.

18. The composition of claim 17, wherein the ratio between the iodine and the hydroiodic acid is between about 1 : 1 and 1 :2.

19. The composition of any one of claims 1 to 18, being in the form of a solution, an emulsion, a gel, a cream, and an ointment

20. The composition of any one of claims 1 to 19 for use in treating fungal- associated skin condition.

21. The composition of claim. 20, wherein said fungal -associated skin condition is caused by dermatophytes.

22. The composition of claim 20 or 21, wherein said fungal -associated skin condition is selected from Tinea pedis (athlete's foot), Tinea unguium (onychomycosis). Tinea corporis, Tinea cruris (jock itch), Tinea manuum, and Tinea capitis.

23. The composition of claim 22, wherein said fungal-associated skin condition is Tinea pedis. Tinea manuum or Tinea unguium.

24. The composition of any one of claims 1 to 19 for use in balancing skin flora.

25. Use of a composition of any one of claims 1 to 19 for the preparation of a topically-applied formulation for treating fungal-associated skin disorders.

26. A method of preventing, treating or ameliorating a fungal -associated skin condition, the method comprising topically applying the composition of any one of claims 1 to 19 onto a skin or nail area of a subject infected with said fungal-associated skin condition.

27. A kit comprising a container containing a composition of any one of claims 1 to 19, and instructions for use.

28. The kit of claim 27, further comprising means for topically applying the composition.

29. A patch for applying onto skin, the patch comprising a composition of any one of claims 1 to 19.

30. A method of preparing a composition of any one of claims 1 to 19, the method comprising:

dissolving iodine in at least one organic acid to obtain a solution;

adding hydroiodic acid to the solution and mixing to obtain a homogenous mixture; and

mixing the mixture with at least one emollient to obtain the composition.