WO2013173881A1

WO2013173881A1 - A dermatological composition

Info

Publication number: WO2013173881A1
Application number: PCT/AU2013/000552
Authority: WO
Inventors: Andrew Tuan Anh LE
Original assignee: Le Andrew Tuan Anh
Priority date: 2012-05-25
Filing date: 2013-05-24
Publication date: 2013-11-28
Also published as: AU2013266023A1

Abstract

A topical composition for the treatment of skin conditions. The composition comprises an antifungal agent and an antimicrobial agent together with a pharmaceutically acceptable excipient.

Description

"A Dermatological Composition"

Cross-Reference to Related Applications The present application claims priority from AU2012902147 the contents of which are incorporated herein by reference.

Field The present disclosure relates to a topical compound for the treatment of various skin conditions.

Background Various skin conditions such as rash, eczema, and dermatitis are commonly treated by compounds containing topical steroids. Indeed steroid creams have historically been the most commonly prescribed topical medications for the treatment of eczema. While topical steroids have anti-inflammatory properties and achieve at least a short term improvement in symptoms, there are numerous side effects ranging from the severe to relatively mild associated with topical steroidal use.

For eczema other current treatments include antihistamines taken by mouth to alleviate itching, topical immunomodulators (TIMs) including tacrolimus and pimecrolimus, barrier repair creams, antibiotic creams or immunosuppressants such as cyclosporine, methotrexate or mycophenolate mofetil are used.

None of the above treat the underlying condition of, for example, eczema or other forms of dermatitis but instead alleviate the symptoms. The present inventor has previously developed a composition which utilises at least three active agents to combat the underlying disease, the invention being the subject of PCT/AU201 1/001567, the contents of which are incorporated herein. However, in developing the invention, the unexpected finding was made that a composition for treating a skin disorder may still be achievable without the need for a topical steroid.

Substitute Sheet

(Rule 26) RO/AU Summary of the Disclosure

In one aspect, there is provided a topical composition for the treatment of a skin condition, said composition comprising:

at least one antifungal agent;

an antimicrobial agent of the general formula:

and a pharmaceutically acceptable excipient; wherein said composition does not include an anti-inflammatory agent selected from a steroid.

The composition typically does not include an anti-inflammatory selected from a steroid including Hydrocortisone, Alclometasone dipropionate, Triamcinolone acetonide, Fluocinolone acetonide, Fluticasone propionate, Hydrocortisone valerate, Hydrocortisone butyrate, Flurandrenolide, Mometasone furoate, Betamethasone, Fluocinonide, Halcinonide, Amcinonide, Desoximetasone, Clobetasol propionate, Halobetasol proprionate, Diflorasone diacetate, Diflucortolone valerate, Hydrocortisone 17-butyrate, Methylprednisolone aceponate or Clobetasone butyrate or a combination thereof.

In a second aspect, there is provided a topical composition for the treatment of skin condition, said composition consisting essentially of:

at least one antifungal agent;

an antimicrobial agent of the general formula:

and a pharmaceutically acceptable excipient. In a further aspect, there is provided a topical composition for the treatment of a skin condition, said composition comprising:

at least one antifungal agent;

a Vitamin D derivative;

an antimicrobial agent of the general formula:

In yet another aspect, there is provided a topical composition for the treatment of a skin condition, said composition consisting essentially of:

at least one antifungal agent;

a Vitamin D derivative;

an antimicrobial agent of the general formula:

and a pharmaceutically acceptable excipient. In a further embodiment, the at least one antifungal agent comprises

Terbinafine. Alternatively, the antifungal agent may comprise Itraconazole, Ketaconazole Ciclopirox, Clotrimazole, Fxonazole, Miconazole, Naftifme, Nystatin, Oxiconazole, Sertaconozole, Sulconazole or Tonaftate or a combination thereof. The at least one anti-fungal may be present at less than 5%wt of the composition. Typically, the antifungal agent is present at less than 4%wt, or less than 3%wt. Still further, the antifungal may be at a concentration of less than 2%wt or less than l%wt. The antifungal agent may be present in a range of from 0.5%wt to 1.5%wt. In another embodiment, the range may be 0.6%wt to 1.4%wt; or 0.7%wt to 1.3%wt; or 0.8%wt to 1.2%wt; or 0.8%wt to l.l%wt; or 0.85%wt to L0%wt; or 0.85%wt to 0.9%wt. The antifungal may be present in a concentration of 0.86%wt.

In a particular embodiment, the at least one antifungal agent comprises Terbinafine hydrochloride at a concentration range of from 0.5%wt to l %wt of the composition. In another embodiment, said Terbinafine hydrochloride may be at a concentration ranging from 0.8%wt to 0.9%wt. In one preferred embodiment the terbinafine of the composition comprises 0.86% wt.

In a particular embodiment, the at least one antifungal agent comprises ketoconazole at a concentration range of from 0.5%wt to l%wt of the composition. In another embodiment, said ketoconazole may be at a concentration ranging from 0.8%wt to 0.9%wt. In one preferred embodiment the ketoconazole of the composition comprises 0.86% wt. Other naturally occurring antifungal agents may be included in the composition including one or more of allicin, tea tree oil, citronella oil, iodine, olive leaf, orange oil, palmarosa oil, patchouli, lemon myrtle, neem seed oil, coconut oil, zinc, or selenium The antimicrobial agent of the composition is typically Merbromine which is commonly marketed under the trade name Mercurochrome™.

The antimicrobial agent may be present in the composition at a concentration of less than 5%wt. Still further, the antimicrobial agent may be present at a concentration of 4%. In another embodiment the antimicrobial agent is at a concentration of 3%. Still further, the antimicrobial agent is at a concentration of 2%. The antimicrobial agent may also be present at a concentration of less than 2 %. The antimicrobial agent may be at a concentration of between 1 % and 2%. The antimicrobial agent may be at a concentration of l %wt. In one embodiment, the composition comprises said antimicrobial agent at a concentration in the range of 0.1 %wt to 1.0%wt. In a further embodiment the range of concentration of said antimicrobial agent is 0.2%wt to 0.9%wt; or 0.3%wt to 0.8%wt; or 0.4%wt to 0.6%wt; or 0.4%wt to 0.5%wt.

In one preferred embodiment the composition comprises Merbromine at a concentration of approximately l%wt. In another embodiment, the Merbromine is present in a concentration of 2%.

In one embodiment, the composition comprises 2%wt antimicrobial and 0.86%wtantifungal. In another embodiment, the composition comprises 2% antimicrobial and or l%wt antifungal.

In another embodiment, the composition comprises l%wt antimicrobial and 0.86%wt antifungal. In another embodiment, the composition comprises l %wt antimicrobial and or l%wt antifungal;

In one embodiment, the composition comprises Merbromine at a concentration of 2%wt or l %wt and terbinafine at 0.86%wt. In a further embodiment, the composition comprises Merbromine at a, concentration of 2%wt and terbinafine at l %wt. In another embodiment, the composition comprises Merbromine at 2%wt or l%wt and ketoeonazole at l%wt. In another embodiment, the composition comprises Merbromine at 2% and ketoeonazole at 2%. The composition may further include a Vitamin D derivative. The Vitamin D derivative may comprise an analog of Vitamin Di. Alternatively the Vitamin derivative may be based on Vitamin D₂, Vitamin D₃ or Vitamin D4. An example of a suitable Vitamin D derivative for use in the present composition comprises a synthetic derivative of calcitriol and includes calcipotriol.

The Vitamin D derivative may be present in the composition at a concentration of less than l%wt. Typically, the concentration of the Vitamin D derivative is less than 0.5%wt and further, less than 0.3%wt, 0.2% wt, 0.1%vvt. The concentration of the Vitamin D derivative may be less than 0.005%wt. Still further, the concentration of Vitamin D derivative may be less than 0.00 l%wt. In another embodiment, the concentration of the Vitamin D derivative is less than 0.0001%wt. Still further, the Vitamin D derivative may be at a concentration of 0.00005%wt or less.

For the treatment of psoriasis 0.00005% calcipotriol (50mcg/g) may be used in combination with an anti-fungal and Merbromine. A steroid agent may still be added to this triple therapy if desired and such a steroid may include betamethasone valerate at a concentration of 0.1 % or less.

The pharmaceutically acceptable excipient of the composition may comprise any one or more of an emulsifier, emollient, solvent, or humectant.

Examples of suitable emollients include paraffinum liquidum, petrolatum, proplylene glycol, fatty acid esters, mineral oil including dimethicone, waxes including white wax, spermacetic wax, squalene, cetearyl alcohol, cetostearyl alcohol or stearyl alcohol.

Examples of suitable emulsifiers include ceteth-20, laureth-3, glyceryl stearate, polyethylene glycol or stearic acid. Examples of suitable solvents include isopropyl alcohol, propylene glycol, butylene glycol, hexylene glycol, carbomer 934P or polyethylene glycols. Examples of humectants include glycerin and sorbitol.

The composition may further include pH adjuster agents such as buffering agents including sodium phosphate monobasic dehydrate; acids such as phosphoric acid hydrochloric acid or bases such as sodium hydroxide.

The composition may further include one or more preservatives. Examples of suitable preservatives include benzyl alcohols including dichlorobenzyl alcohol or parabens including methyl paraben.

In another embodiment, the composition may further include purified water and hydroxypropyl cellulose. In a still further embodiment, the composition may contain one or more antibacterial agents. For example, the composition may contain one or more antibiotics. The antibiotic may be selected from one or more of the classes that include but are not limited to penicillins, cephalosporins, carbapenems, aminoglycosides, sulfonamides, quinolones, or oxazolidinones.

The composition may also include one or more anti-viral agents. An example of an antiviral is acyclovir.

Still further, the composition may contain an antihistamine agent. The antihistamine may be selected from the group comprising piperazines, alkylamines or phenothiazines. Alternatively, an oral antihistamine may be administered concurrently with topical administering of the composition of the present invention.

The composition for topical application may comprise a cream. Alternatively, the composition may comprise an ointment. Still further, the composition may be in the form of a lotion, paste, gel, spray or powder.

The composition of the present invention may be used in a number of skin conditions. The composition has particular application in eczema. Further conditions which may be treated by the composition include but are not limited to: Contact dermatitis;

Rashes;

Psoriasis;

Impetigo;

Fungal infections;

Bacterial skin infections; ■ ^' -

Viral skin infection;

Yeast infections;

Trauma or injury to the skin;

Pityriasis vesicolor;

Nappy rash;

Ilyperhydrosis;

Smelly armpits or feet;

Acne;

Idiopathic itchy skin;

Skin burns; or

Scarring.

Brief Description of the Drawings

Figure 1 is a photograph of an affected area of skin of Patient I ;

Figure 2 is a microscopic view of a biopsied sample of the affected area of Patient 1 ; Figure 3 is a further low power microscopic view of Figure 2;

Figure 4 is a photograph of the affected area of skin of Patient 1 following treatment with the present composition; Figure 5 is a microscopic view of a biopsied sample of the affected area of skin following treatment with the present composition;

Figure 6 is a photograph showing an affected area of skin of Patient 2; Figure 7 is a microscopic view of a biopsied sample of the affected skin of Patient 2 Figure 8 is a photograph of the affected area of skin of Patient 2 following treatment with the present composition;

Figure 9 is a microscopic view of the area of skin shown in Figure 8;

Figure 10 is a photograph of an affected area of skin of Patient 3;

Figure 1 1 is a microscopic view of a biopsied sample of the affected area of skin of Patient 3 shown in Figure 10;

Figure 12 is a further microscopic view of the sample of Figure 1 1 but in low power;

Figure 13 is a photograph of the area of affected skin of Patient 3 following treatment with the present composition; and

Figure 14 is a microscopic view of a biopsied sample of the skin shown in Figure 13 Examples Example 1

Composition A

A composition for topical application was formulated including active ingredients:

1% Merbromine; and

1 % Terbinafine hydrochloride.

In some embodiments the above actives may be mixed with a base excipient which included:

Petrolatum;

Refined mineral oil;

Cetostearyl alcohol;

Glyceryl monostearate (self ernulsifying);

Squalane;

Stearic acid;

Purified water; Dichlorobenzyl alcohol;

Macrogol cetostearyl ether;

Glyceryl monostearate 40-55;

Macrogol lauryl ether;

Methyl parahydroxybenzoate E218; and

Dimethicone

The base used in Example 1 is QV™ cream sold by Ego Pharmaceuticals. Composition B

In a further composition, Composition B, the active ingredients were:

0.5% Merbromine; and

1% Terbinafine hydrochloride.

Case Studies Patient 1 Figure 1 is a photograph of a right knee of a male with an abnormal patch of skin 10. The visual examination led to a preliminary diagnosis of psoriasis and two punch biopsies of skin were taken for histological examination.

Figures 2 and 3 show the histological sections of the biopsied area at high power and low power respectively. As can be seen from the histological sections moderate psoriasiform epidermal hyperplasia 9 and elongation of the dermal papillae with thinning of supra-papillary plates and overlying mounds of parakeratosis 1 1 some of which contain neutrophils 12 was observed. Vascular telangiectasia 13 within the papillary dermis and a mild perivascular lymphohistiocytic infiltrate 14 within the upper dermis was present. These features were in keeping with a diagnosis of psoriasis.

Patient 1 commenced a treatment program of 2 applications of Composition A each day for 2 weeks. Figure 4 is a photograph of the affected knee two weeks after commencement of treatment.

Figure 5 shows a histological section of a punch biopsy of the skin taken at the same time as the photograph and two weeks after commencement of the treatment. The histological examination showed mild psoriasiform epidermal hyperplasia 9 with a single small mound of parakeratosis 1 1 which did not contain inflammatory cells. There was no vascular telangiectasia within the papillary dermis and only a minor perivascular lymphohistiocytic infiltrate 15 within the upper dermis 3. The mid dermis 2 and lower dermis 3 appeared normal. The characteristics were in keeping with psoriasis showing a good treatment response with significantly less epidermal hyperplasia, less overlying parakeratotic scale and less inflammation than the biopsies shown in Figure 2 and 3. Patient 2

A photograph of part of an arm of a patient showing an affected area of skin 20 is shown in Figure 6. A punch biopsy of the affected skin was taken and histological sections of the biopsy provided in Figure 7.

Moderate psoriasiform epidermal hyperplasia 9, mild spongiosis (intercellular oedema) 21, superficial mounds of parakeratosis 11 containing neutrophils, thinning of supra-papillary plates, papillary dermal vascular telangiectasia 13 and a moderate mixed perivascular inflammatory infiltrate 22 of lymphocytes, histiocytes and occasional plasma cells within the upper dermis was observed. The characteristics of this section were in keeping with a diagnosis of psoriasis.

Patient 2 commenced a treatment regimen of 2 applications of Composition A each day for 3 months.

Figure 8 shows a photograph of Patient 2 3 months after commencement of treatment. Visually the affected area appears well healed.

A punch biopsy of skin of the affected area 20 was taken and viewed histologically as seen in Figure 9. There was significantly reduced hyperkeratosis 1 1 and the epidermis 4 appeared normal with no epidermal hyperplasia. The upper dermis 3 appeared normal with no elongation of papillae. The appearance was indicative of almost resolved psoriasis. Patient 3

Figure 10 shows a photograph of a patient 3 presenting with an affected area of skin 30 with inflamed skin, excoriation marks, loss of skin marking, early

linchenification and superficial scars from scratching. The presentation was suggestive of atopic dermatitis.

A punch biopsy was taken of the affected area 30 and shown in Figures 1 1 and 12. Mild epidermal spongiosis 21 with a small intraepi dermal pustule 31 containing neutrophilic debris and bacteria with overlying parakeratosis 1 1 at one edge was observed. There was mild perivascular lymphohistiocytic infiltrate 22 with moderate numbers of perivascular and interstitial eosinophils 32 within the upper dermis 3.

The characteristics were in keeping with a diagnosis of spongiotic dermatitis. Patient 3 commenced a treatment regimen of 2 applications of Composition B each day for 2 weeks.

Figure 13 is a photograph of the affected area 30 after 2 weeks of treatment. The skin had normal marking and no inflammation and no excoriation. There were multiple post inflammatory hyperpigmentation spots from resolved scratch wounds.

Figure 14 shows minor spongiosis 21 and no overlying parakeratosis. There was no significant dermal inflammation and such features were in keeping with almost complete resolution of the dermatitis.

Claims

1. A topical composition for the treatment of a skin condition, said composition comprising:

at least one antifungal agent;

an antimicrobial agent of the general formula:

2. A topical composition for the treatment of a skin condition, said composition consisting essentially of:

at least one antifungal agent;

an antimicrobial agent of the general formula:

and a pharmaceutically acceptable excipient.

3. The composition of claim 1 or claim 2 wherein the at least one antifungal agent comprises Terbinafine. o

4. The composition of claim 1 or claim 2 wherein the at least one antifungal agent comprises Itraconazole, Ketaconazole Ciclopirox, Clotrimazole, Econazole, Miconazole, Naftifine, Nystatin, Oxiconazole, Sertaconozole, Sulconazole or Tonaftate or a combination thereof.

5. The composition of any one of the preceding claims wherein the at least one anti-fungal is present at less than 5%wt of the composition.

6. The composition of any one of the preceding claims wherein the at least one antifungal agent is present at less than 4%wt, or less than 3%wt of the composition.

7. The composition of any one of the preceding claims wherein the concentration of the antifungal in said composition is less than l%wt.

8. The composition of any one of the preceding claims wherein the concentration of the antifungal agent in said composition is 0.86%wt.

9. The composition of claim 1 or claim 2 wherein said anti-fungal agent comprises terbinafine hydrochloride at a concentration range of between 0.5%wt to l%wt of the composition.

10. The composition of claim 8 wherein the anti -fungal agent comprises terbinafine hydrochloride. -

1 1. The composition of claim 1 or claim 2 wherein the at least one antifungal agent comprises ketoconazole at a concentration range of from 0.5%wt to l%wt of the composition.

12. The composition of any one of the preceding claims wherein the antimicrobial agent of the composition comprises Merbromine.

13. The composition of any one of the preceding claims wherein the antimicrobial agent is at a concentration of less than 5%wt of said composition

14. The composition of any one of the preceding claims wherein the antimicrobial agent is at a concentration of less than 2 %wt of the composition.

15. The composition of any one of claims 1 to 12 wherein the antimicrobial agent is at a concentration of from l%wt to 2%wt of the composition.

16. The composition of any one of claims 1 to 12 wherein the antimicrobial agent is at a concentration of l %wt of the composition.

17. The composition of claim 1 or claim 2 wherein the composition comprises 2%wt of said antimicrobial agent and 0.86%wt of said antifungal agent.

1 8. The composition of claim 1 or claim 2 wherein the composition comprises 2% of said antimicrobial agent and or l %wt of said antifungal agent.

19. The composition of claim 1 or claim 2 wherein the composition comprises l %wt of said antimicrobial agent and 0.86%wt of said antifungal agent.

20. The composition of claim 1 or claim 2 wherein the composition comprises l%wt of said antimicrobial agent and or 1 %wt of said antifungal agent.

21. The composition of any one of the preceding claims further including a Vitamin D derivative.

22. The composition of claim 21 wherein the Vitamin D derivative comprises an analog of Vitamin Di .

23. The composition of claim 21 wherein the composition comprises a synthetic derivative of calcitriol.

24. The composition of any one of claims 21 to 23 wherein the Vitamin D derivative is present in the composition at a concentration of less than l%wt.

25. The composition of any one of claims 21 to 23 wherein the concentration of the Vitamin D derivative is less than 0.5%wt

26. The composition of any one of claims 21 to 23 wherein the concentration of the Vitamin D derivative is less than 0.005%wt.

27. The composition of any one of claims 21 to 23 wherein the concentration of the Vitamin D derivative is 0.00005%wt or less.

28. The composition of any one of the preceding claims for use in the treatment of eczema.

29. The composition of any one of the preceding claims for use in the treatment of psoriasis.

30. The composition of any one of the preceding claims for use in the treatment of any one of the group selected from contact dermatitis; skin rashes; impetigo; fungal skin infections; bacterial skin infections; viral skin infection; yeast infections; trauma or injury to the skin; pityriasis vesicolor; nappy rash; hyperhydrosis; smelly armpits or feet; acne; idiopathic itchy skin; skin burns; or scarring.

31. A method of treating a skin condition comprising applying a composition according to any one of the preceding claims to an affected area of skin.