WO1997035597A1

WO1997035597A1 - Acne treatment

Info

Publication number: WO1997035597A1
Application number: PCT/AU1997/000190
Authority: WO
Inventors: John Alexander Staton; James Steven Rowe
Original assignee: Mainstar One Investments Pty. Ltd.
Priority date: 1996-03-25
Filing date: 1997-03-24
Publication date: 1997-10-02
Also published as: AUPN892496A0; NZ332353A; PL328964A1; ZA972515B; JP2000507248A; CN1219880A; EP0901377A1; CA2250383A1; EA199800869A1

Abstract

A composition for topical treatment of acne, said composition comprising 0.5-20 % w/w of NAD, NADP or a precursor which generates NAD or NADP in use, 0.1-25 % w/w tea tree oil and a pharmaceutically acceptable carrier.

Description

TITLE "ACNE TREATMENT" FIELD OF THE INVENTION THIS INVENTION relates to a topical composition for the treatment of acne and related conditions, the composition comprising melaleuca (tea tree) oil and NAD, NADP or a precursor which generates NAD or NADP in use inclusive of nicotinamide, nicotinic acid or lower C_r C₄ alkyl nicotinate.

BACKGROUND OF THE INVENTION Acne is a self-limiting condition of the sebaceous follicles.

The characteristic lesion is the comedo, a collection of sebaceous secretions and dead cells retained in the hair follicle and excretory duct of the sebaceous gland. Pimples are the common name for non¬ inflammatory comedomes and can be open (blackheads) or closed (whiteheads). If bacteria are present, the bacteria can cause breakout of the oily sebaceous materials resulting in the release of free fatty acids. The release of free fatty acids results in inflammation causing erythema and swelling around the comedomes. If the comedomes are ruptured, skin may become elevated (papules), filled with pus (pustules) or cysts may form.

The main causes of acne are generally considered to be oily skin, hyperkeratosis of the follicular wall and bacterial infection, particularly by the anaerobic Propionibacterium acnes. Treatment is with peeling agents and topically applied antiseptics such as benzoyl peroxide, salicylic acid, resorcinol and triclosan. Severe cases can be treated systemically with antibiotics such as minocycline, tetracycline, erythromycin or retinoic acid. Topical treatment with erythromycin or clindamycin can also be employed.

Carson, C.F. and Riley, T.V., 1994, Letters in Applied Microbiology 19 have shown the effectiveness of tea tree oil against P. acnes, the common organism associated with the condition. It was found that the minimum bactericidal concentration (MBC) of tea tree oil against P. acnes was between 0.25 and 0.5%.

Clinical studies conducted at the Royal Prince Alfred Hospital in Sydney, Australia, compared a 5% tea tree oil gel with a commercially available 5% benzoyl peroxide cream (Basset et al., 1990, Medical Journal of Australia 153). The studies concluded that "both 5% tea tree oil and 5% benzoyl peroxide had a significant effect on ameliorating the patient's acne by reducing the number of inflamed lesions (open and closed comedomes)". The results indicated that tea tree oil had a slightly slower onset of action but significantly less side effects than benzoyl peroxide. The main side effects associated with benzoyl peroxide are skin irritation and sensitisation which may often produce skin rashes thereby precluding further treatment with benzoyl peroxide. Benzoyl peroxide has another disadvantage in that it can dry out the skin leaving it rough and flaky.

Dermatologists have noted the topical anti-inflammatory effects of nicotinamide (Berk, M.A. and Lorincz, A.L, 1986, Arch. Dermatol. 122 670-674) as well as nicotinic acid and other pyridine compounds (Johnson, M.H. and Binkley, G.W., 1950, J. Invest. Dermatol. 14 233-238). A study by Fivenson er al., 1994, Arch. Dermatol. 130 753-

758) supports the efficacy of the combination of nicotinamide and tetracycline in the treatment of bullous pemphigoid by means of a randomised comparative trial against prednisone. Bullous pemphigoid is a chronic autoimmune disease characterised by erythematous plaques, vesicles and lense bullae.

Reference also may be made to U.S. Patent 4607101 which refers to a method of treatment of acne vulgaris which comprises administration of 1-15% by volume of a carrier of carbamide peroxide alone or in combination with nicotinic acid or nicotinamide in o concentrations of 1 -10% by volume of the carrier.

U.S. Patent 4505896 refers to a method of treatment of acne vulgaris using nicotinamide and/or nicotinic acid in concentrations of from 1-7% by volume of the carrier in combination with sulfur salicylic acid, benzoyl peroxide, vitamin A acid, erythromycin base, clindamycin and tetracycline. Reference may also be made to U.S. Patent 5240945 which shows that topical application of a lower alkyl nicotinate, such as methyl nicotinate, to an acne papule can effect rapid improvement to the lesion and often reduce the pain associated with such lesions. The amount of lower alkyl nicotinate utilized is from 5-2.2 by weight of a composition including a suitable carrier.

U.S. Patent 5459153 refers to the treatment of acne vulgaris using a composition comprising pantothenic acid or derivative thereof together with nicotinic acid or derivative thereof which may generate NAD or NADP. The concentration of nicotinic acid utilized in the composition is from 0.5-10% by weight of the composition.

More recently, Shalita, A.R. and Smith G., 1995, J. Dermatol. 36(6) 434-437, have compared the safety and efficacy of topically applied 4% nicotinamide gel to a 1% clindamycin gel for the treatment of mild acne vulgaris. The workers concluded that 4% nicotinamide gel was of comparable efficacy to 1% clindamycin gel in the treatment of acne vulgaris. Because clindamycin, like other anti¬ microbials, is associated with emergence of resistant micro-organisms, nicotinamide gel is a desirable alternative for the treatment of acne vulgaris. DISCLOSURE OF THE INVENTION

The inventors have found that tea tree oil and NAD, NADP or precursor thereof in combination are unexpectedly effective in the treatment of acne when compared to treatment with tea tree oil or nicotinamide alone. In a first aspect, the present invention consists in a composition for the topical treatment of acne, said composition comprising 0.5-20% w/w of NAD, NADP or a precursor thereof which generates NAD or NADP in use, which precursor may include nicotinamide, nicotinic acid or lower C_rC₄ alkyl nicotinate. The composition may also comprise 0.1- 25% w/w tea tree oil and a pharmaceutically acceptable carrier. The concentration of nicotinamide is preferably in the range of 2-7% w/w, most preferably 5% w/w. The concentration of tea tree oil is preferably 2-20% w/w, most preferably 5% w/w. The tea tree oil is preferably Melaleuca alternifolia oil of Australian Standard (AS) 2782, i.e. Intemational Standard (DIS) 4730. However, tea tree oil may be used in any of its natural forms which are obtained from any other appropriate Melaleuca species or Leptospermum species, such as, for example, M. linariifolia, M. dessitafolia as well as modified extracts thereof. The term "tea tree oil" as used herein may also include one or more active components thereof, such as terpinen-4-ol and/or alpha terpineol. The composition may be in any conventional form suitable for topical application such as in the form of a cream, stick, gel, ointment, paint, lotion or spray. The balance of ingredients up to 100% may include additives and excipients conventionally found in topical formulations such as emulsifiers, surfactants, thickening agents, emollients, stabilisers, humectants and preservatives.

The composition of the invention may be used as a clear aqueous solution. Usually such a clear aqueous solution may comprise 1- 20% surfactant, emulsifier or solubilising agent and, more preferably, a non-ionic surfactant, such as POLYSORBATE or TWEEN. More preferably, this may comprise 1-10% of surfactant and, most preferably, 1- 5% of surfactant.

In addition to the aforementioned surfactant, the composition of the invention may include 1-10% of an emollient which moisturizes the skin or, more preferably, 1-5% of the emollient. A suitable emollient is CETIOL or PEG 7 glyceryl cocoate. There also may be included 1-10% and, more preferably, 1-5% of a humectant, such as glycerol or . propylene glycol and 1-5% of a thickener or viscosity increasing agent, such as a gum, in the form of a guar gum, gum tregacanth, xanthan gum, or galactomannan gum. There also may be included 1-15% of a detergent, such as sodium lauryl ether sulphate and/or ammonium lauryl sulphate. There also may be provided from 1- 5% of a cleaning agent, such as coconut diethanolamide.

When used as a cream, the composition may include waxes, such as 1-10% and, more preferably, 1-5% of cetyl alcohol or stearyl alcohols. There also may be included essential oils, herbs, vitamins, such as Vitamin E or Vitamin A, hydrolysed collagen, amino acids, panthenol and other nutritional factors as may be required.

In a second aspect, the present invention consists in a method of treating or reducing incidence of acne comprising applying an effective amount of a composition to skin in need of such treatment, said composition comprising 0.5-20% w/w of NAD, NADP or the abovementioned precursor which generates NAD or NADP in use, which precursor preferably comprises nicotinamide, nicotinic acid or lower C^C-₄ alkyl nicotinate. The composition also includes 0.1-20% w/w tea tree oil and a pharmaceutically acceptable carrier.

According to this aspect of the invention, the composition is applied directly to the lesions and preferably also the surrounding areas of skin. The composition can also be applied to skin susceptible to acne outbreak to reduce the incidence of lesions. The desired frequency of application will vary with the severity of the acne. Application once to three times per day is recommended for milder cases, with more frequent application for severe cases. Where the composition is in the form of a skin wash, including appropriate surfactants, the composition may be applied to acne affected areas or areas susceptible to acne and then rinsed off with water. Washing with such a composition can be repeated once to three times per day, or more often if desired. .Without being bound by theory, it is hypothesized that the mechanism of action of nicotinamide and related compounds as described above is associated with its ability to form NAD or NADP in use which is an enzymatic co-factor.

Preferred forms of the invention will now be described by way of examples.

EXAMPLES

Example 1

A suitable gel composition of the present invention is as follows :-

Polymeric 0.25% supplied by B. F. Goodrich under emulsifiers the name PEMULEN TR-1

Carboxypolymer 0.6% supplied by B. F. Goodrich under the name CARBOPOL

Nicotinamide BP or 5.0% USP

Tea tree oil AS2782 5.0%

Humectant 5.0% supplied by Unichema (glycerol)

Ethanol 10.0%

Purified water up to 100.0%

Example 2

A suitable cream composition of the present invention is as follows:-

Nicotinamide BP 5.0%

Cetomacrogol emulsifying wax 15.0%

Cetyl alcohol 1.0%

Tea tree oil 5.0% Glyceryl monostearate 3.0%

Preservative qs supplied by International

Speciality Products under the name GERMABEN 11E

Purified water 71.0%

Example 3

A suitable lotion composition of the present invention is as follows:-

Nicotinamide BP 5.0%

Tea tree oil 5.0%

PEG-6-stearate (and) glycol stearate 8.0%

Stearic acid 1.0%

Glyceryl monostearate 3.0%

Preservative (as specified in Example qs 2)

Purified water 78.0%

Example 4

The anti-bacterial activity of a composition containing 5% w/w tea tree oil and 5% w/w nicotinamide was compared with the activity of 5% w/w tea tree oil, 5% w/w nicotinamide and two commercial preparations containing benzoyl peroxide as the active ingredient. The comparison was by way of a suspension test using P. acnes ATCC6919. Tea tree oil was AS2782 grade. The current ISO standard reference is DIS (draft International Standard) 4730.

The results are shown in Table 1.

The test was repeated for tea tree oil without nicotinamide and the combination of tea tree oil and nicotinamide. The results are shown in Table 2. As can be seen from the results, the base without any active ingredients has no anti-bacterial activity. Tea tree oil alone has some activity whereas nicotinamide has very little anti-bacterial activity.

There is a greatly enhanced anti-bacterial effect from the combination of tea tree oil and nicotinamide. The effect is similar to that of the commercial benzoyl peroxide compositions.

Example 5 The ratio of nicotinamide to tea tree oil was varied as shown in Table 3 in this Example such that the ratio of tea tree oil to nicotinamide varied between 5:5 to 1.25:5 on a weight for weight basis. Results of a P. acnes suspension test show that there is no significant difference between any one of the results when the content of nicotinamide was at least 5.0%.

Example 6 Further studies as shown in Table 4 using the P. acnes suspension test show that at concentrations below 5%, nicotinamide was not as effective as concentrations at 5% or above. Concentrations of nicotinamide in excess of 5% did not appear to enhance the activity of the combination. Example 7

The effect of analogues of nicotinamide are shown in this Example in Table 5, again utilising the P. acnes suspension test in that N substituted and ring substituted derivatives were subjected to a suspension test using P. acnes as the test organism. It is shown the parent compound nicotinic acid is very effective as is the N substituted moiety. The ring substituted moieties (1 -methyl and 6- methylnicotinamide) are, however, ineffective. All compounds were formulated in a conventional cream base as described in Example 2 with the concentration of tea tree oil being 5% in each case. Example 8

The effect of pH was evaluated on a composition containing 5% w/w tea. tree^' oil, 5% nicotinamide, 5% Etocas (PEG-35-Castor Oil) with the balance being water. The pH of this composition was adjusted to 3.0 with HCl and it was ascertained that the resulting composition met the requirements of the United States Pharmacopoeia (USP) and British Pharmacopoeia (BP) in relation to preservative efficacy.

In relation to the same composition, the effect of pH on each composition was evaluated in regard to adjustment of the pH to pH 7.0 using lactic acid in combination with sodium lactate. Again, the resulting composition met the requirements of the USP and BP. In relation to the same composition, the pH was adjusted to pH 9.0 using potassium hydroxide and it was noted that the resulting formulation met the requirements of the USP and BP.

It was also noted that when the same composition was adjusted to pH 3.0 using lactic acid, while the requirements of the USP were met, the requirements of the BP which is a far more stringent test in regard to preservative efficacy were not met. Similar conclusions applied in regard to adjustment of the pH of the composition to (i) 5.0 using HCl, (ii) to 5.0 using lactic acid, (iii) to 7.0 with HCl and 9.0 with sodium lactate.

Thus, it would appear from this Example that when the pH of the composition is adjusted to extreme pH values using an inorganic acid such as HCl or inorganic base such as KOH, the resulting composition is satisfactory in relation to preservative efficacy. When the pH is adjusted to extreme pH values using an organic acid in the case of lactic acid or an organic base in the case of sodium lactate, the resulting composition is unsatisfactory in relation to preservative efficacy with regard to the BP requirements.

However, when the pH is adjusted to neutral such as pH 7.0 with lactic acid or sodium lactate, the resulting composition is satisfactory in relation to preservative efficacy for both the BP and the USP. In regard to the testing of the compositions described above which passed the BP preservative efficacy test,, the results of these evaluations are reproduced in Tables 6 and 7.

The effect of other variables on the activity of the combination is also important. These include the effect of pH, other excipients and the method of preparation of the final formulation. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. Example 9

Seven patients presented with mild to moderate symptoms of acne vulgaris in a community pharmacy requested treatment. All patients were provided with the formulation as described in Example 1 and were instructed to apply the formulation topically to the affected areas. After periods of between one and three weeks, the patients were re-assessed on a subjective basis. In six cases out of seven, there was a noticeable improvement in their condition with some patients being completely clear of symptoms.

TAPIES

TABLE 1 Challenge inoculumn 8.7 x 10⁶

TABLE 2 Challenge inoculum 1.1 x 10⁷

Base + TTO 4.7x10* 2.8x10* 1.4x10* 2.0 x10^s 1.6 x10⁴

Base + TTO + 2.2x10* 2.7 x10³ 5.0 x10¹ <10 <10 Nicotin TABLE 3 Inoculum control (placebo) 9.3 x 10⁷

Ratio Surviving organisms/reductions at time intervals TTO:Nicotinamide

5 mins 15 mins 30 mins 45 mins 60 mins

5:5 cfu/mL 550 <100 <100 <100 <100 log₁₀ reduction 5.6 >6.0 >6.0 >6.0 >6.0

5:10 cfu/mL 44000 500 <100 <100 <100 log,₀ reduction 3.7 5.6 >6.0 >6.0 >6.0

2.5:5.0 cfu/mL 1400 300 <100 <100 <100 log₁₀ reduction 4.9 5.8 >6.0 >6.0 >6.0

1.25:5.0 cfu/ML 1000 <100 <100 <100 <100 log₁₀ reduction 4.9 >6.0 >6.0 >6.0 >6.0

TABLE 4

Ratio Surviving organisms/reductions at time intervals 7TO:Nicotinamide

5 mins 15 mins 30 mins 45 mins 60 mins

5:0 cfu/mL 43000 14000 100 <100 <100 log₁₀ reduction 3.7 3.9 5.9 >6.0 >6.0

5:1 cfu/mL 33000 800 150 <100 <100 log₁₀ reduction 3.8 5.1 5.9 >6.0 >6.0

5:2.5 cfu/mL 58000 2800 150 200 <100 log₁₀ reduction 3.5 3.8 5.9 5.9 >6.0

5:5 cfu/ML <100 <100 <100 <100 <100 log_i0 reduction 6.0 >6.0 >6.0 >6.0 >6.0

5:7.5 cfu/ML 1600 <100 <100 <100 <100 log₁₀ reduction 3.9 >6.0 >6.0 >6.0 >6.0

5:10 cfu/ML <100 <100 <100 <100 <100 log₁₀ reduction >6.0 >6.0 >6.0 >6.0 >6.0

TABLE 5

Ratio Surviving organisms/reductions at time intervals TTO:Nicotinamide

5 mins 15 mins 30 mins 45 mins 60 mins

Nicotinic Acid cfu/mL 1100 100 <100 <100 <100 log₁₀ reduction 4.5 5.5 >6.0 >6.0 >6.0

N-methyl nicotinamide cfu/mL >25000000 20000 10000 1200 <100 log₁₀ reduction <0.1 2.2 3.5 4.4 >6.0

L -methyl nicotinamide cfu/mL 1500000 1300000 140000 990000 810000 log₁₀ reduction 1.3 1.4 1.4 1.5 1.6

6-methyl nicotinamide cfu/ML 1200000 1200000 1100000 1000000 770000 log₁₀ reduction 1.4 1.4 1.5 1.5 1.6

TABLE 6 Preservative Efficacy Test - BP/USP (Sample at pH 3) adjusted with HCl

Time S. aureus P. aeruginosa E. coli C. albicans A. niger Point ATCC6538 ATCC9027 ATCC8739 ATCC10231 ATCC 16404

Inoculum 1.5 x 10* 1.4 x 10* 1.1 x 10* 1.3 x 10* 2.0 x 10*

O hr 3.8 x 10⁴ 6.7 x 10⁴ - 3.2 x 10* 4.0 x 10^s

48 hr <100 <100 - - -

7 dy <100 <100 <100 <100 1.4 x 10^s

14 dy <100 <100 <100 <100 7.0 x 10³

21 dy <100 <100 <100 <100 4.0 x 10²

28 dy <100 <100 <100 <100 <100 TABLE 7 Preservative Efficacy Test - BP/USP (Sample at pH 7) adjusted with lactic acid/sodium lactate

Time S. aureus P. aeruginosa E. coli C. albicans A. niger Point ATCC6538 ATCC9027 ATCC8739 ATCC 10231 ATCC 1640

4

Inoculum 1.5x10* 1.4x10* 1.1 x10* 1.3x10* 2.0 x 10*

Ohr 8.3x10* 3.3x10* - 1.3 x10^s 9.0x10⁵

48 hr <100 <100 - - -

7dy <100 <100 <100 <100 <100

14 dy <100 <100 <100 <100 <100

21 dy <100 <100 <100 <100 <100

28 dy <100 <100 <100 <100 <100

LEGENDS

TABLE 2 cfu colony forming units TTO tea tree oil Nicotin nicotinamide TABLE 4 cfu colony forming units

Log₁₀ reduction organisms killed at different time points with respect to comparison control (placebo), expressed to 1 decimal place. A 3 log₁₀ reduction is equivalent to 99.9% and a 61 log₁₀ reduction is equivalent to 99.9999%.

Claims

1. A composition for topical treatment of acne, said composition comprising 0.5-20% w/w of a precursor which generates NAD or NADP in vivo, 0.1-25% w/w tea tree oil and a pharmaceutically acceptable carrier.

2. A composition as claimed in claim 1 wherein the precursor is selected from nicotinamide, nicotinic acid or lower (C_rC₄) alkyl nicotinate.

3. A composition as claimed in Claim 2 wherein the precursor is nicotinamide.

4. A composition as claimed in Claim 2 wherein the concentration of precursor is from 2-7% w/w.

5. A composition as claimed in Claim 2 wherein the concentration of precursor is 5% w/w.

6. A composition as claimed in Claim 1 wherein the concentration of tea tree oil is from 2-20% w/w.

7. A composition as claimed in Claim 6 wherein the concentration of tea tree oil is 5% w/w.

8. A method of heating or reducing incidence of acne comprising applying an effective amount of a composition to a skin in need of such treatment, said composition comprising the composition of any preceding claim.

9. A composition as claimed in Claim 1 substantially as herein described with any one of Examples 1-3.