New Zealand Paient Spedficaiion for Paient Number 332353
WO 97/35597 PCT/AU97/00190 -
TITLE "ACNE TREATMENT FI51D OF THE INVENTION THIS INVENTION relates to a topical composition for the 5 treatment of acne and related conditions, the composition compnsing 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,-Q, alkyl nicotinate
BACKGROUND OF THE INVENTION 10 Acne is a self-limiting condition of the sebaceous follicles
The charactenstic lesion is the comedo, a collection of sebaceous secretions and deacTdehKTGteined in the hair follicle and excretory duct of the sebaceous. I Pimples are the common name for noninflammatory comedomes and can be open (blackheads) or closed 15 (whiteheads) If bacteria are present, the bactena can cause breakout of the oily sebaceous matenals 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 2 o 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 topics'ly.applied antiseptics such as benzoyl peroxide, 25 salicylic acid, resorcinol and tnclosan 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, CF and Riley, TV, 1994, Letters in Apolied 30 Microbiology 19 have shown the effectiveness of tea tree oil against P acnes, the common organism associated with the condition It was found
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that the minimum bactencidal 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 5 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 io 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 imtation 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 15 out the skin leaving it rough and flaky
Dermatologists have noted the topical anti-inflammatory effects of nicotinamide (Berk, MA and Lonncz, AL, 1986, Arch Dermatol 122 670-674) as well as nicotinic acid and other pyndine compounds (Johnson, M H and Binkley, G W , 1950, J Invest Dermatol 20 14 233-238) A study by Fivenson et 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 charactensed by erythematous plaques, 25 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 compnses administration of 1-15% by volume of a carrier of carbamide peroxide alone or in combination with nicotinic acid or nicotinamide in 3 o concentrations of 1 -10% by volume of the earner
U S Patent 4505896 refers to a method of treatment of
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acne vulgaris using nicotinamide and/or nicotinic acid in concentrations of from 1-7% by volume of the earner 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 lessons The amount of lower alkyl nicotinate utilized is from 5-2 2 by weight of a composition 10 including a suitable earner
U S Patent 5459153 refers to the treatment of acne vulgans using a composition compnsing pantothenic acid or derivative thereof together with nicotinic acid or denvative thereof which may generate NAD or NADP The concentration of nicotinic acid utilized in the composition is 15 from 0 5-10% by weight of the composition
More recently, Shalita, AR 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% 20 nicotinamide gel was of comparable efficacy to 1% clindamycin gel in the treatment of acne vulgans Because clindamycin, like other antimicrobials, is associated with emergence of resistant micro-organisms, nicotinamide gel is a desirable alternative for the treatment of acne vulgans
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 compnsing
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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.,-C4 alkyl nicotinate The composition may also compnse 0 1-25% w/w tea tree oil and a pharmaceutical^ acceptable earner 5 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 alternifoha oil of Australian Standard (AS) 2782, i e International Standard (DIS) 4730 However, tea tree oil may be used in 10 any of its natural forms which are obtained from any other appropnate Melaleuca species or Leptospermum species, such as, for example, M hnanifoha, M dessttafoha 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 15 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, sjrfactants, thickening agents, emollients, stabilisers, 20 humectants and preservatives
The composition of the invention may be used as a clear aqueous solution Usually such a clear aqueous solution may compnse 1-20% surfactant, emulsifler or solubilising agent and, more preferably, a non-ionic surfactant, such as POLYSORBATE or 'TWEEN More 25 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 moistunzes the skin or, more preferably, 1-5% of the emollient A suitable 30 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
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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 5 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 £ or Vitamin A, hydrolysed collagen, ammo acids, panthenol and other nutntional factors as may be required
In a second aspect, the present invention consists in a method of treating or reducing incidence of acne compnsing applying an 15 effective amount of a composition to skin in need of such treatment, said composition compnsing 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,-C4 alkyl nicotinate The composition also includes 0 1-20% w/w tea tree oil 20 and a pharmaceutical^ acceptable earner
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 25 application will vary with the seventy 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 30 rinsed off with water Washing with such a composition can be repeated once to three times per day, or more often if desired
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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 5 Preferred forms of the invention will now be described by way of examples
EXAMPLE?
Example 1
A suitable gel composition of the present invention is as io follows -
Polymenc emulsifiers
0 25%
supplied by B F Goodnch under the name PEMULEN TR-1
Carboxypolymer
0 6%
supplied by B F Goodnch under the name CARBOPOL
Nicotinamide BP or USP
0%
Tea tree oil AS2782
0%
Humectant (glycerol)
0%
supplied by Unichema
Ethanol
0%
Purified water up to 100 0%
Examgfe 2
A suitable cream composition of the present invention is as follows -
Nicotinamide BP
0%
Cetomacrogol emulsifying wax
0%
Cetyl alcohol
1 0%
Tea tree oil
0%
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Glyceryl monostearate
3 0%
Preservative qs supplied by International Speciality Products under the name GERMABEN 11E
Punfied water
71 0%
Example 3
A suitable lotion composition of the present invention is as follows -
Nicotinamide BP
0%
Tea tree oil
0%
PEG-6-stearate (and) glycol stearate
8 0%
Steanc acid
1 0%
Glyceryl monostearate
3 0%
Preservative (as specified in Example 2)
qs
Punfied water
78 0%
Exampte 4
The anti-bactena! 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 25 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. 30 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
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As can be seen from the results, the base without any active ingredients has no anti-bactenal 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 5 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 vaned as shown in Table 3 in this Example such that the ratio of tea tree oil to nicotinamide 10 vaned 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 denvatives were subjected to a suspension test using P acnes as the test organism It is shown the 25 parent compound nicotinic acid is very effective as is the N substituted moiety The nng substituted moieties (1-methyl and 6-methylmcotinamtde) are, however, ineffective All compounds were formulated in a conventional cream base as descnbed in Example 2 with the concentration of tea tree oil being 5% in each case 30 Example 8
The effect of pH was evaluated on a composition containing
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% w/w teajree 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 HCI 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 HCI, (n) to 5 0 using lactic acid, (in) to 7 0 with HCI 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 HCI 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
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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 5 appreciated by persons skilled in th3 art that numerous vanations and/or modifications may bs made to the invention as shown in the specific embodiments without deporting from the spirit or scope of the invention as broadly descnbed The wjsent embodiment: =T5, 'Njrefore, to be considered in all respects £.$ illustrative and not restrictive io Exmpfol
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 descnbed in Example 1 and were instructed to apply the formulation topically to the affected 15 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 oticeable improvement in their condition with some patients being completely clear of symptoms
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TAPLES
TABLE 1 Challenge moculumn 8 7 x 106
MM
:v J,!.
IS
*:v :'t
'V-'' ~
*■' J.i.
Saline solution
83x 10s
1
1 5x 107
-
1 6 x 107
Base alone
>2 5 x 10s
>2 5x10®
^2 5x10®
>2 5x10®
>2 5x 10®
Base + TTO
first run second run
27x10® 4 7x10®
2 5x10® i 2 8x10®
2 2x10® 1 4x 10®
82x10s 2 0 x 10s
3 1 x 10s 1 6x104
Base + Nicotin
43x10s
3 4 x 10®
3 5x 10®
3 1 x106
1 3x10®
Base +TTO + Nicotin first run second run
18x10®
22x10s
68 X 104 2 7 x 103
2 6x 103 5 Ox 101
1 1 x 10s <10
60x 10' <10
Benzac ™ W10 (10% benzoyl peroxide)
2 5 x 102
<10
<10
<10
<10
Ultra Clearasil™ (5% benzoyl peroxide)
1 8x10®
4 7 x 103
10X103
2 0 x 101
<10
TABLE 2 Challenge inoculum 1 1 x 107
. yi.'.;,. ..f/w
'tVv i'iJT
w-t:3
TV'. \V; " j t><* :•/
(• v •». f « •: • r e
V1..}. ■.'&*&*+ -y .V ; •; ^
c-;'; '»• ^
ktv -s-
f.t
M ''•"*: y
'.-v.*;
<*'•■• ■'>•.}"c.> ::•.•>-• .'.w
-;3
iw.v
Base +■ TTO
4 7x 10s
28x10®
1 4x10®
20x10s
1 6 x 104
Base + TTO + Nicotin
22x10®
2 7 x 103
50x10'
! <10
<10
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TABLE 3
12
Inoculum control (placebo) 9 3 x 107
Ratio TTO Nicotinamide
Surviving organisms/reductions at time intervals
mins
mlns
mins
45 mins
60 mins
55
cfu/mL log10 reduction
550 56
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
10
cfu/mL log,0 reduction
44000 37
500 56
<100 >6 0
<100 >6 0
<100 >6 0
50
cfu/mL log10 reduction
1400 4 9
300 58
<100 >6 0
<100 >60
<100 >6 0
1 25 5 0
cfu/ML log,0 reduction
1000 49
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
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TABLE 4
Ratio TTO Nicotinamide
Surviving organisms/reductions at time intervals
mins
mins
mins
45 mins
60 mins
50
cfu/mL logl0 reduction
43000 37
14000 39
100 59
<100 >6 0
<100 >6 0
51
cfu/mL log10 reduction
33000 38
BOO 5 1
150 59
<100 >6 0
<100 >6 0
:2 5
cfu/mL log10 reduction
58000 35
2800 38
150 59
200 59
<100 >6 0
.S
cfu/ML log,6 reduction
<100 60
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
7 5
cfu/ML log,0 reduction
1600 39
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
10
cfu/ML log,0 reduction
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
<100 >6 0
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TABLE 5
Ratio TTO Nicotinamide
Surviving organisms/reductions at time intervals
mins
mins
mins
45 mins
60 mins
Nicotinic Acid cfu/mL log,0 reduction
1100 45
100 55
<100 >6 0
<100 >6 0
<100 >6 0
N-methyl nicotinamide cfu/mL log,0 reduction
>25000000 <01
20000 22
10000 35
1200 44
<100 >6 0
L-methyl nicotinamide cfu/mL log1D reduction
1500000 1 3
1300000 1 4
140000 1 4
990000 1 5
810000 1 6
6-methyl nicotinamide cfu/ML logI0 reduction
1200000 1 4
1200000 1 4
1100000 1 5
1000000 1 5
770000 1 6
TABLE 6 Preservative Efficacy Test - BP/USP (Sample at pH 3) adjusted with HCI
Time Point
aureus ATCC6538
P aeruginosa ATCC9027
E coll ATCC8739
C albicans ATCC10231
A mger ATCC16404
Inoculum
1 5 x 10s
1 4 x10s
1 1 x 10s
1 3x 10s
x10s
0 hr
3 8 X 10*
6 7 x 104
-
32x 10®
40x 10s
48 hr
<100
<100
-
-
-
7 dy
<100
<100
<100
<100
1 4 x 10s
14 dy
<100
<100
<100
<100
70x10s
21 dy
<100
<100
<100
<100
40x10*
28 dy
<100
<100
<100
<100
<100
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TABLE 7 Preservative Efficacy Test - BP/USP (Sample at pH 7) adjusted with lactic acid/sodium lactate
Time Point
S aureus ATCC6538
P aeruginosa ATCC9027
E coh ATCC8739
C albicans ATCC10231
A niger ATCC1640 4
Inoculum
1 5 x 10s
1 4 x 10s
1 1 x 10 6
1 3 X 10"
2 0x10s
Ohr
8 3 x 106
3 3 x 10*
-
13x10s
9 0 x 10s
48 hr
<100
<100
-
-
-
7 dy
<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
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