Note: Descriptions are shown in the official language in which they were submitted.
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. TITLE
"ACNE TREATMENT"
FIELD OF THE INVENTION
THIS INVENTION relates to a topical composition for the
5 treatment of acne and related conditions, the con,position 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,-
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 n,alerials 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 topically applied antiseptics such as benzoyl peroxide,
25 salicylic acid, resorcinol and triclosan. Severe cases can be treated
sy~te" ,ically 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
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 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 a/., 1990,
Medical ~ournal 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 nurnber of inflamed
lesions (open and closed comedomes)". ~he 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 sensilis~lion 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-inflammator,v
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 e~ al., 1994, Arch. Dermatol. 130 7~3-
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
concentrations of 1-10% by volume of the carrier.
U.S. Patent 4505896 refers to a method of treatment of
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acne vulgaris using nicotinamide and/or nicotinic acid in concenl,alions 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 ~240945 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) 434~37, 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%
2 o 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 altemative for the treatment of acne
vulgaris.
2 5 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 consisls in a
co"~position for the topical treatment of acne, said composition comprising
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0.5-20% wlvll 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 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.
International Standard (DIS) 4730. However, tea tree oil may be used in
l0 any of its natural forms which are obtained from any other appropriate
Melaleuca species or Leptospermum species, such as, for example, M.
Iinariifolia, M. dessifafolia 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~-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,
2 o 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
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
moisturizes 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
inciuded 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 viscosily
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.
10There 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 comprisi"g 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,-C4
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 aiso 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 a-ffected 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.
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 byB. F. Goodrich under
the name CARBOPOL
Nicotinamide BP or 5.0%
USP
Tea tree oil AS2782 5.0%
Humectant 5.0%supplied byUnichema
2 o(glycerol)
Ethanol 1 0.0%
Purified water up to 100.0%
Example 2
A suitable cream composition of the present invention is as
follows:-
30Nicotinamide BP 5.0%
Cetomacrogol emulsifying wax 15.0%
Cetyl alcohol 1.0%
Tea tree oil 5.0%
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Glyceryl monostearate 3.0%
Preservative qs supplied by International
Speciality Products under
the name GERMABEN 11 E
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%
15Glyceryl 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) 473û.
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.
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.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
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 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 concenlrdlions 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.
2 o 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
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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 HCI and it was ascertained that the resulting col"posilion met the
requirements of the United States Pharmacopoeia (USP) and British
5 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,
(ii) to 5.0 using lactic acid, (iii) 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
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. ~fter 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.
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TABLES
TABLE 1 Challenge inoculumn 8.7 x 1 o6
-
Saline solution 8.3 x 1 o6 - 1.5 x 10' - 1.6 x 107
Base alone >2.5 x 106 >2.5 x 106>2.5 x 106>2.5 x 106 ~2.5 x 106
Base + l~O
frstrun 2.7 X1062.5 X1062.2 x 106 8.2 x 105 3.1 x 105
second run 4.7 x 1 o6 2.8 x 1 o61.4 x 1 o6 2.0 x 105 1.6 x 104
Base + Nicotin 4.3 x 1063.4 x 1063.5 x 1063.1 x105 1.3 x 106
Base +TTO +
Nicotin
frstrun 1.8 x 1066.8 x 1042.6 x 1031.1X102 6.0 x 10
second run 2.2 x 1062.7 x 1035.0 x 10' <10 c10
Benzac TM W10 2.5 x 102<10 <10 <10 <10
(10% benzoyl
peroxide)
Ultra ClearasilTM 1.8 X105 4.7 x 103 1.0 x 103 2.0 x 10' <10
(5% benzoyl
peroxide)
TABLE 2 Challenge inoculum 1.1 x 107
Base + rro 4.7 x 106 2.8 x 106 1 4 x 106 2.0 x 105 1.6 X104
Base + TTO + 2.2 x 106 2.7 x 103 5.0 x 10' <10 c10
Nicotin
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TABLE 3 .Inoculum control (placebo) 9.3 x 107
Ratio Surviving orya~ s/reductions at time intervals
TTO:Nico~ m:~o
5 mins 15 mins 30 mins 45 mins 60 mins
5:5
cfu/mL 550 ~100 <100 c100 ~100
log,0 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
log,Oreduction 4.g 5.8 >6.0 >6.0 >6.0
1 .25:5.0
cfu/ML 1000 <100 <100 <100 <100
log,0 reduction 4.9 >6.0 >6.0 >6.0 >6.0
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TABLE 4
RatioSurviving ory~tni~" ,s/reductions at time intervals
rrO: Nicoli"ar, .: de
5 mins 15 mins 30 mins 45 mins 60 mins
5:0
cfu/mL 43000 14000 100 C100 c100
log,0 reduction 3.7 3.9 5.9 >6.0 >6.0
5:1
cfulmL 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
log,0 reduction 3.5 3.8 5.9 5.9 >6.0
5:5
cfu/ML c100 <100 <100 <100 <100
logtO reduction 6.0 >6.0 >6.0 >6.0 >6.0
5:7.5
cfu/ML 1600 ~100 <100 C100 <100
log,Oreduction 3.9 ~6.0 ~6.0 ~6.0 ~6.0
5:10
cfu/ML <100 <100 <100 <100 ~100
log10reduction ~6.0 ~6.0 >6.0 >6.0 >6.0
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TABLE 5
Ratio Surviving ory~r,i~. "s/reductions at time intervals
TTO:Nicolil,a", :le
5 mins 15 mins 30 mins45 mins 60 mins
Nicotinic Acid
cfu/mL 1100 100 ~100 <100 <100
log,0 reduction 4.5 5.5 ~6.0 ~6.0 ~6.0
N-methyl nicoti.,a...ide
cfu/mL ~25000000 20000 10000 1200 <100
log,0 reduction <0.1 2.2 3.5 4.4 ~6.0
L-methyl nitoti..ar..i~le
cfu/mL 1500000 1300000 140000 990000 810000
log,0 reduction 1.3 1.4 1.4 1.5 1.6
6-methyl nicGli--a,-.;de
cfu/ML 1200000 1200000 11000001000000 770000
log,0 reduction 1.4 1.4 1.5 1.5 1.6
TABLE 6 Preservative Efficacy Test - BP/USP (Sample at pH 3)
adjusted with HCI
Time S. aureus P. aeruginosa E. coli C. albicans A. niger
Point ATCC6538 ATCC9027 ATCC8739 ATCC10231 ATCC16404
Inoculum1.5 x 1 o6 1.4 x 1 o6 1 ~1 x 1o6 1.3 x 1 o6 2.0 x 1 o6
0 hr 3.8 x 104 6.7 x 104 _ 3.2 x 106 4.0 x 105
48 hr ~100 ~100 - - -
7 dy ~100 ~100 ~100 ~100 1.4 x 105
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
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TABLE 7 -Preservative Efficacy Test - BP/USP (Sample at pH 7)
adjusted with lactic acid/sodium lactate
Time s. aureusP. aeruginosa E. coli C. albicans A. niger
Point ATCC6538 ATCC9027 ATCC8739 ATCC10231 ATCC1640
Inoculum 1.5x106 1.4x 106 1.1x106 1.3x 106 2.0x106
Ohr 8.3x106 3.3x106 1.3x 105 9.0X105
48hr <100 <100
7dy c100 c100 ~100 <100 ~100
14dy <100 <100 <100 <100 <100
21dy <100 <100 <100 <100 <100
28dy <100 <100 <100 <100 <100
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16
LEGENDS
TABLE 2
cfu colony forming units
1~0 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 log~O
reduction is equivalent to 99.9% and a 61 log~O
reduction is equivalent to 99.9999%.
