TOPICAL OIL COMPOSITIONS FOR THE TREATMENT OF FUNGAL INFECTIONS
FIELD OF THE INVENTION
The present invention provides topical compositions comprising an antifi~ngala gent, an oil and
excipients or additives, for the treatment of filngal infections. The present invention filrther
provides compositions devoid of more than C-10 fatty acids or their esters for the treatment of
topical fungal infections. The present invention further provides antifungal compositions
comprising an antifungal agent, a fatty acid or its ester with less than Cll chain length and
excipients or additives.
BACKGROUND OF THE INVENTION
Fungal infections of the skin are also known as 'mycoses'. They are common and generally mild.
In sick or otherwise immune-suppressed individuals, however, hngi can sometimes cause
serious disease. Fungal infections in humans range from superficial, i.e., skin surface to deeply
invasive type or disseminated infection.
In general, superficial fungal infections (also known as cutaneous mycosis) can affect the outer
layers of skin, nails and hair. The main groups of fungi causing superficial fungal infections are
dermatophytes (tinea), yeasts, e.g., candida, mnalassezia, piedra, etc. and moulds. These infections
include dandrufflseborrheic dermatitis (DISD), ringworm, onychomysis, intertrigo, and those in
psoriasis amongst others.
Seborrheic dermatitis is a common, chronic, superficial skin disorder causing scaly, itchy, red
skin on the scalp, eyebrows, nasolabial creases, lips, ears, stei-nal area, axillae, submammary
folds, umbilicus, groins, and gluteul crease. The disease is characterized by many shapes, sizes,
and surface textures and is often crust-like, yellowish, and accompanied by itching. Seborrheic
dermatitis is one of the leading causes of stubborn dandruff and occurs in all age groups. This
condition primarily affects the sebaceous cysts present in the skin.
Currently, fungi of the genus Malassezia are believed to be the most likely responsible agents for
causing dandruff (Dawson T.L., J. Investig. Dermatol. Symp. Proc. (2007), 12: 15 19). Most cases
of seborrhoeic dermatitis likely involve an inflammatory reaction to the proliferation of the yeast
Malassezia. These fungi are highly dependent on external lipids for in vitro growth (Chen T.A.
and Hill P.V., Vet Dermatol, (2005), 16:4). Further, the inability to synthesize fatty acids may be
complimented by the presence of multiple .secreted lipases to aid in utilizing host lipids.
Consequently, these fungi metabolize triglycerides present in sebum through these lipases
resulting in lipid by-products. Penetration of the top layer of the epidermis, the stratum comeum,
by these lipid by-products results in an inflammatory response in susceptible persons, which
disturbs homeostasis causing erratic cleavage of stratum corneum cells, further leading to
dandruff and seborrheic dermatitis.
The most common treatment of fungal infections is the topical application of antifungal agents
that reduce the level of Malassezia on the scalp. Maintaining the scalp clean is mandatory for
sufferers of seborrheic dermatitis. Use of effective anti-dandruff shampoos is, therefore, a
significant way of preventing this condition.
Typically, the antikngal agent is applied to the scalp as a component of a shampoo or other hair
care composition. The disadvantage of such shampoo formulations is that during normal usage
the formulation does not remain on the scalp for a period of time sufficient to allow the
antifungal agent to achieve its maximal therapeutic effect (Ralph M. Triieb, JDDG, (2007),
5:356). These arc designed to be applied, for example, in the shower or bath, and shortly
thereafter rinsed off with water. Typically, the application instructions for such shampoos
suggest that the formulation be removed after 3-5 minutes.
One of the antifungal agents, ketoconazole is among the most potent and widely used in antidandruff
shampoos. However, the exposure time of shampoo is less, due to which the efficacy is
poor and relapse rates are higher.
In the past we found that, fatty acids and their derivatives (e.g. lnethylated and hydroxyl fatty
acids) are known to possess antibacterial and antifungal activity as they target the cell membrane
leading to increase in membrane fluidity (Douglas and Marshalland, "Antimicrobials in Food",
3'd edition, CRC Press 2005 Pg. no. 327 - 360).
In context to another review, the pelargonic and capric acid on Micro.sporum gypseum were
found to be effective when tested in-vitro cell culture (Chandeganipour and Haims, "Mycoses",
2001, Vol~tine 44, Issue 3-4, pages 109-1 12). Similar reports were found with reference to
Candida albicans when exposed to inonoesters of glycerides of capric (C10 saturated medium
chain fatty acid) (Bergsson et al., Antimicrobial agents and Chemotherapy, 2001, Vol45 pg. no.
3209 - 3212).
U.S. Patent Application 2010/0016271 discloses hair conditioning coinpositions coinprising
cationic surfactant, triglyceride oil and an anti-dandruff agent. These colnpositions contain
triglyceride oil, which are fatty acid esters of glycerol, and hence act as nutrients and aid in the
growth of the fungus. These colnpositions contain fatty inaterial up to 10% having carbon chains
from 8 to 30 carbon atoms.
U.S. Patent No. 5,624,666 describes shampoo compositions containing anionic surfactants,
cationic polymers, and zinc pyridinethione as an anti-dandruff agent. It describes that
conditioning agents such as silicone fluids can optionally be incorporated into the coi~~positions
therein. Head & shouldersB Dandruff Shainpoo Plus Conditioner is an example of a marketed
product which provides both anti-dandruff and conditioning benefits upon application of the
shampoo to hair. The exposure time of shampoos is less than required for effective antifungal
activity, hence relapse rates are higher.
U.S. Patent No. 7547752 refers to synergistic coinbination of an anti-dandruff agent with
conjugated linoleic acid for prevention or treatment of dandruff and scalp itching.
European Patent No. 1923043Al discloses cationic conditioning agents and an anti-dandruff
agent with surfactants, silloxanes and natural and lipophillic oily coinponcnts and their .
derivatives for the treatment or prevention of dandruff with conditioning.
European Patent No 01 16439 discloses fatty acids like petroselinic and linoleic and saturated and
unsaturated derivatives which alleviate dandruff and stimulate hair growth.
Cominercially available formulations for the treatment of dandruff are leave-on hair formulations
such as hair oils, styling gels, etc. These formulations also contain anti-dandruff or antifungal
agents. Convcntional leave-on formulations, especially oils or creams, contain fatty acid or their
cstcrs as an csscntial ingrcdicnt. Thcsc fatty acid and cstcrs aid thc growth of dandruff-causing
fungus (Malassezia furfur) and work as nutrients.
Accordingly, there remains a need for an antifungal composition that provides improved
cleansing and optimal anti-dandruff efficacy. The present invention addresses this need by
providing topical compositions having antifilngal agents and is devoid of fungus nutrients.
OBJECTIVE OF THE INVENTION
The primary objective of the invention is to provide antifungal cotnpositions comprising an
antifungal agent, an oil and excipients or additives, for the treatment of fungal infections
Yet another objective of the invention is to provide antifungal compositions devoid of Inore than
C-10 fatty acids or their esters for the treatment of topical fungal infections.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photograph showing the effect of nutrients provided in the culture tnedia on the
growth of MFurhr
Figure 2 is a photograph showing the effect of 2% caprylic acid (C8) (A), 2% Capric acid (C1 O),
(B) and 2% lnonocaprylate of propylene glycol (C). Olive oil (D) and no oil supplement (E) were
used as controls.
Figure 3 is a photograph showing the growth of M fuifur depending on the nutrients provided in
the culture media.
BRIEF DESCRIPTION OF THE TABLES
Table I : Piroctone olamine - oil compositions
Table 2: Ketoconazole - oil colnpositions
Table 3: Results of MIC for oil compositions of piroctone olamine
Table 4: Results of MIC for oil compositions of ketoconazole
Table 5: Oil compositions containing piroctone olainine as antifungal agent
Table 6: MIC of oil coiiipositions containing piroctone olalnine against M. furfur
Table 7: MIC for oil coinpositions containing piroctone olalnine against M obtuse
Table 8: Oil conipositions containing ketoconazole as antifungal agent
Table 9: Oil compositions containing piroctone olamine and ketoconazole in combination
Table 10: Oil conipositions containing piroctone olamine as antifungal agent and Minoxidil
Table 11: Gel cotnpositions containing antifi~ngal agents devoid of C-1 1 or greater fatty
aciddesters
Table 12: Zone of inhibition of gel compositions containing piroctone olamine against M fiil-fur
Table 13: Preparation of cream compositions containing antifungal agents Piroctone olamnine or
ketoconazole.
SUMMARY OF THE INVENTION
The present invention provides antifungal compositions that are devoid of C-1 1 or greater fatty
acids and their esters as these fatty acidslesters serve as nutrients for the growth of the fungus.
The present invention hrther provides topical antifungal oil compositions that eliminate existing
dandruff on the scalp, or prevent or reduce relapse of dandruff formation. The present invention
fi~rtherp rovides antifi~ngacl ompositions comprising an antifungal agent, a fatty acid or its ester
with less than C-1 1 chain length, and excipients or additives.
DETAILED DESCRIPTION OF THE INVENTION
While the invention is susceptible to various modifications and alternative forms, specific aspect
thereof has been shown by way of example and drawings and will be described in detail below. It
should be understood, however that it is not intended to limit the invention to the particular
forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and
alternative falling within the spirit and the scope of the invention as defined by the appended
claims.
The Applicants would like to mention that the examples are mentioned to show only those
specific details that are pertinent to understanding the aspects of the present invention so as not
to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the
art having benefit of the description herein.
In the following detailed description of the aspects of the invention, reference is made to the
accompanying drawings and graphs that form part hereof and in which are shown by way of
illustration specific aspects in which the invention may be practiced. The aspects are described in
sufficient details to enable those skilled in the art to practice the invention, and it is to be
understood that other aspects may be utilized and that charges may be made without departing
from the scope of the present invention. The following description is, therefore, not to be taken
in a limiting sense, and the scope of the present invention is defined only by the appended
claims.
Accordingly the present invention is directed to compositions for the treatment of fungal
infections, comprising:
(A) at least one antifungal agent;
(B) at least one oil and;
(C) at least one excipient
where said composition being devoid of C- 1 1 fatty acids and their esters.
Another aspect of the present invention is to provide an anti dandruff oil composition
comprising:
(A) at least one antifungal agent;
(B) at least one C10 or lower fatty acid or its ester; and
(C) at least one excipient.
Yet another aspect of the present invention is to provide methods for the treatment of fungal
infections comprising administering to a patient in need thereof an antifungal composition of the
present invention.
Antifi~ngal agent as used herein includes, but is not limited to piroctone olamine, ciclopirox
olamine, ketoconazole, climbazole, miconazole nitrate, itraconazole, fluconazole, econazole,
terconazole, saperconazole, amorolfinc, oxiconazole, clotrimazole, luliconazole, terbinafine,
butenafine, naftifine, selenium disulfide, salicylic acid, sulfur, tar preparations, capric acid and
derivatives, caprylic acid and derivatives, zinc pyrithione, hinokitol. and chemical compounds
froin natural sources, such as extract of arnica, walnut shells, tea tree oil, roseinaty oil, birch.
Other antifungal agents known to the art-skilled may also be used in the co~npositionso f the
present invention.
In one embodiment, the antifilngal agent used in the composition of the present invention is
piroctone olamine. In another embodiment, the antifkngal agent is ketoconazole. In yet anothcr
embodiment of the present invention, the composition comprises a combination of piroctone
olalnine and ketoconazole.
The amount of antifungal agent used in the compositions of the present invention is in the range
of from about 0.01% to about 10% by weight of the total composition. In one embodiment, the
antifungal agent is in the range of from about 0.01% to about 5% by weight of the total
composition. In a further embodiment, the antifungal agent is in the range of about 0.01% to
about 2% by weight of the total composition.
Oil as used herein includes, but is not limited to, paraffin oil, silicone oils, terpenes, fatty
alcohols, dibutyl adipate, dioctyl adipate, fatty acidslesters (devoid of inore than ClO-) or a
combination thereof.
As used herein, less than Cl1 fatty acid andlor its ester includes, but is not limited to propionic
acid, butyric acid, pentanoic acid, hexanoic acid, heptanoic acid, caprylic acid, nonanoic acid,
capric acid, Monoldi ester of these acids with propylene glycol, monoldiltri esters of these acids
with glycerol, and co~nbinationsth ereof.
Essential oils as used herein include, but are not limited to, natural and synthetic oils such as
eucalyptus oil, rosemary oil, pine needle oil, tea tree oil, sage oil, cinnamon oil, lemon oil, lime
oil, orange oil, peppermint oil, spearmint oil, wintergreen oil, sweet birch oil, clove leaf oil,
camphor oil, cardamon oil, cedar leaf oil, sweet birch oil and others known to the art-skilled.
The amount of oil used in the compositions of the present invention is in the range of about 0.5%
to about 99% by weight of the total composition, more preferably 50% to 99% when formulated
as oil, 5% to 50% when formulated as creamlointment or 0.5 % to 20 % when formulated as
gellsen~mdspray.
As used herein, excipient includes, but is not liinited to, solvents, surfactants and additives used
in pharmaceutical and cosmetic formulations. The amount of excipients used in the coinpositions
of the present invention is in the range of about 0.5% to about 99% by weight of the total
composition.
Solvents as used herein include, but are not limited to, C-1 to C-6 lower aliphatic alcohols, such
as, for example, ethanol, isopropyl alcohol, butanol and the like, lower alkyl acetate, ethers,
carboxylic acid and derivatives containing carbon chain length less than C11 (caprylic acid,
capric acid and the like) or mixhlre/s thereof, fatty alcohols such as undecanol, oleyl alcohol,
lauryl alcohol or combinations thereof,
Additives as used herein include, but are not limited to, thickeners, antioxidants,
perfi~mes/fragrances, essential oils, pH adjusters, herbal extracts, preserving agents, hair
conditioning substances, hair care adjuncts, skin care adjuncts, emollient, dyestuffs, moisturizers,
vitamins, sphingoceryls, sunscreens, surfactants, oil-sol~lblep olymers which are compatible with
the base oil andlor skin care agents including skin-nutrient agents, anti-wrinkle agents, light and
dust protectors.
For example, compositions of the present invention may contain additives such as thickeners (for
example, bentonite, cellulose and the like), antioxidants (for example, butylated hydroxytoluene
(BHT), butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), fenllic acid, Vitamin
A, Vitamin E (Tocopherol)), preservatives (for example, methyl p-hydroxybenzoate or propyl phydroxybenzoate,
sorbic acid and the like), hair care ingredients (for example, fatty alcohols,
peptides, proteins, vitamins and mixtures thereof), light protective agents or sunscreens (for
example, p-inethoxycinamic acid isoamyl ester and the like).
Surfactants as used herein include, but are not limited to, cetearths, ceteth, isoceteths, laureths,
oleths, steareths, lauramide DEA, linoleamide DEA and other surfactants which are suitable for
topical application.
As used herein, pH adjusters include, but are not limited to, inorganic or organic acids (e.g.,
citric acid, lactic acid, succinic acid, acetic acid, fumaric acid, glycolic acid, benzoic acid), bases,
salts and/or buffers thereof.
Herbal extracts as used herein include, but are not limited to, Amla h i t extract, Arnica Extract,
Brahini extract and others known to the art-skilled.
Hair care adjuncts as used herein include, but are not limited to, ingredients beneficial in the
treatment of hair loss or the promotion of hair growth such as taurine, caffeine, minoxidil, azelaic
acid, marine cartilage, hydrolysed keratin, biotin, niacin, panthenol, vitamin B6, zinc, copper,
peptides, horsetail silica, beta sitosterols, pycnogenol, PABA, green tea extract, folic acid, iron,
L-cysteine, magnesium, ginseng and others known to the art-skilled.
Skin care adjuncts as used herein include, but are not limited to, those that are beneficial for the
treatment of various skin conditions (like dry skin, oily skin, fine lines, pigmentation, etc.) such
as proteins, vitamins (e.g., A, B, C, D, E, and K), trace metals (e.g., zinc, calcium and selenium),
inoisturizers (e.g., emollients, humectants, film formers, occlusive agents, and agents that affect
the natural moisturization mechanisms of the skin), UV absorbers (physical and chemical
absorbers such as paraminobenzoic acid (PABA), titanium dioxide, zinc oxide, etc.), antiirritants
(e.g., steroids and non-steroidal anti-inflammatories), botanical extracts (e.g., aloe Vera,
chamomile, cucumber extract, ginkgo biloba, ginseng, and rosemary), absorbents (e.g.,
alurnin~~sitna rch octenylsuccinate, kaolin, corn starch, oat starch, cyclodextrin, talc, and zeolite),
skin bleaching and lightening agents (e.g., hydroquinone and niacinamide lactate), humectants
(e.g., sorbitol, urea, and manitol), exfoliants, skin conditioning agents (e.g., aloe extracts,
allantoin, bisabolol, ceramides, dimethicone, hyaluronic acid, and dipotassium glycyrrhizate) and
other natural components (e.g., oatmeal) known to the art-skilled.
In yet another embodiment of the present invention, the topical anti-dandruff hair oil
composition comprising:
(a) antifungal agent selected from the group consisting of piroctone olamine, ketoconazole,
zinc pyrithione or combination thereof; wherein said antifungal agent is present in the range of
0.01 % to about lo%, more preferably in the range of 0.0 1 % to 5%, more preferably in the range
of 0.01% to 2% by weight of the total composition.
(b) oil selected from the group consisting of paraffin oil, salicylic acid, capric acid and
derivatives, caprylic acid and derivatives, fatty acid or esters having carbon chain length less
then C-10 or a combination thereof wherein said oil is present in the range of 1 % to 99%;
(c) solvent selected from the group of lower aliphatic alcohols, lower alkyl acetate, ethers,
carboxylic acid or derivatives containing carbon chain length less than Cll, fatty alcohols or a
combination thereof; and
(d) additive selected from the group of thickener, antioxidant, perfurnelfragrance, essential
oil, pH adjuster, herbal extract, preserving agent, hair conditioning substance, hair care adjunct,
skin care adjunct, skin care agent, skin-nutrient agent, emollient, dyestuff, moisturizer, vitamin,
sphingoceryl, sunscreen, surfactant, oil-soluble polymer, anti-wrinkle agent, light or dust
protector or a coi~lbinationt hereeof.
In yet another embodiment of the present invention provides methods for the treatment of fungal
infections comprising administering to a patient in need thereof an antifungal composition of the
present invention, said composition comprising at least one antifungal agent, at least one oil and
at least one excipient, said composition being devoid of C11 or higher fatty acids and their esters.
The term "treatment" covers any topical fungal treatment in a mammal, such as a human.
The topical compositions of the present invention are used in the treatment of diseases
associated with Malassezia including, but not limited to, tiilea pedis, tinea capitis, tinea ci-uris,
tinea glabrosa, tinea coi-poris, onychomycosis, pityriasis capitis, pityriasis vesicolor,
pityrosporzim folliczilitis, seborrheic dermatitis. Compositions of the present invention are also
used in the treatment of diseases associated with other fungi like Trychophyton i-zlbrum or
Trychophyton nzentagrophytes or Microspoiwm species, or Epidemzophyton species, or Candida
albicans, etc. and other nonderlnatophyte molds.
The compositions of the present invention are also of veterinary use in the topical treatment of
der~natologicaflu ngal infections.
Compositions of the present invention provide better retention and penetration of antifi~ngal
agent onto the hair, skin, scalp and nails. Accordingly, the present invention provides
compositions and methods of treating fungal infections of the skin, scalp, hair or nail. In one
embodiment of the present invention, the antifungal composition is topical hair oil. In another
embodiment, the antifungal composition of the present invention is anti-dandruff oil. In yet
another embodiment, the composition of the present invention is a hair gel. In a further
einbodiment, the composition of the present invention is a nail varnish.
The compositions of the present invention can be in the form of oils, creams, lotions, serums,
gels, ointments, foams, sprays or aerosols.
The following examples serve to fi~rther illustrate the present invention and are not to be
construed to limit the scope of the present invention.
EXAMPLES
Example 1: Preparation of various oil compositions containing Piroctone Olamine
The compositions were prepared by dissolving the active agent in ethanol or isopropyl alcohol
(IPA). The oleyl alcohol was then added and stirred until a homogenous solution was obtained.
Other excipients or additives were added and stirred to get clear solution except liquid paraffin.
Weight was finally made up with liquid paraffin and stirred until ho~nogenous solution was
obtained. Final fonnulations were clear transparent oil solutions. Table 1 describes anti-fungal
clear oil colnpositions containing piroctone olainine as anti-f~lngala gent using various excipients
or additives.
Result:
1. Compositions using liquid paraffin as base oil containing piroctone olamine, were clear oil
solutions.
2. Addition of other excipients such as tea tree oil, cyclomethicone (D4), tocopherol acetate etc.
did not affect the physical stability of formulations as compositions appeared as clear oil
solution.
Example: 2 Preparation of various oil compositions containing ketoconazole
The compositions were prepared by dissolving the active agent in ethanol. The oleyl alcohol was
then added and stirred until homogenous solution was obtained. Other excipients or additives
were added and stirred to get clear solution except liquid paraffin. Weight was finally made up
with liquid paraffin and stirred until homogenous solution was obtained. Final formulations were
clear transparent oil solutions. Table 2 describes anti-fungal clear oil coinpositions containing
ketoconazole as anti-fungal agent using various excipients or additives.
Result:
1. Compositions using liquid paraffin as base oil containing ketoconazole, were clear oil
solutions.
2. Addition of other excipients such as tea tree oil, terpene-4-01, capiylic acid, cyclomethicone
(D4) etc. did not affect the physical stability of forlnulations and colnpositions appeared as
clear oil solution.
Example 3: Study of oil containing fatty acid/esters as a source of nutrients for the growth
of M. furfur under in vitro condition.
Malassezia species are lipophilic unipolar yeasts recognized as commensals of skin that may be
pathogenic under certain conditions (Indian Journal of Medical Microbiology, (2004) 22
(3):179-181). To compare lipid requirements of the fungus most closely associated with
dandrufflseborrheic dermatitis, the best studied Malassezia species is M. r r . Lipid
assimilation in vitro assay was designed to investigate lipid effect on growth of M ful$lr (MTCC
1374).
Method: Briefly, Sabouraud Dextrose containing low-melt agar was melted, cooled to 38OC.
Fatty acidslesters constituents eg, capric acid, caprylic acid, linoleic acid, oleic acid, lauric acid,
palmitic acid,ethyl oleate, isopropyl myristate and oils containing fatty acidlesters eg, coconut
oil, mustard oil etc., were added to study the growth of the fungus (Kaw Bing CHUA, et a1
Malaysian J Path01 (2005) 27(2): 99). After solidification, agar plates were streaked with
Mfilrfilr innoculum adjusted to appropriate cfidml, aseptically. Positive control with 2% olive
oil and negative control without fatty substance were also maintained.
Results:
1. Results showed that there was no growth of M. furjiur in absence of fatty acidslesters or oils
in in vitro condition (Fig. 1) up to 6 days.
2. Culture media which contained fatty acids or esters eg, linoleic acid, oleic acid, lauric acid,
palmitic acid, ethyl oleate, isopropyl myristate and oils containing fatty acidlesters eg,
coconut oil, n~ustardo il etc. were showed confluent growth of fungus up to G days.
3. Culture media with lower carbon fatty acids (C110) eg, caprylic acid (C8) and capric (ClO)
were failed to provide nutrient for the growth of fungus and no growth was observed up to 6
days.
Example 4: Bioactivity of oil compositions described in Example 1 against M. furfur
The Minimum Inhibitory Concentration (MIC) is considered as an index for indicating Antifi~
ngael fficacy. Therefore lower the value of MIC of the composition, the better is its anti-fitngal
efficacy.
Method: The in vitro activities of some of the oil compositions containing piroctone olamine
against Malassezia furfur (MTCC 1374) were determined by agar dilution methods (Jan
Faergemann, et a1 Acta Derrn Venereal, (2006), 86:312; Irith Wiegand, et a1 Nature Protocols
(2008), 3:163) Appropriate dilutions of solubilized antifi~ngal compositions were added to
inolten Leeming Notman Medium. Once the plates were set, Mfurfur innoculum adjusted to
appropriate cfulml was streaked on the agar plates and incubated for 6 days. After incubation, the
plates were observed at day 3 and day 6 for visible Mfur-ir growth. The MIC is defined as as
the lowest concentration of antifungal agents that inhibits visible growth of fungus.
Results:
1. Piroctone olamine containing oil compositions VPO-0 18, VPO-022, and VPO-028 with
different solvents isopropyl alcohol, oleyl alcohol, and ethanol, respectively, showed
MIC at 32gglml which is similar to the MIC of positive control where drug is dissblved
in DMSO at the same concentration as shown in Table 3.
Addition of other additives such as caprylic acid, cyclomethicone (D4), tocopherol acetate etc.
did not affect the MIC of oil compositions when used in concentration shown in table 1.
Example 5: Bioactivity of oil compositions described in Example 2 against M. furfur
Method: The in vitro activities of some of the oil coinpositions containing ketoconazole against
Malassezia furfur (MTCC 1374) were determined by agar dilution methods. Appropriate
dilutions of antifungal coinpositions were added to molten Leeming Notman Medium. Once the
plates were set, Mfiirfiw innoculum adjusted to appropriate cfulml was streaked on the agar
plates and incubated for 6 days. After incubation, the plates were observed at day 3 and day 6 for
visible Mfirfur growth. The MIC is defined as the lowest tested dilution of antifungal active that
yields no growth.
Result:
1. Kctoconazolc containing oil compositions showcd MIC at 0.25/~glml, which is similar to
the MIC of positive control where dnlg is dissolved in DMSO at the saine eonccntration
as shown in Table 4.
Example 6: Effect of various fatty acidslesters on the in vitro growth of M. furfur
A) Study of various oils which are glycerol or glycol esters (less than C-11 carbon number)
on the growth of M. furfur under in vitro conditions
Malassezia species are lipophilic, unipolar yeasts recognized as commensals of skin that may be
pathogenic under certain conditions. To compare lipid requirements of the fungus most closely
associated with dandruffheborrheic dermatitis, the best studied Malassezia species is M fiirfur.
A lipid assiniilation in vitro assay was designed to investigate lipid effect C-10 fatty acid or
their esters-on growth of M furfur (MTCC 1374). Sabouraud Dextrose containing low-melt agar
was melted and cooled to 3S°C. Fatty acidslesters constituents, e.g. fatty acids or esters, such as
lauric acid, palmitic acid, myristic acid, oleic acid, linoleic acid, isopropyl myristate, ethyl oleatc,
mustard oils, coconut oil were added at different concentration to study the growth of the fi~ngus.
Positive control with 2% olive oil and negative control without fatty substance were also
maintained. After solidification, agar plates were streaked with M furfur innoculum adjusted to
appropriate cfidml, aseptically.
Culture media with higher carbon fatty acids and esters (more than C-10) such as lauric acid,
palmitic acid, myristic acid, oleic acid, linoleic acid, isopropyl myristate, ethyl oleate, showed
confluent growth of fbngus for up to 6 days. Interestingly vegetable oils such as mustard oils,
coconut oil also showed confluent growth of Mfii~fura s shown in Figure 3. In addition inedia
supplemented with 2% olive oil showed confluent growth of fiingus in the same duration while
the inedia without oil supplement did not show any growth.
Example 7: Preparation of oil compositions devoid of C-11 or greater fatty acids/esters
containing antifungal agent or combination thereof.
A) Preparation of oil compositions devoid of C-11 or greater fatty acids/esters containing
piroctone olamine as antifungal agent.
These coinpositions were prepared by dissolving the active agent in ethanol or other suitable
solvent. The oleyl alcohol was then added and stirred until a homogenous solution was obtained.
Other excipients or additives were added and stirred to obtain a clear solution except liquid
paraffin. The total volume was finally made up with liquid paraffin and stirred until homogenous
solution was obtained. Final formulations were clear transparent oil solutions and coded as lP,
2P, 3P and 4P as given in Table 5. All compositions are clear transparent solutions. In compositions
1P and 2P, caprylic acid was added to balance the pH of the fortnulations.
B) Study of MIC of oil compositions devoid of C-11 or greater fatty acidslesters containing
antifungal agent piroctone olaminc against M. furfur under in vifro conditions.
As shown in Table 6 and Table 7, oil compositions containing piroctone olamine devoid of C-11
or greater fatty acids or their esters showed MIC in the range of 16-32 pglml against M furfur
and in the range of 8-16 pglinl against M.obtzlsa. Composition having similar amount of
piroctone olamine with 5% sunflower oil and 10% oleic acid were showed MIC at 64pglml
against both the strains. These results show that the presence of vegetable oil (sunflower) which
is rich in triglycerideslfree fatty acids above C-10, has an adverse effect on the activity of the
antifungal agent. Similarly, the presence of fatty acids above C-10 (such as oleic acid) also has
an adverse effect on the activity of the antifungal agent.
C) Preparation of oil compositions devoid of C-11 or greater fatty acidslesters containing
ketoconazolc as antifungal agcnt.
These compositions were prepared by dissolving the active agent in ethanol or other suitable
solvent. The oleyl alcohol was then added and stirred until a homogenous solution was obtained.
Other excipients or additives were added and stirred to obtain a clear solution except liquid
paraffin. The total volume was finally made up with liquid paraffin and stirred until homogenous
solution was obtained. Final formulations were clear transparent oil solutions and coded as lK,
2K, as given in Table 8. All compositions are clear transparent solutions.
D) Preparation of oil compositions devoid of C-11 or greater fatty acidslesters containing
piroctone olamine and ketoconazole as antifungal agents in combination.
These compositions were prepared by dissolving the active agent in ethanol or other suitable
solvent. The oleyl alcohol was then added and stirred until a homogenous solution was obtained.
Other excipients or additives were added and stirred to obtain a clear solution except liquid
paraffin. The total volume was finally made up with liquid paraffin and stirred until homogenous
solution was obtained. Final formulations were clear transparent oil solutions and coded as 1PK,
2PK, as given in Table 9.
E) Preparation of oil compositions devoid of C-11 or greater fatty acidslesters containing
antifungal agent with hair growth promoter, Minoxidil.
The compositions were prepared as described above and coded as IPM, 2PM and 3PM, as given
in Table 10.
Example 8
A) Preparation of various gel compositions devoid of C-11 or greater fatty acidslesters
containing different antifungal agents.
Initially, carbopol was added to the water and allowed to swell for 24 hours. Antidandruff agent
was dissolved in minimum quantity of solvent and added to the carbopol base, followed by
neutralization with a dilute aqueous solution of triethanolainine or sodium hydroxide to obtain
pH 5.0-7.0. The gel coinpositions were coded as IG, 2G, 3G, 4G, 5G and 6G as shown in Table
11.
B) Study of zonc of inhibition (ZOI) of gel compositions devoid of C-11 or grcatcr fatty
acids/cstcrs containing antifungal agent piroctonc olaminc against M. furfur under in vitro
conditions.
To study the efficacy of gel coinpositions, ZOI was determination by Agar Well Diffusion
method. Observations were shown in Table 12.
Results: As shown in Table 12, gel coniposition (1G) containing piroctone olainine showed ZOI
(zone of inhibition) in the range of 1.2-0.9 cm against M &r&r. Whereas, conlposition (2G)
with similar amount of piroctone olainine along with 4% propylene glycol mono caprylate
showed ZOI 1.5-1.3 cm against M furfur. After incorporation of 10 % oleic acid with base
formulation lG, zone of inhibition was not observed. These results showed that the presence of
oleic acid which is free fatty acids above C-10 has an adverse effect on ,the activity of the
antifungal agent.
Example 9: Preparation of various cream compositions devoid of C-11 or greater fatty
acidslesters containing different antifungal agents
Creams were prepared by fusion method, where all oil soluble ingredients were weighed and
melt at a temperature of 60-80°C. Aqueous phase was maintained at the same temperature and oil
phase was poured into aqueous phase with constant stirring, followed by slow cooling with
inoderate stirring. The cream compositions were coded as IC, 2C, 3C, 4C as shown in Table 13.
The antifungal coillpositions as disclosed in the invention are thus attained in a practical, and
facile manner. While preferred aspects and example configurations have been shown and
described, it is to be understood that various further modifications and additional configurations
will be apparent to those skilled in the art. It is intended that the specific ernbodilnents and
configurations herein disclosed are illustrative of the preferred nature and best mode of
practicing the invention, and should not be interpreted as limitations on the scope of the
invention.
Table 1: Piroctone olamine - oil compositions
C- Clear, ST- Slight turbid, PO- Piroctone olamine, IPA-Isopropyl alcohol, OA-oleyl alcohol, Cap.A- Caprylic acid,
Toco. Ace.-Tocopherol acetate, TTO-tea tree oil, LLP-light liquid paraflin, App-appearance
Table 2: Ketoconazole - oil compositions
C-Clear transparent, ST-Slight turbid
Formulati
oncode
(ml) 1 acetate (m, 1 '"'" 1 2)
Terpen
e-4-01
FITKeto
(mg)
Tocoph
erol
Oleyl
Alco
(mu
Ethan
ol
(mu
Cyclom
ethicone
Caprylic
acid
(ml)
Liq.
Paraffin
Tea
Tree
Oil
Table 3: Results of MIC for oil compositions of piroctone olamine
I 1 Concentration ((yglml) I
Formulation Codes
VPO-00 1
VPO-0 1 8
VPO-022
VPO-028
VPO-03 0
VPO-03 1
VPO-032
VPO-033
VPO-034
VPO-03 5
VPO-NC
(Negative control)
PO in DMSO (Positive
control)
"+" indicates growth
64
- -
- -
- -
- -
--
--
--
--
- -
- -
+
--
8
+
-I-
+
+
+
+
+
+
+
+
+
+
of fungus and " -"
16
+
+
+
+
+
+
-I-
+
+
+
t
+
indicates no
32
--
--
- -
- -
- -
- -
--
--
--
--
+
--
growth of fungus
Table 4: Results of MIC for oil compositions of ketoconazole
"+" indicates growth of fungus and " - -" indicates no growth of fungus
Formulation
Concentration (pglml)
Table 5: Oil compositions containing piroctone olamine as antifungal agent
Ingredients
Piroctone olamine (mg)
Oleyl alcohol (~nl)
Ethanol (ml)
Caprylic acid (ml)
Compositions
Propylene glycol mono
caprylate (inl)
Tocopherol acetate
(antioxidant)
Butylated hydroxy toluene
(Preservative)
Light liquid paraffin
(ml, Up to)
0.5
0.3
0.08
1 P
50
*q.s. Quantity sufficient
--
q.s.*
q.s.
100
3P
50
2P
5 0
0.5
0.3
0.08
4P
50
--
q.s.
q.s.
100
2
0.75
--
3
0.75
--
4
q.s.
q.s.
100
4
q.s.
q.s.
100
Table 6: MIC of oil compositions containing piroctone olamine against M. furfur
concentration (pglml)
Compositions
1P
2P
3P
4P
Base formulation with 5 %
sunflower oil
Base for~nulationw ith
10 % oleic acid
Piroctone olamine
in DMSO
(Positive control)
"+" indicates growth of fungus
8
+
+
+
+
+
+
+
and " --" indicates
16
+
+
--
--
+
+
+
no growth
32
- -
- -
- -
--
+
+
- -
of fungus
Table 7: MIC for oil compositions containing piroctone olamine against M. obtrrsa
Compositions Concentration (pglml)
1 P
2P
3P
4P
Base formulation with
5 % sunflower oil
Base formulation with
10 % oleic acid
Piroctone ola~ninein
DMSO
(positive control)
"+" indicates growth of fungus and " -" indicates no growth of fungus
64
--
--
--
--
--
--
--
4
+
+
+
+
+
+
+
8
+
+
--
--
+
+
+
16
--
--
--
--
+
+
+
32
--
--
--
--
+
+
--
Table 8: Oil compositions containing ketoconazole as antifungal agent
Ingredients
Ketoconazole ( i g )
Oleyl alcohol (ml)
Ethanol (ml)
Caprylic acid (ml)
I Tocopherol acetate (antioxidant) I q.s. I q.s. I
Compositions
Propylene glycol mono caprylate
(ml)
1K
20
0.5
0.3
0.5
2K
20
0.5
0.3
0.7
4
Butylated hydroxy toluene
(Preservative)
Light liquid paraffin (ml, Up to)
4
*q.s. Quantity sufficient
q.s.
100
q.s.
100
Table 9: Oil compositions
Ingredients
Piroctone olamine (mg)
Kctoconazole (mg)
Oleyl alcohol (ml)
Ethanol (ml)
Caprylic acid (tnl)
Propylene glycol mono
caprylate (ml)
Tocopherol acetate
(antioxidant)
Butylated hydroxy
toluene (Preservative)
Light liquid paraffin (ml,
UP to)
"q.s. Quantity sufficient
containing piroctone olamine and ketoconazole in combination
Compositions
1PK
5 0
20
2
1
0.1
- m
q.s.
q.s.
100
2PK
5 0
20
2
1
0.1
4
q.s.
q.s.
100
Table 10: Oil compositions containing piroctone olamine as antifungal agent and Minoxidil
Ingredients
Minoxidil (mg)
Compositions
1PM
Piroctone olamine (mg)
Ethanol (ml)
2PM
Propylene glycol I --
Tocopherol Aetate (mg) I 4.'.
5 0
10
- -
Oleyl alcohol (ml)
Caprylic Acid (ml)
50
15
Light liquid paraffin (ml, upto) 1 loo 1
10
5.0
Monoldiglycerides of caprylic acid
(ml)
I I
kq.s. Quantity sufficient
20
5.0
-- --
Table 11: Gel compositions containing antifungal agents devoid of C-11 or greater fatty
*q.s. Quantity sufficient
Ingredients
Piroctone Olamine
Ketoconazole
Zinc Pyrithione
Ethanol
Propylene glycol
PEG-I 00
Propylene glycol
mono caprylate
Polymeric
surfactant
Carbopols
Triethanolaminel
sodium hydroxide
(pH adjuster)
Water
Compositions (wtOh)
1G
0.05
--
--
10.0
--
- -
--
--
0.3
q,s
q.s.
4G
0.05
--
--
4.0
--
--
4.0
0.2
0.5
q.S
q.s.
(Balance)
2G
0.05
- -
- -
4.0
--
- -
4.0
0.2
0.3
q.S
q.s.
(Balance)
5G
--
--
0.016
--
- -
10.8
4.0
0.2
0.5
q.S
q.s.
(Balance)
3G
0.05
--
--
4.0
--
--
4.0
0.2
0.4
q.S
q.s.
(Balance)
6G
0.0 16
--
- -
10
4.0
0.2
0.5
(4.S
q.s.
(Balance)
Table 12: Zone of inhibition of gel compositions containing piroctone olamine against M.
furfur
Formulations
IG
2G
1G with 10 %
oleic acid
Gel base without
anti-fungal agent
(negative
control)
Zone of Inhibition (in cm)
Setup1
1.2
1.4
--
--
Setup2
1 .O
1.5
--
--
Setup3
0.9
1.3
--
--
Table 13: Preparation of cream compositions containing antifungal agents Piroctone
olaminc or kctoconazole.
Ingredient
Piroctone Olalnine
Ketoconazole
Laurvl alcohol
Compositions (Ohwt)
Steryl alcohol
Trialvceride of ca~rvlica cid
--
6
Cyclomethicone
PEG2 ether of stearic acid
2 I I I I
Water I q.s. (Balance) I q.s. (Balance) I q.s. (Balance) I q.s. (Balance) I
4C
--
7
1 .O
PEG21 ether of stearic acid
Propylene glycol
Carbopol
pH adjuster (sodium
hvdroxide or citric acid)
*q.s. Quantity sufficient
3C
--
1C
0.05
--
6
7
0.5
2C
0.1
7
1.0
2.5
5.0
0.25
q.s.
2.0
6
7
0.5
1 .O
6
7
1 .O
2.5
5.0
0.25
q.s.
7
1 .O
7
0.5
7
0.5
2.5
5.0
0.25
q.s.
2.5
5.0
0.25
q.s.
CLAIMS AMENDED UNDER ARTICLE 34
WE CLAIM
1. An antifungal composition comprising at least one antifungal agent, at least one oil
wherein said oil is a fntty acid or cstor thereof having carbon chain length ranging
Irom C-1 to 12-10, and at least one excipient, and wherein said composition is devoid
of C-I 1 or greater fatty add or cster thercof.
2. The antifungal composition of clai~n 1, wherein the composition comprises about 0.01
'% to about 10% by weight of said antifungal agent.
The antifungal composition of claim 1, whercin said antifungal agenl is piroctono
olun~ine, ciclopirox olamine, ketoco~~aiole, olimbazole, mioonuola nitrate,
itraconazole, fluconmole, econazolo, terconrmle, ~~~erconazolao~, ~~orolfinc,
oxicouazole, dotrimazole, luliconazole, terbiinfine, bulenafine, naf?iiine, selenium
disulfidc, salicylic acid, sulfur, lar, undecmoic acid, zinc pyrithione, hinoltitol, arnica
extract, walnut shell extract, tea tree oil, roscmry oil, birch oil or any combiaation
thereof.
4. The nl~tif~~tlgccaoli nposition of claim 3, wherein said antif~mgala gent is piroclone
olmine.
5. The antifingal conlpositian of claim 3, wherein said antif6ngal agelent is ketoconazole.
6. The antifungal cornposition of claim 1, whercin said fatty acid or aster thereof having
carbon ol-rain length ranging from C-1 to C-10 is propionic ncid, butyric acid,
pentanoic acid, hexanoic acid, hcptamic acid, cnprylic acid, nonanoic acid, capric
acid or any combination thereof.
7. The nntifungnl composition of claim 1, wherein said excipient is solvent, additivc or a
combination thereof.
WPLACEMENT SHEETS
CLAIMS AMENDED UNDER ARTICLE 34
8, The antifingal composition of claim 1, whcrein the cornposition cornprism about
0.5% to about 99% by weight of said excipient.
9, l'hc antifungal composition of'clczim 1, %herein said composition is fonnuIaled into
crcam, oil, lotion, serum, gel, shampoo, nail varnish, oinlment, roam, spray or tierosal.
10. The antlfungd coti~positiono f claim 9, whcrein said colnposition is end-dmdrufl' ail.
11. The nntiddruff oil composition of claim 10, wherein said miifingal agent is
piroctono olarnine, ci~iopiroxo lrunine, ketoconazole, climbazole, miconuiole nitrate,
itrwonmlc, fluoonw~lt, econwlo, terconazole, saperconazole, amorolfine,
oxiconazole, crlotrimmole, luliconaeole, terbinafine, butenafine, nafiifine, sclenium
disulfide, salicylic acid, sdfur, tar, undecanoic acid, zinc pyrithione, hinokitol, arnica
extract, walnut shell extract, tca tree oil, rosemary oil, birch oil or any combination
thereof,
12. The antifungal composition as claimed in claim 1 for use in a rne&od for reducing
@a1 growth promoted by a composition devoid of C-1 to (2-10 fatty acid or cstw
thcrcof and optionally oonlprising at least one C11 or. w t e r fatly acid or ester
thereof, said use cornprising act of:
a. adding at least onc fatty acid or ester. thcreof having carbon chain length ranging
from C-1 to (2-10o;r
b. replacing said C11 or greater fatty acid or ester thereof in the compasiliall with
at least one fatty acid or ester thcrcof hwing carbon chain length rmghg from
C-1 to C-10.
13, A method For reducing fungal growth promoted by a composition devoid of C-1 to C-
10 ratty wid OT esler thereof and optionally comprising at least one C11 or greater
klty acid or ester thereof, said metllod colnprising act 01';
a. adding at least one fatty mid or cstcr thereof ]&ing carbon chain length ranging
from C-1 to C-10; or
KEPLACEMENT STEETS
CLAIMS AMENDED UNDER ARTICLE 34
b. replacing the C11 or greater fatty acid or ester Ll~ereofi n the composition with at
least one fatty acid or ester thereof having carbon ohain leq$h ranging from C-1
to C-10.