Antifungal treatment of nails

16 Pages·2013·1.74 MB·English

US008333981B2
(12) United States Patent (10) Patent N0.: US 8,333,981 B2
Trimble (45) Date of Patent: Dec. 18, 2012
(54) ANTIFUNGAL TREATMENT OF NAILS Aly, R. 1999. Ecology, epidemiology and diagnosis of tinea capitis.
Pediat Inf. Dis J. 18:180-185.
(75) Inventor: John Olin Trimble, Texarkana, TX (US) Aly, R., R. J. Hay, A. Del Palacio, and R. Galimberti. 2000. Epide
miology oftinea capitis. Med Mycol. 38:183-188.
(73) Assignee: Humco Holding Group, Inc., Aman, S., T. S. Haroon, I. Hussain, M. A. Bokhari, and K. Khurshid.
Texarkana, TX (US) 2001. Tinea unguium in Lahore, Pakistan. Med Mycol. 39:177-180.
British Journal of Dermatology, vol. 85 Issue 5 p. 437-449, Nov.
( * ) Notice: Subject to any disclaimer, the term of this 1971.
Chem Pharm Bull (Tokyo). Nov. 1998; 46(1 1): 1797-802.
patent is extended or adjusted under 35
U.S.C. 154(b) by 0 days. Indian J Pathol Microbio. Apr. 2002; 45(2):l69-72.
Int J Pharm. Oct. 1, 2002; 245(1-2):25-36.
(21) Appl.No.: 12/246,382 International Journal ofPharmaceutics, Mar. 6, 2007; 322(1-2): 196
201.
Journal of the American Podiatric Medical Association, vol. 89, Issue
(22) Filed: Oct. 6, 2008
3 124-130,1999.
J Invest Dermatol. Feb. 1981; 76(2):76-9.
(65) Prior Publication Data
J Pharm Pharmacol. Jan. 1983; 35(l):28-33.
US 2009/0092576 A1 Apr. 9, 2009 J Pharm Pharmacol. Nov. 1985; 37(1 l):77l-5.
J Pharm Pharmacol. Mar. 1999; 5l(3):27l-8.
Related US. Application Data Nail Swelling as a Pre-formulation Screen for the Selection and
Optimisation of Ungual Penetration Enhancers, Journal of Pharma
(60) Provisional application No. 60/998,199, ?led on Oct. ceutical Research, Jul. 2007, pp. 2207-2212.
9, 2007. Ramsewak RS, et al. In vitro antagonistic activity of monoterpenes
and their mixtures against ‘toe nail fungus’ pathogens. Phytother Res.
(51) Int. Cl. Apr. 2003; 17(4):376-9.
A01N 25/24 (2006.01) Robbins CR.Chemical & Physical behavior of human nail, 3rd edi
A61K 0/10 (2006.01) tion, New York: Springer-verlag 1997 pp. 93-130.
A61K 49/00 (2006.01) Thymus Vulgaris. PDR for Herbal Medicine. Montvale, NJ: Medical
A61K 47/00 (2006.01) Economics Company. p. 1184.
A61Q 3/02 (2006.01) Weitzman, L, and R. C. Summerbell. 1995. The dermatophytes. Clin
Microbiol Rev. 8:240-59.
(52) US. Cl. ......... .. 424/400; 424/61; 424/92; 514/770;
Mohorcic et al., “An investigation into keratinolytic..”, Int’l Jour. of
5 14/947
Pharmaceutics, Elsevier BV, NL, vol. 332,No. l-2, Feb. 13, 2007,pp.
(58) Field of Classi?cation Search ......... .. None 196-201, ISSN 0378-5173.
See application ?le for complete search h1story. Greeves, M. Bontanicalcom, “Thyme, Garden. Botanical: Thymus
Vulgaris (Linn) Family: N.O. Labiale.” [online], 1995-2010
(56) References Cited [retrieved on Jul. 23, 2010]. Retrieved from the Internet: http://www.
botanical.com/botanical/mgmh/t/thygarl6.html, pp. l-9 of9.
U.S. PATENT DOCUMENTS International Search Report and Written Opinion, European Patent
Of?ce, Jan. 7, 2009, Application No. PCT/US2008/078960.
5,322,689 A 6/1994 Hughes et a1.
European Patent Of?ce, Of?cial Action, Serial No. 088378807, May
5,696,164 A 12/1997 Sun et a1.
5,814,305 A 9/1998 Laugier et al. 20, 2010.
5,993,790 A 11/1999 Strauss et al. European Patent Of?ce, Response to Of?cial Action, Serial No.
6,042,845 A 3/2000 Sun et a1. 088378807, Jun. 24, 2010.
6,143,793 A ll/2000 Laugier et al.
6,224,887 B1 5/2001 Samour et a1. * cited by examiner
6,284,258 B1 9/2001 Rose et a1.
6,284,802 B1 * 9/2001 Bissett et a1.
6,296,838 B1 10/2001 Bindra et a1. Primary Examiner * Jeffrey S. Lundgren
6,372,234 B1 4/2002 Deckers et al.
6,455,592 B1 9/2002 Laugier et al. Assistant Examiner * Gregg Polansky
6,495,124 B1 12/2002 Samour et a1. (74) Attorney, Agent, or Firm * Jackson Walker L.L.P.
6,676,953 B2 l/2004 Hexamer et al.
7,048,913 B2 5/2006 Hexamer et al.
7,074,392 B1 7/ 2006 Friedman et al. (57) ABSTRACT
2005/0208110 A1 9/2005 Singh et al.
2006/0057075 A1 3/ 2006 Arkin et al. A fungus treatment composition used to deliver active drugs
2006/0182766 Al* 8/2006 Modi
trans-nail as well as a method for producing the fungus treat
2008/0207537 Al* 8/2008 Turner et al.
ment composition, which may contain up to 50% additive
FOREIGN PATENT DOCUMENTS ingredients. Preferred embodiments of the invention may
include fungus treatment compositions which provide high
EP 1138314 10/2001
GB 2 124 485 A 2/1984 nail penetrating power, which have antifungal agents, which
W0 WO 97/42934 ll/l997 have antifungal essential oils, which have optimum drying
WO WO/02/22115 3/2002 and barrier properties, which have pharmaceutically elegant
OTHER PUBLICATIONS properties, or most preferably an embodiment having a total
combination thereof.
Rowe et al. (Eds), Handbook of Pharmaceutical Excipients, 5th
Edition, 2006, “Bentonite”, pp. 58-60, “Hydroxypropyl Cellulose”,
pp. 336-340, and “Hypromellose”, pp. 346-349.* 8 Claims, 5 Drawing Sheets

U S. Patent Dec. 18,2012 Sheet 5 of5 US 8,333,981 B2
EmsmE
US 8,333,981 B2
1 2
ANTIFUNGAL TREATMENT OF NAILS Candida is thin-Walled yeast that reproduces by budding.
No more than ten species of Candida cause disease in humans
This application claims priority to Us. Provisional Patent With any frequency even though there are more than 150
Application Ser. No. 60/998,199, entitled “ANTIFUNGAL species (KWon-Chung, K. 1., and J. E. Bennett. 1992. Medical
TREATMENT OF NAILS” ?led on Oct. 9, 2007, the entire Mycology. Lea & Febiger, Philadelphia).
content of Which is hereby incorporated by reference. Cutaneous candidiasis is arguably the most common form
of candidiasis. The infection involves the very outer-most
BACKGROUND layers of the skin. Healthy skin is quite resistant to candidal
infection and in essentially all cases a predisposing factor is
The present invention relates to a method for the topical present. These forms of localiZed candiasis can be very irri
treatment of fungal diseases in nails. This invention relates in tating to the patient although neither invasive nor life-threat
particular to a composition for enhancing the permeation rate ening. The most common and important form of candidal skin
of antifungal agents in nails and to an apparatus adapted for infections is erosio interdigitalis blastomycetica in the ?nger
use With the testing of the invention. or toe Webspace With eroded erythematous area surrounded
All living things can be classi?ed into one of ?ve funda With macerated skin.
mental kingdoms of life and the term fungus refers generi
cally to all members of the Kingdom Fungi. There are more Antifungal Agents
than a million species of fungi but only about 400 cause
diseases relevant to man. There are a number of topical agents used in treatment of
Infections of the nail are so important that they get their super?cial cutaneous mycoses. The super?cial cutaneous
oWn name. The term onychomycosis is used both to refer to 20 mycoses that respond to topical therapy include the localiZed
non-dermatophyte nail infections and to any fungal nail infec infections of nails and epidermis due to the dermatophytes
tion caused by any fungus. The term tinea unguium can be and Candida. These topical agents are of distinct chemical
applied only if the infection is due to a dermatophyte. The classes. The major characteristics of the currently available
distinction is narroW and technical. The leading yeast cause of topical antifungal agents that are in general effective in treat
onychomycosis is candida albicans. It is not uncommon to ment of super?cial cutaneous mycoses and/ or candidiasis are
25
have more than one fungus species jointly causing the infec shown below:
tion. (a) Amphotericin Biindicated for cutaneous candidiasis.
The dermatophytes are not a particular fungus but rather a (b) Nystatiniindicated for cutaneous candidiasis.
common short-hand label for a group of three genera of fungi (c) ClotrimaZoleiindicated for dermatophytosis and cuta
that commonly cause skin disease of people: neous candidiasis.
(a) Epidermophylon?occosum is a common cause of der 30 (d) Econazoleiindicated for dermatophyto sis and cutane
matophyto sis in otherWise healthy individuals. It infects ous candidiasis.
skin and nails. The infection is restricted to the nonliving (e) Ketoconazoleiindicated for dermatophytosis and
corni?ed layers of epidermis since the fungus lacks the cutaneous candidiasis.
ability to penetrate the viable tissues of the immunocom (f) MiconaZoleiindicated for dermatophytosis and cuta
petent host (Aman, S., T. S. Haroon, I. Hussain, M. A. 35 neous candidiasis.
Bokhari, and K. Khurshid. 2001. Tinea unguium in (g) OXiconaZoleiindicated for dermatophytosis and cuta
Lahore, Pakistan. Med Mycol. 391177-180). Dissemi neous candidiasis.
nated infections due to any of the dermatophytes are (h) SulconaZoleiindicated for dermatophyto sis and cuta
very unlikely due to the restriction of the infection to neous candidiasis.
keratiniZed tissues. Epidermophylon ?occosum infec (i) Butena?ne HCliindicated for dermatophytosis.
40
tions are communicable and usually transmitted by con (j) Nafti?neiindicated for dermatophytosis.
tact. (k) Terbina?neiindicated for dermatophytosis.
(b) Trichophylon is a causative agent of dermatophytosis (l) Ciclopirox olamineiindicated for dermatophytosis
and infects the skin and nails (Aly, R., R. J. Hay, A. Del and cutaneous candidiasis.
Palacio, and R. Galimberti. 2000. Epidemiology of tinea (m) Haloproginiindicated for dermatophytosis and cuta
45
capitis. Med Mycol. 381183-188). Trichophylon is a neous candidiasis.
keratinophilic ?lamentous fungus. Ability to invade (n) Tolnaftateiindicated for dermatophytosis.
keratiniZed tissues and the possession of several (o) Undecylenateiindicated for dermatophytosis.
enZymes are the major virulence factors of these fungi Antifungal aromatic molecules that make up chemotyped
(WeitZman, 1., and R. C. Summerbell. 1995. The der essential oils are shown below:
matophytes. Clin Microbiol Rev. 81240-59). (a) Phenols
(c) Microsporum is a genus that causes dermatophytosis. i. Thymol: Trachyspermum ammi (AjoWan)
Dermatophytosis is a general term used to de?ne the ii. Carvacrol1 Origanum compaclum (Oregano)
infection in skin or nails due to any dermatophyte spe Origanum heracleolicum (Greek Oregano)
cies. Microsporum has the ability to degrade keratin and Corydolhymus capilalus (Spanish Oregano)
thus can reside on skin and its appendages and remains 55
Salureja monlana (Winter or mountain savory)
noninvasive. Proteinases and elastases of the fungus
Thymus serpyllum (Wild thyme or mother-of-thyme)
may act as virulence factors. Microsporum spp. mostly
infects the skin. Nail infections are very rare. The patho
genesis of the infection depends on the natural reservoir
of the species. Geophilic spp. is acquired via contact 60 (5O H
With soil. Zoophilic species are transmitted from the
infected animal. Direct or indirect human-to-human
transmission is of concern for anthropophilic species.
Asymptomatic carriage may be observed. Otherwise
healthy hosts are infected (Aly, R. 1999. Ecology, epi 65
demiology and diagnosis of tinea capitis. Pediat Inf. Dis
J. 181180-185).
US 8,333,981 B2
3 4
(b) Terpenic Alcohols State University have studied the antifungal effects of Men
i. Linalool: Aniba rosaeodora (Rosewood) thol. They proved that Menthol speci?cally inhibits the
Coriandrum salivum (Coriander) growth of a multitude of fungi known to cause onychomyco
ii. Geraniol: Cymbopogon marlinii (Palmarosa) sis (Phytother Res. 2003 April; 17 (4):376-9).
iii. Thujanol: Origanum majorana (Sweet marjoram or 5 Tea-tree oil is a known antifungal with activity against
oregano) various infectious organisms. Tea-tree has been tested against
iv. Borneol: Thymus salureioides (Thym bomeol-car 58 disease causing fungal organisms. These are the same
vacrol type) fungi thriving within the toenail. 57 isolates were inhibited by
Inula graveolens (Sweet inula) tea-tree.
Eucalyptus oil is known as a powerful antifungal. It is
V. Menthol: Menlha x piperila (Peppermint)
excellent for Athletes Foot and other fungal infections. Euca
Menlha arvensis (Field mint or commint)
lyptus leaves were crushed by the Aborigines to heal wounds
vi. Citronnellol: Pelargonium asperum (Geranium)
and ?ght infection.
vii. Terpineneol: Melaleuca allemifolia (Tea Tree)
Camphor has little or no detectable anti-fungal activity. A
Origanum majorana (Sweet marjoram or oregano)
composition of 4% Menthol with 2% Camphor is signi?
viii. ot-Terpineol: Ravensara aromalica (Ravensara)
cantly more potent in its ability to kill toenail fungus. The
Eucalyptus radiala (Black or peppermint eucalyptus)
camphor also likely acts as a penetration agent allowing better
access of the Menthol to the fungus under the toenail bed
(lntemational Patent No. WO/2002/022115 to McKenzie, et
(3O H 20 al., issued Mar. 21, 2002).
Several different compositions for fungus treatments have
been described.
US. Pat. No. 5,696,164 to Sun, et al., issued Dec. 9, 1997,
discloses a method for the treatment of fungal diseases in
25 nails, which comprises the topical administration to the nail
and, if desired, also to the surrounding skin, of (1) a sulfhydryl
containing amino acid or a derivative thereof, the pharmaceu
(c) Aromatic Aldehydes tically acceptable salts or esters thereof, or stereoisomers
i. Cinnamaldehyde: Cinnamomum verum (Ceylon cin thereof, (2) urea, (1) and (2) being administered in an amount
namon) 30 suf?cient to enhance the permeation of antifungal drugs
through nail tissue, either prior to or, preferably, concurrently
Cinnamomum cassia (Chinese cinnamon)
with the topical administration to the nail of (3) an effective
Cinnamomum loureirii (Vietnamese cinnamon)
ii. Cuminal: Cuminum cyminum (Cumin) amount of an antifungal drug. There is also disclosed a ban
Eucalyptus polybraclea (Blue or mallee eucalyptus) dage adapted for the topical administration of medication to
the nail, said bandage comprising a T-shaped adhesive back
iii. Phellandral: Eucalypluspolybraclea (Blue or mallee
eucalyptus) ing, and a ?exible pad having an impervious backing and a
nail-shaped cavity backed by said impervious backing,
wherein said nail-shaped cavity contains absorptive means
having absorbed therein urea and a sulfhydryl containing
CHC
40 amino acid or a derivative thereof, a pharmaceutically accept
able salt or ester thereof, or a stereoisomer thereof.
US. Pat. No. 5,814,305 to Laugier, et al., issued Sep. 29,
1 998, describes the improved penetration of antifungal agents
through the nails using hydrophilic penetration agents cus
Thymol is known as a powerful antifungal. The essential 45 tomarily used for the transcutaneous penetration of active
oil of common thyme is made up of 20-55% thymol (Thymus ingredients. A corresponding dermatological composition
Vulgaris. PDR for Herbal Medicine. Montvale, N.J.: Medical contains at least one antifungal agent chosen, in particular,
Economics Company. p. 1 184). It was used to medicate ban from among those of the allylamine family, such as terbin
dages before the advent of modern antibiotics (Grieve, Maud a?ne-HCl and nafti?ne-HCl; at least one hydrophilic penetra
(Mrs.). Thyme. A Modern Herbal. Hypertext version of the 50 tion agent chosen, in particular, from among the glycols,
1931 edition. Accessed: Dec. 14, 2006). It has also been glycol monoethers, glycol diethers, dimethylsulphoxide,
shown to be effective against the fungus that commonly caprolactam, dimethylisosorbide, isopropylidene glycerol,
infects toenails (Ramsewak R S, et al. In vitro antagonistic dimethylimidaZolidinone, ethyl lactate, the polyoxyethylena
activity of monoterpenes and their mixtures against ‘toe nail ted CS-Cl0 glycerides, polyethylene glycol 20 glyceryl lau
fungus’ pathogens. Phytother Res. 2003 April; 17 (4):376-9). 55 rate and dimethylacetamide; and a water-alcohol solvent
Oregano oil is antifungal. It has been tested against a vari medium which dissolves the said antifungal agent(s) and in
ety of microorganisms and is found to exert a high degree of which the said penetration agent(s) is (or are) at least partially
anti-fungal actions (“The Cure is in the Cupboard: How to miscible.
Use Oregano for Better Health” by Dr. Cass Ingram). US. Pat. No. 5,993,790 to Strauss, et al., issued Nov. 30,
Oregano is perhaps the most powerful herbal anti-fungal 60 1999, discloses a composition comprising water based nail
agent known. lts effectiveness is enhanced by its safety since lacquer and urea, which is useful in the partial or complete
it is non-toxic. Oregano is such a potent anti fungal agent that evulsion of the nails, and in the treatment of fungal, yeast and
it is capable of destroying even resistant fungal forms such as bacterial infections of the nails and the nail beds. Also dis
the mutated fungi which result from antibiotic therapy. closed are methods for evulsing nails, and for treating anti
Menthol penetrates into the nail to kill the fungal elements 65 fungal and antibacterial infections, comprising the adminis
that cause damage. Workers at the Department of Horticulture tration of the composition of the invention to the toenails or
and National Food Safety and Toxicology Center at Michigan ?ngernails of a mammal.
US 8,333,981 B2
5 6
Us. Pat. No. 6,042,845 to Sun, et al., issued Mar. 28, 2000, part may also be useful to impart skin strengthening effect
discloses a method for the treatment of fungal diseases in (e.g., from shear forces) or as Wound healing agents.
nails, Which comprises the topical administration to the nail U.S. Pat. No. 6,296,838 to Bindra, et al., issued Oct. 2,
and, if desired, also to the surrounding skin, of (1) a sulfhydryl 2001 , discloses an antifungal composition for the treatment of
containing amino acid or a derivative thereof, the pharmaceu human nails containing extracts of Walnut hull, pulveriZed
tically acceptable salts or esters thereof, or stereoisomers roots of Nardoslachys jalamansi or Veliveria zizanioides or
Calharanlhus roseus, polyols, ?xed oil, non-ionic emulsi?
thereof, (2) urea, (1) and (2) being administered in an amount
ers, thickening agent plasticiZer and base. The invention also
suf?cient to enhance the permeation of antifungal drugs
relates to a process for the preparation of the above synergistic
through nail tissue, either prior to or, preferably, concurrently
composition.
With the topical administration to the nail of (3) an effective
U.S. Pat. No. 6,455,592 to Laugier, et al., issued Sep. 24,
amount of an antifungal drug. There is also disclosed a ban
2002, describes the improved penetration of antifungal agents
dage adapted for the topical administration of medication to
through the nails using hydrophilic penetration agents cus
the nail, said bandage comprising a T-shaped adhesive back
tomarily used for the transcutaneous penetration of active
ing, and a ?exible pad having an impervious backing and a ingredients. A corresponding dermatological composition
nail-shaped cavity backed by said impervious backing,
contains at least one antifungal agent chosen, in particular,
Wherein said nail-shaped cavity contains absorptive means from among those of the allylamine family, such as terbin
having absorbed therein urea and a sulfhydryl containing a?ne-HCl and nafti?ne-HCl; at least one hydrophilic penetra
amino acid or a derivative thereof, a pharmaceutically accept tion agent chosen, in particular, from among the glycols,
able salt or ester thereof, or a stereoisomer thereof. 20 glycol monoethers, glycol diethers, dimethylsulphoxide,
U.S. Pat. No. 6,143,793 to Laugier, et al., issued Nov. 7, caprolactam, dimethylisosorbide, isopropylidene glycerol,
2000, describes the improved penetration of antifungal agents dimethylimidaZolidinone, ethyl lactate, the polyoxyethylena
through the nails using hydrophilic penetration agents cus ted CS-Cl0 glycerides, polyethylene glycol 20 glyceryl lau
tomarily used for the transcutaneous penetration of active rate and dimethylacetamide; and a Water-alcohol solvent
ingredients. A corresponding dermatological composition 25 medium Which dissolves the said antifungal agent(s) and in
contains at least one antifungal agent chosen, in particular, Which the said penetration agent(s) is (or are) at least partially
from among those of the allylamine family, such as terbin miscible.
a?ne-HCl and nafti?ne-HCl; at least one hydrophilic penetra U.S. Pat. No. 6,495,124 to Samour, et al., issued Dec. 17,
tion agent chosen, in particular, from among the glycols, 2002, discloses a nail lacquer for the treatment or prevention
glycol monoethers, glycol diethers, dimethylsulphoxide, 30 of fungal infections, such as, onychomycosis, Which includes
caprolactam, dimethylisosorbide, isopropylidene glycerol, fungicidally effective amount of ciclopirox, econaZole, or
dimethylimidazolidinone, ethyl lactate, the polyoxyethylena other antifungal agent in a compatible ?lm-forming lacquer
ted CS-Cl0 glycerides, polyethylene glycol 20 glyceryl lau vehicle Which includes a Water-insoluble ?lm-forming poly
rate and dimethylacetamide; and a Water-alcohol solvent mer; pentadecalactone, or similar cyclic lactone compound or
medium Which dissolves the said antifungal agent(s) and in 35 derivative thereof, and volatile solvent. The pentadecalactone
Which the said penetration agent(s) is (or are) at least partially functions as a plasticiZer for the ?lm-forming polymer and as
miscible. a penetration enhancer for the antifungal agent. The compo
U.S. Pat. No. 6,224,887 to Samour, et al., issued May 1, sition, When applied to the nails provides a hard, clear, Water
2001, discloses a nail lacquer effective for the treatment or resistant ?lm containing the antifungal agent. The composi
prevention of fungal infections, such as, onychomycosis, 40 tions are used for the treatment of onychomycosis.
Which includes a fungicidally effective amount of ciclopirox, U.S. Pat. No. 6,676,953 to Hexamer, et al., issued Jan. 13,
econaZole, or other antifungal agent in a clear, stable, ?lm 2004, discloses an antifungal composition for the treatment of
forming lacquer vehicle Which includes a Water-insoluble fungal infections in, around and under human nails, in Which
?lm-forming polymer; 2-n-nonyl-1,3-dioxolane or similar the composition comprises an aqueous solution of a Wetting
penetration enhancer; and volatile solvent. A plasticiZer for 45 agent such as alcohol and a source of ?uoride ions suf?cient
the ?lm-forming polymer Which is also compatible With the to establish a pH ranging from about 2.8 to about 3.5 in the
other components may be included although the preferred composition. A preferred source of ?uoride ions is stannous
penetration enhancers may also function as plasticiZer. The ?uoride or stannous ?uoride in an amount suf?cient to satu
composition, When applied to the nails provides a hard, clear, rate the solution. According to the method of the invention,
Water-resistant ?lm containing the antifungal agent. The ?lm 50 one or more drops of the subject solution are topically applied
is resistant to multiple Washings and is effective in the treat to the infected nail and surrounding cuticular area periodi
ment of onychomycosis. cally until the infection abates.
U.S. Pat. No. 6,284,258 to Rose, et al., issued Sep. 4, 2001, U.S. Pat. No. 7,048,913 to Hexamer, et al., issued May 23,
discloses compounds that are tWo-part molecules, and com 2006, discloses an antifungal composition for the treatment of
positions containing such compounds, in Which one part is 55 fungal infections in, around and under human nails, in Which
designed to become covalently bonded to the skin (bonding the composition comprises an aqueous solution of a Wetting
agent) and the other part (a characteristic use agent) is agent such as alcohol and a source of ?uoride ions suf?cient
designed to impart some characteristic use, such as emol to establish a pH ranging from about 2.8 to about 3.5 in the
liency, moisturizing effect, anti-acne, anti-Wrinkle, anti-pain, composition. A preferred source of ?uoride ions is stannous
antimicrobial, antifungal, antiviral, anti-irritation, skin tan 60 ?uoride or stannous ?uoride in an amount suf?cient to satu
ning and skin lightening effects, extended protection of the rate the solution. According to the method of the invention,
skin (e.g., from ultraviolet light, by incorporation of a sun one or more drops of the subject solution are topically applied
screen component; from toxic and/or irritating substances; to the infected nail and surrounding cuticular area periodi
from insects and skin parasites, by incorporation of insecti cally until the infection abates.
cides and/or insect repellants; from free radicals or other 65 U.S. Pat. No. 7,074,392 to Friedman, et al., issued Jul. 11,
agents, as in aging, by incorporation of antioxidants), or 2006, discloses a topical sustained release delivery system for
dyeing of hair, skin nails, Wool or fur. The covalently bonded delivery of antifungal agents to the ?nger or toenails achiev
US 8,333,981 B2
7 8
ing high penetration through the nails by combining the anti tolnaftate. This product is trademarked as DR. SCHOLL’S
fungal agent With a keratolytic agent and a humectant. The (fungal nail management kit, Schering-Plough). It contains a
pharmaceutical sustained release topical preparation is pro nail revitaliZer cream, a nail brush applicator, a nail ?le, and
vided in a varnish or spray form for treating the nail and a tolnaftate antifungal cream.
surrounding tissues, Where the active ingredient is an antifun 5 Eulactol USA Inc. manufactures the over-the-counter
gal agent, a keratolytic agent, or preferably a combination of maximum strength anti-fungal liquid, With 25.0% unde
an antifungal and a keratolytic agent. The composition may cylenic acid. This product is trademarked as FLEXITOL
further comprise an antibacterial, an antiviral, an antipsoriatic (anti-fungal liquid, Eulactol USA Inc., Boca Raton, Fla.). It
agents, or combinations thereof. contains nature’ s healers, tea tree oil, aloe vera and vitamin E.
P?zer manufactures the prescription antifungal agent, ?u Alva manufactures the over-the-counter extra strength
conaZole. This product is trademarked as DIFLUCAN (?u anti-fungal liquid, With 12.5% undecylenic acid, and the over
conaZole tablets, P?zer, NeW York). It is for the treatment of the-counter professional formula anti-fungal liquid, With
oropharyngeal and esophageal candidiasis. FluconaZole is 15.0% undecylenic acid. These products are trademarked as
also effective for the treatment of serious systemic candidal FUNGICURE (anti-fungal liquid, Alva, Niles, Ill.). Both the
infections, including urinary tract infection, peritonitis and extra strength and the professional formula contain aloe and
pneumonia. vitamin E.
Schering manufactures the prescription antifungal antibi Kramer Laboratories, Inc. manufactures the over-the
otic, griseofulvin. This product is trademarked as FULVICIN counter double strength anti-fungal solution, With 25.0%
(griseofulvin, Schering-Plough, KenilWor‘th, N.J.). It is orally undecylenic acid. This product is trademarked as FUNGI
effective against super?cial infections caused by those fungi 20 NAIL (anti-fungal solution, Kramer Laboratories, Inc. Miami
responsible for dermatomycoses in man and animals, Fla.).
namely: M canis, M gypseum, M audouini, E. ?occosum, T WoodWard Laboratories manufactures the over-the
Zonsurans, T rubrum, T menlagrophyles, T megninii, T galli counter antifungal treatment, With 1 .0% tolnaftate. This prod
nae, T verrucosum, T sulfureum, T inlerdigilale, T Schoen uct is trademarked as MYCOCIDE NS (antimicrobial nail
leinii, T craleriform. Griseofulvinis inactive against: C. albi 25 solution, WoodWard Laboratories, Aliso Viejo, Calif.). It con
cans (monilia), C. neoformans, B. dermalilidis, A. israelii, H. tains a patented penetrating delivery system and the soothing
capsulalum, C. immilis, M furfur (tinea versicolor) and bac allantoin difference.
teria. The drug is useful in the treatment of fungal infections NDC Laboratories manufactures the over-the-counter
of the scalp and those of the glabrous skin. The drug is less medical strength antifungal solution, With 1.0% clotrimaZole.
effective in chronic infections of the feet, palms, and nails. 30 This product is trademarked as RECLEAR AF (antifungal
Since these chronic fungal infections tend to cause hyperk solution, NDC Laboratories, Anaheim, Calif.).
eratosis, concomitant topical keratolytic therapy is almost Del Laboratories, Inc. manufactures the over-the-counter
alWays necessary. antifungal liquid, With 25.0% undecylenic acid. This product
Novartis Pharmaceuticals manufactures the prescription is trademarked as SALLY HANSEN NO MORE FUNGUS
antifungal, terbina?ne HCl. This product is trademarked as 35 (antifungal liquid, Del Laboratories, Inc., NeW York, NY).
LAMISIL (terbina?ne HCl solution, Novartis, Basel, SWit Blaine Labs, Inc. manufactures the over-the-counter anti
Zerland). It is for the treatment of fungal infections of the skin fungal cream, With 10.0% undecylenic acid. This product is
and nails caused by dermatophytes such as Trichophylon trademarked as TINEACIDE (antifungal cream, Blaine Labs,
(e.g., T rubrum, T menlagrophyles, T verrucosum, T viola Inc. Santa Fe Springs, Calif.).
ceum), M canis and E. ?occosum. 40 Almost all of the above commercial products to treat ony
Sano?-Aventis manufactures the prescription antifungal chomycosis including ciclopirox, clotrimaZole, ?uconaZole,
agent, ciclopirox. This product is trademarked as PENLAC griseofulvin, itraconaZole, miconaZole nitrate, terbina?ne
(ciclopirox topical solution, Sano?-Aventis, BridgeWater, HCl, tolnaftate, and undecylenic acid have problems.
N.J.). It is a component of a comprehensive management Ciclopirox reportedly has only a 14% cure rate after several
program, and is indicated as topical treatment in immuno 45 months of use. Up to 48 Weeks of daily applications With
competent patients With mild to moderate onychomycosis of ciclopirox topical solution and professional removal of the
?ngernails and toenails Without lunula involvement, due to unattached nail are considered the full treatment needed to
Tr i chophylon rubrum. The comprehensive management pro achieve a clear or almost clear nail (PENLAC Nail Lacquer
gram includes removal of the unattached, infected nails as (ciclopirox) Topical Solution, 8% Prescribing Information).
frequently as monthly, by a health care professional Who has 50 ClotrimaZole reportedly has only 30.55% of dermatophyte
special competence in the diagnosis and treatment of nail isolates being sensitive (IndianJ Pathol Microbio. 2002 April;
disorders, including minor nail procedures. 45 (2):169-72).
Janssen-Ortho manufactures the prescription antifungal, FluconaZole reportedly is effective only for the treatment
itraconaZole. This product is trademarked as SPORANOX of serious systemic candidal infections. Sixteen percent of
(itraconaZole capsules, Janssen-Or‘tho, Raritan, N.J.). It is for 55 over 4000 patients treated With ?uconaZole in clinical trials of
the treatment of oral and/or esophageal candidiasis in adult 7 days or more experienced adverse events (DIFLUCAN
HIV-positive or other immunocompromised patients. (?uconaZole) Capsule Prescribing Information).
Ganeden Biotech, Inc. manufactures the over-the-counter Griseofulvin reportedly has poor cure rates and requires
military strength fungus treatment, With 2.0% miconaZole 10-18 months of use. The drug is less effective in chronic
nitrate, and the over-the-counter triple action fungus treat 60 infections of the nails. Concomitant topical keratolytic
ment, With 1.0% clotrimaZole. These products are trade therapy is almost alWays necessary since these chronic fungal
marked as CLEARLY CONFIDENT (antifungal lotion, infections tend to cause hyperkeratosis (FULVICIN (griseof
Ganeden Biotech, May?eld Heights, Ohio). The military ulvin) Tablet Prescribing Information).
strength is Emu Oil patented formulation, and the triple action ItraconaZole reportedly is unsafe for patients With compro
contains benZalkonium chloride, emu oil, and tea tree oil. 65 mised liver function or patients With gastroesophageal re?ux
Schering-Plough HealthCare Products, Inc. manufactures disease on a proton pump inhibitor. The total observed inci
the over-the-counter fungal nail management kit, With 1.0% dence of adverse events that are possibly or directly drug