United States Patent
`DeVincentis et al.
`
`[19]
`
`I IIlllllllllllllllllllllllllllllllllllHlllUlllllllllllMIIIIIIIllllll
`
`US005391367A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,391,367
`Feb. 21, 1995
`
`ANTIFUNGAL NAIL SOLUTION
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,914,131 10/1975 Hutchison ........................... 106/268
`4,721,724 1/1988 Stettendorf et al ................. 514/396
`
`FOREIGN PATENT DOCUMENTS
`
`0440298 8/1991 European Pat. Off..
`8702580 5/1987 WIPO.
`8704617 8/1987 WIPO.
`
`Primary Examiner--Gollamudd S. Kishore
`Assistant Examiner--Jyothsna Venkat
`Attorney, Agent, or Firm--Peter C. Richardson; Gregg
`C. Benson; Robert F. Sheyka
`
`[54]
`
`[75]
`
`Inventors: Teresa J. DeVincentis, Flanders;
`Darius D. Dubash, Pine Brook;
`Debbie L Burnett, Basking Ridge;
`Athanasios S. Ladas, Parsippany, all
`of N.J.
`
`[73]
`
`Assignee: Pfizer Inc., New York, N.Y.
`
`[21]
`
`Appl. No.: 97,422
`
`[22]
`
`Filed:
`
`Jul. 28, 1993
`
`[57]
`
`ABSTRACT
`
`[51]
`[52]
`[58]
`
`Int. 0.6 ................................................ A61K 7/04
`U.S. C1 ....................................... 424/61; 514/397;
`514/777
`Field of Search ................... 424/61; 514/397, 777
`
`A composition useful in the treatment of onychomyco-
`sis comprises tioconazote, a gel-forming agent and a
`hydro-aleoholie vehicle.
`
`5 Claims, No Drawings
`
`ARGENTUM EX1013
`
`Page 1
`
`

`

`5,391,367
`
`1
`
`ANTIFUNGAL NAIL SOLUTION
`
`BACKGROUND OF THE INVENTION
`
`2
`said composition when applied to the nails of a human
`infected with onychomycosis creating a reservoir from
`which tioconazole continuously penetrates the nails.
`A preferred alcohol for use in the composition of the
`present invention is ethanol.
`A preferred gel-forming agent for use in the composi-
`tion of the present invention is hydroxypropyl cellulose.
`Further preferred is the composition of the present
`invention which further comprises a plasticizer, prefera-
`10 bly at from about 0.5 to about !0 weight percent, with
`an especially preferred plasticizer being propylene gly-
`col dipelargonate.
`In another embodiment, the present invention is also
`directed to a method for the treatment of onychomyco-
`15 sis comprising the application to the nails of a human in
`need of such treatment a composition of the present
`invention.
`
`The present invention relates to a topical solution for 5
`fungal infections. More specifically, it relates to a topi-
`cal solution for the treatment of fungal infections of the
`nails, or onychomycosis.
`Onychomycosis, also called ringworm of nails, or
`tinea unguium, is a fungus infection of the nails causing
`thickening, roughness and splitting usually caused by
`Trichophyton rubrum or Trichophyton mentagrophytes.
`European Patent Application No. 515312 refers to a
`topical formulation such as a nail varnish for treating
`onychomycosis comprising tertinafme and a polymeric
`film former such as polyvinylacetate or (moth)acrylic
`acid alkyl ester copolymerizates with quaternary am-
`monium groups or methylvinylethermaleic acid mono-
`alkyl ester copolymerizates.
`European Patent Application No. 440298 refers to a
`topical composition for the treatment of onychomycosis
`which comprises oxiconazole and a film-forming com-
`position.
`European Patent Application No. 292495 refers to a 25
`composition containing urea and propylene glycol and-
`/or polyethylene glycol for the treatment of onychomy-
`¯ cosis.
`European Patent Application No. 247142 refers to a
`vehicle for applying drugs to human nails for the treat- 30
`ment of onychomycosis. The vehicle comprises from
`2% to about 40% by weight ofa hydrophilic, film-form-
`ing resin, and a pharmaceutically acceptable solvent for
`the resin. Upon drying, the vehicle is said to form a
`continuous self-supporting dry film. The vehicle has 35
`incorporated therein at least one antimycotic drug se-
`lected from the group consisting of sodium propionate,
`sodium pyrithone and cicloperox. U.S. Pat. No.
`4,721,724 issued Jan. 26, 1988 refers to an antifungal
`composition containing clotrimazole, urea, a hpophilic 40
`wetting agent and a consistency imparting component.
`
`20
`
`SUMMARY OF THE INVENTION
`
`45
`
`In one embodiment, the present invention is directed
`to an antifungal composition comprising
`(a) an effective amount of tioconazole;
`(b) water;
`(c) an alcohol, and
`(d) a gel-forming agent, said composition when ap-
`plied to the nails of a haman infected with onycho- 50
`mycosis creating a reservoir from which ti-
`oconazole continuously penetrates the nail.
`Preferred is the composition wherein the alcoho! is
`ethanol
`Also preferred is the composition wherein said gel- 55
`forming agent is hydroxypropyl cellulose.
`Further preferred is the composition further compris-
`ing the addition of a plasticizer with an especially pre-
`ferred plasticizer being propylene glycol dipelargonate.
`In another embodiment, the present invention is di- 60
`retted to an antifungal composition comprising
`(a) from about 15 to about 30 weight percent ti-
`oconazole;
`(b) from about 1 to about 10 weight percent water;
`(c) from about 50 to about 90 weight percent alcohol, 65
`and
`(d) from about 0.5 to about 5 weight percent of a
`gel-forming agent,
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`1-{2,4-dichloro-B-[(2-chloro-3-thenyl)-oxy]phene-
`thyl}imidazole or tioconazole, its synthesis and formu-
`lation into a number of dosage forms, including creams,
`is described in U.S. Pat. No. 4,062,966 issued Dec. 13,
`1977, the disclosure of this patent being incorporated
`herein by reference.
`It has now been found by in vitro microbiologica!
`tests that a topical tioconazole formulation is effective
`in the treatment of onychomycosis. The present formu-
`lation contains a hydro-alcoholic vehicle in conjunction
`with a hydrophilic gel-forming agent. It has been shown
`that this aqueous vehicle delivers about twice the quan-
`tity of tioconazole to the nail, as opposed to an organic
`based formulation.
`The present formulation also provides other advan-
`tages over organic based vehicles which tend to dehy-
`drate the nail. The use of a hydro-alcoholic vehicle in
`combination with the hydrophilic gel forming agent
`aids in maintaining a higher state of hydration. As a
`result of this higher state of hydration, flux studies have
`shown that there is a shorter lag period and a reservoir
`effect is created from which ticconazole continuously
`penetrates the nail. While not wishing to be bound by
`theory, it is believed this reservoir effect has a positive
`impact on the product’s therapeutic efficacy.
`The amount of tioconazole in the formulation can
`range from about 15 to about 30 weight percent. Prefer-
`ably, the amount of tioconazole is about 20 weight per-
`cent.
`The amount of water in the formulation can range
`from about I to about 10 weight percent. Preferably, the
`amount of water is about 4 weight percent.
`Since the formulation of the present invention uses a
`hydro-alcoholic vehicle, the alcohol used in the formu-
`lation should be substantially water-free. Preferably, a
`200 proof (100%) alcohol is used. An especially pre-
`ferred alcohol is ethanol. If ethanol is used, the amount
`in the formulation can range from about 50 to about 90
`weight percent, preferably about 70 weight percent.
`The hydrophilic gel forming agent which is used in
`the formulation of the present invention may be any
`water-soluble resin derived from natural substances
`including cellulose, glucose, and sucrose. The preferred
`gel forming agent, hydroxypropyl cellulose (Klu-
`col (~)JF, Aqualon Co.), is a nonionic water-soluble
`propylene glycol ether of cellulose made by reacting
`alkali cellulose with propylene oxide at elevated tem-
`peratures and pressures. There are many viscosity
`
`Page 2
`
`

`

`3
`grades available of hydroxypropyl cellulose which may
`be used in the formulations of the present invention. If
`hydroxypropyl cellulose is used, it is present in the
`formulation at from about 0.5 to about 5 weight percent,
`preferably at about 1.0 weight percent.
`If desired, a plasticizer may also be added to the
`formulation of the present invention. The plasticizer
`aids in forming a continuous film when the formulation
`is applied to the nail. An especially preferred plasticizer
`is propylene glycol dipelargonate. If propylene glycol
`dipelargonate is used as the plasticizer, it is present at
`from about 0.5 to about 10 weight percent, preferably at
`about 5 weight percent.
`Additionally, the formulation of the present invention
`may contain an emollient such as glycerin which, if
`present, is present at a concentration of from about 0.5
`to about 5 weight percent, preferably at about 1.0
`weight percent.
`The formulation of the present invention may be
`packaged in a number of containers. It may be supplied
`in a bottle with a brush applicator similar to a nail pol-
`ish. It may also be supplied in an applicator tipped bot-
`tle. It may also be supplied in a glass rod applicator
`bottle.
`Having described the invention in general terms,
`reference is now made to specific examples. It is to be
`understood that these examples are not meant to limit
`the present invention, the scope of which is determined
`by the appended claims.
`
`5,391,367
`
`4
`Proof. To this was slowly added and dissolved 13000.0
`grams of tioconazole with the aid of an air-driven
`Lightnin Mixer. The solution was mixed for approxi-
`mately twenty-five minutes to solubilize the ti-
`5 oconazole. To the alcoholic solution from the previous
`steps was added 650.0 grams of glycerin, 2600.0 grams
`of purified water, and 3250.0 grams of propylene glycol
`dipelargonate with constant agitation provided by a
`Lightnin Mixer.
`The final step was to add and completely hydrate
`with constant agitation 650.0 grams of hydroxypropyl
`cellulose and mix for approximately one and one half
`hours. The entire batch was filtered through a pro-sanit-
`ized, in-line stainless steel filtering unit fitted with #100
`15 mesh screen; and the fdtrate was collected in a pro-
`sanitized, tared holding tank.
`Each 5 ml bottle was filled with approximately 4.48
`grams of filtered solution to within ___2% of the in-
`tended fill weight using a suitable liquid filling machine.
`20 10 ml bottles were also f’filed. Each bottle was capped
`
`I0
`
`25
`
`and torqued at approximately 8 -16 inch-lb, and in-
`spected for fill abnormalities.
`We claim:
`1. A topical antifungal composition comprising:
`(a) from about 15 to about 30 weight percent ti-
`oeonazole;
`0a) from about 1 to about 10 weight percent water;
`¯ (c) from about 50 to about 90 weight percent alcohol;
`30 (d) from about 0.5 to about 5 weight percent of a
`water-soluble gel-forming agent which is hydroxy
`propyl cellulose and
`(e) from about 0.5 to about 10 weight percent of
`propylene glycol dipelargonate as the plasticizer,
`said composition when applied to the nails of a
`human infected with onychomycosis creating a
`reservoir from which tioconazole continuously
`penetrates the nail.
`2. A composition according to claim 1 wherein said
`40 alcohol is ethanol.
`3. A composition according to claim 1 further com-
`prising the addition of glycerin.
`4. A composition according to claim 3 wherein glyc-
`erin is present at a coneentration of from about 0.5 to
`45 about 5.0 weight percent.
`5. A method for the treatment of onychomycosis
`comprising the application to the nails of a human in
`need of such treatment an effective amount of the com-
`position of claim 1.
`
`35
`
`EXAMPLE 1
`
`TIOCONAZOLE 20% w/w, NAIL SOLUTION
`(Tioconazole 20%)
`
`Ingredient
`
`Grade Manufacturer
`
`Alcohol SDA
`40,200 Proof I
`Tioconazole
`Glycerin
`Purified Water
`Propylene Glycol
`Dipelargormte 2
`Hydroxypropyl
`Cellulose 3
`
`--
`
`USP
`USP
`USP
`--
`
`NF
`
`Union Carbide
`Corporation
`Pfizer Limited
`Procter & Gamble
`Pfizer, Inc.
`Henkel Corp.-
`Emery Group
`Aqualon
`Company
`TOTAL
`
`1. Ethanol 2130 PF SY SDA-40-2
`2. Emerest ® 2388
`3. Klueel ~) JF
`
`%
`w/w
`
`Weight
`(GM)
`
`69.0
`
`44850.0
`
`20.0
`1.0
`4.0
`5.0
`
`13000.0
`650.0
`2600.0
`3250.0
`
`1.0
`
`650.0
`
`100.0
`
`65000.0
`
`In a pro-sanitized, suitable sized stainless steel tank
`was introduced 44850.0 grams of alcohol SDA 40,200 50
`
`55
`
`6O
`
`65
`
`Page 3
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`