(19) United States
`(12) Patent Application Publication (10) Pub. N0.: US 2002/0165121 A1
`(43) Pub. Date:
`Nov. 7, 2002
`Brehove
`
`US 20020165121A1
`
`(54) TOPICAL APPLICATION FOR TREATING
`TOENAIL FUNGUS
`
`(76) Inventor: James Edward Brehove, Succasunna,
`NJ (US)
`
`Correspondence Address:
`Ernest D. Bu?'
`Ernest D. Bu?' & Associates, LLC
`245 South Street
`Morristown, NJ 07960 (US)
`
`(21) Appl. No.:
`
`10/077,521
`
`(22) Filed:
`
`Feb. 15, 2002
`
`Related US. Application Data
`
`(60) Provisional application No. 60/274,391, ?led on Mar.
`10, 2001.
`
`Publication Classi?cation
`
`....A61K 31/00
`(51) Int. Cl? .
`(52) Us. 01. ................................................................ .. 514/1
`
`(57)
`
`ABSTRACT
`
`Atopical applications is used to treat and prevent the spread
`of nail infections or onychomycosis caused by bacteria,
`fungi and other pathogens. The topical application has a
`composition that comprises, as an active ingredient, at least
`one species selected from the group consisting of 2,2‘
`(alkyldioxy) bis-(alkyl-l,3,2-dioXaborinane) and 2,2‘-oXy
`bis(a1kyl-1,3,2-dioxaborinane). More speci?cally, the com
`position comprises, as an active ingredient, at least one
`member selected from the group consisting of 2,2‘-(1
`methyltrimethylene dioXy) bis-(4-methyl-1, 3, 2-dioXabori
`nane) and 2,2‘-oXybis (4, 4, 6-trimethyl-1, 3, 2-dioXabori
`nane).
`
`MYLAN - Ex. 1008, p. 1
`
`

`

`US 2002/0165121 A1
`
`Nov. 7, 2002
`
`TOPICAL APPLICATION FOR TREATING
`TOENAIL FUNGUS
`
`the preferred species of the present invention in combination
`With an ethylene glycol monoalkylether.
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`[0001] This application claims the bene?t of US. Provi
`sional Patent Application No. 60/274,391, ?led Mar. 10,
`2001, entitled “Topical Application For Treating Toenail
`Fungus”.
`
`BACKGROUND OF THE INVENTION
`
`[0002] 1. Field of the Invention
`
`[0003] This invention relates to the treatment of human
`?ngernails and toenails; and more particularly, to topical
`applications and methods to cure or prevent the spread of
`nail infections, such as onychomycosis, caused by bacteria,
`fungi and other pathogens.
`[0004] 2. Description of the Related Art
`
`[0005] Onychomycosis is a nail disease of the toes and
`?ngers typically caused by the organisms Candida albicans,
`Trichophyton mentagrophytes, Trichophyton rubrum, or
`Epidermpophyton ?occusum. The nails become thickened
`and lusterless, and debris accumulates under the free edge.
`Nail plates becomes separated and the nails may be
`destroyed. It is acknowledged that the therapy of onycho
`mycosis is difficult and protracted. Oral therapy With anit
`mycotics requires months of administration and must be
`closely monitored for side effects.
`[0006] Topical compositions have long been used With the
`objective of treating onychomycosis. Representative com
`positions used for this purpose are disclosed by US. Pat.
`Nos. 5,346,692; 5,391,367; 5,464,610; 5,487,776; 5,696,
`105; 5,760,052; 5,840,283; 5,866,105; 5,874,476; 5,916,
`545; 5,972,317; and 6,022,549. Such prior art topical appli
`cations have been largely unsuccessful because the nail is a
`dif?cult barrier for anti-fungal compounds to penetrate. To
`be effective a topical treatment for onychomycosis should
`exhibit a poWerful potency for pathogens. It must also be
`permeable through the nail barrier, and safe for patient use.
`There exists a need in the art for a topical application that
`combines these traits in high degree.
`[0007] Members of the class of organo-boron compounds
`have long been knoWn to exhibit biocidal activity. Yet, none
`of the prior art teachings on treatment of onychomycosis
`discloses use of compositions containing an organo-boron
`compound for this purpose, or employs a composition that
`contains an organo-boron compound as a constituent.
`
`[0008] US. Pat. No. 3,189,637 to Bengelsdorf et al.
`describes cycloalkenyl glycol boric acid esters including
`2,2‘-(alkyldioxy) bis-(alkyl-1, 3, 2-dioxaborinane) deriva
`tives having utility in a variety of applications, including
`fungicides.
`[0009] US. Pat. No. 3,877,890 to Maisey et al. describes
`biocide compositions for controlling and preventing the
`groWth of micro-organisms in jet fuel. The organo-boron
`compounds of the Maisey et al. patent do not include the
`dioxaborinane genus of the present invention.
`
`[0010] US. Pat. No. 4,718,919 to DeLue et al. discloses an
`anti-icing and biocidal and fungicidal fuel additive including
`
`[0011] US. Pat. No. 4,742,044 to Boden discloses 1,3,2
`dioxaborinane derivatives useful in augmenting or enhanc
`ing the aroma of perfume compositions, and perfumed
`articles.
`
`[0012] In none of the references describing dioxaborinane
`compounds is a use for treatment of onychomycosis dis
`closed or suggested.
`
`[0013] The safety and non-toxicity of organo-boron com
`pounds has been questioned.
`[0014] One reference, ‘“‘Sax’s Dangerous Properties of
`Industrial Materials”, Tenth Edition, John Wiley & Sons,
`NeW York, 2000. R546, reports that the “Safety Pro?le” of
`“Boron Compounds” is “very toxic”, and that “Boron Com
`pounds are therefore considered an industrial poison.”
`
`[0015] On the other hand, an article entitled, “Recherces
`Parmacologiques Sur Les Derives Organiques Du Bore”,
`T herapie (Paris) 15, 791-802 (1960), discusses the toxicity
`of the compound 2-(p-tolyl)-(5-methyl, 5-propyl)-1,3,2,
`dioxiborinane (termed LS. 813). When tested for use as a
`possible sedative, it Was found that the toxicity of LS. 813
`Was very loW. Finally, a fuel additive Biobor® J F containing
`a combination of 2,2‘-(1-methyltrimethylene dioxy) bis-(4
`methyl-1, 3, 2-dioxaborinane) and 2,2‘-oxybis (4, 4, 6-trim
`ethyl-1, 3, 2-dioxaborinane) With naphtha is sold commer
`cially by Hammonds Fuel Additive Inc., Houston, Tex. The
`material safety data sheet for this combination identi?es as
`a haZard “Skin Contact: May cause slight to mild irritation.
`Prolonged or repeated contact may dry the skin and lead to
`irritation (i.e. dermatitis)”.
`[0016] There remains a need in the art for a topical
`application Which can be safely applied to nails of ?ngers
`and toes, and Which exhibits in combination permeability
`and potency for pathogens required to effectively cure, or
`prevent the spread of onychomycosis.
`
`SUMMARY OF THE INVENTION
`
`[0017] The present invention provides a topical composi
`tion for treatment of nail infections. The composition com
`prises, as an active ingredient, at least one species selected
`from the group consisting of 2,2‘-(alkyldioxy) bis-(alkyl-1,
`3,2-dioxaborinane) and 2,2‘-oxybis(alkyl-1,3,2-dioxabori
`nane). More speci?cally, the composition comprises, as an
`active ingredient, at least one member selected from the
`group consisting of 2,2‘-(1-methyltrimethylene dioxy) bis
`(4-methyl-1, 3, 2-dioxaborinane) and 2,2‘-oxybis (4, 4, 6-tri
`methyl-1, 3, 2-dioxaborinane). The invention also comprises
`a method of treating onychomycosis by topical application
`of a composition containing, as an active ingredient, at least
`one member selected from the group consisting of 2,2‘-(1
`methyltrimethylene dioxy) bis-(4-methyl-1, 3, 2-dioxabori
`nane) and 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxabori
`nane).
`[0018] The compositions and method of the invention
`provide a unique means for treating onychomycosis. Advan
`tageously, such means provides, in combination, certain
`characteristics, including safety, effectiveness, convenience,
`and freedom from toxicity, Which have been unavailable
`heretofore. Through in vitro microbiological tests it is noW
`
`MYLAN - Ex. 1008, p. 2
`
`

`

`US 2002/0165121 A1
`
`Nov. 7, 2002
`
`found that a topical formulation containing as active ingre
`dient at least one member selected from the group consisting
`of 2,2‘-(1-methyltrimethylene dioxy) bis-(4-methyl-1, 3,
`2-dioxaborinane) and 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3,
`2-dioxaborinane has powerful potency against Candida
`albicans. That is to say, it is found in accordance With the
`invention, that active constituents of certain compositions
`effectively kill the most common pathogen causing onycho
`mycosis. It is also found by in vivo tests on a volunteer that
`formulations of the invention achieve ef?cacy in the treat
`ment of onychomycosis Without skin irritation or noticeable
`side effects. One formulation is conveniently applied nightly
`in a petroleum jelly or mineral oil base. Dilute compositions
`of the active compounds in alcohol or acetone base has the
`ability to deliver concentrated active ingredient as the sol
`vent evaporates. Another formulation is conveniently
`applied once per Week in a cellulose acetate lacquer base.
`Both formulations are effective in curing the onychomycosis
`Without skin irritation and evident side effects.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0019] In accordance With the present invention, there is
`provided a topical composition for treatment of nail infec
`tions. Generally stated, the composition comprises, as an
`active ingredient, at least one species selected from the
`group consisting of 2,2‘-(alkyldioxy) bis-(alkyl-1,3,2-diox
`aborinane) and 2,2‘-oxybis(alkyl-1,3,2-dioxaborinane). The
`active ingredient in one composition of the invention has the
`following general formula:
`
`[0020] Where R1 is a primary, or secondary alkyl group
`having from 3 to 20 carbon atoms, X represents
`
`[0021] and Where R2, R3 and R 4 are de?ned the same as R1
`above and may be the same or different primary, or second
`ary alkyl groups.
`[0022] More speci?cally, the composition comprises, as
`an active ingredient, at least one member selected from the
`group consisting of 2,2‘-(1-methyltrimethylene dioxy) bis
`(4-methyl-1, 3, 2-dioxaborinane) and 2,2‘-oxybis (4, 4, 6-tri
`methyl-1, 3, 2-dioxaborinane).
`[0023] The synthesis of 2,2‘-(alkyldioxy) bis-(alkyl-1,3,2
`dioxaborinane) and 2,2‘-oxybis(alkyl-1,3,2-dioxaborinane)
`derivatives has been described in US. Pat. No. 2,741,548,
`Which description is hereby incorporated by reference; but
`only to the extent it is not incompatible hereWith. Example
`2 of US. Pat. No. 2,741,548 expressly describes the syn
`thesis of 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxabori
`nane).
`
`[0024] It is noW found by in vitro microbiological tests
`that a topical formulation containing as active ingredient at
`least one member selected from the group consisting of
`2,2‘-(1-methyltrimethylene dioxy) bis-(4-methyl-1, 3, 2-di
`oxaborinane) and 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3, 2-di
`oxaborinane) is effective against Candida albicans. It is also
`found by in vivo tests on a volunteer that a formulation of
`the invention is effective in the treatment of onychomycosis
`Without skin irritation or noticeable side effects.
`
`[0025] In one embodiment, the composition of the inven
`tion contains as an active ingredient at least one member
`selected from the group consisting of 2,2‘-(1-methyltrimeth
`ylene dioxy) bis-(4-methyl-1, 3, 2-dioxaborinane) and 2,2‘
`oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxaborinane) in combi
`nation With at least one member selected from the group
`consisting of White mineral oil, petroleum jelly and paraf?n
`Wax or volatile solvent such as alcohol or acetone. The
`mineral oil, petroleum jelly and paraf?n Wax help protect the
`skin against irritation or drying and serve as a reservoir for
`the active ingredient permitting extended continuous diffu
`sion and penetration into the nail. The volatile solvents
`provide more concentrated availability of the active ingre
`dient from dilute solutions as the solvent evaporates.
`
`[0026] In another embodiment, the composition of the
`invention contains as an active ingredient at least one
`member selected from the group consisting of 2,2‘-(1
`methyltrimethylene dioxy) bis-(4-methyl-1, 3, 2-dioxabori
`nane) and 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxabori
`nane) in combination With an organic ?lm former. The
`organic ?lm former serves as a long lasting reservoir for the
`active ingredient, permitting extended continuous diffusion
`and penetration into the nail. Many suitable ?lm-forming
`polymers are knoWn. Among those ?lm formers considered
`to be suitable are polymers and copolymers of vinyl acetate,
`polymethyl methacrylate, polyvinyl butyral, polyvinyl pyr
`rolidone, cellulose acetate, and cellulose butyrate.
`[0027] In yet another embodiment, the composition of the
`invention contains as an active ingredient at least one
`member selected from the group consisting of 2,2‘-(1
`methyltrimethylene dioxy) bis-(4-methyl-1, 3, 2-dioxabori
`nane) and 2,2‘-oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxabori
`nane) in combination With a penetration enhancer. As used
`herein, the term “penetration enhancer” means a chemical
`compound that increases the permeability of the skin to a
`drug. Several different penetration enhancers have been
`reported, including dimethyl sulfoxide, and N-methyl-2
`pyrrolidone.
`[0028] The active dioxaborinane ingredient preferably
`constitutes at least about 0.1 Wt. % of a composition of the
`invention. More preferably, the dioxaborinane ingredient
`constitutes betWeen about 0.1 Wt % and 75 Wt % of the
`composition. Yet more preferably, the dioxaborinane ingre
`dient constitutes betWeen about 0.1 Wt % and 50 Wt % of the
`composition. Most preferably, dioxaborinane ingredient
`constitutes betWeen about 0.1 Wt % and 25 Wt % of the
`composition.
`[0029] The folloWing examples are presented to provide a
`more complete understanding of the invention. The speci?c
`techniques, conditions, materials, proportions and reported
`data set forth to illustrate the principles and practice of the
`invention are exemplary and should not be construed as
`limiting the scope of the invention.
`
`MYLAN - Ex. 1008, p. 3
`
`

`

`US 2002/0165121 A1
`
`Nov. 7, 2002
`
`EXAMPLES
`
`Examples 1-15
`[0030] 2,2‘-(1-methyltrimethylene dioxy) bis-(4-methyl-1,
`3, 2-dioxaborinane) (hereinafter compound S1) and 2,2‘
`oxybis (4, 4, 6-trimethyl-1, 3, 2-dioxaborinane) (hereinafter
`compound S2) are each prepared and puri?ed according to
`the procedures described in US. Pat. No. 2,741,548. One or
`both of the dioxaborinanes is mixed With a sterile U.S.P.
`grade of White mineral oil in varying proportions as shoWn
`in Table I beloW to form compositions of the invention. The
`mineral oil is produced by E. R. Squibb & Sons Inc.,
`Princeton, NJ. Acontrol composition consists of the mineral
`oil alone.
`
`[0031] The compositions are evaluated according to an
`approved surface carrier disinfection test (Of?cial Methods
`of Analysis of the Association of Official Analytical Chem
`ists protocol 991.47: Hard surface carrier test method).
`Cultures of Candida albicans are groWn for 24 hours at
`room temperature in trypsin soy broth to a density of
`approximately McFarland standard #10. Sterile glass cylin
`ders (Belco Cat. #2090-S0012) serve as carriers. The carri
`ers are coated With the test composition or the control
`composition and subsequently submerged in 5 ml of the
`stock culture and alloWed to remain there for 15 minutes.
`
`[0032] The carriers are aseptically transferred to sterile,
`dry Whatman #1 ?lter paper, and excess droplets of the
`inoculation medium are removed. The carriers are dried at
`37° C. for 40 minutes and then aseptically transferred to 5
`ml of trypsin soy broth. They are then sonicated for 10
`minutes in as Water bath at 25° C. Tubes containing the
`sonicated carriers are vortexed, and a portion of the medium
`is placed onto trypsin soy agar plates, and incubated over
`night at 37° C. Microbial groWth is assessed by counting
`colonies. The results are presented in Table I.
`
`TABLE I
`
`Example Test Compound
`
`Comparative Mineral oil (control)
`1 S1
`2 S1
`3 S1
`4 S1
`5 S1
`6 S1
`7 S2
`8 S2
`9 S2
`10 S2
`11 S2
`12 S2
`13 25/75 W/W 51/52
`14 50/50 W/W 51/52
`15 75/25 W/W 51/52
`
`Wt. % Of 51/52 In
`Mineral Oil
`
`Colonies Of
`Candida
`Albicans
`Observed
`
`0
`0.1
`1.0
`10
`25
`50
`75
`0 1
`1 0
`10
`25
`50
`75
`25
`25
`25
`
`1203
`8
`2
`0
`0
`0
`0
`11
`1
`0
`0
`0
`0
`0
`0
`0
`
`[0033] The results indicate that each of the formulations in
`Examples 1-15 of the invention is highly effective in sup
`pressing groWth of Candida albicans in vitro.
`
`is applied a mixture consisting of 25 Wt % of compounds S1
`and S2 in 50/50 W/W proportion, and 75 Wt. % of loW
`viscosity petroleum jelly. Selection of this composition is
`based on the examples of 1-15, Which indicates that a 25%
`loading of either S1 or S2 or combinations thereof com
`pletely destroys the fungus. The clinical tests are done to
`evaluate effectiveness and skin reactions, if any. This mix
`ture is reapplied nightly. To the toenails of the right foot is
`applied a mixture of 25 Wt % of compounds S1 and S2 in
`50/50 W/W proportion, 70 Wt % acetone and 5 Wt % cellulose
`acetate. This mixture is applied once per Week after the
`previous Week’s application is removed With acetone. At the
`end of 6 Weeks of treatment, the toenails of each foot have
`a clear, uninfected Zone of 2 mm in Width. At the end of 12
`Weeks of treatment, the clear Zone is 4 mm in Width. At the
`end of 20 Weeks of treatment, the toenails on both feet are
`free of infected areas. During the progression of the nail
`groWth a ridge in the nail is seen betWeen the neWly groWn
`clear nail Which is closely attached to the skin beloW and the
`infected nail Which is more detached from the skin. No skin
`irritation is seen on either foot and no side effects are
`evident.
`
`Example 17
`[0035] A male volunteer 58 years old has onychomycosis
`on both feet. At least four toes in each foot are infected. He
`applies the solution, Which has 25% of active ingredients in
`mineral oil With a 50/50 S1/S2 ratio, to both feet once a day.
`The application included painting the entire toenail and the
`cuticle for approximately 3 mm beyond the nail. After 90
`days 3 mm of clear infection free nail could be seen. After
`125 days, more than three-quarter of the nail is clear, free
`from infection. The boundary betWeen the infected portion
`and the clear portion is not smooth and shoWs structure. In
`250 days, the nail is fully-groWn, completely free from any
`infection. No skin irritation is observed.
`
`Example 18
`[0036] A female volunteer 35 years old has onychomyco
`sis on big toe of right foot near the top one third of the nail.
`She applies the solution, Which has 25% active ingredients
`in mineral oil With a 50/50 S1/S2 ratio, to both feet once a
`day. The application included painting the entire toenail and
`the cuticle for approximately 3 mm beyond the nail. After 90
`days the infection on the top third of the nail cleared aWay
`With clear nails. The treatment is continued for a total of 180
`days at Which time no trace of fungus is seen. No skin
`irritation is observed.
`
`Example 19
`[0037] A male volunteer 85 years old has onychomycosis
`on left side of big toe of right feet. He applies the solution,
`Which has 12.5% active ingredients in mineral oil With 50/50
`S1/S2 ratio, once a day. The diluted composition is selected
`to establish the loWer limit of anti-fungal activity. He applies
`the solution for 90 days With clear evidence of destruction of
`fungus. The ease of fungus destruction is attributed to the
`closeness of the fungus to the left cuticle, Which permitted
`easy penetration of the solution in spite of its loWer con
`centration of the active ingredient. No irritation of the skin
`is observed.
`
`Example 16
`[0034] A male volunteer 43 years old has onychomycosis
`of the toenails on both feet. To the toenails of the left foot
`
`Example 20
`[0038] A female volunteer 50 years old has onychomyco
`sis on big toe and the adjacent toe of left feet. She applies
`
`MYLAN - Ex. 1008, p. 4
`
`

`

`US 2002/0165121 A1
`
`Nov. 7, 2002
`
`the solution, Which has 25% active ingredients in mineral oil
`With 50/50 51/52 ratio, once a day. She applies the solution
`for 245 days With clear evidence of destruction of fungus on
`the big toe and the adjacent toe. Onset of clear nail could be
`seen as early as 92 days When approximately 2 mm of clear
`nail is observed. Half of the big toe nail is clear in 125 days.
`No irritation of the skin is observed.
`
`[0039] Having thus described the invention in rather full
`detail, it Will be understood that such detail need not be
`strictly adhered to, but that additional changes and modi?
`cations may suggest themselves to one skilled in the art, all
`falling Within the scope of the invention as de?ned by the
`subjoined claims.
`What is claimed is:
`1. A topical composition for treatment of nail infections
`comprising as an active ingredient at least one species
`selected from the group consisting of 2,2‘-(alkyldioXy) bis
`(alkyl-1,3,2-dioXaborinane) and 2,2‘-oXybis(alkyl-1,3,2-di
`oXaborinane).
`2. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said active ingredient is at least
`one member selected from the group consisting of 2,2‘-(1
`methyltrimethylene dioXy) bis-(4-methyl-1, 3, 2-dioXabori
`nane) and 2,2‘-oXybis (4, 4, 6-trimethyl-1, 3, 2-dioXabori
`nane).
`3. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said active ingredient is 2,2‘-(1
`methyltrimethylene dioXy) bis-4-methyl-1, 3, 2-dioXabori
`nane).
`4. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said active ingredient is 2,2‘
`oXybis (4, 4, 6-trimethyl-1, 3, 2-dioXaborinane).
`5. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said composition contains at
`least one member selected from the group consisting of
`White mineral oil, petroleum jelly and paraf?n Wax.
`6. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said composition contains vola
`tile solvent
`7. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said composition contains an
`organic ?lm former.
`
`8. Atopical composition for treatment of nail infections as
`recited by claim 6, Wherein said organic ?lm former is
`selected from the group consisting of polymers and copoly
`mers of vinyl acetate, polymethyl methacrylate, polyvinyl
`butyral, polyvinyl pyrrolidone, cellulose acetate, and cellu
`lose butyrate.
`9. Atopical composition for treatment of nail infections as
`recited by claim 1, Wherein said composition contains a
`penetration enhancer.
`10. A topical composition for treatment of nail infections
`as recited by claim 1, Wherein said penetration enhancer is
`selected from the group consisting of dimethyl sulfoXide and
`N-methyl-2-pyrrolidone.
`11. A topical composition for treatment of nail infections
`as recited by claim 1, Wherein the concentration of the active
`ingredient is at least about 0.1 Wt % of the composition.
`12. A topical composition for treatment of nail infections
`as recited by claim 1, Wherein the active ingredient is
`betWeen 0.1 Wt % and 75 Wt % of the composition
`13. A topical composition for treatment of nail infections
`as recited by claim 1, Wherein the active ingredient is
`betWeen 0.1 Wt % and 50 Wt % of the composition.
`14. A topical composition for treatment of nail infections
`as recited by claim 1 Wherein the active ingredient is
`betWeen 0.1 Wt % and 25 Wt % of the composition.
`15. A method for the treatment of nail infections com
`prising: periodically applying to the infected nail a compo
`sition comprising as active ingredient at least one species
`selected from the group consisting of 2,2‘-(alkyldioXy) bis
`(alkyl-1,3,2-dioXaborinane) and 2,2‘-oXybis(alkyl-1,3,2-di
`oXaborinane) for a period sufficient to end the infection.
`16. Amethod for the treatment of nail infections as recited
`by claim 14 Wherein the composition applied comprises as
`active ingredient at least one member selected from the
`group consisting of 2,2‘-(1-methyltrimethylene dioXy) bis
`(4-methyl-1, 3, 2-dioXaborinane) and 2,2‘-oXybis (4, 4, 6-tri
`methyl-1, 3, 2-dioXaborinane).
`
`MYLAN - Ex. 1008, p. 5
`
`