Ulllted States Patent
`
`[19]
`
`[11] Patent Number:
`
`6,143,794
`
`Chaudhuri et al.
`
`[45] Date of Patent:
`
`Nov. 7, 2000
`
`US006143794A
`
`[54] TOPICAL FORMULATIONS FOR THE
`TREATMENT OF NAIL FUNGAL DISEASES
`
`WO 96/19186
`
`6/1996 WIPO .
`OTHER PUBLICATIONS
`
`Hisamitsu Pharmaceutical Co., Inc., “JP 07 206711: Com-
`position for Treatment of Trichophytosis Unguium,” Patent
`abstracts of Japan, Vol. 095, No. 011, Dec. 26, 1995.
`Hisamitsu Pharmaceutical Co., Inc., “JP 06 211651: Com-
`position for Treatment Nail Trichophytosis,” Patent
`Abstracts of Japan, Vol. 018, No. 575, Nov. 04, 1994.
`Miyata et al, “External Preparation for Nail Ringworm,
`”Chemcial Abstracts, Vol. 125, No. 6, Abstract No. 67762,
`1996.
`Syed et al., “Management of Toenail Onychomycosis with
`2% Butenafine and 20% Urea Cream: APlacebo—controlled,
`]6);’§1b61;b1$‘g8S‘“dy> J°“ma1 Of D‘°'rma‘°1°gy> V01" 25> PP"
`Meyersoil, “Open—1abe1 Study of the Safety and Efficacy of
`Naftifine Hydrochloride 1 Percent Gel
`in Patients with
`Distal Subungual Onychomychosis of the Fingers”, Thera-
`peutics for the Clinician, Vol. 51, pp. 205-207, Mar. 1993.
`Saunders, “Polyurethanes: Chemistry and Technology, Vol.
`16
`.65—67 I
`'
`P bl' h
`” 1962.
`’pp
`’ mersclence “ 15 as ’
`Sr1'7"”y %“m".m_TJhe°‘.1f"reIg'i Cums
`55‘5"’”’
`’“”"‘””_.‘°'““1 er
`‘I1
`Attorney, Agent, or FLrm—Cooley Godward LLP
`
`ABSTRACT
`[57]
`Stable topical formulations useful for treating a nail fungal
`.
`’
`.
`.
`.
`.
`._
`giseasle are dlsclgsei Tthle Ccgmposlillons C°mtP“jf an am:
`“ga °‘.”‘.1P°““
`an.
`a “S One 1’ “mace” 1.“ Y ac“? '
`able excipient sufficient to form a gel. The antifungal com-
`pound 15 represented by the fefmula
`
`R1
`
`R3
`
`Ar
`
`XY
`
`N
`I2
`R
`
`[75]
`
`IHVCIHOTS3 Bhaskal‘ Chaudhuri, CUPCTHHO; M1118
`F31 Chima San FFaI1C1SC0; Daniel
`Bucksa Mfllbraea an of Cahfi
`B t k Ph
`t_
`1
`I
`far 9
`. armaceu ‘ca 5’ “C”
`C1135 Cahfi
`
`F t
`05 er
`
`73] AS .
`Slgneei
`
`1
`
`[21] Appl. NOJ 09/239,205
`.
`filed’
`
`[22]
`
`Apt 9’ 1999
`Related US_ Application Data
`Provisional application No. 60/082,187, Apr. 17, 1998.
`[60]
`Int. CL7 ......................... A61K 31/13; A61K 31/135
`[51]
`[52] U.S. Cl.
`............................................................ .. 514/655
`[58] Field of Search ............................................. .. 514/655
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`3/1978 Emmons et a1.
`....................... 260/29.6
`4,079,028
`5/1979 Emmons et a1.
`. 240/29.2
`4,155,892
`5/1988 Haggiage et al.
`.
`N 424/449
`4,746,509
`4/1989 Arita et a1.
`............................ .. 514/655
`4,822,822
`9/1990 Bohn et a1.
`............................. .. 424/61
`4,957,730
`439629178 10/1990 Harisiades ‘ ‘ ‘ ‘ ‘ ‘
`‘ ‘ ‘ " 528/33
`4,971,800
`11/1990 Chess et a1.
`.. 424/449
`5,002,938
`3/1991 Wang et a1.
`.. 514/171
`5,021,458
`6/1991 Maeda et a1.
`.. 514/655
`5,045,317
`9/1991 Chess et al.
`N 424/401
`5,051,260
`9/1991 Chess et a1.
`.. 424/449
`5,106,866
`4/1992 Maeda et al.
`.. 514/443
`5,286,787
`2/1994 Podola et al.
`.... .. 524/773
`5,322,685
`6/1994 Nakagawa et al.
`424/78.03
`5,334,628
`8/1994 Maeda et al.
`.. 514/311
`5,639,740
`6/1997 Crandall
`. . . . .
`. . . .. 514/78
`5,696,164 12/1997 Sun et a1.
`.. 514/562
`5,916,545
`6/1999 Burnett et a1.
`.......................... .. 424/61
`
`
`
`..
`
`..
`
`FOREIGN PATENT DOCUMENTS
`
`10/1984 Canada ~
`1 175 355
`8/1984 European Pat 03- -
`0 055 397 B1
`0
`$18 8/1991
`European Pat‘ Off‘ ‘
`A1
`8/1997 Germany .
`2 202 743
`10/1988 United Kingdom .
`WO 93/11735
`6/1993 WIPO .
`
`,
`3
`2
`1
`Where R , R , and R are independently hydrogen or lower
`alkyl; X is —(CH2)n— in which n is 0, 1 or 2; Y is aryl or
`heteroaryl; and Ar is aryl or heteroaryl. The composition is
`applied to the afflicted nail for once a day until the fungal
`disease is cured.
`
`22 Claims, N0 Drawings
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2144 - 1/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2144 - 1/9
`
`

`
`6,143,794
`
`1
`TOPICAL FORMULATIONS FOR THE
`TREATMENT OF NAIL FUNGAL DISEASES
`
`This application claims the benefit of U.S. Provisional
`Application No. 60/082187, filed Apr. 17, 1998.
`TECHNICAL FIELD
`
`The invention relates to stable topical formulations useful
`for the treatment of nail fungal diseases and a method of
`treating fungal diseases in nails.
`BACKGROUND
`
`Many methods are known for the treatment of fungal
`infections, including the oral and topical use of antibiotics
`(e.g. nystatin and amphotericin B),
`imidazole antifungal
`agents such as miconazole, clotrimazole,
`fluconazole,
`econazole and sulconazole, and non-imidazole fungal agents
`such as the allylamine derivatives terbinafine and naftifine,
`and the benzylamine butenafine.
`infection of the nail unit
`Onychomycosis is a fungal
`caused by yeast, dermatophytes, or other molds, and repre-
`sents approximately 50% of all nail disorders. Toenail
`infection accounts for approximately 80% of onychomyco-
`sis incidence, while fingernails are affected in about 20% of
`the cases. Dermatophytes are the most frequent cause of nail
`plate invasion, particularly in toenail onychomycosis. Ony-
`chomycosis caused by a dermatophyte is termed tinea
`unguium. Trichophyton rubrum is by far the most frequently
`isolated dermatophyte, followed by T mentagrophytes. Dis-
`tal subungual onychomycosis is the most common presen-
`tation of tinea unguium, with the main site of entry through
`the hyponychium, progressing in time to involve the nail bed
`and the nail plate. The disease is characterized by
`discoloration, onycholysis, accumulation of subungual
`debris and nail plate dystrophy. Diagnosis can be confirmed
`by KOH (potassium hydroxide) preparations and mycologic
`culture. The disease adversely affects the quality of life of its
`victims, with subject complaints ranging from unsightly
`nails and discomfort with footwear, to more serious com-
`plications including secondary bacterial infections.
`Onychomycosis has proved to be resistant to treatment.
`Nail fungal infections reside in an area difficult to access by
`conventional topical treatment, and antifungal drugs cannot
`readily penetrate the nail plate to reach the infection sites
`under the nail. Therefore, onychomycosis has traditionally
`been treated by oral administration of antifungal drugs;
`however, clearly this is undesirable due to the potential for
`side effects of such drugs, in particular those caused by the
`more potent antifungal drugs such as itraconazole and
`ketoconazole. An alternative method of treatment of ony-
`chomycosis is by removal of the nail before treating with a
`topically active antifungal agent; such a method of treatment
`is equally undesirable.
`Onychomycoses do not resolve spontaneously, and even
`if successfully treated, tend to recur. Treatment of onycho-
`mycosis is often a challenging endeavor for the clinician.
`Systemic antimycotic agents require prolonged use and have
`the potential for significant side effects. Topical agents have
`usually been of little benefit.
`It would therefore be advantageous to have a topical
`formulation that is capable of penetrating the nail barrier and
`effectively treating nail fungal diseases, thus avoiding oral
`administration of antifungal drugs and the necessity of
`removing the nail. It would be preferable if such treatment
`required only nightly applications of the formulation, i.e.
`effective treatment did not require that the formulation be
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`resident 24 hours per day on the nails over a long period of
`time. This patent application describes such a formulation.
`Publications of interest are WO 96/19186, U.S. Pat. No.
`4,746,509, U.S. Pat. No. 4,822,822, U.S. Pat. No. 5,322,685,
`PCT Application US92/10989, EP Patent Application
`55,397, GbB2, 202, 743A; and CA 1,175,355.
`SUMMARY OF THE INVENTION
`
`invention relates to a composition and a
`The present
`method for treating a fungal disease in a nail of a mammal,
`particularly a human. In particular, the invention relates to a
`stable topical formulation useful for the treatment of a nail
`fungal disease, comprising an antifungal agent and one or
`more pharmaceutically acceptable excipients sufficient to
`form a gel capable of delivering the antifungal through the
`nail barrier.
`
`One aspect of the invention relates to a topical antifungal
`composition that comprises
`(a) an antifungal compound of the formula:
`
`R1
`
`R3
`
`ANA
`
`XY
`
`R2
`
`wherein:
`
`R1, R2, and R3 are independently hydrogen or lower alkyl;
`X is —(CH2)n—, in which n is 0, 1 or 2;
`Y is aryl or heteroaryl; and
`Ar is aryl or heteroaryl, or a pharmaceutically acceptable
`salt thereof, in combination with
`(b) one or more pharmaceutical excipients sufficient to
`form a composition capable of adhering to the sur-
`face of the nail to deliver the antifungal through the
`nail barrier.
`
`Another aspect of the invention is a method of treating a
`nail fungal disease by application to the nail of a mammal
`the claimed topical composition. The process comprises
`(a) applying a therapeutically-effective amount of the
`antifungal composition to the surface of the nail to be
`treated,
`(b) maintaining the composition on the nail for up to about
`24 hours (preferably about 4 to about 12 hours),
`(c) removing the composition for a short time, preferably
`for about 4 to about 12 hours, and
`(d) repeating steps (a) through (c) until the fungal disease
`has been successfully treated.
`Yet another aspect of the invention pertains to the use of
`the antifungal compound for the preparation of a topical
`composition for the treatment of a nail fungal disease,
`wherein a therapeutically-effective amount of the topical
`composition is (a) applied to the surface of the nail to be
`treated, (b) maintained on the nail for up to about 24 hours
`(preferably about 4 to about 12 hours), (c) removed for a
`short time, preferably for about 4 to about 12 hours, and (d)
`steps (a) through (c) are repeated until the fungal disease has
`been successfully treated.
`Another aspect of the invention is an article of manufac-
`ture comprising the claimed topical composition in a con-
`tainer in combination with labeling instructions for applica-
`tion of the topical compositions in the treatment of nail
`fungal diseases.
`Another aspect of the invention is an article of manufac-
`ture comprising the composition in combination with a
`covering device to retain the composition on the nail.
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2144 - 2/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2144 - 2/9
`
`

`
`6,143,794
`
`3
`DETAILED DESCRIPTION AND PRESENTLY
`PREFERRED EMBODIMENTS
`
`topically treating
`for
`This invention is useful
`onychomycosis, i.e. a flngal infection of the nail plate on the
`hands or feet of mammals, particularly humans. The nail
`fungal disease is usually caused by Epidermophyton,
`Microsporum, and/or Trichophyton and produces nails that
`are opaque, white, thickened, friable and brittle. Onycho-
`mycosis is sometimes called ringworm of the nails or tinea
`unguis. The composition delivers an antifungal compound to
`the nail plate (the stratum corneum unguis) and to the nail
`bed (the modified area of the epidermis beneath the nail,
`over which the nail plate slides as it grows) through the nail
`plate and around the nail periphery. Desirably the antifungal
`compound is also concurrently delivered to the nail matrix,
`the cuticle and the hyponychium (the thickened epidermis
`underneath the free distal end of a nail).
`is the
`The invention has several aspects. One aspect
`composition itself. Another aspect is the use of the compo-
`sition to treat onychomycosis. Still another aspect is, an
`article of manufacture, i.e., the composition in combination
`with printed labeling instructions explaining how to use the
`composition for the desired results. Still another aspect is an
`article of manufacture that comprises the combination of the
`composition with a covering adapted to retain the compo-
`sition on the nail for an extended period of time.
`
`Definitions
`
`As used herein:
`
`“Alkyl” means a branched or unbranched saturated
`monovalent hydrocarbon radical containing 1 to 12 carbon
`atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl,
`butyl, n-hexyl, dodecyl, and the like, unless otherwise
`indicated.
`
`“Lower alkyl” means a branched or unbranched saturated
`monovalent hydrocarbon radical containing 1 to 6 carbon
`atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl,
`butyl, n-hexyl and the like, unless otherwise indicated.
`“Lower alkoxy” means the group —O—(lower alkyl)
`wherein lower alkyl is as herein defined.
`“Lower alkyl ethers of propylene glycol” refers to com-
`pounds of the formula (lower alkyl)—O—CH2—CH2
`(CH3)—O—(lower alkyl).
`“Lower fatty acid esters of propylene glycol” refers to
`compounds of the formula (lower alkyl)—C(O)O—CH2—
`CH2(CH3)—OC(O)—(lower alkyl).
`“Alkylene” means a branched or unbranched saturated
`divalent hydrocarbon radical containing 1 to 12 carbon
`atoms, such as methylene, ethylene, 1,2-propylene, 1,4-
`butylene, 1,3-butylene, 1,5-pentylene, 1,3-pentylene, 1,6-
`hexylene, 1,12-dodecylene, and the like.
`“Alkenylene” means a branched or unbranched unsatur-
`ated divalent hydrocarbon radical containing 2 to 12 carbon
`atoms, such as ethene, 1-propene, 1-butene, 3-methylbut-1-
`ene, 1-pentene, 2-methylpent-1-ene, 1-hexene, 1-dodecene,
`and the like.
`
`“Halo” means fluoro, chloro, bromo, or iodo.
`The term “aryl” refers to a monovalent unsaturated aro-
`matic carbocyclic radical having a single ring (e.g., phenyl)
`or two rings (e.g., naphthyl, biphenyl,
`indanyl, 1,2,3,4-
`tetrahydronaphthyl, benzocycloheptane), which can option-
`ally be mono-, di- or tri-substituted, independently, with OH,
`COOH,
`lower alkyl,
`lower alkoxy, halo, nitro, amino,
`alkylamino, dialkylamino, trifluoromethyl and/or cyano.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`The term “heteroaryl” refers to a monovalent aromatic
`carbocyclic radical having 1-3 heteroatoms within one or
`two rings,
`(e.g.,
`thiophenyl, fuiranyl, pyridyl,
`thiazolyl,
`pyrimidine, oxazolyl, benzoxazole, benzofuran,
`benzothiophene, indolinyl, quinoline), which can optionally
`be mono-, di- or tri-substituted, independently, with OH,
`COOH,
`lower alkyl,
`lower alkoxy, halo, nitro, amino,
`alkylamino, dialkylamino, trifluoromethyl and/or cyano.
`The term “heteroatom” refers to oxygen, sulfur or
`nitrogen, unless otherwise specified.
`“Optional” or “optionally” means that the subsequently
`described event or circumstance may or may not occur, and
`that the description includes instances where said event or
`circumstance occurs and instances in which it does not. For
`
`example, “optionally substituted phenyl” or “optionally sub-
`stituted naphthyl” means that the phenyl or naphthyl may or
`may not be mono-, di- or tri-substituted, independently, with
`OH, COOH, lower alkyl, lower alkoxy, halo, nitro, amino,
`and trifluoromethyl, and that the description includes both
`unsubstituted phenyl and naphthyl and substituted phenyl
`and naphthyl.
`The term “pharmaceutically-acceptable” salt means a salt
`of an active compound that retains the biological effective-
`ness of the compound and that is not pharmacologically
`undesirable. A pharmaceutically-acceptable acid addition
`salt is one prepared from an organic or inorganic acid that
`pairs with an appropriate base, e.g., an amino group in the
`active compound. Inorganic salts derived are from inorganic
`acids such as hydrochloric acid, hydrobromic acid, sulfuric
`acid, nitric acid, phosphoric acid and the like. Organic salts
`are derived from acids such as acetic acid, propionic acid,
`glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic
`acid, succinic acid, maleic acid, fumaric acid, tartaric acid,
`citric acid, benzoic acid, cinnamic acid, mandelic acid,
`methanesulfonic acid, ethanesulfonic acid,
`p-toluenesulfonic acid, salicylic acid, lactic acid and the like.
`
`The Composition
`
`the composition comprises a therapeutically
`Broadly,
`effective amount of an antifungal compound, or a pharma-
`ceutically acceptable salt thereof, and at least one pharma-
`ceutically acceptable excipient to provide a mixture having
`a consistency sufficient to adhere to the surface of a nail so
`that the antifungal is delivered through the nail plate. Gen-
`erally the composition is a liquid or semisolid, such as a
`cream, ointment, lotion, or gel (preferably a gel) having a
`solvent in which the antifungal compound, or its salt, is
`dissolved. Thus, the composition will contain at least the
`antifungal compound, a solvent for the compound, and a
`gelling agent. Preferably, the composition is water-based,
`which means that the solvent is preferably water-miscible. In
`addition, the composition may include a surfactant to aid in
`the delivery of the antifungal through the nailplate; a kera-
`tolytic agent to aid in the loosening, disintegration or decom-
`position of the thickened nailplate; a film-forming agent; a
`buffering agent to adjust the pH of the composition; and an
`adherence-promoting agent to assist in adhering the com-
`position to the nailplate. The composition may be applied
`directly to the nail or applied in an absorbent pad.
`The antifungal compound useful in this invention is one
`that is effective when applied topically to treat the fungal
`infection. The amount of the compound present
`in the
`composition will be the amount
`that
`is therapeutically
`effective,
`i.e. an amount that will result in the effective
`treatment of the onychomycosis when applied in accordance
`with the instructions described herein. The term “treatment”
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2144 - 3/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2144 - 3/9
`
`

`
`6,143,794
`
`5
`as used herein covers any treatment of onychomycosis in a
`mammal, particularly a human, and includes:
`(i) preventing the disease from occurring in a subject
`which may be predisposed to the disease but has not yet
`been diagnosed as having it;
`(ii) inhibiting the disease, i.e. arresting its development;
`and
`
`(iii) relieving the disease, i.e. causing regression of the
`disease.
`
`The therapeutically effective amount will vary depending
`on the subject and the severity of the affliction and may be
`determined routinely by one of ordinary skill in the art in
`light of the teaching herein. Generally, a therapeutically
`effective amount will be from about one-half percent by
`weight (0.5% wt.) to about fifteen percent by weight (15%
`wt.) based on the total final weight of the composition.
`Preferably, the amount will be about 1% to about 10% by
`weight and more preferably about 2% to about 8% by
`weight. The amount present
`in the composition will be
`dependent in part on the length of the treatment, as discussed
`hereinafter.
`
`The antifungal agents of particular utility in this invention
`have a structure represented by Formula (I), below, and the
`pharmaceutically-acceptable salts thereof. These include a
`benzylamine moiety (for example butenafine and related
`compounds are disclosed in U.S. Pat. Nos. 5,021,458 and
`5,106,866). Each of the foregoing patents is incorporated by
`reference. Antifungal of particular interest include, but are
`not
`limited to, butenafine and the pharmaceutically-
`acceptable salts thereof. Such compounds are represented by
`Formula (I) as follows:
`
`(1)
`
`R1 J1:
`ArJ\T
`
`R2
`
`XY
`
`wherein Ar is aryl; R1 is alkil or hydrogen; R2 is hydrogen
`or alkyl, R3 is hydrogen or alkyl; X is a covalent bond; and
`Y is aryl or heteroaryl.
`Butenafine is a preferred compound of Formula I wherein
`Ar is 1-naphthyl, R1 is hydrogen, R2 is methyl, R3 is
`hydrogen, X is —(CH2)n— in which n is 0, (i.e., a covalent
`bond) and Y is 4-(t-butyl)phenyl, and has the structure:
`
`H3C
`
`CH3
`
`CH3
`
`CH3
`
`Of these compounds butenafine hydrochloride is pre-
`ferred.
`
`The pharmaceutically-acceptable solvent used in the com-
`position of this invention is preferably miscible with water
`and will be present in an amount sufficient to dissolve the
`antifungal compound. Generally this amount will vary from
`about 20-80% by weight, preferably about 30% by weight
`
`6
`to about 70% by weight, more preferably about 40% by
`weight
`to about 60% by weight. Examples of suitable
`solvents include pharmaceutically acceptable lower alkanols
`of one to four carbon atoms (e.g., ethanol, n-propanol,
`isopropanol, and n-butanol; preferably ethanol), pharmaceu-
`tically acceptable dihydroxylacohols (e.g., alkylene glycols
`such as hexylene glycol, propylene glycol, butylene glycol,
`and the like), benzylalcohol, propylene carbonate, polyeth-
`ylene glycols (e.g., PEG 400), polypropylene glycols (e.g.,
`PPG 725), and the like. Others may be apparent to one of
`ordinary skill upon reading this specification. Ethanol is
`preferred.
`In addition to the antifungal compound and a
`pharmaceutically-acceptable solvent,
`the composition of
`this invention also includes a gelling agent in an amount
`sufficient to form a gel. Preferably the gel is a single-phase
`gel, i.e., it consists of organic macromolecules distributed
`throughout the composition in such a manner that no appar-
`ent boundaries exist between the dispersed macromolecules
`and the liquid. The gelling agent may be a synthetic mac-
`romolecule or a natural macromolecule, e.g., a gum, resin,
`polyacrylamide, mitrocellulose, or other cellulose deriva-
`tives. The gel is a semisolid preferably having a high degree
`of clarity, ease of application, and ease of removal. The
`amount of the gelling agent will vary depending on the type
`of solvent used,
`the type of gelling agent used to be
`appropriate with the solvent, and whether the system is
`aqueous or nonaqueous. Based on these considerations and
`others known to one of skill in the art, the gelling agent will
`be present in an amount from about 0.1% by weight to about
`20% by weight, preferably about 0.5% by weight to about
`15% by weight. Usually no more than about 10% by weight
`is used. Gels of this invention can be prepared from a
`number of pharmaceutical agents such as tragacanth about 2
`to 5% wt., sodium alginate about 2 to 10% wt., gelatin about
`2 to 15% wt., methylcellulose about 3 to 5% wt., sodium
`carboxymethylcellulose about 2 to 5% wt., carbomer about
`0.3 to 5% wt., or polyvinyl alcohols about 10 to 20% wt.
`Other gelling agents include hydroxyethylmethyl cellulose,
`polyoxyethylene-polyoxypropylene block copolymers
`(polaxomers), ethylcellulose, and hydroxyethylcellulose.
`Preferably the gelling agent is chosen from methylcellulose,
`ethylcellulose, hydroxyethylcellulose, hydroxypropyl-
`cellulose, hydroxypropylmethylcellulose, carboxymethyl-
`cellulose and carbomer.
`
`The gel composition of this invention is characterized by
`its ability to adhere to the nail being treated. Preferably, the
`composition will
`include a pharmaceutically-acceptable
`excipient to aid in improving adhesion properties. Certain
`polyurethane compounds provide superior adhesion proper-
`ties and also aid in cutaneous penetration. Such a polyure-
`thane compound would include any conventional polyure-
`thane compound formed by reaction of a diisocyanate with
`a compound having an active hydrogen, for example as
`disclosed in U.S. Pat. No. 4,079,028 to Emmons, which is
`incorporated herein by reference. A compound having an
`active hydrogen includes alcohols, diols,
`triols, amines,
`hydroxy-terminated polyesters, silanols, carboxylic acids,
`and the like. More particularly, the polyurethane compound
`includes compounds having the formula:
`
`H [
`
`(YR)m OC(O)NH X NHC(O)],,
`
`(YR)m OC(O)NH X NHC(O)
`
`(RY)m
`
`[C(O)NH X NHC(O)O (RY)m ],,. H
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2144 - 4/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2144 - 4/9
`
`

`
`6,143,794
`
`wherein:
`
`7
`
`X is an alkylene or alkenylene radical containing from 1
`to about 20 carbon atoms, or a cycloalkylene or
`cycloalkenylene radical containing from about 5 to 20
`carbon atoms, or a mononuclear or fused ring arylene
`radical containing from about 6 to about 10 carbon
`atoms, unsubstituted or substituted with one or more
`lower alkyl,
`lower alkoxy,
`lower alkoxy-substituted
`lower alkyl, nitro or arnino groups or halogen atoms;
`Y is oxygen, sulfur, silicon, or —NH—;
`each R is the same or different, and is chosen from
`alkylene, alkenylene, —SiR2R3—, and —CR2R3—
`NR4—CR2R3—, wherein R2, R3 and R4 are indepen-
`dently hydrogen or lower alkyl;
`m is an integer selected to provide a (YR) moiety having
`a molecular weight of from about 40 to about 6,000;
`and
`
`n and n‘ are the same or a different integer from 0-30
`inclusive, correlated with m so as to provide a poly-
`urethane compound having a molecular weight of up to
`about 200,000. Polyurethane compounds where YR is
`SiR2R3
`or
`CRZR3 NR4 CRZR3
`are well
`
`known in the art (See for example U.S. Pat. No.
`5,286,787 to Padolo and Majolo; U.S. Pat. No. 4,962,
`178 to Harisiades; U.S. Pat. No. 4,155,892 to Emmons,
`et. al., and “Polyurethanes Chemistry and Technology”
`by J. H. Saunders and K. C. Frisch,
`Interscience
`Publishers, pp. 65-67.) Preferred are polyurethanes that
`are hydroxy-terminated polyurethanes, i.e. where Y is
`oxygen, especially those where R is alkylene or
`alkenylene, which are disclosed in U.S. Pat. Nos.
`4,971,800, 5,045,317, and 5,051,260,
`the complete
`disclosures of which are hereby incorporated by refer-
`ence. Also useful are those disclosed in U.S. Pat.
`4,079,028 issued March 1978, to Emmons, et al. This,
`too, is incorporated herein by reference.
`A preferred hydroxy-terminated polyurethane has the
`above formula where X is 4,4‘-dicyclohexylmethane, Y is
`oxygen, R is 1,2-propylene, m is 1-4, n and n‘ are both 12.
`It has a tradename of polyolprepolymer-2, and is prepared
`by the reaction of 2 moles of polypropylene glycol and 1
`mole of dicyclohexylmethane diisocyanate in the presence
`of stannous octoate, as detailed in U.S. Pat. No. 4,971,800,
`Examples 1 and 5. It has a CAS# 9042-82-4, and a CAS
`name poly[oxy(methyl-1,2-ethanediyl)], ot-hydro-u)-
`hydroxy-, polymer with 1,1‘-methylene-bis-[4-
`socyanatocyclohexane]. Also preferred is
`polyolprepolymer-14, which has the same CAS# and name,
`but a higher molecular weight (a weight average molecular
`weight of 14,000 as opposed to 4,000 for polyolprepolymer-
`2), and polyolprepolymer-15, which has a CAS# 39444-87-
`6, and is named poly(oxy-1,2-ethanediyl), ot-hydro-u)-
`hydroxy-, polymer with 1,1‘-methylene-bis-[4-
`isocyanatocyclohexane]. Generally, the optional adhesion-
`promoting agent will be present in an amount of 0% wt. to
`about 15%wt., preferably about 0.5% wt. to about 10% wt.,
`and more preferably about 0.5% wt. to about 5% wt.
`To further aid in retaining the gel composition of this
`invention on the surface of the nail, the composition may
`optionally include a film-forming agent in an amount suf-
`ficient to form a film on the surface of the gel exposed to air.
`Representative optional film forming agents include povi-
`done (1-ethyenyl-2-pyrrolidone polymers, e.g., PVP K-90)
`polyvinyl alcohol, polyvinyl acetate, polyvinylethyl ether,
`polyvinyistearyl ether, vinylpyrrolidonel vinylacetate
`copolymers, nitrocellulose and the like. Generally,
`the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`optional film forming agent will be present in an amount of
`from 0% by wt. to about 5% by wt., preferably about 0.1%
`by wt. to about 3% by wt., more preferably about 0.1—2% by
`wt.
`
`The gel composition of this invention may optionally
`include a surfactant to aid in the penetration of the antifungal
`compound through the nail plate. Representative surfactants
`include anionic and nonionic surfactants that are compatible
`with other components in the composition. Generally, the
`surfactant will be present in an amount of about 0% by wt
`to about 10% by wt., preferably about 0.5% wt to about 5%
`wt., more preferably about. to about 1% wt. to about 5% wt.
`Representatives examples of anionic surfactants include
`sodium lauryl sulfate, sodium laureth n-sulfate (where n is
`5-12), sulfonates, sarcosinates, and sulfosuccinates. Non-
`ionic surfactants include polysorbates, polyoxyethylene 4
`lauryl ether, and the like.
`The composition of this invention may optionally include
`a keratolytic agent, i.e., a desquamating agent, that loosen
`keratin in the nail and aids in the process of desquamation
`or the removal of the upper layers of the damaged or
`diseased nail. Examples of keratolytic agents include urea,
`benzoylperoxide, salicylic acid, resorcinol,
`tretinoin, and
`others that may be found in “Remington: The Science and
`Practice of Pharmacy, Nineteenth Edition, pp. 878-879. The
`optional keratytic agent will be present in an amount of 0%
`wt. to about 25% wt., preferably about 0% wt. to about 20%
`wt., more preferably about 1% wt. to about 20% wt.
`Other excipients optionally present in the composition
`include a buffer for aqueous compositions to adjust the pH
`of the composition and a preservative. The pH will be
`non-irritating and is preferably adjusted to about 3.0-8.0
`using an acid e.g. hydrochloric acid, phosphoric acid, lactic
`acid, or a base e.g. diethanolamine, triethanolamine, sodium
`hydroxide, or known buffering agents, e.g. phosphates such
`as monobasic sodium phosphate, and dibasic sodium
`phosphate, lactates and citrates well known in the art. A
`preservative may also be present,
`for example benzyl
`alcohol, sodium benzoate, methyl paraben, propyl paraben,
`and the like.
`
`In summary, the gel formulation according to this inven-
`tion exhibits a composition range shown in Table A.
`
`TABLE A
`
`Component
`
`Antifungal
`Solvent
`Gelling Agent
`Adhesion-Promoting Agent
`Film Forming Agent
`Surfactant
`Keratolytic Agent
`Water
`
`Broad
`
`0.5—15
`20-80
`0.1—20
`0-15
`0-5
`0-10
`0-25
`0-qs
`
`Percent Weight
`
`Preferred Most Preferred
`
`1-10
`30-70
`0.5—15
`0.5—10
`0.1-3
`0.5-5
`0-20
`qs
`
`2-8
`40-60
`0.5—10
`0.5-5
`0.1-2
`1-5
`1-20
`qs
`
`The gel formulation according to this invention can also
`have a composition shown in Tables B and C.
`
`TABLE B
`
`Ingredients
`
`Water
`Propylene glycol
`Hydroxypropylcellulose
`Ethanol
`
`Wt %
`
`qs
`5-20
`1-5
`20-80
`
`CFAD V. Anacor, |PR2015-01776 ANACOR EX. 2144 - 5/9
`
`CFAD v. Anacor, IPR2015-01776 ANACOR EX. 2144 - 5/9
`
`

`
`9
`
`TABLE B-continued
`
`Ingredients
`
`Polyolprepolymer-2
`Sodium laureth sulfate
`Benzyl alcohol
`Lactic acid
`Sodium lactate
`Povidone
`Antifungal
`
`TABLE C
`
`Ingredients
`
`Water
`Propylene glycol
`Hydroxypropylcellulose
`Ethanol
`Polyolprepolymer-2
`Sodium laureth sulfate
`Benzyl alcohol
`Lactic acid
`Sodium lactate
`Povidone
`Antifungal
`
`Wt %
`
`0-10
`0-5
`0-10
`0.1-1
`1 5-15
`0-5
`0.5-15
`
`Wt %
`
`qs
`5-15
`2-5
`40-60
`0-3
`0-3
`0.5-5
`0.2-0.8
`3-12
`0.2-1
`1-10
`
`A preferred gel formulation is shown in Table D.
`
`TABLE D
`
`Ingredients
`Water
`Propylene glycol
`Hydroxypropylcellulose
`Ethanol
`Polyolprepolymer-2
`Sodium laureth sulfate
`Benzyl alcohol
`Lactic acid
`Sodium lactate
`Povidone
`Butenafine HCl
`
`Wt %
`19.86
`10
`2
`50
`1
`1
`1
`0.58
`9.36
`0.2
`5
`
`Another preferred gel formulation is shown in Table E.
`
`TABLE E
`
`Ingredients
`Water
`Propylene glycol
`Hydroxypropylcellulose
`Ethanol
`Polyolprepolymer-2
`Sodium laureth sulfate
`Benzyl alcohol
`Lactic acid
`Sodium lactate
`Povidone
`Butenafine HCl
`
`Wt %
`21.83
`10
`2
`50
`1
`1
`1
`0.29
`4.68
`0.2
`8
`
`Treatment of Onychomycosis
`Another aspect of this invention is a method for treating
`a nail fungus disease in a mammal. The method comprises
`(a) applying a composition as discussed hereinbefore to
`the surface of the nail to be treated,
`(b) maintaining the composition on a nail for at least up
`to about 24 hours, preferably about 4 to about 12 hours,
`(C) removing the composition from the nail for a short
`time, about 4 to 12 hours, and
`
`6,143,794
`
`10
`
`(d) repeating steps (a) through (C) until the nail fungus has
`been successfully treated.
`in
`This method of treatment may be used alone or
`conjunction with other antifungal treatments. For example,
`at the same time a patient is being treated using the topical
`composition of this invention, he or she may also be taking
`oral antifungals to attack the disease systemically. While
`such a combination may be used, the composition of this
`invention is useful without any combination therapy.
`In applying the composition to the nail, the entire surface
`of the nail is covered and the cuticle in the hyponychium will
`also be covered in whole or in part. Once the composition is
`applied to the nail area to be treated, depending on the type
`of composition it may be left alone to form a relatively stable
`gel composition that stays on the nail with a film forming on
`the surface if a film former is present. Optionally,
`the
`composition, once applied to the nail,
`is covered by a
`covering material that will aid in keeping the gel composi-
`tion in place on the nail for the period of time desired. The
`covering may be occlusive or semi-occlusive, but will be of
`nature that will retain the composition on the nail. Thus, a
`simple bandage which has adhesive arms that will stick to
`the skin of a human finger or toe and has a covering area that
`will cover the entire nail is useful. Alternatively, the area
`designed to cover the nail may have a recessed portion into
`which a therapeutically effective amount of the composition
`is placed and the covering is then placed on the nai