(12)
`
`United States Patent
`Samour et a1.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,224,887 B1
`May 1, 2001
`
`US006224887B1
`
`(54) ANTIFUNGAL NAIL LACQUER AND
`METHOD USING SAME
`
`11/1998 Sorenson et al. .................... .. 424/61
`5,840,283
`5,993,787 * 11/1999 Sun etal. ............................. .. 424/59
`
`(75) Inventors: Carlos M. Samour, Bedford; Scott F.
`Krauser> Tyngsb0r0> both of MA (Us)
`_
`_
`_
`(73) Assrgnee: MacroChem Corporation, Lexington,
`MA (Us)
`Subject to any disclaimer, the term of this
`
`patent is extended or adjusted under 35 U_S_C_ 154(k)) by 0 days'
`
`( * ) Notice:
`
`(21) Appl' NO‘: 09/245,714
`
`(22) Filed:
`
`Feb. 8, 1999
`
`Related US. Application Data
`(60) Provisional application No. 60/074,025, ?led on Feb. 9,
`1998.
`
`7
`Int. Cl- ............................. ..
`
`A61K 7/04; A01N 25/34
`(52) US. Cl. ........................... .. 424/401; 424/61; 424/404
`(58) Field Of Search ............................. .. 424/61, 401, 404
`
`(56)
`
`.
`References Clted
`U.S. PATENT DOCUMENTS
`
`313g; 33;; g; 311- ------------------------ -- 53353?
`1,333,353
`3/1991 Wang et al'
`""'514/171
`5’002’938
`5/1992 Wang et a1:
`514/171
`511103309
`6/1992 Ferro et al. .......................... .. 424/61
`5,120,530
`6/1993 Shah et al. ......................... .. 514/399
`5,219,877
`5,264,206 * 11/1993 Bohn etal. ..... ..
`.. 424/61
`5,346,692
`9/1994 WOhlTab et a1
`~- 424/61
`574647610
`11/1995 Hfiyesg 1L ct a1~
`424/61
`2’487’776 * 1/1996 Nlmm """"""" "
`' 1956/1825
`5,252,???
`32211511; .............................. ..
`514/562
`5:696:164 * 12/1997 Sun et al.
`5,753,256
`5/1998 Cordes et al. ..................... .. 424/443
`
`OTHER PUBLICATIONS
`K.A. Walter, et al., Permeability characteristics of the human
`nail plate, Int. Journal of Cosmetic Science, 5, 231—246
`(1983)'
`Jean—Paul L. Marty, Amorol?ne nail lacquer: a novel for
`niulamz éournlai
`uggliearigAggad' of Dam‘ and venere
`
`O Ogy’ (_upp ' ) Mast, Nail Products, pp. 277—280. _ ’ (
`
`
`.
`.
`Walters, Kenneth A., Penetration of chemicals into, and
`through, the nail, Pharm'Int. Apr. 1985; p. 85—89. .
`Kligman, Albert M., Topical Pharmacology and Toxicology
`of Dimethyl SulfoXide—Part I,Am. J. Med.Ass., 193, 1965,
`pp. 796—804.
`
`* Cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner_si Howard
`(74) Attorney, Agent, or Firm—Sherman & ShalloWay
`
`(57)
`
`ABSTRACT
`
`A nail lacquer effective for the treatment or prevention of
`fungal infections, such as, onychomycosis, includes fungi
`cidally effective amount of ciclopiroX, econaZole, or other
`
`ii‘??‘égvilniiiil?hei f i331;51355155153113121125121113?
`mer; 2-n-nonyl-1,3-dioXolane or similar penetration
`enhancer; and volatile solvent. A plasticiZer for the ?lm
`formlng Polymer WhICh 15 also Compa?ble Wlth the other
`components may be included although the preferred pen
`etration enhancers may also function as plasticiZer. The
`composition, When applied to the nails provides a hard,
`clear, Water-resistant ?lm containing the antifungal agent.
`The ?lm is resistant to multiple Washings and is effective in
`the treatment of onychomycosis'
`
`40 Claims, 2 Drawing Sheets
`
`200
`
`175
`
`1 5O
`
`1 25
`
`1 00
`
`75
`
`50
`
`25
`
`
`
`Release of drug (pg/h)
`
`>
`
`5
`
`8
`
`16
`12
`Time (h)
`
`20
`
`24
`
`—I— 5% Econazole Lacquer
`
`MYLAN - Ex. 1010, p. 1
`
`

`

`U.S. Patent
`
`May 1, 2001
`
`Sheet 1 0f 2
`
`US 6,224,887 B1
`
`
`
`Release of drug (pg/h)
`
`51‘ 8 2°; IHHIHUIHHII
`
`+ 5% Econazole Lacquer
`
`FIGURE 1
`
`MYLAN - Ex. 1010, p. 2
`
`

`

`U.S. Patent
`
`May 1, 2001
`
`Sheet 2 0f 2
`
`US 6,224,887 B1
`
`8 8 4l...|...l...l...|... Illilllilllilllilllillljz
`
`
`
`Cumulative amount (% dose)
`
`00 O
`
`A 0
`
`0
`
`o
`
`4
`
`a
`
`16
`
`12
`Time (h)
`
`2o
`
`24
`
`—I— 5% Econazole Lacquer
`
`1
`
`FIGURE 2
`
`MYLAN - Ex. 1010, p. 3
`
`

`

`US 6,224,887 B1
`
`1
`ANTIFUNGAL NAIL LACQUER AND
`METHOD USING SAME
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application claims the bene?t of provisional appli
`cation Ser. No. 60/074,025, ?led Feb. 9, 1998.
`
`BACKGROUND OF THE INVENTION
`
`(1). Field of Invention
`This invention relates to antifungal nail lacquer compo
`sitions and to the treatment of onychomycoses or other
`fungal infestations affecting toe nails or ?nger nails using the
`nail lacquer composition. More particularly, the invention
`relates to antifungal nail lacquers Which When applied to
`nails form strongly adherent, Water-resistant, clear ?lms; and
`to the method for treating or preventing fungal infestations
`of animal nails by applying the antifungal composition to the
`infected nail or to the fungal susceptible nail.
`(2). State of the Prior Art
`Fungal infection of the nails, commonly referred to as
`onychomycosis, is most frequently caused by dermatophytes
`but also can be caused by molds and Candida. Mixed
`infections also occur. Onychomycosis includes dermato
`phyte infection of the nail plate and includes infection of
`nails by any fungus, including yeast or molds. Thus, for
`example, onychomycosis serves as a reservoir for dermato
`phytes and contributes to treatment failure and recurrence of
`tinea pedis.
`Most common causes of tinea unguium are Trichophyton
`rubrum (most frequent), T mentagrophytes, and Epiderma
`phyton ?occusum. Onychomycosis due to nondermato
`phytes is usually caused by Candida species.
`Nail lacquers for the treatment of onychomycoses and
`similar fungal infections affecting nails (toe nails and/or
`?nger nails) of humans, in particular, or other animals, are
`knoWn. Representative examples are described in the patent
`literature, of Which the following US. Pat. Nos. can be
`mentioned: 4,957,730 (1-hydroxy-2-pyridone in Water
`insoluble ?lm-former); 5,120,530 (amorol?ne in quaternary
`ammonium acrylic copolymer); 5,264,206 (tioconaZole,
`econaZole, oxiconaZole, miconaZole, tolnaftate, nafti?ne
`hydrochloride, in Water-insoluble ?lm-former); 5,346,692
`(With urea and dibutyl phthalate plasticiZer); 5,487,776
`(griseofulvin as colloidal suspension).
`Other US. Pat. Nos. Which relate to antifungal products
`include, for example, 4,636,520 (combination of imidaZole
`and pyrrolnitrin); 5,002,938 (gel, combination of imidaZole
`and 17-ester corticosteroid antiin?ammatory agent); 5,110,
`809 (antifungal gel plus steroid); 5,219,877 (gel product
`With imidaZole antifungal optionally With steroidal
`antiin?ammatory, in a vehicle system that includes lauryl
`alcohol); 5,391,367 (aqueous alcoholic gel With
`tioconaZole); 5,464,610 (salicylic acid plaster); 5,696,105
`(mometasone furoate).
`Effectiveness of nail lacquers as a delivery vehicle for
`topically administering the antifungal agent amorol?ne is
`described by Jean-Paul L. Marty, J. of the European Acad
`emy of Dermatology and Venereology, 4(Suppl. 1),
`pp.S17—S21 (1995). As described by the author, the ?lm
`generating solution as the lacquer base for the active prin
`ciple basically consists of volatile solvent (ethanol, ethyl/
`butyl/methyl acetate, methylene chloride, methyl ethyl
`ketone, isopropanol), and a non-Water-soluble polymer
`(methacrylic acid copolymers, vinyl polymers) Which leaves
`
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`
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`
`60
`
`65
`
`2
`a thin continuous ?lm folloWing evaporation of the solvent.
`PlasticiZers (triacetin, dibutyl phthalate) impart suf?cient
`mechanical ?exibility to prevent ?aking and removal. Marty
`further notes the similarity of the ?lm-generating solution to
`the nail lacquers used in cosmetics.
`It is further explained that the speci?c aims addressed in
`formulating the ?lm-generating solution of the anti-fungal
`nail lacquer include obtaining maximal af?nity of the active
`principle to the nail keratin and obtaining the highest pos
`sible thermodynamic activity compatible With maintaining
`the active principle in true or supersaturated solution.
`Differences in diffusion characteristics betWeen nail and
`skin are also discussed in the Marty article. The nail struc
`ture is characteriZed as a Water-gel in Which Water facilitates
`diffusion of at least polar compounds. In contrast, the skin
`tends to more readily facilitate diffusion of lipophilic, non
`polar molecules, through the extracellular lipids of the
`stratum corneum. Thus, since the absolute transmission of
`Water vapor through nails is about 10 times that through
`skin, and since nails are approximately 100 times as thick as
`stratum corneum, the permeability of nails to Water vapor is
`about 1000 times greater.
`Therefore, Marty reports that “excipients developed for
`use on skin are thus inappropriate for releasing active
`principles on the nail, as shoWn by the inef?cacy of diffusion
`promoters such as DMSO” (citing Walters KA, Penetration
`of chemicals into, and through, the nail plate. Pharm Int.
`1985; April, p. 85—89).
`It has also been suggested in the literature (Mast, “Nail
`Products”. .
`. ) that “[a]s a Working hypothesis, it should be
`assumed that nails are, in general, quite permeable to polar
`and semipolar loW molecular Weight chemicals.” See also,
`Walters KA and Flynn G L, “Permeability characteristics of
`the human nail plate” Intl J. of Cosmetic Science, 5,
`231—246 (1983) for a revieW of the structure and character
`istics of the nail and a discussion of permeation through the
`nail plate of various chemicals and permeation coef?cients
`of C1—C12-alcohols.
`These authors conclude, on the basis of the accumulated
`data that in connection With the successful formulation of
`drugs used in the treatment of nail infections, “that solvents
`With proven efficacy as skin ‘penetration enhancers’ shoW
`little promise as enhancers of nail plate permeability” (citing
`to Walters, KA and Flynn G L, J. Pharm. Pharmac. 33 6P
`(1981) and Kligman, AM J. Amm. Med. Ass. 193 796—804
`(1965).
`Nevertheless, there remains a need for more effective and
`more durable (longer lasting) nail lacquer formulations
`Which incorporate an antifungal agent.
`There also remains a need for an antifungal nail lacquer
`formulation Which provides clear and glossy ?lms Which are
`capable of resisting multiple Washings.
`It is also knoWn in the art, as indicated by several of the
`patent documents discussed above, that the overall effec
`tiveness of antimycotic products for treating fungal infec
`tions of the skin may often be improved by combining the
`antifungal agent With a steroidal antiin?ammatory agent. To
`date hoWever such combination products have not been
`formulated into a lacquer type product for the treatment of
`onychomycosis but, rather, have been limited to gels,
`lotions, creams and other topically applied solutions.
`
`DESCRIPTION OF THE DRAWING
`FIG. 1 is a graphical presentation of release rate (lug/h) of
`econaZole as a function of time from the invention lacquer
`of Example 2; and
`
`MYLAN - Ex. 1010, p. 4
`
`

`

`US 6,224,887 B1
`
`3
`FIG. 2 is a graphical presentation of the release rate (%
`dose) of econaZole as a function of time from the invention
`lacquer of Example 2.
`
`SUMMARY OF INVENTION
`
`The present invention aims to solving the above needs.
`Thus, according to the present invention there is provided a
`stable, nail lacquer formulation incorporating an antifungal
`agent, Which formulation, When applied to nails yields a
`hard, durable, substantially clear, long lasting ?lm, effective
`in the treatment or prevention of fungal infestations or
`infections on or associated With nails.
`In particular, the present invention provides a composition
`effective for the treatment or prevention of fungal infections
`of nails, comprising:
`(a) at least one antifungal agent effective in the treatment
`or prevention of onychomycoses;
`(b) penetration enhancing agent selected from the group
`consisting of C7—C4-hydrocarbyl substituted 1,3-dioxolane,
`C7-C14-hydrocarbyl substituted 1,3-dioxane and C7-C1‘,
`substituted acetal;
`(c) Water-insoluble, ?lm-forming polymer; and,
`(d) volatile solvent, the composition, When applied to
`nails, forming, upon evaporation of the volatile solvent, a
`hard, Water-resistant ?lm from Which the antifungal agent is
`releasable and becomes available to treat or prevent fungal
`infection.
`In a particular embodiment of the invention a nail lacquer
`composition is provided Which includes a combination of an
`antifungal or antimycotic agent and a steroidal antiin?am
`matory agent in a solution of ?lm-forming polymer in at
`least one volatile solvent; the composition may also include
`at least one penetration enhancing agent selected from the
`group consisting of C7—C14-hydrocarbyl substituted 1,3
`dioxolane, C7—C14-hydrocarbyl substituted 1,3-dioxane and
`C7—C14-substituted acetal. AplasticiZer for the ?lm-forming
`polymer may also be included.
`The invention also provides lacquer compositions effec
`tive for providing long-lasting, Water-resistant adherent
`?lms on animal (e.g., human) skin and nails comprising a
`substantially non-aqueous solution of Water-resistant, ?lm
`forming polymer, and plasticiZing effective amount of at
`least one compound selected from the group consisting of
`C7—C14-hydrocarbyl substituted 1,3-dioxolane, C7—C14
`hydrocarbyl substituted 1,3-dioxane and C7—C14-substituted
`acetal in volatile solvent.
`The resulting Water-resistant, adherent ?lms provide
`novel products especially suitable as a delivery matrix for
`drugs, including the antifungal agents and others. When
`such ?lm With drug incorporated therein, is deposited on
`animal, especially human or other mammal, skin or nail, the
`drug Will leach from the ?lm and Will be capable of being
`absorbed by or transported into and through the skin or nail.
`
`DETAILED DESCRIPTION AND PREFERRED
`EMBODIMENTS
`The present invention provides still further improvements
`in the physical properties (e.g., durability, Water-resistance,
`?exibility) of Water-insoluble adherent ?lms provided upon
`evaporation of the volatile solvent from the ?lm-generating
`solution of nail lacquer composition, as Well as improved
`diffusion characteristics of active principle(s) included in the
`lacquer composition from the resulting ?lm.
`The present invention makes it possible to effectively
`incorporate tWo, generally chemically dissimilar active prin
`
`10
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`25
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`30
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`35
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`50
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`
`60
`
`65
`
`4
`ciples: an antifungal agent and a steroidal antiin?ammatory
`agent in a nail lacquer effective in treatment of onychomy
`cosis.
`The improvement in nail lacquer products according to
`the present invention is, in part, made possible by the
`incorporation into the ?lm-generating solution of a speci?c
`class of penetration enhancing agent, namely, C7—C14
`hydrocarbyl substituted 1,3-dioxolanes, 1,3-dioxanes and
`acetals, Which have previously been described as enhancers
`for penetration of various pharmacologically active prin
`ciples through the skin, and commercially available from
`MacroChem Corporation, Lexington, Mass., under the
`SEPA® trademark. The SEPA® skin penetration enhancers
`(hereinafter may be referred to as SPE’s) are the subject
`matter of several issued US. Pat. Nos., including, 4,861,
`764, 5,391,567, 4,910,020, and 5,620,980, issued to one or
`more of the current inventors, and the disclosures of Which
`are incorporated herein by reference thereto.
`The preferred SPE’s for use in the present invention may
`be represented by the folloWing general formulas:
`2-substituted 1,3-dioxolanes of the formula (I):
`
`2-substituted 1,3-dioxanes of the formula (II):
`
`(II)
`
`substituted-acetals of the formula (III):
`
`In the above formulas (I), (II) and (III) R preferably
`represents a C7 to C14 hydrocarbyl group,
`R0, R1, R2, R3, R4, R5, and R6, each, independently,
`represent hydrogen or a C1 to C4 alkyl group.
`R‘1 and R2, each, independently, represent C1 to C4 alkyl
`group.
`The hydrocarbyl group for R may be a straight or
`branched chain alkyl, alkenyl or alkynyl group, especially
`alkyl or alkenyl. Preferably, R represents a C7 to C12
`aliphatic group; especially C7 to C10 aliphatic group.
`Examples of suitable alkyl groups include, for example,
`n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,
`2-methyl-octyl, 4-ethyl-decyl, 8-methyl-decyl, and the like.
`The straight chain alkyl groups, such as n-heptyl, n-octyl,
`n-nonyl and n-decyl, are especially preferred. Examples of
`alkenyl groups include, for example, 2-hexenyl, 2-heptenyl,
`
`MYLAN - Ex. 1010, p. 5
`
`

`

`US 6,224,887 B1
`
`5
`2-octenyl, 2-nonenyl, 2‘,6‘-dimethyl-2‘,6‘-heptadienyl, 2‘,6‘
`dimethyl-2‘, heptenyl, and the like. The R group may also be
`substituted by, for example, halo, hydroxy, carboxy, car
`boxamide and carboalkoxy.
`The C1 to C4 alkyl group may be, for example, methyl,
`ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, and the like.
`The preferred alkyl groups for R0, and for R1 to R6 and for
`R‘1 and R‘2 are alkyl having 1 or 2 carbon atoms, most
`especially ethyl. R0, and R1 to R6 may also, preferably, all
`be hydrogen.
`Speci?c enhancer compounds include, for example, 2-n
`heptyl-1, 3-dioxolane, 2-n-nonyl-1,3-dioxolane, 2-n
`undecyl-1,3-dioxolane, 2-n-nonyl-1,3-dioxane, 2-n
`undecyl-1,3-dioxane, 2-n-heptylaldehyde-acetal, 2-n-octyl
`aldehyde-acetals, e.g., 2-n-octyl-aldehyde-dimethylacetal;
`2-n-nonylaldehyde-acetals, 2-n-decylaldehyde-acetals, 3,7
`dimethyl-2,6-octadienal (citral) acetals, citronal acetals and
`the like. 2-n-nonyl-1,3-dioxolane (2-NND), and decanal
`dimethyl or diethyl acetals are especially preferred. Mix
`tures of these compounds may also be used.
`The amount of enhancer compound is selected to provide
`the desired delivery rate for the active compound but, taking
`into consideration such additional factors as, product
`stability, side effects, carrier system and the like. Generally,
`depending on the particular antifungal agent and ?lm
`forming polymer, amounts of the enhancer compound in the
`range of from about 0.5 to 35%, preferably from about 2 or
`3 up to about 25 or 30 percent, especially from about 5 to 20
`or 25 percent, by Weight of the total composition, Will
`provide optimal transungal delivery of the active principle
`over the duration of the ?lm on the nail. From a practical
`matter, using the preferred enhancer compounds and ?lm
`forming polymers, optimum results (release and skin per
`meation characteristics) may usually be achieved Without
`incorporating additional co-solvents or plasticiZers, using
`amount of enhancer in the range of from about 12% to about
`24% by Weight, especially, from about 15% to about 20% by
`Weight, based on the total Weight of the composition, of the
`enhancer compound.
`In this regard, it has been found that the SEPA® SPE’s are
`not only effective to facilitate diffusion of the active agent(s)
`transungually but, quite surprisingly, in addition, the SEPA®
`family of compounds, function as adhesion promoters and,
`as plasticiZers, for the ?lm-forming polymer of the subject
`nail lacquer compositions, especially for compatible acrylate
`and methacrylate copolymers and copolymers of maleate
`esters With vinyl ethers. Compatibility betWeen the ?lm
`forming polymer and the SEPAenhancer compounds may be
`readily determined by one of ordinary skill in the art, such
`as, for example, by formation of a single homogenous phase
`When the polymer and enhancer are mixed together. As Will
`be appreciated by those skilled in the art, various factors,
`such as, for example, polarity of “mer” units of the polymer,
`molecular Weight, and the like, Will be considered for
`compatibility.
`Although the reason for the enhanced transungual diffu
`sion has not yet been fully elucidated, it is hypothesiZed that
`the SEPA® compounds function as plasticiZing agents for
`the ?lm-forming polymer and as solubiliZing agent for the
`antifungal agent and other active principles, if any, upon
`evaporation of the volatile solvent, thereby making it easier
`for the active agent(s) to diffuse through and be released
`from the dry lacquer ?lm. At the interface betWeen the
`lacquer ?lm and the nail the combination of SPE and active
`agent becomes available to penetrate into and through the
`nail.
`The plasticiZing and adhesion promoting functions, of the
`subject hydrocarbyl substituted 1,3-dioxolanes, 1,3
`
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`6
`dioxanes and acetals are not, of course, restricted to the
`resulting ?lms incorporating antifungal agent used as anti
`fungal nail lacquers, but also are more generally exhibited
`With the beloW-described ?lm-forming polymers, for virtu
`ally any drug Which may be dissolved in the polymer/
`enhancer compound matrix, With or Without the assistance
`of solvents or co-solvents. Thus, drugs Which may be
`topically administered to the skin as Well as drugs Which are
`adapted for use in treating nails for onychomycoses or other
`ailments, may be incorporated into the nail and skin
`adherent polymer plus enhancer compound ?lm-forming
`composition of this invention.
`The ?lm-forming polymers Which may be used in the
`present invention are not particularly limited and may be
`chosen from among any of the ?lm-forming polymers
`previously used in or useful for nail lacquer ?lm-forming
`polymers and Which are compatible With the SPE and Which
`have good adhesion to nail keratin (and/or skin) and form
`Water-insoluble and/or Water-resistant ?lms Which permit
`release of the antifungal agent and also the steroidal antiin
`?ammatory agent, if present.
`Examples of Water-insoluble, ?lm-forming polymers
`Which may be used in the nail lacquer compositions of this
`invention, include, for example, polyvinyl acetate, mixed
`polymers (or copolymers) of vinyl acetate With acrylic or
`methacrylic acid, copolymers of (meth)acrylic acid and
`(meth)acrylate esters, copolymers of (meth)acrylic acid
`esters With amino group and/or quaternary ammonium
`group- containing comonomers, and the like. These poly
`mers may be used alone or in mixtures With each other or
`With other ?lm-forming polymers that Will not impair the
`objectives of this invention.
`As used in this application, the term “loWer” in connec
`tion With “alkyl”, etc., refers generally to carbon chain
`lengths of up to 6 carbon atoms, hoWever, the preferred
`loWer alkyl groups typically have from 1 to 4 carbon atoms.
`Especially preferred ?lm-forming polymers include acry
`late (co)polymers, methacrylate (co)polymers, and copoly
`mers of alkyl vinyl ether and maleic anhydride. For
`example, a preferred acrylic copolymer comprises recurring
`units of at least one of the folloWing moieties (IV) and (V):
`
`(V)
`
`R1
`
`cooR2
`
`Wherein R1 represents H or CH3; and R2 represents an
`alkyl group of from 1 to about 12 carbon atoms, preferably
`from about 2 to about 12 carbon atoms, especially
`preferably, from about 4 to about 10 carbon atoms. The alkyl
`group may be linear or branched. Examples of alkyl groups
`for R2 include methyl, ethyl, propyl, isopropyl, t-butyl,
`isobutyl, n-butyl, n-pentyl, 4-methyl-n-pentyl, n-hexyl,
`n-heptyl, n-octyl, 2-methyloctyl, n-nonyl, n-decyl,
`n-dodecyl, and the like.
`Another useful acrylic copolymer comprises recurring
`units of a moiety of formula (VI)
`
`MYLAN - Ex. 1010, p. 6
`
`

`

`US 6,224,887 B1
`
`CONHR3
`
`wherein R3 represents an alkyl group, such as, for
`example, the alkyl groups described above for R2; prefer
`ably an alkyl group of at least tWo and up to about 12 carbon
`atoms, especially preferably C4 to C10 alkyl.
`Acrylic copolymers Which comprise recurring units of
`formula (V) or formula (VI) or both formulas (V) and (VI),
`and, optionally, recurring units of formula (IV), as de?ned
`above, Wherein at least one of R2 and R3 represents an alkyl
`group having at least 4 carbon atoms, are particularly
`preferred.
`Another preferred class of acrylic copolymer comprises
`recurring units of acrylic and/or methacrylic acid esters and
`recurring units of a moiety containing a cationic amine
`and/or quaternary ammonium group, such as, for example,
`carboethoxy-t-butyl ammonium. As is Well knoWn in the art,
`the cationic amine group may be quaterniZed by reaction of
`the amine With an alkylating agent or other appropriate
`reagent to form a salt.
`For example, any of the Water-insoluble quaternary
`ammonium group containing acrylic copolymers disclosed
`in the aforementioned US. Pat. No. 5,120,530, the disclo
`sure of Which is incorporated herein by reference thereto,
`may be used as the ?lm-forming copolymer in the compo
`sitions of the present invention.
`Another preferred example of the Water-insoluble, ?lm
`forming polymer comprises a copolymer of alkyl vinyl
`ether, such as, for example, methyl vinyl ether or ethyl vinyl
`ether, and at least one comonomer of a monoester of a
`dicarboxylic acid. Examples of such comonomer of a
`monoester of a dicarboxylic acid are shoWn by the folloWing
`formula (VII):
`
`COOH cooR4
`
`Wherein R4 represents a loWer alkyl group, especially an
`alkyl group of from 1 to 4 carbon atoms, such as, for
`example, methyl, ethyl, propyl.
`See also the ?lm-forming polymers disclosed in the
`aforementioned US. Pat. Nos., 5,264,206, and the other
`patents mentioned above, Which may also be used in this
`invention.
`Film-forming polymers useful in the present invention are
`commercially available, such as, for example, the acrylic
`copolymers sold by National Starch Co. under the trade
`name Dermacryl, e.g., Dermacryl 79, Dermacryl LT; the
`amine or quaternary ammonium group containing acrylic
`copolymers sold by Rohm (a division of Huls Group) under
`the tradename Eudragit, e.g., Eudragits E, RS, RL,; the
`methylvinyl ether copolymers sold by ISP Corp. under the
`tradename GantreZ, e.g., GantreZ ES-335I, GantreZ ES-425,
`ES-435; the quaternary ammonium acrylic copolymers sold
`by National Starch Co. under the tradename Amphomer,
`e.g., Amphomer LV-71. Particularly good results have been
`obtained With each of the folloWing commercially available
`products:
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`Gantrez ES-425:
`
`COZH
`
`Eudragit RL:
`
`Me
`
`Me
`
`Cationic
`
`Dermacryl 79 &
`Dermacryl LT:
`
`cozn co2R CONHC8H17
`
`Anio nic
`
`Amphomer LV-71:
`
`Me
`
`CO2
`
`COZR CO2‘
`
`CONHC8H17
`
`+
`
`CH2CH2NH2C4H9
`
`Ampho teric
`
`The amount of ?lm-forming polymer Will depend on such
`factors as, for example, the molecular Weight of the polymer,
`the desired thickness of the resulting ?lm, the degree of
`Water-resistance and the intended duration and delivery rate
`of the active agent(s), the compatibility With the other
`ingredients, and the like. Usually, hoWever, satisfactory
`results are obtained When the amount of ?lm-forming poly
`mer is in the range of from about 10 to about 70 percent,
`preferably from about 15 to about 50 percent, especially
`from about 20 to 40 percent by Weight of the total nail
`lacquer composition.
`In terms of Weight ratio betWeen ?lm-forming polymer
`and penetration enhancing (and plasticiZing) dioxolane,
`dioxane or acetal compound, suitable values of
`polymer:enhancer/plasticiZer generally range from about 4: 1
`to about 1:1, preferably from about 3:1 to about 1.2:1,
`especially preferably from about 2:1 to about 1.2:1. The
`plasticiZing function of the enhancer compounds is exhibited
`over generally the same or someWhat higher concentrations
`as the skin penetration enhancing function. Therefore, When
`other plasticiZing additives, as described beloW, are included
`in the compositions of this invention, the ratio of polymer to
`enhancer may be someWhat higher than the above ranges,
`for example, from about 5:1 to about 1:1.
`Conventional plasticiZers compatible (e.g., forming a
`homogenous ?lm) With ?lm-forming polymers may be
`included in the compositions of this invention to provide
`additional ?exibility to the dried polymer ?lm upon evapo
`ration of the solvent, and/or additional releasability of the
`antifungal agent (and antiin?ammatory, When present) as
`Well as for the SPE compound. Suitable plasticiZers include,
`for example, 1,2,3-propanetriol triacetate (triacetin), dibutyl
`phthalate, dioctyl phthalate, dibutoxy ethyl phthalate,
`diamyl phthalate, sucrose acetate isobutyrate, butyl acetyl
`
`MYLAN - Ex. 1010, p. 7
`
`

`

`US 6,224,887 B1
`
`ricinoleate, butyl stearate, triethyl citrate, dibutyl tartrate,
`polyethylene glycol, dipropylene glycol, polypropylene
`glycols, propylene glycol, glycol fatty acid esters, such as,
`propylene glycol dipelargonate, and the like.
`Particularly preferred plasticiZers are glycols, such as
`propylene glycol and dipropylene glycol, glycol esters,
`phthalate esters, citrate esters, polyethylene glycols, and
`polypropylene glycols.
`The type and amount of plasticiZer, When present in the
`formulation, affects resistance of the dried polymer ?lm to
`Water and also affects the release rate of the active drug
`ingredients as Well as that of the SPE. Those skilled in the
`art Will recogniZe that the degree of Water resistance can also
`be controlled by the type and amount of the plasticiZer(s),
`the nature of the active principles, the choice of polymer
`(e.g., amount of acid groups in the polymer, etc.), the
`amount of the polymer, and the like.
`When the additional plasticiZer is present it Will generally
`be used in amounts Which depend on the types and amounts
`of the ?lm-forming polymer and the SPE, most usually in
`the range of from about 0.5 to about 20 percent, preferably
`from about 2 to 10 percent, especially, from about 4 to 8
`percent, based on the total Weight of the composition.
`While additional plasticiZers may be incorporated in the
`invention compositions, as noted above, in vieW of the
`surprising plasticiZing effect of the subject skin penetration
`enhancing compounds, suf?cient ?exibility and adhesion, as
`Well as compatibility (both Wet and dry) betWeen the respec
`tive ingredients, is usually achieved Without the addition of
`conventional plasticiZers.
`Solvents Which may be used in the nail lacquer compo
`sitions of this invention are also not particularly critical but
`may be selected from among the usual physiologically safe
`organic solvents for lacquer compositions, so long as the
`active principles and ?lm-forming polymers are soluble
`therein and so long as the lacquer is easy to apply and
`sufficiently volatile to provide acceptable drying times,
`usually dry to the touch in less than about 5 minutes,
`preferably less than about 2 minutes. As examples of such
`solvents mention may be made of loWer alkanols, e.g.,
`ethanol, propanol, isopropanol, butanol, isobutanol; loWer
`alkyl esters of loWer carboxylic acids, e.g., ethyl acetate,
`propyl acetate, n-butyl acetate, n-amyl acetate; loWer alkyl
`ethers, e.g., methyl ether, methyl ethyl ether; loWer alkyl
`ketones, e.g., methyl ethyl ketone; halogenated
`hydrocarbons, e.g., methylene chloride, methyl chloroform;
`aromatic hydrocarbons, e.g., toluene; cyclic ethers, such as,
`tetrahydrofuran, 1,4-dioxane; and mixtures thereof. Anhy
`drous ethanol (EtOH) is especially preferred.
`The solvents used in the nail lacquer formulations of this
`invention are generally and preferably non-aqueous.
`HoWever, in some cases small amounts of Water, generally
`less than about 10%, preferably less than about 5% by
`Weight of total solvents, may be used if not substantially
`impairing the homogeneity, clarity and solubility of the
`various ingredients in the lacquer solution. For example,
`ethanol When used may sometimes be added in the form of
`a 95% ethanol solution.
`Again, in vieW of the good compatibility betWeen the
`?lm-forming polymer and the dioxolane, dioxane and acetal
`enhancer/plasticiZer compounds, use of co-solvents, such as
`propylene glycol, in addition to solvent, e.g., ethanol, are
`usually not required and, therefore, may be omitted.
`On the other hand, hoWever, it may be desirable and, in
`some cases, preferred, to decrease the Water-resistance of the
`dried polymer ?lm, for example, to facilitate removal of the
`?lm after release of all or most of the active ingredients.
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`10
`Thus, it is envisioned that in addition to a lacquer ?lm from
`Which the active ingredients are released over periods of
`several days to about 1 Week or longer, lacquer ?lms from
`Which the active ingredient is released over shorter periods
`of time, such as one day, may be desirable since many
`individuals are accustomed to and prefer treatments requir
`ing applications of a drug on a daily basis.
`Techniques for increasing the availability of the active
`ingredients for transungual delivery have been described
`above. When the active ingredient is exhausted from the ?lm
`or mostly exhausted the ?lm may be removed by application
`of suitable solvents, such as those described above, such as
`alcohols, acetone, ketones, etc., and/or by scraping or
`brushing, as also