JflP~ql4~I~ L~qN~u~qG~ L~flL ~IJPPO~T IIIID (ONiilLilN~
`
`BRENDA K, SEAT, ESI~.
`
`Certification
`
`We the undersigned do hereby certify the following: We are fluent in the
`
`English and Japanese languages. We have translated and/or reviewed the
`
`translation of the Japanese document identified as: JP- 10-226639 ~_and find
`
`it to be a true and accurate translation to the best of our knowledge and
`
`ability.
`
`We certify under penalty of perjury that the foregoing is tree and correct.
`
`Signature: ~& ~@
`Misa Foley
`
`Date: 2/2. >/2o 1~
`
`Signature
`
`Brenda K. Seat, Esq.
`
`Date: August 23, 2016
`
`SIX WHITEHALL BOURT, SILVER SPRING, MARYLAND 20901 ~ TEL.: 301-593-3980 FAX; 3FIl-6Fll-9243
`
`BSEAT@~HINSHUSERVII3EN.ElrnM ’ WWW, SHINSHU~ERVICEN.BOM
`
`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1011
`IPR Petition for
`U.S. Patent No. 7,214,506
`
`1 of 49
`
`
`
`BRENDA K, SEAT, ESI~.
`
`Certification
`
`We the undersigned do hereby certify the following: We are fluent in the
`
`English and Japanese languages. We have translated and/or reviewed the
`
`translation of the Japanese document identified as: JP- 10-226639 ~_and find
`
`it to be a true and accurate translation to the best of our knowledge and
`
`ability.
`
`We certify under penalty of perjury that the foregoing is tree and correct.
`
`Signature: ~& ~@
`Misa Foley
`
`Date: 2/2. >/2o 1~
`
`Signature
`
`Brenda K. Seat, Esq.
`
`Date: August 23, 2016
`
`SIX WHITEHALL BOURT, SILVER SPRING, MARYLAND 20901 ~ TEL.: 301-593-3980 FAX; 3FIl-6Fll-9243
`
`BSEAT@~HINSHUSERVII3EN.ElrnM ’ WWW, SHINSHU~ERVICEN.BOM
`
`ACRUX DDS PTY LTD. et al.
`EXHIBIT 1011
`IPR Petition for
`U.S. Patent No. 7,214,506
`
`1 of 49
`
`
`
`(19) Japan Patent Office (JP)
`
`(11 ) Patent Application Publication Number
`Hei 10-226639
`(12) Published Unexamined Patent Application (A)
`
`(51) Int. C1.6:
`
`Identification Number
`
`FI
`
`(43) Publication Date:
`
`August 25, 1998
`Theme Code
`(for reference)
`
`A61K 9/70 389 A61K 9/70 389
`47/10
`47/10
`47/12
`47/12
`//A61K 31/415
`31/415
`
`ADZ
`
`Z
`Z
`
`Request for Examination: Not Requested
`
`Number of Claims: 14 FD (Total 12 pages)
`
`Hei 9-347043
`
`(71) Applicant:
`
`000001959
`
`SHISEIDO CO., LTD.
`7-5-5 Ginza, Chuo-ku, Tokyo
`
`000001395
`KYORIN PHARMACEUTICAL CO.,
`LTD.
`2-5 Kmada Surugadai, Chiyoda-ku, Tokyo
`
`Yoichi Ohta
`c/o SHISEIDO CO., LTD., 2na Research
`Center
`2-12-1 Fukuura, Kanazawa-ku,
`Yokohama-shi, Kanagawa-ken
`
`Yuka~i Tsutsumi
`c/o SHISEIDO CO., LTD., 2na Research
`Center
`2-12-1 Fukuura, Kanazawa-ku,
`Yokohama-shi, Kanagawa-ken
`
`(21 ) Application
`Number:
`(22) Filing Date:
`
`(31) Priority No.:
`
`December 1, 1997
`
`JP Application No.
`Hei 8-351902
`
`(71) Applicant:
`
`(32) Priority date:
`(33) Priority Country:
`
`December 10, 1996
`Japan
`
`(72) Inventor:
`
`(72) Inventor:
`
`(74) Attorney/Agent Patent Attorney, Yuji Iwahashi, et al.
`
`(54) [Title of the Invention] FILM FORMING ANTIFUNGAL AGENT COMPOSITION
`
`Continue to the last page
`
`(57) [Abstract]
`[Objective]
`To provide a film forming antifungal agent composition, which has no stickiness upon
`application, is excellent in adhesiveness, can form a film having excellent releasability of the
`antifungal agent and high penetrability to the keratinous layers and is effective in treatment of
`trichophytosis, especially, tinea unguium.
`
`2 of 49
`
`
`
`[Structure]
`A film forming antifungal agent composition comprising a film forming compound
`having a tertiary amine, an antifungal agent and water, characterized in that the pH value of the
`composition falls in a pH range wherein said film forming compound can be dissolved or
`partially dissolved.
`
`3 of 49
`
`
`
`[Claims of the Invention]
`
`[Claim 1]
`
`A film forming antifungal agent composition comprising a film forming compound
`
`having a tertiary amine, an antifungal agent and water, characterized in that the pH value of the
`
`composition falls in a pH range wherein said film forming compound can be dissolved or
`
`partially dissolved.
`
`[Claim 2]
`
`The film forming antifungal agent composition, as set forth in claim 1, characterized in
`
`that said film forming compound is an alkylester methacrylate copolymer containing a tertiary
`
`amine and/or polyvinylacetaldiethylaminoacetate.
`
`[Claim 3]
`
`The film forming antifungal agent composition, as set forth in claim 2, characterized in
`
`that said film forming compound is a methylmethacrylate-butylmethacrylate-
`
`dimethylaminoethylmethacrylate copolymer and the pH value of the composition is 6.2 or lower.
`
`[Claim 4]
`
`The film forming antifungal agent composition, as set forth in claim 2, characterized in
`
`that said film forming compound is polyvinylacetaldiethylaminoacetate and the pH value of the
`
`composition is 5.8 or lower.
`
`[Claim 5]
`
`The film forming antifungal agent composition, as set forth in one of claims 1 to 4,
`
`characterized in that the antifungal agent is amorolfine hydrochloride.
`
`[Claim 6]
`
`4 of 49
`
`
`
`The film forming antifungal agent composition, as set forth in one of claims 1 to 5,
`
`characterized by comprising a lower alcohol.
`
`[Claim 7]
`
`The film forming antifungal agent composition, as set forth in claim 6, characterized in
`
`that the lower alcohol is ethanol and/or isopropyl alcohol.
`
`[Claim 8]
`
`The film forming antifungal agent composition, as set forth in one of claims 1 to 7,
`
`characterized by comprising a wetting agent.
`
`[Claim 9]
`
`The film forming antifungal agent composition, as set forth in claim 8, characterized in
`
`that the wetting agent is at least one type selected from propylene glycol, dipropylene glycol and
`
`1, 3-butylene glycol.
`
`[Claim 10]
`
`The film forming antifungal agent composition, as set forth in one of claims 1 to 9,
`
`characterized by comprising a keratinolytic agent.
`
`[Claim 11]
`
`The film forming antifungal agent composition, as set forth in claim 10, characterized in
`
`that the keratinolytic agent is at least one type selected from urea, salicylic acid, sodium
`
`salicylate and resorcinol.
`
`[Claim 12]
`
`The film forming antifungal agent composition, as set forth in one of claims 1 to 11,
`
`characterized by comprising a surfactant.
`
`[Claim 13]
`
`5 of 49
`
`
`
`The film forming antifungal agent composition, as set forth in claim 12, characterized in
`
`that the surfactant is a combination of one type or more of anionic surfactant and one type or
`
`more of amphoteric surfactant.
`
`[Claim 14]
`
`A therapeutic agent for tinea unguium comprising the film forming antifungal agent
`
`composition as set forth in one of claims 1 to 13.
`
`[Detailed Description of the Invention]
`
`[0001]
`
`[Field of the Invention]
`
`The present invention relates to a film forming antifungal agent composition for
`
`treatment of mycosis of nails and the surrounding region, or more particularly, improvement of
`
`releasability of the antifungal agent from the film and penetrability to the keratinous layers.
`
`[0002]
`
`[Conventional Technology]
`
`Conventionally, it is known that treatment of mycosis in dermatology, or especially,
`
`topical treatment of tinea unguium is difficult. This is attributable to the fact that nails, by their
`
`very nature, work as significant barriers against entry of foreign matter from the outside and their
`
`keratinous layers are extremely hard compared with the skin and, therefore, even if
`
`trichophytosis, which breeds inside the keratinous layers of the nails, is topically treated with an
`
`external medicine, the antifungal agent is hard to penetrate the keratinous layers.
`
`[0003]
`
`To solve this problem, recently, attempts are made to improve topical therapy by an
`
`antifungal agent. In other words, instead of the conventional cream and ointment base, attempts
`
`6 of 49
`
`
`
`are made to obtain a film forming composition such as nail lacquer preparation or nail enamel
`
`preparation with high compliance and a manicure preparation.
`
`[0004]
`
`For example, Japanese Unexamined Patent Application Publication No. Hei 3-77820
`
`discloses a skin care preparation, which is obtained by formulating active components to a base
`
`component comprising an acryl series and methacryl series copolymer mixture, a lower alcohol
`
`and water. Japanese Unexamined Patent Application Publication No. Hei 6-211651 discloses a
`
`composition for treatment of tinea unguium, which is obtained by formulating omoconazole
`
`nitrate or butenafine hydrochloride to a base comprising a hydrophobic film forming agent and a
`
`solvent. Japanese Unexamined Patent Application Publication No. Hei 7-277975 discloses a skin
`
`care preparation comprising two types or more of film forming agents having low water
`
`solubility, water, a plasticizing agent, an antifungal agent and alcohol. Each of the film forming
`
`preparations described above uses a water insoluble, hydrophobic film forming agent as a film
`
`forming compound so as to obtain the film strength and water resistance.
`
`[0005]
`
`[Problem to be Solved by the Invention]
`
`However, when a composition using the above described hydrophobic film forming
`
`compound is applied to nails, the network structure inside the film formed on the applied surface
`
`inhibits diffusion of the antifungal agent inside the film so that the release of the antifungal agent
`
`from the film and its penetration to the keratinous layers are not sufficient. In addition, when the
`
`above described composition is applied to nails in layers, accumulation of the previously-formed
`
`films inhibits penetration of the antifungal agent in the newly formed film. Therefore, even if the
`
`composition is continuously used, it is not possible to obtain the sufficient effect for that.
`
`7 of 49
`
`
`
`[0006]
`
`Furthermore, when an organic solvent such as acetone, ethylacetate and toluene is used as
`
`a solvent for the hydrophobic film forming compound, it is known that it dehydrates and hardens
`
`nails, thereby delaying penetration of the antifungal agent. Therefore, it is preferable that the
`
`composition does not contain the above described solvent. The present invention was created
`
`considering the above described problems of the conventional technology. The objective of the
`
`present invention is to provide a film forming antifungal agent composition, which has excellent
`
`releasability of the antifungal agent from the film and high penetrability to the keratinous layers
`
`and is effective in treatment of trichophytosis, especially, tinea unguium.
`
`[0007]
`
`[Means to Achieve the Obj ective]
`
`The inventors of the present invention devoted themselves to studies to achieve the above
`
`described objective. As a result, they found that a composition, which comprises a film forming
`
`compound having a tertiary amine, an antifungal agent and water and has a pH value adjusted to
`
`a prescribed pH range, forms a film having an excellent penetrability of the antifungal agent to
`
`the keratinous layers when applied to the affected area. Consequently, the present invention was
`
`completed.
`
`[ooo8]
`
`In other words, the film forming antifungal agent composition of the present invention
`
`comprises a film forming compound having a tertiary amine, an antifungal agent and water and
`
`is characterized in that the pH value of the composition falls in a pH range wherein said film
`
`forming compound can be dissolved or partially dissolved. Here, according to the present
`
`invention, a pH value is defined as the one obtained by diluting the composition with purified
`
`8 of 49
`
`
`
`water by 10 times and then measuring it by a pH meter. According to the present invention, it is
`
`preferable that the above described film forming compound is an alkylester methacrylate
`
`copolymer containing a tertiary amine and/or polyvinylacetaldiethylaminoacetate.
`
`[0009]
`
`In addition, it is preferable that the film forming compound is a methylmethacrylate-
`
`butylmethacrylate-dimethylaminoethylmethacrylate copolymer and the pH value of the
`
`composition is 6.2 or lower. Furthermore, it is preferable that the film forming compound is
`
`polyvinylacetaldiethylaminoacetate and the pH value of the composition is 5.8 or lower.
`
`[0010]
`
`Moreover, according to the present invention, it is preferable that the antifungal agent is
`
`amorolfine hydrochloride. In addition, it is preferable that the film forming antifungal agent
`
`composition of the present invention comprises a lower alcohol. As the lower alcohol, it is
`
`preferable to use ethanol and/or isopropyl alcohol.
`
`Furthermore, it is preferable that the film forming antifungal agent composition of the
`
`present invention comprises a wetting agent. As the wetting agent, it is preferable to use at least
`
`one type selected from propylene glycol, dipropylene glycol and 1, 3-butylene glycol. Moreover,
`
`it is preferable that the film forming antifungal agent composition of the present invention
`
`comprises a keratinolytic agent. As the keratinolytic agent, it is preferable to use at least one type
`
`selected from urea, salicylic acid, sodium salicylate and resorcinol.
`
`[0012]
`
`In addition, it is preferable that the film forming antifungal agent composition of the
`
`present invention comprises a surfactant. As the surfactant, it is preferable to use a combination
`
`9 of 49
`
`
`
`of one type or more of anionic surfactant and one type or more of amphoteric surfactant.
`
`According to the present invention, the therapeutic agent for tinea unguium is characterized by
`
`comprising the above described film forming antifungal agent composition.
`
`[0013]
`
`[Preferred Embodiment of the Invention]
`
`The film forming compound used in the present invention is a polymer having a tertiary
`
`amine in the molecule. As the compound described above, it is preferable to use EUDRAGIT
`
`(brand name) E100 (made by R0hm pharma GmbH, chemical name: methylmethacryl-
`
`butylmethacryl-dimethylaminoethylmethacryl copolymer (molar ratio: 1:1:2)) or AEA
`
`"SANKYO" (brand name) (made by Sankyo Co., Ltd., chemical name:
`
`polyvinylacetaldiethylaminoacetate).
`
`[0014]
`
`Each of the above described compounds is known as a film coating agent and has poor
`
`solubility to water. EUDRAOIT El00 and AEA "SANKYO" become scarcely-water soluble at a
`
`pH value of 5.0 or lower and that of 5.8 or lower respectively and are mainly used as gastric-
`
`soluble coating agents for oral medicines. In addition, EUDRAGIT El00 is normally insoluble to
`
`water at a pH value of 5.0 or higher, but has translucent properties at a pH value of around 6 and
`
`sustainedly releases the coated medicine. According to the present invention, the above described
`
`state wherein a compound exhibits the same behavior as when it is dissolved is called "partial
`
`dissolution".
`
`[0015]
`
`The above described pH-dependent solubility arises from the tertiary amine inside the
`
`film forming compound. According to the present invention, by using the film forming
`
`10 of 49
`
`
`
`compound having said tertiary amine and adjusting the pH value of the composition to a pH
`
`range wherein the film forming compound can be dissolved or partially dissolved, it is possible
`
`to increase the penetrability of the antifungal agent to keratin from the film, which is formed
`
`upon application of the antifungal agent. Here, in the composition of the present invention, a pH
`
`value is defined as the one obtained by diluting the composition with purified water by 10 times
`
`(hereinafter, may be called measurement system) and then measuring it by a pH meter. This
`
`method is a measurement method, which is normally recommended in a pH measurement of a
`
`compound containing a large amount of ethanol, and the like.
`
`[oo16]
`
`In the case of an antifungal agent composition comprising EUDRAGIT E100, if the pH
`
`value in the above described measurement system is 6.2 or lower, it is possible to obtain
`
`releasability of the antifungal agent from the film and penetrability to keratin or nails. When the
`
`pH value is further decreased, the releasability and penetrability of the antifungal agent are
`
`increased. When the pH value is made to 5 or lower, the effect is significantly increased.
`
`Therefore, when EUDRAGIT El00 is used as the film forming compound, the pH value in the
`
`measurement system of the composition is 6.2 or lower, or preferably, 6.0 or lower, or more
`
`preferably, 5.0 or lower. Similarly, when AEA "SANKYO" is used, it is preferable that the pH
`
`value in the measurement system of the composition is 5.8 or lower.
`
`[0017]
`
`The amount of the film forming compound used in the present invention is 1 to 30 w/v %,
`
`or preferably, 2 to 20 w/v %, or more preferably, 3 to 15 w/v % relative to the total amount of the
`
`composition. If the amount of the film forming compound is small, film formation is not
`
`sufficiently performed. If the amount of the film forming compound is too large, the
`
`10
`
`11 of 49
`
`
`
`concentration of the antifungal agent in the film is relatively decreased. Therefore, this is not
`
`desirable. As the antifungal agent, which is an active component of the present invention, it is
`
`preferable to use amorolfine hydrochloride, terbinafine hydrochloride, miconazole nitrate,
`
`isoconazole nitrate, sulconazole nitrate, oxiconazole nitrate, econazole nitrate, croconazole
`
`nitrate, neticonazole nitrate, and the like. One type or two or more types selected from the above
`
`described antifungal agents may be used. It is preferable to use them as salt such as
`
`hydrochloride and nitrate.
`
`[ools]
`
`According to the present invention, it is preferable to use amorolfine hydrochloride as an
`
`antifungal agent. Amorolfine hydrochloride is an antifungal agent having extremely high water
`
`solubility in an acidic region. It is especially preferable to use this antifungal agent considering
`
`the compatibility with the pH-dependency of the film forming compound used in the present
`
`invention. In the film forming antifungal agent composition of the present invention, the amount
`
`of the antifungal agent is 0.1 to 10 w/v %, or preferably, 0.5 to 8 w/v %, or more preferably, 1 to
`
`6 w/v % relative to the total amount of the composition. If the amount of the antifungal agent is
`
`small, the resultant antifungal activity is not sufficient. If the amount is too large, there may be
`
`economical and safety problems and problems of stability such as deposition of crystals.
`
`Therefore, this is not desirable.
`
`[0019]
`
`The amount of water, which is one of the essential components of the present invention,
`
`is appropriately adjusted in accordance with the amount of other components. Normally, the
`
`amount of water is 1 to 30 w/v %, or preferably, 2 to 15 w/v %, or more preferably, 3 to 10
`
`w/v % relative to the total amount of the composition. If the amount of water is small, the
`
`11
`
`12 of 49
`
`
`
`resultant softening effect on the nails and skin and releasability of the antifungal agent from the
`
`film as well as penetrability to the keratinous layers are not sufficient. In addition, if the amount
`
`of water is too large, the film is not easily dried.
`
`[0020]
`
`When the pH value of the composition of the present invention cannot be adjusted to a
`
`desirable one only by using the above described essential components, it is necessary to adjust
`
`the humoral by using a pH adjuster, and the like. As the pH adjuster, it is possible to
`
`appropriately select the one, which is commonly used in a skin care preparation or a cosmetic
`
`product. Examples of the pH adjuster include an inorganic acid such as chloric acid, sulfuric acid,
`
`nitric acid, and phosphoric acid and an organic acid such as acetic acid, propionic acid, citric
`
`acid, lactic acid, oxalic acid, succinic acid, tartaric acid, malonic acid and malic acid. One type or
`
`two or more types of pH adjusters may be used. One of the characteristics of the film forming
`
`antifungal agent composition of the present invention is that a film forming compound having a
`
`tertiary amine is used and the pH value of the composition in the measurement system falls in a
`
`pH range wherein the film forming compound can be dissolved or partially dissolved.
`
`[0021]
`
`Conventionally, when a film forming compound is used, it is normally dissolved in an
`
`organic solvent capable of dissolving the film forming compound so as to form a nail enamel
`
`preparation. Even when water is added to improve the transparency, and the like, conventionally,
`
`the humoral is not deliberately adjusted to a pH range wherein the film forming compound is
`
`dissolved. This is because such pH adjustment will generally suggest poor film formability.
`
`[0022]
`
`12
`
`13 of 49
`
`
`
`For example, there is a known antifungal agent composition comprising EUDRAGIT
`
`El00. Japanese Unexamined Patent Application Publication No. Sho 63-258814 discloses a
`
`varnish type antifungal agent composition comprising 2 % of miconazole nitrate, 10 % of water,
`
`10 % of urea, 64 % of anhydrous alcohol, 2 % of glycerol and 12 % of EUDRAGIT El00.
`
`However, the purpose of this composition is to use urea as a solubilizing agent so that
`
`miconazole nitrate as a scarcely-water soluble antifungal agent can exist in dissolved condition
`
`in an aqueous solution. The pH value of the composition in the measurement system is 7 or
`
`higher. In other words, the pH value of the above described composition does not fall in a pH
`
`range wherein EUDRAGIT El00 can be dissolved or partially dissolved and no study on the
`
`effect of the existence of a film forming compound (EUDRAGIT E 100) is made. The film made
`
`from the above described composition is the same as an ordinary hydrophobic film and does not
`
`sufficiently demonstrate releasability of the antifungal agent and penetrability to keratin and nails.
`
`[0023]
`
`In the meantime, the inventors of the present invention found that, by using a film
`
`forming compound having a tertiary amine and adjusting the pH value of the composition to a
`
`pH range wherein the film forming compound can be dissolved or partially dissolved, it is
`
`possible to obtain unexpectedly good film formability and, thus, obtain a film forming antifungal
`
`agent composition, which has no stickiness after drying without being attached to a contact
`
`object, is excellent in adhesiveness to nails and, further, has high penetrability of the antifungal
`
`agent to keratin compared with the case wherein the pH value is not adjusted to the above
`
`described pH range.
`
`[0024]
`
`13
`
`14 of 49
`
`
`
`Although the action [ability] to express the above described effects is not clear, it appears
`
`to be as described below. In other words, upon applying the composition of the present invention
`
`on a nail, as a solvent such as alcohol and water is volatilized, a film is formed on the nail.
`
`Although the pH value of the composition of the present invention is adjusted to a pH range
`
`wherein the film forming compound can be dissolved or partially dissolved, the amount of water
`
`capable of dissolving the film forming compound does not exist in the above described state
`
`wherein almost all the solvent is dissolved. Consequently, a film which appears to be an ordinary
`
`hydrophobic film is formed. Nevertheless, the film forming compound in this film is in a water-
`
`soluble or partially water-soluble state, that is, in a state with a high degree of freedom.
`
`Therefore, it is believed that, due to the above described existence of the film forming compound,
`
`diffusion of the medicine in the film and release of the medicine from the film are not inhibited
`
`and the high medicine releasability is exerted.
`
`[0025]
`
`In addition, it is inferred that the following factors play important roles as well: so called
`
`ODT (occlusive dressing technique) wherein the nail is covered with the film is applied; since
`
`the film itself comes into contact with the nail while containing a small amount of moisture, the
`
`hard nail plate receives a sufficient moisturizing effect and swells so that the antifungal agent can
`
`be very easily transferred from the film to the nail; and the film has extremely high adhesiveness
`
`to the nail and is not easily peeled off.
`
`[0026]
`
`In addition to the above described essential components, it is preferable that the film
`
`forming antifungal agent composition of the present invention contains lower alcohol. The lower
`
`alcohol is not limited to specific one as long as it contributes to quick formation of the film and
`
`14
`
`15 of 49
`
`
`
`has the function as a solvent. It is preferable to use ethanol and/or isopropyl alcohol. The amount
`
`of the lower alcohol is appropriately adjusted in accordance with the characteristics of the target
`
`composition, amounts of the antifungal agent and film forming compound, and the like.
`
`Normally, the amount of the lower alcohol is 17 to 89 w/v %, or preferably, 30 to 80 w/v %, or
`
`more preferably, 50 to 75 w/v %.
`
`[0027]
`
`Furthermore, in addition to the above described essential components, to increase the
`
`penetrability of the antifungal agent to the keratinous layers, a wetting agent, a keratolytic agent
`
`and a surfactant may be added to the film forming antifungal agent composition of the present
`
`invention. Examples of the wetting agent include propylene glycol, dipropylene glycol, 1, 3-
`
`butylene glycol, glycerin, diglycerin, triglycerin, polyethylene glycol, sorbitol, glucose, fructose,
`
`maltose, xylitol, erythritol, threitol, MABIT and mannitol. One type or two or more types of the
`
`above described wetting agents may be used. It is preferable to use propylene glycol, dipropylene
`
`glycol and 1, 3-butylene glycol. The wetting agent has a skin and nail softening effect and an
`
`improved effect on penetrability of the antifungal agent.
`
`[0028]
`
`The amount of the wetting agent of the present invention is 1 to 20 w/v %, or preferably,
`
`2 to 15 w/v %, or more preferably, 5 to 10 w/v % relative to the total amount of the composition.
`
`If the amount of the wetting agent is small, a sufficient softening effect on the nails is not
`
`obtained and noticeable improvement of the medicine penetrability is not observed. In addition,
`
`if the amount is too large, the film is not easily dried, but the stickiness is increased. This is not
`
`desirable.
`
`[0029]
`
`15
`
`16 of 49
`
`
`
`Furthermore, examples of the keratinolytic agent include urea, salicylic acid, sodium
`
`salicylate and resorcinol. They may be used singly or arbitrarily mixed. The keratinolyic agent
`
`can soften the keratinous layer on the nail surface and increase penetration of the antifungal
`
`agent. According to the present invention, the amount of the keratinolytic agent is 0.2 to 10
`
`w/v %, or preferably, 0.5 to 5 w/v %, or more preferably, 1 to 3 w/v % relative to the total
`
`amount of the composition. If the amount of the keratinolytic agent is small, the medicine
`
`penetrability to the nail is not sufficient. If the amount is too large, the film is not easily dried,
`
`but the stickiness is increased. This is not desirable.
`
`[0030]
`
`The surfactant used in the present invention is not limited to a specific one. It is
`
`preferable to use a hydrophilic surfactant. Examples of the hydrophilic surfactant include a
`
`nonionic surfactant, an ionic surfactant and an amphoteric surfactant. They may be used singly or
`
`arbitrarily mixed. Examples of the nonionic surfactant include a polyoxyalkylene series
`
`surfactant, polyglycerol fatty acid ester, a Tween series surfactant and a sugar ester series
`
`surfactant. In addition, examples of the ionic surfactant include fatty acid soap, alkylsulfonate
`
`salt, ether phosphate, fatty acid salt of basic amino acid, triethanolamine soap and quaternary
`
`alkylammonium salt. Examples of the amphoteric surfactant include betaine, amino carboxylate
`
`and alkyldimethylamineoxide. It is preferable to use a combination of an anionic surfactant and
`
`an amphoteric surfactant. The surfactant can activate the keratinous surface of a nail and increase
`
`the penetrability of the medicine to the nail.
`
`[0031]
`
`The amount of the surfactant used in the present invention is 0.1 to 5 w/v %, or
`
`preferably, 0.2 to 3 w/v %, or more preferably, 0.3 to 1 w/v %. If the amount of the surfactant is
`
`16
`
`17 of 49
`
`
`
`small, the medicine penetrability to the nail is not sufficient. If the amount is too large, the film is
`
`not easily dried, but the stickiness is increased. In addition, if necessary, the film forming
`
`antifungal agent composition of the present invention may contain other chemicals (for example,
`
`an antihistamine, an antipruritic agent, an anti-inflammatory agent and a local anesthetic), an
`
`absorption promotor, a plasticizer, a buffering agent, a tonic, an antioxidant, a gelling agent, a
`
`cheating agent, oil, a solvent, a polymer, perfume, a coloring agent, and the like without
`
`damaging the effects of the present invention.
`
`[0032]
`
`Examples of the above described plasticizer include ethylene carbonate, propylene
`
`carbonate, triethyl citrate, triacetin, crotamiton, diisopropyl sebacate, diethyl sebacate and
`
`diisopropyl adipate. One type or two or more types of the above described plasticizers may be
`
`used. It is preferable to use ethylene carbonate and propylene carbonate. As the dosage form, the
`
`film forming antifungal agent composition of the present invention can be formulated into a
`
`composition having appropriate viscosity such as a liquid-state preparation having low viscosity
`
`and a gel preparation having high viscosity.
`
`[0033]
`
`The method for applying the film forming antifungal agent composition of the present
`
`invention to the affected area is not limited to a specific one. Examples of the application method
`
`include brush application, application by an applicator such as a cotton swab and a spatula, roll-
`
`on type application, direct application from a container and spray application. In addition,
`
`different from the conventional enamel film, it is possible to wash the film which is formed upon
`
`applying the composition of the present invention by repeatedly bathing it or washing it with
`
`water. Especially, it is possible to easily wash the film with the composition having the pH value
`
`17
`
`18 of 49
`
`
`
`of 5.0 or lower. The usage is not limited to specific one. When the composition must be
`
`repeatedly applied, in order to constantly bring the highly-concentrated antifungal agent into
`
`contact with the affected area, it is preferable that the film is washed with water once to several
`
`times a day depending on the condition of a disease and then the composition is reapplied to the
`
`affected area. Here, since the film of the present invention has excellent adhesiveness to the skin
`
`and nails, it is not suitable for the peel-off type. In addition, after the composition is applied to
`
`nails, and the like, it may be wrapped by a bandage or a wrapping film.
`
`[0034]
`
`Next, a practical example of the present invention will be described by using amorolfine
`
`hydrochloride as an antifungal agent, EUDRAGIT El00 and AEA "SANKYO" as film forming
`
`compounds. Here, the formulating amount is expressed by weight (g) unless otherwise specified.
`
`[0038
`
`[Test Example 1]
`
`First, stickiness of the film forming antifungal agent composition of the present invention,
`
`its adhesiveness to nails and penetrability to keratin were examined. Here, each of the test
`
`methods is as follows:
`
`[Stickiness]
`
`The sample was applied to nails and the stickiness of the film after natural drying was
`
`evaluated based on the following criteria:
`
`@:No stickiness
`
`O: Nearly no stickiness
`
`/k: Slight stickiness
`
`X: Noticeable stickiness
`
`18
`
`19 of 49
`
`
`
`[0036]
`
`[Adhesiveness to nails]
`
`The sample was applied to nails and the state of the film after natural drying was
`
`observed by the naked eye and the adhesiveness to the nails was evaluated based on the
`
`following criteria:
`
`©: High adhesiveness (no wrinkles in the film)
`
`O: Sufficiently high adhesiveness (slight wrinkles in the film)
`
`A: Low adhesiveness (wrinkles in the film)
`
`X: No adhesiveness (the film was easily peeled off from the nails)
`
`[0037]
`
`[Test on the penetrability to keratin]
`
`The skin removed from the back of an 8-week-old male hairless mouse was placed in a
`
`Franz type diffusion cell. A physiological saline solution was used as a receptor solution and
`
`0.15 ml of sample was applied in an open system for 24 hours. To examine the amount of the
`
`antifungal agent, which passed through the skin and was transferred to the receptor solution,
`
`samples of the receptor solution were taken over time and the concentration of the antifungal
`
`agent in the receptor solution was measured by the HPLC method. Based on the concentration of
`
`the antifungal agent in the receptor solution after the elapse of 24 hours, the penetrability to
`
`keratin was evaluated in accordance with the following criteria:
`
`©: Concentration of the antifungal agent was 5 gm/ml or higher
`
`O: Concentration of the antifungal agent was 3 gm/ml or higher but lower than 5 gm/ml
`
`A: Concentration of the antifungal agent was 1 gm/ml or higher but lower than 3 gm/ml
`
`X : Concentration of the antifungal agent was lower than 1 gm/ml
`
`19
`
`20 of 49
`
`
`
`[0038]
`
`[pH measurement method]
`
`The sample was diluted with purified water by 10 times and measured by using a pH
`
`meter (F-8 AT type, made by Horiba, Ltd.).
`
`[0039]
`
`[Table 1]
`
`Sample No.
`Structural component 1 2 3 4 5 6
`1
`5
`5
`5
`5
`5
`(1) amorolfme hydrochloride
`10
`10
`11
`10
`-
`(2) EUDRAGIT El00
`-
`10
`(3) A
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