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`ACRUX DDS PTY LTD. et al.
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`EXHIBIT 1513
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`

`

`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
`ISSN 0386-9784
`
` The Nishinihon Journal of Dermatology
`Vol. 52/990
`
`FUKUOKA JAPAN
`
`Volume 52 July 1990 No. 3
`
`[Illustration theory]
`
`Necrotizing Fasciitis………………………………………………………………………………………………….Tanahashi Tomoko and others………447
`[General Opinion]
`Necrotizing Fasciitis………………………………………………………………………………............................Tanahashi Tomoko and others ………449
`[Case]
`Case that is considered as Necrotizing Fasciitis……………………………………………………………………...Naoko Kato and others…………...…457
`Two cases of sporotrichosis showing atypical clinical picture…………………………………………….................Masaki Haruyuki and others....……..462
`Children with Mycobacterium marinum skin infection with excavable ulcer…………………..................................Fujimoto Wataru and others………..467
`10-year-old male malignant melanoma………………………………………………………….................................Nakamura Sawako and others………473
`Merkel Cell Tumor……………………………………………………………………………………………………Fukuro Shuuhei and others………....478
`Seborrheic Keratosis in which crack formation and abnormal keratinocytes were observed………………………...Kurata Yukimi and others…………..484
`Bowen pattern generated from seborrheic keratosis…………………………………………………………………..Kurata Yukimi and others…………..488
`Eccrine sweat pore tumor secondary sebaceous nevus………………………………………………………………..Mamata Akira and others…………..491
`Pandemic annular granuloma with diabetes mellitus and herpes zoster………………………………………………Morita Boshi and others……………495
`Rheumatoid arthritis and rheumatic seborrhea · pyoderma gangrenosum with uveitis……………………………….Kanazawa Yuki and others…………500
`Buerger Pain…………………………………………………………………………………………………………...Kawahara Kenichi and others……...503
`Koax powder thin rash measles to be enhanced by exercise load……………………………………………………..Ichikawa Hirouki and others……….509
`Health sandal dermatitis caused by dialysis room staff……………………………………………………………….Yamashita Naoko and others……….514
`[Study]
`Hair shell keratin and hair follicle tumor (5)………………………………………………………………………….Aso Kazuo and others………………518
`New test method and analysis on autonomic function in alopecia areata…………………………………………….Akasu Reiko and others…………..…527
`Skin local injection of shingles………………………………………………………………………………………..Shimada Gibo and others…………...533
`External synthetic glucocorticoid agent Difluprednate and its metabolite cultivated human fibroblasts
`Effect on DNA synthesis………………………………………………………………………………………………Koui Kou and others…………….…540
`A Study on Antimicrobial Activity of Topical Antibacterial Agents for Topical Application………………………..Masa Yuuka and others………….…545
`[Course]
`From the site of diagnosis of collagen disease (3)……………………………………………………………………..Uki Hiromei and others……………550
`
`[Statistics]
`Statistics of herpes zoster in 5 years at Hiroshima citizen's hospital………………………………………………….Morishita Keiko and others………...555
`Statistical observation of pustular psoriasis……………………………………………………………………………Nishikawa Takeshi and others…….560
`[Treatment]
`Clinical study of Ketotifen-MR for skin diseases………………………………………………………………………Kubota Hiromi and others………...565
`Clinical effect of ciprofloxacin on skin / soft tissue infection………………………………………………………….Yasumoto Ichiro and others…….…572
`Nifedipine (Adalat capsule) Therapeutic effect on topical cryotherapy………………………………………………..Hosu Kayushi and others………….577
`Clinical effect of anti-fungal agent KP-363 cream on tinea pedis
`New anti-external agent KP -363 (Butenafme hydrochloride) against creams and liquid formulations for skin mycoses
` The formation of Phase II clinical trial…………………………………………………………………………………
`[Conference]
`The 92nd Shikoku Regional Meeting of the Japan Skin Science Society
`The 70th Miyazaki Regional Association of the Japan Skin Science Society
`Japan Skin Science Society 53, 54 th Saga Regional Association
`Japan Skin Science Association 268, 269 th Fukuoka Regional Association
`[Other]
`Prosecution rule:596 Scientists in the world
`Literature Abstract:623 Miscellaneous
`
`Nishi Nihon Journal of Dermatology
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 2 of 13
`
`

`

`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
` Antibacterial activity of topical antifungal agent in the infected sites – Study
`
`545
`
`--- Skin permeability and absorption to horny materials ---
`
`Central research laboratories, Kaken Pharmaceuticals Co., Ltd.,
`
`(Director: Michio Nakanishi)
`
`Tadashi Arika • Toyoji Hase • Mamoru Yokoo
`
`The skin’s permeability and retention of Butenafine hydrochloride (KP-363: N -4-tert-butylbenzyl-N-1-methyl-
`1-naphthalene-methylamine hydrochloride) were investigated using 14C-KP-363. 1% 14C-KP-363 0.2 ml (2 mg)
`was hermetically attached to the dorsal skin of the guinea pig for 6 hours and when the distribution of the skin to
`each layer was examined, it was proved that KP - 363 was present at 50 μg / g or more in the epidermal layer
`including the stratum corneum, which is the habitat of ringworm and even after 24 hours of application (18 hours
`after the end of application), 10 μg / g or more of drug remained in the epidermis layer, and it was found that this
`drug was easy to be accumulated in the skin layer containing the barrier. On the other hand, when the adsorption
`property between the antifungal agent and horny substance was examined using human hair powder, KP-363,
`tolnaftate, clotrimazole and bifonazole were observed to be strongly adsorbed by the hair. The antimicrobial
`power of KP - 363, tolnaftate, clotrimazole and bifonazole adsorbed on the hair was 4.0, 15.6, 62.5 and 62.5 μg /
`g (hair), respectively and it was reduced compared to the antibacterial activity (0.0125, 0.05, 0.39 and 0.39 μg /
`ml) measured with Sabouraud liquid medium. However, it turned out that the concentration of KP - 363 in the
`stratum corneum obtained when 1% KP - 363 was applied was still sufficient to prevent the development of T.
`mentagrophytes.
`
`Introduction
`As factors determining the acceptability of external
`antifungal agents, A) having a strong in vitro
`antibacterial activity, B) little irritation, C) poor
`sensitization, D) it does not have strong skin
`permeability, Takahashi pointed out that it has
`affinity for the stratum corneum, which is a parasitic
`part of the fungus, and that it will stay there for a
`long time. Butenafine hydrochloride (KP - 363: N -
`4 - tert - butylbenzyl - N - methyl - 1 -
`naphthalenemethylamine hydrochloride) shows a
`wide antifungal spectrum in many fungi including
`dermatophytes and excellent therapeutic effects in
`experimental guinea pig dorsal and tinea pedis with
`treatment once a day2); given that it completely
`protects infection of T.mentagrophytes in one
`external application before 24 or 48 hours, the in
`vivo effect of KP-363 is presumed to be due to the
`high skin retention as well as the strength of the
`antibacterial activity of this product3)4). On the other
`hand, in the measurement of the medium skin
`concentration after application of KP - 363, the skin
`concentration in the skin after 24, 48 and 72 hours
`of application of 1% KP - 363 0.2 ml was 31.5, 18.2
`and 8.8 µg / g respectively and it was 730 times
`higher than the bactericidal concentration (0.012 µg
`/ ml) of T. mentagrophytes even after 72 hours of
`application. Despite
`the presence of high
`concentrations of drug in the skin, when T.
`
`infected 72 hours after
`mentagrophytes was
`application of KP-363, the observation of the
`presence of
`the specimen
`that developed
`it
`suggested that the antifungal activity of KP-363
`may be decreased in the skin. In this study, we
`examined the penetrability into the skin of KP-363,
`using
`retention
`property
`14C-KP-363,
`and
`compared with
`tolnaftate,
`clotrimazole
`and
`bifonazole which are widely used as an external
`antifungal agent and we examined the absorbability
`of KP-363 to horny matter and the reduction of
`antifungal activity when adsorbed with horny matter.
`
`Materials and methods
`
`1) Drug
`KP-363 (Lot 2000), clotrimazole (Lot 840614) and
`bifonazole (Lot 870306) were synthesized in our
`laboratory. Tolnaftate (Lot 8509) was purchased
`from Sagami Chemical Industry. Each drug was
`dissolved in dimethylsulfoxide (DMSO; Wako Pure
`Chemical Industries) in such a way that it becomes
`10mg/ml concentrated solution. After diluting the
`concentrated solution in DMSO two times, it was
`diluted with 0.1% Tween 80 distilled water to
`prepare a chemical solution of 1,000 to 0.03 ug / ml.
`14C-KP-363
`(Lot
`881111,
`specific
`activity
`concentration 44.3 µCi / mg) was labeled at our
`laboratory, and was dissolved in Macrogol 400:
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 3 of 13
`
`

`

`1 hour of shaking (120 rpm / min) at 30 ° C to
`absorb the agent and the hair in solution A, 0.2 ml
`(2 x 104 cells / tube) of T. mentagrophytes
`suspension was inoculated, and cultured at 30 ° C.
`for 7 days. In another experiment, drugs and hair
`were shaken for 1 hour at 30 ° C, unabsorbed drug
`was removed by centrifugation, 2 ml of solution A
`was added, and shake was carried out at 60 ° C for 3
`hours. After shaking, the supernatant was removed
`by centrifugation; 1.8 ml of Solution A and 0.2 ml
`of bacteria were added and incubated at 30 for 7
`days. Under this condition, T. mentagrophytes
`develops only hair fiber as a nutrient source.
`Presence or absence of bacterial growth was
`examined macroscopically or microscopically, and
`it was defined as
`the minimum
`inhibitory
`concentration
`(MIC) with
`the minimum
`concentration of the agent that does not show
`bacterial growth. As a control, MIC in sub-liquid
`medium (1% polypeptone, Japan Pharmaceutical,
`3% Glucose, Wako Pure Chemical, PH 6.0) was
`examined by liquid medium dilution method.
`
`Result
`1. Investigation of drug permeability after applying
`KP-363 to guinea pig skin
`To observe the distribution of KP-363 in the skin
`after 0.2 ml of 1% 14C-KP-363 solution was sealed
`and pasted for 6 hours and 18 hours after
`completion of the application, the skin specimen
`was sliced parallel to the skin surface at a thickness
`of 50 µm and the radioactivity of each section was
`measured with a liquid scintillation counter. As
`shown in Fig. 1, the results showed that after 6
`
`Dpm: 50µm skin section
`
`Skin thickness
`(µm)
`Figure 1 KP-363 Guinea pig skin concentration
`distribution after application
`14C-KP-363 1% sealed and attached to guinea pig skin for 6 hours. Cut
`the skin at 6 hours of application and 24 hours after application (18
`hours after application), prepare 50 am frozen sections parallel to the
`skin surface, and measure the radioactivity of each section with a liquid
`scintillation counter.
`▲ - ▲ Skin KP - 363 distribution 6 hours after application
`-
`-
` distribution of skin KP - 363 after 24 hours of application
`
`546
`
`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
`ethanol: distilled water 30: 20: 50 mixture
`solution in such a way that it becomes 1%.
`2) Study on percutaneous absorbability of KP-363
`Hair of the back skin of the male Hartley type
`guinea pigs was depilated using electric hair
`clippers, an electric shaver and a depilatory cream
`to avoid irritation as much as possible. The next day,
`the 14C - KP – 363 1% solutions, 0.2 ml (20 µCi / 2
`mg / 0.2 ml) was applied to the gauze 2 × 2 cm, and
`it was hermetically sealed at the same site for 6
`hours with parafilm and elastopore (Nichiban). The
`unabsorbed drug was removed with absorbent
`cotton and alcoholic cotton 6 hours after application.
`Animals were slaughtered 6 and 24 hours after
`application (18 hours after the end of application),
`the skin at the application site was cut out and 50
`µm frozen segment were prepared parallel to the
`skin surface. Each section was solubilized with
`Soluene-100® (Packard), neutralized with acetic
`acid and radioactivity was measured with a liquid
`scintillation counter (Beckman LS 9000).
`3) Anti-Trichophyton mentagrophytes activity of
`antifungal agent adsorbed to the hair
`a) Preparation of used strain and bacterial solution
`Trichophyton mentagrophytes strain KD - 04 was a
`clinical isolate and cultured in Sabouraud medium
`at 27 ° C for 2 weeks was used. Saline containing
`0.1% Tween 80 was added dropwise, the surface
`was rubbed with a platinum loop, the conidia were
`suspended, gauze filtered, and small conidia were
`counted on a leukocyte calculation plate to prepare
`105 cells / ml.
`B) Preparation of crushed hair
`Since it is difficult to obtain a large amount of
`normal horny layer, human hair was used. Human
`hair was degreased several times with ethanol •
`ether (50:50, vol / vol). After degreasing, it was
`thoroughly rinsed with distilled water. Subsequently,
`the hair frozen with liquid nitrogen was ground in a
`mortar to prepare crushed pieces.
`C) Measurement of antimicrobial properties of hair
`with adsorbed drug
`100 mg of crushed hair was taken in a test tube
`(inner diameter 18 mm), and a solution A (0.2% di-
`potassium phosphate, Wako Pure Chemical
`Industries, 0.005% magnesium sulfate, Wako Pure
`Chemical Industries, 0.005% calcium chloride,
`Hayashi Pure Chemicals, PH 6.0) was added, and
`autoclave sterilization was carried out. After
`sterilization, two times diluted KP-363, tolnaftate,
`clotrimazole or bifonazole solution 0.2ml (200,100,
`50, …0.006 µg/100mg) (hair / tube) was added after
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 4 of 13
`
`

`

`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
`hours of application, drugs were present at several
`um of the surface layer at a high degree and next,
`after reserving storage up to 200 to 400 µm which
`seems to be a sebaceous gland existing site, it will
`spread rapidly but several peaks which appeared to
`be adsorbed in the hair were observed at the site of
`1,000 to 2,000 µm as discussed in detail. A spread
`of 50 µg / g or more was found in terms of the
`concentration of KP - 363 in the total epidermis
`including the stratum cornea, which is the habitat of
`dermatophytes. The distribution pattern of KP-363
`in the skin at 18 hours after the sealing and
`application of KP-363 for 6 hours was almost the
`same as after 6 hours of application, the whole
`concentration showed a moderate decrease, and
`suggesting high sustainability in the skin. In the
`epidermis containing
`the stratum corneum, a
`distribution of 10 µg / g or more in terms of the
`concentration of KP-363 was found, and a trend
`with high affinity was observed in the same site.
`2. Anti-T. Mentagrophytes Activity of Antifungal
`Agents Adsorbed on the Hair
`The anti- T. mentagrophytes activity of KP-363,
`and bifonazole was
`tolnaftate,
`clotrimazole
`investigated and the results are shown in Table 1.
`As shown in C of Table 1, KP-363 had the strongest
`antibacterial activity in the Sabouraud medium, and
`inhibited the growth of the fungus at 0.0125 µg / ml.
`Its antibacterial activity was 4 to 32 times stronger
`than that of the control drug. Then, when examining
`the antimicrobial effect of the drug adsorbed on the
`hair in a medium using the hair as a nutrient source,
`as shown in A in Table 1, KP-363 had a MIC of 4
`µg / g (hair) on the hair follicle and a 320-fold
`in the Sabouraud
`increase compared to MIC
`medium. A similar tendency was observed for the
`control drugs, and tolnaftate, clotrimazole and
`bifonazole showed increases of 312 times, 160
`times and 160 times, respectively. Even when
`treating the hair and the absorbed drug for 3 hours
`remained
`its antibacterial activity
`at 60°C,
`unchanged and its adsorption was considered to be
`strong (B in Table 1).
`Table 1 Effect of Milled Hair on Anti-Trichophyton
`mentagrophytes Activity of KP-363, tolnaftate, clotrimazole
`and bifonazole
`(µg/g hair) MIC (µg/ml) (Sabouraud medium)
`
`Medicine MIC
`(medium)
`Hair grinding
` A*
` B**
`
` C***
`4.0
`zKP-363
`4.0
`0.0125
`Tolnaftate 15.6 15.6
`0.05
`Clotrimazole 62.5 62.5
`0.39
`Bifonazole 62.5 62.5
`0.39
`
`547
`
`*: Add 1- step dilution series of medicinal solution to the crushed piece,
`add T. mentagrophytes 2 × 104 cells after 30 minutes at 30°C, incubate
`for 7 days at 30°C, then MIC measurement from the presence or
`absence of bacterial growth
`**: Add chemical solution of two-step dilution series to crushed pieces
`and shake for 60 minutes at 30°C. Removed unapplied medicine in hair,
`further inoculated at 60°C, shake for 3 hours, inoculated with 2 x 104 T.
`mentagrophytes, and judged after culturing for 7 days
`***: Add 2-step dilution series of drug solution to Sabouraud liquid
`medium, shake for 60 minutes at 30°C, then contact 2 × 104 T.
`mentagrophytes
`Concept
`Regarding the adsorption ability of horny and
`antifungal agents, Freedman et al.6) tested the
`adsorption between human hair and griseofulvin
`and when griseofulvin was added at a concentration
`of 16.5 µg / ml, it was reported that it can absorb
`from 20 to 30% and recover 70 to 80% by
`extraction with 60 °C of distilled water. In the study
`of the anti - T. mentagrophytes activity of the drug
`adsorbed to the hair and the hair’s ability to absorb
`thiomersal, an organic mercurial agent, halogen
`phenolic pentachlorphenol soda (PCP - Na) and
`antiseptic soap benzethonium chloride, Takahashi
`has reported that there is a difference in adsorption
`of these drugs to the hair, 15% by thiomersal, 79%
`by PCP - Na, 80% by benzethonium chloride is
`adsorbed to the hair, and thiomersal has a low
`adsorption rate but the binding rate is high. The
`antimicrobial effect of the drug adsorbed on the hair
`was 64 μg / g (hair) of thiomersal, 500 µg / g of
`PCP - Na, 3,600 µg / g of penicillium chloride, and
`the MIC of the above - 10 and 25 µg / ml, and it
`was revealed that the antimicrobial concentration
`per unit hair amount of medicine adsorbed to hair
`decreased by 42 times, 50 times and 144 times
`respectively compared with those in liquid state and
`in order to expect a reliable antimicrobial effect, it
`is suggested that the intracellular degree showing
`growth inhibition in in vivo experiments on hair
`rather than in vitro solution must be obtained by
`application of an antibacterial agent. When KP-363
`1% solution 0.2 ml (2 mg) was hermetically
`attached to the back skin of the guinea pig for 6
`hours, the presence of KP-363 of 50 µg / g or more
`was observed on the surface skin (FIG. 1). As with
`tolnaftate, clotrimazole and bifonazole, KP-363
`decreased its antimicrobial activity by adsorbing
`with keratin (Table 1) but nevertheless, considering
`the
`inhibition of
`the development of T.
`mentagrophytes at 4 µg / g, it was revealed that the
`1% solution of KP-363 had sufficient concentration
`to show antimicrobial effect
`in keratin after
`application. In addition, since KP - 363 adsorbed by
`hair does not change antibacterial effect even with
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 5 of 13
`
`

`

`548
`
`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
`treatment at 60 ° C for 3 hours, the adsorption of KP
`- 363 and hair is considered to be strong. Even after
`18 hours of sealing application of KP-363 to the
`skin of guinea pigs for 6 hours, the concentration of
`each part remained only moderately compared with
`the distribution after 6 hours and distribution of 10
`ug / g or more was observed as KP - 363 in the
`epidermal layer and it was evident that KP-363 has
`high retention in the skin and it was suggested that
`KP - 363 exerts its effect sufficiently once a day for
`that
`external application.
`It
`is well known
`percutaneous absorption has trans-appendage (Hair
`transfusion IP absorption, hair growth absorption)
`Its
`absorption and
`transepidermal absorption.
`on
`absorption
`pattern
`is mainly
`based
`transepidermal absorption, those with absorption of
`hair follicle mainly, and mixed type.7) ~9) In the case
`the parasitic part of the
`of aseptic mycosis,
`pathogenic bacteria is extremely shallow, and it is
`restricted only in the stratum corneum and partly in
`the hair follicle. Therefore, it is ideal that drugs are
`distributed only to the same part but as clearly
`shown in Fig. 1, distribution of extremely high
`concentration of drug was observed in 6 and 24
`hours on the epidermal stratum corneum layer for
`several microns from the skin surface, and there are
`not many studies in this field in the past but
`sebaceous glands near 200 to 400 um are high as
`this medicine is also absorbed by hair follicle and it
`is inferred that in the guinea pig there is a large
`number of hair follicles that it is higher than
`pigs.7)~9) The peak at 1,000 to 1,500 um deep after
`24 hours in Figure 1 tells us that the labeling
`substance that penetrated deep into the hair follicle
`is at this level during that time. Thus, it can be seen
`that this product is active both in absorption through
`the hair follicle and in the epidermis.
`When the percutaneous absorption of KP-363 was
`observed using liquid scintillation graph, the agent
`was at high level in the epidermis part even after 6
`and 24 hours and it penetrates into the hair follicle
`and is a substance having a nature that it transfers
`into the sebaceous gland and eventually into the hair
`follicle. In addition, in adsorption experiments on
`hair sweat as a model of keratin, since it shows high
`adsorption, the role of the stratum corneum in the
`epidermal storage site is considered to be high and it
`was inferred that it can exert its preventive effect
`against parasitic bacteria which cause antimicrobial
`activity for 24 hours against parasitic bacteria living
`
`in the stratum corneum and live in the hair follicle
`and cause recurrence the following year.
`I would like to acknowledge Professor Takahashi of
`Teikyo University School of Medicine Department
`of Teikyo University Medical School who gave me
`guidance and review of this research.
`
`Reference
`1) Takahashi Hisashi: Problems of anti-fungal
`topical medicine, Therapeutics 20: 435-439, 1988.
`2) Maeda T et al: Synthesis and antifungal activity
`of butenafine hydrochloride (KP - 363), a new
`benzylamine antifungal agent. Chem Pharma Bull is
`posting.
`3) Arika T et al; Effects of butenafine (KP-363), a
`new benzylamine derivative, on experimental
`dermato-phytosis in guinea pigs. Antimicrob Agents
`Chemother
`Posting.
`4) Arika T et al: Effects of butenafine (KP-363), a
`new benzylamine derivative, on experimental tinea
`pedis of guinea pigs. Antimicrob Agents Chemother
`now submitted
`5) Takahashi Hisashi: Some considerations on the
`action of anti-tinea psyllium for external application.
`Journal of Nikka 82: 421137, 1972.
`6) Freedman MHt Baxter RM and Walker GC: In
`vitro adsorption of griseofulvin by keratin substrates.
`J Invest Dermatol 38: 199-208, 1962.
`7) Hisashi Takahashi et al: Percutaneous absorption
`of isotubic-labeled antibiotic soft sound, Journal of
`Japan Society 85: 517-524, 1975.
`8) Hisashi Takahashi et al: On the hair absorption of
`salicylic acid, Journal of Nikka 85: 413-415, 1975.
`9) Takahashi H et al: in vitro and in vivo evaluation
`of antifungal agents, (Iwata. K. and H. Vanden
`Bossche. Ed), Elsevier Publishers, Amsterdam,
`1986, 227-240.
`10) Bronaugh RL and Maibach HI: Percutaneous
`absorption-mechanism-method logy-drug delivery,
`Marcel Decker, New York, 1985, 1-579.
`(Receipt on March 5, 1990 · special mention)
`
`Request for reprinting: 〒 607 Kyoto City Yamashina-ku,
`Shinonomiya Minamikawara-machi 14 Central Research
`Laboratory, Kagaku Seiyaku Co., Ltd.
`Authorized
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 6 of 13
`
`

`

`Nishi Nihon Journal of Dermatology Vol. 52/3/1990
`
`Activity of Topical Antifungals on Infected Sites —Skin Permeability and Adsorption to Horny Materials—
`
`Anti-fungal agent for external use
`
`549
`
`Tadashi ARIKA，Toyoji HASE and Mamoru YOKOO
`
`Central Research Laboratories, Kaken Pharmaceutical Co., Ltd.
`
`Kyoto 607, Japan (Director: Dr. M. Nakanishi)
`
`The permeability and retentivity of butenafine hydrochloride (KP-363, N-4-tert-butylbenzyl-N-methyl -1-
`naphthalenemethylamine hydrochloride) on the skin layer of guinea pigs were examined following percutaneous
`application. Two-tenths ml of a 1% 14C-KP-363 solution was applied for 6 hours on a hair removed area of the
`dorsal skin of guinea pigs. At 6 hours after application, a high radioactivity corresponding to 50 µg/g or more of
`KP-363 was observed in the epidermis including the horny layer in which dermatophytes were lodged. Even at
`24 hours, 10 µg/nil or more of KP-363 still remained in the horny layer, indicating its high affinity to and long
`retention in this layer. Furthermore, the adsorption of various antifungal agents to the horny materials was also
`examined using powdered human hair. KP-363, tolnaftate, clotrimazole and bifonazole showed a strong
`adsorption to the hair. Anti- Trichophyton mentagrophytes activity of the agents decreased when adsorbed into
`the hair; i. e. the activity of KP-363 (MIC 0.0125 µg/ ml in Sabouraud dextrose broth) dropped to 4.0 µg/g hair,
`tolnaftate (0.05 µg/ml) to 15.6 µg/g, clotrimazole (0.39 µg/ml) to 62.5 µg/g and bifonazole (0.39 µg/ml) to 62.5
`µg/g. It was, however, clarified that the concentration of KP-363 in the horny layer after topical application of
`1% solution was high enough to inhibit the growth of T. mentagrophytes.
`
`______________________________________________________
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Page 7 of 13
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`The Nishinihon Journal of Dermatology
`FUKUOKA JAPAN
`
`ISSN 0386-9784
`
`Vol. 52/1990
`
`
`
`Necrotizing Fasciitis-:::::ssscrsserrrrsrttreeeseeeeeseeneeeeesseescees Thebes eee e cee eeeeneneeteeresneseeuenseeesenenesBEG HA+fit--- 449
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`Subject US Copyright Lerws
`
`Page 8 of 13
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`{the 540
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`Page 8 of 13
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`

`

`(PG ABZ] + 5228 3 4 + 1990)
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