TRANSPERFECT
`
`AFFIDAVIT OF ACCURACY
`
`I, Ashley Braun, hereby certify that the following is, to the best of my knowledge
`and belief, a true and accurate translation of the enclosed documents from
`Japanese into English:
`
`"New Drugs in Japan- 2001"
`
`Ashley Braun
`TransPerfect Translations, Inc.
`700 61
`h Street NW
`Washington, DC 20001
`
`Sworn to before me this
`7th day of February 2014
`
`LISA CHAN
`NOTARY PUBLIC
`District of Columbia
`My Commission Expires Feb. 14. 2018
`
`,,,,. ,t t•unh,,,.
`"•,..
`,~''
`
`Stamp, Notary Public
`•. ·····~ •. -:-ic"·· . .t$;>.. Washington, D.C.
`···.' .\
`!:i!':~~v
`· ,..) :'Q.
`. "'~ \ ·'\
`'j .....
`.
`.
`.
`. ...
`of : ,._ ~ '< f'J
`:
`: l.l
`~, : d: . ~ r.
`...J
`';fi··~ ~~., .. ~ .: . )
`r1~ ··.~ON'" / .1<
`.. .:t:,f:··.!·· ·•··!···~ .
`'·-'J};:" ,, ((.~,.
`
`~..w-
`700 6TH STREET, NW, 5TH FLOOR, W ASHINGTO N, DC 20001 I T +1 202.347.2300 I F +1 202.347.6861 l WWW.TRANSPERFECTLEGAL.COM
`O FFICES IN 80 CITI ES WO RLDWIDE
`
`LUPIN EX 1053
`
`Page 1 of 6
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Recent New Drugs
`2001
` Japanese Pharmacopoeia
` 2001 Edition
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Yakuji Nippo Limited
`
`
`
`Page 2 of 6
`
`

`
`Preface to “Recent New Drugs 2001”
`
`During the half-century since 1949, “Recent New Drugs” has annually collated, edited and published
`
`newly approved and newly marketed pharmaceuticals (for medical and non-prescription uses) in the broadest
`possible scope.
`On the occasion of the 50th anniversary of the inaugural issue in 2000, the character of a “new drug
`
`yearbook” introducing pharmaceuticals newly put on the market during the previous year was more sharply
`defined, and a new start was made by updating listing methods, classifications, and appearance, as well as
`enlarging the format to B5-size. “Recent New Drugs 2001” – the second volume since the relaunch – is an
`introductory new drug yearbook which collects, classifies, and arranges in the broadest possible scope the new
`drugs (for medical and non-prescription uses) that were approved and newly marketed during the previous year
`(2000) within Japan.
`
`Editorial guidelines are as follows.
`1. Classification method
`
`Listed pharmaceuticals are broadly classified into: I. pharmaceuticals containing new active ingredients
`(new substances) (excluding new administration routes and new standards); II. newly marketed
`pharmaceuticals for medical use (excluding the pharmaceuticals containing new active ingredients of I); and
`III. non-prescription pharmaceuticals. Medical-use pharmaceuticals are arranged by pharmacoefficacy
`classification in conformity with the Japan Standard Commodity Classification (June 1990 Revision), and non-
`prescription pharmaceuticals broadly conform to the order of the “Standards for manufacturing (importation)
`approval of non-prescription pharmaceuticals” with suitable adjustments.
`2. Listing system
` With respect to pharmaceuticals containing new active ingredients, not only are package inserts (including
`reference literature) recorded for the pertinent pharmaceuticals, but also the development background,
`reexamination period, basis for drug price calculation, and so on.
` With respect to other medical-use pharmaceuticals, there is listing of efficacy/effects, usage/dosage,
`foreign name of pertinent product, regulation, manufacturing (import sales) origin / sales (marketing) origin,
`approval date, sales initiation date, date of price listing, price standard listing pharmaceutical code, and
`packaging, and this is done by unit of generic name classified/arranged in the order of pharmacoefficacy
`classification.
`
`Beginning with this issue, we have created a page for introducing pharmaceuticals with newly added
`efficacies (medical-use pharmaceuticals that have been given added efficacy during January-December 2000).
` With respect to non-prescription pharmaceuticals, there is listing of manufacturing (import sales) origin /
`sales (marketing) origin, approval date, sales initiation date, product characteristics, ingredients and quantities,
`additives, usage/dosage, and packaging.
`3. Descriptive content
`
`“Cautions for use” pertaining to pharmaceuticals containing new active ingredients are in principle
`recorded as in the description of the package insert, and are omitted with respect to other new drugs. The
`method for tracing to back numbers of this publication was discontinued. The so-called commentary up to the
`50th compilation is not included in the editing of package insert compliance.
`
`As described above, publication was made as a “new drug yearbook” of what was newly approved and
`marketed over a one-year period, and we await the comments and requests of all our readers with respect to
`this volume.
`
`This volume was edited based on the studies and information gathering conducted by our company with
`respect to the various pharmaceutical manufacturing / sales (marketing) companies. Hereafter, we will request
`a still greater number of pharmaceutical companies to cooperate with our studies.
`
`Finally, we would like to express our deep gratitude to all our readers and all the pharmaceutical
`companies that have cooperated with our studies over this past half-century to the present, and to Tohoku
`University Honorary Professor Mitsuru Ozawa who has written for us over the half century since the inaugural
`issue, and who also provided useful advice on the occasion of this edition.
` We appeal for the cooperation and support of everyone as we seek to further enhance this publication.
`
`May 2001
`
`Yakuji Nippo Limited
`
`- i -
`
`Page 3 of 6
`
`

`
`Acitazanolast hydrate
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`(Remarks)
`as pruritus and conjunctival chemosis due to allergic
`Product characteristics
`conjunctivitis
`(1) It is an ophthalmic solution of Acitazanolast
`(3) Inhibits release of platelet-activating factors
`which is an in vivo activating metabolite of the oral
`(PAF), histamine, leukotriene B4, leukotriene D4 (in
`vitro; rats, guinea pigs)
`anti-allergic agent Tazanolast.
`(2) Improves subjective and objective symptoms such
`
`Bromfenac sodium hydrate
`Non-steroidal anti-inflammatory ophthalmic agent
`
`Sales initiation
`July 3, 2000
`
`Price listing
`May 2, 2000
`
`Price code
`1319743Q1025
`
`Approval No.
`21200AMZ00168
`
`Japan Standard Commodity Classification No.
`871319
`Bronuck ophthalmic solution – Bronuck (Instructions) (Notations) Senju Pharmaceutical Co. (manufacture) –
`Takeda Pharmaceutical Co. (sale)
`
`Approval date
`
`March 10, 2000
`
`[Development background]
` With respect to treatment of ocular inflammation,
`both steroidal ophthalmic agents and non-steroidal
`anti-inflammatory drug (NSAID) ophthalmic agents
`are currently in general use. However, compared to
`steroidal ophthalmic agents, there are fewer types of
`NSAID ophthalmic agents, and options are limited.
`Thus, development of NSAID ophthalmic agents
`having broad efficacy and strong anti-inflammatory
`action relative to inflammatory ailments of the
`external eye and anterior eye is desirable.
` Bromfenac sodium hydrate which is the active
`ingredient of Bronuck ophthalmic solution was
`discovered by A.H. Robins Co. (now Wyeth-Ayerst
`Co.) as a novel NSAID that powerfully inhibits
`production of prostaglandin which is an inflammatory
`mediator. By modifying bromine at the 4th position of
`the benzoyl group of Amfenac, which is the basic
`skeleton,
`this drug strives
`to
`reinforce anti-
`inflammatory action and sustain analgesic action.
` Focusing on this strong prostaglandin production
`inhibiting
`action, Senju Pharmaceutical Co.
`proceeded with development of this drug from 1987.
`Bronuck ophthalmic solution was approved in March
`2000 as a symptomatic therapeutic agent that is
`effective at two ocular instillations per day with
`respect
`to blepharitis,
`conjunctivitis,
`scleritis
`(including
`episcleritis),
`and
`postoperative
`inflammation.
`[Reexamination period] 6 years
`
`[Contraindication (do not administer to the following
`patients)]
`Patients with a previous history of hypersensitivity to
`ingredients of this drug
`
`Formulation
`Color
`pH
`Other
`[Efficacy / effects]
` Symptomatic treatment of inflammatory ailments of
`the external eye and anterior eye (blepharitis,
`conjunctivitis, scleritis (including episcleritis), and
`postoperative inflammation)
`[Usage /dosage]
` Ordinarily, 1-2 drops per administration, and 2
`ocular instillations per day.
`[Cautions for use]
`1. Important basic cautions
`(1) Keeping in mind that treatment by this drug is
`symptomatic treatment rather than causal treatment,
`and that it is reported that serious liver damage
`(including death) has been observed in patients
`subjected to long-term administration of 1 month or
`more with the oral agent of bromfenac sodium,
`continuous administration of 4 weeks or more is in
`principle not conducted. Although the aforementioned
`adverse effects observed with the foreign oral agent
`were due to long-term administration exceeding the
`approved usage and dosage, sales have been
`voluntarily suspended.
`(2) As there is risk that eye infection may become
`inapparent, in case of use on inflammation resulting
`
`[Composition / Properties]
`Ingredients / content
`Bromfenac sodium hydrate 1 mg
`(in 1 ml)
`Additives
`
`Boric acid, borax, dried sodium
`sulfite, sodium edetate,
`povidone, polysorbate 80,
`benzalkonium chloride
`Aqueous ophthalmic agent
`Clear yellow
`8.0-8.6
`Aseptic preparation
`
`- 27 -
`
`Page 4 of 6
`
`

`
` Novel Substances • Drugs Affecting Sensory Organs
`
`Bromfenac
`sodium hydrate
`
`concentration
`
`Cornea
`
`Conjuctiva
`
`Anterior sclera
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`from infection, administration is to be conducted
`carefully with sufficient observation.
`2. Adverse effects
` At the time of approval, adverse effects had been
`observed in 16 out of a total of 423 cases (3.78%).
` With respect to the content of adverse effects, there
`were 3 cases of blepharitis (0.71%), 3 cases of
`conjunctival hyperemia (0.71%), 3 cases of irritation
`(0.71%), 3 cases of ocular pain (temporary) (0.71%),
`2 cases of corneal inflammation (0.47%), 1 case of
`corneal epithelial abrasion (0.24%), 1 case of
`superficial punctate keratitis (0.24%), 1 case of
`conjunctival follicle (0.24%), 1 case of pruritus
`(0.24%), and 1 case of heat sensation (eyelids)
`(0.24%) (at the time of approval).
` The following adverse effects were observed in the
`foregoing study.
` 0.1% to less than 5%
`hyperemia,
`conjunctival
` Ocular*
`blepharitis,
`irritation,
`ocular
`pain
`(temporary),
`corneal
`inflammation, corneal epithelial abrasion, superficial
`punctate keratitis, conjunctival follicle, pruritus, and
`heat sensation (eyelids)
`*When manifested, administration is suspended.
`3. Administration to pregnant, parturient, and
`nursing women
` Administration is to be conducted to pregnant
`woman or women who may have conceived and to
`women who are nursing only when it is judged that
`the benefits of treatment outweigh the risks.
`(The safety of administration during pregnancy and
`lactation has not been established.)
`4. Administration to children
` Safety relative to children has not been established
`(there is little experience with use).
`5. Cautions for use
`(1) Administration route: only to be used for ocular
`installation
`(2) At
`time of administration: during ocular
`installation, take care so that the tip of the container
`does not directly contact the eye.
`[Pharmacokinetics]
`(Reference)
`Intraocular migration <rabbits>1)
` In testing wherein ocular installation of 0.05 mL of
`0.1% 14C-bromfenac sodium hydrate ophthalmic
`solution was conducted once a day to both eyes of a
`rabbit, and radioactivity was measured after 15
`minutes, 30 minutes, and 1, 2, 4, 8, 12, 24, 48, and 72
`hours, elevated values were observed in the cornea,
`conjunctiva, and anterior sclera.
` At 72 hours after ocular installation, all ocular
`tissue except for the lens was below the detection
`limit (0.1 ng eq./g or ml).
`
`Hours after ocular instillation
`[Clinical effects]
` A summary of results with respect to 291 cases
`including double-blind comparative testing are shown
`in the table.
` For the most part, daily dosage and administration
`period were 1 drop per administration and 2
`administrations per day over a 2-week period.
`Table: Clinical effects by ailment
`Name of ailment
`Efficacy rate (%) and
`effectiveness
`66.7 (6/9)
`Blepharitis
`63.2 (60/95)
`Conjunctivitis
`63.6 (7/11)
`Scleritis (including episcleritis)
`86.4 (152/176)
`Postoperative inflammation
`77.3 (225/291)
`Total
`[Pharmacoefficacy and pharmacology]
`1. Pharmacological action
`(1) Experimental anti-inflammatory action relative to
`conjunctival chemosis in rats2)
`It was observed that Bronuck ophthalmic solution
`exhibited anti-inflammatory action
`relative
`to
`experimental acute conjunctival chemosis in rats
`induced by arachidonic acid and carrageenin.
`(2) Inhibitory effects relative to increases in aqueous
`humor protein concentration in rabbits after anterior
`chamber paracentesis or after laser irradiation2)
`It was observed that Bronuck ophthalmic solution
`almost completely inhibited increases in aqueous
`humor protein concentration in rabbits after anterior
`chamber paracentesis or after laser irradiation.
`2. Mechanism of action
`In tests using rabbit iris-ciliary bodies2) and bovine
`seminal vesicles, it was confirmed that inhibitory
`action was
`exhibited
`against production of
`prostaglandin
`inflammatory
`mediators
`via
`cyclooxygenase (in vitro).
`[Physicochemical
`findings relative
`ingredients]
`Generic name: Bromfenac Sodium Hydrate (JAN)
`- 28 -
`
`
`(hours)
`
`to active
`
`Page 5 of 6
`
`

`
`
`
`Dorzolamide Chloride
`
`
`Chemical name: sodium 2-amino-3-(4-bromobenzoyl)
`phenylacetate sesquihydrate
`Molecular formula: C15H11BrNNaO3 ⋅ 1½ H2O
`Molecular weight: 383.17
`Structural formula:
`
`expiration date, to be used promptly after opening).
`•According to package insert prepared in May 2000
`[Drug price] 0.1% 1 mL 139.00 yen, price
`determination by comparable drug (comparable drug:
`Niflan ophthalmic solution (Pranoprofen))
`[Comments]
`Product characteristics
`(1) Efficacy has been confirmed with respect to
`inflammatory ailments of the external eye and the
`anterior eye (efficacy rate 77.3%)
`(2) Anti-inflammatory action is exhibited against
`post-operative inflammation, and inhibits occurrence
`of aqueous humor protein (flare)
`(3) Remission of symptoms is observed by third day
`of administration with respect
`to
`inflammatory
`ailments of the external eye
`(4) Anti-inflammatory action is exhibited with respect
`to experimental conjunctival chemosis (rats) and
`experimental post-operative inflammation (rabbits)
`(5) Cyclooxygenase is blocked, and production of PG
`inflammatory mediators beginning with prostaglandin
`(PG) E2 is inhibited (rabbits, cows in vitro)
`(6) Efficacy is observed with 2 ocular instillations per
`day.
`
`
`
`
`Properties: Bromfenac Sodium Hydrate is an odorless
`crystalline powder of yellow-orange color.
`It easily dissolves in water, and somewhat easily
`dissolves in methanol, but dissolves with difficulty in
`ethanol anhydride, and hardly dissolves at all in
`acetonitrile or ether.
`[Packaging]
`5 mL × 10, 5 mL ×50
`[Principal literature]
`1) Mitsuyoshi Isaka et al.: Pharmacokinetics, 14 (1)
`32, 1999.
`2) Takahiro Ogawa et al.: Journal of Japan
`Ophthalmology Society, 99, 406, 1995.
`[Storage method] Room temperature storage
`[Expiration] To be used within the expiration date
`displayed on the exterior package (even within
`
`
`
`- 29 -
`
`Page 6 of 6