`
`TRANSPERFECT
`
`County of Kings, City of New York, State ofNew York
`
`Translation Certificate
`
`1, Philip Schnell, am fluent in the Japanese and English languages and have
`personal knowledge of the facts stated herein.
`
`
`
`Sworn to before me this
`
`lst day of November 2019
`
`M S
`
`ignature, Notary Public
`
`GENEROBER‘IS
`mmmumm
`mammal
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`thmm 'LL
`Managua).
`
`Stamp, Notary Public
`
`LANGUAGE AND TECHNOLOGY SOLUTIONS FOR GLOBAL BUSINESS
`THREE PARK AVENUE, 39TH FLOOR, NEW YORK, NY 10016 | T 212.689.5555 | F 212.689.1059 |
`WWW.TRANSPERFECT.COM
`OFFICES IN 80 CITIES WORLDWIDE
`
`Page 1 of 37
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`{54) Title: SUSTAINED RELEASE PREPARATIONS
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`(57) Abstract: pH-independent sustained release preparations capable of releasing a drug independently from the pH value in the
`gastric tract. These sustained release preparations are characterized in that a drug-containing core is coated with 1) a first layer made
`of a water-insoluble polymer, and 2) a second layer made of an enteric polymer and a water-soluble polymer.
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`6
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`wo 01/76557
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`7
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`3 3 7 . 5
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`
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`5
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`25
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`wo 01/76557
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`PCT/JPOl/03024
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`8
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`10
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`wo 01/76557
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`9
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`25
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`x -r Jv-tJv o- .All<~¥;~
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`wo 01/76557
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`
`11
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`*JlfiX ( 1 1)
`:J- ?' 7 1) Jv~:J~ 1) ?~ L D
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`15
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`25
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`(li!fl%71' : 2 7 g)
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`g
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`wo 01/76557
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`12
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`~Dfl!fjtl7
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`:1Ji!~::ct~, vi:G70:i=---Jf~/~B';ff9~~Jm*'19 10 g~1~ko
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`~iifJ:/0\ G, *JlPX: ( 1 4) 0) :J -7-1 /?"~~A 7° v- G, J!~::*JlPX; ( 1 5) 0) :J -7
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`wo 01/76557
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`(12) International Application Published Under the Patent Cooperation Treaty
`
`(19) World Intellectual Property
`Organization
`
`International Bureau WWWWMWWWWWWWWMWM
`
`(10) International Publication Number
`WO 01/76557 Al
`PCT
`(43) International Publication Date
`October 18, 2001 (10.18.2001)
`(74) Agent: NAKAMURA, Toshio; c/o Sumitomo
`(51) International Patent Classification7: A61K 9/14,
`Pharmaceuticals CO., Ltd. Intellectual Property Department,
`9/16, 9/36, 47/32, 47/38, 31/4178, 31/496, 31/506, 31/5377
`1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka-511i,
`Osaka—fu 554-0022 (JP).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ,
`DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR,
`HU, ID, IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR, LS, LT,
`LU, LV, MA, MD, MG, MK, MN, MW, MX, M2, NO, NZ,
`PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT,
`TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`(84) Designated States (regional): ARIPO patent (GH, GM, KE,
`LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian patent
`(AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European patent
`(AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, BR, IE, IT, LU,
`MC, NL, PT, SE, TR), OAPI patent (BF, Bl, CF, CG, CI,
`CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Documents published with:
`— International search report
`
`(21) International Application
`Number:
`
`(22) International Filing Date:
`
`PCT/JP01/03024
`
`April 9, 2001
`(04.09.2001)
`
`(25) International Filing Language:
`
`Japanese
`
`(26) International Publication Language:
`
`Japanese
`
`(30) Priority Data:
`Patent Application 2000-107671, April 10, 2000
`(04.10.2000) JP
`
`(71) Applicant (for all designated states except US):
`SUMITOMO PHARMACEUTICALS CO., LTD.
`[JP/JP]; 2—8 Dosho-machi 2-chome, Chuo-ku, Osaka-
`shi, Osaka-fu 541-8510 (JP).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): NISHII,
`Hiroyuki [JP/JP]; 51—11 Ankoji-cho 4-chome,
`Takatsuki—shi, Osaka-fu 569—1029 (JP).
`KOBAYASHI, Hirohisa [JP/JP]; 12—10 Nakatsu-
`cho, Ibaraki-shi, Osaka-fu 567—0824 (JP). OTODA,
`Kazuya [JP/JP]; 1-10 Nakayama Sakuradai S-chome,
`Takarazuka—shi, I'Iyogoeken 665—0877 (JP).
`
`
`For two~letter codes and other abbreviations, refer to the
`“Guidance Notes on Codes and Abbreviations” appearing at
`the beginning of each regular issue of the PCT Gazette.
`
`[bilingualz] (54) Title of the invention: SUSTAINED RELEASE PREPARATIONS
`
`[bilinguah]
`(57) Abstract: pll-independent sustained release preparations capable of releasing a drug independently from the pll value in the
`gastric tract. These sustained release preparations are characterized in that a drug-containing core is coated with l) a first layer made
`of a water-insoluble polymer, and 2) a second layer made of an enteric polymer and a water-soluble polymer.
`
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`1
`
`DESCRIPTION
`
`SUSTAINED RELEASE PREPARATIONS
`
`Technical field
`
`The present invention relates to pH—independent sustained release preparations of basic drug substances,
`
`or salts thereof, which have lower solubility in intestinal juice than in gastric juice.
`
`Background art
`
`Many basic drug substances and salts thereof exhibit valying solubility depending on the pH and
`
`composition of the dissolution medium. Therefore, sustained release preparations of such drugs often have
`
`irregular release characteristics depending on pH changes in the gastrointestinal tract, individual differences
`
`in pH of digestive juices, and the like. Many attempts have been previously made to resolve this problem.
`
`For example, for drug substances which have solubility that is high near the pH of gastric juice and decreases
`
`going towards the pH of intestinal juice, the method of dispersing the drug substance in an enteric ingredient,
`
`the method of incorporating acidic ingredients along with the main drug in the pharmaceutical preparation
`
`(Japanese Unexamined Patent Application Publication H2—223533, Japanese Unexamined Patent Application
`
`Publication H3-204810, etc.), and the like have been disclosed.
`
`However, with these techniques, release control is provided by the matrix, so single-unit formulations
`
`such as tablets have to be used, and it is generally assumed that incorporation of acidic ingredients may harm
`
`the stability of the main drug. Furthermore, osmotic pumps (Japanese Unexamined Patent Application
`
`Publication SSS-16259, etc.) are known as a method more reliably applicable to a broad range of drug
`
`substances, but these require an extremely complicated production process in many cases. Furthermore, the
`
`technique of coating an inner core with a double layer of water-insoluble polymer and enteric polymer
`
`(Japanese Patent No. 2657057) has been disclosed, but this achieves selective dissolution in the intestines
`
`and is far from providing a formulation which exhibits pH-independent dissolution.
`
`Therefore, the development of pH-independent sustained release preparations which can be produced by
`
`the usual methods and in which the release of drug substance will not be affected by pH in the
`
`gastrointestinal tract has been desired.
`
`Disclosure of the invention
`
`The present inventors, as a result of concerted research efforts intended to resolve the aforementioned
`
`problem, discovered that sustained release preparations exhibiting a pH-independent dissolution profile can
`
`be obtained by coating an inner core containing the drug substance with a first layer comprising a sustained
`
`release polymer and a second layer comprising an enteric polymer and a water—soluble polymer, and
`
`completed the present invention.
`
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`Namely, the present invention is as follows.
`
`(1) A sustained release preparation characterized in that an inner core which contains a drug
`
`substance is coated with 1) a first layer comprising a water—insoluble polymer and 2) a second layer
`
`comprising an enteric polymer and a water—soluble polymer.
`
`(2) The sustained release preparation as set forth in (1), wherein the drug substance is a basic drug
`
`substance or a salt thereof.
`
`(3) The sustained release preparation as set forth in any one of claims ( 1) through (2), wherein the
`
`first layer comprises a water-insoluble polymer and a water-soluble substance.
`
`(4) The sustained release preparation as set forth in any one of (1) through (3), wherein the water—
`
`insoluble polymer of the first
`
`layer is ethyl cellulose, an aminoalkyl methacrylate copolymer, or
`
`cellulose acetate.
`
`(5) The sustained release preparation as set forth in any one of (1) through (4), wherein the enteric
`
`polymer of the second layer is hydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose
`
`acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, a methacrylic acid—methyl
`
`methacrylate copolymer, or a methacrylic acid~ethyl acrylate copolymer
`
`(6) The sustained release preparation as set forth in any one of (1) through (5), wherein the water-
`
`soluble polymer of the first layer and second layer is hydroxypropyl methyl cellulose, hydroxypropyl
`
`cellulose, methyl cellulose, polyvinyl pyrrolidone, or polyvinyl alcohol.
`
`(7) The sustained release preparation as set forth in any one of (1) through (6), wherein the weight
`
`ratio of water—insoluble polymer to water—soluble polymer in the first layer is between 1:0 and 1:1.
`
`(8) The sustained release preparation as set forth in any one of (1) through (7), wherein the weight
`
`ratio of enteric polymer to water-soluble polymer in the second layer is between 1:0.05 and 1:1.
`
`(9) The sustained release preparation as set forth in any one of (1) through (8), wherein the weight
`
`ratio of the first layer to the second layer is between 1:0.1 and 1:2.
`
`(10) The sustained release preparation as set for