`
`(19) World Intellectual Property Organization
`International Bureau
`
`26 April 2001 (26.04.2001) URACA
`
`(43) International Publication Date
`
`(10) International Publication Number
`WO 01/28563 Al
`
`
`(51) International Patent Classification’:
`9/51, 47/38
`
`AG61K 31/58,
`
`ISHIDA, Takashi et al.; A. Aoki, Ishida &
`(74) Agents:
`Asscoiates, Toranomon 37 Mori Bldg., 5-1, Toranomon
`3-chome, Minato-ku, Tokyo 105-8423 (JP).
`
`(22) International Filing Date: 20 October 2000 (20.10.2000)
`
`(21) International Application Number:=PCT/JP00/07351
`(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, MZ, 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.
`
`.
`(25) Filing Language:
`
`(26) Publication Language:
`
`.
`English
`
`English
`
`(30) Priority Data:
`11/298186
`
`20 October 1999 (20.10.1999)
`
`JP
`
`(71) Applicant(for all designated States except US): TEIJIN
`LIMITED [JP/JP]; 6-7, Minamihommachi 1-chome,
`Chuo-ku, Osaka-shi, Osaka 541-0054(JP).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): NAGANO, At-
`suhiro [JP/JP]; Teijin Limited, Tokyo Research Center,
`3-2, Asahigaoka 4-chome, Hino-shi, Tokyo 191-0065 (JP).
`NISHIBE, Yoshihisa [JP/JP]; Teijin Limited,
`Iwakuni
`Research Center, 2-1, Hinode-cho,
`Iwakuni-shi, Yam-
`aguchi 740-0014 (JP). TAKANASHI, Kazuya [JP/JP];
`Teijin Limited, Tokyo Research Center, 3-2, Asahigaoka
`4-chome, Hino-shi, Tokyo 191-0065 (JP).
`
`(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, GR,IE,
`IT, LU, MC,NL,PT, SE), OAPI patent (BF, BJ, CF, CG,
`CI, CM, GA, GN, GW, ML, MR,NE,SN, TD, TG).
`
`Published:
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments.
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`
`
`(54) Title: CICLESONIDE-CONTAINING AQUEOUS PHARMACEUTICAL COMPOSITION
`
`RAATAE
`
`01/28563Al
`
`© (57) Abstract: The present invention provides an aqueous pharmaceutical composition containing ciclesonide and hydroxypropyl-
`methylcellulose, wherein the ciclesonide is dispersed in an aqueous medium in the form ofsolid particles. The compositionis able to
`avoid variations in the concentrations of ciclesonide during production as well as avoid decreases in the recovery rate of ciclesonide.
`Exhibit 1156
`Exhibit 1156
`IPR2017-00807
`IPR2017-00807
`ARGENTUM
`ARGENTUM
`
`000001
`
`000001
`
`
`
`WO 01/28563
`
`PCT/JP00/07351
`
`DESCRIPTION
`
`CICLESONIDE-CONTAINING AQUEOUS PHARMACEUTICAL COMPOSITION
`
`Field of Invention
`The present invention relates to a ciclesonide-
`containing aqueous pharmaceutical composition for use in
`drug therapy that contains ciclesonide and
`hydroxypropylmethylcellulose, wherein said ciclesonide is
`dispersed in an aqueous medium in the form of solid
`particles. More particularly,
`the present invention
`relates to a ciclesonide-containing aqueous
`pharmaceutical composition having excellent ciclesonide
`dispersivity during production as compared with
`conventional aqueous pharmaceutical compositions.
`Background Art
`Ciclesonide aqueous pharmaceutical compositions
`containing ciclesonide dispersed in an aqueous medium in
`a form of solid particles are expected to represent a
`useful drug form for reasons that include 1) it is not
`necessary to completely dissolve ciclesonide, 2) it can
`be directly administered to an affected site by spraying
`and so forth for treatment of local diseases such as
`those of the nasal mucosa, eyes and epidermis, and 3)
`they are easier to swallow than tablets or granule and so
`forth.
`When present in an aqueous medium, ciclesonide is
`resistant to wetting and easily aggregates.
`The addition
`of wetting agent such as Polysorbate 80 and powerful
`stirring and so forth during production have been used in
`the prior art for the purpose of dispersing drug having
`such properties in an aqueous medium in a stable state.
`Improvement of drug dispersivity of aqueous
`pharmaceutical compositions containing a drug dispersed
`in an aqueous medium in form of solid particles by
`addition of cellulose-based polymer is disclosed in
`Morishima et al. patent specification of WO99-37286.
`However,
`this patent relates to the redispersion of a
`
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`drug that has settled during storage, and is
`fundamentally different from the present invention which
`relates to overcoming drawbacks of the migration of
`ciclesonide towards bubbles formed by powerful stirring
`during the production, and the adsorption of ciclesonide
`to the walls of the production apparatus. Moreover,
`the
`concentration of the cellulose-based polymer in the
`patent specification of Morishima et al.
`is 0.0001 to
`0.003%, and methylcellulose can be used in place of
`hydroxypropylmethylcellulose for the cellulose-based
`polymer, while the addition of a nonionic surfactant is
`also required.
`It is not easy to deduce the present
`invention from this patent in which the optimum value of
`the hydroxypropylmethylcellulose concentration is from
`0.01% w/w to 0.5% w/w, and does not require a surfactant.
`Disclosure of the Invention
`During the course of production of ciclesonide
`aqueous pharmaceutical compositions, high shearing force
`is required to disperse ciclesonide and it is necessary
`to powerfully stir ciclesonide-containing aqueous
`pharmaceutical composition. Ciclesonide migrates to the
`bubbles formed at this time.
`Since this results in an
`
`increased concentration of ciclesonide in the upper
`portion of the ciclesonide aqueous pharmaceutical
`composition being higher than that in the lower portion,
`variation occurs in the ciclesonide concentration of
`ciclesonide aqueous pharmaceutical compositions produced.
`Moreover,
`the recovery rate decreases due to adsorption
`of ciclesonide to the walls and so forth of the
`
`production apparatus.
`These variations in ciclesonide concentration and
`adsorption of ciclesonide to the production apparatus
`were hardly improved at all by the addition of wetting
`agents such as Polysorbate 80 that have been used in the
`prior art. Conversely,
`the amount of formed bubbles
`increases resulting in promotion of further variation in
`ciclesonide concentration.
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`there is a considerable need for the
`Therefore,
`development of a ciclesonide aqueous pharmaceutical
`composition that is able to avoid variations in
`ciclesonide concentrations during production as well as
`
`the decrease in ciclesonide recovery rate.
`Namely,
`the object of the present invention is to
`provide a ciclesonide aqueous pharmaceutical composition
`that avoids variations in ciclesonide concentration
`during production as well as decreases in the ciclesonide
`
`recovery rate.
`As a result of earnest studies to solve the above
`problems,
`the inventors of the present invention found
`that a ciclesonide aqueous pharmaceutical composition can
`be provided that avoids variations in ciclesonide
`concentrations during production as well as decreases in
`the ciclesonide recovery rate, by using a ciclesonide
`aqueous pharmaceutical composition containing ciclesonide
`and hydroxypropylmethylcellulose,
`thereby leading to
`completion of the present invention.
`Namely,
`the present invention relates to an aqueous
`pharmaceutical composition containing ciclesonide and
`hydroxypropylmethylcellulose, wherein said ciclesonide is
`dispersed in an aqueous medium in form of solid
`particles.
`Embodiment for Carrying Out the Invention
`It is essential that composition of the present
`invention contain ciclesonide, while water-soluble,
`
`water-low soluble or water-insoluble drugs other than
`ciclesonide can be added. Specific examples of these
`include vasoconstrictors, bronchodilators, anti-allergic
`
`agents and expectorants.
`Although the ciclesonide particles that can be used
`in the present invention may be of any size,
`they are
`preferably within the range of 10 nm to 100 pum, and
`particularly preferably within the range of 10 nm to 10
`
`um.
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`Although any substances may be used for the water-
`insoluble or water-low soluble substance that can be used
`
`in the present invention, a preferable example is a
`cellulose, and a particularly preferable example is
`
`crystalline cellulose.
`the concentration of
`In the present invention,
`water-insoluble substance and/or water-low soluble
`
`substance present in form of solid particles in an
`aqueous medium is preferably 0.3% w/w and above, and
`particularly preferably 1% w/w to 10% w/w, relative to
`the total amount of the composition.
`In addition, an aqueous polymer substance can also
`be added in the present pharmaceutical composition.
`Specific examples of such include propylene glycol
`alginate, pectin,
`low methoxyl pectin, gua gum, gum
`arabic, carrageenan, methylcellulose,
`carboxymethylcellulose sodium, xanthan gum and
`hydroxypropylcellulose, while particularly preferable
`examples include carboxymethylcellulose sodium,
`In
`polyethylene glycol and hydroxypropylcellulose.
`addition, crystalline cellulose carmellose sodium,
`example of a combination of these water-soluble
`substances and water-insoluble substances that can be
`
`is an
`
`used in the present invention, and it consists of a
`mixture of carboxymethylcellulose sodium and crystalline
`cellulose.
`Furthermore,
`in the case of adding these
`water-soluble polymer substances,
`the concentration of
`said substance is preferably 1% w/w to 30% w/w relative
`to the water-insoluble substance and/or water-low soluble
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`
`substance.
`
`The ciclesonide-containing aqueous pharmaceutical
`composition of the present invention is also required to
`contain hydroxypropylmethylcellulose. Although this may
`be of any grade, a specific example is
`hydroxypropylmethylcellulose 2910.
`Although said hydroxypropylmethylcellulose may be
`present at any concentration, its concentration is
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`-5-
`
`preferably from 0.01% w/w to 30% w/w, particularly
`preferably from 0.01% w/w to 5% w/w, more particularly
`preferably from 0.01% w/w to 1% w/w, and most preferably
`from 0.01% w/w to 0.5% w/w, relative to the total amount
`
`of composition.
`A wetting agent, although not essential in the
`present invention, can be added, specific examples of
`which include Polysorbate 80, glycerin monostearate,
`polyoxyl stearate,
`lauromacrogol, sorbitan oleate and
`sucrose fatty acid esters.
`In the present invention, a substance for
`controlling osmotic pressure (osmotic pressure-
`controlling agent) can be added to control osmotic
`pressure, specific examples of which include salts such
`as sodium chloride and water-soluble sugars such as
`glucose, with glucose being a particularly preferable
`example.
`An effective amount of ciclesonide used in the
`present invention can be determined according to the type
`and degree of the respective disease, as well as the age
`and body weight of the patient, and so forth.
`The concentration of ciclesonide of the present
`invention is preferably from 0.01% w/w to 1% w/w, and
`particularly preferably from 0.05% w/w to 0.5% w/w,
`relative to the total amount of the composition.
`Any method for dispersing a water-insoluble
`substance and/or water-low soluble substance in an
`aqueous medium may be used for the production of the
`ciclesonide-containing aqueous pharmaceutical composition
`in the present invention, a specific example of which is
`a method that uses a homomixer.
`Known antiseptics, pH controlling agents,
`preservatives, buffers, colorants, smell corrigents and
`so forth may be added as necessary to the composition of
`the present invention to improve its physical properties,
`appearance or odor and so forth of the formulation.
`Examples of antiseptics include benzalkonium chloride,
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`examples of pH controlling agents include hydrochloric
`acid and sodium hydroxide, examples of preservatives
`include ascorbic acid, examples of buffers include
`phosphoric acid and its salt, examples of colorants
`include red dye no. 2, and examples of smell corrigents
`
`include menthol.
`
`According to the present invention as described
`above, a ciclesonide aqueous pharmaceutical composition
`is provided that avoids variations in ciclesonide
`concentration during production as well as decreases in
`the recovery rate of ciclesonide more effectively than
`aqueous pharmaceutical compositions of the prior art.
`These effects also lead to improved quality as well as
`
`decreased production cost due to the higher recovery
`rate.
`
`the present invention has extremely high
`Thus,
`significance in terms of both quality and economy for the
`production of ciclesonide aqueous pharmaceutical
`
`compositions.
`
`Examples
`The following provides an explanation of the present
`
`invention through its Examples.
`Ciclesonide used in the present invention was
`manufactured by Byk Gulden Co.,
`the crystalline cellulose
`carmellose sodium by Asahi Chemical Industry Co., Ltd.
`
`(Avicel™ RC-A591NF), hydroxypropylmethylcellulose 2910
`
`by Shin-Etsu Chemical Co., Ltd.
`
`(TC-5RW™ or Metrose
`
`60SH-4000™), Polysorbate 80 by Nippon Surfactant Co.,
`
`Ltd., and the sorbitan trioleate by Nikko Chemical Co.,
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`
`Ltd.
`
`ROBOMICS™ manufactured by Tokushu Kika Kogyo Co.,
`
`Ltd. was used for the homomixer.
`
`Example 1
`Ciclesonide aqueous pharmaceutical compositions
`containing the components indicated below were prepared
`on a 300 ml scale by processing with a homomixer.
`Homomixer processing was performed at 6000 rpm for 30
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`minutes.
`
`Composition (1)
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Hydroxypropylmethylcellulose 2910 (TC-5RW™):
`
`0.01% w/w
`
`Composition (2)
`
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Hydroxypropylmethylcellulose 2910 (TC-5RW™):
`
`0.1% w/w
`
`Composition (3)
`
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Hydroxypropylmethylcellulose 2910 (TC-5RW™):
`1% w/w
`
`Composition (4)
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Hydroxypropylmethylcellulose 2910 (Metrose 60SH-
`
`4000™): 0.01% w/w
`
`Composition (5)
`
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Hydroxypropylmethylcellulose 2910 (Metrose 60SH~
`
`4000™): 0.13 w/w
`
`Immediately after processing compositions 1 to 5
`with the homomixer,
`the ciclesonide aqueous
`pharmaceutical compositions were collected from the upper
`and lower portions of the emulsification tank,
`followed
`by quantification of the ciclesonide concentrations by
`HPLC.
`The value for the upper portion of the
`emulsification tank was calculated by taking the
`ciclesonide concentration in the lower portion of the
`
`emulsification tank to be 100%.
`
`Subsequently,
`
`the ciclesonide concentrations of the
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`ciclesonide aqueous pharmaceutical compositions recovered
`from the emulsification tank were quantified by HPLC, and
`the ciclesonide recovery rates were determined based on
`the theoretical value of the ciclesonide concentration as
`
`calculated from the charged amount.
`
`Those values are shown in Table l.
`
`Comparative Example 1
`Ciclesonide aqueous pharmaceutical compositions
`containing the components indicated below were prepared
`on a 300 ml scale by processing with a homomixer.
`Homomixer processing was performed at 6000 rpm for 30
`minutes.
`
`Composition (6)
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Polysorbate 80: 0.1% w/w
`Composition (7)
`Ciclesonide: 0.1% w/w
`Crystalline cellulose carmellose sodium: 1.7% w/w
`Sorbitan trioleate: 0.1% w/w
`Immediately after processing compositions 6 and 7
`with the homomixer,
`the ciclesonide aqueous
`pharmaceutical compositions were collected from the upper
`and lower portions of the emulsification tank,
`followed
`by quantification of the ciclesonide concentrations by
`HPLC.
`The value for the upper portion of the
`emulsification tank was calculated by taking the
`ciclesonide concentration in the lower portion of the
`
`emulsification tank to be 100%.
`Subsequently,
`the ciclesonide concentrations of the
`ciclesonide aqueous pharmaceutical compositions recovered
`from the emulsification tank were quantified by HPLC, and
`the ciclesonide recovery rates were determined based on
`the theoretical value of the ciclesonide concentration as
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`calculated from the charged amount.
`
`Those values are shown in Table l.
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`Table 1
`
`
`
`
`Ciclesonide concentration
`Recovery
`Preparation
`rate (%)
`
`
`immediately after processing
`
`
`
`
`(%)
`
`Upper portion|Lower portion
`ef emulsi-
`of emulsi-
`
`
`
`fication tank|fication tank
`
`
`Embodiment 1|Composition 1
`
`
`
`Composition 2
`100.3
`
`
`
`
` Comparative
`
`
`Composition 4
`
`
`
`
`
`
`
`
`Example 1
`
`
`147.9
`
`100.4
`
`100.0
`
`100.8
`
`
`
`
`
`
`3 and 5, which
`In the case of compositions 2,
`contained 0.1 to 1% w/w of hydroxypropylmethylcellulose
`2910,
`the ciclesonide concentrations in the
`emulsification tank immediately after homomixer
`
`processing were uniform, and the recovery rates were
`almost 100%.
`In addition,
`in the case of compositions 1
`and 4, which contained 0.01% w/w of
`hydroxypropylmethylcellulose 2910, although the
`ciclesonide concentrations in the emulsification tank
`
`immediately after homomixer processing were somewhat non-
`uniform,
`the recovery rates were almost 100%.
`In
`contrast,
`in the case of composition 6, which contained
`0.1% w/w of Polysorbate 80,
`the ciclesonide concentration
`in the upper portion of the emulsification tank
`immediately after homomixer processing was more than 30%
`higher than in the lower portion.
`In addition,
`the
`recovery rate decreased by about 20%.
`In the case of
`composition 7, which contained 0.1% w/w of sorbitan
`trioleate,
`the ciclesonide concentration in the upper
`portion of the emulsification tank immediately after
`homomixer processing was more than 40% higher than in the
`lower portion, and the recovery rate decreased by more
`than half.
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`Based on these results, it was determined that the
`
`use of a composition containing
`hydroxypropylmethylcellulose made it possible to avoid
`variation in the concentration of ciclesonide during
`
`production as well as avoid a decrease in the recovery
`
`rate of ciclesonide.
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`-il1-
`
`CLAIMS
`
`An aqueous pharmaceutical composition
`l.
`containing ciclesonide and hydroxypropylmethylcellulose,
`wherein said ciclesonide is dispersed in an aqueous
`
`medium in form of solid particles.
`2.
`An aqueous pharmaceutical composition according
`to claim 1 wherein said hydroxypropylmethylcellulose
`concentration is from 0.01% w/w to 30% w/w, relative to
`
`the total amount of the composition.
`3.
`An aqueous pharmaceutical composition according
`to claim 1 wherein said hydroxypropylmethylcellulose
`concentration is from 0.01% w/w to 5% w/w, relative to
`
`the total amount of the composition.
`4.
`An aqueous pharmaceutical composition according
`to claim 1 wherein said hydroxypropylmethylcellulose
`concentration is from 0.01% w/w to 1% w/w, relative to
`
`the total amount of the composition.
`5.
`An aqueous pharmaceutical composition according
`to claim 1 wherein said hydroxypropylmethylcellulose
`concentration is from 0.01% w/w to 0.5% w/w, relative to
`
`the total amount of the composition.
`6.
`An aqueous pharmaceutical composition according
`to any of claims 1
`through 5 additionally containing one
`or more types of a water-insoluble substance and/or
`water-low soluble substance.
`7.
`An aqueous pharmaceutical composition according
`to claim 6 wherein said water-insoluble substance and/or
`
`water-low soluble substance is a cellulose.
`8.
`An aqueous pharmaceutical composition according
`to claim 7 wherein said cellulose is crystalline
`
`cellulose.
`An aqueous pharmaceutical composition according
`9.
`to any of claims 1
`through 8 additionally containing
`water-soluble polymer substance.
`10.
`An aqueous pharmaceutical composition according
`to claim 9 wherein said water-soluble polymer substance
`is one or more types selected from the group consisting
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`- 12 -
`
`of polyethylene glycol, propylene glycol alginate,
`pectin,
`low methoxyl pectin, gua gum, gum arabic,
`carrageenan, methylcellulose, carboxymethylcellulose
`sodium, xanthan gum and hydroxypropylcellulose.
`11.
`An aqueous pharmaceutical composition according
`to claim 9 wherein said water-soluble polymer substance
`is carboxymethylcellulose sodium.
`12.
`An aqueous pharmaceutical composition according
`to claim 9 wherein said water-soluble polymer substance
`
`is polyethylene glycol.
`13.
`An aqueous pharmaceutical composition according
`to claim 9 wherein said water-soluble polymer substance
`
`is hydroxypropylcellulose.
`14.
`An aqueous pharmaceutical composition according
`to any of claims 1 through 13 wherein the combination of
`said water-insoluble substance and said water-soluble
`polymer substance is crystalline cellulose carmellose
`sodium.
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`
`CLASSIFICATION OF SUBJECT MATTER
`TPC 7
` A61K31/58
`A61K9/51
`
`A61K47/38
`
`B. FIELDS SEARCHED
`
`Internati.
`
`Application No
`
`PCT/JP 00/07351
`
` INTERNATIONAL SEARCH REPORT
`
` Accordingto International Patent Classification (IPC) or to both national classification and IPC
`
`
`
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 7
`A61K
`
`
`
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
`
`
`
`WPI Data, PAJ, CHEM ABS Data
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`Category °|Citation of document, with indication, where appropniate, of the relevant passages
`
`Relevantto claim No.
`
`
`
`1-14
`
`
`
`
`
`
`
`X
`
`
`
`WO 99 25359 A (ASTRA)
`27 May 1999 (1999-05-27)
`page 4,
`line 21
`claims 1,3,7,9-12,28-31
`page 8,
`line 4 - line 28
`page 9,
`line 19 -page 10,
`examples 4,5
`
`line 3
`
`
`
`
`
`
`
`
`
`
`
`WO 98 52542 A (MINNESOTA MINING AND
`
`
`MANUFACTURING COMPANY )
`26 November 1998 (1998-11-26)
`
`
`claims
`
`examples
`
`
`WO 99 47144 A (PHARMALINK )
`23 September 1999 (1999-09-23)
`claims 1,2,6,14,16,18,22,23,25,28
`page 5,
`line 12 -page 6,
`line 7
`
`A
`
`A
`
`Further documentsarelisted in the continuation of box C.
`
`Patent family members arelisted in annex.
`
`a.
`,
`.
`.
`° Special categories of cited documents:
`"T" later document published after the internationalfiling date
`
`
`date and not in conflict with the application but
`or
`priority
`a
`tae
`.
`ited OOeesiond the principle or theory underlying the
`A" documentdefining the general state of the art which is not
`
`
`
`
`invention
`consideredto beof particular relevance
`*x* documentofparticular relevance: the claimed invention
`°E" earnerGocument but published onorafter the international
`
`
`cannot be considered novel or cannot be considered to
`iting date
`
`
`
`
`involve an inventive step when the documentis taken alone
`"L* document which may throw doubts on priority claim(s) or
`*y* documentof particular relevance: the claimed invention
`which is cles to establish the publicationcate of another
`
`
`cannot be consideredto involve an inventive step when the
`citation or other special reason (as specified)
`
`
`documentis combined with one or more other such docu—
`"©" documentreferring to an oral disclosure, use, exhibition or
`
`
`ments, such combination being obvious to a person skilled
`other means
`
`
`*P" document publishedprior to the internationalfiling date but
`in the art.
`
`
`"3." document memberof the same patentfamily
`later than the priority date ciaimed
` Dateof the actual completion of the international search
`
`Date of mailing of the international search report
`
`
`23/03/2001
`13 March 2001
`Authorized officer
`
`
`Nameand mailing address of the ISA
`European Patent Office, P.B. 5818 Patentlaan 2
`
`NL - 2280 HV Rijswijk
`
`
`
`Tel. (431-70) 340-2040, Tx. 31 651 epo ni,
`Scarponi, U
`
`
`
`Fax: (31-70) 340-3016
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`000014
`
`page I of2
`
`000014
`
`
`
`INTERNATIONAL SEARCH REPORT
`
`
`
`
` internatic
`PCT/JP 00/07351
`
`Application No
`
`
`
`
`
`
`C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`
`Category °|Citation of document. with indication,where appropriate, of the relevant passages Relevant to claim No.
`
`
`
`
`
`
`
`
`
`
`DATABASE WPI
`Section Ch, Week 199938
`Derwent Publications Ltd., London, GB;
`Class All, AN 1999-458604
`XP002162689
`& WO 99 37286 A (SANTEN PHARM CO LTD),
`29 July 1999 (1999-07-29)
`cited in the application
`abstract
`
`
`
`
`
`
`
`
`
`Form PCT/ISA/210 (continuation of second sheet) (July 1992)
`
`000015
`
`page 2 of 2°°
`
`
`
`000015
`
`
`
`Patent document
`cited in search report
`
`WO 9925359
`
`A
`
`
`
`
`Internatic
`Application No
`
`
`
`PCT/JP 00/07351
`Publication
`date
`
`
`
`
`
`
`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`Publication
`Patent family
`member(s)
`date
`07-06-1999
`27-05-1999
`AU
`1266699 A
`
`03-10-2000
`BR
`9814118 A
`
`28-02-2001
`CN
`1285750 T
`06-09-2000
`EP
`1032396 A
`NO
`20002470 A
`05-07-2000
`
`
`9810217 A 14-05-1999
`
`
`
`
`
`
`WO 9947144
`A
`23-09-1999
`SE
`514128 C
`08-01-2001
`AU
`2968699 A
`11-10-1999
`
`BR
`9908838 A
`12-12-2000
`
`EP
`1056461 A
`06-12-2000
`
`9800905 A
`18-09-1999
`
`
`
`
`WO 9852542
`A
`26-11-1998
`AU
`726835 B
`23-11-2000
`AU
`7496298 A
`11-12-1998
`BG
`103902 A
`31-05-2000
`BR
`9809448 A
`20-06-2000
`
`CN
`1257421 T
`21-06-2000
`
`EP
`0983058 A
`08-03-2000
`
`NO
`995667 A
`18-11-1999
`
`PL
`336885 A
`17-07-2000
`
`157699 A
`16-05-2000
`SK
`
`6120752 A
`19-09-2000
`
`
`
`
`
`
`WO 9937286
`
`A
`
`29-07-1999
`
`08-11-2000
`1050299 A
`EP
`JP
`11279052 A
`12-10-1999
`
`NO
`20003650 A
`
`05-09-2000
`
`Form PCT/SA/210 (patent family annex) (July 1992)
`
`000016
`
`000016
`
`