PCT
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 98/48839
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`(51) International Patent Classification 6 :
`A61K 45/06, 31/57, 31/58, 31/135, 31/35, Al
`31/245, 31/09, 31/38, 31/195, 31/47,
`31/445, 31/55, 31/44, 31/615, 31/415
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`5 November 1998 (05.11.98)
`
`(21) International Application Number:
`
`PCT/US98/06483
`
`(22) International Filing Date:
`
`2 April 1998 (02.04.98)
`
`(30) Priority Data:
`60/044,306
`
`30 April 1997 (30.04.97)
`
`us
`
`except US):
`States
`designated
`all
`(for
`(71) Applicant
`[US/US];
`201
`WARNER-LAMBERT COMPANY
`Tabor Road, Morris Plains, NJ 07950 (US).
`
`(72) Inventor; and
`(75) Inventor/Applicant (for US only): SEGAL, Catherine, A.
`[US/US]; 60 Shawnee Avenue, Rockaway, NJ 07866 (US).
`
`(74) Agents: RYAN, M., Andrea; Warner-Lambert Company, 201
`Tabor Road, Morris Plains, NJ 07950 (US) et al.
`
`(81) Designated States: AL, AU, BA, BB, BG, BR, CA, CN, CZ,
`EE, GE, GW, HU, ID, IL, IS, JP, KR, LC, LK, LR, LT,
`LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL,
`TR, TI, UA, US, UZ, VN, YU, ARIPO patent (GH, GM,
`KE, LS, MW, SD, SZ, 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, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`
`(54) Title: TOPICAL NASAL ANTIINFLAMMATORY COMPOSITIONS
`
`(57) Abstract
`
`The present invention provides· topically applicable nasal compositions comprising a therapeutically effective amount of an
`antiinflammatory agent and a therapeutically effective amount of at least one agent selected from the group consisting of a vasoconstrictor,
`a neuramidinase inhibitor, a leukotriene inhibitor, an antihistamine, an antiallergic agent, an anticholinergic agent, an anesthetic and a
`mucolytic agent. The present compositions are useful as nasal sprays and nose drops for the treatment of nasal and sinus conditions.
`
`

`

`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cu
`CZ
`DE
`DK
`EE
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cl\te d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`IL
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People's
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`TM
`TR
`TT
`UA
`UG
`us
`uz
`VN
`YU
`zw
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`

`

`WO98/48839
`
`PCT/US98/06483
`
`1
`
`TOPICAL NASAL ANTIINFLAMMATORY
`
`COMPOSITIONS
`
`SPECIFICATION
`
`BACKGROUND OF THE INVENTION
`Topical nasal antiinflammatory preparations are known in the art for
`
`5
`
`the treatment of inflammatory conditions of the nasal mucous membranes, and in
`
`particular for relief of the symptoms of nasal and sinus conditions such as rhinitis.
`
`However, nasal and sinus conditions may be characterized by diverse symptoms
`
`requiring treatment with multiple therapeutic agents. For example, allergic rhinitis
`
`may be characterized by rhinorrhea, nasal itching, sneezing, congestion and postnasal
`
`10
`
`drip and treatment may require antihistamines, decongestants, antiallergics and
`
`anesthetics in addition to antiinflammatories.
`
`The use of multiple topical nasal preparations to administer multiple
`
`therapeutic agents suffers from significant disadvantages. The volume of liquid that
`
`can effectively be applied nasally is limited by the surface area of the nostril and the
`
`15
`
`bioadhesiveness of the liquid. In addition, a sufficient contact time between topical
`
`preparations and the surface area of the nostril is required to assure adequate dosing
`
`of a therapeutic agent. Further, spray formulations require a threshold surface
`
`tension to form droplets. Accordingly, the delivery volume per actuation is limited to
`
`the volume that will be retained in the nostril without premature drainage. Thus
`
`20
`
`multiple topical nasal preparations cannot be effectively administered simultaneously.
`
`

`

`WO 98/48839
`
`PCT /US98/06483
`
`2
`
`Another disadvantage of the administration of multiple topical nasal
`preparations is patient inconvenience. Patient compliance may be compromised by
`the inconvenience of applying multiple spray products or nose drops. Patients
`complain when excess spray drains into their throats where it can be tasted, resulting
`in a need for flavor masking of bitter medicaments.
`
`Accordingly, a need exists for a convenient means of nasal
`administration of multiple therapeutic agents.
`
`SUMMARY OF THE INVENTION
`The present invention provides topically applicable nasal compositions
`comprising a therapeutically effective amount of a topical antiinflammatory agent and
`a therapeutically effective amount of at least one agent suitable for topical nasal
`administration and selected from the group consisting of a vasoconstrictor, a
`neuramidinase inhibitor, an anticholinergic agent, a leukotriene inhibitor, an
`antihistamine, an antiallergic agent, an anesthetic, and a mucolytic agent.
`
`DETAILED DESCRIJYI'ION OF THE INVENTION
`The present invention provides topically applicable nasal compositions
`comprising a topical antiinflammatory agent and at least one additional therapeutic
`agent. The present compositions are useful for the treatment of nasal and sinus
`conditions, for example allergic rhinitis or the common cold.
`
`The topical antiinflammatory agents in the compositions of the present
`invention are corticosteroids known in the art to suppress inflammation. In a
`preferred embodiment the topical antiinflammatory agent is beclomethasone
`diproprionate, budesonide, dexamethasone, mometasone furoate, fluticasone
`proprionate or triamcinolone acetonide. The compositions contain a therapeutically
`effective amount of the selected antiinflammatory agent. Those of ordinary skill in
`the art can determine an amount that is therapeutically effective for the suppression
`of inflammation. The precise amount will depend upon the method of administration
`and the age, weight and condition of the subject to be treated. Generally the
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO98/48839
`
`PCT/US98/06483
`
`3
`
`antiintlammatory agents are utilized in dosages known in the art to be therapeutically
`effective upon nasal administration.
`
`The compositions of the invention further comprise at least one
`additional therapeutic agent, and thus allow the convenient administration of an
`antiintlammatory agent and at least one additional therapeutic agent in a single topical
`nasal composition. The additional therapeutical agent is suitable for topical nasal
`administration and is selected from the group consisting of a vasoconstrictor, a
`neuramidinase inhibitor, a leukotriene inhibitor, an anticholinergic agent, an
`antihistamine, an antiallergic agent, a local anesthetic and a mucolytic agent. The use
`of an additional therapeutic agent in combination with an antiintlammatory agent
`provides additive and synergistic effects in the treatment of nasal and sinus
`conditions.
`
`Vasoconstrictors suitable for topical nasal administration in the
`compositions of the present invention are oxymetazoline naphazoline,
`xylometazoline, and phenylephrine. Leukotriene inhibitors include zafirlukast, a
`selective, competitive receptor antagonist of the three leukotrienes C4, D4, and E4;
`pranlukast, a selective, competitive receptor antagonist ofD4; and zileuton, a
`leukotriene inhibitor. A neuramidinase inhibitor includes zanamivir (GG-167).
`Suitable antihistamines are diphenhydramine, chlorpheniramine, cetirizine terfenadine,
`fenofexadine, astemizole norastemizole, azelastine, and azatidine. Antiallergic agents
`include cromolyn sodium and nedocromil levocabastine. An anticholinergic agent
`useful in the compositions of the present invention is ipratropium bromide. Local
`topical anesthetics include dyclonine, pramoxine, and benzocaine. Mucolytic agents
`suitable for topical nasal administration are acetylcysteine, guaifenisin and
`mucocysteine. The therapeutically effect amount of foregoing agents can be
`determined by the ordinarily skilled artisan with regard to the known use of these
`agents in the art and taking into account the method of administration and the age,
`weight and condition of the subject to be treated.
`
`The compositions of the present invention are formulated as aqueous
`
`solutions comprising an antiintlammatory agent and at least one additional
`therapeutic agent and further comprising a pharmaceutically acceptable nasal carrier.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 98/48839
`
`PCT /US98/06483
`
`4
`
`The formulation of pharmaceutical compositions is generally known in the art and
`
`reference can be conveniently made to standard text such as Remington's
`
`Pharmaceutical Sciences, 1985, 17th ed., Mack Publishing Co., Easton, Pennsylvania.
`
`Preferred nasal formulations are nose drops or nasal sprays containing
`
`5
`
`a water buffered aqueous solution as a carrier. The compositions are preferably
`
`isotonic. Isotonic agents such as a sugars and sodium chloride are known in the art
`
`and may be included in the subject compositions.
`
`The compositions of the present invention may also contain a
`
`humectant to increase viscosity and effect moisturization and ciliary vitality. Suitable
`
`10
`
`humectants include glycerin, polyethylene glycol, propylene glycol and mixtures
`
`15
`
`20
`
`thereof
`
`Additional agents including pharmaceutically acceptable preservatives,
`
`stabilizers, flavoring agents, and pH adjusters are known in the art and may be
`
`included in the present compositions.
`
`Another embodiment of the present invention provides preservative(cid:173)
`
`free compositions comprising an anti-inflammatory agent and at least one additional
`
`therapeutic agent. Preservative-free compositions are preferred due to reduced
`
`sensitivity and increased patient acceptance. These can be prepared in unit dose or in
`
`systems which prevent contamination of the reservoir of solution.
`
`The compositions of the present invention can be conveniently
`
`administered nasally to a human subject in dosage unit form to elicit the desired
`
`therapeutic effect of the antiinflammatory agent and the additional therapeutic agents
`
`described above. The compositions may be administered in the form of a nasal spray
`
`or nose drops. Nasal sprays may be provided as squeeze bottles or metered dose
`
`25
`
`manual nasal spray pumps designed to deliver the desired dose in one or two sprays,
`
`for example. The composition may also be administered as aerosol spray
`
`formulations, for example as metered dose pressurized aerosols containing
`
`propellants such as halogenated hydrocarbons.
`
`

`

`WO98/48839
`
`PCT /US98/06483
`
`5
`
`WHAT IS CLAIMED IS:
`
`1. A topically applicable nasal composition comprising a
`
`therapeutically effective amount of a topical antiinflammatory agent and a
`
`therapeutically effective amount of at least one agent suitable for topical nasal
`
`administration and selected from the group consisting of a vasoconstrictor, a
`
`neuramidinase inhibitor, a leukotriene inhibitor, an antihistamine, an antiallergic
`
`agent, an cholinergic agent, an anesthetic and a mucolytic agent.
`
`2. The composition of Claim 1 wherein said topical antiinflammatory
`
`agent is selected from the group consisting ofbeclomethasone diproprionate,
`
`budesonide, dexamethasone, mometasone furoate, fluticasone proprionate and
`
`triamcinolone acetonide.
`
`3. The composition of Claim 1 wherein said vasoconstrictor is
`
`selected from the group consisting of oxymetazoline, naphazoline, xylometazoline,
`
`and phenylephrine.
`
`4. The composition of Claim 1 wherein said antihistamine is selected
`
`from the group consisting of diphenhydramine, chlorpheniramine, terfenadine,
`
`azelastine, norastemizole, fexofenadine, cetirazine, astemizole and azatidine.
`
`5. The composition of Claim 1 wherein said antiallergic agent is
`
`selected from the group consisting of cromolyn sodium, levocabastine, and
`
`nedocromil.
`
`ipratropium.
`
`6. The composition of Claim 1 wherein said anticholinergic agent is
`
`7. The composition of Claim 1 wherein said topical anesthetic is
`
`selected from the group consisting of dyclonine, pramosine, and benzocaine.
`
`

`

`WO 98/48839
`
`PCT/US98/06483
`
`6
`
`8. The composition of Claim 1 wherein said mucolytic agent is
`
`selected from the group consisting of acetylcysteine, guaifenesin and mucocysteine.
`
`9. The composition of Claim 1 wherein said leukotriene inhibitor is
`
`selected from the group consisting of zafirlukast, pranlukah, and zileuton.
`
`10. The composition of Claim 1 wherein said neuramidinace inhibitor
`
`is zanamivir.
`
`11. A topically applicable nasal composition comprising a
`
`therapeutically effective amount of a topical antiinflammatory agent selected from the
`
`group consisting ofbeclomethasone diproprionate, budesonide, dexamethasone,
`
`mometasone furoate, fluticasone proprionate and triamcinolone acetonide and a
`
`therapeutically effective amount of at least one agent selected from the group
`
`consisting of oxymetazoline, phenylephrine, diphenhydramine, chlorpheniramine,
`
`terfenadine, astemizole, azatidine, cromolyn sodium, nedocromil, ipratropium
`
`bromide, dyclonine, benzocaine, acetylcysteine, guaifenesin and mucocysteine.
`
`12. The composition of Claim 1 or 11 further comprising at least one
`
`humectant.
`
`13 . The composition of Claim 12 wherein said humectant is selected
`
`from the group consisting of glycerin, polyethylene glycol and propylene glycol.
`
`14. The composition of Claim 1 or 11 comprising a pharmaceutically
`
`acceptable carrier.
`
`15. The composition of Claim 1 or 11 formulated for application as a
`
`nasal spray.
`
`

`

`WO98/48839
`
`PCT/US98/06483
`
`7
`
`16. The composition of Claim 1 or 11 formulated for application as
`
`nose drops.
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`lnt11rr,a,1onal Application No
`PCT/US 98/06483
`
`A. CLASSIFICATION OF itBJECT MATTER
`/
`IPC 6 A61K45 06
`A61K31/58
`A61K31 57
`A61K31/135 A61K31/35
`A61K31/245 A61K31/09
`A61K31/38
`A61K31/195 A61K31/47
`A61K31/445 A61K31/55
`A61K31/44
`A61K31/615 A61K31/415
`According to International Patent Classification(IPC) or to both national classilication and IPC
`B. FIELDS SEARCHED
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 6 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)
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category 0 Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`X
`
`X
`
`X
`
`WO 97 01337 A (MCNEIL-PPC, INC.) 16
`January 1997
`see abstract
`see page 2, 1 i ne 8 - 1 i ne 18
`see page 8, line 2 - line 24
`---
`WO 97 01341 A (MCNEIL-PPC, INC.) 16
`January 1997
`see page 2, 1 i ne 5 - 1 i ne 14
`see page 8, line 2 - line 19
`---
`WO 93 09764 A (CENTER FOR INNOVATIVE
`TECHNOLOGY) 27 May 1993
`see page 6, 1 i ne 10 - 1 i ne 14
`see page 6, line 30
`see page 22, 1 i ne 23 - line 33
`see page 26, line 23 -
`line 25
`see claims 1,2,4-8,13-23
`---
`
`1,2,4,
`11-16
`
`1,2, 5,
`11-16
`
`1,3,4,6,
`14-16
`
`[]] Further documents are listed in the continuation of box C.
`
`0 Special categories of ctted documents :
`
`"A" document defining the general state of the art which is not
`considered to be of particular relevance
`"E" earlier document but published on or after the international
`filing date
`"L" document which may throw doubts on priorrty claim(s) or
`which is cited to establish the publication date of another
`citation or other special reason (as specified)
`"O" document referring to an oral disclosure, use. exhibrtion or
`other means
`"P" document published prior to the international filing date but
`later than the priority date claimed
`
`-/--
`[] Patent family members are listed in annex.
`
`"T" later document published after the international filing date
`or priority date and not in conflict with the application but
`crted to understand the principle or theory underlying the
`invention
`"X" document of particular relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`involve an inventive step when the document is taken alone
`"Y" document of particular relevance; the claimed invention
`cannot be considered to involve an inventive step when the
`document is combined wtth one or more other such docu-
`ments, such combination being obvious to a person skilled
`in the art.
`"&" document member of the same patent family
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`11 June 1998
`
`Name and mailing address of the ISA
`European Patent Office, P.B . 5818 Patentlaan 2
`NL - 2280 HV Rijswijk
`Tel. (+31-70) 340-2040, Tx. 31 651 epo nl ,
`Fax: (+31-70) 340-3016
`
`1
`
`Fann PCTnSA/210 (second sheet) (July 1992)
`
`22/06/1998
`
`Authorized officer
`
`Alvarez Alvarez, C
`
`page 1 of 2
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`lnterto",1onal AppUcatlon No
`PCT/US 98/06483
`
`C.(Contlnuatlon) DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category • Citation of document, with indication.where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`X
`
`X
`
`A
`
`X
`
`X
`
`X
`
`A
`
`X
`
`X,P
`
`IND. CO.
`
`DATABASE WPI
`Week 8733
`Derwent Publications Ltd., London, GB;
`AN 87-230755
`XP002067758
`& JP 62 153 227 A (SEKISUI CHEM.
`LTD.) , 8 July 1987
`see abstract
`WO 95 07103 A (THE PROCTER & GAMBLE
`COMPANY) 16 March 1995
`see abstract
`see page 4, line 7 - line 13
`see page 5, line 11 - line 31
`see page 7, line 16 - line 18
`see page 7, line 20
`see examples 1-5
`
`US 3 482 015 A (FREDERICK W. BOLLINGER ET
`AL.) 2 December 1969
`see the whole document
`
`WO 85 04589 A (SUNSHINE ET AL.) 24 October
`1985
`see claims 1,14,15,17-19
`
`WO 97 09067 A (BAYER AG. ET AL) 13 March
`1997
`see claims 1,5
`
`US 4 053 628 A (NEIL ARTHUR STEVENSON ET
`AL.) 11 October 1977
`see column 3, line 10 - line 18
`see claim 2
`EP O 780 127 A (THE PROCTER & GAMBLE
`COMPANY) 25 June 1997
`see page 2, line 35 - line 46
`see page 3, line 14 - line 30
`see page 4, line 5 - line 32
`see page 4, line 38 - line 40
`see page 5, line 7 - line 9
`see claims 1-6
`
`1,2,4,7
`
`1,3,4,8,
`12-14
`
`7
`
`1-3,11,
`12,14,15
`
`1,3,4,8,
`14
`
`1,2
`
`9
`
`1,5
`
`1-5,8,
`11-16
`
`1
`
`Form PCT~SA/210 (continuation of second sheet) (July 1992)
`
`page 2 of 2
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`lnterr.k.,onal Application No
`PCT/US 98/06483
`
`Publication
`date
`
`I
`
`I
`
`Patent family
`member(s)
`
`Patent document
`cited in search report
`
`WO 9701337
`
`WO 9701341
`
`WO 9309764
`
`A
`
`A
`
`A
`
`16-01-1997
`
`16-01-1997
`
`27-05-1993
`
`WO 9507103
`
`A
`
`16-03-1995
`
`us 3482015
`
`A
`
`02-12-1969
`
`WO 8504589
`
`A
`
`24-10-1985
`
`AU
`
`AU
`us
`CA
`EP
`JP
`us
`us
`AU
`BR
`CA
`CN
`EP
`JP
`
`DE
`FR
`GB
`NL
`us
`AU
`AU
`AU
`CA
`DE
`EP
`JP
`us
`us
`us
`us
`us
`us
`us
`us
`us
`
`6392496 A
`
`6290396 A
`
`5240694 A
`2122719 A
`0661967 A
`8508007 T
`5422097 A
`5492689 A
`
`7604094 A
`9407414 A
`2170488 A
`1130354 A
`0719156 A
`9502201 T
`
`1617610 A
`1481087 A
`1089043 A
`6601472 A
`
`4552899 A
`2029195 A
`589554 B
`4120085 A
`1258430 A
`3585495 A
`0180597 A
`61501913 T
`4749697 A
`4839354 A
`4749722 A
`4749711 A
`4749723 A
`4749720 A
`4749721 A
`4783465 A
`4920149 A
`
`Publication
`date
`
`I
`
`30-01-1997
`
`30-01-1997
`
`31-08-1993
`27-05-1993
`12-07-1995
`27-08-1996
`06-06-1995
`20-02-1996
`
`27-03-1995
`12-11-1996
`16-03-1995
`04-09-1996
`03-07-1996
`04-03-1997
`
`20-04-1972
`09-08-1967
`
`09-08-1966
`
`12-11-1985
`03-08-1995
`19-10-1989
`01-11-1985
`15-08-1989
`09-04-1992
`14-05-1986
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`07-06-1988
`13-06-1989
`07-06-1988
`07-06-1988
`07-06-1988
`07-06-1988
`07-06-1988
`08-11-1988
`24-04-1990
`
`Fonn PCT nSA/21 o (patent family annex) (July 1992)
`
`page 1 of 2
`
`

`

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`Patent document
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`
`A
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`-Publication
`date
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`I
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`I
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`WO 9709067
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`us 4053628
`
`A
`
`A
`
`13-03-1997
`
`11-10-1977
`
`---
`EP 780127
`
`A
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`25-06-1997
`
`NONE
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`lnterna,1onal Appllcatlon No
`PCT/US 98/06483
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`date
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`I
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`Patent family
`member(s)
`
`us
`us
`us
`us
`us
`DE
`AU
`
`GB
`GB
`us
`AU
`AU
`BE
`CA
`CY
`DE
`DE
`DK
`FR
`HK
`NL
`SE
`ZA
`DE
`FR
`JP
`JP
`JP
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`4840962 A
`4871733 A
`5025019 A
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`-
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`Fonn PCTnSA/210 (patent family annex) (July 1992)
`
`page 2 of 2
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`