WO1998019680A1 - Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma - Google Patents
Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma Download PDFInfo
- Publication number
- WO1998019680A1 WO1998019680A1 PCT/US1997/015793 US9715793W WO9819680A1 WO 1998019680 A1 WO1998019680 A1 WO 1998019680A1 US 9715793 W US9715793 W US 9715793W WO 9819680 A1 WO9819680 A1 WO 9819680A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carbonic anhydrase
- prostaglandins
- isopropyl
- hydroxy
- prostaglandin
- Prior art date
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Definitions
- the present invention relates to the field of ophthalmology.
- the invention relates to the treatment of persons suffering from glaucoma and associated elevations of intraocular pressure (IOP) and/or ocular hypertension.
- IOP intraocular pressure
- Glaucoma Although the underlying causes of glaucoma are not understood, its symptoms often include elevated IOP, which may be caused either by over-production or inadequate outflow of aqueous humor. If left untreated, or if inadequately treated, glaucoma can lead to blindness or significant loss of vision. There is therefore a continuing need for therapies which control the elevated intraocular pressure associated with glaucoma.
- glaucoma and ocular hypertension there are currently a number of drugs used in the treatment of glaucoma and ocular hypertension, including: miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase inhibitors); sympathomimetics (e.g., epinephrine, dipivalylepinephrine, and para-amino clonidine); beta-blockers (e.g., betaxolol, levobunolol, and timolol); and carbonic anhydrase inhibitors (CAIs) e.g., acetazolamide, methazolamide and ethoxzolamide systemically and dorzolamide topically.
- Prostaglandins (PGs) are currently being developed for use in treating persons with glaucoma and the PG, latanoprost, marketed as Xalatan ® , is available from Pharmacia-Upjohn
- Miotics and sympathomimetics are believed to lower IOP by increasing the outflow of aqueous humor, while beta-blockers and carbonic anhydrase inhibitors are believed to lower IOP by decreasing the formation of aqueous humor.
- All four types of drugs have potentially serious side effects.
- Miotics, such as pilocarpine can cause brow ache, blurring of vision, and other visual side effects, which may lead either to decreased patient compliance or to therapy termination.
- Systemically administered carbonic anhydrase inhibitors can also cause serious side effects which affect patient compliance and/or necessitate the withdrawal of treatment.
- Beta-blockers can be irritating.
- Sympathomimetics can cause allergic responses and sedation.
- Side effects associated with PGs include edema, hyperemia, and foreign body sensation.
- a significant number of glaucoma patients require the administration of more than one type of drug in order to achieve therapeutic control over their IOP because a single drug does not provide adequate IOP control.
- the use of two drugs, each of which affects IOP by a different mechanism, would be useful m. treating these patients.
- the present invention is directed to such use, either by administration of the drugs separately or in combination.
- the present invention is directed to methods for treating patients with glaucoma or ocular hypertension wherein their IOP can only be controlled by the use of two IOP lowering drugs, namely, carbonic anhydrase inhibitors and prostaglandins. These drugs may be dosed simultaneously or at different times and may also be formulated in a single composition to provide for convenience and patient compliance.
- Prostaglandins are metabolic derivatives of arachidonic acid.
- the arachidonic acid cascade is initiated by the conversion of arachidonic acid to prostaglandin G 2 and its subsequent conversion to prostaglandin H 2 .
- Other naturally occurring prostaglandins are derivatives of prostaglandin H 2 .
- a number of different types of prostaglandins have been discovered including A, B, D, E, F and I-Series prostaglandins.
- the prostaglandins which are useful according to the present invention include all prostaglandins which exhibit similar IOP lowering mechanisms as PGD 2 (I) or PGF 2 ⁇ (II):
- D-prostaglandins are believed to inhibit aqueous humor formation and may have an affect on its outflow.
- F-prostaglandins (“FP-agonist”) are believed to increase the outflow of aqueous humor from the eye.
- the DP-agonists of the present invention are useful in lowering IOP in humans and other mammals.
- the DP-agonists of the present invention are functionally defined by their ability to bind to prostaglandin-D 2 receptors of cells and evoke similar responses as when PGD 2 binds to these receptors inducing the lowering of IOP.
- Various assays may be used for the determination of DP-agonists.
- Binding assays may be used to elucidate DP-agonists of the present invention.
- Sharif, et al. have described a receptor binding assay in: Sharif, N.A., Williams, G.W. and DeSantis, L.M, Neurochemistry Research, volume 20, pages 669-674 (1995), the entire contents of which are incorporated herein by reference, and may be modified as described below, for the elucidation of DP-agonists of the present invention. Briefly, the binding assays are conducted in 25 mM Tris HCl (pH 7.4) containing 138 mM NaCI, 5 mM MgCl2, and 1 mM EDTA.
- Frozen-thawed expired human blood platelets (40-60 mg/ml stock) are incubated in a total volume of 500 ml with 2-10 nM [ ⁇ H]PGD2 in the absence and presence of 100 mM unlabeled PGD2 to define total and non-specific binding, respectively.
- the incubations (20 minutes at 23°C) are terminated by rapid vacuum filtration, using a Whatman GF/B glass fiber filter previously soaked in 1% polyethyleneimine and 0.1% BSA, and the receptor-bound radioactivity is then determined by scintillation spectrometry.
- the binding data are analyzed using a non-linear, iterative curve-fitting computer program to define the receptor binding affinity (Kj) of the compounds.
- Kj receptor binding affinity
- the DP-agonists of the present invention may also be defined functionally, by their ability to stimulate adenylate cyclase activity.
- Sharif, et al. have described this type of functional assay in: Sharif, N.A., Xu, S. and Yanni, J.M., Journal of Ocular Pharmacology, volume 10, pages 653-664 (1994), the entire contents of which are incorporated herein by reference, and which may be modified as described below, for the elucidation of DP-agonists of the present invention.
- functional adenylate cyclase activity is determined using embryonic bovine tracheal cells (EbTr) cells. Cultured cells are stimulated with the test compound for 15 minutes at 23°C.
- EC 50 concentration which produces 50% of the maximum response of PGD 2
- efficacy of the compounds Compounds which exhibit EC50 values of less than or equal to about 10 mM are within the DP-agonist definition of the present invention.
- Preferred DP-agonists include: [lR-[l. .(Z),2.15.(lE,3S),3.o(.,5.o(.]]-[[4-[5-chloro- 2-(3-cyclohexyl-3-hydroxy-propyl)-3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, t- butyl ester (see EP0299 914B1) and ([lR-[l.o(.(Z),2. ⁇ .(3S),3.
- Preferred FP-agonists include: latanoprost (Xalatan ® , available from Upjohn- Pharmacia) (see U.S. Patent No. 5,296,504), and the compounds disclosed in U.S. Patent No.
- CAIs which are useful in the compositions and methods of the present invention include all thiophene sulfonamides and thienothiazines which lower and control
- Preferred CAIs of the present invention are those disclosed in U.S. Patent No. 5 ,378 ,703 , particularly, R-(+)-4-ethylamino-3 ,4-dihy dro-2-(3 -methoxypropyl)-2H- thieno[3 ,2,e]- 1 ,2-tl ⁇ azine-6-surfonamide- 1 , 1 -dioxide (brinzolamide).
- the PGs and CAIs of the present invention may be formulated either separately or in the same pharmaceutical compositions. Thus, they can be administered simultaneously or sequentially to humans and other mammals suffering from glaucoma or ocular hypertension.
- the drugs When formulated separately the drugs may be administered 1) concomitantly; 2) within a short delay between one agent and the other; or 3) in an offset manner. It is preferred that the PG be dosed at night.
- the PG concentration in a formulation is between about 0.00005 and about 0.5 percent by weight (wt.%), preferably between about 0.0003 and 0.3% wt.%, most preferably between about 0.0005 and 0.03 wt.%.
- the CAI concentration in a formulation is between about 0.1 and 10.0 wt.%, preferably between about 0.25 and 3 wt.%, most preferably between about 0.5 and 2.0 wt.%.
- the PG concentration can be between 0.0005 and 0.03 wt.% and the CAI 0.5 and 1.5 wt.%.
- the anti-glaucoma compositions of the present invention may further comprise various formulatory ingredients, such as antimicrobial preservatives and tonicity agents.
- suitable antimicrobial preservatives include: benzalkonium chloride, thirnerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
- suitable agents which may be used to adjust the tonicity or osmolality of the formulations include: sodium chloride, potassium chloride, mannitol, dextrose, glycerin, and propylene glycol. Such agents, if used, will typically be employed in an amount between about 0.1 to 10.0 wt%.
- viscosity enhancers such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and carbomers, may be used, and when they are, the prostaglandin concentration can be substantially reduced.
- Stabilizing agents may also be employed, such as, polyethoxylated castor oils like cremaphor EL.
- compositions may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels, and erodible solid ocular inserts.
- Combination compositions preferably are aqueous suspensions, have a pH between 5.0 to 7.8, preferably 6.5 to 7.6, and an osmolality between 280 to 320 milliOsmoles per kilogram (mOsm/kg).
- Example 1 The following examples further illustrate the anti-glaucoma compositions of the present invention, but are not limiting.
- Example 1
- the following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
- the following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
- the following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
- Formulation B Ingredient Amount (wt%)
- the following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP52136398A JP2001504100A (en) | 1996-11-01 | 1997-09-05 | Use of a combination of a carbonic anhydrase inhibitor and a prostaglandin to treat glaucoma |
AU42573/97A AU734789B2 (en) | 1996-11-01 | 1997-09-05 | Use of a combination of carbonic anhydrease inhibitors and prostaglandins for treating glaucoma |
EP97940895A EP0948333A1 (en) | 1996-11-01 | 1997-09-05 | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
CA002270349A CA2270349A1 (en) | 1996-11-01 | 1997-09-05 | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2953896P | 1996-11-01 | 1996-11-01 | |
US60/029,538 | 1996-11-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998019680A1 true WO1998019680A1 (en) | 1998-05-14 |
Family
ID=21849545
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/015793 WO1998019680A1 (en) | 1996-11-01 | 1997-09-05 | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0948333A1 (en) |
JP (1) | JP2001504100A (en) |
AU (1) | AU734789B2 (en) |
CA (1) | CA2270349A1 (en) |
WO (1) | WO1998019680A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009117316A2 (en) | 2008-03-17 | 2009-09-24 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
USRE43372E1 (en) | 1999-03-05 | 2012-05-08 | Duke University | C16 unsaturated FP-selective prostaglandins analogs |
US8906962B2 (en) | 2000-03-31 | 2014-12-09 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US9346837B2 (en) | 2000-03-31 | 2016-05-24 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0501678A2 (en) * | 1991-03-01 | 1992-09-02 | R-Tech Ueno Ltd. | Treatment of ocular hypertension with a synergistic combination |
CN1075634A (en) * | 1992-02-13 | 1993-09-01 | 麦克公司 | The ophthalmic composition that contains carbonic anhydrase inhibitors and prostaglandin or derivatives thereof |
EP0590786A1 (en) * | 1992-08-28 | 1994-04-06 | Alcon Laboratories, Inc. | Use of certain anionic surfactants to enhance antimicrobial effectiveness of opthalmic compositions |
US5378703A (en) * | 1990-04-09 | 1995-01-03 | Alcon Laboratories, Inc. | Sulfonamides useful as carbonic anhydrase inhibitors |
EP0667160A2 (en) * | 1993-12-15 | 1995-08-16 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
US5510383A (en) * | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
WO1997023223A1 (en) * | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
-
1997
- 1997-09-05 AU AU42573/97A patent/AU734789B2/en not_active Ceased
- 1997-09-05 JP JP52136398A patent/JP2001504100A/en active Pending
- 1997-09-05 CA CA002270349A patent/CA2270349A1/en not_active Abandoned
- 1997-09-05 WO PCT/US1997/015793 patent/WO1998019680A1/en not_active Application Discontinuation
- 1997-09-05 EP EP97940895A patent/EP0948333A1/en not_active Withdrawn
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5378703A (en) * | 1990-04-09 | 1995-01-03 | Alcon Laboratories, Inc. | Sulfonamides useful as carbonic anhydrase inhibitors |
EP0501678A2 (en) * | 1991-03-01 | 1992-09-02 | R-Tech Ueno Ltd. | Treatment of ocular hypertension with a synergistic combination |
CN1075634A (en) * | 1992-02-13 | 1993-09-01 | 麦克公司 | The ophthalmic composition that contains carbonic anhydrase inhibitors and prostaglandin or derivatives thereof |
EP0590786A1 (en) * | 1992-08-28 | 1994-04-06 | Alcon Laboratories, Inc. | Use of certain anionic surfactants to enhance antimicrobial effectiveness of opthalmic compositions |
US5510383A (en) * | 1993-08-03 | 1996-04-23 | Alcon Laboratories, Inc. | Use of cloprostenol, fluprostenol and their salts and esters to treat glaucoma and ocular hypertension |
EP0667160A2 (en) * | 1993-12-15 | 1995-08-16 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
WO1997023223A1 (en) * | 1995-12-22 | 1997-07-03 | Alcon Laboratories, Inc. | Substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
Non-Patent Citations (4)
Title |
---|
DATABASE EPODOC EPO; 1993, MERCK & CO: "Ophthalmic Compositions Comprising Combinations of a Carbonic Anhydrase Inhibitor and a Prostaglandin or Prostaglandin Derivative", XP002052576 * |
HOYNG, RULO, GREVE ET AL: "The Additive IOP-Lowering Effect of Latanoprost in Combined Therapy with Other Ocular Hypotensive Agents", SURVEY OF OPHTHALMOLOGY, vol. 41, no. S2, February 1997 (1997-02-01), pages S93 - S98, XP002052573 * |
N. PFEIFFER: "The Potential for Topical CAI in Glaucoma Therapy", CURRENT OPINION IN OPHTHALMOLOGY, vol. 5, no. 2, April 1994 (1994-04-01), pages 20 - 25, XP002052574 * |
VON DER ELTZ: "Drug Therapy of Glaucoma: Old and New Agents", PHARMAZEUTISCHE ZEITUNG, vol. 141, no. 8, February 1996 (1996-02-01), pages 11 - 16,18, XP002052575 * |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
USRE43372E1 (en) | 1999-03-05 | 2012-05-08 | Duke University | C16 unsaturated FP-selective prostaglandins analogs |
US8906962B2 (en) | 2000-03-31 | 2014-12-09 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US9675539B2 (en) | 2000-03-31 | 2017-06-13 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
US9579270B2 (en) | 2000-03-31 | 2017-02-28 | Duke University | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
US9346837B2 (en) | 2000-03-31 | 2016-05-24 | Duke University | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
US8722735B2 (en) | 2008-03-17 | 2014-05-13 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
RU2503453C2 (en) * | 2008-03-17 | 2014-01-10 | Алькон Рисерч, Лтд. | Pharmaceutical compositions possessing desirable bioavailability |
EP2705836A1 (en) * | 2008-03-17 | 2014-03-12 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
WO2009117316A2 (en) | 2008-03-17 | 2009-09-24 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
US8754123B2 (en) | 2008-03-17 | 2014-06-17 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
US20140243409A1 (en) * | 2008-03-17 | 2014-08-28 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
EP2599475A3 (en) * | 2008-03-17 | 2013-08-21 | Alcon Research, Ltd. | Pharmaceutical composition having desirable bioavailability |
US9144561B2 (en) | 2008-03-17 | 2015-09-29 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
CN105012964A (en) * | 2008-03-17 | 2015-11-04 | 爱尔康研究有限公司 | Pharmaceutical compositions having desirable bioavailability |
US8178582B2 (en) | 2008-03-17 | 2012-05-15 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
EP3042646A1 (en) * | 2008-03-17 | 2016-07-13 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
CN101977588A (en) * | 2008-03-17 | 2011-02-16 | 爱尔康研究有限公司 | Pharmaceutical compositions having desirable bioavailability |
WO2009117316A3 (en) * | 2008-03-17 | 2010-09-10 | Alcon Research, Ltd. | Pharmaceutical compositions having desirable bioavailability |
Also Published As
Publication number | Publication date |
---|---|
EP0948333A1 (en) | 1999-10-13 |
CA2270349A1 (en) | 1998-05-14 |
AU4257397A (en) | 1998-05-29 |
AU734789B2 (en) | 2001-06-21 |
JP2001504100A (en) | 2001-03-27 |
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