EP0948333A1 - 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 glaucomaInfo
- Publication number
- EP0948333A1 EP0948333A1 EP97940895A EP97940895A EP0948333A1 EP 0948333 A1 EP0948333 A1 EP 0948333A1 EP 97940895 A EP97940895 A EP 97940895A EP 97940895 A EP97940895 A EP 97940895A EP 0948333 A1 EP0948333 A1 EP 0948333A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbonic anhydrase
- prostaglandins
- isopropyl
- hydroxy
- prostaglandin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
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
Abstract
Compositions and methods for treating persons suffering from glaucoma or ocular hypertension are disclosed. In particular, the persons are treated with prostaglandins and carbonic anhydrase inhibitors to control their intraocular pressure.
Description
SE OF A COMBINATION OF CARBONIC ANHYDRASE INHIBITORS AND PROSTAGLANDINS FOR TREATING
GLAUCOMA
Background of the Invention
The present invention relates to the field of ophthalmology. In particular, the invention relates to the treatment of persons suffering from glaucoma and associated elevations of intraocular pressure (IOP) and/or ocular hypertension.
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.
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.
Summary of the Invention
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.
Detailed Description of the Invention
Prostaglandins are metabolic derivatives of arachidonic acid. The arachidonic acid cascade is initiated by the conversion of arachidonic acid to prostaglandin G2 and its subsequent conversion to prostaglandin H2. Other naturally occurring prostaglandins are derivatives of prostaglandin H2. 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 PGD2(I) or PGF2α(II):
While Applicants do not wish to be bound by any theory, the D-prostaglandins ("DP-agonist") 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-D2 receptors of cells and evoke similar responses as when PGD2 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. Compounds which exhibit Kj values in this assay of less than or equal to about 20 μM are within the definition of DP-agonists of the present invention.
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. Briefly, 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. The reaction is then stopped and the cAMP generated is determined by a radioimmunoassay kit. Data are analyzed using a non-linear, iterative curve-fitting computer program to define the potency ("EC50", concentration which produces 50% of the maximum response of PGD2) and 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.β.(3S),3. .,5.o(.]]-[[4-[5-chloro-2-(3- cyclohexyl-3-hydroxy-propyl)-3-hydroxycyclopentyl]-2-butenyl]oxy]-acetic acid, isopropyl ester) (see commonly assigned U.S. Patent No. 5,627,209).
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. 5,510,383, particularly isopropyl esters of cloprostenol and fluprostenol and their individual isomers and the compounds disclosed in WO 97/23223. Most preferred compounds are (+)-isopropyl fluprostenol and compound VHI on page 9 of WO 97/23223
(Isopropyl [2R(lE,3R),3S(4Z),4R]-7-[Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-l- buteny 1] -4-hy droxy-3 -fur any 1] -4-heptenoate).
The CAIs which are useful in the compositions and methods of the present invention include all thiophene sulfonamides and thienothiazines which lower and control
IOP by inhibiting carbonic anhydrase when administered topically. Representative CAIs are disclosed in: U.S. Patent Nos. 4,797,413 (Baldwin, et al.), 4,847,289 (Baldwin, et al.), and 4,731,368 (Hoffman, Jr., et al.); U.S. Patent Nos. 5,153,192 (Dean, et al.), 5,240,923 (Dean, et al.), and 5,378,703 (Dean, et al.); PCT/US91/02262 (filed 9 April 1990); and EP 452 151 (published 16 October 1991). The entire contents of each of the above-mentioned patents and patent applications are incorporated herein by reference.
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-tlήazine-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. 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.
In general, 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.%. In a combination formula, the PG concentration can be between 0.0005 and 0.03 wt.% and the CAI 0.5 and 1.5 wt.%.
In addition to the above-described principal ingredients, the anti-glaucoma compositions of the present invention may further comprise various formulatory ingredients, such as antimicrobial preservatives and tonicity agents. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thirnerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
Onamer M® and other agents equally well-known to those skilled in the art. Such preservatives, if used, will typically be employed in an amount between about 0.001 to 1.0 wt.%. Examples of 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%. Also, 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.
As will be appreciated by those skilled in the art, the 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).
The following examples further illustrate the anti-glaucoma compositions of the present invention, but are not limiting.
Example 1
Ophthalmic Suspension
Ingredient Concentration (wt %)
Brinzolamide 1.0 ([lR-[l.o(.(Z),2.β.(3S),3. .,5. .]]-[[4-
[5 -chloro-2-(3 -cy clohexyl-3 -hy droxy-propy 1)
-3 -hydroxy cy clopenty 1] -2-buteny 1] oxy] -acetic acid, isopropyl ester) 0.01
Hydroxy propy l ethy lcellulose 0.5 Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01 Cremaphor 0.1
NaOH/HCl pH 7.1
Example 2 Ophthalmic Suspension
Ingredient - Concentration (wt %)
Brinzolamide 1.0
(+)-Isopropyl Fluprostenol 0.005
Hydroxypropylmethylcellulose 0.5
Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01
Cremaphor 0.1
NaOH/HCl pH 7.1
Example 3
Ophthalmic Suspension
Ingredient - Concentration (wt %)
Brinzolamide 1.0
Isopropyl [2R(lE,3R),3S(4Z),4R]-7- [Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy- 1 -butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate 0.01
Hydroxypropylmethylcellulose 0.5
Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01
Cremaphor 0.1 NaOH/HCl pH 7.1
Example 4
An example of two formulations to be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Amount (wt%
(+)-Isopropyl Fluprostenol 0.005
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate (anhydrous) 0.15
Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremophor EL 0.1
Benzalkonium chloride 0.01
HCl and/or NaOH pH 7.3 - 7.4
Purified water q.s. to 100%
Formulation B
Ingredient Concentration (wt %)
Brinzolamide 1.0
Hydroxypropylmethylcellulose 0.5
Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01
Cremaphor 0.1
NaOH/HCl pH 7.1
Example 5
The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Concentration (wt %)
Brinzolamide 1.0
Hydroxypropylmethylcellulose 0.5 Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01 Cremaphor 0.1
NaOH/HCl pH 7.1
Formulation B
Ingredient Amount (wt%^
(+)-Isopropyl Fluprostenol 0.001
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate (anhydrous) 0.15
Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremaphor EL 0.1
Benzalkonium chloride 0.01
HCl and/or NaOH pH 7.3 - 7.4
Purified water q.s. to 100%
Example 6
The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A ingredient Concentration (wt %)
Brinzolamide 1.0
Hydroxypropylmethylcellulose 0.5 Dibasic Sodium Phosphate 0.2
Disodium Edetate 0.01
Sodium Chloride 0.8
Purified Water q.s
Benzalkonium Chloride 0.01 Cremaphor 0.1
NaOH HCl pH 7.1
Formulation B
Ingredient Amount (wt%)
Isopropyl [2R(lE,3R),3S(4Z),4R]-7- [Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy- 1 -butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate 0.01
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate (anhydrous) 0.15
Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremaphor EL 0.1
Benzalkonium chloride 0.01
HCl and/or NaOH pH 7.3 - 7.4
Purified water q.s. to 100%
Example 7
The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Concentration (wt %)
Brinzolamide 1.0
Mannitol 3.3 Carbopol 974P 0.4
Tyloxapol 0.025
Benzalkonium Chloride 0.1% + 5%xs
Disodium EDTA (Edetate Disodium) 0.01
Sodium Hydroxide pH 7.5 +/- .2 Hydrochloric Acid pH 7.5 +/- .2
Sodium Chloride 0.25
Purified Water q.s. to 100%
Formulation B Ingredient Amount (wt%)
(+)-Isopropyl Fluprostenol 0.005
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate (anhydrous) 0.15 Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremaphor EL 0.1
Benzalkonium chloride 0.01
HCl and/or NaOH pH 7.3 - 7.4 Purified water q.s. to 100%
Example 8
The following two formulations can be used concomitantly, within 30 minutes, or offset by more than 1 hour.
Formulation A
Ingredient Concentration (wt %)
Brinzolamide 1.0
Mannitol 3.3
Carbopol 974P 0.4 Tyloxapol 0.025
Benzalkonium Chloride 0.1% + 5%xs
Disodium EDTA (Edetate Disodium) 0.01
Sodium Hydroxide pH 7.5 +/- .2
Hydrochloric Acid pH 7.5 +/- .2 Sodium Chloride 0.25
Purified Water q.s. to 100%
Formulation B
Ingredient Amount (wt%)
Isopropyl [2R(lE,3R),3S(4Z),4R]-7- [Tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy- 1 -butenyl]-4-hydroxy-3 -furanyl]-4-heptenoate 0.01
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate (anhydrous) 0.15
Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremaphor EL 0.1
Benzalkonium chloride 0.01
HCl and/or NaOH pH 7.3 - 7.4
Purified water q.s. to 100%
Claims
1. A method for lowering IOP in persons suffering from glaucoma or ocular hypertension, which comprises, administering topically to the eye a pharmaceutically effective amount of a prostaglandin and a carbonic anhydrase inhibitor.
2. The method of Claim 1 wherein the prostaglandin is (+)-isopropyl fluprostenol.
3. The method of Claim 1 wherein the prostaglandin is isopropyl
[2R(lE,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-l-butenyl]-4- hy droxy-3 -furany 1] -4-heptenoate.
4. The method of Claim 1 wherein the carbonic anhydrase inhibitor is brinzolamide.
5. The method of Claim 1 wherein the prostaglandin is (+)-isopropyl fluprostenol and the carbonic anhydrase inhibitor is brinzolamide.
6. The method of Claim 1 wherein the prostaglandin is isopropyl
[2R(lE,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-l-butenyl]-4- hydroxy-3 -f rany 1] -4-heptenoate and the carbonic anhydrase inhibitor is brinzolamide.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US2953896P | 1996-11-01 | 1996-11-01 | |
| US29538P | 1996-11-01 | ||
| PCT/US1997/015793 WO1998019680A1 (en) | 1996-11-01 | 1997-09-05 | Use of a combination of carbonic anhydrase inhibitors and prostaglandins for treating glaucoma |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0948333A1 true EP0948333A1 (en) | 1999-10-13 |
Family
ID=21849545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP97940895A Withdrawn EP0948333A1 (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) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL350917A1 (en) | 1999-03-05 | 2003-02-10 | Procter & Gamble | C16 unsaturated fp-selective prostaglandins analogs |
| US20020172693A1 (en) | 2000-03-31 | 2002-11-21 | Delong Michell Anthony | Compositions and methods for treating hair loss using non-naturally occurring prostaglandins |
| US20020013294A1 (en) | 2000-03-31 | 2002-01-31 | Delong Mitchell Anthony | Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives |
| TWI544927B (en) * | 2008-03-17 | 2016-08-11 | 愛爾康研究有限公司 | Pharmaceutical compositions having low concentration of surfactants for promoting bioavailability of therapeutic agents |
Family Cites Families (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 |
| TW210287B (en) * | 1991-03-01 | 1993-08-01 | Kabushikaisha Ueno Seiyaku Oyo Kenkyujo | |
| IL104648A0 (en) * | 1992-02-13 | 1993-06-10 | Merck & Co Inc | Ophthalmic compositions comprising combinations of a carbonic anhydrase inhibitor and a prostaglandin or prostaglandin derivative |
| AU666957B2 (en) * | 1992-08-28 | 1996-02-29 | Alcon Laboratories, Inc. | Use of certain anionic surfactants to enhance antimicrobial effectiveness of ophthalmic 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 |
| AU687906B2 (en) * | 1993-12-15 | 1998-03-05 | Alcon Laboratories, Inc. | Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension |
| DE69633136T2 (en) * | 1995-12-22 | 2005-09-01 | Alcon Laboratories, Inc., Fort Worth | SUBSTITUTED TETRAHYDROFURAN ANALOGS OF PROSTAGLANDINES AS EYE PRESENTING MEDICAMENTS |
-
1997
- 1997-09-05 WO PCT/US1997/015793 patent/WO1998019680A1/en not_active Application Discontinuation
- 1997-09-05 JP JP52136398A patent/JP2001504100A/en active Pending
- 1997-09-05 EP EP97940895A patent/EP0948333A1/en not_active Withdrawn
- 1997-09-05 CA CA002270349A patent/CA2270349A1/en not_active Abandoned
- 1997-09-05 AU AU42573/97A patent/AU734789B2/en not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9819680A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU734789B2 (en) | 2001-06-21 |
| AU4257397A (en) | 1998-05-29 |
| WO1998019680A1 (en) | 1998-05-14 |
| JP2001504100A (en) | 2001-03-27 |
| CA2270349A1 (en) | 1998-05-14 |
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