EP0359766A1 - Viskoelastische flüssigkeit für die ophthalmische chirurgie und methode zur anwendung derselben - Google Patents
Viskoelastische flüssigkeit für die ophthalmische chirurgie und methode zur anwendung derselbenInfo
- Publication number
- EP0359766A1 EP0359766A1 EP88904341A EP88904341A EP0359766A1 EP 0359766 A1 EP0359766 A1 EP 0359766A1 EP 88904341 A EP88904341 A EP 88904341A EP 88904341 A EP88904341 A EP 88904341A EP 0359766 A1 EP0359766 A1 EP 0359766A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- approximately
- ophthalmic surgery
- polyethylene oxide
- surgery
- viscoelastic
- 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- Withdrawn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
- 238000001356 surgical procedure Methods 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 6
- 239000012530 fluid Substances 0.000 title description 6
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims abstract description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 12
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 12
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 12
- 210000004087 cornea Anatomy 0.000 claims abstract description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 6
- 239000000243 solution Substances 0.000 claims description 10
- 239000003855 balanced salt solution Substances 0.000 claims description 7
- 238000009736 wetting Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 13
- 230000001050 lubricating effect Effects 0.000 abstract 1
- 210000001519 tissue Anatomy 0.000 description 12
- 229920000609 methyl cellulose Polymers 0.000 description 10
- 239000001923 methylcellulose Substances 0.000 description 10
- 229920002385 Sodium hyaluronate Polymers 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 229940010747 sodium hyaluronate Drugs 0.000 description 9
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 description 9
- 230000000699 topical effect Effects 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 230000003020 moisturizing effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- WCDDVEOXEIYWFB-VXORFPGASA-N (2s,3s,4r,5r,6r)-3-[(2s,3r,5s,6r)-3-acetamido-5-hydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-4,5,6-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@@H]1C[C@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O)[C@H](O)[C@H]1O WCDDVEOXEIYWFB-VXORFPGASA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 229940014041 hyaluronate Drugs 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229940100613 topical solution Drugs 0.000 description 3
- 239000003190 viscoelastic substance Substances 0.000 description 3
- 208000002177 Cataract Diseases 0.000 description 2
- 241000287828 Gallus gallus Species 0.000 description 2
- 210000002159 anterior chamber Anatomy 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 210000001520 comb Anatomy 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000004406 elevated intraocular pressure Effects 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 230000009974 thixotropic effect Effects 0.000 description 2
- 239000008154 viscoelastic solution Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZOAXTOPVRCPOQX-UHFFFAOYSA-N 5-hydroxy-1,3-benzothiazole-2-sulfonamide Chemical compound OC1=CC=C2SC(S(=O)(=O)N)=NC2=C1 ZOAXTOPVRCPOQX-UHFFFAOYSA-N 0.000 description 1
- NOOBQTYVTDBXTL-UHFFFAOYSA-N 6-hydroxy-1,3-benzothiazole-2-sulfonamide Chemical compound C1=C(O)C=C2SC(S(=O)(=O)N)=NC2=C1 NOOBQTYVTDBXTL-UHFFFAOYSA-N 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 239000000607 artificial tear Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000000882 contact lens solution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 210000000871 endothelium corneal Anatomy 0.000 description 1
- 210000003560 epithelium corneal Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000004410 intraocular pressure Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 229940023490 ophthalmic product Drugs 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 239000011241 protective layer Substances 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F9/00—Methods or devices for treatment of the eyes; Devices for putting in contact-lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
- A61F9/007—Methods or devices for eye surgery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/14—Macromolecular materials
- A61L27/26—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2430/00—Materials or treatment for tissue regeneration
- A61L2430/16—Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea
Definitions
- the outer epithelial surface of the cornea must be lubricated continuously with some type of moisturizing agent to keep it from drying out under the heat generated by the operating microscope light.
- Methylcellulose has a long history of safe and effective use for ophthalmic applications.
- Dr. Kenneth C. Swan studied the effects of methylcellulose on the ocular tissues of rabbit eyes. He suggested its use as a vehicle for ophthalmic drugs, to treat keratoconjunctiviti ⁇ sicca and as an emollient.
- Flemming, Merrill and Girard reported on further studies of methylcellulose in relation to irritation, hypersensitivity and its outflow from the anterior chamber of the rabbit eye.
- methylcellulose as an intraocular lens coating serving to protect the corneal endothelium in rabbits was made by Drs. Kaufman and Katz in 1976. In the following year Dr. Paul Fechner reported upon the first human clinical use of methylcellulose to coat an intraocular lens prior to implantation.
- Dr. Scott M. MacRae who compared the efficacy and toxicity of sodium hyaluronate, methylcellulose and chrondroitin sulfate, all three of which are used as protective substances suitable for use in ophthalmic surgery.
- Drs. Smith and Lindstrom evaluated the safety and efficacy of 2% methylcellulose in cat and monkey implant surgery with favorable results.
- the present invention relates to an improved viscoelastic formulation which when used in dilute form as a topical solution in place of balanced salt solution to keep the corneal surfaces moist lasts up to ten times as long in the eye before having to be renewed.
- the same unique formulation when used in a different concentration has proven to be equally as good if not better than sodium hyaluronate for use as a protective agent for the inner endothelial corneal surface and other delicate inner eye structures during ophthalmic surgery and considerably less expensive.
- the invention also encompasses the novel method of using the two different yet compatible solutions together during ophthalmic surgery so as to simultaneously protect the cornea and irrigate it without obscuring the surgeon's view of the site in any way.
- the Woltersdorf patent also mentions the use of hydroxypropylmethyl cellulose and polyethylene oxide as solid water soluble carriers for the active medicament of the invention, namely, the carbonates of 6 or 5-hydroxy-2- benzothiazolesulfonamide for use in the reduction of elevated intraocular pressure of the type often associated with glaucoma.
- these high molecular weight substances are used merely as a base for the active ingredient when used as a solid insert as opposed to a solution administered in the form of drops. There is no mention of them being used together nor is their elastic property of any consequence in this application.
- This invention encompasses a novel fluid viscoelastic formulation of variable viscosity for use in ophthalmic surgery containing as its active ingredients a mixture of both hydroxypropylme h l cellulose and polyethylene oxide together with a physiologic buffered saline solution.
- Hydroxypropylmethyl cellulose is clear, non-toxic and quite viscous, however, it is also essentially non-elastic.
- polyethylene oxide which is a thixotropic material having a nominal molecular weight of 4 million, greatly improves the elasticity of the mixture and makes it comparable, if not superior, to sodium hyaluronate for use as a viscoelastic material in ophthalmic surgery.
- different relative concentrations of the two active ingredients in the aforesaid composition have proven to be far superior to balanced salt solution for topical application to keep the tissues moist during surgery by maintaining a smooth, hydrated cornea under the heat of the operating room microscope light.
- the two solutions contain the same active ingredients, they are fully compatible and can be used simultaneously to both protect and irrigate the delicate corneal tissues.
- the principal object of the present invention to provide an improved viscoelastic solution for use in ophthalmic surgery which is made up in two different concentrations and administered simultaneously to both protect and irrigate the corneal tissues.
- a second object is to provide a solution of the type aforementioned which is susceptible of being made up in selected viscosities by changing the relative concentrations of the active ingredients to adapt it for use as either a topical moisturizing agent or a protective shield for the delicate corneal surfaces and epithelial cells within the inner eye.
- Another objective of the invention herein disclosed and claimed is that of providing a topical moisturizing agent which remains effective many times longer than the conventional balanced salt solution while, at the same time, doing a better job.
- Still another objective of the within-described invention is to provide a protective solution for intracorneal use in eye surgery which has excellent clarity and transparency but, more importantly, much improved elasticity when compared with hydroxypropylmethyl cellulose alone.
- An additional object is to provide a high-molecular weight viscoelastic mixture which is equally effective if not, in fact, superior to sodium hyaluronate-based products at a fraction of the cost.
- the anterior chamber of the eye is filled with circulating aqueous, whereas its posterior chamber with vitreous.
- the endothelial cell layer of the cornea is easily damaged and, once lost, these cells do not regenerate.
- the surgical procedures used in cataract surgery, corneal transplants and other types of ophthalmic surgery are likely to result in damage to these delicate cells unless measures are taken to protect them in the manner in which aqueous does naturally.
- hyaluronate-based products The main problem with hyaluronate-based products is their cost which at the present time runs around $70 or so for less than a cubic centimeter of material. While attempts have been made to use various methylcellulose derivatives as less expensive viscoelastic substitutes, they have not been well accepted nor do they work as well as hyaluronate.
- the other problem encountered in ophthalmic surgery is that of keeping the external tissues of the eye moist under the drying effect of the operating microscope. As previously noted, this is generally handled on a more-or-less continuous basis by irrigating the external corneal tissues with a balanced salt solution, sometimes as often as twice a minute.
- a carefully modified mixture used as the intraocular viscoelastic material for the internal tissues can be advantageously used as a topical solution to keep the external corneal tissues moist many times longer than the balanced salt solution by merely varying the relative concentrations and, therefore, the resulting viscosity of the previously-mentioned intraocular viscoelastic solution that acts as a supplement and substitute for the naturally-occurring vitreous.
- the topical solution will contain approximately 1% hydroxypropylmethyl cellulose and 20 ppm polyethylene oxide carried in a physiologic saline solution.
- the intraocular viscoelastic composition will have the concentration of the hydroxypropylmethyl cellulose increased to 2% while the concentration of the polyethylene oxide is reduced to only 10 ppm.
- a unique method of simultaneously irrigating and protecting the delicate corneal tissues is taught using two fully compatible solutions containing the same active ingredients but in different concentrations. When this is done, the stroirta and entire cornea is hydrated while the fluid loss through the incision is minimized. It also acts as a tamponade on the scleral flap area.
- a non-toxic and physiologically inert tinting material may be added so that the surgeon can be surer that he or she has removed most of the fluid added during the surgery.
- the resulting compositions, with or without the dye have proven to be every bit as effective as hyaluronate-based preparations while being far less expensive and, at the same time, lowering operating room costs due to the more efficient use of personnel that results from the less frequent need for irrigation of the corneal tissues.
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Ophthalmology & Optometry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Surgery (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Transplantation (AREA)
- Vascular Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Materials For Medical Uses (AREA)
- Prostheses (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US4532687A | 1987-05-04 | 1987-05-04 | |
| US45326 | 1987-05-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0359766A1 true EP0359766A1 (de) | 1990-03-28 |
| EP0359766A4 EP0359766A4 (en) | 1990-12-19 |
Family
ID=21937238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19880904341 Withdrawn EP0359766A4 (en) | 1987-05-04 | 1988-04-27 | Improved viscoelastic fluid for ophthalmic surgery and method of using same |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0359766A4 (de) |
| JP (1) | JPS6464653A (de) |
| AU (1) | AU1726088A (de) |
| CA (1) | CA1317226C (de) |
| GB (1) | GB2204238A (de) |
| WO (1) | WO1988008709A1 (de) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4020623C2 (de) * | 1990-06-29 | 1996-06-05 | Mezotraslevoj Nt Kompleks Mikr | Hornhaut-Protektor und Verfahren zu dessen Herstellung |
| CA2161774C (en) * | 1993-04-30 | 2000-01-04 | Nestle S.A. | Synthetic viscoelastic material for ophthalmic applications |
| RU2115413C1 (ru) * | 1997-03-03 | 1998-07-20 | Малое государственное предприятие "Научно-экспериментальное производство" | Ирригационный раствор "интрасол" |
| EP1132065A1 (de) * | 2000-03-07 | 2001-09-12 | Gerrit Reinold Jacob Melles | Farbige visko-elastische Zusammensetzung |
| AU2002239601B2 (en) * | 2000-12-20 | 2005-09-01 | Alcon Inc. | Intraocular irrigating solution having improved flow characteristics |
| AU2002228955B2 (en) | 2000-12-20 | 2005-09-29 | Alcon Inc. | Solution for removing cataracts via liquefracture |
| US7084130B2 (en) | 2001-12-11 | 2006-08-01 | Alcon, Inc. | Intraocular irrigating solution having improved flow characteristics |
| TWI544922B (zh) | 2011-05-19 | 2016-08-11 | 愛爾康研究有限公司 | 高濃度歐羅派特錠(olopatadine)眼用組成物 |
| CN105749360B (zh) * | 2016-03-28 | 2019-06-18 | 赛克赛斯生物科技股份有限公司 | 一种保护角膜的组合物及其制备方法与应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1340517A (en) * | 1969-12-01 | 1973-12-12 | Burton Parsons Chemicals Inc | Ophthalmic solution |
| US3856919A (en) * | 1970-06-08 | 1974-12-24 | Burton Parsons Chemicals Inc | Ophthalmic solution |
| US3947573A (en) * | 1969-12-01 | 1976-03-30 | Burton, Parsons And Company, Inc. | Opthalmic solution |
| NL188266C (nl) * | 1975-07-29 | 1992-05-18 | Merck & Co Inc | Werkwijze ter bereiding van een oogheelkundig inplantaat. |
| US4287175A (en) * | 1978-06-22 | 1981-09-01 | Merck & Co., Inc. | Contact lens wetting agents |
| US4629623A (en) * | 1984-06-11 | 1986-12-16 | Biomatrix, Inc. | Hyaluronate-poly (ethylene oxide) compositions and cosmetic formulations thereof |
| GB2167300B (en) * | 1984-11-23 | 1988-11-23 | Fisons Plc | Formulations |
-
1988
- 1988-03-30 CA CA000562926A patent/CA1317226C/en not_active Expired - Fee Related
- 1988-04-15 GB GB08808983A patent/GB2204238A/en not_active Withdrawn
- 1988-04-27 WO PCT/US1988/001389 patent/WO1988008709A1/en not_active Ceased
- 1988-04-27 AU AU17260/88A patent/AU1726088A/en not_active Abandoned
- 1988-04-27 EP EP19880904341 patent/EP0359766A4/en not_active Withdrawn
- 1988-05-02 JP JP63107739A patent/JPS6464653A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6464653A (en) | 1989-03-10 |
| GB2204238A (en) | 1988-11-09 |
| CA1317226C (en) | 1993-05-04 |
| WO1988008709A1 (en) | 1988-11-17 |
| EP0359766A4 (en) | 1990-12-19 |
| AU1726088A (en) | 1988-12-06 |
| GB8808983D0 (en) | 1988-05-18 |
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Legal Events
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| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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| 17P | Request for examination filed |
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| 18D | Application deemed to be withdrawn |
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