WO1988008709A1 - Improved viscoelastic fluid for ophthalmic surgery and method of using same - Google Patents

Improved viscoelastic fluid for ophthalmic surgery and method of using same Download PDF

Info

Publication number
WO1988008709A1
WO1988008709A1 PCT/US1988/001389 US8801389W WO8808709A1 WO 1988008709 A1 WO1988008709 A1 WO 1988008709A1 US 8801389 W US8801389 W US 8801389W WO 8808709 A1 WO8808709 A1 WO 8808709A1
Authority
WO
WIPO (PCT)
Prior art keywords
approximately
polyethylene oxide
use
ophthalmic surgery
surgery
Prior art date
Application number
PCT/US1988/001389
Other languages
French (fr)
Inventor
Phillip E. Pennell
John M. Blackmore
Original Assignee
Mdr Group, Inc.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority to US4532687A priority Critical
Priority to US045,326 priority
Application filed by Mdr Group, Inc. filed Critical Mdr Group, Inc.
Publication of WO1988008709A1 publication Critical patent/WO1988008709A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61FFILTERS 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
    • A61F9/00Methods 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
    • A61F9/007Methods or devices for eye surgery
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0048Eye, e.g. artificial tears
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L27/00Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14Macromolecular materials
    • A61L27/26Mixtures of macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2430/00Materials or treatment for tissue regeneration
    • A61L2430/16Materials or treatment for tissue regeneration for reconstruction of eye parts, e.g. intraocular lens, cornea

Abstract

This invention relates to an improved viscoelastic vitreous substitute for use in ophthalmic surgery which consists of a mixture of hydroxypropylmethyl cellulose and polyethylene oxide in selected concentrations not to exceed approximately 2 % and 200 ppm, respectively, contained in a physiologic balanced salt solution. It also encompasses the novel method of protecting and lubricating the corneal tissues during surgery with uses of different concentrations of the same solution introduced simultaneously to protect the inner cornea while periodically irrigating the outer cornea, all without obscuring the surgeon's view of the site.

Description

IMPROVED VISCOELASTIC FLUID FOR OPHTHALMIC SURGERY AND METHOD OF USING SAME '

BACKGROUND OF THE INVENTION There are a number of surgical procedures performed on the eyes by skilled ophthalmic surgeons. Among these are cataract surgery, vitreo-retinal surgery and radial keratotomy to reduce myopia. In all of these surgical procedures except for radial keratotomy in which the corneal tissue is not penetrated, the recommended practice is to use an intraocular viscoelastic fluid for protecting the inner endothelial corneal surface and the delicate inner eye structures.

In addition, 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. In 1945, 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 keratoconjunctivitiε sicca and as an emollient. Then in 1959, 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.

The first reported use of 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.

Then in November of 1982, Dr. Danielle Aron-Rosa reported using methylcellulose in extracapsular surgery instead of high molecular weight sodium hyaluronate extracted from rooster combs which is very expensive. Shortly thereafter, Dr. Fechner amplified upon his earlier findings describing the use of methylcellulose as a viscous cushioning material in ophthalmic surgery.

Additional work confirming these earlier results has been conducted by 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. Finally Drs. Smith and Lindstrom evaluated the safety and efficacy of 2% methylcellulose in cat and monkey implant surgery with favorable results.

Despite the high cost of viscoelastic products based upon sodium hyaluronate, all commercially available ones in common use have it as the sole or at least principal ingredient. Some manufacturers of viscoelastic materials are believed to be engaged in experimentation with a bioengineered form of sodium hyaluronate but so ' far it appears that efforts at producing it with a sufficiently high molecular weight have been only marginally successful. A polyacrylamide material is evidently being tested as a material having hydroxypropyl methylcellulose as its basic ingredient.

On the other hand, as far as topical solutions for use in surgery to lubricate the corneal epithelium and protect them from the heat generated by the operating microscope, to applicants knowledge the only product used at the present time is a balanced salt solution which must be administered as often as every 30 to 45 seconds by an assisting surgeon or scrub nurse.

FIELD OF THE INVENTION 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.

DESCRIPTION OF THE RELATED ART As already noted, the use of methylcellulose derivatives as protective cushioning materials to protect the inner eye structures during ophthalmic surgery is old and well known. On the other hand, use of methylcellulose as one ingredient of a topical surgical solution which, in a more dilute form, is used to keep the corneal tissues moist as an adjunct to surgery is, once again, so far as applicant is aware, heretofore unknown in the art although it is, of course, used as an ingredient in so-called "artifical tears" for treating dry eyes and as a component of contact lens solutions. The closest and most pertinent prior art known to applicant is contained in two U.S. Patents, specifically. Patent No. 4,500,538 issued February 19, 1985 to Otto W. Woltersdorf under the title of "Benzothiazolesulfonamide Derivatives for the Topical Treatment of Elevated Intraocular Pressure" and Irving Katz Patent No. 4,287,175 issued September 1, 1981 for "Contact Lens Wetting Agents", both of the aforementioned patents being assigned to Merck & Co., Inc. The earlier Katz patent teaches the use of hydroxypropylmethy1 cellulose or polyethylene oxide among other polymeric viscosity building agents as a solid water soluble insert as a wetting agent for contact lens wearers or so-called "artificial tears". These wetting agents are, however, used in solid form and, as such, are totally unsuitable for use in protecting the delicate epithelial cells in ophalmic surgery. Moreover, there is no suggestion that they be used together or that any useful result whatsoever would be achieved by so doing. As a matter of fact, the elastic properties of the two in combination or, for that matter either one alone, is not a factor in their use as wetting agents.

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. Here again, 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. Most significant, however, is that the formulation of the Woltersdorf patent would be unsuitable for use as a viscoelastic coating to protect the delicate inner eye surfaces during opthalmic surgery or, for that matter, as a topical moisturizing agent to be used during such surgery as a long-lasting moisturizing agent. SUMMARY OF THE INVENTION

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. It has now been found in accordance with the teaching of the present invention that, quite unexpectedly, the addition of 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. In addition, 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. Moreover, since 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.

It is, therefore, 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.

Further objects are to provide a solution for use in ophthalmic surgery which is safe, non-toxic, readily absorbed, easy to administer, versatile in its application, requires no refrigeration and has a long shelf life. Other objects will be in part apparent and in part pointed out specifically hereinafter in connection with the detailed description of the preferred embodiments which follow.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 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.

Of the several prior art substances that have been developed as substitutes for aqueous and vitreous both as a protective layer covering the endothelial cells and as a coating on the surgical instruments and implanted material, undoubtedly the most widely used is sodium hyaluronate extracted from rooster combs, mixtures thereof or bioengineered forms of the naturally-occurring substance. Once the surgical procedure is completed, the remaining vitreous/aqueous substitute is aspirated from the site using a syringe while what is left over is merely resorbed by the body in time without ill effect.

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.

It has now been found that a vastly improved material having greatly improved elasticity at least equivalent to sodium hyaluronate, but at a fraction of its cost, can be made by the simple, yet unobvious, expedient of combining the relatively non-elastic hydroxypropylmethyl cellulose with a high viscosity thixotropic elasticizer, specifically polyethylene oxide, both in a carrier comprising physiologic buffered saline solution.

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. Unexpectedly, applicant has discovered that 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. Specifically, the topical solution will contain approximately 1% hydroxypropylmethyl cellulose and 20 ppm polyethylene oxide carried in a physiologic saline solution. By way of contrast, 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. In accordance with the teaching found herein, 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.

Since these fluids are aspirated from the eye upon completion of the surgery in order to minimize the incidence of intraocular pressure increases, 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.

Claims

CLAIMS What is is claimed is:
1. The viscoelastic aqueous/vitreous substitute for ophthalmic surgery which comprises: a solution containing at least approximately 1% hydroxypropylmethyl cellulose and at least approximately 100 ppm polyethylene oxide in a physiologic balanced salt solution.
2. The viscoelastic aqueous/vitreous substitute as set forth in claim 1 in which: the concentration of the hydroxypropylmethyl cellulose is approximately 2%.
3. The viscoelastic aqueous/vitreous substitute as set forth in claim 1 in which: the concentration of the polyethylene oxide is approximately 200 ppm.
4. The method of irrigating and protecting the corneal tissues during ophthalmic surgery which comprises: covering the inner cornea with a physiologic saline solution containing approximately 2% hydroxypropylmethyl cellulose and approximately 10 ppm polyethylene oxide while simultaneously periodically wetting the outer cornea with a compatible physiologic saline solution containing approximately half the hydroxypropylmethyl cellulose and approximately twice the polyethylene oxide.
PCT/US1988/001389 1987-05-04 1988-04-27 Improved viscoelastic fluid for ophthalmic surgery and method of using same WO1988008709A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US4532687A true 1987-05-04 1987-05-04
US045,326 1987-05-04

Publications (1)

Publication Number Publication Date
WO1988008709A1 true WO1988008709A1 (en) 1988-11-17

Family

ID=21937238

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1988/001389 WO1988008709A1 (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 (en)
JP (1) JPS6464653A (en)
AU (1) AU1726088A (en)
CA (1) CA1317226C (en)
GB (1) GB2204238A (en)
WO (1) WO1988008709A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8791154B2 (en) 2011-05-19 2014-07-29 Alcon Research, Ltd. High concentration olopatadine ophthalmic composition

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4020623C2 (en) * 1990-06-29 1996-06-05 Mezotraslevoj Nt Kompleks Mikr Corneal protector and process for its preparation
DE69432188T2 (en) 1993-04-30 2004-01-22 Nestle S.A. Synthetic Viskoseelastisches material for physiological applications such as ophthalmology applications
EP1132065A1 (en) * 2000-03-07 2001-09-12 Gerrit Reinold Jacob Melles Coloured visco-elastic composition
JP2005502581A (en) * 2000-12-20 2005-01-27 アルコン、インコーポレイテッド Intraocular perfusion solution with improved flow properties
US7084130B2 (en) 2001-12-11 2006-08-01 Alcon, Inc. Intraocular irrigating solution having improved flow characteristics
JP4169596B2 (en) 2000-12-20 2008-10-22 アルコン、インコーポレイテッド Solution for removing by liquefaction destroy cataracts
CN105749360A (en) * 2016-03-28 2016-07-13 山东赛克赛斯药业科技有限公司 Cornea protecting composition as well as preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
US4343787A (en) * 1975-07-29 1982-08-10 Merck & Co., Inc. Shaped ophthalmic inserts for treating dry eye syndrome
US4629623A (en) * 1984-06-11 1986-12-16 Biomatrix, Inc. Hyaluronate-poly (ethylene oxide) compositions and cosmetic formulations thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1340517A (en) * 1969-12-01 1973-12-12 Burton Parsons Chemicals Inc Ophthalmic solution
US4287175A (en) * 1978-06-22 1981-09-01 Merck & Co., Inc. Contact lens wetting agents
GB2167300B (en) * 1984-11-23 1988-11-23 Fisons Plc Formulations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3947573A (en) * 1969-12-01 1976-03-30 Burton, Parsons And Company, Inc. Opthalmic solution
US3856919A (en) * 1970-06-08 1974-12-24 Burton Parsons Chemicals Inc Ophthalmic solution
US4343787A (en) * 1975-07-29 1982-08-10 Merck & Co., Inc. Shaped ophthalmic inserts for treating dry eye syndrome
US4629623A (en) * 1984-06-11 1986-12-16 Biomatrix, Inc. Hyaluronate-poly (ethylene oxide) compositions and cosmetic formulations thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
International Ophtal. Clin., Volume 13, issued 1973, M. LEMP, "Tear Substituents in the Treatment of Dry Eyes. See entire document. *
See also references of EP0359766A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8791154B2 (en) 2011-05-19 2014-07-29 Alcon Research, Ltd. High concentration olopatadine ophthalmic composition
US9533053B2 (en) 2011-05-19 2017-01-03 Alcon Research, Ltd. High concentration olopatadine ophthalmic composition

Also Published As

Publication number Publication date
AU1726088A (en) 1988-12-06
EP0359766A1 (en) 1990-03-28
GB8808983D0 (en) 1988-05-18
JPS6464653A (en) 1989-03-10
GB2204238A (en) 1988-11-09
CA1317226C (en) 1993-05-04
EP0359766A4 (en) 1990-12-19

Similar Documents

Publication Publication Date Title
El Danasoury et al. Comparison of photorefractive keratectomy with excimer laser in situ keratomileusis in correcting low myopia (from− 2.00 to− 5.50 diopters): a randomized study
Wang et al. Comparison of laser in situ keratomileusis and photorefractive keratectomy to correct myopia from-1.25 to-6.00 diopters
Fluorouracil Filtering Surgery Study Group Three-year follow-up of the Fluorouracil Filtering Surgery Study
Uusitalo et al. Implantable contact lens for high myopia
Uy et al. Comparison of fibrin glue and sutures for attaching conjunctival autografts after pterygium excision
Allemann et al. Myopic angle-supported intraocular lenses: two-year follow-up
Koranyi et al. The cut‐and‐paste method for primary pterygium surgery: long‐term follow‐up
Sher et al. Excimer laser photorefractive keratectomy in high myopia: a multicenter study
US5972326A (en) Controlled release of pharmaceuticals in the anterior chamber of the eye
US6060463A (en) Treatment of conditions of abnormally increased intraocular pressure by administration of phosphonylmethoxyalkyl nucleoside analogs and related nucleoside analogs
Lohmann et al. Regression after LASIK for the treatment of myopia: the role of the corneal epithelium
Salz et al. A two-year experience with excimer laser photorefractive keratectomy for myopia
Pruett et al. Hyaluronic acid vitreous substitute: A six-year clinical evaluation
Mardelli et al. Slit-lamp needle revision of failed filtering blebs using mitomycin C
Malecaze et al. A randomized paired eye comparison of two techniques for treating moderately high myopia: LASIK and artisan phakic lens
Pallikaris et al. A corneal flap technique for laser in situ keratomileusis: human studies
Knorz et al. Laser in situ keratomileusis to correct myopia of-6.00 to-29.00 diopters
Autrata et al. Laser-assisted subepithelial keratectomy for myopia: two-year follow-up
Pfleger et al. Long-term course of induced astigmatism after clear corneal incision cataract surgery
Shields et al. Clinical and histopathologic observations concerning hypotony after trabeculectomy with adjunctive mitomycin C
US5965152A (en) Controlled release of miotic and mydriatic drugs in the anterior chamber
CA1298202C (en) Extraocular methods of treating the eye with liquid perfluorocarbons
EP1972344A1 (en) Ophthalmic formulation for the prevention and treatment of ocular conditions
Hilton et al. Pneumatic retinopexy: a two-step outpatient operation without conjunctival incision
US4965253A (en) Viscoelastic material for ophthalmic surgery

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LU NL SE

WWE Wipo information: entry into national phase

Ref document number: 1988904341

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1988904341

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1988904341

Country of ref document: EP