US20040071778A1 - Ophthalmic compound with extended dwell time on the eye - Google Patents

Ophthalmic compound with extended dwell time on the eye Download PDF

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Publication number
US20040071778A1
US20040071778A1 US10/625,634 US62563403A US2004071778A1 US 20040071778 A1 US20040071778 A1 US 20040071778A1 US 62563403 A US62563403 A US 62563403A US 2004071778 A1 US2004071778 A1 US 2004071778A1
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Prior art keywords
preservative
eye
weight
ophthalmic composition
composition according
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US10/625,634
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Gunther Bellmann
Gudrun Claus-Herz
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Bausch and Lomb Inc
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Bausch and Lomb Inc
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Priority to US10/625,634 priority Critical patent/US20040071778A1/en
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • 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
    • 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

Definitions

  • the invention relates to an ophthalmic composition with prolonged residence time on the eye, in particular in the form of a gel which can be administered as drops, of an ointment or the like, containing a free-flowing vehicle with increased viscosity and a preservative, and, where appropriate, one or more active ingredients and conventional additives such as tonicity agents, substances to adjust the pH etc.
  • the invention additionally relates to the use of a benzyllauryldimethylammonium salt for producing ophthalmic compositions.
  • Ophthalmic compositions may, like other pharmaceutical products too, be contaminated by microorganisms of a wide variety of species. The possibility of such microorganisms entering the eye and getting onto the mucosa of the eye on use of the ophthalmic composition must be avoided. Ophthalmic products must therefore comply with strict sterility requirements. This is why products of this type are always produced under sterile conditions.
  • ophthalmic compositions which show prolonged (by comparison with products which can easily be washed out by tear fluid, such as, for example, conventional aqueous dropper solutions) residence time on or in the eye after a single use.
  • tear fluid such as, for example, conventional aqueous dropper solutions
  • Products of this type are, with regard to their consistency, adjusted to have an increased viscosity.
  • aqueous products which are gelatinously thickened by adding water-soluble polymers, in particular gels which can be administered as drops.
  • ointments usually in the form of spreadable emulsions.
  • Preservatives used for such purposes are, for example, thiomersal, cetrimide and similar substances.
  • Another preservative which is frequently suggested for ophthalmic products is benzalkonium chloride.
  • Benzalkonium chloride is the international nonproprietory name for N-alkyl-N-benzyl-N,N-dimethyl-ammonium chloride with alkyl radicals between C 8 H 17 and C 18 H 37 .
  • Benzalkonium chloride is normally obtained from natural fats or oils and is a mixture of varying composition, depending on the raw materials used, of the quaternary compounds described above.
  • benzalkonium in this application always means such a mixture with different alkyl radicals, with the number of carbon atoms in the alkyl radical varying from C 8 to C 18 .
  • U.S. Pat. No. 4,053,628 discloses a clear solution of sodium cromoglicate to which a large number of preservatives can be added. Suggested and exemplified besides thiomersal, cetrimide, benzetkonium chloride and others is also benzalkonium chloride. The possibility of adjusting the viscosity of such solutions is mentioned in general; however, the examples relate exclusively to solutions without viscosity-modifying additives. The risk of eye irritation due to the preservative is not mentioned in this publication.
  • U.S. Pat. No. 4,271,143 has disclosed the use of benzalkonium chloride as preservative in an ophthalmic gel for delayed release of active ingredient. There is no report of eye irritation with the envisaged long residence time in the eye. The tests on the eye described in U.S. Pat. No. 4,271,143 each lasted only a few hours. This is possibly the reason why the problems which occur with such gels on prolonged use apparently were not observed.
  • Benzalkonium chloride has excellent antiseptic properties even in ophthalmic preparations, especially in aqueous ophthalmic preparations.
  • benzalkonium chloride is, as has emerged since publication of the abovementioned patents, poorly tolerated and may lead to irritation and even damage of the eye.
  • B. Lopez et al. (Current Eye Research, 1991, 10 (7) 645 to 656) report on the injurious effect of preservatives in simulated tear fluids on the cornea of rabbits. The effect of tear fluids preserved with 0.01%. benzalkonium chloride, 0.001% polyquat or 0.004% thiomersal was related to that in a comparison group in which the simulated tear fluid was used without preservative.
  • the measure chosen for the damage to the cornea was the increase in the ability to take up carboxyfluorescein. Simulated tears which contained polyquat or thiomersal brought about an increase in uptake of one to four-fold. Simulated tears which contained benzalkonium chloride brought about an increase in uptake of about 10 to 100-fold.
  • JP-A 1246227 describes a method for avoiding incompatibilities in liquid aqueous ophthalmic compositions, especially eye drops, which contain benzalkonium chloride.
  • a large number of medicinal active ingredients shows incompatibility with benzalkonium chloride in the dosage form as aqueous solution, leading to the formation and flocculation of soluble compounds. It is therefore impossible to use benzalkonium chloride as preservative in such aqueous compositions.
  • benzyllauryldimethylammonium chloride that is to say the C 12 homologue from the benzalkonium, chloride mixture, is used, the described incompatibilities do not occur. It is thus possible to preserve eye drops whose active ingredient is incompatible with benzalkonium chloride by using benzyllauryldimethylammonium chloride.
  • the invention therefore makes it possible in particular to preserve those ophthalmic compositions intended to have a prolonged residence time on the eye by comparison with eye drops or the like. It is possible, in particular in this way to produce gels which can be administered as drops, ointments and the like to which the eye is exposed for a very long time after a single use, because they are only slowly washed out by the tear fluid, the preservative having all the advantages of the known benzalkonium chloride but without eye-irritant or even eye-damaging effect.
  • the ophthalmic compositions according to the invention are preferably those which have as vehicle an aqueous basis for a gel which can be administered as drops.
  • a viscosity-increasing synthetic or natural polymer in aqueous solution or aqueous dispersion will be employed in a known manner.
  • carboxyvinyl polymers already known as gel formers especially carboxypolymethylenes which are commercially available under the trade name “Carbopol”. It is alternatively possible to employ the ethylene/maleic anhydride copolymers which are commercially available under the trade name “EMA”.
  • Particularly suitable natural polymers are the various cellulose derivatives which are in turn already known for ophthalmic gels, especially alkylcelluloses, hydroxycelluloses, hydroxyalkylcelluloses etc. It is possible with advantage to use in addition or as alternative natural gums such as, for example, guar gum, xanthan gum etc.
  • natural polymers which can be used advantageously according to the invention are dextran and its derivatives.
  • the ophthalmic composition according to the invention may be advantageous to formulate as in principle a single-phase aqueous liquid in which the other ingredients occur in solution or as dispersed particles.
  • composition it is an alternative and often even more advantageous possibility to build up the composition as a two-phase liquid with an aqueous and a hydrophobic phase.
  • the product contains particular active ingredients such as, for example, vitamin A
  • Suitable as hydrophobic phase are oils, medium chain-length triglycerides etc.
  • Medium chain-length triglycerides will advantageously be used as hydrophobic phase particularly in products which contain vitamin A as active ingredient.
  • the concentration of the benzyllauryldimethylammonium salt corresponds to the usual concentrations employed for benzalkonium chloride.
  • the benzyllauryldimethylammonium salt is preferably simply the chloride.
  • the advantage of the invention can also be utilized for those ophthalmic compositions which, although they contain no viscosity-increasing ingredients (which thus, delay washing out), must be used repeatedly over lengthy periods and thus likewise result in a continuously elevated level of preservative in the eye. Products of this type may also lead to irritation or even tissue damage if harmful preservatives are present, and therefore the advantage of the invention may also be used for such products by employing the benzyllauryldimethylammonium salt as preservative in place of these preservatives.
  • Ophthalmic Composition with 0.01% Benzyllauryldimethylammonium Chloride Batch size: 2 kg Ingredients Amount in grams Carbopol 980 NF 4.00 Benzyllauryldimethylammonium chloride 0.2000 Sorbitol 80.00 NaOH, solid 1.57 Water (remainder up to batch size)
  • Ophthalmic Composition with 0.005% Benzyllauryldimethylammonium Chloride Batch size: 2 kg Ingredients Amount in grams Carbopol 980 NF 4.00 Benzyllauryldimethylammonium chloride 0.1000 Sorbitol 80.00 NaOH, solid 1.57 Water (remainder up to batch size)

Abstract

Ophthalmic composition with prolonged residence time on the eye, in particular in the form of a gel which can be administered as drops, of an ointment or the like, containing a free-flowing vehicle with increased viscosity and a preservative, and, where appropriate, one or more active ingredients and conventional additives such as tonicity agents, substances to adjust the pH etc. The preservative is essentially formed according to the invention by a benzyllauryldimethylammonium salt. The invention furthermore relates to the use of a benzyllauryldimethylammonium salt as preservative for producing ophthalmic compositions intended for repeated use over lengthy periods and/or formulated for a lengthy residence time on the eye after each use, whereby irritation and/or damage to the tissue of the eye are avoided.

Description

  • The invention relates to an ophthalmic composition with prolonged residence time on the eye, in particular in the form of a gel which can be administered as drops, of an ointment or the like, containing a free-flowing vehicle with increased viscosity and a preservative, and, where appropriate, one or more active ingredients and conventional additives such as tonicity agents, substances to adjust the pH etc. The invention additionally relates to the use of a benzyllauryldimethylammonium salt for producing ophthalmic compositions. [0001]
  • Ophthalmic compositions may, like other pharmaceutical products too, be contaminated by microorganisms of a wide variety of species. The possibility of such microorganisms entering the eye and getting onto the mucosa of the eye on use of the ophthalmic composition must be avoided. Ophthalmic products must therefore comply with strict sterility requirements. This is why products of this type are always produced under sterile conditions. [0002]
  • In order to increase the sterility and, in particular, the shelf life of ophthalmic products which are not intended for immediate use, preservatives are added to them. On the one hand, the latter must have a sufficiently microbioidal effect to ensure the permanent sterility of the product, and on the other hand they must not themselves lead to irritation or tissue damage in the eye, which is, after all, often already damaged. [0003]
  • These requirements are particularly crucial in the case of ophthalmic compositions which must be used repeatedly over lengthy periods (one or more days or longer) so that a permanent level of preservative is set up in the eye. In this case the risk of irritation or even tissue damage by the preservative is particularly great. [0004]
  • This is similarly true of those ophthalmic compositions which show prolonged (by comparison with products which can easily be washed out by tear fluid, such as, for example, conventional aqueous dropper solutions) residence time on or in the eye after a single use. Products of this type are, with regard to their consistency, adjusted to have an increased viscosity. One example are aqueous products which are gelatinously thickened by adding water-soluble polymers, in particular gels which can be administered as drops. Another example are the well-known ointments, usually in the form of spreadable emulsions. [0005]
  • Preservatives used for such purposes are, for example, thiomersal, cetrimide and similar substances. [0006]
  • Another preservative which is frequently suggested for ophthalmic products is benzalkonium chloride. [0007]
  • Benzalkonium chloride is the international nonproprietory name for N-alkyl-N-benzyl-N,N-dimethyl-ammonium chloride with alkyl radicals between C[0008] 8H17 and C18H37. Benzalkonium chloride is normally obtained from natural fats or oils and is a mixture of varying composition, depending on the raw materials used, of the quaternary compounds described above.
  • Unless other indicated, the term “benzalkonium” in this application always means such a mixture with different alkyl radicals, with the number of carbon atoms in the alkyl radical varying from C[0009] 8 to C18.
  • U.S. Pat. No. 4,053,628 discloses a clear solution of sodium cromoglicate to which a large number of preservatives can be added. Suggested and exemplified besides thiomersal, cetrimide, benzetkonium chloride and others is also benzalkonium chloride. The possibility of adjusting the viscosity of such solutions is mentioned in general; however, the examples relate exclusively to solutions without viscosity-modifying additives. The risk of eye irritation due to the preservative is not mentioned in this publication. [0010]
  • U.S. Pat. No. 4,271,143 has disclosed the use of benzalkonium chloride as preservative in an ophthalmic gel for delayed release of active ingredient. There is no report of eye irritation with the envisaged long residence time in the eye. The tests on the eye described in U.S. Pat. No. 4,271,143 each lasted only a few hours. This is possibly the reason why the problems which occur with such gels on prolonged use apparently were not observed. [0011]
  • Benzalkonium chloride has excellent antiseptic properties even in ophthalmic preparations, especially in aqueous ophthalmic preparations. However, benzalkonium chloride is, as has emerged since publication of the abovementioned patents, poorly tolerated and may lead to irritation and even damage of the eye. B. Lopez et al. (Current Eye Research, 1991, 10 (7) 645 to 656) report on the injurious effect of preservatives in simulated tear fluids on the cornea of rabbits. The effect of tear fluids preserved with 0.01%. benzalkonium chloride, 0.001% polyquat or 0.004% thiomersal was related to that in a comparison group in which the simulated tear fluid was used without preservative. [0012]
  • The measure chosen for the damage to the cornea was the increase in the ability to take up carboxyfluorescein. Simulated tears which contained polyquat or thiomersal brought about an increase in uptake of one to four-fold. Simulated tears which contained benzalkonium chloride brought about an increase in uptake of about 10 to 100-fold. [0013]
  • Checks by examination under the electron microscope demonstrated that the increase in the ability to take up carboxyfluorescein was associated with increased cell damage in the cornea. As a result, urgent advice against the use of benzalkonium salts in ophthalmic products was given. [0014]
  • Individual benzalkonium components have attracted interest recently. Thus, JP-A 1246227 describes a method for avoiding incompatibilities in liquid aqueous ophthalmic compositions, especially eye drops, which contain benzalkonium chloride. A large number of medicinal active ingredients shows incompatibility with benzalkonium chloride in the dosage form as aqueous solution, leading to the formation and flocculation of soluble compounds. It is therefore impossible to use benzalkonium chloride as preservative in such aqueous compositions. When virtually pure benzyllauryldimethylammonium chloride, that is to say the C[0015] 12 homologue from the benzalkonium, chloride mixture, is used, the described incompatibilities do not occur. It is thus possible to preserve eye drops whose active ingredient is incompatible with benzalkonium chloride by using benzyllauryldimethylammonium chloride.
  • This prior art has no relation to the problem of the lack of tolerability of benzalkonium chloride in the eye. [0016]
  • It is an object of the present invention to provide an ophthalmic composition of the type mentioned at the outset which is well tolerated by the eye, even on persistent exposure, and which overcomes the disadvantages of the prior art without, at the same time, losing the advantageous effects of the benzalkonium salts as preservatives. [0017]
  • Achievement of this object is made possible according to the invention by the features of the independent claims. [0018]
  • The independent claims define advantageous embodiments of the invention. [0019]
  • It has been found, surprisingly, that on use or benzyllauryldimethylammonium salts as preservatives in ophthalmic products there is distinctly less or even no irritation and damage in the eve, which are observed, however, on use or other preservatives, including benzalkonium chloride. [0020]
  • The invention therefore makes it possible in particular to preserve those ophthalmic compositions intended to have a prolonged residence time on the eye by comparison with eye drops or the like. It is possible, in particular in this way to produce gels which can be administered as drops, ointments and the like to which the eye is exposed for a very long time after a single use, because they are only slowly washed out by the tear fluid, the preservative having all the advantages of the known benzalkonium chloride but without eye-irritant or even eye-damaging effect. [0021]
  • The ophthalmic compositions according to the invention are preferably those which have as vehicle an aqueous basis for a gel which can be administered as drops. In this case, a viscosity-increasing synthetic or natural polymer in aqueous solution or aqueous dispersion will be employed in a known manner. [0022]
  • Particularly suitable for this purpose are the carboxyvinyl polymers already known as gel formers, especially carboxypolymethylenes which are commercially available under the trade name “Carbopol”. It is alternatively possible to employ the ethylene/maleic anhydride copolymers which are commercially available under the trade name “EMA”. [0023]
  • Particularly suitable natural polymers are the various cellulose derivatives which are in turn already known for ophthalmic gels, especially alkylcelluloses, hydroxycelluloses, hydroxyalkylcelluloses etc. It is possible with advantage to use in addition or as alternative natural gums such as, for example, guar gum, xanthan gum etc. Other examples of natural polymers which can be used advantageously according to the invention are dextran and its derivatives. [0024]
  • It may be advantageous to formulate the ophthalmic composition according to the invention as in principle a single-phase aqueous liquid in which the other ingredients occur in solution or as dispersed particles. [0025]
  • It is an alternative and often even more advantageous possibility to build up the composition as a two-phase liquid with an aqueous and a hydrophobic phase. Especially if the product contains particular active ingredients such as, for example, vitamin A, it will be preferred to provide a continuous aqueous phase with droplets of the hydrophobic phase emulsified therein. Suitable as hydrophobic phase are oils, medium chain-length triglycerides etc. Medium chain-length triglycerides will advantageously be used as hydrophobic phase particularly in products which contain vitamin A as active ingredient. [0026]
  • The concentration of the benzyllauryldimethylammonium salt corresponds to the usual concentrations employed for benzalkonium chloride. The benzyllauryldimethylammonium salt is preferably simply the chloride. [0027]
  • Besides the ophthalmic compositions which have just been described and have been formulated for prolonged residence time on the eye after each use, the advantage of the invention can also be utilized for those ophthalmic compositions which, although they contain no viscosity-increasing ingredients (which thus, delay washing out), must be used repeatedly over lengthy periods and thus likewise result in a continuously elevated level of preservative in the eye. Products of this type may also lead to irritation or even tissue damage if harmful preservatives are present, and therefore the advantage of the invention may also be used for such products by employing the benzyllauryldimethylammonium salt as preservative in place of these preservatives. [0028]
  • Examples thereof are not only eye drops but also simulated tear fluid as in the test reported by Lopez et al.[0029]
  • The following examples serve merely to illustrate the invention and represent no restriction whatsoever. [0030]
    • EXAMPLE 1
  • Ophthalmic Composition with 0.01% Benzyllauryldimethylammonium Chloride. [0031]
    Batch size: 2 kg
    Ingredients Amount in grams
    Carbopol 980 NF 4.00
    Benzyllauryldimethylammonium chloride 0.2000
    Sorbitol 80.00
    NaOH, solid 1.57
    Water (remainder up
    to batch size)
    • EXAMPLE 2
  • Ophthalmic Composition with 0.005% Benzyllauryldimethylammonium Chloride. [0032]
    Batch size: 2 kg
    Ingredients Amount in grams
    Carbopol 980 NF 4.00
    Benzyllauryldimethylammonium chloride 0.1000
    Sorbitol 80.00
    NaOH, solid 1.57
    Water (remainder up
    to batch size)
  • Long-term tests were carried out on experimental rabbits (Charles River) with the compositions of Example 1 and 2. In parallel, comparative tests were carried out with a corresponding control group in which the compositions employed were in every respect the same but differed with regard to the preservative. Instead or benzyllauryldimethylammonium chloride, on the one hand benzalkonium chloride was used in the same concentration, and on the other hand, thiomersal (standard concentration)=40 μg/g was used. [0033]
  • The test lasted 5 weeks. [0034]
  • At the end of the test, seven or eight rabbits in the control group treated with the composition with thiomersal as preservative showed severe irritation, and in some cases also damage to the eye. [0035]
  • the control group which received a product with benzalkonium chloride as preservative, all the rabbits showed severe irritation, and some showed damage to the tissue of the eye, at the end of the investigation. [0036]
  • By contrast, the ophthalmic compositions of Examples 1 and 2 according to the invention led to no detectable irritation in the eye of any rabbit at the end of the test period. Likewise, no tissue damage whatsoever was observed. [0037]

Claims (15)

1. Ophthalmic composition with prolonged residence time on the eye, in particular in the form of a gel which can be administered as drops, of an ointment or the like, containing a free-flowing vehicle with increased viscosity and a preservative, and, where appropriate, one or more active ingredients and conventional additives such as tonicity agents, substances to adjust the pH etc., characterized in that the preservative is essentially formed by a benzyllauryldimethylammonium salt.
2. Ophthalmic composition according to claim 1, characterized in that the composition has as vehicle an aqueous base for a gel which can be administered as drops.
3. Ophthalmic composition according to claim 1 or 2, characterized in that the vehicle of the composition contains at least one viscosity-increasing synthetic or natural polymer in aqueous solution or dispersion.
4. Ophthalmic composition according to claim 3, characterized in that the polymer comprises a carboxyvinyl polymer, in particular a carboxypolymethylene, or an ethylene/maleic anhydride copolymer.
5. Ophthalmic composition according to claim 3, characterized in that the polymer comprises a cellulose derivative, a natural gum such as xanthan, a dextran derivative or the like.
6. Ophthalmic composition according to any of claims 1 to 5, characterized in that the liquid portion of the composition is in the form of a single-phase aqueous liquid.
7. Ophthalmic composition according to any of claims 1 to 5, characterized in that the liquid portion of the composition is in the form of a two-phase liquid, preferably as O/W emulsion.
8. Ophthalmic composition according to any of claims 1 to 7, characterized in that the preservative is benzyllauryldimethylammonium chloride.
9. Ophthalmic composition according to any of claims 1 to 8, characterized in that the concentration of the preservative based on the total amount of the composition is between 0.001% by weight and 0.5% by weight, preferably between 0.01% by weight and 0.05% by weight.
10. Ophthalmic composition according to any of claims 1 to 9, characterized in that the composition contains vitamin A as active ingredient.
11. Ophthalmic composition according to any of claims 1 to 10, characterized in that the composition comprises 0.001 to 1% by weight, preferably 0.1 to 0.5% by weight, of carboxypolyethylene, 0.0005 to 0.05% by weight, preferably 0.001 to 0.01% by weight, of benzyllauryldimethylammonium chloride, 0.1 to 10% by weight, preferably 1 to 5% by weight, of sorbitol, and alkali metal hydroxide or acid to adjust a physiologically acceptable pH and otherwise water.
12. Use of a benzyllauryldimethylammonium salt as preservative for producing ophthalmic compositions intended for repeated use over lengthy periods and/or formulated for a lengthy residence time on the eye after each use, whereby irritation and/or damage to the tissue of the eye are avoided.
13. Use of benzyllauryldimethylammonium chloride according to claim 12.
14. Use of the preservative according to claim 12 or 13 for eye drops having a least one active ingredient.
15. Use of the preservative according to claim 12 or 13 for a simulated tear fluid.
US10/625,634 1996-04-15 2003-07-23 Ophthalmic compound with extended dwell time on the eye Abandoned US20040071778A1 (en)

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DE19614823A DE19614823A1 (en) 1996-04-15 1996-04-15 Ophthalmic composition with prolonged retention time on the eye
US09/171,344 US6599944B1 (en) 1996-04-15 1997-03-06 Ophtalmic compound with extended dwell time on the eye
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US9308165B2 (en) * 2013-08-22 2016-04-12 Therapeutic Vision, Inc. Composition for treating ocular effects of diabetes
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CN1215988A (en) 1999-05-05
AU714093B2 (en) 1999-12-16
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CA2251982C (en) 2008-01-29
PT801948E (en) 2001-10-31
DE19614823A1 (en) 1997-10-16
JP2000508646A (en) 2000-07-11
CA2251982A1 (en) 1997-10-23
PL187339B1 (en) 2004-06-30
AU2024697A (en) 1997-11-07
US6599944B1 (en) 2003-07-29
EP0801948B1 (en) 2001-06-06
PL328656A1 (en) 1999-02-15
JP4582822B2 (en) 2010-11-17
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SI0801948T1 (en) 2001-10-31
GR3036498T3 (en) 2001-11-30

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