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Home , Imidazole, Polyene antimycotic

Europaisches Patentamt (19) European Patent Office Office europeeneen des brevets EP 0 748 588 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) intci.e: A01N 43/90, A23B 4/22, 18.12.1996 Bulletin 1996/51 A23B 7/155, A23C 19/11, A23C 19/16, A23L 3/3463 (21) Application number: 96201301.7 // (A01 N43/90, 43:50) (22) Date of filing: 13.05.1996

(84) Designated Contracting States: (72) Inventor: Stark, Jacobus AT BE CH DE DK ES Fl FR GB GR IE IT LI LU MC 3069 ZM Rotterdam (NL) NL PT SE (74) Representative: (30) Priority: 12.05.1995 EP 95201248 Matulewicz, Emil Rudolf Antonius, Dr. et al Gist-Brocades BV (71) Applicant: GIST-BROCADES B.V. Patents and Trademarks Department NL-2600 MA Delft (NL) Wateringseweg 1 P.O. Box 1 2600 MA Delft (NL)

(54) compositions

(57) Fungicide compositions are disclosed wherein of a polyene agent and an antifungal amount the active component comprises an antifungal amount of an antifungal agent.

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Printed by Jouve, 75001 PARIS (FR) 1 EP 0 748 588 A1 2

Description on treated food products, especially when the conditions in production or storage factories are rel- The present invention relates to antifungal compo- atively optimal for fungal growth. An example of an im- sitions and use of such compositions to treat foods such portant factor which enhances the probability of fungal as cheeses and sausages, feed products, crops and ag- 5 growth is an insufficient control of the relative humidity. ricultural products such as fruits, grain, seed-potatoes, In case of spoilage by moulds the economic losses plants, flowers, flower bulbs, seeds and vegetables. can be considerable and a more efficient antifungal sys- Compositions of the invention can also be used for phar- tem is necessary to protect food products such as maceutical purposes. Also said products treated with cheese against spoilage by relatively natamycin-toler- compositions of the invention are disclosed. 10 ant mould species. An example of such an antifungal system is the Background of the invention combination of natamycin, an acidic antifungal com- pound and an additional acid compound (ref. 14). Natamycin is Imazalil For more then 20 years natamycin has been used to prevent fungal growth on cheeses and sausages (ref . [1 -[2-(2,4-dichlorophenyl)-2-(2-propenyloxy)- ethyl]- 1-12). l-H-lmidazole] (imazalil or enilconazole) is a broad spec- Cheeses are treated by immersion in a suspension trum antimycotic (ref. 15-16), which is used for the pro- of natamycin in water or covered by an emulsion of a 20 tection of crops, like for example strawberries, gherkins, polymer in water, mostly polyvinyl acetate. Sausages cucumbers, melons, plants and flowers. Imazalil is also are mainly treated by immersion or by spray coating with used to prevent fungal growth on seeds, seed-potatoes a suspension of natamycin in water. Usually aqueous and fruits such as citrus fruits, bananas, etc. suspensions for immersion treatments contain 0.1% to The inhibition of moulds on cheese by polyethylene 0.2% w/v of natamycin, while polymer emulsions for 25 films containing the antimycotic imazalil has been de- coating purposes contain 0.01% to 0.05% w/v of na- scribed by Weng and Hotchkiss (ref. 17). They de- tamycin. scribed the inhibition of mould growth on the surface of Mostly these treatments are highly effective in pre- Cheddar cheese by a packaging film containing imazalil. venting fungal growth on the surface of cheeses and However in practice imazalil is not suitable for products sausages. However because of the low solubility of na- 30 which have to be protected against fungal growth on the tamycin, mould species which are less susceptible to surface for long periods. Examples of such products are natamycin are sometimes not fully inhibited. Thus some cheeses and . sausages. Imazalil quickly penetrates in- fungal spoilage may still occur. Examples of fungal spe- to the cheese which means that after several days no cies which exhibit relatively high tolerance towards na- antifungal activity is left at the site where fungal growth tamycin are Verticilium cinnabarinum, Botrytis cinerea 35 occurs: the surface of the food product. and Trichophyton species. Among Aspergillus, Fusari- In summary: natamycin provides an effective um and Penicillium species may also be found species means of controlling common food spoilage fungi, but with this characteristic. An example of a species which is insufficiently soluble in water to inhibit more tolerant sometimes causes mould problems in the cheese indus- species if they are present in large amounts; imazalil is try is Penicillium echinulatum var. discolor. 40 not suitable for the long term protection of food products Because of the low solubility of natamycin a food such as cheeses and sausages against fungal growth, product treated with this antimycotic will be protected because the compound penetrates quickly into the prod- against fungal growth for a long period. Only the na- uct. tamycin which is in solution will be available to exert anti- fungal activity. 45 Description of the invention Natamycin has a MIC (Minimal Inhibitory Concen- tration) of less than 10 ppm for most foodborn fungi, The present invention relates to antifungal compo- while its solubility in water is from 30 to 50 ppm (ref. 1 2). sitions, which comprise an antifungal agent of the poly- After many years of continuous use of this antimycotic, ene type, such as natamycin, and an antifungal agent natamycin-resistant fungi have never been found (ref. so of the imidazole type, such as imazalil. 13). So under normal conditions natamycin will protect Unexpectedly it has been found that the action to- food products like cheese fully against fungal spoilage. wards fungal species of a polyene antifungal agent, in However sometimes the amount of fungi in for ex- particular natamycin, is markedly enhanced when an ample a cheese factory is high. In these circumstances, imidazole antifungal agent, in particular imazalil, is add- the dissolved fraction of natamycin in a conventional na- 55 ed. tamycin-containing antifungal composition could be in- Only the natamycin which is in solution will be avail- sufficient to prevent fungal growth on cheese. In this able to exert antifungal activity. In the case of a fungi- case always the more tolerant mould species will grow cide, e.g. natamycin, with a low solubility one of the fac-

2 3 EP 0 748 588 A1 4 tors which will have an influence on the final fungicide treated first followed by application to the same surface effect is the elimination of the dissolved fungicide. When of a . Preferably, however, the pol- natamycin interacts with a fungal cell the reaction is ir- yene antifungal agent and imidazole antifungal agent reversible which means that the natamycin is not avail- will be employed in the form of a single composition. able for the elimination of other fungal cells anymore. In 5 Thus, the treatment may comprise immersing the most cases the availability of natamycin will not be lim- product to be treated in a liquid composition of the in- ited significantly by solubilisation or diffusion factors, be- vention or such a composition may be sprayed onto the cause the solubility is far higher than the MIC value. product. Elimination of dissolved natamycin will be compensated An antifungal composition of the invention may be sufficiently by dissolution of undissolved natamycin and 10 any kind of composition known to be suitable for treating by diffusion of dissolved natamycin to the site of infec- a food or agriculture product. Particularly preferred are tion. emulsions prepared from coating emulsions commonly However when a very high amount of fungal cells employed in the food industry. For example for the treat- is present, the dissolution of the natamycin and the dif- ment of cheeses an aqueous polymer emulsion of the fusion of the antimycotic to the site of may have 15 polyvinyl acetate type, which can be applied by brushing a limiting effect on the inhibitory activity of the antimy- or with a spray device, may be used. Examples of pol- cotic. The amount of active (dissolved) antimycotic may yvinyl acetate coatings are Plasticoat® and Ceska®. A drop beneath the effective concentration to prevent fun- composition of the invention may also be in the form of gal growth. In these circumstances, if also the conditions a coating emulsion of the oil in water or water in oil type. are optimal for fungal growth, fungi with relatively low 20 For example suitable preparations for treating agricul- susceptibility to polyene , for example Peni- tural products such as fruits are for instance films of pol- cillium echinulatum var. discolor, could grow on for ex- ymeric materials such as for example polyolefins, e.g. ample the surface of cheeses. polyethylene and polypropylene. When employed as an antifungal agent in conven- Further the invention provides foodstuffs such as tional manner, the availability of imazalil is higher than 25 cheeses and sausages, feed products and agricultural the availability of natamycin. The solubility of imazalil is products such as fruits, (kernel) grain, seed-potatoes, higher than the solubility of natamycin which means that plants, flowers, flower bulbs, seeds and vegetables the dissolution of the fungicide and the diffusion of the coated with a composition of the invention. dissolved fungicide to the site of infection have less in- It will be appreciated that compositions of the inven- fluence on the availability of imazalil. However imazalil 30 tion additionally include pharmaceutical preparations, will penetrate rather quickly into the product, e.g. for instance for topical application. Examples of suitable cheese, which means that after a few days no antifungal pharmaceutical preparations are lotions, creams and activity is left on the surface of the product. ointments. The enhanced activity of an antifungal composition The polyene antifungal agent in a composition of of the present invention is presumably due to the com- 35 the invention may be, for example natamycin, , bined effect of the prolonged working time of the polyene lucensomycin or . The preferred polyene antifungal agent, e.g. natamycin, and the high availabil- is natamycin. It will be appreciated that commercial ity in the short term of the imidazole antifungal agent, e. products which contain natamycin such as Delvocid® g. imazalil. The combination of both antimycotics will can be incorporated in a composition of the invention. protect products, e.g. cheese, more effectively against 40 Delvocid® is the brand name of a commercial product fungal spoilage. produced by Gist-Brocades (The Netherlands). Delvo- According to one aspect of the invention, an anti- cid® contains 50% of natamycin. fungal composition is provided wherein the active com- The imidazole antifungal agent in a composition of ponent comprises an antifungal amount of a polyene an- the invention may be, for example, imazalil, an imazalil tifungal agent, e.g. natamycin, in combination with an 45 salt, a derivative of imazalil or . The pre- antifungal amount of an imidazole antifungal agent, e. ferred imidazole is imazalil. Commercial products which g. imazalil. contain imazalil such as Fungaflor®or Fungazil® (Jans- In a further aspect, the invention also provides use sen Pharmaceutica NV, Belgium) can be used in the for- of a polyene antifungal agent, e.g. natamycin, and an mulation of composition of the invention. imidazole antifungal agent, e.g. imazalil, in combination so A composition of the present invention will generally to treat a foodstuff such as cheese or sausage, a feed comprise from 0.005% to 2% by weight of a polyene fun- product, or an agricultural product such as fruit, (kernel) gicide, e.g. natamycin. grain, seed-potato, plant, flower, flower bulb, seed or The amount of polyene fungicide in a liquid compo- vegetable, wherein said antifungal agents are applied sition of the invention for an immersion or spraying treat- to the surface of the product to be treated either simul- 55 ment may be from 0.01% to 2% w/v. Preferably the taneously or sequentially to provide at said surface a amount is from 0.01 % to 1 % w/v. In principle the immer- composition of the invention. Thus, for example, an im- sion liquid may be of any kind. When an aqueous system idazole antimycotic may be applied to the surface to be is used, the addition of a surfactant may be of advan-

3 5 EP 0 748 588 A1 6 tage, in particular for treating objects with a hydrophobic ticoat® composition was applied and evenly spread surface. Useful surfactants are for example anionic ten- over the surface of the cheese by means of a sterile rec- sides such as sodium lauryl sulphate or polyethylene tangular piece of plastic spatula of about 2 by 5 cm. alkyl ethers such as Cetomacrogol® 1000 or polyox- After standing for 2 hours at ambient conditions the yethylene ethers e.g. Tween® 60, 61 and 65. 5 pieces of cheese were incubated at 1 5°C and at a rela- In acoating emulsion according to the invention, the tive humidity of 95 %. amount of polyene fungicide may be from 0.005% to 2% During 14 days, every day the number of visible col- w/v, preferably from 0.01% to 1% w/v and more prefer- onies formed on the pieces of cheese were counted. ably from 0.01% to 0.5% w/v. When the number of colonies on a piece of cheese ex- Depending on the type of application the amount of 10 ceeded 50, the piece of cheese was considered to be imidazolefungicide, e.g. imazalil, may vary from 0.005% totally covered with mould. to 3% w/v, preferably from 0.005% to 1% w/v. The pieces treated with Plasticoat® compositions Preferably the pH of a composition according to the containing no imazalil remained free of mould during 5 invention is from 1 to 10, more preferably from 2 to 8 days and were totally covered with mould on day 6. and most preferably from 3.5 to 7.5. The pH of such a is The pieces which were treated with Plasticoat® composition may be adjusted by any method, e.g. by compositions containing 50 ppm of imazalil remained adding an acidic or a basic compound. Useful acids for free of mould during 8 days and were totally covered this purpose are for example citric acid, , hy- with mould on day 9. drochloric acid, phosphoric acid, sulphuric acid and tar- The pieces which were treated with Plasticoat® taric acid. Useful basic compounds for adjusting the pH 20 compositions containing 100 ppm of imazalil remained of a composition of the invention are for example sodium free of mould during 11 days and were totally covered hydroxide, hydroxide, and calcium with mould on day 12. hydroxide. Useful buffering systems which may be em- These results clearly demonstrate that Plasticoat® ployed in compositions of the invention are for instance containing 50 or 100 ppm of imazalil protects pieces of those of the phosphate and citrate types. 25 cheese respectively 3 and 6 days longer against growth of Penicillium echinulatum var. discolor. However, when COMPARATIVE EXAMPLE 1 fungal growth occurs the pieces of cheese are very quickly totally covered with mould. This example illustrates the effect towards Penicil- lium echinulatum var. discolor on cheese of imazalil. 30 COMPARATIVE EXAMPLE 2 A freshly brined wheel of Gouda cheese was first cut horizontally into two parts. Each part was then cut In the same way as described in Example 1 , exper- into pieces of 5 by 5 cm. Only pieces with a flat original iments were carried out using Plasticoat® compositions surface were taken for the experiment. The pieces of containing natamycin instead of imazalil. Plasticoat® cheese were dipped into a bath of melted paraffin at 35 compositions with the following concentrations of na- 80°C in such a manner that the original surface area tamycin were prepared: 0 ppm, 250 ppm and 500 ppm. remained free of paraffin, while the other five surfaces The pieces treated with Plasticoat® compositions were covered by a thin film of solidified paraffin. containing no natamycin remained free of mould during The original surface area (the rind) was then inoc- 5 days and were totally covered with mould on day 6. ulated with about 6 x 103 CFU (Colony Forming Units) 40 The pieces which were treated with the Plasticoat® per cm2 of a mixture of spores of three strains of Peni- composition containing 250 ppm or 500 ppm of natamy- cillium echinulatum var. discolor (CBS numbers 611 .92, cin remained free of mould during 7 days. Even after 1 4 612.92 and 613.92, deposited on December 8, 1992 days, less than 50 colonies per piece of cheese were with the CBS). The inoculation was performed bv apply- observed. ing 0.15 ml of a spore suspension containing about 106 45 These results clearly demonstrate that Plasticoat® CFU/ml to the surface of the piece of cheese. The inoc- containing 250 ppm or 500 ppm of natamycin protects ulum was evenly divided over the surface by means of cheese up to 2 days longer against growth of Penicillium a sterile swab, which was saturated with the original echinulatum var. discolor. More important is that these spore suspension. results demonstrate that when fungal growth occurs on Plasticoat® compositions with the following con- so pieces of cheese which are treated with Plasticoat® centrations of imazalil were prepared: 0 ppm, 50 ppm containing 250 or 500 ppm of natamycin the number of and 100 ppm. Plasticoat® is an aqueous emulsion of colonies per piece of cheese is always less than 50 even polyvinyl acetate acquired from National Starch & after many days, e.g. 14. Chemical B.V., which is used as a cheese coating. After standing overnight in closed plastic boxes at 55 EXAMPLE 3 about 6°C, the pieces of cheese were treated with the Plasticoat® compositions. For each treatment 2 pieces In the same way as described in Example 1 , exper- of cheese were taken. On each piece 0.8 ml of the Plas- iments were carried out using Plasticoat® compositions

4 7 EP 0 748 588 A1 8 containing both imazalil and natamycin in the following were totally covered with mould on respectively day 15, concentrations: 16 and 18. On the pieces of cheese treated with Plasticoat® * 250 ppm of natamycin and 50 ppm of imazalil containing 500 ppm of natamycin, mould growth was not * 250 ppm of natamycin and 100 ppm of imazalil 5 observed even after 32 days. * 500 ppm of natamycin and 50 ppm of imazalil These results clearly demonstrate that towards a * 500 ppm of natamycin and 100 ppm of imazalil species which is normally susceptible to the action of natamycin a composition according to the invention will The pieces treated with Plasticoat® compositions have no additional advantage in comparison to conven- containing no imazalil and no natamycin remained free 10 tional treatment with natamycin alone. Maximum protec- of mould during 5 days and were totally covered with tion against fungal spoilage can be reached by using mould on day 6. natamycin alone. On all the pieces treated with the different combi- These results also clearly demonstrate that imazalil nations of natamycin and imazalil described above after alone, even at very high concentrations, will not prevent 14 days less than 50 colonies per piece were observed. is spoilage by fungal species. Imazalil penetrates into the The pieces treated with the different Plasticoat® cheese and will not prevent fungal growth at the surface compositions remained free of mould during respective- of the cheese, even when used at very high concentra- ly 9, 11, 9 and 12 days. tions. These results clearly demonstrate that a combina- REFERENCES tion of natamycin and imazalil is very effective in pro- 20 tecting cheese against growth of Penicillium echinula- 1. Jedrychowski, L; Reps, A.; Jarmul, I.; Babu- tum var. discolor. chowski, A. "Use of natamycin for a protection of When compositions as listed above are used on semihard cheeses against moulding". Brief com- pieces of cheese, the cheese is never totally covered munications of the XXIII International Dairy Con- with mould even after 14 days (compare with the results 25 gress, Montreal, October 8-12, 1990, Vol. 1. of Example 1 : pieces of cheese treated with imazalil are always totally covered with mould) and the pieces of 2. Daamen, C. B.G. and Berg, G. van den; "Preven- cheese remain 1 to 5 days longer free of mould com- tion of mould growth on cheese by means of na- pared with pieces which are treated with imazalil or na- tamycin". Voedingsmiddelentechnologie, 18 (2), tamycin alone (compare with the results of Examples 1 30 26-29,(1985). and 2). Therefore the combination of imazalil and na- tamycin provides for an extended antifungal action. 3. Neviani, E.; Emaldi, G.C.; Carini, S.; "Use of pima- ricin as a fungicide on cheese rind: technology and COMPARATIVE EXAMPLE 4 the effects on the cheese surface flora". Latte, 6 35 (5), 335-343, (1981). The experiment as described in Example 1 was re- peated except that the number of visible colonies was 4. Morris, H.A.; Castberg, H.B.; "Control of surface counted during 32 days and the pieces of cheese were growth on Blue cheese using pimaricin". Cultured inoculated with a spore suspension of Aspergillus ver- Diary Products Journal, 15 (2), 21-23, (1980). sicolor (CBS 434.73) instead of a mixture of spores of 40 three strains of Penicillium echinulatum var. discolor. 5. Baldini, P.; Palmia, E; Raczynski, R.G.; Campani- Aspergillus versicolor is an example of a species which ni, M.; "Use of pimaricin for preventing mould is normally susceptible to the action of natamycin. growth on Italian cured meat products". Industria The different compositions used for the treatments Conserve, 54 (4), 305-307, (1979). were: 45 6. Weiss, G.; "Preservation of dairy products with blank Plasticoat® chemicals". Deutsche Molkerei Zeitung 91 (50), Plasticoat® with 50 ppm of imazalil 2351-2356, (1970). Plasticoat® with 100 ppm of imazalil Plasticoat® with 500 ppm of imazalil so 7. Holley, R.A.; "Effect of sorbate and pimaricin on Plasticoat® with 500 ppm of natamycin. surface mould and ripening of Italian dry salami" Lebensmittel Wissenschaft und Technologie 19 The pieces of cheese treated with blank Plasticoat® (1), 59-65, (1986). remained free of mould during 7 days and were totally covered with mould on day 8. 55 8. Ruig, W.G.; Berg, G. van den; "Influence of the fun- The pieces of cheese treated with Plasticoat® con- gicides sorbate and natamycin in cheese coatings taining 50, 100 and 500 ppm of imazalil remained free on the quality of the cheese". Netherlands Milk and of mould during respectively 14, 15 and 17 days and Dairy Journal, 39 (3), 165-172, (1985).

5 9 EP 0 748 588 A1 10

9. Holley, R.A.; "Prevention of surface mould growth 5. A composition as claimed in claim 4, wherein na- on Italian dry sausage by natamycin and potassium tamycin is present at a concentration of about sorbate". Applied and Environmental Microbiology 10-800 ppm and imazalil is present at a concentra- 41 (2), 422-429, (1981). tion of 10-500 ppm. 5 10. Lueck, H.; Cheesman, C.E.; "Mould growth on 6. Use of a polyene antifungal agent and an imidazole cheese as influenced by pimaricin (natamycin) or antifungal agent in combination to treat a food prod- sorbate treatments". South African Journal of Dairy uct, feed product or agricultural product wherein Technology, 10 (3), 143-146, (1978). said antifungal agents are applied to the surface of 10 the product to be treated either simultaneously or 11. Verma, H.S.; Yadav, J.S.; Neelakantan, S.; "Pre- sequentially. servative effect of selected antifungal agents on butter and cheese". Asian Journal of Dairy Re- 7. A food product, feed product or agricultural product search 7 (1), 34-38, (1988). coated with a composition as claimed in any one of is claims 1 to 5. 12. Brik, H.; "Natamycin". Analytical Profiles-of Drug Substances 10, 513-561, (1981). 8. A composition as claimed in claim 1 which is a phar- maceutical composition. 13. De Boer, E.; Stolk-Horsthuis, M.; "Sensitivity to na- tamycin (pimaricin) of fungi isolated in cheese 20 warehouses". J. of Food Prot. 40, 533-536, (1977).

14. Van Rijn, F.T.J. ; Tan, H.S.; Warmerdam, M.J.M.; "A fungicide composition to prevent the growth of mould on foodstuffs and agricultural products" Eu- 25 ropean Patent Application No. 93200220, (1994).

15. Siegel, M.R.; Ragsdale, N.N.; "Antifungal mode of action of imazalil". Pesticide Biochem. Physiol. 9, 48-56,(1978). 30

16. Van Gestel, J.F.E.; Duytschaever, B.D.M.; "Pre- venting fungal decay of food products, particularly harvested fruits". European Patent Specification No. 83200856.9, (1988). 35

17. Weng, Y.M.; Hotchkiss, J.H.; "Inhibition of surface molds on cheese by polyethylene film containing the antimycotic imazalil". J. of Food Prot. 55, 367-369,(1992). 40

Claims

1. An antifungal composition wherein the active com- 45 ponent comprises an antifungal amount of a poly- ene antifungal agent and an antifungal amount of an imidazole antifungal agent.

2. A composition as claimed in claim 1 wherein said so polyene antifungal agent is natamycin.

3. A composition as claimed in claim 1 or claim 2 wherein said imidazole antifungal agent is imazalil. 55 4. A composition as claimed in any one of claims 1 to 3 which is in the form of an aqueous emulsion of polyvinyl acetate suitable for coating a food product.

6 EP 0 748 588 A1

Patent " European EUROPEAN SEARCH REPORT office EP 96 20 1301

DOCUMENTS CONSIDERED TO BE RELEVANT Citation of document with indication, where appropriate, Relevant CLASSIFICATION OF THE Category of relevant passages to claim APPLICATION (Im-Cl.6) X.Y EP-A-0 513 922 (GIST-BROCADES) 1-8 A01N43/90 * page 2, line 3 - line 8 * A23B4/22 * page 3, 1 ine 55 - 1 ine 58 * A23B7/155 A23C19/11 DATABASE CABA 1-8 A23C19/16 CAB International (CABI) A23L3/3463 AN 77:62658, //(A01N43/90, J.M. VAN TUYL: "Genetics of fungal 43:50) resistance to systemic fungicides" XP002013755 * abstract * & MEDEDELINGEN, LANDB0UWH0GESCH00L WAGENINGEN, vol. 77, no. 2, 1977, page 136 PESTICIDE SCIENCE, 1-8 vol. 15, no. 1, February 1984, pages 85-89, XP0G2013754 P. LEROUX AND MICHEL GREDT: "Resistance to Fungicides which Inhibit TECHNICAL FIELDS SEARCHED (Illt.CI.6) in Laboratory Strains of Botrytis cinerea and Ustilago maydis" A01N * page 85, abstract * A23B * table 2 * A23C A23L A EP-A-0 991 503 (GIST-BROCADES) 1-8 * claims; example 13; table 13 *

A WO-A-95 08918 (GIST-BROCADES) 1-8 * claims 1-4 *

A WO-A-91 02518 (BIOGLAN LABORATORIES LTD) 1-8 * claims 8-10 *

D,A EP-A-0 608 944 (GIST-BROCADES)

D,A EP-A-0 101 102 (JANSSEN PHARMACEUTICA)

The present search report has been drawn up for all claims Place of search Date of completion of the search Examiner THE HAGUE 19 September 1996 Muellners, W CATEGORY OF CITED DOCUMENTS T : theory or principle underlying the invention E : earlier patent document, but published on, or X : particularly relevant if taken alone after the filing date ¥ : particularly relevant if combined with anothej D : document cited in the application document of the same category L : document cited for other reasons A : technological background O : non-written disclosure & : member of the same patent family, corresponding P : intermediate document document

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