AU616769B2 - Therapeutic material for covering wounds and skin lesions and process for the preparation thereof - Google Patents

Description

I- I: i' r 6167691 DATE 05/01/90 APPLN. ID 36939 89 pCT AOJP DATE 01/02/90 PCT NUMBER PCT/HU89/00023

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*1 ;13 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/11879 A61L 15/01, 15/03, A61F 13/00 Al (43) International Publication Date: 14 December 1989 (14.12.89) (21) International Application Number: PCT/HU89/00023 (74) Agent: PATENTBUREAU DANUBIA; Bajcsy-Zsilinszky ut 16, H-1051 Budapest V (HU).

(22) International Filing Date: 30 May 1989 (30.05.89) (81) Designated States: AT (European patent). AU, BE (Euro- Priority data: pean patent), CH (European patent), DE (European pa- 2722/88 30 May 1988 (30.05.88) HU tent), DK, FI, FR (European patent), GB (European patent), IT (European patent), JP, KR, LU (European patent), NL (European patent), NO, SE (European patent), (71) Applicant (for all designated States except US): LICENCIA SU, US.

TALALMANYOKAT ERTEKESITO ES INNOVA- CIOS KULKERESKEDELMI VALLALAT [HU/HU]; Bajcsy-Zsilinszky ut 16, H-1368 Budapest Published With international search report.

(72) Inventors; and Inventors/Applicants (for US only) KALISZKY, ZoltAn [HU/HU]; Uri u. 24, H-1014 Budapest CZAP- PAN, Istvan [HU/HU]; Rak6czi ut 62, H-1074 Budapest MIHOLICS, Gizella [HU/HU]; K6rhaz u. 7, H- 1111 Budapest KOVACS, Marta [HU/HU]; Agyagfejt6 u. 20, H- 1108 Budapest SEBESTYEN, Gyula [HU/HU]; Bir6 Lajos u. 29, H-1089 Budapest (HU).

ZAVODSZKYNE SZABO, Anna [HU/HU]; Farkashida u. 17, H-1163 Budapest (HU).

(54) Title: THERAPEUTIC MATERIAL FOR COVERING WOUNDS AND SKIN LESIONS AND PROCESS FOR THE PREPARATION THEREOF (57) Abstract The invention relates to therapeutic material for covering wounds and skin lesions and the preparation thereof. The therapeutical material according to the invention contains a carrier impregnated or laminated with a non-irritating emulsion which optionally may be admixed with an effective amount of biologically active material. The therapeutical material covering wounds does not stick in the surface, is permeable for secretions and easy to handle.

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WO 89/11879 1 PCT/H[189/00023 Therapeutic material for covering wounds and skin lesions and process for the preparation thereof The invention relates to therapeutic material for covering wounds and skin lesions and for the process for the preparation thereof.

According to known methods for treatment of wounds with discharge and injured skin surfaces covering with gauze tapes/sheets, locally impregnated gauze sheets or gauze sheets impregnated with paraffin

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(Jelonet a product of Smith and Nephew) are generally used. In cases when the wound had to be treated also with biologically active material, then the drug has been directly applied to the gauze or wound surface at the place and at the time of the treatment, thereafter the wound thus covered has been dressed with bandage.

i Orawbacks of the known methods are as Ltllows: When removing the bandage the newly produced epithelial layer gets damaged, in many cases the surface gets considerably traumatized; the secretion dries in the conventional gauze layer, it forms a solid surface, not permeable to the secretion; the quantity of the optionally used biologically active materials is not optimal owing to the mode of application; the sterility cannot be assured in all cases.

i -N WO 89/11879 2 PCT/HU89/00023 To eliminate the aforementioned drawbacks the aim of our invention is to provide a therapeutic material for covering wounds and skin.lesions, which does not stick in the wounds, cain be removed from the surface after the treatment simply, without any damage and traumatization; is preamble to secretion; is admixable with any biologically active material i.e.

with water.soluble, oil soluble or fat soluble active ingredients if desired, and so an optimal active ingredient level can be ensured on the surface to be treated; is storable in sterile form for a long time and can be simply used at any time.

We have found that when a carrier, suitable for covering wounds and skin lesions, is laminated or impregnated with an emulsion prepared of the mixture of different polyoxyethylene glycols and an oil in the presence of emulsifying agent(s) of o/w type, having particularly high HLB value HLB>10) and admixed optionally with an effective amount of a biologically active material, the desired aim can be achieved. Moreover, said solution enables the controlled administration and release of the optionally used active ingredient too.

Accordingly the present invention relates to a therapeutic material for covering wounds and skin lesions which comprises a) a carrier made of textile or paper material or 1 i i M I i I C irl onl/ 17n P(T/I- 1199/00023 vr 0 110/7 3 synthetic fibre, laminated or impregnated with b) an emulsion having the following composition: propylene glycol 0-20% by weight polyoxyethylene glycols 5-95% oil 10-25% emulsifying agent 5-20% which is optionally admixed with c) an effective amount of biologically active ingredient, selected from antibiotics, antiseptics, desinfectants, antimycotics, biologically active vegetable extracts and dermatologica.

The therapeutic material for covering wounds and skin lesions according to the invention may be prepared by producing an emulsion from the ingredients listed 'r in point b) by method per se by optionally admixing the emulsion obtained with an effective amount of biologically active material according to point then impregnating the carrier according to point a) with said mixture, thereafter packing the product obtained and optionally sterilizing.

As a carrier a) woven textile materials of different density, prepared of twisted or monofilament yarn, gauze or loose fabrics), or materials without weaving, veil fabrics), paper sheets, viscose sheets both optionally perforated or nets and/or foils made of synthetic materials, may be used.

As polyoxyethylene glycols in emulsion b) a

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r A WO 89/11879 -4 PCT/HU mixture of polyoxyethylene glycols of different degree of polymerization n=300-6000) is used wherein the ratio of polyoxyethylene glycols of lower and higher degree of polymerization is ranging from (1:40) to preferably from to (20:1).

In the emulsion b) accoring to the invention i the oil phase may be any known oil generally used for injection preparations, for example vegetable oils sunflower oil, olive oil, peanut oil, linseed i 10 oil, castor oil, etc.), animal oils fish oil), mineral oils paraffin oil), synthetic oils (e.g.

10-10,oo &p) silicone oil, types Myritol, Levitol, etc.).

In the emulsion b) according to the invention ionic or non-ionic emulsifying agents of a high HLB 15 value HLB'10) may be used, e.g. esters of ethoxylated fatty alcohols, ester prepared from I polyhydric alcohols and fatty acids, ethoxylated dj dianhydrosorbitol-stearates, ethylene oxide adducts, e.g. fatty acid-polyethylene glycols esters, fatty alcohol-ethylene oxide adducts, etc.

The emulsion of o/w type used in the therapeutic material for covering wounds and skin lesions according to the invention makes it possible that optionally any kind of biologically active material, i.e. material being soluble in water, oil or fat, may be admixed with the composition and so the active material may be administered simply to the surface to be treated in an optimal, predetermined 89/00023 WO 89/11879 5 PCT/HU89/00023 amount and the treatment may be carried out by non- -qualified persons too.

The product according to the invention may be produced in any size' and shape as required, so. e.g.

sheets of 13xBcm, 5x6cm and 8xl5cm can be prepared.

The sheets obtained are placed onto cardboard or polymer sheets and packed by covering with metal or polymer foil and sterilized if desired. The products thus obtained form sterile, closed, easy to handle units.

The products according to the invention are well suitable for treating burn wounds, ulcus crusis, surfacial wounds with purulent discharge and different oozing skin lesions, for covering wounds after plastic operations, for use in ambulatory treatments, in first- -aid sets and everywhere where the presence of wound- -treating materials is permanently needed, so e.g.

in army, on ships or traumatology etc.

The details of the invention are illustrated by the following non-limiting Examples. The suitability Sof the therapeutic materials according to the invention Sfor applying to the skin is proved by the following biological Examples.

Biological Examples A) Skin irritation test The tests were carried out on New-Zeland rabbits.

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I WO 89/11879 6 P(7IF/HU89/00023 An area. of 5cm 2 on the back fur of the rabbits was depilated and gauze sheets, each impregnated with of the emulsions according to the following I Examples 1-10, were ,applied thereon and bandaged according to common clinical practice.

24 and 48 hours after the teratments the bandages were removed. 3 animals were used per treatment and per test period.

V It was established that the gauze sheets could easily be removed in every case, they were not dried in and did not cause any irritation on the skin.

B) Microbiological tests 1) Sterility test Prior to the skin irritation tests the sterility of the impregnated gauze sheets to be used was checked in the following way: the gauze sheets, having been welded around with PE foil, were sterilized Sunder aseptic conditions in steril box, thereafter cut 20 into pieces of about 1/2cm by the use of sterile scissors and forceps, thereafter these pieces of gauze were inoculated into sterile liquid soya-casein and Sabouraud culture media. The cultures obtained were incubated at 32 0 C and 26 0 C for one week. Thereafter they were evaluated visually and it was found that all gauze sheets were sterile.

r- WO 89/11879 7 PCT/HU89/00023 2) Microbiological stability test In this experiment by using two different bacterium strains (PSeudomonas aeruginosa and Staphylococcus aureus), it was tested whethe during a supposedly maximal duration of 72 hours of wound- -coverage, the applied material did not serve as a culture medium for the microbas being present.

The material serving for impregnation (e.g.

any of the emulsions according to Examples 1-10) was infected by the above microorganisms and after an incubation for 24, 48 and 72 hours the number of germs was determined.

It was established that growth could not be observed in case of any of the microorganism strains, ti on the contrary the initial number of germs (about 5 -10 6 decreases gradually to a value of 0-10/g.

These results show that the emulsions used for impregnation exhibit some microbiological activity too.

S. Preparation of the emulsion Example 1 Composition: Propylene glycol Polyoxyethylene glycol 400 (Lutrol 400) 59.5% Polyoxyethylene glycol 400 (Lutrol 4000) PCr/H U89/00023 WO089/11879 8 Coit of Example 1 Myritol 318 20.0% Solutol HS 15 Example 2 Composition: Ii Paraffin oil 1 Propylene glycol Lutrol 400 Lutrol 4000 Cremophor RH 60 4% F, Example 3 I Composition: Linseed oil 2% Propylene glycol 4% VLutrol 300 Lutrol 6000 8% Cremophor RH 60 6% K V Example 4 Composition: Propylene glycol Lutrol 300 Lutrol 1540 Myritol 318 Cremophor EL WO089/11879 9 PCr/HU89/00023 Composition: Luvitol. EHO 13% Lutrol 400 5915% Lutrol 4000 18% k Cremophor A 6 9.6% Example 6 Composition: Silicone oil (300 cp) Lutrol 400 7' Lutrol 1540 101-1 Cremophor S 9 Example 7 Composition: .Maize oil Lutrol 400 Lutrol 4000 Solutol HS 15 'V Example 8 Composition: Sesame oil 8% Propylene glycol 2% Lutrol. 400 Lutrol 1540 Solutol, HS 15 WO 89/11879 PCT/HU89/00023 10 Example 9 Composition: Peanut oil Lutrol 300 Lutrol 4000 Polypropylene glycol Solutol HS 15 Example Composition: Sunflower oil 6% Lutrol 300 Lutrol 6000 2% Solutol HS 15 12% j The emulsion according to the above Examples h 1-10 may be prepared by method known per se, e.g. by melting the different polyoxyethylene glycols and admixing the melt obtained under stirring with the i 20 other ingredients.

The chemical composition of the above materials specified by trade marks as follows: Myritol 318: capilicacid-capric acid-trigliceride Solutol HS 15: diethylene glycol-monoethyl ether Cremophor RH 60: polyethylene (660)-12-hydroxy- -stearate Cremophor EL: polyoxyethylene glycerol-' -triricinoleate WO 89/11879 PCT/HU89/00023 Cremophor A 6: mixture of ethoxylated fatty alcohols and free fatty alcohols Cremophor S 9: polyethylene glycol(400)-stearate Preparation of materials for covering wounds Example 11 Onto a polypropylene foil containing holes of a size of 6x6cm a loose-woven gauze sheet is arranged thereafter the gauze sheet is impregnated with the emulsion according to Example 1, then it is covered with P metal foil, cut into pieces and sterilized by radiation.

Example 12 The procedure of Example 11 is followed, with the difference that an effective amount of gentamycin as active ingredient is suspended in the emulsion before impregnation.

Example 13 The procedure of Example 11 is followed, with the difference that a perforated sheet made of synthetic material polypropylene, polyamide, viscose etc.) is used as a carrier.

Example 14 The procedure of Example 12 is followed, with WO 89/11879 12 PCr/HU89/00023 the difference that one of the following ingredients R is used in an effective amount: erithromycin, neomycin, sisomycin, tetrane; chiorohexidine gluconate, benzalconiumchloride, micanozole or metronidazo-le.

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Claims (14)

1. Therapeutical material for covering wounds and skin lesions characterized by containing a) a carrier made of textile or paper or synthetic fibre, impregnated or laminated with b) an emulsion of the following composition: propylene glycol 0-2% by weight polyoxyethylene glycols 5-95 oil 10-25% emulsifying agent(s) 5-20% j which emulsion is optionally admixed with c) an effective amount of biologically active materials selected from antibiotics, antiseptics, dezinfectants, antimycotics, biologically active vegetable extracts, dermatologica.-

2. Therapeutical material according to Claim 1 ch a r act er i z ed in that the support material a) is a textile fabric of different density and made of twisted or monofilament yarn, preferably gauze or loose Scotton fabric.

3. Therapeutical material according to Claim 1, cha r a cteri z ed in that the carrier a) is a perforated viscose sheet or a net made of synthetic fibre. i I~ WO 89/11879 .14 PCT/HU89/00023

4. Therapeutical material according to Claim 1, characterized in that the emulsion b) contains as an oil'a vegetable oil, e.g. sunflower oil, olive oil, maize oil, peanut oil, linseed'oil, animal oil, e.g. fish oil, synthetic oil, e.g. silicone oil (10-10000 cp) or mineral oil, e.g. paraffine oil. Therapeutical material according to Claim 1, c h a ra ct e r i ed in that in the emulsion b) the polyethoxyethylene glycols comprises a mixture of i polyoxyethylene glycols of different degree of polymerization n=300-6000) and the ratio of i polyoxyethylene glycols of lower and higher degree Sv 15 of polymerization is in the range from (1:40) to f-r- n i D-6 -TL-!e l 1 1 t .i characterized by optionally containi:: a biologically active material c) selected from gentamycin, erithromycin, neomycin, risocin, tetrane; /i chlorohexidinegluconate, benzalcon' m chloride; micanozole and metronidozole

7. Process for e preparation of therapeutical material fo overing wounds and skin lesions accord ig to Claim 1, characteri z ed by preparing y. -a (J ''NTf 1O b=^ad=t~^^4n 3 1 15 6. Therapeutic material according to claim 5 wherein the ratio of polyoxyethylene glycols of lower and higher degree of polymerization is in the range from to (20:1). 7. Therapeutical material according to Claim 1, characterized by optionally containing a biologically active material c) selected from gentamycin, erithromycin, neomycin, risomycin, tetrane; chlorohexidinegluconate, benzalconium chloride; micanozole and metronidozole.

8. Process for the preparation of therapeutical material for covering wounds and skin lesions according to Claim 1, characterized by preparing emulsion b) by admixing the ingredients, optionally admixing the emulsion obtained with an effective amount of biologically active material c) laminating said emulsion on carrier a) or impregnating by same and packing the product obtained and sterilizing if desired. DATED this 17th day of July, 1991. t 4 ;a. LICENCIA TALALMANYOKAT ERTEKESITO ES INNOVACIOS KULKERESKEDELMI VALLALAT WATERMARK PATENT TRADEMARK ATTORNEYS, 290 Burwood Road, HAWTHORN. VIC. 3122 AUSTRALIA LCG:KJS:JZ (13/34) 'V LI LI U I ~1 Li LI LI LI r I~. p INTERNATIONAL SEARCH REPORT Inmnelonul Acolcaton No PCT IF/U 89 10 00 I. CASSIFICATION OF SUBJECT MATTER (it severul classification symbols 400ly. indicate all) ACCordift 9 60o bmUoesi PIA&Mn Clossfcaton (lPC) Of t0 both fillnalM Clasificaicri and IPIC IPC 4 A 61 L 15/01, A 61 L 151/03; A 61 F 131/00. II. FIELDS SEARCHEID Minimumi Documentatian Searched Clasasfication System Classification 3ynsheft Int.. A 61 L; A 61 L Documnentation 1loerchad Othery then Minimum Documentation to the Extern that much 0ocuments are Included In the Filds SiteiChed III, DOCUMENTS C~ONIDERED TO 8E RELEVANT' Category' Costaien wl Document."1 with Indketion. where acorortate. of the relevant Passage* 1 Relevant to Claim No. Is X DE, A, 2 351 893 (HURKA) 05 September 1974 I (05.09. 74), see claims. X DE, Al, 3 002 864 (JAPAN SYNTHETIC RUBBER (1,4-7) CO. LTD.) 14 August 1980 (14.08.80), see claims; page 16, lines 14-17. X EP, Al, 0 196 632 (MINNETONKA; INC.) 08 October 1986 (08.10.86), see claims(1 1,8. X EP, A2, 0 138 551 (WARNER -LAMWBERT COMPANY) (1,4) 24 April 1985 (24. 04. 85), see claims I 1,5,6. A IEP, A2, 0 138 740 (ENQUAY PHARMACEUTICAL I(1,5,6) IASSOCIATES) 24 April 1985 (24.04.85), see claims 1,4,9. A AT, E, 26 217, B -(JOHNSON JOHNSON PRODUC'T (1,3-6) INC.) 01 August 1984 (01.08.84), see claims, 1,3,4; page 16, lines 17-31; page 19, lines 12-30. *Specild caolees of ctted documentse: tater documntf Published after the IntoebofiAt filing date document defining the general stiae of the art which is no of orierty data and not In confllict wiht the apeliceten but conederd t beat ertculr rlevncecited to undentitndi the poincilo~a or theory undairtyiti the consderd tobe f Prticlar1414ilfillInvention eariffn documiti but Pubtished on or 5ft the inmlflteThjglj X" document ofParicular relevilfnce: the ellfild iweftf filing date cainnot be conaldered novel isr cannot be copolered to document which may throw doubts on g$01tj ctlm(s) of Inv'olve ant inventive a"e which is cited to sabheh the Pub"~stf SOtW of anlother doue do Paticular .e the claimed Vnoltf itation or other social reason (s 690e111144d) cannot be conldsrs tgo nvoean iNventive age whe the document sofoig teeon dislosourese. ehlibitls or document i'l ceo ned with one er mare O111er Such dOCw- other meena NIefit. such Com nte beling obvious too a erson ehilld ,p documnent pubileftod ier to the infoenaietln filing data but In the art. later t"An the sornty date C&Oime aldocumentf mofmber of the so"e 0~an family IV. CERIFICATION Data of the Actual Compolton of Ithe iMOtAhWAIos Soostl Dat of Mottling of t l n~retio" Sewt ft Rse 08 August 1989 (08.08.89) 16 August 1989 (16.08.89) Inteffistjonal Searching Authoity 241Rg1N j tzdidd Office AUSTRIAN PATENT OFFICE *2cA Form PCTIISA 121 Isecand sheet) poinuoy IONS) In~ternational Application No, PCT IH-U 891I00 023 ill. DOCUMENTS CONSIDERED TO Elf RELEVANT (CONTINUED FROM THE SECOND SHEET Category Cttof 0# Oocufmiott, with jnIdicir, ~ger apopneits. of "ri reievent possaers, Reevn to Cl No DE, C2, 2 755 838 (INSTITUT MERIEUX) 07 November 1985 (0 7.11.85), see claim 1; column 4, lines 6-25. AT, B, 378 122 (KARL OTTO BRAUN KG) June 1985 (25.06.85), see claim 1. (1) (1-3) Form PCTISA/210 (extra sheet) (January 1943) -Anhang zuM inter'natio- nalen Recherchenbericht ilber die internationale Patentanmeldung Nr. In diesem Anhang sind die Mitglieder der Patentfamilien der im obengenannten interna- tionalen Recherchenbe- richt angef'Uhrten Patentdokumente ange- geben. Diese Angaben dienen nr z r Unt.h-Tich- tung und erfolgen ohne Gewahr. Annex to the International Search Report on Interna- tional Patent Application No.PCT/HU 89/00023 This Annex lists the patent family members relating to the patent documents cited in the above-mentioned Inter- national search report. The Austrian Patent Office is in no way liable for these par- ticulars which are merely given for the purpose of in- formation. Annexe au rapport de recherche internationale relatif i la demande de brevet international n*. La prL-sente annexe indique les membres de la famille de brevets relatifs aux docu- ments de brevets cit~s dans le rapport de recherche inter- nationalevis& ci-dessus. Les renseignements fournis sont donn~s A titre indicatif et n'engagent pas la responsa- bilit6 de l'Office autrichien des brevets. In Recherchenbericht Datum der Mitglied(er) der Datum der angefUhrtes Patent- Ver~ffentlichung Patentfamilie Verbiffentlichung dokument Publication Patent family Publication Patent document cited date member(s) date d in search report Date de Membre(s) de la Date de Document de brevet cit& publication famille de publication dans le rapport brevets de recherche AT-B 3233- JCl07-7 7 C--6,163/i2ic B.E_ SA.* j I C) J 15 0 1-74 I -A I. 7r05-6: 9--TA DE- 1~30035 1 G R-Al- -3 47~ 08-S T.1L-A 4-125. 1' 0-7, USA- -I -55 28-o-E& UC- 475 11Z0' EF-A2--. I17q551 2A.-CW-85 EPF-A3- 13 95 5, 14-_01-87 A U--A 1--33 4084/ G I- 1-- I C 0 8 E CA-AlI- 1282 0-C)3 B82 US-A -469 6 821 29F--09-,87 EP-A2--- 17.0 EF-A.- 1,78-740 i_ AU-Ai-33623/94 2 'i-04 AU-B2-- 563517 CA-Al1- 12 4 5158 22 11 8 ES- Al 536773 V01 -04-87" 53677'z 2804-8.7 ES-Al- 8 7'434f C) 73:18LC8 _7i- J P-A2-60135075E 08 109 PH -A 20279:- 1-6 USA 56 -518 US,-A -4172527: 16-02-88 UIS--A 4 7 47 B4f: 3. uS 56--2 US-A 820292 14-89 ZA-A 84075925 -2- zPCT/HU 89/00023 I I' I 'I K K Ix AT-E2- AT-E 26217 AU-Al -22490/83 AU-B2- 565483 CA-Al 1 207263; Df*K-A(O- 5796/83 DK-A 5796/93 EP-Al- 114481 EP-BI-

11.4481 FI-AOD- 834 6 27; FI-A -834623 Fl-P 7783 Fl-C 77783 GB-Al- 2.1701 GB-B2- 2131701 HK-A -632/86 JF'-A2-'.1 '3159 MY-A 121/67 NO-A -834+627 NZ-A 2 4 B G US A 4 5,:38 c) iS 465575 A 47- 4 AU-Al :7 /.0 DE--C2- 275ES38 07-1:1-85 A4 942/7 AT- S, 390 BEAl 86251 CH-- -A2 64 DI 15 2_ C ES- 236E 1 2 7 GE A i 570-.f JR A J P B4 6 10 2' LU--A 788pv: NL-A 7146 NL-B 117S_! NL-C 1 1817233 NO-A -774527 1474D1 NO-C -14 7 4 01) SE-A 7714962 SE-B 421377 S--C -42i3.77 US-A 4214592

15-04-87

21-06-84 7-09-87 C)8-07-86 12-12-83. 17-0-'6-84- C) 1 -08-84 C) 1-0'D4 -67 15-12-87, 17-06-84 1. )-0-5-e9

25-01-84

27-06-84 12-03-86 C0'5-0f'9-86 11-07-84 .341-l2-87 18 -06-84 11-04-86 13-0586 070487 2-11 **39' 7 6 ,37 7 1 3C 0'~x E

125- 81 J. 7 7 8 8 SO3 1 -7 9-. lI-- 0 6- F, 7 13-04-83 0)2-07 -78 21-12-8 1 01-04-92 AT1 2 5 066- 5 AT-A -2610/81 15-,11-84 A T-A 2 7:3 9 1 15-11-84 AT-B -378121 25--Q-6-85 AT-A -4489/78 1.5-0)1-82 AT-B -367?90 f PE-Al-- 868707 13- 1-78 CA-Al 1' 07C0217 0 1 E?0r OH-A 642532 30-104-84. DE-Al- 2 773 0 2,7 '5-01-79 DE-C2- 2730277 14-03-85

4742- 16.--0.z:-79 FR-Al- 23.9654 02-02-707 FR-B1-- 239654.. 12-07--E5 GB-Al1- 20310 o?3 4-07--79 rGR-rB2- 2010:9:7 27-10-82 NL-A 780726 '9--01-7ci U PCT 89100023 AT-B 378 122 25-06-85 SE-A- SE-B SE-C- US-A- DE-A 1- DE-C2- DE-Al- DE-C2- DE-A 1- DE-C2- 780:7497

44371.9 44:48718 27-.726S) 27-37268 27369.3 27 38S9.3-! 2 656043 2656043 :19-06-76 1 CI P 0 1 037 27-02-B6 15-06-7e 22-11 5-4 For mare details abaut this armey.; see 0-ficial Journal c- the European Patent Office, No. 12/82.