AU697290B2

AU697290B2 - Pharmaceuticals

Info

Publication number: AU697290B2
Application number: AU13834/95A
Authority: AU
Inventors: Ronald James Boon; David Ronald John Griffin
Original assignee: SmithKline Beecham Ltd
Current assignee: Novartis International Pharmaceutical Ltd
Priority date: 1993-12-22
Filing date: 1994-12-14
Publication date: 1998-10-01
Anticipated expiration: 2014-12-14
Also published as: ZA9410113B; CA2179282A1; JPH09506883A; WO1995017190A1; CN1142769A; GB9326177D0; AU1383495A; CN1084622C; EP0735878A1

Description

WO 95/17190 PCT/EP94/04163

PHARMACEUTICALS

This invention relates to treatment of zoster associated pain, and to the use of compounds in the preparation of a medicament for use in the treatment of this condition.

When used herein, 'treatment' includes prophylaxis as appropriate.

EP-A-141927 (Beecham Group discloses penciclovir, the compound of formula 0 N NH N N

NH

2 (CH2)2

HO-CH

2 2-OY H

(A)

and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group Penciclovir and its antiviral activity is also disclosed in Abstract P.V11-5 p. 193 of 'Abstracts of 14th Int.

Congress of Microbiology', Manchester, England 7-13 September 1986 (Boyd et. al.).

Orally active bioprecursors of the compound of formula are of formula x N N NH, NI C t

.K

CH

2 )2 -2 HOCH,-CH2

-CHOH

(B)

C t C t C

U

i; WO 95/17190 PCT/EP94/04163 and salts and derivatives thereof as defined under formula wherein X is C1-6 alkoxy,

NH

2 or hydrogen. The compounds of formula wherein X is C1-6 alkoxy or NH 2 are disclosed in EP-A-141927 and the compounds of formula wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Group are preferred prodrugs. A particularly preferred example of a compound of formula is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as famciclovir.

The compounds of formulae and and salts and derivatives thereof have been described as useful in the treatment of infections caused by herpesviruses, such as herpes simplex type 1, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.

Zoster associated pain (ZAP) is considered to consist of the pain associated with zoster infection and includes the acute phase pain and post-herpetic neuralgia (PHN), which is by far the most common complication of herpes zoster infection and one of the most intractable pain disorders (Strommen et al, Pharmacotherapy. 1988;8:52-68). Patients who develop PHN suffer from a debilitating and often intractable pain which can persist for months or even years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply with increasing age.

Huff et al, Journal of Medical Virology, Supplement 1:93-96 (1993) and Crooks et al, Scand J Infect Suppl. 78:000-000, 1991 describe the effects of acyclovir in ZAP.

It has now been discovered that the above compounds are particularly effective in reducing the duration of ZAP when given to the patient during the acute infection.

Accordingly, the present invention provides a method of treatment of ZAP in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula O0

N

NH

N N

NH

2

(CH

2 2

HO-CH

2 2

-OH

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.

2 -2a- In another aspect, the invention contemplates use of compound of formula (A)

O

NH

N N- NH 2 "2)2 HO-CH2-1H-OH

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either thereof, in the manufacture of a medicament for reducing the duration of zosterassociated pain (ZAP) in mammals, including humans, wherein the medicament is administered with 72 hours of zoster rash onset.

a I a 3* ta

S..

k. l.ic lit" rtrl -181898 r WO 95/17190 PCT/EP94/04163 The term 'acyl derivative' is used herein to include any derivative of the compounds of formula in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula in addition to those derivatives which are per se biologically active.

The compound of formula may be in one of the forms disclosed in EP-A-216459 (Beecham Group Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.

A particular compound of formula of interest is 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-aminopurine, known as famciclovir (FCV), the wellabsorbed oral form of penciclovir (PCV).

The compound of formua bioprecursors, salts and derivatives may be prepared as described in the aforementioned European Patent references.

The compound, in particular, famciclovir, may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule. When in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. Sustained release formulations, for example tablets containing an enteric coating, are also envisaged.

For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a d suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

Preferred parenteral formulations include aqueous formulations using sterile water or 3 h'r .i WO 95/17190 PCTEP94/04163 normal saline, at a pH of around 7.4 or greater, in particular, containing penciclovir sodium salt hydrate.

As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.

A suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to 500mg. Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day. The effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mg/kg per day. in the case of famciclovir, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.

The treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset.

The treatment period is usually 7 days.

The treatment is particularly effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be demonstrated further in patients greater than years of age, especially patients of greater than 70 years of age.

The present invention also provides the use of a compound of formula or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of ZAP.

Such treatment may be carried out in the manner as hereinbefore described.

The present invention further provides a pharmaceutical composition for use in the I treatment of ZAP, which comprises an effective amount of a compound of formula or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described.

The compound of formula and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention. Such products are described in EP-A-271270 (Beecham Group The following clinical data illustrate the invention.

Clinical Data Study 1 is described in Degreef et al, 'International Journal of Microbial Agents, Volume 4, No. 4 (1994), pp 241-246.

4 !iZ I i I, c WO 95/17190 PCT/EP94/04163 A prospective, randomized, double-blind study (study 2) was conducted to compare FCV dosed at 500 mg and 750 mg tid for 7 days with placebo in the treatment of uncomplicated herpes zoster. 419 immunocompetent patients, aged 18 years whose zoster rash had been present for 72 hours were enrolled. Patients were assessed for lesion condition and pain pre-therapy, daily during week 1, daily until full crusting during week 2 and then weekly until all crust had been lost. Both FCV doses were equally effective and significantly reduced the duration of VZV recovery from zoster lesions and the time to healing of zoster lesions compared with the placebo-treated group. In addition, a statistically significant decrease in the duration of acute phase pain was detected for famciclovir-treated patients presenting with severe rash when compared with placebo. The effect of famciclovir on PHN (defined as pain at or after healing) was evaluated by assessing pain at 5 monthly visits after healing. The duration of PHN for all age groups was significantly reduced from 128 days to 62 and 55 days following treatment with FCV 500 mg and 750 mg, respectively.

There were no significant differences in the safety profiles between famciclovir and placebo.

"The median time to loss of pain from enrolment time to loss of ZAP) was 21 days and 27 days for famciclovir doses of 500 mg and 750 mg respectively compared with 30 days for placebo. In conclusion, this study demonstrates that famciclovir dosed tid is an effective and well tolerated treatment for patients with acute herpes zoster infection, significantly decreasing the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as

ZAP.

The table below summarises the results in ZAP from clinical studies with famciclovir.

Endpoint Sub-group ACV FCV FCV FCV PCB (Study/Population) 250 500 750 TLZAP (Study 1/EE) -501 60 49 28 29 TLZAP (Study 1/EE) <48hrs 2 69 12* 17* 28* TLZAP (Study 1/EE) <48/-503 69 28* 1 56*2 29 TLZAP (Study 2/EE) <48hrs 2 26* 28* 64 TLZAP (Study 2/EE) 501 28* 57* 76 r' 4' ["i it I i~ WO 95/17190 PCT/EP94/04163 1 Patients aged 50 years or more treated within 72 hours 2 Patients of all ages treated within 48 hours of rash onset 3 Patients aged 50 years or more who were treated within 48 hours of rash onset *1 Significant by Wilcoxon test *2 Significant by Log Rank Test ITT Intention to treat population EE Efficacy evaluable population ACV Acyclovir 800mg five times daily for seven days PCB Placebo treatment TLZAP Time to loss of ZAP (time to loss of pain from enrolment) Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

1

I

.1 Cr c C CC C C; C Co cC C C S 'S

'C

Claims

1. A method of reducing the duration of zoster-associated pain (ZAP), in mammals, including humans, which method comprises administering to the mammal an effective amount of a compound of formula 10 10 1 (CH 2 2 HO-CHz-.H 2 -OH (A) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either thereof, within 72 hours of zoster rash onset.

2. A method according to claim 1 wherein the Compound is administered within 48 hours of rash onset.

3. A method according to claim 1 or 2 wherein the administration period is 7 days.

4. A method according to any one of claims 1 to 3 wherein the administration is carried out on patients of greater than 50 years of age.

5. A method according to claim 4 wherein the administration is carried out on patients of greater than 60 years of age.

6. A method according to claim 5 wherein the administration is carried out on patients of greater than 70 years of age. CL ct C r t I L p F'; h P:\OPER\PDB\I3834-95.209 18/8/98 8

7. A method ac~(irding to any one of claims 1 to 6 wherein the Compound is famciclovir.

8. A method according to claim 7 wherein famiclovir is administeredlat a dose of 250 mg or 750 mg, once, twice or three times a day.

9. A method according to claim 8 wherein famiclovir is administered at a dose of 250 mg three times a day.

A method according to claim 8 wherein famiclovir is administered at a dose of 500 mg three times a day.

11. A method according to claim 8 wherein famiclovir is administered at a dose 500 mg twice a day.

12. A method according to claim 8 wherein famiclovir is administered at a dose of 750 mg once a day.

13. Use of a compound of formula 0 N N NH 2 (-12 HO-Cl -OH I' PAOPMkDU384-95209. /IM9 or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either thereof, in the manufacture of a medicament for reducing the duration of zoster-associated pain (ZAP) in mammals, including humans, wherein the medicament is administered with 72 hours of zoster rash onset. DATED this Eighteenth day of August, 1998. SmithKline Beecham plc by their Patent Attorneys DAVIES COLLISON CAVE *4 4 4 4 b$4 4 4. 4 44 4 4 4 4444 44 44 4 444444 $4 4I 44 44 4$ 44 44 ''44 4? Li N- INTERNATIONAL SEARCH REPORT I A- 94/04163 intcm Apgji 1p 94/04163 A. CLASSIFICATION OF SUBJECT MATTER A 61 K 31/52,C 07 D 473/18,C 07 D 473/32 According to International Patent Classficaton (IPC) or to both national clasafication and IPC 6 3. FIELDS SEARCIIED Minimum documentation searched (classification system followed by clasification symbols) A 61 K,C 07 D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category' Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y,X EP, A, 0 182 024 1-13 (BEECHAM GROUP.PLC) 28 May 1986 (28.05.86), abstract; claims 1,7-10; example 2; page 1, line 1 page 2, last line; page lines page lines 21-30 (cited in the application). Y AUSTRIA CODEX 1992/1993 1-13 FACHINFORMATION, vol. 3, issued 1992, OSTERREICHISCHE APOTHEKER- VERLAGSGESELLSCHAFT M.B.H., Wien, "Zovirax"-preparations, pages 3251-3257, especially pages 3253-3254, Further documents are listed in the ontinuation of box C. Patent family members are listed in annex. Special categories of cited documents: Secial categor cited doctment later document published after the intemational filing date A document dening the general state of the art which is no or priority date and not in conflict with the applicaton but A document defining the general state of the a which is not cited to understand the principle or theory underlying the considered to be of paracular relevance invention E earlier document but published on or after the international *X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to docum nt which may throw doubts on priority caim(s) or involve an inventive step when the document is taken alone which is cited to establish the publicaton date of another Y document of particular relevance; the claimed invention citaon or other pecial reason (as specified) cannot be considered to involve an inventive step when the document referring to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the intemational filing date but in the art later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 06 March 1995 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5811 Patentlaan 2 NL 2280 HV Rijswijk Tel.(+31-70) 340-2040, Tx. 31 651 epo nl, M ZUC .h Fax (+31-70)340-3016 MAZZUCCO e.h. Form PCTISA&2LO (tecond sheet) tuly 1992) Ki INTERNATIONAL SEARCH REPORT Iter a io C 94o6 No 9 PC/P 94/04163 C.(Continuauon) DOCUMENTS CONSIDERED TO BE RELEVANT Category' Citation of document. with indicauon, wher appropnate, of the relevant pasages Relevant to claim No. paragraphs "DO". X WO, A, 93/00 905 (SMITHKLINE BEECHAM. PLC) 21 January 1993 (21.01.93), abstract; claims 1,9-12; page 6, lines 34-38. X EP, A, 0 416 739 (BEECHAM GROUP.PLC) 13 March 1991 (13.03.91), claims 1,8-10; page 1, lines 1-14; page 4, lines 34-36. x WO, A, 91/11 187 (BEECHAM GROUP PLC) 08 August 1991 (08.08.1991), claims 1-6,9-11; page 1, lines 3-36; page 8, lines 7-13. X EP, A, 0 271 270 (BEECHAM GROUP PLC) 15 June 1988 (15.06.88), page 1, line 6 page 2, line 33; claims 1-4 (cited in the application). X EP, A, 0 141 927 (BEECHAM GROUP PLC) 22 May 1985 (22.05.85), abstract; claims 1,10-12; page 15, last paragraph page 17, line 11 (cited in the application). X EP, A, 0 216 459 (BEECHAM GROUP PLC) 01 April 1987 (01.04.87), abstract; claims 8-10 (cited in the application). X EP, A, 0 388 049 (BEECHAM GROUP PLC) 10-13 19 September 1990 (19.09.90), abstract; claims 1,5-8; page 3, lines 51-58. X WO, A, 92/00 742 3, (BEECHAM GROUP PLC) 10-13 23 January 1992 (23.01.92), claims 3-12; page 2, Fo PCT1SA/210 (eninuadon cC sean.d atiw) (luly 1992) '1 MRL- INTERNATIONAL SEARCH REPORT Itndnl'-cdnN PCT/EP 94/04163 C.(Coniution) DOCUMCNT'S CONSIDERED TO BE1 RELEVANT ca-tegor-y Qtion of doctumcnt, with indicatoN. where appropriate. of the ttlcvazn pauagcs 1 ecat to clam No. lines 12-22; page 3, line 21 page 4, line page 5, lines 34-37. A A FOrm PCTIASA/2IQ (mrntinuatioo of e mng shmt) (July 1992) PCT/EP 94/04163 INTERNATIONAL SEARCH REPORT IBox I Observations wherec eritain claims were found unsearchable (Continuation or item I or first sheet) This international search report ha~s not been established in respect or certain claims under Article 17(2X&) ror the following reason 1. Claims Nos-- because they relate to subject maztter not required to be searched by this Authority. namely. Although claims 1 and partially 4-13 are directed to a method of treatmen of the human or animal body by therapy (Rule 39.1 (iv) PCT) the search ha been carried out and based on the alleged effects of the composition. 2. DClaim: No.: because they relate to pauts or the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specfically. 3. Claims No. because they are dependent claims and ame not drafted in accordance with the second and third sentences of.Rule 6A(4)L t s t O b--6servations where unity of invention is lacking (Continuation of item 2 -of first sheet) This International Searching Authority round multiple inventions in this international application. as follows: 1. As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claints. 2. DAs all searchable claims could be searches without effort justifyinig an additional fee, this Authority did not invite pay or any addiuional ree. 3. As only some of the required additional seach fee were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims NoL.: 4. No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims, itis: covered by claims Nos.: Remark on Protest D The additional search fees were cmpanied by the applicant's M .No protest accompanied the payment of additional search fees. Ient protest. Form PCT/ISA/21O (continuation of first sheet (July 1992) Ac M

14 Ar JEr-=X A 'N r_=XE IF zum internationalen Recherchen- bericht ajber die internationale Patentanmeldung Nr. to the International Search Report to the International Patent Apolication No. au rapport de recherche inter- natiohal relatif A la demande de brevet international no PCT/EP 94/04163 SAE 102053 In diesem Anhang sind die )itglieder der Patentfamilien der im obenge- nannten international en Recherchenbericht angel Qhrten Patentdokumente angegeben. Diese Angaben dienen nur zur Unter- richtung und erfolgen ohne Gew~hr, This Annex lists the patent family members relating to the patent documents cited in the above-mentioned inter- national search report, The Office is in no way liable for these particulars which are given merely for the purpose of informat ion. La pr~sente annexe indique lee membres de la f amille de brevets relatifs aux documents de brevets cites dans le rapport de recherche inter- national viske ci-dessus. Les reseigne- ments fournis sant donn~s A titre indica- tif et n~ennagent. pas la responsibilit6 de l'Dffice: Im Recherchenbericht Datum der Iitalied(er) der Datum der angefrihrtes Patentdokument Yerbffentlichung Pafentfami lie Ver~ffentlichung Patent document cited Publication Pat~.nt family Publication in search report date member(s) date Document de brevet cit6 Date de Ilembre(s) de la Date de dane le rapport de recherche publication famille de brevets publication EF- A2 1832024 2e-0:5-86 AU Al1 47560/85 27-03-86 AU R2 5893-71 12-10-89 CA Al 1262899 14-11-89 CS A3 9103915 13-05-92 DE CO 3582399 66-65~-91 DK A0 4246/85 18 -09-85 WD' A 4246/85 21 (03-B6 D 1K, 81 1670 19 16-08-93 EP A3 182024 EF, B1 18 2024 03'-04-9 1 ES Al 547128 ol-03-07 ES A5 547128 u1-04-87 ES Al 8703876 16-05-e7 BB Ao 8520618 25-09-83 GR A 852272 21-01-e6 H-K A 1286/93 26-11-93 1 E B 58141 14-07-93 JFP A2 6 10853588 30-04-86 JP' B4 5086792 14-12-93 JP A2 6025241 01-02-94 MX B 165116 11-08-93 NZ A 213529 29-03-89 FT A 81160 0)1 -1I0-85 PT B 831160 22-0 1-88 [is A 5250688 05-10-93 GB AO 8510331 30-05-85 GB A0 8423833 24-10-84 ZA A 8507149 27-08-86 US A 5246937 21-09-93 NO Ai 93,00905 21-01-93 AU Al 22307/92 11-02-93 CA AA 21 13080O 21-01-93 EP Al 593562 27-04-94 GB A0 9114939 28-08)-91 JP T2 6508845 06-10-94 M'lX Al1 9204030 06-05-93 PT A 100670 29-10-937 EP Al 416739 13-03-91 AU Al 60129/90 07-02-91 CA AA 2022632 06-02-91 GB A0 8917959 20-09-89 JP A2 3066618 22-03-91 NZ A 234767 25-09-92 PT A 94911 22-05-91 ZA A 90061283 31-07-91 NO Al 9111187 08-08-91 AP AO 9000236 31-01-91 AU Al 71558/91 21-08-91 AU B2 643975 02-12-93 CA AA 2074503 27-07-91 CN A 1053547 07-08-91 EP Al 511991 11-11-92 F1 A 923371 24-07-92 FI AO 923371 24-07-92 G B AO 9001866 28-03--90 HU Aci 9202431 28-10-92 HU A2 62472 28-05-93 IL AO 97008 29-03-92 JP T2 5503695 17-06-93 PT A 96563 15-10-91 ZA A 9100525 26-02-92 I EP A2 271270 15-06-88 AT E 74%1 AU Al 81912iS7

15-04-92 02-06-88 PCT/EP 94/04163 AU B2 606629 14-02-91 CA Al 1318850 0-06-93 DE CO 3777769 30-04-92 DK AO 6279/87 30-11-87 DK A 6279/87 03-06-8 DD 91 166715 05-07-93 EP A3 271270 27-09-89 EP B1 271270 25-03-92 ES T3 2037095 16-06-93 GB AO 8628826 07-01-87 IE B 59943 04-05-94 JP A2 63145279 17-06-88 NZ A 222741 26-10-90 PT A 86232 01-12-87 PT B 86232 07-11-90 US A 4957733 18-09-90 ZA A 8708983 31-08-88 EP A2 141927 22-05-85 CZ A3 9103914 13-01-93 DE CO 3485225 05-12-91 EP A3 141927 12-03-86 EP E1 141927 30-10-91 ES Al 535283 01-12-85 ES AS 535283 31-12-85 ES Al 543213 01-0 1-86 ES Al 543214 01-01-86 ES A5 543213 31-01-86 ES AS 543214 31-01-86 ES Al 9602791 16-03-86 ES Al 860:3887 16-05-86 ES Al 8603888 16-05-86 GB AO 8408322 10-05-84 GR A 80121 17-12-84 HK A 1260/93 19-11-93 IE B 58334 08-09-93 JP A2 60058982 05-04-85 JP A2 6293764 21-10-94 MIIX A 160431 22-02-90 NZ A 209248 08-01-88 US A 5075445 24-1 2-91 AU Al 31973/84 21-02-85 AU 82 577303 22-09-88 GB AC) 8325271 26-10-83 GB AO 8322199 21-09-83 ZA A 8406374 28-08-85 EP Ai 216459 01-04-87 AU Al 60557/86 29-0:1-87 AU 92 596366 03-05-90 CA Al 1262172 03-10-89 DE CO 3671227 21-06-90 DK AO 3566/86 25-07-86 DK A 3566/86 28-01-87 DK 81 167925 03-01-94 EP 21 216459 16-05-90 ES AF 2000759 16-03-88 G AO 8530491 22-01-86 GR A 861963 26-11-86 IE B 58639 20-10-93 JP A2 62036381 17-02-87 JP 94 6070057 07-09-94 MX B 165149 11-08-93 NZ A 216979 29-01-90 PT A 83073 01-08-86 PT B 83073 28-02-89 US A 4942166 17-07-90 GB AO 8519011 o4-09-85 ZA A 8605557 24-06-87 EP A2 388049 19-09-90 AU Al 50600/90 01-11-90 AU B2 628137 10-09-92 CA AA 2011238 03-09-90 EP A3 388049 06-11-91 GB AO 8904855 12-04-89 HU AO 901252 28-05-90 HU A2 53522 28-11-90 HU B 205715 29-06-92 IL AO 93594 23-12-90 JP A2 2275821 09-11-90 ZA A 9001572 27-03-91 WO Al 9200742 23-01-92 AR AO 9100290 31-07-91 AP A 291 29-12-93 AU Al 81032/91 04-02-92 AU B2 647807 31-03-94 CA AA 2086756 08-01-92 EP Al 538305 28-04-93 GB AO 9015051 29-08-90 IL AO 98749 15-07-92 JP T2 5507719 04-11-93 r PCT/EP 94/04163 Z c?105214 T-4-06-92 I 1 A