AU623627B2 - Orthostatic lavage solutions - Google Patents

Description

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PCT

w OPI DATE 19/07/89 APPLN. ID 29008 89 AOJP DATE 17/08/89 .1TERNATIONAL APPLICATI(. O W A I PCT NUMBER PCT/AU88/00484 (51) International Patent Classificatio nati Publication Number: A61K 47/00 A61K 31/045 (43) International Publication Date: WO 89/ 05659 29 June 1989 (29.06.89) (21) International Application Number: PCT/AU88/00484 (22) International Filing Date: 20 December 1988 (20.12.88) (31) Priority Application Number: PI 6088 HU, IT (European patent), JP, KP, KR, LK, LU, LU (European patent), MC, MG, ML (OAPI patent), MR (OAPI patent), MW, NL, NL (European patent), NO, RO, SD, SE, SE (European patent), SN (OAPI patent), SU, TD (OAPI patent), TG (OAPI patent), US.

Published With international sear-h report.

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments.

(32) Priority Date: (33) Priority Country: 24 December 1987 (24.12.87) (71)(72) Applicant and Inventor: BORODY, Thomas, Julius [AU/AU]; 144 Great North Road, Five Dock, NSW 2046 (AU).

(74) Agent: SPRUSON FERGUSON; G.P.O. Box 3898, Sydney, NSW 2001 (AU).

(81) Designated States: AT, AT (European patent), AU, BB, BE (European patent), BG, BJ (OAPI patent), BR, CF (OAPI patent), CG (OAPI patent), CH, CH (European patent), CM (OAPI patent), DE, DE (European patent), DK, FI, FR (European patent), GA (OAPI patent), GB, GB (European patent), (54) Title: ORTHOSTATIC LAVAGE SOLUTIONS (57) Abstract The present invention provides a formulation for colon evacuation or for treatment of bowel diseases and/or disorders characterized in that it contains ascorbic acid or a salt thereof, with the proviso that, due to problems of instability, in a dry formulation, the ascorbic acid is packaged separately from the other components or coated. The formulation may be used in a method of whole bowel irrigation or in the treatment of bacterial or inflammatory bowel diseases.

WO 89/05659 PCT/AU88/00484 ORTHOSTATIC LAVAGE SOLUTIONS TECHNICAL FIELD The present invention relates to orthostatic lavage solutions or colon evacuants for cleansing the gastrointestinal tract, or for treatment of bowel diseases and/or disorders.

BACKGROUND ART Orthostatic lavage solutions or colon evacuants for cleansing the gastrointestinal tract were introduced into medical practice only within the last five years. The available solutions which seek to produce volumogenic diarrhoea by ingestion of relatively large volumes of electrolyte solution are almost all identical in their contents of salts, formulated so that they are relatively isotonic, and include poorly absorbable polyethylene glycol. Solutions which are commonly employed include 0.9% sodium chloride, balanced electrolyte solutions, lactated Ringers, mannitol and polyethylene glycol containing electrolyte solutions.

These solutions induce copious diarrhoea when the volume of the solution is greater than the bowel's capacity to distend and absorb it.

Generally about 4 to 5 litre of the solution is necessary to obtain adequate cleansing of the gastrointestinal tract for colonoscopy or bowel surgery. Apart from the necessary diarrhoeagenic effect, the large volume required and the particularly unpleasant taste of the solutions contribute to the chief side effects of nausea and vomiting. These side effects are counter productive in reaching the desired aim of complete and rapid purging and cleansing of the bowel. The unpalatability of the solutions also result in poor patient compliance.

Flavouring the currently used solution with standard agents is difficult due to the large destabilizing amount of flavouring agents required to block the unpleasant nauseating taste of salts. Sugar based flavours are not acceptable since delivery of unabsorbed sugars to the colon provides a substrate for bacteria to elaborate explosive gases such as hydrogen and methane. In fact, recent studies Crowe et al. have indicated that even the unflavoureo polyethylene glycol solutions currently in use may create hydrogen and methane in potentially explosive concentrations when cautery is used within the colon.

Furthermore, most bowel preparations using orthostatic lavage precede either colonoscopy or bowel surgery with a lesser usage in barium-enema bowel radiology. Since patients reauiring such procedures are usually in the older age group and may be canaidates for surgery after discovery of a bowel cancer, for example, it would be of advantage if the solution had

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-2bacteriocidal properties and/or could simultaneously replace nutrients necessary for repair.

Therefore it would be desirable to provide a colon evacuant wherein the unpleasant taste of the normally used isotonic solutions containing PEG is masked, wherein it has endogenous diarrhoea producing properties, and wherein it confers bacteriostatic or bacteriocidal properties to reduce bowel gas production of post-operative infection and yet can replace some nutrient value pre-operatively.

It is an object of the present invention to provide an agent which may be combined with flavouring and sweetening agents, which significantly reduces the potential for explosion due to a reduction of explosive gasses secondary to a bacteriostatic effect on bowel bacteria, and which allows a reduction in the volume of standard lavage solutions containing polyethylene glycol by at least about Thus providing a more palatable and effective formulation, with fewer side effects, greater patient compliance and less risk cf explosion.

DISCLOSURE OF THE INVENTION According to a first embodiment of this invention, there is provided an oral formulation for colon evacuation or for treatment of bowel diseases and/or disorders, said formulation consisting essentially of 30 to 60 parts by weight of a high molecular weight polyethylene glycol, 0.2 to 20.0 parts by weight of at least one electrolyte having at least one alkali metal salt and 0.25 to 50 parts by weight of ascorbic acid or a salt thereof.

According to a second embodiment of this invention, there is provided a formulation for colon evacuation or for treatment of bowel diseases and/or disorders, characterised in that it has the following composition: polyethylene glycol 30-60, sodium chloride 0.5-3.0, potassium chloride 0.2-2.0, sodium hydrogen carbonate 0.5-5.0, sodium sulfate (anhydrous) 2.0-10.0, ascorbic acid 0.25-50.0; g/l of water.

According to a third embodiment of this invention, there is provided a formulation for colon evacuation or for treatment of bowel diseases and/or disorders, characterised in that it has the following composition: polyethylene glycol 54, sodium chloride 1.46, potassium chloride 0.745, sodium hydrogen carbonate 1.68, sodium sulfate (anhydrous) 5.68, ascorbic acid 6.6; g/1 of water.

Because of the poor stability of ascorbic acid in solution, it should be packaged separately from the other components of the formulation or coated in dry formulations.

In liquid formulations, it should not be added until just before use.

The formulations of the invention also contain electrolytes, for example those having an isotonic profile. The formulations may also contain sweetening and/or flavouring agents.

If the uncoated ascorbic acid is employed in the formulations of the invention it can cross react in the dry form with other components of the formulation.

i ~sl-gz, ~3e;"nA"~ ~11~7 ~U .b, F rl~ L_ _I r -3- The present invention has found that the addition of ascorbic acid in larger than usual doses to typical lavage solutions tends to reduce the required volume for satisfactory colon evacuation. With the typical polyethylene glycol electrolyte lavage solutions, the required volume for appropriate colon preparation is about 4 litre. The addition of ascorbic acid to the lavage solution has been shown to reduce the required volume to about 3 litre or less.

According to a fourth embodiment of this invention, there is provided a method of whole bowel irrigation in a patient requiring such irrigation wherein a volume of about 2 to 3.5 litres of a formulation according to any one of the first, second or third embodiments, is administered over a period of time to induce volumogenic diarrhoea.

Generally this period of time will be about 1.5 to 4 hours.

According to a fifth embodiment of this invention, there is provided a method of treating small bowel bacterial overgrowth or irritable bowel syndrome, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to any one of the first, second or third embodiments.

According to a sixth embodiment of this invention, there is provided a method of treating acute or chronic bacterial bowel infection, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to any one of the first, second or third embodiments.

Accc.rding to a seventh embodiment of this invention, there is provided a method of treating chronic inflammatory bowel disease, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a 25 formulation according to any one of the first, second or third embodiments.

BEST MODES OF CARRYING OUT" THE INVENTION In the preferred formulations of the present invention, ascorbic acid is incorporated in larger than usual oral concentrations to give a composition in the lavage solution of between about 0.25 to 50g/l, especially 1 to 25g/1 for colon evacuants or 20 to 35g/ for treatment of bowel diseases and/or disorders. Since only a single dose is given during the lavage and the human intestine is capable of absorbing at most about 3g of ascorbic acid (Hornig D. et al.

2 the remainder of the dose contributes to the diarrhoea and inhibits bacterial gas generation and reproduction. The excess ascorbic acid is passed without doing harm to the patient whilst the absorbed quantity is available as a specific nutrient and could be advantageous in the post-operative healing stage.

Typically, lavage solutions are provided in powdered form which are reconstituted to the required volume immediately prior to use. The lavage solutions of the present invention when made up ready for use will generally contain at least about 0.25g/1 ascorbic acid. More preferably they will contain from 5 to 50g per 3 litre of solution when made up, more preferably about 20g per 3 litre when made up.

jr ,1~ 9"~ 7 3a For dry formulations the ascorbic acid must be coated. Silicone or ethyl cellulose form suitable coatings to prevent reaction between the ascorbic acid and other components of the formulation.

Suitable coated ascorbic acid is available from Roche Products Pty Ltd as Coated Ascorbic Acid, Type EC and Coated Ascorbic Acid, Type SC.

Preferred lavage solutions of the present invention also contain high molecular weight polyethylene glycol such as polyethylene glycol having molecular weights greater than about 2000. Preferred polyethylene glycol has a molecular weight of about 3000 to 4500 such as PEG 3350, or PEG 4000.

Preferred lavage solutions of the present invention also contain a number of electrolytes and preferably have an isotonic electrolyte profile.

Preferred solutions have the following constituents in the range as specified.

RANGE OF CONCENTRATION 15 g/litre H20 of made up solution Polyethylene glycol 30 Sodium chloride 0.5 Potassium chloride 0.2 4 4 4 4 4 4 44 OyA4 -v 1-/lt -,t4I £4 ii ii

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WO 89/05659 4 PCT/AU88/004 8 4 Sodium hydrogen carbonate 0.5 Sodium sulfate (anhydrous) 2.0 10.0 Ascorbic acid 0.25 50.0 Preferably, the polyethylene glycol in the standard lavage solutions is adjusted so as to result in an osmolality of approximately 289m osm/ litre.

It is also possible to add flavourings to the lavage solutions of 'he present invention so long as these flavourings are not metabolized to an explosive gas such as hydrogen or methane in the bowel. For example aspartame may be added in a concentration of about 0.05 to Lemon flavour (SD Natural lemon powder flavour No. 12606) or pineapple flavour TO (10966) may also be added at concentrations of 0.5 to 4.0% or cyclamates may be added to increase the palatability of the lavage solution.

The lavage solutions of the present invention are also useful in the treatment of certain gastrointestinal conditions such as small bowel bacterial overgrowth and irritable bowel syndrome as well as useful in treating acute or chronic bacterial bowel infections, for example, infection of the bowel with one or more bacteria including Campylobacter jejuni, Yersinia enterocolitica, Clostridium difficile, Cryptosporidium isoscora belli. The lavage solutions of the present invention can also be used in the treatment of chronic inflammatory bowel disease such as Crohns ZO disease or ulcerative colitis. In treating these conditions, ascorbic acid or its salts is used in a wide range of concentrations depending on the specific r-ndition and may vary from about Ig to about 50g per litre, preferably from 20g to 35g per litre. Therefore, the lavage solutions useful in methods to treat the acute or chronic bacterial bowel infections or chronic inflammatory bowel disease will contain ascorbic acids or a salt thereof in a range so that when made up as ready for ingestion, the concentration of ascorbic acid will be from about 1 to 50g per litre.

These lavage solutions useful in these treatments will also preferably be isotoric and include high molecular weight polyethylene glycol.

The invention will further be described by reference to the fc'lowing examples.

EXAMPLE 1 A solution having the following composition was made up: g/L Water Polyethylene glycol Sodium chloride 1.46 WO 89/05659 PCT/AU88/00484 i t i

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Potassium chloride 0.745 Sodium hydrogen carbonate 1.68 Sodium sulfate 5.68 Ascorbic acid 6.6 A total of 3 litre was administered to the patient over 2 to 5 hours and the bowel preparation quality was found to be comparable to that requiring 4 litre of the standard available preparation. Ingestion was greatly facilitated due to the pleasant acidic taste which masked the usual S nauseating taste of the salty polyethylene glycol solution. Colon hydrogen levels were acceptably low. Biopsies of colon obtained from the ascending transverse and descending colon sites were normal and without mucosal oedema.

EXAMPLE 2 TO A solution having the following composition was made up and administered as in Example 1.

Polyethylene glycol Sodium chlorida Potassium chloride Sodium hydrogen carbonate Sodium sulfate Ascorbic acid Lemon flavour 38 0.95 1.63 3.42 2.75 EXAMPLE 3 A solution having the following composition was made up and administered as in Example 1.

o/L Water Polyethylene glycol Sodium chloride Potassium chloride Sodium hydrogen carbonate Sodium sulfate Ascorbic acid Pineapple flavour 49 2.4 1.2 2.82 7.41 37.1 I- ?1' WO 89/05659 PCT/AU88/00484 -6- EXAMPLE 4 A solution having the following composition was made up and administered as in Example 1.

q/L Water Polyethylene glycol Sodium chloride Potassium chloride Sodium hydrogen carbonate Sodium sulfate Ascorbic acid Cyclamate 32 0.6 0.23 0.65 2.25 0.8 EXAMPLE A solution having the following composition was made up and administered as in Example 1.

q/L Water Polyethylene glycol Sodium chloride Potassium chloride Sodium hydrogen carbonate Sodium sulfate Ascorbic acid Aspartame 57 2.7 1.8 4.45 46.5 EXAMPLE 6 A dry formulation having the following composition was made up: Potassium chloride 2.092 K Sodium chloride 4.127 Sodium hydrogen carbonate 4.748 Sodium sulphate 16.054 (Anhydrous) Ascorbic acid 16.959 (Silicone coated) Lemon flavour 12606 2.826 Aspartame .565 Polyethylene qlycol 152.629 4000 Total 200.000 WO 89/056.

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j j'| 59 PGT/AJ88/004 8 4 -7- EXAMPLE 7 dry formulation having the following composition was made up; Potassium chloride 2.092 Kq Sodium chloride 4.127 Sodium hydrogen carbonate 4.748 Sodium sulfate 16.054 (Anhydrous) Ascorbic acid 16.959 (Silicone coated) Pineapple flavour 10966 1.979 Aspartame .565 Polyethylene glycol 152.629 4000 Total 199.153 Individual doses of the dry formulations were made up to a volume of E 3 litre with water, and the resultant solution was kept cold to increase palatability. The solution was administered to the patient over a period of 1 to 5 hours.

The formulation may be packaged for single applications in sachets, plastic bags or in a 3-4 litre jug to which water may be added to be made lT up to a specific volume. Alternatively the formulation may be packaged in screw top boxes or cartons, preferably with an air tight seal. Vitamin C can be kept separately in an air tight sachet to be added at the time of mixing particularly if it is uncoated by ethyl cellulose or silicone. It can also be packaged in sachets lined by agents such as Mylar to prevent water absorption.

REFERENCES

1. J. Crowe et al.; A Study of Intracolonic Hydrogen and Methane Concentrations in Patients. GUT 1987; 28: A1370.

2. Hornig D. et al.; Int. J. Vit. Nutr. Res. 1980; 50: 309.

Claims (20)

1. An oral formulation for colon evacuation or for treatment of bowel diseases and/or disorders, said formulation comprising 30 to 60 parts by weight of a high molecular weight polyethylene glycol, 0.2 to 20.0 parts by weight of at least one electrolyte having at least one alkali metal salt and 0.25 to 50 parts by weight of ascorbic acid or a salt thereof.

2. The formulation according to claim 1, provided in solution.

3. The formulation acccrding to claim 1 or 2, wherein the concentration of ascorbic acid is about 1 to 25g/1.

4. The formulation according to claim 1 or 2, wherein the concentration of ascorbic acid is about 20 to 35g/l. The formulation according to any one of claims 1 to 4, wherein said electrolyte has an isotonic profile.

6. The formulation according to claim 5, wherein said electrolyte is selected from the following: sodium chloride, potassium chloride, sodium hydrogen carbonate, sodium sulfate.

7. The formulation according to any one of claims 1 to 6, wherein said polyethylene glycol has a molecular weight greater than about 2000.

8. The formulation according to claim 7, wherein said polyethylene gl-,ol has a molecular weight of about 3000 to 4500.

9. The formulation according to any one of claims 1 to 8, wherein the polyethylene glycol is present in an amount so as to result in an osmolality of about 289m osm/l. 25 10. The formulation according to any one of claims 1 to 9, further comprising sweetening and/or flavouring agents not metabolized to an explosive gas.

11. The formulation according to claim 10, wherein said sweetening agent and/or flavouring agent is selected from the following: aspartame, pineapple flavour 10966, lemon flavour 12606 or cyclamates.

12. A formulation for colon evacuation or for treatment of bowel diseases and/or disorders, characterised in that it has the following composition: polyethylene glycol sodium chloride 0.5-3.0, potassium chloride 0.2-2.0, sodium hydrogen carbonate 0.5-5.0, sodium sulfate (anhydrous) 2.0-10.0, ascorbic acid 0.25-50.0; g/l of water.

13. A formulation for colon evacuation or for treatment of bowel diseases and/or disorders, characterised in that it has the following composition: polyethylene glycol 54, sodium chloride 1.46, potassium chloride 0.745, sodium hydrogen carbonate 1.68, sodium sulfate (anhydrous) 5.68, ascorbic acid 6.6; g/l of water.,

14. The formulation according to claim 1, provided in powdered form. The formulation according to claim 14, wherein the ascorbic acid is coated 40 with silicone or ethyl cellulose. wher 1 to aboul synch to sai 10 requi effec a a a a a a. requi effect Crohi and/o I to 7 treatn descri 15 one diffic where 30 admin syndn to sai( 35 requir effecti requir effecti 'L~-r i'? -1, h~ i i -9-

16. A method of whole bowel irrigation in a patient requiring such irrigation wherein a volume of about 2 to 3.5 litres of a formulation according to any one of claims 1 to 15, is administered over a period of time to induce volumogenic diarrhoea.

17. A method according to claim 16 wherein the formulation is administered over about 1.5 to 4 hours.

18. A method of treating small bowel bacterial overgrowth or irritable bowel syndrome, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to any one of claims 1 to

19. A. method of treating acute or chronic bacterial bowel infection, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to any one of claims 1 to A method according to claim 19, wherein said infection is caused by at least 15 one of the following: Campylobacter jejuni, Yersinia enterocolitica, Clostridium .difficile, Cryptosporidiwn isospora belli.

21. A method of treating chronic inflammatory bowel disease, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to any one of claims 1 to 20 22. A method according to claim 21, wherein the inflammatory bowel disease is Crohns disease or Ulcerative colitis. "23. An oral formulation for colon evacuation or for treatment of a bowel disease and/or disorder, substantially as herein described with reference to any one of Examples 1 to 7. 25 24. A process of preparing an oral formulation for colon evacuation or for treatment of a bowel disease and/or disorder, which process is substantially as herein described with reference to any one of Examples 1 to 7. A method of whole bowel irrigation in a patient requiring such irrigation wherein a volume of about 2 to 3.5 litres of a formulation according to claim 23, is administered over a period of time to induce volumogenic diarrhoea.

26. A method of treating small bowel bacterial overgrowth or irritable bowel syndrome, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to claim 23.

27. A method of treating acute or chronic bacterial bowel infection, in a patient requiring said treatment, which method comprises administering to said paticnt an effective amount of a formulation according to claim 23.

28. A method of treating a chronic inflammatory bowel disease, in a patient requiring said treatment, which method comprises administering to said patient an effective amount of a formulation according to claim 23. .^^xU DATED this THIRD day of MARCH 1992 Thomas Julius Borody Patent Attorneys for the Applicant SPRUSON FERGUSON ,4 4. S 4 4 4. fl 4 4 S 4. 9 44 9 S 5* 4 44 44 4 a S 4. 4 4 4 4 4 4 4* S. 4 5 4 4 9 4 4 S .4.4 r INTERNATIONAL SEARCH REPORT International Application No PCT/AU 88/00484 1. CLASSIFICATION OF SUBJECT MATTER (if several classific~lion sy Buis apply. Indicate all) According to International Patent Classification (IPC) at to both National Classification and [PC. Int. C.4 A61K 47/00 A61K 31/045 II. FIELDS SEARCHED Minimum Documentation Searched Classification System JClassification Symbols IPC A61K 47/00, 31/045, 31/375 Documentation Saarched other than Minimum Documentation to the Extent that auch Documents are Included In the Fields SearchedI AU :IPC as above; Australian Classification 87.16-0 (SF120) Ill. DOCUMENTS CONSIDERED TO BE RELEVANT' rategory Citation of Document."1 with Indication. where appropriate. of the relevant passages 12 Relevant to Claim No."s X AU,B, 73343/81 (544544) (ERWIN GUNTHER WALLICZEK) (1) February 1982 (25.02.82) See especially page 2 lines 1-15, and page 5 lines 7-12. P,Y AU,A, 13063/88 (HAMILTON 15 September 1988(1 (15.09.88) P,Y WO,A, 88/08715 (PROCYTE CORP.) 17 November 1988(1 (17.11.88) A AU,B, 30504/84 (569747) (UNIV. OF SOUTHERN CALIFORNIA) (1 17 January 1985 (17.01.85) A Patents Abstracts of Japan, C-20, page 338(1 IJP,A, 59-81648 (KAO SEKKEN 9 November 1985 I(09.11.85) Special categories of cited documents: 0 later document Published attar the International filino date document defining the general state of the art which as not or ptiority date and nct In conflict with the application but cons~.te tobe o paticuar elevncecited to understand the principle or theory underlying the consdere tobe o paticuar elevnceInvention E' earlier document but published on or atear the International IX" document of particular relevance: the claimed invention iling date cannot be considered novel or cannot be considered to IL document which may throw doubts on priority claim(s) or Involve an Inventive stop which Is cited to establish the publi~cation date of another document of Particular relevance-' the claimed Invention Citation or other special reason (as1 specified) cannot be considered to Involve an Inventive atep when the "0 document refrring to an oral disclosure, use. exhibition or document is combined with one or more other such docu- zther means ments, auch combination being obvious to a person skilled IP document Published prior to the international iling date but In the art. later than the priority date claimed IV document member at the same patent family IV. Date ot the Actual Completion of the international Search 6 April .1989 (06.04.89) International Searching Authority I Australian Patent Office Form PCTjISAI2t0 (second sheet) (January 1985) Date of Mailing ot this International Search Report o uhorized Officar J..PULV IRENTI Wnernational Apolication No. PCT/AU 88/00484 ft. FURTHER INFORMATION CONTINUED FROM THE SECOND SHEET V.OBSERVATIONS WHERE CERTAIN CLAIMS WERE FOUND UNSEARCHABLE 1 This International seaxrch report has not been established In respect of certain clms under Article 17(2) for the following reaseons: 125Claim numrbrs.9--5 because they relate to sub jt" rnatter not required to be searched by this AuthotIty. namely: Method of treatment of the animal body by therapy. 2nClaim numbers- because they relate to parts of the International application that do not complIy with the prescribed require- ments to such an extent that no meaningful International search can be carried out. speclically: Claim numbers-... because they are dependet cIaims and are not drafted I accordance yWfth th* secono andl thir sentences of PCT Rule 6.4(s). VICJ OBSERVATIONS WHERE UNITY OF INVENTION IS LACKING 2 This International Searching Authority found multiple inventions In this International application as follows: 1.n As all required additional search fees were timely paid by the applicant. this internatIonal search report covers all searchable claims of the International application. As only some of the required additional search fees were timely paid by the applicant, this Intyrnatlonal search report covers only those claims of the International application for which fees were paid, specifically claims: 34J No required additional search fees were timely paid by the applicant. Consequently. this international search report to restricted to the Invention first mentioned In the claims; ilaI covered by claim numbers: As all searchable claims could be searched without effort justifying an additional tee, the International Searching Authority did not Invite payment of any additional tee. Remark oan Protest nThe addItlonal search fees were accompanied by applicant's protest. 0No crosat accompanied the payment of additional search lees. Farm PCTIISA1210 (supplemental @heet (January t985). ANNEX TO0 THE INrEHN IAL SEARCH REPORT ON IlNERATICNAL APPLICATION NOK. PCT/AU 88/00484 This Annex lists the I~~wn publication level patent family members relating to the patent documents cited in the abve-mrentioned international search report. The Australian Patent office is in no way liable for these particulars which are merely given for the purpose of information. Patent Document Cited in Search Patent Family Members Report AU 73343/81 EP 46409 JP 57075914 AU 13063,/88 ZA 8801828 WO 8808715 AU 17995/88 AU 30504/84 CA 1237988 DE 4535745 FR 2548897 GB 2144990 Ml 72355 JP 60100514 US 4504493 JP 59-81648 JP 60224614 JP 61240285 EP 241029 JP 62240441 US 4729358 JP 63246133 END OF ANNEX 8,23?119/4