WO1996040281B1 - Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients - Google Patents

Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients

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Publication number
WO1996040281B1
WO1996040281B1 PCT/US1996/009068 US9609068W WO9640281B1 WO 1996040281 B1 WO1996040281 B1 WO 1996040281B1 US 9609068 W US9609068 W US 9609068W WO 9640281 B1 WO9640281 B1 WO 9640281B1
Authority
WO
WIPO (PCT)
Prior art keywords
ocf
chf
och
gas
surfactant
Prior art date
Application number
PCT/US1996/009068
Other languages
French (fr)
Other versions
WO1996040281A3 (en
WO1996040281A9 (en
WO1996040281A2 (en
Inventor
Alexey Kabalnov
Ernest George Schutt
Jeffry Greg Weers
Original Assignee
Alliance Pharma
Alexey Kabalnov
Ernest George Schutt
Jeffry Greg Weers
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DK96918164T priority Critical patent/DK0833669T3/en
Priority to PL96323868A priority patent/PL185883B1/en
Application filed by Alliance Pharma, Alexey Kabalnov, Ernest George Schutt, Jeffry Greg Weers filed Critical Alliance Pharma
Priority to AU60487/96A priority patent/AU712946B2/en
Priority to IL13534296A priority patent/IL135342A0/en
Priority to EP96918164A priority patent/EP0833669B1/en
Priority to DE69621015T priority patent/DE69621015T2/en
Priority to IL12221796A priority patent/IL122217A/en
Priority to AT96918164T priority patent/ATE216894T1/en
Priority to US08/973,281 priority patent/US6193952B1/en
Priority to JP50147797A priority patent/JP4067116B2/en
Publication of WO1996040281A2 publication Critical patent/WO1996040281A2/en
Publication of WO1996040281A9 publication Critical patent/WO1996040281A9/en
Publication of WO1996040281A3 publication Critical patent/WO1996040281A3/en
Priority to NO975317A priority patent/NO975317L/en
Priority to US09/746,215 priority patent/US20020119102A1/en
Publication of WO1996040281B1 publication Critical patent/WO1996040281B1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1806—Suspensions, emulsions, colloids, dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels

Abstract

Long lasting gas emulsions for ultrasound and magnetic resonance imaging contrast enhancement utilize low Ostwald coefficient fluoromono- and fluoropolyether compounds. Gas emulsions comprising microbubble preparations are disclosed wherein the microbubbles comprise fluoroethers such as perfluorodiglyme (CF3(OCF2CF2)2OCF3), perfluoromonoglyme (CF3OCF2CF2OCF3), perfluorodiethylether C2F5OC2F5, perfluoroethylmethylether CF3OC2F5, perfluorodimethylether CF3OCF3, as well as CF3OCF2OCF3 and fluoropolyethers CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, and CF3(OCF2)4OCF3.

Claims

AMENDED CLAIMS
[received by the International Bureau on 5 February 1997 (05.02.97); original claims 1-42 replaced by new claims 1-54 (6 pages)]
1. A gas emulsion for ultrasound contrast enhancement comprising a plurality of gas bubbles in a liquid medium, said gas bubbles comprising a fluoroether.
2. The gas emulsion of Claim 1 wherein said gas bubbles comprise a perfluoroether.
3. The gas emulsion of Claim 1 wherein said fluoroether is selected from the group consisting of CH3CH2OCF2CHF2, CH3CH2OCF2CF3, CHF2CH2OCF2CHF2, CF3CH2OCF2CH2F, CF3CH2OCH2CF3, CF3CH2OCF2CHF2, CHF2CH2OCF2CF3, CF3CH2OCF2CF3, CH3OCH2CF2CHF2, CH3OCH2CF2CF3, CH3OCF2CF2CHF2, CH3OCF2CHFCF3, CH3OCF2CF2CF3, CHF2OCH2CF2CHF2, CHF2OCH2CF2CF3,
CF3OCH2CF2CHF2, CF3OCH2CF2CF3, CH3OCH(CF3)2, CH3OCF(CF3)2, CHF2OCH(CF3)2, CH3OCH2CHF2, CH3OCF2CH2F, CH3OCH2CF3, CH3OCF2CHF2, CHF2OCH2CHF2, CHF2OCF2CH ,F, CHF2OCH2CF3, CHF2OCHFCF3, CF3OCH2CHF2, CH3OCF2CF3, CF3OCH2CF3, CF3OCHFCF3, CF3OCF2OCF3, CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, CF3(OCF2)4OCF3 and mixtures thereof.
4. The gas emulsion of Claim 1 wherein the fluoroether is selected from the group consisting of perfluorodiethylethers, perfluorodimethyiethers, perfluorodiglymes, perfluoromethylethylethers, and perfluoromonoglymes.
5. The gas emulsion of Claim 1, wherein the gas bubbles additionally comprise air or nitrogen.
6. The gas emulsion of Claim 1 wherein the gas bubbles are surrounded by a surfactant layer.
7. The gas emulsion of Claim 6 wherein the surfactant layer comprises a surfactant selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
8. The gas emulsion of Claim 6, wherein said surfactant layer comprises a non- Newtonian surfactant.
9. The gas emulsion of Claim 6 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters. -47-
10. The gas emulsion of Claim 6, wherein the surfactant layer comprises at least a first and a second surfactant, the first surfactant consisting essentially of a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and wherein the second surfactant is more water soluble than the first surfactant.
11. The gas emulsion of Claim 10, wherein said second surfactant is selected from the group consisting of fatty acids, salts of a fatty acids, a sugar esters of fatty acids, polyoxypropylene-polyoxyethylene copolymers, nonionic alkylglucosides, polysorbate, and combinations thereof.
12. The gas emulsion of claim 1 wherein said gas bubbles are free gas bubbles.
13. The gas emulsion of Claim 1 wherein said gas bubbles further comprise microspheres. 15. The gas emulsion of Claim 13 wherein said microspheres comprise a protein.
16. The gas emulsion of Claim 1 wherein said gas bubbles further comprise a liposome.
17. The gas emulsion of Claim 1 wherein said gas bubbles are formed through the solubilization of void containing structures.
18. The gas emulsion of Claim 1 wherein said gas bubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and said fluoroether.
19. The gas emulsion of Claim 1 wherein said microbubbles are formed through sonication.
20. A method for forming a gas emulsion comprising the steps of: providing a container having therein a structural material defining a plurality of voids, a surfactant and a gas or gas mixture comprising a fluoroether dispersed in said voids; adding an aqueous liquid to said container; and, admixing said structural material, said surfactant and said aqueous liquid, thereby -48-
forming a gas emulsion in said container, said gas emulsion comprising bubbles of said gas or gas mixture surrounded by a layer of the surfactant.
21. The method of Claim 20 wherein said structural material is substantially water soluble. 22. The method of Claim 20 wherein said fluoroether is selected from the group consisting of CH3CH2OCF2CHF2, CH3CH2OCF2CF3, CHF2CH2OCF2CHF2, CF3CH2OCF2CH2F, CF3CH2OCH2CF3, CF3CH2OCF2CHF2, CHF2CH2OCF2CF3, CF3CH2OCF2CF3, CH3OCH2CF2CHF2, CH3OCH2CF2CF3, CH3OCF2CF2CHF2, CH3OCF2CHFCF3, CH3OCF2CF2CF3, CHF2OCH 2CF2CHF2, CHF2OCH2CF2CF3, CF3OCH2CF2CHF2, CF3OCH2CF2CF3, CH3OCH(CF3)2, CH3OCF(CF3)2,
CHF2OCH(CF3)2, CH3OCH2CHF2, CH3OCF2CH2F, CH3OCH2CF3, CH3OCF2CHF2, CHF2OCH2CHF2, CHF2OCF2CH 2F, CHF2OCH2CF3, CHF2OCHFCF3, CF3OCH2CHF2, CH3OCF2CF3, CF3OCH2CF3, CF3OCHFCF3, CF3OCF2OCF3, CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, CF3(OCF2)4OCF3 and mixtures thereof. 23. The method of Claim 20 wherein the fluoroether is selected from the group consisting of perfluorodiethylethers, perfluorodimethyiethers, perfluoromethylethylethers, perfluoromonoglymes and perfluorodiglymes.
24. The method of Claim 20 wherein said structural material comprises said surfactant. 25. The method of Claim 20 wherein the surfactant is selected from the group consisting of phospholipids, phosphocholines. lysophospholipids, nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
26. The method of Claim 20 wherein said material is selected from the group comprising void-containing structures and soluble void-forming structures.
27. The method of Claim 20 wherein said structural material is selected from the group consisting of sugars, spray dried microspheres, lyophilized powders, lyophilized cake, powdered and granulated sugars, protein microspheres, and dried porous hyaluronic acid. 28. A microbubble precursor composition comprising: a structural material defining a plurality of voids; a gas or gas mixture comprising a fluoroether dispersed in said voids; and a surfactant, wherein said material, said gas or gas mixture and said surfactant are together adapted to form microbubbles upon addition to said container of a liquid.
29. The composition of Claim 28 wherein said structural material is substantially water soluble.
30. The composition of Claim 28 wherein said fluoroether is selected from the group consisting of CH3CH2OCF2CHF2, CH3CH2OCF2CF3, CHF2CH2OCF2CHF2, CF3CH2OCF2CH2F, CF3CH2OCH2CF3, CF3CH2OCF2CHF2, CHF2CH2OCF2CF3, CF3CH2OCF2CF3, CH3OCH2CF2CHF2, CH3OCH2CF2CF3, CH3OCF2CF2CHF2,
CH3OCF2CHFCF3, CH3OCF2CF2CF3, CHF2OCH2CF2CHF2, CHF2OCH2CF2CF3, CF3OCH2CF2CHF2, CF3OCH2CF2CF3, CH3OCH(CF3)2, CH3OCF(CF3)2, CHF2OCH(CF3)2, CH3OCH2CHF2, CH3OCF2CH2F, CH3OCH2CF3, CH3OCF2CHF2, CHF2OCH2CHF2, CHF2OCF2CH 2F, CHF2OCH2CF3, CHF2OCHFCF3, CF3OCH2CHF2, CH3OCF2CF3, CF3OCH2CF3, CF3OCHFCF3, CF3OCF2OCF3, CF^OCF^OCF^
CF3(OCF2)3OCF3, CF3(OCF2)4OCF3 and mixtures thereof.
31. The composition of Claim 28 wherein the fluoroether is selected from the group consisting of perfluorodiethylethers, perfluorodimethyiethers, perfluoromethylethylethers, perfluoromonoglymes and perfluorodiglymes. 32. The composition of Claim 28 wherein said structural material comprises said surfactant.
33. The composition of Claim 28 wherein the surfactant is selected from the group consisting of phospholipids, phosphocholines, lysophospholipids, nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
34. The composition of Claim 28 wherein said structural material is selected from the group of void-containing structures and water soluble void- forming structures.
35. The composition of Claim 28 wherein said structural material is selected from the group consisting of spray dried microspheres, granulated and powdered sugars, lyophilized powders, lyophilized cakes, protein microspheres and dried porous hyaluronic acid.
36. The composition of Claim 35 wherein said structural material comprises spray dried microspheres and said spray dried microspheres comprise a compound selected from the group consisting of starches, derivatized starches and sugar esters. 37. A method for ultrasonically imaging an object or body comprising the steps of: introducing the contrast medium of Claim 1 into said object or body; and, imaging at least a portion of said object or body.
38. The method of Claim 37 wherein said imaging step comprises ultrasonic harmonic imaging.
39. A method for magnetic resonance imaging an object or body comprising the steps of: introducing the contrast medium of Claim 1 into said object or body; and, imaging at least a portion of said object or body. 40. A microbubble composition for use in imaging comprising a plurality of microbubbles in a biocompatible liquid medium wherein said microbubbles comprise at least one fluoroether gas osmotic agent and at least one modifier gas.
41. The microbubble composition of Claim 40 wherein said fluoroether gas osmotic agent comprises a perfluoroether. 42. The microbubble composition of Claim 40 wherein said fluoroether gas osmotic agent is selected from the group consisting of CF£3CH2OCF2CHF2,
CH3CH2OCF2CF3, CHF2CH2OCF2CHF2, CF3CH2OCF2CH2F, CF3CH2OCH2CF3,
CF3CH2OCF2CHF2, CHF2CH2OCF2CF3, CF3CH2OCF2CF3, CH3OCH2CF2CHF2,
CH3OCH2CF2CF3, CH3OCF2CF2CHF2, CH3OCF2CHFCF3, CH3OCF2CF2CF3, CHF2OCH2CF2CHF2, CHF2OCH2CF2CF3, CF3OCH2CF2CHF2, CF3OCH2CF2CF3,
CH3OCH(CF3)2, CH3OCF(CF3)2, CHF2OCH(CF3)2, CH3OCH2CHF2, CH3OCF2CH2F,
CH3OCH2CF3, CH3OCF2CHF2, CHF2OCH2CHF2, CHF2OCF2CH2F, CHF2OCH2CF3,
CHF2OCHFCF3, CF3OCH2CHF2, CH3OCF2CF3, CF3OCH2CF3, CF3OCHFCF3,
CF3OCF2OCF3, CF3(OCF2)2OCF3, CF3(OCF2)3OCF3, CF3(OCF2)4OCF3 and mixtures thereof.
43. The microbubble composition of Claim 40 wherein said microbubbles -51- further comprise microspheres.
44. The microbubble composition of Claim 43 wherein said microspheres comprise a protein.
45. The microbubble composition of Claim 40 wherein said microbubbles further comprise a liposome.
46. The microbubble composition of Claim 40 wherein said microbubbles are formed through the solubilization of void containing structures.
47. The microbubble composition of Claim 40 wherein said microbubbles are formed by altering the pressure on an emulsified liquid comprising an aqueous phase and said fluoroether gas osmotic agent.
48. The microbubble composition of Claim 40 wherein said microbubbles are formed through sonication.
49. The microbubble composition of Claim 40 wherein said microbubbles further comprise a surfactant layer. 50. The microbubble composition of Claim 49 wherein said surfactant layer comprises a compound selected from the group consisting of nonionic surfactants, neutral surfactants, anionic surfactants, neutral fluorinated surfactants, anionic fluorinated surfactants and combinations thereof.
51. The microbubble composition of Claim 49, wherein said surfactant layer comprises a non-Newtonian surfactant.
52. The microbubble composition of Claim 49 wherein said surfactant layer comprises a compound selected from the group consisting of phospholipids, fatty acids, block copolymers and sugar esters.
53. The microbubble composition of Claim 40 wherein said modifier gas comprises oxygen.
54. The microbubble composition of Claim 40 wherein said modifier gas comprises nitrogen. -52-
STATEMENT UNDER ARTICLE 19 (1)
Independent claim 1, directed to gas emulsions comprising compounds with relatively low Ostwald coefficients has been deleted. As such, all the currently pending claims are directed to gas emulsions (or microbubble preparations) comprising a fluoroether gas or vapor as well as methods of their formation and use.
With respect to the cited art, it is respectfully submitted that none of the references, either alone or in combination, suggest or disclose gas emulsions comprising fluorinated ethers. Specifically, WO 96/26746, WO 94/09703, WO 96/09793, WO 93/05819 and WO 94/28939 were only held to be relevant to originally filed claim 1, directed to low Ostwald coefficient compounds, or claims dependent thereon. However, as alluded to above, originally filed claim 1 has been deleted and the remaining claims amended to clarify that the present invention is directed to gas emulsions comprising fluoroethers. As none of the aforementioned references contemplates the use of fluoroether gases or vapors to provide long lasting gas emulsions for use in imaging, Applicants submit they are not relevant to the claimed subject matter. Notice to that effect is requested.
Nor are the remaining references particularly relevant to the claimed gas emulsions. For example, WO 94/21301 is directed to conventional oil-in-water emulsions that incorporate a lipophilic liquid solvent in the oil phase. These lipophilic solvents, which may comprise perfluoroethers, are only used to dissolve or condense the oil-soluble gas that eventually constitutes the gaseous phase of the microbubble. Moreover, the reference appears to teach that conventional ethers (i.e. hydrocarbons, not fluoroethers) may be used to provide the gas phase. Yet, the application absolutely fails to suggest that fluoroether gases or vapors may be used to form long lasting microbubble preparations. As such it cannot suggest Applicants presently claimed invention.
Similarly, EP 0 052 575 and DE 44 06 474 do not disclose or suggest the use of fluoroethers to form gas emulsions. Rather, both references are merely directed to microbubble precursors comprising solid powders. In the case of EP 0 052 575 there is no disclosure of any gases other than air since the bubbles are formed due to local supersaturation of the surrounding liquid. Similarly, although DE 4406474 does disclose the use of fluorocarbons in conjunction with powders, it does not provide any suggestion that fluorinated ethers could be use in combination with void-containing structures to provide the microbubble preparations of the instant invention. Accordingly, Applicants submit that these references are not of particular relevance as is suggested in the subject search report.
PCT/US1996/009068 1995-06-07 1996-06-05 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients WO1996040281A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
US08/973,281 US6193952B1 (en) 1995-06-07 1996-06-05 Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement
AT96918164T ATE216894T1 (en) 1995-06-07 1996-06-05 GAS EMULSIONS STABILIZED BY FLUORINATED ETHERS WITH LOW OSTWALD COEFFICIENTS
AU60487/96A AU712946B2 (en) 1995-06-07 1996-06-05 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients
PL96323868A PL185883B1 (en) 1995-06-07 1996-06-05 Emulsions of gases stabilise by means of fluorinated ethers of low ostwald coefficient
EP96918164A EP0833669B1 (en) 1995-06-07 1996-06-05 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients
DE69621015T DE69621015T2 (en) 1995-06-07 1996-06-05 GAS EMULSIONS STABILIZED BY FLUORINE ETHERS WITH LOW EAST FOREST COEFFICIENTS
JP50147797A JP4067116B2 (en) 1995-06-07 1996-06-05 Gas emulsion stabilized with fluorinated ether with low Ostwald coefficient
DK96918164T DK0833669T3 (en) 1995-06-07 1996-06-05 Gas emulsions stabilized with fluorinated ethers with low Ostwald coefficients
IL13534296A IL135342A0 (en) 1995-06-07 1996-06-05 A microbubble precursor
IL12221796A IL122217A (en) 1995-06-07 1996-06-05 Gas emulsions for ultrasound contrast enhancement stabilized with fluorinated ethers
NO975317A NO975317L (en) 1995-06-07 1997-11-19 Gas emulsions stabilized with fluorinated ethers with low cheese forest coefficients
US09/746,215 US20020119102A1 (en) 1996-06-05 2000-12-22 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/479,621 US5804162A (en) 1995-06-07 1995-06-07 Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients
US08/479,621 1995-06-07

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US08/479,621 Continuation-In-Part US5804162A (en) 1995-06-07 1995-06-07 Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients

Related Child Applications (3)

Application Number Title Priority Date Filing Date
US08/973,281 Continuation US6193952B1 (en) 1995-06-07 1996-06-05 Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement
US08/973,281 A-371-Of-International US6193952B1 (en) 1995-06-07 1996-06-05 Stabilized gas emulsions containing phospholipid for ultrasound contrast enhancement
US09/746,215 Continuation US20020119102A1 (en) 1995-06-07 2000-12-22 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients

Publications (4)

Publication Number Publication Date
WO1996040281A2 WO1996040281A2 (en) 1996-12-19
WO1996040281A9 WO1996040281A9 (en) 1997-02-06
WO1996040281A3 WO1996040281A3 (en) 1997-03-13
WO1996040281B1 true WO1996040281B1 (en) 2001-04-05

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PCT/US1996/009068 WO1996040281A2 (en) 1995-06-07 1996-06-05 Gas emulsions stabilized with fluorinated ethers having low ostwald coefficients

Country Status (18)

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US (2) US5804162A (en)
EP (2) EP1174153B1 (en)
JP (1) JP4067116B2 (en)
KR (1) KR100401429B1 (en)
CN (1) CN1087954C (en)
AT (2) ATE337018T1 (en)
AU (1) AU712946B2 (en)
CA (1) CA2222186A1 (en)
CZ (1) CZ391397A3 (en)
DE (2) DE69636486T2 (en)
DK (1) DK0833669T3 (en)
ES (2) ES2176462T3 (en)
HU (1) HUP9900848A3 (en)
IL (1) IL122217A (en)
NO (1) NO975317L (en)
PL (1) PL185883B1 (en)
PT (1) PT833669E (en)
WO (1) WO1996040281A2 (en)

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