WO1986003938A1 - Procede de conservation de liposomes - Google Patents

Procede de conservation de liposomes Download PDF

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Publication number
WO1986003938A1
WO1986003938A1 PCT/US1986/000016 US8600016W WO8603938A1 WO 1986003938 A1 WO1986003938 A1 WO 1986003938A1 US 8600016 W US8600016 W US 8600016W WO 8603938 A1 WO8603938 A1 WO 8603938A1
Authority
WO
WIPO (PCT)
Prior art keywords
liposomes
trehalose
preserving
initial
preserving agent
Prior art date
Application number
PCT/US1986/000016
Other languages
English (en)
Inventor
John H. Crowe
Lois M. Crowe
Original Assignee
The Regents Of The University Of California
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
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Priority to KR1019860700622A priority Critical patent/KR920002300B1/ko
Publication of WO1986003938A1 publication Critical patent/WO1986003938A1/fr
Priority to DK198604283A priority patent/DK175799B1/da

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K49/227—Liposomes, lipoprotein vesicles, e.g. LDL or HDL lipoproteins, micelles, e.g. phospholipidic or polymeric

Definitions

  • the present invention relates generally to liposomes, and more particularly relates to a method of preserving liposomes containing biologically active mol ⁇ ecules. This process is useful in applications such as in vivo drug delivery and preservation of diagnostic agents.
  • Liposomes are unilamellar or multila ⁇ iellar lipid vesicles which enclose a fluid space.
  • the walls of the vesicles are formed by a bimolecular layer of one or more lipid components having polar heads and non-polar tails.
  • the polar heads of one layer orient outwardly to extend into the surrounding medium, and the non-polar tail portions of the lipids associate with each other, thus providing a polar surface and a non-polar core in the wall of the vesicle.
  • Unilamellar liposomes have one such bimolecu ⁇ lar layer, whereas multilamellar liposomes generally have a plurality of substantially concentric bimolecular layers.
  • Liposomes are well recognized as useful for encapsulation of drugs and other therapeutic agents and for carrying these agents to in vivo sites. For example.
  • U.S. Patent 3,993,754 inventors Rahman et al., issued November 23, 1976, discloses an improved chemotherapy method in which an anti-tumor drug is encapsulated within liposomes and then injected.
  • Liposomes have also been used successfully for introducing various chemicals, biochemicals, genetic material and the like into viable cells _ir ⁇ vitro, and as carriers for diagnostic agents.
  • a preserving agent such as trehalose
  • a method for preserving liposomes includes freeze-drying liposomes in the presence"of a preserving agent capable of preserving structure and function in biological mem ⁇ branes.
  • Preferred preserving agents include carbohy ⁇ drates having at least two monosaccharide units, and especially preferred compounds include the disaccharides sucrose, maltose, and trehalose.
  • the method comprises freeze-drying liposomes which in addi ⁇ tion to containing biologically active molecules or therapeutic agents contain a preserving agent such as trehalose internally.
  • a preserving agent such as trehalose internally.
  • an appropriate compound such as trehal ⁇ ose is present both inside and outside the lipid membrane; preferred weight ratios of total preserving agent to lipid range from about 0.1:1 to 3.0:1. An especially preferred weight ratio is about 1.0:1.0.
  • the invention also embodies a lyophilized composition such that when reconstituted by rehydration, resultant liposomes retain substantially all of their originally encapsulated material.
  • a lyophilized composition may be prepared by the method as outlined above.
  • the invention comprises a method for preserving liposomes containing biologically active molecules using a preserving agent.
  • the method involves either freeze- drying liposomes in the presence of a preserving agent, or freeze-drying liposomes which contain a preserving agent internally in addition to encapsulated medicaments, or both.
  • Preferred preserving agents are carbohydrates having at least two monosaccharide units joined in glycosidic linkage, and particularly preferred pre ⁇ serving agents include sucrose, maltose and trehalose. Of these, trehalose has been found to be the most effective preserving agent for use with the inventive method.
  • Trehalose is a naturally occurring sugar found at high concentrations in organisms capable of surviving dehydration. Trehalose is especially effective in pre ⁇ serving structure and function in dry biological mem ⁇ branes. Liposomes which are freeze-dried in the presence of trehalose and which additionally contain encapsulated trehalose, exhibit particularly good retention of encap ⁇ sulates. That is, when liposomes are exposed to tre ⁇ halose both internally and externally during freeze- drying, they can retain as much as 100% of their original encapsulated contents upon rehydration. This is in sharp contrast to liposomes which are freeze-dried without any preserving agent, which show extensive fusion between liposomes and loss of contents to the surrounding medium.
  • Representative phospholipids used in forming liposomes which may be used in this process include phos- phatidylcholine, phosphatidylserine, phosphatidic acid and mixtures thereof. Both natural and synthetic phos ⁇ pholipids may be successfully used.
  • the biologically active or therapeutic encap ⁇ sulated material is preferably water soluble.
  • suitable therapeutic agents include sympathomimetic drugs such as amphetamine sulfate, epi- nephrine hy ⁇ rochloride, or ephedrine hydrochloride; an- tispasmodics such as atropine or scopalamine; broncho- dilators such as isoproternol; vasodilators such as dilthiazen; hormones such as insulin; and antineoplastic drugs such as adria ycin.
  • Suitable biologically active molecules include, for example, RNA, DNA, enzymes and immunoglobulins.
  • Small unilamellar vesicles are pre ⁇ pared as starting materials prior to encapsulation of trehalose, and may be prepared by any of the available techniques. Suitable techniques include injection of the lipid in an organic solvent into water, extrusion from a French pressure cell, and sonication.
  • the material to be trapped may be added at any stage during preparation of the small unilamellar vesicles, but in practice it is most convenient to mix the small unilamellar vesicles with an aqueous solution of the material to be trapped immedi ⁇ ately before preparation of large unilamellar vesicles.
  • Preferred weight ratios of encapsulate to lipid are about 1.0:1.0.
  • LUV's Large unilamellar vesicles with in ⁇ creased trapping efficiency may then be prepared by either freeze-thawing or rotary evaporation.
  • An exemplary rotary evaporation method and one which is especially effective in conjunction with the method disclosed herein is illustrated in Deamer, D. ., "A Novel Method for Encapsulation of Macromolecules in Liposomes" in Gregori- adis, G. (ed.) Liposome Technology (1984).
  • the method comprises providing a polar solution having initial liposomes and a quantity of material to be encapsulated. Substantially all of the solution is removed, and the resultant liposomes are then recovered by hydration of the concentrated admixture.
  • Trehalose may be added at any stage during preparation of the large unilamellar vesicles, but greatly improved preservation is attained with trehalose present on both sides of the phospholipid bilayer. Therefore, trehalose is preferably added before the large
  • unilamellar vesicles are prepared, so that trehalose is trapped inside.
  • the preferred weight ratio of total trehalose to lipid ranges from about 0.1:1 to about 3.0:1; a particularly preferred weight ratio is approximately 1.0:1.0.
  • the large unilamellar vesicles are then frozen in liquid nitrogen and lyophilized. Under some circum ⁇ stances, as when lipids are used which are susceptible to damage due to the presence of oxygen, it may be desirable to seal the dry preparations under vacuum. Rehydration is accomplished simply by adding water to the dry mixture.
  • the liposomes are exposed to trehalose
  • preserving agents including carbohydrate compounds which are composed of at least two monosac ⁇ charide units.
  • sucrose and maltose are suitable alternatives.
  • Example 1 A phopholipid mixture consisting of approximately 40 mg. dipalmitoyl phosphatidylcholine and phosphatidic acid in a molar ratio of 95:5 was sonicated to optical clarity in a bath sonicator. Large unilamellar vesicles were prepared by freeze-thawing in a 50 mM solution of isocitric acid in water as the compound to be encap ⁇ sulated. Excess isocitric acid was removed by dialysis.
  • Trehalose 2.0:1.0 trehalose:phospholipid weight ratio
  • Isocitric acid was assayed by adding isocitrate dehydrogenase and NADP to the outside of the vesicles according to the method of Plaut, et al. (Eds.), Methods in Enzy ology, Volume 5 (New York: Aca ⁇ demic Press).
  • Isocitrate external to the vesicles was oxidized by the isocitrate dehydrogenase, resulting in reduction of NADP to NADPH, the rate and amount of which may be recorded fluorometrically.
  • Total isocitric acid in the vesicles was assayed following addition of Triton X-100 (octylphenoxy polyethoxyethanol, a detergent and emulsifier manufactured by Rohm & Haas Co., Philadelphia, PA; "TRITON” is a registered trademark of Rohm & Haas Co.), which releases the trapped isocitric acid into the surrounding medium.
  • Triton X-100 octylphenoxy polyethoxyethanol, a detergent and emulsifier manufactured by Rohm & Haas Co., Philadelphia, PA; "TRITON” is a registered trademark of Rohm & Haas Co.
  • Example 2 Small unilamellar vesicles of were made by sonication of 43 mg egg phosphatidylcholine in 4 ml of water. Large unilamellar vesicles were prepared by rotary drying the phospholipid in the presence of 32 mg of trehalose and 13 mg of isocitric acid. The weight ratios of phospholipid:trehalose:isocitric acid were approxi ⁇ mately 4:3:1. Excess isocitric acid and trehalose were removed by dialysis against distilled water, and the amount of isocitric acid trapped in the vesicles was determined by the enzyme assay described in Example 1.
  • Trehalose was added to the dialyzed liposomes to give a final weight ratio of phospholipid:trehalose of 1.0:1.4, and the sample was lyophilized. The sample was then rehydrated with distilled water, and the amount of isocitric acid remaining in the liposomes was determined by enzyme assay. The lyophilized vesicles retained 75% of their original contents.
  • Example 3 A phospholipid mixture of palmitoyloleoyl phosphatidylcholine (90%) and phosphatidylserine (10%) was hydrated to 10 mg./ l., and small unilamellar vesicles were then prepared by sonication. Large uni ⁇ lamellar vesicles were prepared by rotary drying in the presence of isocitric acid, which served as the encap ⁇ sulated molecule. Essentially the same techniques as previously described in Examples 1 and 2 were used. Efficiency of retention of isocitric acid following lyophilization and rehydration was recorded as before, with large unilamellar vesicles lyophilized first in the presence and then in the absence of trehalose. As may be seen in Table 2, the results show that 100% of the trapped
  • isocitric acid is retained when the large unilamellar vesicles are lyophilized and rehydrated under the stated conditions.
  • tre ⁇ halose is preferably present both externally and inter ⁇ nally to optimize retention of the encapsulate.
  • Example 4 One of the damaging events presumed to be occurring during lyophilization is close approach of the large unilamellar vesicles to each other, leading to fusion and leakage of the vesicular contents. Fusion has been assayed by resonance energy transfer, a fluorescence method which depends upon energy transfer from an excited probe (the "donor probe") to a second probe (the “acceptor probe”). The acceptor probe fluoresces when the energy transfer occurs. In order for the transfer to occur the two probes must be in close proximity. Thus probe intermixing can be used as an assay for fusion between vesicles during lyophilization.
  • Example 5 A further experiment was carried out identical to that set forth in Example 3, with first maltose and then sucrose as the preserving agent. Results are set forth in Tables 4 and 5. As may be concluded from those tables, both maltose and sucrose provide good retention of encapsulated material following lyophilization.

Abstract

Nouveau procédé de conservation de liposomes contenant des molécules biologiquement actives, tel que les structures des liposomes, une fois réhydratées, conservent pratiquement toutes les substances initialement encapsulées. Un agent de conservation possédant au moins deux éléments de monosaccharide est utilisé soit de manière interne soit de manière externe ou les deux. Dans un mode préférentiel de réalisation, on utilise comme agent de conservation du tréhalose, à la fois à l'intérieur des liposomes sous forme d'une substance encapsulée et de manière externe, en solution, pendant la lyophilisation. L'invention concerne également une composition lyophilisée préparée à l'aide du procédé ci-décrit.
PCT/US1986/000016 1985-01-11 1986-01-08 Procede de conservation de liposomes WO1986003938A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
KR1019860700622A KR920002300B1 (ko) 1985-01-11 1986-01-08 리포좀의 보존방법
DK198604283A DK175799B1 (da) 1985-01-11 1986-09-08 Fremgangsmåde til præservering og fremgangsmåde til fremstilling af liposomer samt en lyophiliseret sammensætning og en præserveret sammensætning

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69067985A 1985-01-11 1985-01-11
US690,679 1985-01-11

Publications (1)

Publication Number Publication Date
WO1986003938A1 true WO1986003938A1 (fr) 1986-07-17

Family

ID=24773483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1986/000016 WO1986003938A1 (fr) 1985-01-11 1986-01-08 Procede de conservation de liposomes

Country Status (6)

Country Link
EP (1) EP0208764A4 (fr)
JP (1) JPS62501631A (fr)
AU (1) AU587600B2 (fr)
CA (1) CA1275248C (fr)
DK (1) DK175799B1 (fr)
WO (1) WO1986003938A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1987005300A2 (fr) * 1986-02-28 1987-09-11 Biocompatibles Limited Conservation de proteines
WO1990004329A1 (fr) * 1988-10-20 1990-05-03 Coulter Corporation Cellules mammiferes lyophilisees stabilisees et procede pour leur fabrication
EP0438497A1 (fr) * 1988-10-11 1991-07-31 Univ Southern California Conjugues ameliorant la permeabilite vasculaire.
EP0660714A1 (fr) * 1991-06-18 1995-07-05 ImaRx Pharmaceutical Corp. Nouveaux systemes d'apport de medicaments aux liposomes
WO1995027721A1 (fr) * 1994-04-07 1995-10-19 Akzo Nobel N.V. Compositions lyophilisees comprenant de l'arn
US5484432A (en) * 1985-09-27 1996-01-16 Laser Biotech, Inc. Collagen treatment apparatus
WO1998034478A1 (fr) * 1997-02-07 1998-08-13 Quadrant Holdings Cambridge Limited Procedes et compositions permettant de produire des plaquettes sechees et stables au stockage
US5817334A (en) * 1988-10-05 1998-10-06 Nexstar Pharmaceuticals, Inc. Method of making liposomes with improved stability during drying
US6007817A (en) * 1988-10-11 1999-12-28 University Of Southern California Vasopermeability enhancing immunoconjugates
US6497898B1 (en) 1993-10-07 2002-12-24 Kanebo Ltd Surfactant, and an emulsion-type cosmetic composition and a lipsome containing said surfactant
US6623753B1 (en) 1991-05-30 2003-09-23 Novartis Ag Allylamine-containing liposomes
US6710038B1 (en) 1999-12-14 2004-03-23 Kibun Food Chemifa Co., Ltd. Emulsification method using propylene glycol hyaluronate
US6723497B2 (en) 2000-02-10 2004-04-20 The Regents Of The University Of California Therapeutic platelets and methods
US6770478B2 (en) 2000-02-10 2004-08-03 The Regents Of The University Of California Erythrocytic cells and method for preserving cells
WO2010150051A1 (fr) * 2009-06-24 2010-12-29 Lipoid Gmbh Composition pour applications cosmétiques, pharmaceutiques ou diététiques
US10166184B2 (en) 2011-10-21 2019-01-01 Celator Pharmaceuticals Inc. Method of lyophilizing liposomes
US10448631B2 (en) 2015-09-22 2019-10-22 East Carolina University Cryopreservation using sucralose
WO2020002353A1 (fr) 2018-06-27 2020-01-02 Breath Therapeutics Gmbh Compositions pharmaceutiques sous forme lyophilisée

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1260393A (fr) * 1984-10-16 1989-09-26 Lajos Tarcsay Liposomes de lipides synthetiques
CA1321351C (fr) * 1987-02-23 1993-08-17 Helmut Otmar Hauser Mode de deshydratation de preparations vesiculaires en vue d'un stockage de longue duree
GB9813100D0 (en) * 1998-06-18 1998-08-19 Secr Defence Method of forming liposomes
CA2427467C (fr) * 2000-11-09 2010-01-12 Neopharm, Inc. Complexes lipidiques a base de sn-38 et procedes d'utilisation
JP2007522085A (ja) * 2003-06-27 2007-08-09 スミスクライン・ビーチャム・コーポレイション 安定化されたトポテカンリポソーム組成物および方法
WO2008026310A1 (fr) * 2006-08-29 2008-03-06 Cellex K.K. Agent protecteur pour une muqueuse orale contenant du tréhalose

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US4411894A (en) * 1979-06-22 1983-10-25 Hoffmann-La Roche Inc. Pharmaceutical preparations
US4515736A (en) * 1983-05-12 1985-05-07 The Regents Of The University Of California Method for encapsulating materials into liposomes

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Title
Archives of Biochemistry and Biophysics, Vol. 220, No. 2, issued 01 February 1983, J. H. CROWE et al., "Preservation of Structural and Functional Activity in Lyophilized Sarcoplasmic Reticulum", pages 477-484. *
Archives of Biochemistry and Biophysics, Vol. 242, No. 1, issued October 1985, L.M. CROWE et al., "Presevation of Freeze-Dried Liposomes by Trehalose", pages 240-247. *
Biochimica et Biophysica Acta, Vol. 769, issued 11 January 1984, L.M. CROWE et al., "Effects of Carbohydrates on Membrane Stability at Low Water Activities", pages 141-150 *
CHEMICAL ABSTRACTS, Vol. 101, NO. 24, issued 1984, December 12 (Columnbus, Ohio, U.S.A), CROMMELIN, D.J.A. et al., "Stability of Liposomes on Storage: Freeze-Dried, Frozen or as on Aqueous Dispersion" see page 307, column 2, the Abstract No. 216308h, Pharm. Res. 1984, (4), 159-63(Eng). *
CHEMICAL ABSTRACTS, Vol. 97, No. 2, issued 1982, July 12 (Columbus, Ohio, U.S.A.), Jpn. Kokai Tokkyo Koho JP 8246, 921, 17 March 1982, see pages 370, column 1, the Abstract No. 11851g. *
CHEMICAL ABSTRACTS, Vol. 97, No. 2, issued 1982, July 12 (Columbus, Ohio, U.S.A.). Jpn. Kokai Tokkyo Koho JP 8246, 921, 17 March 1982, see page 370, column 1, the Abstract No. 11851g. *
CHEMICAL ABSTRACTS, Vol. 99, No. 20, issued 1983, November 12 (Columbus, Ohio, U.S.A.), TSYGANENKO, A. YA. et al., "Preparation and Low-Temperature Storage of Rifampicin-Containing Liposomes", see page 340, column 1, the Abstract No. 163956z Antibiotiki (Moscow) 1983, 28(8), 577-81 (Russ). *
See also references of EP0208764A4 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5484432A (en) * 1985-09-27 1996-01-16 Laser Biotech, Inc. Collagen treatment apparatus
US5618284A (en) * 1985-09-27 1997-04-08 Sunrise Technologies Collagen treatment apparatus
WO1987005300A3 (fr) * 1986-02-28 1987-10-22 Biocompatibles Ltd Conservation de proteines
WO1987005300A2 (fr) * 1986-02-28 1987-09-11 Biocompatibles Limited Conservation de proteines
US5817334A (en) * 1988-10-05 1998-10-06 Nexstar Pharmaceuticals, Inc. Method of making liposomes with improved stability during drying
US6524823B2 (en) 1988-10-11 2003-02-25 The University Of Southern California Vasopermeability-enhancing conjugates
EP0438497A4 (en) * 1988-10-11 1992-02-26 University Of Southern California Vasopermeability-enhancing conjugates
EP0438497A1 (fr) * 1988-10-11 1991-07-31 Univ Southern California Conjugues ameliorant la permeabilite vasculaire.
US6007817A (en) * 1988-10-11 1999-12-28 University Of Southern California Vasopermeability enhancing immunoconjugates
US6696276B2 (en) 1988-10-11 2004-02-24 University Of Southern California Vasopermeability-enhancing conjugates
WO1990004329A1 (fr) * 1988-10-20 1990-05-03 Coulter Corporation Cellules mammiferes lyophilisees stabilisees et procede pour leur fabrication
US6623753B1 (en) 1991-05-30 2003-09-23 Novartis Ag Allylamine-containing liposomes
EP0660714A1 (fr) * 1991-06-18 1995-07-05 ImaRx Pharmaceutical Corp. Nouveaux systemes d'apport de medicaments aux liposomes
EP0660714B1 (fr) * 1991-06-18 2003-07-02 ImaRx Pharmaceutical Corp. Nouveaux systemes d'apport de medicaments aux liposomes
US6497898B1 (en) 1993-10-07 2002-12-24 Kanebo Ltd Surfactant, and an emulsion-type cosmetic composition and a lipsome containing said surfactant
WO1995027721A1 (fr) * 1994-04-07 1995-10-19 Akzo Nobel N.V. Compositions lyophilisees comprenant de l'arn
WO1998034478A1 (fr) * 1997-02-07 1998-08-13 Quadrant Holdings Cambridge Limited Procedes et compositions permettant de produire des plaquettes sechees et stables au stockage
US6221575B1 (en) 1997-02-07 2001-04-24 Quadrant Holdings Cambridge Ltd. Methods for producing dried storage-stable platelets and compositions obtained thereby
US6710038B1 (en) 1999-12-14 2004-03-23 Kibun Food Chemifa Co., Ltd. Emulsification method using propylene glycol hyaluronate
US6723497B2 (en) 2000-02-10 2004-04-20 The Regents Of The University Of California Therapeutic platelets and methods
US6770478B2 (en) 2000-02-10 2004-08-03 The Regents Of The University Of California Erythrocytic cells and method for preserving cells
WO2010150051A1 (fr) * 2009-06-24 2010-12-29 Lipoid Gmbh Composition pour applications cosmétiques, pharmaceutiques ou diététiques
US8652494B2 (en) 2009-06-24 2014-02-18 Lipoid Gmbh Composition for cosmetic, pharmaceutical or dietary applications
US9433570B2 (en) 2009-06-24 2016-09-06 Lipoid Gmbh Composition for cosmetic, pharmaceutical and dietary applications
US10166184B2 (en) 2011-10-21 2019-01-01 Celator Pharmaceuticals Inc. Method of lyophilizing liposomes
US10835492B2 (en) 2011-10-21 2020-11-17 Celator Pharmaceuticals, Inc. Method of lyophilizing liposomes
US10448631B2 (en) 2015-09-22 2019-10-22 East Carolina University Cryopreservation using sucralose
US11185069B2 (en) 2015-09-22 2021-11-30 East Carolina University Cryopreservation using sucralose
US11284615B2 (en) 2015-09-22 2022-03-29 East Carolina University Cryopreservation using sucralose
WO2020002353A1 (fr) 2018-06-27 2020-01-02 Breath Therapeutics Gmbh Compositions pharmaceutiques sous forme lyophilisée

Also Published As

Publication number Publication date
EP0208764A1 (fr) 1987-01-21
DK428386A (da) 1986-11-11
CA1275248C (fr) 1990-10-16
DK175799B1 (da) 2005-02-28
DK428386D0 (da) 1986-09-08
JPS62501631A (ja) 1987-07-02
AU5318386A (en) 1986-07-29
EP0208764A4 (fr) 1987-10-08
AU587600B2 (en) 1989-08-24

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