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WO1990010645A1 - Insulines glycosylees - Google Patents

Insulines glycosylees Download PDF

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Publication number
WO1990010645A1
WO1990010645A1 PCT/DK1990/000062 DK9000062W WO9010645A1 WO 1990010645 A1 WO1990010645 A1 WO 1990010645A1 DK 9000062 W DK9000062 W DK 9000062W WO 9010645 A1 WO9010645 A1 WO 9010645A1
Authority
WO
WIPO (PCT)
Prior art keywords
insulin
glycosylated
phe
human insulin
gly
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/DK1990/000062
Other languages
English (en)
Inventor
John Broberg HALSTRØM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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 Novo Nordisk AS filed Critical Novo Nordisk AS
Priority to FI914226A priority Critical patent/FI914226A0/fi
Priority to KR1019910701014A priority patent/KR920701249A/ko
Publication of WO1990010645A1 publication Critical patent/WO1990010645A1/fr
Priority to NO91913517A priority patent/NO913517L/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to specifically glyco ⁇ sylated insulins and combinations thereof, pharmaceutical prep ⁇ arations containing such glycosylated compounds and a method for their preparation.
  • insulin analogues have been suggested for the treatment of diabetes ellitus.
  • the pur ⁇ pose of developing such insulin analogues has been to improve the insulin replacement therapy by making available insulin analogues with either a more rapid or a more protracted insulin action compared to especially human insulin.
  • insulin has a very short half life time in circulating blood, it can not be excluded that a small amount of insulin is glycosylated in vivo not only in diabetic patients as postulated by Nakayama et al. (Nonenzymatic glyco- sylation of insulin in "Current topics in clinical and experi ⁇ mental aspects of diabetes mellitus” (1985), 201 - 204, Saka ⁇ moto, Min and Baba, Eds., Elsevier Science Publishers B.V.) but also in non-diabetics. It is therefore possible that the organ ⁇ ism has developed mechanisms to suppress the formation of anti- bodies against glycosylated insulin. It is furthermore possible that the conformational changes of the saccharide part will be able to camouflage the antigen.
  • Nakayama et al. investigated non-enzymatic glycosylation of insulin in vitro and in vivo (diabetic patients) and concluded that glucose was incorporated into the insulin molecule in vivo under pathological conditions.
  • 3 molecules of glucose were found to be in ⁇ corporated per molecule of insulin.
  • glycosylated insulin preparations will all be inhomo- geneous mixtures of glycosylated insulin molecules.
  • Glycosylated insulin derivatives for self-regulating insulin delivery systems have been described by Kim et al. (Journal of Controlled Release 1 (1984), 57 - 66, and US patent specification Nos. 4,483,792; 4,478,830; 4,478,746 and 4,489,063).
  • glucose or mannose is coupled with insulin via a spacer group derived from di- carboxylic acids, acid anhydrides or phenyl amines or a combi ⁇ nation thereof.
  • European patent application No. 84200328 having pub- lication No. 119,650 relates to galactosyl insulins which like the glycosylated insulins described by Kim (supra) contain a spacer group.
  • insu ⁇ lin derivatives having improved properties. More specifically, it is the purpose of the present invention to develop non-im- munogenic insulin derivatives. It is furthermore the purpose of the present invention to develop insulin derivatives with a faster onset of insulin action than native insulin and to im ⁇ prove the solubility of less soluble insulins in order to allow the use of highly concentrated solutions, for example in insu ⁇ lin pumps. A still further purpose of this invention is to pre ⁇ pare insulin derivatives with an improved stability against fi ⁇ brillation.
  • the present invention provides specifically glyco- sylated insulins.
  • specifically glycosy ⁇ lated insulins designates insulins having the carbohydrate sub- stituent in a specific position in the insulin molecule.
  • specifically glycosylated insulins offer cer ⁇ tain therapeutical advantages as will be apparent from the fol- lowing description and examples.
  • the present invention provides specifically glycosylated insulins.
  • the present invention provides insulin derivatives being either monoglycosylated in position Al, Bl or B29; diglycosylated in position Al and Bl; Al and B29; or Bl and B29 or triglycosy- lated in position Al, Bl and B29.
  • the glycosylated insulins described by Kim et al. and dealt with above are remote from the insulins of the present invention, which utilizes the aldehyde function of the sugar itself to form a covalent bond to insulin, without the use of artificial spacer groups.
  • a further advantage of the present invention over the insulins of Kim et al. is the retention of the natural charge distribution of the insulin molecule.
  • the amino groups involved which by the glycosylation reaction are converted into secondary amino groups are still capable of being protonated, as in normal insulin.
  • the present insulin derivatives may in each of the three positions contain a monosaccharide or an oligosaccharide with up to three sugar residues.
  • Suitable monosaccharides are glucose, mannose and galactose.
  • Suitable oligosaccharides are maltose, isomaltose, lactose, maltotriose, melibiose and cello- biose.
  • the specifically glycosylated insulin derivatives of this invention may be used as such for the treatment of dia- betes mellitus. With the purpose of monitoring the insulin therapy, selected mixtures of the individual specifically gly ⁇ cosylated compounds may however also be used.
  • the expression insulins is meant to cover native forms of insulin such as human, bovine and porcine insulin, but also derivatives thereof wherein one or more amino acid residues have been substituted, added or deleted, compared with native insulin, for example as described in European patent applications having publication Nos. 0194864A and 0214826A.
  • native insulins have three poten ⁇ tial glycosylation sites, namely the two N-terminal amino acid residues in the A- and B-chain and the lysine residue in posi ⁇ tion B29.
  • the number of potential glycosy ⁇ lation sites in insulin analogues of the above described type may be from two (the two N-terminal residues) and upwards de- pending on how many lysine residues are present in the modified insulin molecule, lysine being the only naturally occurring amino acid with a free primary amino group in the side chain.
  • the chain structure is the reactive component
  • insulin 1 deoxy-D-fructosyl insulin (glucose insulin) "insulin" designates desamino insulin.
  • glycosylated insu- lins are:
  • Phe(Bl) glucose human insulin Phe(Bl) mannose human insulin.
  • Gly(Al) ,Phe(Bl) ,Lys(B29) triglucose human insulin
  • Gly(Al) ,Phe(Bl) ,Lys(B29) trimaltose human insulin Gly(Al) ,Phe(Bl) ,Lys(B29) trilactose human insulin
  • Gly(Al) ,Phe(Bl) ,Lys(B29) trimannose human insulin
  • Gly(Al) ,Phe(Bl) ,Lys(B29) triisomaltose human insulin Phe(Bl) glucose [Asp B1 °] human insulin
  • the present glycosylated insulins may be prepared by reacting insulin or an insulin analogue with an excess of the selected monosaccharide or oligosaccharide in a suitable or ⁇ ganic or aqueous medium.
  • the temperature may vary from 20 to 60°C.
  • organic solvents lower carboxylic acids, for example acetic acid and propionic acid, lower aliphatic alcohols, for example methanol, ethanol and 2-propanol, ethylene glycol and propylene glycol may be used. However, phenols may also be used.
  • the duration of the reaction and the composition of the reaction mixture will depend on whether a mono-, di- or triglycosylated end product is desired.
  • the reaction may con- veniently be followed by reversed phase high pressure liquid chromatography (hereinafter designated RP HPLC) to determine the point of maximum formation of each of the individual glyco ⁇ sylated products.
  • RP HPLC reversed phase high pressure liquid chromatography
  • reaction is stopped by cooling, for example to -20°C, and the reaction mixture is concentrated to dryness whereupon the major components of the reaction mixture are iso ⁇ lated and purified by preparative RP HPLC. After desalting, the products are characterized by fast atom bombardment mass spec- trometry (hereinafter designated FAB-MS) , quantitative amino acid analysis after borohydride reduction and bioassays.
  • FAB-MS fast atom bombardment mass spec- trometry
  • the present glycosylated insulins and mixtures there ⁇ of may be substituted for the human or porcine insulin in the insulin preparations heretofore known in the art to prepare novel insulin preparations.
  • novel insulin preparations will contain the glycosylated insulin or a pharmaceutically acceptable salt thereof in an aqueous solution, preferably at a neutral pH value.
  • the aqueous medium is made isoto- nic, for example with sodium chloride, sodium acetate or gly- cerol.
  • the aqueous medium may contain zinc ions, buffer components such as acetate or phosphate and a preserva ⁇ tive such as m-cresol, methylparaben or phenol.
  • the pH value of the preparation may be adjusted to the desired value and the preparation can be sterilized by filtration.
  • the insulin preparation of the present invention can be used similarly to the use of the known insulin preparations.
  • Human insulin (0.1 mmol) was suspended in methanol (30 ml) and glacial acetic acid (5 ml) was added at ambient temperature. The mixture was gently stirred until the insulin had dissolved. Then, a further quantity of methanol (35 ml) was added and after addition of D-glucose (2.2 mmol), the mixture was gently stirred at 40°C for 8 hours, by which the title com ⁇ pound became the main component.
  • the solution was concentrated almost to dryness on a rotatory evaporator.
  • the residue was dissolved in water and fractionated by preparative RP HPLC. Column: 16 x 250 mm with 7 ⁇ m 100 A C 18 particles. Temperature 30°C. Mobile phase. A: 0.04 M phosphoric acid, 0.2 M sodium sulphate, 10% acetonitrile, pH value adjusted to 2.5 with ethanol amine. B: 50% acetonitrile. The fraction corresponding to the central part of the major peak was desalted and lyophilized. The yield was 0.02 mmol.
  • the product was characterized by FAB-MS and quantitative amino acid analysis after borohydride reduction. The amino acid analysis showed the presence of two phenylalanine residues (i.e. one less phenylalanine residue compared to human insulin) proving substitution in Phe(Bl) . The molecular weight was found to be 5970 (calculated: 5970) .
  • the amino acid analysis showed the presence of one less Phe and one less Gly residue proving a substitution in po- sition Al and Bl.
  • the molecular weight measured was 6132 (calculated: 6132) .
  • the subcutaneous absorption was measured in pigs by injection of 125 l labelled Phe(Bl) ,Gly(Al) diglucose insulin prepared using the iodate method essentially as described (J ⁇ r- gensen et al., Diabetologia JL9 (1980), 546 - 554).
  • the absorp- tion rate after subcutaneous injection into pigs of 1 J -2 ⁇ "5 J ⁇ human insulin and 125I Phe(Bl) ,Gly(Al) diglucose human insulin is shown in Table 1, below.
  • the T 75 , T 50 and T 5 values given in Table 1 are the time (in hours) elapsed from the moment of in- 10
  • Table 2 shows the fast action of diglucose insulin compared with human insulin.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Diabetes (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des insulines glycosylées spécifiquement ainsi que leurs préparations pharmaceutiques. Les nouvelles insulines sont de préférence mono-, bi- ou triglycosylées, et contiennent un groupe de monosaccharides ou un groupe d'oligosaccharides doté de deux ou de trois unités de sucre. Les insulines glycosylées spécifiquement ont une solubilité élevée et un départ d'action insulinique plus rapide que l'insuline humaine par exemple.
PCT/DK1990/000062 1989-03-08 1990-03-06 Insulines glycosylees Ceased WO1990010645A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
FI914226A FI914226A0 (fi) 1989-03-08 1990-03-06 Glykosylerade insulin.
KR1019910701014A KR920701249A (ko) 1989-03-08 1990-03-06 글리코실화 인슐린
NO91913517A NO913517L (no) 1989-03-08 1991-09-06 Glykosylerte insuliner.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK1114/89 1989-03-08
DK111489A DK111489D0 (da) 1989-03-08 1989-03-08 Peptider

Publications (1)

Publication Number Publication Date
WO1990010645A1 true WO1990010645A1 (fr) 1990-09-20

Family

ID=8101165

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1990/000062 Ceased WO1990010645A1 (fr) 1989-03-08 1990-03-06 Insulines glycosylees

Country Status (19)

Country Link
EP (1) EP0462192A1 (fr)
JP (1) JPH04504117A (fr)
KR (1) KR920701249A (fr)
CN (1) CN1045586A (fr)
AU (1) AU638701B2 (fr)
CA (1) CA2049937A1 (fr)
CS (1) CS114290A3 (fr)
DD (1) DD296933A5 (fr)
DK (1) DK111489D0 (fr)
FI (1) FI914226A0 (fr)
GR (1) GR1000604B (fr)
HU (1) HUT59942A (fr)
IL (1) IL93674A0 (fr)
NO (1) NO913517L (fr)
NZ (1) NZ232808A (fr)
PT (1) PT93366A (fr)
WO (1) WO1990010645A1 (fr)
YU (1) YU45490A (fr)
ZA (1) ZA901737B (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2033662A1 (fr) 2004-01-21 2009-03-11 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
EP2093235A1 (fr) 2006-02-08 2009-08-26 Alios Biopharma Inc. Variantes hyperglycosylées du interferon alfacon-1
US8569231B2 (en) 2009-03-20 2013-10-29 Smartcells, Inc. Soluble non-depot insulin conjugates and uses thereof
US8623345B2 (en) 2009-03-20 2014-01-07 Smartcells Terminally-functionalized conjugates and uses thereof
WO2014088836A1 (fr) 2012-12-03 2014-06-12 Merck Sharp & Dohme Corp. Insuline et analogues d'insuline à base de peptide à partie terminale carboxy (ptc) o-glycosylée
US8846103B2 (en) 2009-01-28 2014-09-30 Smartcells, Inc. Exogenously triggered controlled release materials and uses thereof
WO2014160185A2 (fr) 2013-03-14 2014-10-02 The Board Of Trustees Of The Leland Stanford Junior University Modulateurs de l'aldéhyde déshydrogénase-2 mitochondriale et leurs procédés d'utilisation
US8906850B2 (en) 2009-01-28 2014-12-09 Smartcells, Inc. Crystalline insulin-conjugates
US8933207B2 (en) 2010-07-28 2015-01-13 Smartcells, Inc. Drug-ligand conjugates, synthesis thereof, and intermediates thereto
US9050370B2 (en) 2009-01-28 2015-06-09 Smartcells, Inc. Conjugate based systems for controlled drug delivery
US9068013B2 (en) 2010-07-28 2015-06-30 Smart Cells, Inc. Recombinant lectins, binding-site modified lectins and uses thereof
US9074015B2 (en) 2010-07-28 2015-07-07 Smartcells, Inc. Recombinantly expressed insulin polypeptides and uses thereof
EP2877200A4 (fr) * 2012-07-17 2016-03-09 Michael Weiss Analogues de l'insuline modifiés par un glucide relié à l'oxygène
US9427475B2 (en) 2013-10-04 2016-08-30 Merck Sharp & Dohme Corp. Glucose-responsive insulin conjugates
US9624287B2 (en) 2012-07-17 2017-04-18 Case Western Reserve University O-linked carbohydrate-modified insulin analogues
US9700599B2 (en) 2012-11-13 2017-07-11 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
US9795678B2 (en) 2014-05-14 2017-10-24 Adocia Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound
US10525133B2 (en) 2014-05-14 2020-01-07 Adocia Aqueous composition comprising at least one protein and one solubilizing agent, preparation thereof and uses thereof
US10792335B2 (en) 2015-11-16 2020-10-06 Adocia Rapid-acting insulin composition comprising a substituted citrate
US11090364B2 (en) 2016-06-02 2021-08-17 Sanofi Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105597080A (zh) 2016-01-29 2016-05-25 程潜 一种用于治疗尿毒症和尿蛋白的药物
CN105535927A (zh) * 2016-01-29 2016-05-04 山东中海制药有限公司 一种用于治疗流感、上呼吸道感染、病毒性肺炎的药物
CN105709207A (zh) * 2016-01-29 2016-06-29 徐宝贞 一种用于治疗痛风的药物

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3847890A (en) * 1971-11-01 1974-11-12 A Green Acidic monosaccharide-substituted proteins
WO1984001896A1 (fr) * 1982-11-17 1984-05-24 Univ Utah Derives d'insuline glycosylee
EP0119650A2 (fr) * 1983-03-21 1984-09-26 THE PROCTER & GAMBLE COMPANY Conjugués de galactosyl-insuline utilisés dans le traitement des diabétiques
WO1988002756A2 (fr) * 1986-10-13 1988-04-21 Sandoz Ag Derives peptidiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3847890A (en) * 1971-11-01 1974-11-12 A Green Acidic monosaccharide-substituted proteins
WO1984001896A1 (fr) * 1982-11-17 1984-05-24 Univ Utah Derives d'insuline glycosylee
EP0119650A2 (fr) * 1983-03-21 1984-09-26 THE PROCTER & GAMBLE COMPANY Conjugués de galactosyl-insuline utilisés dans le traitement des diabétiques
WO1988002756A2 (fr) * 1986-10-13 1988-04-21 Sandoz Ag Derives peptidiques

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2033662A1 (fr) 2004-01-21 2009-03-11 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
EP2368579A1 (fr) 2004-01-21 2011-09-28 Novo Nordisk Health Care AG Conjugaison au moyen de transglutaminase de peptides
EP2093235A1 (fr) 2006-02-08 2009-08-26 Alios Biopharma Inc. Variantes hyperglycosylées du interferon alfacon-1
US9463249B2 (en) 2009-01-28 2016-10-11 Smartcells, Inc. Crystalline insulin-conjugates
US9579391B2 (en) 2009-01-28 2017-02-28 Smartcells, Inc. Conjugate based systems for controlled drug delivery
US10398781B2 (en) 2009-01-28 2019-09-03 Smartcells, Inc. Conjugate based systems for controlled drug delivery
US8846103B2 (en) 2009-01-28 2014-09-30 Smartcells, Inc. Exogenously triggered controlled release materials and uses thereof
US9050370B2 (en) 2009-01-28 2015-06-09 Smartcells, Inc. Conjugate based systems for controlled drug delivery
US8906850B2 (en) 2009-01-28 2014-12-09 Smartcells, Inc. Crystalline insulin-conjugates
US8623345B2 (en) 2009-03-20 2014-01-07 Smartcells Terminally-functionalized conjugates and uses thereof
US8569231B2 (en) 2009-03-20 2013-10-29 Smartcells, Inc. Soluble non-depot insulin conjugates and uses thereof
US9068013B2 (en) 2010-07-28 2015-06-30 Smart Cells, Inc. Recombinant lectins, binding-site modified lectins and uses thereof
US9074015B2 (en) 2010-07-28 2015-07-07 Smartcells, Inc. Recombinantly expressed insulin polypeptides and uses thereof
US8933207B2 (en) 2010-07-28 2015-01-13 Smartcells, Inc. Drug-ligand conjugates, synthesis thereof, and intermediates thereto
US9624287B2 (en) 2012-07-17 2017-04-18 Case Western Reserve University O-linked carbohydrate-modified insulin analogues
EP2877200A4 (fr) * 2012-07-17 2016-03-09 Michael Weiss Analogues de l'insuline modifiés par un glucide relié à l'oxygène
US10583175B2 (en) 2012-11-13 2020-03-10 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
US9700599B2 (en) 2012-11-13 2017-07-11 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
US11324808B2 (en) 2012-11-13 2022-05-10 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
US10881716B2 (en) 2012-11-13 2021-01-05 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
US10646551B2 (en) 2012-11-13 2020-05-12 Adocia Rapid-acting insulin formulation comprising a substituted anionic compound
WO2014088836A1 (fr) 2012-12-03 2014-06-12 Merck Sharp & Dohme Corp. Insuline et analogues d'insuline à base de peptide à partie terminale carboxy (ptc) o-glycosylée
WO2014160185A2 (fr) 2013-03-14 2014-10-02 The Board Of Trustees Of The Leland Stanford Junior University Modulateurs de l'aldéhyde déshydrogénase-2 mitochondriale et leurs procédés d'utilisation
US9427475B2 (en) 2013-10-04 2016-08-30 Merck Sharp & Dohme Corp. Glucose-responsive insulin conjugates
US9889205B2 (en) 2013-10-04 2018-02-13 Merck Sharp & Dohme Corp. Glucose-responsive insulin conjugates
US9884125B2 (en) 2013-10-04 2018-02-06 Merck Sharp & Dohme Corp. Glucose-responsive insulin conjugates
US10525133B2 (en) 2014-05-14 2020-01-07 Adocia Aqueous composition comprising at least one protein and one solubilizing agent, preparation thereof and uses thereof
US9795678B2 (en) 2014-05-14 2017-10-24 Adocia Fast-acting insulin composition comprising a substituted anionic compound and a polyanionic compound
US10792335B2 (en) 2015-11-16 2020-10-06 Adocia Rapid-acting insulin composition comprising a substituted citrate
US11090364B2 (en) 2016-06-02 2021-08-17 Sanofi Conjugates of a pharmaceutical agent and a moiety capable of binding to a glucose sensing protein

Also Published As

Publication number Publication date
PT93366A (pt) 1990-11-07
NO913517L (no) 1991-11-06
GR900100159A (en) 1990-07-31
ZA901737B (en) 1990-11-28
GR1000604B (el) 1992-08-26
CA2049937A1 (fr) 1990-09-09
YU45490A (en) 1991-10-31
AU638701B2 (en) 1993-07-08
NO913517D0 (no) 1991-09-06
CN1045586A (zh) 1990-09-26
FI914226A7 (fi) 1991-09-06
DD296933A5 (de) 1991-12-19
HUT59942A (en) 1992-07-28
HU902787D0 (en) 1991-11-28
DK111489D0 (da) 1989-03-08
NZ232808A (en) 1992-04-28
IL93674A0 (en) 1990-12-23
JPH04504117A (ja) 1992-07-23
CS114290A3 (en) 1992-02-19
EP0462192A1 (fr) 1991-12-27
KR920701249A (ko) 1992-08-11
FI914226A0 (fi) 1991-09-06
AU5280790A (en) 1990-10-09

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