WO1993011757A1 - Drug formulations for parenteral use - Google Patents

Drug formulations for parenteral use Download PDF

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Publication number
WO1993011757A1
WO1993011757A1 PCT/FI1992/000339 FI9200339W WO9311757A1 WO 1993011757 A1 WO1993011757 A1 WO 1993011757A1 FI 9200339 W FI9200339 W FI 9200339W WO 9311757 A1 WO9311757 A1 WO 9311757A1
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WIPO (PCT)
Prior art keywords
toremifene
drug
cyclodextrin
hydroxypropyl
formulation
Prior art date
Application number
PCT/FI1992/000339
Other languages
French (fr)
Inventor
Harry Gösta JALONEN
Terttu Marita HEIKKILÄ
Hannu Uolevi Jalonen
Lauri Veikko Matti Kangas
Risto Arvo Sakari Lammintausta
Kauko Oiva Antero Kurkela
Original Assignee
Orion-Yhtymä Oy
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 Orion-Yhtymä Oy filed Critical Orion-Yhtymä Oy
Priority to DE69218241T priority Critical patent/DE69218241T2/en
Priority to US08/244,549 priority patent/US5571534A/en
Priority to JP51065093A priority patent/JP3558344B2/en
Priority to CA002125408A priority patent/CA2125408C/en
Priority to AU31599/93A priority patent/AU667861B2/en
Priority to EP93900114A priority patent/EP0616529B1/en
Publication of WO1993011757A1 publication Critical patent/WO1993011757A1/en
Priority to NO942155A priority patent/NO308578B1/en
Priority to FI942728A priority patent/FI942728A0/en

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    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • This invention relates to drug formulations of antiestrogens, ⁇ particularly antiestrogens comprising a triphenylbutene moiety, for use in parenteral administration.
  • Toremifene, desmethyl toremifene, desmethyl tamoxifen and tamoxifen are all examples of substituted triphenylbutenes useful in cancer therapy.
  • toremifene CH3 Cl desmethyl toremifene H Cl tamoxifen CH3 H desmethyl tamoxifen H H
  • toremifene may well be used together with other anticancer drugs to enhance their efficacy
  • parenteral drug formulations according to this invention include emulsions, aqueous solutions of cyclodextrin - drug complexes and liposomes.
  • Cyclodextrins are all cyclic oligomers of glucose.
  • the cyclodextrins can form inclusion complexes with drugs in that the drug molecule is included in the lipophile-seeking cavities of the cyclodextrin molecule. Therefore the cyclodextrins effectively solubilize lipophilic drugs into aqueous media.
  • the use of cyclodextrins in the pharmaceutical field has been described e.g. in Drug Development and Industrial Pharmacy, 17(11), 1503-1549, 1991.
  • One object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably 2-hydroxypropyl ⁇ -cyclodextrin or 2-hydroxypropyl-r- cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyltoremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present in an aqueous solution.
  • Emulsions of the antiestrogens mentioned above can be made by dispersing the drug or a cylodextrin complex of said drug into a pharmaceutically acceptable emulsifier, and optionally adding a stabilizing agent.
  • Liposomes are spherical particles in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment.
  • the lipid surface may be either unilamellar or multilamellar.
  • the liposomes may be loaded with either hydrophobic or hydrophilic drug substances.
  • Another object of the invention is a parenteral formulation based on the drug substance as such loaded into liposomes .
  • DMPG diristoylphosphatidylglycerol
  • POPC l-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine
  • liposomes can be made directly by dissolving the drug or the drug-cyclodextrin complex and phospholipid component directly in water without foregoing dissolving into chlor
  • Another object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably 2- hydroxypropyl ⁇ -cyclodextrin or 2-hydroxypropyl r-cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non- toxic salt thereof, said complex being loaded into a liposome.
  • the fully automated HPLC apparatus (Hewlett-Packard, USA) consisted of a pump 1090, an autosampler and autoinjector (79847A) with an injection volume of 10 ul and a fixed wavelength UV detector, 280 nm (79881A) .
  • the chromatograms and peak areas were recorded with an integrator 3393.
  • the separations were carried out at room temperature on a 35 * 4.6 mm stainless steel column (packed with 3-pm spherical octadecylsilanebonded silica particles; HS-3 C-18, (Perkin- Elmer, USA)
  • the mobile phase consisted of a mixture of acetonitrile : 0.05 aqueous phosphate buffer containing 0.004 M of dimethyloctyl amine with a pH of 7.4.
  • the flow rate was 0.8 ml/min.
  • 2-hydroxypropyl- ⁇ -cyclodextrin (12 mg), POPC (32 mg), choleste ⁇ rol (4 mg), DMPG (dimyristoylphosphatidylglycerol) (8 mg) and toremifene citrate (2 mg) were dissolved in choloroform - met ⁇ hanol (2:1) and evaporated. The residue was dissolved in water and homogenized by sonication (Labsonic U, 50 W) . The stability of the solution was good; no turbidity was observed after one month in room temperature.
  • cyclodextrin-free liposomes can be made by mixing the ingredients first in chloroform/ thanol (2:1) as described above for the cyclodextrin-containing liposomes.
  • Emulsions prepared by dissolving the drug in a commercial fat emulsion are prepared by dissolving the drug in a commercial fat emulsion.
  • Emulsan® 20 % manufactured by Emulsan
  • Different amounts of toremifene citrate were dissolved in Emulsan solution and homogenized by sonication (Labsonic U, 50 W) .
  • the toremifene concentrations were 10 mg/ml, 14 mg/ml and 20 mg/ml. After the homogenization the samples were filtered through the 0.2 ⁇ , 0.45 ⁇ m and 1.2 ⁇ m filters.
  • the concentration of toremifene was determined from the filtrate with a spectrofotometric method using the wave length of 278 nm.
  • the samples were dissolved in methanol and diluted in the concentration of 0.02 mg/ml.

Abstract

This invention relates to parenteral preparations of antiestrogens such as toremifene, desmethyl toremifene, tamoxifen or desmethyltamoxifen. The preparations can be emulsions, liposomes or aqueous solutions of cyclodextrin-drug complexes. Particularly the invention relates to a parenteral drug formulation comprising a complex having a 2-hydroxypropyl cyclodextrin component and including an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present either in an aqueous solution or emulsion or loaded into a liposome.

Description

Drug formulations for parenteral use
This invention relates to drug formulations of antiestrogens, < particularly antiestrogens comprising a triphenylbutene moiety, for use in parenteral administration.
Toremifene, desmethyl toremifene, desmethyl tamoxifen and tamoxifen are all examples of substituted triphenylbutenes useful in cancer therapy. Reference is made to US 4696949, US 4990538 and US 4356516. They can all be described with the formula
Figure imgf000003_0001
in which R-_ *i-s CH3 or H and R2 *s H or cl-
The compounds mentioned above have the following values of
R-L and R2;
Rλ R2
toremifene CH3 Cl desmethyl toremifene H Cl tamoxifen CH3 H desmethyl tamoxifen H H
A common feature of these antiestrogens is their poor solubility in water. Thus, parenteral administration of these drugs cannot be accomplished simply by an aqueous solution of the active ingredients.
There is a clear need for parenteral formulations of the anticancer antiestrogens. Injectable high-concentration toremifene formulations will have important clinical benefit
1) in the attempts to reach high concentrations in tissue. This is necessary especially when combinations of toremifene with c totoxic dru s are given to a patient. As shown by DeGregorio et al (J Clinical Oncology, vol 7, No 9,1989: 1359 - 1364.) high plasma concentrations are more effective in reversing multidrug resistance than low concentrations. An i jectable formulation enables high peak concentrations in blood and tissues without exposing the patient to long-term treatmen ;
2) when given locally into a tumor. This enables a high and efficacious concentration in the tumor to be achieved;
3) when used topically in a benign estrogen-dependent lesion like cystic mastalgia, where toremifene can be injected directly into a painful cyst;
4) when spreading toremifene topically onto palpable and subcutaneous breast cancer metastases;
5) when an intravesical installation is given for the therapy of superficial bladder cancer. In this indication toremifene may well be used together with other anticancer drugs to enhance their efficacy;
6) when an intraperitoneal solution is given for the treatment of certain types of overian cancer;
7) when other topical, estrogen-dependent lesions are treated with an antiestrogen.
The parenteral drug formulations according to this invention include emulsions, aqueous solutions of cyclodextrin - drug complexes and liposomes.
Dissolution properties of drugs can be significantly improved by complexation of the drug substance with cyclodextrins. Cyclodextrins (including ., β and r cyclodextrins and their derivatives) are all cyclic oligomers of glucose. The cyclodextrins can form inclusion complexes with drugs in that the drug molecule is included in the lipophile-seeking cavities of the cyclodextrin molecule. Therefore the cyclodextrins effectively solubilize lipophilic drugs into aqueous media. The use of cyclodextrins in the pharmaceutical field has been described e.g. in Drug Development and Industrial Pharmacy, 17(11), 1503-1549, 1991.
With respect to the antiestrogens mentioned above, however, no parenteral drug formulations based on complexation of the active drug substance with 2-hydroxypropyl cyclodextrins are known in the art. One object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably 2-hydroxypropyl β-cyclodextrin or 2-hydroxypropyl-r- cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyltoremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof, said complex being present in an aqueous solution.
Emulsions of the antiestrogens mentioned above can be made by dispersing the drug or a cylodextrin complex of said drug into a pharmaceutically acceptable emulsifier, and optionally adding a stabilizing agent.
Parenteral administration of the drugs mentioned above may also be accomplished by aqueous solutions of liposomes containing said drug or a salt thereof. Liposomes are spherical particles in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment. The lipid surface may be either unilamellar or multilamellar. The liposomes may be loaded with either hydrophobic or hydrophilic drug substances.
Another object of the invention is a parenteral formulation based on the drug substance as such loaded into liposomes . Such liposomes can be made by dissolving the drug or drug- cyclodextrin. complex together with a phospholipid component, preferably DMPG (dimyristoylphosphatidylglycerol) and/or POPC (= l-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine) , in a chloroform - methanol mixture, evaporating the solvent, dissolving the residue into water followed by homogenization. According to this invention liposomes can be made directly by dissolving the drug or the drug-cyclodextrin complex and phospholipid component directly in water without foregoing dissolving into chloroform - methanol mixture.
Another object of this invention is a parenteral formulation based on a 2-hydroxypropyl cyclodextrin, preferably 2- hydroxypropyl β-cyclodextrin or 2-hydroxypropyl r-cyclodextrin, complex including an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non- toxic salt thereof, said complex being loaded into a liposome.
Preparation of the antiestrogen-2-hydroxypropyl cyclodextrin complexes;
A weighed amount of 2-hydroxypropyl cyclodextrin was dissolved into distilled water by shaking with a shaker. The so formed clear solution was equilibrated with a large excess of antiestrogen at the boiling point. After removing the almost clear solution the excess of antiestrogen started to precipitate. The solution was kept overnight at room temperature and the excess of precipitated antiestrogen was removed by centrif gatio .
Measurement by HPLC of the solubility of the anti-estrogen in an aqueous solution of 2-hydroxypropyl cyclodextrin.
The fully automated HPLC apparatus (Hewlett-Packard, USA) consisted of a pump 1090, an autosampler and autoinjector (79847A) with an injection volume of 10 ul and a fixed wavelength UV detector, 280 nm (79881A) . The chromatograms and peak areas were recorded with an integrator 3393. The separations were carried out at room temperature on a 35 * 4.6 mm stainless steel column (packed with 3-pm spherical octadecylsilanebonded silica particles; HS-3 C-18, (Perkin- Elmer, USA)
The mobile phase consisted of a mixture of acetonitrile : 0.05 aqueous phosphate buffer containing 0.004 M of dimethyloctyl amine with a pH of 7.4. The flow rate was 0.8 ml/min.
Preparation of the liposomes;
1) Liposomes based on cyclodextrin - drug complexes and prepared by dissolving the components in an organic solution
2-hydroxypropyl-β-cyclodextrin (12 mg), POPC (32 mg), choleste¬ rol (4 mg), DMPG (dimyristoylphosphatidylglycerol) (8 mg) and toremifene citrate (2 mg) were dissolved in choloroform - met¬ hanol (2:1) and evaporated. The residue was dissolved in water and homogenized by sonication (Labsonic U, 50 W) . The stability of the solution was good; no turbidity was observed after one month in room temperature.
2) Liposomes based on cyclodextrin - drug complexes and prepared by dissolving and homogenizing components directly in water
2-hydroxypropyl-β-cyclodextrin (24 mg), DMPG (dimyristo- ylphosphatidylglycerol) (16 mg) and toremifene citrate (2 mg) were simultaneously dissolved in 2 ml water and homogenized by sonication (Labsonic U, 50 W) . The final solution was as clear as the solution above. The mean particle diameter of these two solutions were about 100 n (Nicomp 370/HPL high power laser option). The solution was stable after one week storage at room temperature.
3) Liposomes which were not based on cyclodextrin complexes Preparation of these solutions was attempted by dissolving the components directly into water. The only composition which gave a clear or slightly opalescent solution was DMPG (16 or 32 mg) , toremifene citrate (2 mg) dissolved and homogenized by sonication (50 W) in 2 ml water. The stability of the solutions were not however good enough; solutions became a bit turbid in one month storage at room temperature, e.g., the composition toremifene citrate (2 mg) , DMPG (32 mg) and cholesterol (4 mg) was not able to dissolve and homogenized in 2 ml water.
These results indicate that stable liposomes cannot be achieved in the absence of a cyclodextrin component especially if the drug and phosphiolipid are mixed directly into water.
However, cyclodextrin-free liposomes can be made by mixing the ingredients first in chloroform/ thanol (2:1) as described above for the cyclodextrin-containing liposomes.
Solubility results
Formulation Toremifene solubility m of toremifene
Figure imgf000009_0001
r-HPC = 2-hydroxypropyl-r-cyclodextrin
Tamoxifen solubility mg of tamoxifen ml of cyclodextrin-water soln.
500 mg β-HPC/ml of aqueous soln 67
250 43
125 23
63 13
25 6 0 < 1
Desmethyl toremifene solubility mg of desmethyl toremifene ml of cyclodextrin-water soln.
125 mg β-HPC/ml of aqueous soln. 21.0
The pharmacokinetics of the toremifene formulations described above, when give intravenously, resemble closely those of perorally given toremifene. However, during the first minutes and 1-2 hours the concentrations of the intravenously given drug are high, while the drug, when given per os, has not yet been absorbed completely from the gastrointestinal tract. Preparation of emulsions:
Emulsions prepared by dissolving the drug in a commercial fat emulsion.
The commercial fat emulsion used was Emulsan® 20 % (manufacturer Leiras-Kabi Infusion Ltd., Finland) . Different amounts of toremifene citrate were dissolved in Emulsan solution and homogenized by sonication (Labsonic U, 50 W) . The toremifene concentrations were 10 mg/ml, 14 mg/ml and 20 mg/ml. After the homogenization the samples were filtered through the 0.2 μ , 0.45 μm and 1.2 μm filters.
The concentration of toremifene was determined from the filtrate with a spectrofotometric method using the wave length of 278 nm. The samples were dissolved in methanol and diluted in the concentration of 0.02 mg/ml.
The results are presented in the following table:
Figure imgf000010_0001
The results show that the solubility of toremifene can be increased considerably by encapsulating the toremifene in an emulsion droplet.

Claims

Claims
A parenteral drug preparation in the form of an emulsion or liposome of an active drug substance selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof.
A preparation according to claim 1 where the drug is toremifene or its non-toxic, pharmaceutically acceptable salt.
A parenteral drug formulation comprising an aqueous solution of a complex which comprises a 2-hydroxypropyl cyclodextrin component and an active drug component in which the active drug is selected from the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyl tamoxifen or a pharmaceutically acceptable non-toxic salt thereof.
A formulation according to claim 3 where the 2- hydroxypropyl cyclodextrin component is 2- hydroxypropyl-β-cyclodextrin.
A formulation according to claim 3 where the 2- hydroxypropyl cyclodextrin component is 2- hydroxypropyl-r-cyclodextrin.
A formulation according to claim 3 to 5 where the drug is toremifene or its non-toxic pharmaceutically acceptable salt.
A parental drug formulation comprising an emulsion or liposome comprising a complex which comprises a 2-hydroxypropyl cyclodextrin component and an active . drug component in which the active drug is selected fr the group consisting of toremifene, desmethyl toremifene, tamoxifen and desmethyltamoxifen or a pharmaceutically acceptable non-toxic salt thereof.
8. A formulation according to claim 7 where the 2- hydroxypropyl cyclodextrin component is 2- hydroxypropyl-β-cyclodextrin.
9. A formulation according to claim 7 or 8 where the drug is toremifene or its non-toxic pharmaceutically acceptable salt.
10. A method of treatment of an estrogen-dependent tumor in a mammal comprising administering parenterally to said mammal an amount of a formulation as claimed in claim 1 sufficient to produce the desired effect.
11. A method of treatment of an estrogen-dependent tumor in a mammal comprising administering parenterally to said mammal an amount of a formulation as claimed in claim 3 sufficient to produce the desired effect.
12. A method of treatment of an estrogen-dependent tumor in a mammal comprising administering parenterally to said mammal an amount of a formulation as claimed in claim 6 sufficient to produce the desired effect.
PCT/FI1992/000339 1991-12-10 1992-12-10 Drug formulations for parenteral use WO1993011757A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
DE69218241T DE69218241T2 (en) 1991-12-10 1992-12-10 MEDICINE FORMULATION FOR PARENTERAL USE
US08/244,549 US5571534A (en) 1991-12-10 1992-12-10 Drug formulations for parenteral use
JP51065093A JP3558344B2 (en) 1991-12-10 1992-12-10 Parenteral drug formulations
CA002125408A CA2125408C (en) 1991-12-10 1992-12-10 Drug formulations for parenteral use
AU31599/93A AU667861B2 (en) 1991-12-10 1992-12-10 Drug formulations for parenteral use
EP93900114A EP0616529B1 (en) 1991-12-10 1992-12-10 Drug formulations for parenteral use
NO942155A NO308578B1 (en) 1991-12-10 1994-06-09 Parenteral drug preparation
FI942728A FI942728A0 (en) 1991-12-10 1994-06-10 Pharmaceutical compositions for parenteral use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919126209A GB9126209D0 (en) 1991-12-10 1991-12-10 Drug formulations for parenteral use
GB9126209.7 1991-12-10

Publications (1)

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WO1993011757A1 true WO1993011757A1 (en) 1993-06-24

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Country Status (11)

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US (1) US5571534A (en)
EP (1) EP0616529B1 (en)
JP (1) JP3558344B2 (en)
AT (1) ATE149828T1 (en)
AU (1) AU667861B2 (en)
CA (1) CA2125408C (en)
DE (1) DE69218241T2 (en)
GB (1) GB9126209D0 (en)
NO (1) NO308578B1 (en)
WO (1) WO1993011757A1 (en)
ZA (1) ZA929592B (en)

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EP0616529A1 (en) 1994-09-28
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JP3558344B2 (en) 2004-08-25
NO942155L (en) 1994-06-10
AU667861B2 (en) 1996-04-18
AU3159993A (en) 1993-07-19
GB9126209D0 (en) 1992-02-12
ATE149828T1 (en) 1997-03-15
CA2125408A1 (en) 1993-06-23
EP0616529B1 (en) 1997-03-12
ZA929592B (en) 1993-08-06
CA2125408C (en) 2004-04-20
DE69218241D1 (en) 1997-04-17
US5571534A (en) 1996-11-05
NO308578B1 (en) 2000-10-02

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