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WO1996034626A1 - Composition of tyrosine and polymerised allergen - Google Patents

Composition of tyrosine and polymerised allergen Download PDF

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Publication number
WO1996034626A1
WO1996034626A1 PCT/EP1996/001733 EP9601733W WO9634626A1 WO 1996034626 A1 WO1996034626 A1 WO 1996034626A1 EP 9601733 W EP9601733 W EP 9601733W WO 9634626 A1 WO9634626 A1 WO 9634626A1
Authority
WO
WIPO (PCT)
Prior art keywords
allergen
tyrosine
solution
polymerised
composition according
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/EP1996/001733
Other languages
French (fr)
Inventor
Alan Worland Wheeler
Iain Taylor
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.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 NZ308080A priority Critical patent/NZ308080A/en
Priority to BR9608123A priority patent/BR9608123A/en
Priority to HK98112143.4A priority patent/HK1010834B/en
Priority to SK1461-97A priority patent/SK281877B6/en
Priority to EP96914124A priority patent/EP0825874A1/en
Priority to MX9708336A priority patent/MX9708336A/en
Priority to PL96323104A priority patent/PL183484B1/en
Priority to AU57616/96A priority patent/AU705873B2/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to JP8532981A priority patent/JPH11504338A/en
Priority to EA199700271A priority patent/EA199700271A1/en
Publication of WO1996034626A1 publication Critical patent/WO1996034626A1/en
Priority to NO974893A priority patent/NO974893L/en
Priority to BG102004A priority patent/BG63990B1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A61K39/36—Allergens from pollen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • This invention relates to novel compositions for use in desensitisation therapy of allergy sufferers.
  • GB-A-1 492 973 describes a process for preparing coprecipitates of tyrosine having a modified allergen dispersed therein.
  • the allergen has been modified by treatment with an agent, such as glutaraldehyde, which causes intra-molecular cross- linking and reduces the allergenicity of the product relative to the unmodified allergen.
  • EP-A-0 367 306 and Nakada et al describe processes for preparing polymerised allergens by prolonged treatment with a cross- linking agent to cause intermolecular cross-linking, followed by filtration or dialysis to remove unpolymerised product.
  • the polymerised allergens are described as having reduced allergenicity.
  • a pharmaceutical composition comprising tyrosine and a polymerised allergen.
  • the allergen is coated with and /or adsorbed onto tyrosine, for example by co-precipitation.
  • the allergen may be derived from any allergy causing substance, such as a pollen (e.g. ragweed or birch pollen), food, insect venom, mould, animal fur, or house dust mite (D. farinae or D. pteronyssinus).
  • a pollen e.g. ragweed or birch pollen
  • food insect venom, mould, animal fur, or house dust mite
  • D. farinae or D. pteronyssinus derived from D. pteronyssinus.
  • allergen includes a mixture of allergens which may be from a single source or more than one source.
  • a further aspect of the invention provides a process for the preparation of a pharmaceutical composition in accordance with the invention, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier.
  • physiologically acceptable carriers include phenol-saline and sterile water.
  • the allergen is polymerised by treatment with a dialdehyde such as glutaraldehyde, in aqueous solution at a pH of 3 to 10, typically 7*1 and a temperature of between 0 and 100 °C, typically between 4 and 37 °C. for up to 10 hours, for example about two hours at room temperature.
  • a dialdehyde such as glutaraldehyde
  • the ratio of allergen to glutaraldehyde is typically in the range 1:25 to 1:2, for example about 1 :4 w/w, although higher allergen ratios may be used in conjunction with a longer reaction time (see for instance EP-A-0 367 306, which uses ratios of about 3:1 and a reaction time of about seven hours).
  • Low molecular weight product is then removed by gel filtration or dialysis, for example, tangential flow dialysis, and the product freeze dried or used directly in the next stage.
  • the molecular weight cut off is typically at least 100 kDaltons, for example at least 250 kDaltons, more preferably 300 kDaltons.
  • a solution of the polymerised allergen at pH 7 ⁇ 1, obtained either as the reaction mixture from the polymerisation process or from the solvation of a solid, is then mixed with a solution of tyrosine in a strong aqueous acid.
  • the strong acid is usually an inorganic acid, preferably hydrochloric acid.
  • the solution of polymerised allergen used in this step typically contains between 0.1 ⁇ g ml and 100 ⁇ g/ml allergen protein.
  • the ratio of allergen: tyrosine in the mixture is typically in the range 1:4 x 10 5 to 1:4 x 10 2 w/w.
  • the resulting mixture of solutions of allergen and tyrosine is neutralised.
  • neutralisation is meant an adjustment of pH to a value within the range 4.0 to 7.5. It is important that, at no time, or at least at no prolonged time, during the neutralisation does the pH of the solution rise appreciably above 7.5. This condition can be met by vigorous stirring of the solution and by the use only of the required amount of base, if desired.
  • Various buffering agents can usefully be added to the solutions of allergen to assist in pH control during the mixing and neutralising stages.
  • a particularly useful method of carrying out the neutralisation is for separate streams of the solution of tyrosine in acid and the neutralising base to be run into the solution of allergen.
  • the rates of flow of the added solutions are controlled by pH- state, that is by equipment which regulates the flow of one or both of the solutions so that the pH of the reaction mixture remains substantially constant at a predetermined level.
  • pH- state that is by equipment which regulates the flow of one or both of the solutions so that the pH of the reaction mixture remains substantially constant at a predetermined level.
  • the result of the neutralisation is the immediate precipitation of the tyrosine, within and or upon which the solution of allergen is occluded and/or adsorbed.
  • the mixture is either washed immediately or allowed to stand for a period of from a few hours to a day or two prior to washing.
  • the precipitate is obtained as fine as possible and this is achieved by rapid neutralisation of the solution coupled with vigorous agitation while this is being carried out.
  • the resulting precipitate may be removed from the solution by centrifugation or filtration and washed, e.g. with phenol-saline, before being resuspended in a physiologically-acceptable carrier such as phenol-saline, or sterile water, to produce an injectable composition suitable for use in desensitisation therapy.
  • a physiologically-acceptable carrier such as phenol-saline, or sterile water
  • Example 1 illustrates the present invention.
  • a neutral solution of approximately 2.5 mg/ml D. pteronyssinus extract protein which had been partially purified by dialysis or fractionation was polymerised by the addition of an equal volume of 1% w/v glutaraldehyde and the mixture stirred for approximately 2 hours at room temperature. The reaction was quenched by the addition of an equal volume of 2% w/v glycine and the mixture stirred for a further one hour at room temperature. Low molecular weight material was removed by diafiltration across a membrane with a molecular weight exclusion of 300 kDaltons. The mixture was then sterile filtered and freeze dried.
  • a solution of the polymerised allergen was prepared either directly from the sterile filtered solution or by reconstitution of the freeze dried solid. This solution contained lO ⁇ g/ml in phosphate buffer pH 7 ⁇ 1.
  • the allergen solution was co- precipitated with tyrosine by the simultaneous addition of one volume of L-tyrosine in HCl (prepared by dissolving 24g L-tyrosine to 100ml with 3.4M HCl) and one volume of 3.2M NaOH, to four volumes of allergen solution, with vigorous agitation.
  • the suspension so formed was centrifuged, washed repeatedly with buffered saline to remove contaminants and resuspended to the original volume in buffered saline pH6 ⁇ 1.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A pharmaceutical composition comprising tyrosine and a polymerised allergen is prepared by (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier.

Description

COMPOSITION OF TYROSINE AND POLYMERISED ALLERGEN
This invention relates to novel compositions for use in desensitisation therapy of allergy sufferers.
GB-A-1 492 973 describes a process for preparing coprecipitates of tyrosine having a modified allergen dispersed therein. The allergen has been modified by treatment with an agent, such as glutaraldehyde, which causes intra-molecular cross- linking and reduces the allergenicity of the product relative to the unmodified allergen.
EP-A-0 367 306 and Nakada et al (Allergy, 54 [1985] 437 et seq.) describe processes for preparing polymerised allergens by prolonged treatment with a cross- linking agent to cause intermolecular cross-linking, followed by filtration or dialysis to remove unpolymerised product. The polymerised allergens are described as having reduced allergenicity.
According to the present invention there is provided a pharmaceutical composition comprising tyrosine and a polymerised allergen. Typically, the allergen is coated with and /or adsorbed onto tyrosine, for example by co-precipitation.
The allergen may be derived from any allergy causing substance, such as a pollen (e.g. ragweed or birch pollen), food, insect venom, mould, animal fur, or house dust mite (D. farinae or D. pteronyssinus). In a particular aspect the allergen is derived from D. pteronyssinus. As used herein, "allergen" includes a mixture of allergens which may be from a single source or more than one source.
A further aspect of the invention provides a process for the preparation of a pharmaceutical composition in accordance with the invention, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier. Suitable physiologically acceptable carriers include phenol-saline and sterile water.
The allergen is polymerised by treatment with a dialdehyde such as glutaraldehyde, in aqueous solution at a pH of 3 to 10, typically 7*1 and a temperature of between 0 and 100 °C, typically between 4 and 37 °C. for up to 10 hours, for example about two hours at room temperature. The ratio of allergen to glutaraldehyde is typically in the range 1:25 to 1:2, for example about 1 :4 w/w, although higher allergen ratios may be used in conjunction with a longer reaction time (see for instance EP-A-0 367 306, which uses ratios of about 3:1 and a reaction time of about seven hours). Low molecular weight product is then removed by gel filtration or dialysis, for example, tangential flow dialysis, and the product freeze dried or used directly in the next stage. The molecular weight cut off is typically at least 100 kDaltons, for example at least 250 kDaltons, more preferably 300 kDaltons. A solution of the polymerised allergen at pH 7±1, obtained either as the reaction mixture from the polymerisation process or from the solvation of a solid, is then mixed with a solution of tyrosine in a strong aqueous acid. The strong acid is usually an inorganic acid, preferably hydrochloric acid. The solution of polymerised allergen used in this step typically contains between 0.1 μg ml and 100 μg/ml allergen protein. The ratio of allergen: tyrosine in the mixture is typically in the range 1:4 x 105 to 1:4 x 102 w/w.
The resulting mixture of solutions of allergen and tyrosine is neutralised. By neutralisation is meant an adjustment of pH to a value within the range 4.0 to 7.5. It is important that, at no time, or at least at no prolonged time, during the neutralisation does the pH of the solution rise appreciably above 7.5. This condition can be met by vigorous stirring of the solution and by the use only of the required amount of base, if desired. Various buffering agents can usefully be added to the solutions of allergen to assist in pH control during the mixing and neutralising stages.
A particularly useful method of carrying out the neutralisation is for separate streams of the solution of tyrosine in acid and the neutralising base to be run into the solution of allergen. The rates of flow of the added solutions are controlled by pH- state, that is by equipment which regulates the flow of one or both of the solutions so that the pH of the reaction mixture remains substantially constant at a predetermined level. We have found that optimum results are usually obtained by pH control within the range 6.5 to 7.5 though the precise pH may vary according to the nature of the allergen.
The result of the neutralisation is the immediate precipitation of the tyrosine, within and or upon which the solution of allergen is occluded and/or adsorbed. After the precipitation the mixture is either washed immediately or allowed to stand for a period of from a few hours to a day or two prior to washing. Desirably the precipitate is obtained as fine as possible and this is achieved by rapid neutralisation of the solution coupled with vigorous agitation while this is being carried out.
The resulting precipitate may be removed from the solution by centrifugation or filtration and washed, e.g. with phenol-saline, before being resuspended in a physiologically-acceptable carrier such as phenol-saline, or sterile water, to produce an injectable composition suitable for use in desensitisation therapy.
The following Example illustrates the present invention: Example
A neutral solution of approximately 2.5 mg/ml D. pteronyssinus extract protein which had been partially purified by dialysis or fractionation was polymerised by the addition of an equal volume of 1% w/v glutaraldehyde and the mixture stirred for approximately 2 hours at room temperature. The reaction was quenched by the addition of an equal volume of 2% w/v glycine and the mixture stirred for a further one hour at room temperature. Low molecular weight material was removed by diafiltration across a membrane with a molecular weight exclusion of 300 kDaltons. The mixture was then sterile filtered and freeze dried.
A solution of the polymerised allergen was prepared either directly from the sterile filtered solution or by reconstitution of the freeze dried solid. This solution contained lOμg/ml in phosphate buffer pH 7±1. The allergen solution was co- precipitated with tyrosine by the simultaneous addition of one volume of L-tyrosine in HCl (prepared by dissolving 24g L-tyrosine to 100ml with 3.4M HCl) and one volume of 3.2M NaOH, to four volumes of allergen solution, with vigorous agitation. The suspension so formed was centrifuged, washed repeatedly with buffered saline to remove contaminants and resuspended to the original volume in buffered saline pH6 ±1.

Claims

Claims
1. A pharmaceutical composition comprising tyrosine and a polymerised allergen.
2. A composition according to claim 1 wherein the allergen is coated with and/or adsorbed onto tyrosine.
3. A composition according to claim 1 or 2 wherein the allergen is derived from D. pteronyssinus.
4. A process for the preparation of a pharmaceutical composition according to any one of the preceding claims, which process comprises (a) polymerising an allergen, (b) mixing an aqueous solution of the allergen with a solution of tyrosine in a strong aqueous acid, (c) neutralising the mixture of solutions, thereby co-precipitating tyrosine and polymerised allergen, and (d) optionally, mixing the product with a physiologically acceptable carrier.
5. A composition according to any one of claims 1 to 3, for use in therapy.
6. A composition according to any one of claims 1 to 3, for use in desensitization therapy of allergy sufferers.
7. Use of a composition according to any one of claims 1 to 3 in the manufacture of a medicament for use in desensitization therapy of allergy sufferers.
PCT/EP1996/001733 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen Ceased WO1996034626A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
PL96323104A PL183484B1 (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen
HK98112143.4A HK1010834B (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen
SK1461-97A SK281877B6 (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen, method for its production and its use
EP96914124A EP0825874A1 (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen
MX9708336A MX9708336A (en) 1996-04-25 1996-04-25 Composition of tyrosine and polymerised allergen.
AU57616/96A AU705873B2 (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen
JP8532981A JPH11504338A (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerized allergen
NZ308080A NZ308080A (en) 1995-04-29 1996-04-25 Composition containing tyrosine and a polymerised allergen
BR9608123A BR9608123A (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerized allergen
EA199700271A EA199700271A1 (en) 1995-04-29 1996-04-25 COMPOSITIONS CONTAINING FROM TYROSINE AND POLYMERIZED ALLERGEN
NO974893A NO974893L (en) 1995-04-29 1997-10-23 Preparation of tyrosine and polymerized allergen
BG102004A BG63990B1 (en) 1995-04-29 1997-10-29 Pharmaceutical compound, method for its preparation and appliication thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9508785.4A GB9508785D0 (en) 1995-04-29 1995-04-29 Novel compositions
GB9508785.4 1995-04-29

Publications (1)

Publication Number Publication Date
WO1996034626A1 true WO1996034626A1 (en) 1996-11-07

Family

ID=10773769

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/001733 Ceased WO1996034626A1 (en) 1995-04-29 1996-04-25 Composition of tyrosine and polymerised allergen

Country Status (19)

Country Link
EP (1) EP0825874A1 (en)
JP (1) JPH11504338A (en)
KR (1) KR19990008120A (en)
CN (1) CN1132629C (en)
AU (1) AU705873B2 (en)
BG (1) BG63990B1 (en)
BR (1) BR9608123A (en)
CA (1) CA2217388A1 (en)
CZ (1) CZ288401B6 (en)
EA (1) EA199700271A1 (en)
GB (1) GB9508785D0 (en)
HU (1) HUP9802237A3 (en)
NO (1) NO974893L (en)
NZ (1) NZ308080A (en)
PL (1) PL183484B1 (en)
SK (1) SK281877B6 (en)
TR (1) TR199701265T1 (en)
WO (1) WO1996034626A1 (en)
ZA (1) ZA963340B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998044947A1 (en) * 1997-04-05 1998-10-15 Allergy Therapeutics Limited Allergen formulation
EP0988862A3 (en) * 1998-09-21 2001-06-20 Allergy Therapeutics Limited Formulation for use in immunisation
US8470331B2 (en) 2000-01-14 2013-06-25 Allergy Therapeutics (Uk) Limited Composition of antigen and glycolipid adjuvant for sublingual administration
US9731004B2 (en) 2011-04-21 2017-08-15 Allergy Therapeutics (Uk) Limited Process for preparing vaccine composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2145555A1 (en) * 1971-07-13 1973-02-23 Beecham Group Ltd
US4070455A (en) * 1974-02-16 1978-01-24 Beecham Group Limited Process for preparing injectable desensitizing compositions and products thereof in microparticle form
EP0058021A2 (en) * 1981-02-06 1982-08-18 Beecham Group Plc Pharmaceutical compositions
EP0367306A2 (en) * 1988-11-04 1990-05-09 Corporacion Biologica Farmaceutica, Sa (C.B.F. , S.A.) Procedure for polymerized allergenis production

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2145555A1 (en) * 1971-07-13 1973-02-23 Beecham Group Ltd
US4070455A (en) * 1974-02-16 1978-01-24 Beecham Group Limited Process for preparing injectable desensitizing compositions and products thereof in microparticle form
EP0058021A2 (en) * 1981-02-06 1982-08-18 Beecham Group Plc Pharmaceutical compositions
EP0367306A2 (en) * 1988-11-04 1990-05-09 Corporacion Biologica Farmaceutica, Sa (C.B.F. , S.A.) Procedure for polymerized allergenis production

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998044947A1 (en) * 1997-04-05 1998-10-15 Allergy Therapeutics Limited Allergen formulation
AU729631B2 (en) * 1997-04-05 2001-02-08 Allergy Therapeutics Limited Allergen formulation
JP2001519797A (en) * 1997-04-05 2001-10-23 アラージー・セラピューティックス・リミテッド Allergen prescription
US7718178B2 (en) 1997-04-05 2010-05-18 Allergy Therapeutics Limited Allergen formulation
US8105605B2 (en) 1997-04-05 2012-01-31 Allergy Therapeutics (Uk) Ltd. Allergen formulation
EP0988862A3 (en) * 1998-09-21 2001-06-20 Allergy Therapeutics Limited Formulation for use in immunisation
US6440426B1 (en) 1998-09-21 2002-08-27 Allergy Therapeutics Limited Antigen-containing formulation and methods of use thereof
US7815920B2 (en) 1998-09-21 2010-10-19 Allergy Therapeutics (UK) Ltd Method of preparing an antigen-containing formulation
US8470331B2 (en) 2000-01-14 2013-06-25 Allergy Therapeutics (Uk) Limited Composition of antigen and glycolipid adjuvant for sublingual administration
US9731004B2 (en) 2011-04-21 2017-08-15 Allergy Therapeutics (Uk) Limited Process for preparing vaccine composition

Also Published As

Publication number Publication date
SK281877B6 (en) 2001-08-06
CZ288401B6 (en) 2001-06-13
CN1183046A (en) 1998-05-27
GB9508785D0 (en) 1995-06-21
NO974893D0 (en) 1997-10-23
HUP9802237A2 (en) 1999-02-01
BG102004A (en) 1998-11-30
PL323104A1 (en) 1998-03-16
NO974893L (en) 1997-10-23
TR199701265T1 (en) 1998-02-21
CN1132629C (en) 2003-12-31
JPH11504338A (en) 1999-04-20
CZ342997A3 (en) 1998-03-18
AU5761696A (en) 1996-11-21
NZ308080A (en) 1999-05-28
HUP9802237A3 (en) 2000-06-28
SK146197A3 (en) 1998-05-06
ZA963340B (en) 1997-03-27
AU705873B2 (en) 1999-06-03
KR19990008120A (en) 1999-01-25
PL183484B1 (en) 2002-06-28
BG63990B1 (en) 2003-09-30
EP0825874A1 (en) 1998-03-04
CA2217388A1 (en) 1996-11-07
EA199700271A1 (en) 1998-04-30
HK1010834A1 (en) 1999-07-02
BR9608123A (en) 1999-02-09

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