WO1994012168A1 - Syrup containing n-acetyl-cysteine - Google Patents

Syrup containing n-acetyl-cysteine Download PDF

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Publication number
WO1994012168A1
WO1994012168A1 PCT/EP1993/003280 EP9303280W WO9412168A1 WO 1994012168 A1 WO1994012168 A1 WO 1994012168A1 EP 9303280 W EP9303280 W EP 9303280W WO 9412168 A1 WO9412168 A1 WO 9412168A1
Authority
WO
WIPO (PCT)
Prior art keywords
nac
solution
syrup
sodium
cysteine
Prior art date
Application number
PCT/EP1993/003280
Other languages
French (fr)
Inventor
Federico Stroppolo
Daniele Bonadeo
Alessandro Saudino
Annibale Gazzaniga
Original Assignee
Zambon Group S.P.A.
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 GB9509822A priority Critical patent/GB2288977B/en
Priority to AT0906093A priority patent/AT407113B/en
Priority to AU56266/94A priority patent/AU667611B2/en
Priority to MD96-0265A priority patent/MD1714G2/en
Priority to JP6512747A priority patent/JPH08503703A/en
Priority to NL9320052A priority patent/NL194957C/en
Priority to DE4396086T priority patent/DE4396086T1/en
Priority to HU9501586A priority patent/HU221484B/en
Priority to CA002150462A priority patent/CA2150462C/en
Application filed by Zambon Group S.P.A. filed Critical Zambon Group S.P.A.
Priority to RU95114406A priority patent/RU2108777C1/en
Priority to DE4396086A priority patent/DE4396086B3/en
Priority to CH2423/94A priority patent/CH685371A5/en
Priority to UA95062994A priority patent/UA27142C2/en
Priority to LU88618A priority patent/LU88618A1/en
Publication of WO1994012168A1 publication Critical patent/WO1994012168A1/en
Priority to DK199500614A priority patent/DK176247B1/en
Priority to NO19952183A priority patent/NO314018B1/en
Priority to SE9502001A priority patent/SE520834C2/en

Links

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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/12—Mucolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to a composition in the form of a syrup containing N-acetyl-cysteine as active ingredient .
  • NAC N-acetyl-cysteine
  • NAC In the treatment of cold diseases, NAC showed to be useful thanks TO its mucolytic properties.
  • One of the pharmaceutical forms largely used in the therapy of cold diseases is syrup, particularly suitable also for pediatric use.
  • NAC is available in several pharmaceutical forms, however the high reactivity of the molecule, the relative instability and the characteristic sulphureous smell and taste make extremely troublesome the achievement of liquid forms for oral use which are time-stable and with a good palatability.
  • the only syrup formulation containing NAC on the market consists in a composition to be prepared at the moment of use by dissolution in water of a granulate. After preparation, the extemporaneous syrup must be used within 3 weeks.
  • object of the present invention is a composition in the form of a syrup containing (each 100 ml) :
  • a thickening agent selected among: sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1 -A g/100 mi and optionally:
  • flavouring agent 0.1 -0.4 g/100 ml - a preservative 0.05-0.5 g/100 ml and further
  • the above solution results to be stable in a closed bottle under inert gas for at least 2 years under environmental conditions.
  • the solution shows to have a pleasant taste and to be free from bad smells; NAC maintains the initial titre and the open syrup results to be stable for at least 5 weeks.
  • sweetening agent we mean a substance able to give a sweet taste to the solution but wich does not contain sugars.
  • Specific examples of sweetening agents are saccharin, sodium saccharin and cyclamates or mixtures thereof.
  • the amount of sweetening agent will be the minimum amount sufficient to give a pleasant taste to the solution.
  • the thickening agent is selected among sodium carboxymethylcellulose methylcellulose and hydroxypropylmethylcellulose or mixtures thereof. Surprisingly, these substances showed to be compatible with
  • NAC sweetening agent
  • thickening agent water
  • NAC sweetening agent
  • sweetening agent a base component that can be added up to the selected volume, by optionally rectifying the resultant pH so that it is maintained within the interval from 5 to 8.
  • pH will be from 6.5 to 7.
  • the syrup could also, but not necessarily, contain a flavouring agent in order to improve the palatability, especially for pediatric use.
  • phar acopoeiae require the compulsory presence of a preservative.
  • the preservative is further required to assure the microbiological quality during the time of use by the patient.
  • preservatives selected among sodium benzoate, methyl • -hydroxybenzoate, propyl •.-hydroxybenzoate and mixtures thereof will be preferably used.
  • preservatives selected among sodium benzoate, methyl • -hydroxybenzoate, propyl •.-hydroxybenzoate and mixtures thereof.
  • sodium EDTA could be used in addition to or in partial substitution of the above preservatives.
  • the preparation of the syrup according to the present invention is carried out under inert gas by simple dissolution of the substances in the predetermined amount of water.
  • the resultant solution is shared into multidose bottles or in single-dose containers.
  • the packaging of multi-dose bottles could provide the contemporaneous supplying of a graduated measure for the correct dosage of the single doses for grown-up people (for example 10 ml) or for children - A -
  • Water q.s. to 100 ml were prepared by simple dissolution of the substances in purified and de-aerated water under nitrogen atmosphere.
  • the solution was shared at the rate of 150 ml/bottle.
  • the syrup also after 2 years of storage, showed to have a pleasant taste and smell and a good general palatability.
  • Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and de-aerated water, under nitrogen atmosphere.
  • the pH of the solution was rectified to pH 6.5 with sodium hydroxide.
  • Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and de-aerated water, under nitrogen atmosphere.
  • the pH of the solution was rectified to pH 6.5 with sodium hydroxide.
  • the solution was shared into single-dose glass vials of 10 ml with rubber stopper each containing about 200 mg of NAC.
  • Example 4 By working as described in Example 1, 10 1 of syrup having the following composition (each 100 ml) were prepared: NAC 4.2 g
  • the pH of the solution was rectified to pH 6.5 with sodium hydroxide.
  • the solution was shared into bottles at the rate of 150 ml each bottle.
  • Example 5 By working as described in Example 2, 10 1 of syrup having the following composition (each 100 ml) were prepared: NAC 2.10 g
  • the pH of the solution was rectified to pH 7 with sodium hydroxide.
  • the solution was shared into bottles at the rate of 450 ml each bottle.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Jellies, Jams, And Syrups (AREA)
  • Food Preservation Except Freezing, Refrigeration, And Drying (AREA)

Abstract

A syrup containing N-acetyl-cysteine, stable for at least two years, having pleasant taste and smell, consists of an aqueous solution of NAC, a sweetening agent and a thickening agent. The solution can also contain a flavouring agent and a preservative. The pH is between 5 and 8.

Description

SYRUP CONTAINING N-ACETYL-CYSTEINE The present invention relates to a composition in the form of a syrup containing N-acetyl-cysteine as active ingredient .
N-acetyl-cysteine (hereinafter briefly referred to as NAC) is a compound endowed with several useful pharmacological properties, making it a widely used drug. •
In the treatment of cold diseases, NAC showed to be useful thanks TO its mucolytic properties.
One of the pharmaceutical forms largely used in the therapy of cold diseases is syrup, particularly suitable also for pediatric use.
NAC is available in several pharmaceutical forms, however the high reactivity of the molecule, the relative instability and the characteristic sulphureous smell and taste make extremely troublesome the achievement of liquid forms for oral use which are time-stable and with a good palatability.
The preparation of a syrup provides, practically in ail the cases, the use of a disaccharide (sucrose) or of a simple sugar as a sweetening and thickening agent of the aqueous solution of the drug. However, the interaction of NAC with sugars gives to the solution an unacceptable brown colouring and the titre of NAC decreases.
Thus, it is not possible to leave NAC in solution for a long time in the presence of sucrose.
Similarly, the reactions giving brown colour and causing bad smell take place also between NAC and the monosaccharides whose use is described in the French patent application No. 2631831 in the name of Calco Anstalt.
As far as we know, the only syrup formulation containing NAC on the market consists in a composition to be prepared at the moment of use by dissolution in water of a granulate. After preparation, the extemporaneous syrup must be used within 3 weeks.
We have now surprisingly found that it is possible to prepare a time-stable NAC syrup having a pleasant taste without using sugars.
Therefore, object of the present invention is a composition in the form of a syrup containing (each 100 ml) :
- N-acetyl-cysteine 2 -4.2 g/100 ml
- a sweetening agent 0.02-0.3 g/100 ml
- a thickening agent selected among: sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1 -A g/100 mi and optionally:
- a flavouring agent 0.1 -0.4 g/100 ml - a preservative 0.05-0.5 g/100 ml and further
- water q.s. to 100 ml pH being settled within the interval 5-8.
The above solution results to be stable in a closed bottle under inert gas for at least 2 years under environmental conditions. When the bottle is opened, the solution shows to have a pleasant taste and to be free from bad smells; NAC maintains the initial titre and the open syrup results to be stable for at least 5 weeks.
For sweetening agent we mean a substance able to give a sweet taste to the solution but wich does not contain sugars. Specific examples of sweetening agents are saccharin, sodium saccharin and cyclamates or mixtures thereof.
The amount of sweetening agent will be the minimum amount sufficient to give a pleasant taste to the solution. The thickening agent is selected among sodium carboxymethylcellulose methylcellulose and hydroxypropylmethylcellulose or mixtures thereof. Surprisingly, these substances showed to be compatible with
NAC and to be able to give to the solution a thickness suitable for ς the usual palatability of a syrup.
To these three base components (NAC, sweetening agent and thickening agent) water can be added up to the selected volume, by optionally rectifying the resultant pH so that it is maintained within the interval from 5 to 8. Preferably, pH will be from 6.5 to 7. The syrup could also, but not necessarily, contain a flavouring agent in order to improve the palatability, especially for pediatric use.
Since the syrup is generally manufactured in absence of asepsis, phar acopoeiae require the compulsory presence of a preservative. The preservative is further required to assure the microbiological quality during the time of use by the patient.
In this case, preservatives selected among sodium benzoate, methyl • -hydroxybenzoate, propyl •.-hydroxybenzoate and mixtures thereof will be preferably used. With the double function of preservative and of metal chelating agent also sodium EDTA could be used in addition to or in partial substitution of the above preservatives.
The preparation of the syrup according to the present invention is carried out under inert gas by simple dissolution of the substances in the predetermined amount of water.
The resultant solution is shared into multidose bottles or in single-dose containers.
The packaging of multi-dose bottles could provide the contemporaneous supplying of a graduated measure for the correct dosage of the single doses for grown-up people (for example 10 ml) or for children - A -
( for example 5 ml ) .
In order to better illustrate the present invention the following examples are now given. ς
Example 1
10 liters of a syrup containing (each 100 ml):
NAC 2.1 g
Saccharin 0.04 g
Sodium carboxymethylcellulose 0.2 g Sodium benzoate 0.15 g
Sodium edetate 0.1 g
Raspberry flavour 0.25 g
Water q.s. to 100 ml were prepared by simple dissolution of the substances in purified and de-aerated water under nitrogen atmosphere.
The pH of the resultant solution was rectified to the correct value
6.5 by addition of sodium hydroxide.
The solution was shared at the rate of 150 ml/bottle.
The bottles were stored for 2 years at room temperature. After this period, the titre of NAC resulted to be higher than 95% of the initial one.
Such a titre resulted to be higher than 90% of the initial one also after 5 weeks from the opening of the bottle.
The syrup, also after 2 years of storage, showed to have a pleasant taste and smell and a good general palatability.
Example 2
10 1 of a syrup having the following composition (each 100 ml):
NAC 2.1 g
Sodium saccharin 0.04 g
Hydroxypropyl ethylcellulose 0.2 g Methyl 4-hydroxybenzoate 0.1 g Sodium edetate 0.1 g
Apricot flavour 0.1 g
Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and de-aerated water, under nitrogen atmosphere.
The pH of the solution was rectified to pH 6.5 with sodium hydroxide.
The solution was shared into single-dose sachets of 10 ml each containing about 200 mg of NAC. Example 3
10 1 of a syrup having the following composition (each 100 ml):
NAC 2.1 g
Sodium saccharin 0.04 g
Hydroxypropylmethylcellulose 0.2 g Sodium edetate 0.1 g
Apricot flavour 0.1 g
Water q.s. to 100 ml were prepared by dispersion of hydroxypropylmethylcellulose in a part of boiling water which was cooled to room temperature. After hydration of hydroxypropylmethylcellulose, it was poured into a solution obtained by dissolving all the remaining substances in purified and de-aerated water, under nitrogen atmosphere.
The pH of the solution was rectified to pH 6.5 with sodium hydroxide. The solution was shared into single-dose glass vials of 10 ml with rubber stopper each containing about 200 mg of NAC.
Example 4 By working as described in Example 1, 10 1 of syrup having the following composition (each 100 ml) were prepared: NAC 4.2 g
Sodium saccharin 0.08 g
Sodium carboxymethylcellulose 0.20 g Sodium benzoate 0.15 g
Sodium edetate 0.10 g
Raspberry flavour 0.4 g
Water q.s. to 100 ml
The pH of the solution was rectified to pH 6.5 with sodium hydroxide.
The solution was shared into bottles at the rate of 150 ml each bottle.
Example 5 By working as described in Example 2, 10 1 of syrup having the following composition (each 100 ml) were prepared: NAC 2.10 g
Saccharin 0.04 g
Hydroxypropylmethylcellulose 0.40 g Methyl 4-hydroxybenzoate 0.10 g Banana flavour 0.4 g Water q.s. to 100 ml
The pH of the solution was rectified to pH 7 with sodium hydroxide. The solution was shared into bottles at the rate of 450 ml each bottle.

Claims

Claims
1) A composition in the form of a syrup containing (each 100 mi):
- N-acetyl-cysteine 2 -4.2 g/100 mi
5 - a sweetening agent 0.02-0.3 g/100 mi
- a thickening agent selected among: sodium carboxymethylcellulose and hydroxypropylmethylcellulose or mixtures thereof 0.1 -4 g/100 mi
10 and optionally:
- a flavouring agent 0.1 -0.4 g/100 mi
- a preservative 0.05-0.5 g/100 ml and further
- water q.s. to 100 ml
•5 pH being settled within the interval 5-8.
2) A composition according to claim 1 wherein the sweetening agent is selected among saccharin, sodium saccharin, cyclamates or mixtures thereof.
3) A composition according to claim 1 wherein the preservative is 0 selected among sodium edetate, sodium benzoate, methyl
4-hydroxybenzoate, propyl 4-hydroxybenzoate and mixtures thereof.
4) A composition according to claim 1 wherein the pH is between 6.5 and 7.
5
0
PCT/EP1993/003280 1992-12-02 1993-11-23 Syrup containing n-acetyl-cysteine WO1994012168A1 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
CA002150462A CA2150462C (en) 1992-12-02 1993-11-23 Syrup containing n-acetyl-cysteine
AU56266/94A AU667611B2 (en) 1992-12-02 1993-11-23 Syrup containing N-acetyl-cysteine
RU95114406A RU2108777C1 (en) 1992-12-02 1993-11-23 Curative composition as a syrup
JP6512747A JPH08503703A (en) 1992-12-02 1993-11-23 Syrup containing N-acetyl cysteine
NL9320052A NL194957C (en) 1992-12-02 1993-11-23 N-acetyl-cysteine-containing syrup.
DE4396086T DE4396086T1 (en) 1992-12-02 1993-11-23 Syrup with N-acetylcysteine
HU9501586A HU221484B (en) 1992-12-02 1993-11-23 Syrup containing n-acetyl-cysteine
GB9509822A GB2288977B (en) 1992-12-02 1993-11-23 Stable sweetened solutions of N-acetyl-cysteine
MD96-0265A MD1714G2 (en) 1992-12-02 1993-11-23 Therapeutical composition in the form of syrup, containing N-acetylcysteine
AT0906093A AT407113B (en) 1992-12-02 1993-11-23 COMPOSITION IN THE FORM OF AN AQUEOUS THICKENED PREPARATION FOR PERORAL ADMINISTRATION WITH N-ACETYLCYSTONE
DE4396086A DE4396086B3 (en) 1992-12-02 1993-11-23 Syrup with N-acetylcysteine
CH2423/94A CH685371A5 (en) 1992-12-02 1993-11-23 Syrup contg. N-acetyl cysteine for treating colds
UA95062994A UA27142C2 (en) 1992-12-02 1993-11-23 Pharmaceutical composition
LU88618A LU88618A1 (en) 1992-12-02 1994-05-24 Syrup with N-acetylcysteine
DK199500614A DK176247B1 (en) 1992-12-02 1995-05-31 Syrup containing N-acetylcysteine
NO19952183A NO314018B1 (en) 1992-12-02 1995-06-01 Syrup containing N-acetyl-cysteine
SE9502001A SE520834C2 (en) 1992-12-02 1995-06-01 Syrup containing N-acetylcysteine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI92A002758 1992-12-02
ITMI922758A IT1256616B (en) 1992-12-02 1992-12-02 SYRUP CONTAINING N-ACETYL-CISTEIN

Publications (1)

Publication Number Publication Date
WO1994012168A1 true WO1994012168A1 (en) 1994-06-09

Family

ID=11364395

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1993/003280 WO1994012168A1 (en) 1992-12-02 1993-11-23 Syrup containing n-acetyl-cysteine

Country Status (23)

Country Link
JP (1) JPH08503703A (en)
AT (1) AT407113B (en)
AU (1) AU667611B2 (en)
BE (1) BE1006799A3 (en)
CA (1) CA2150462C (en)
CH (1) CH685371A5 (en)
CZ (1) CZ282550B6 (en)
DE (2) DE4396086T1 (en)
DK (1) DK176247B1 (en)
ES (1) ES2070806B1 (en)
FR (1) FR2698545B1 (en)
GB (1) GB2288977B (en)
HU (2) HU221484B (en)
IT (1) IT1256616B (en)
LU (1) LU88618A1 (en)
MD (1) MD1714G2 (en)
NL (1) NL194957C (en)
NO (1) NO314018B1 (en)
NZ (1) NZ258544A (en)
RU (1) RU2108777C1 (en)
SE (1) SE520834C2 (en)
UA (1) UA27142C2 (en)
WO (1) WO1994012168A1 (en)

Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN102233139A (en) * 2010-04-21 2011-11-09 重庆健能医药开发有限公司 Acetylcysteine effervescent tablet and preparation method and application thereof

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ATE210975T1 (en) * 1994-06-23 2002-01-15 Procter & Gamble TOPICAL PREPARATIONS CONTAINING N-ACETYL-L-CYSTEIN
JP4501023B2 (en) * 2002-11-14 2010-07-14 小林製薬株式会社 Composition with reduced bitterness and odor of cysteines
JP4501024B2 (en) * 2002-11-14 2010-07-14 小林製薬株式会社 Composition with reduced bitterness and odor of cysteines
US8148356B2 (en) * 2005-08-24 2012-04-03 Cumberland Pharmaceuticals, Inc. Acetylcysteine composition and uses therefor
RU2611411C1 (en) * 2016-01-11 2017-02-21 Общество с ограниченной ответственностью "Трейдсервис" Dispersible in water acetylcysteine tablet and method of manufacturing thereof

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GB2192789A (en) * 1986-07-24 1988-01-27 Inpharzam Int Sa Acetylcysteine compositions
GB2192790A (en) * 1986-07-24 1988-01-27 Inpharzam Int Sa Acetylcysteine compositions
FR2631831A1 (en) * 1988-05-31 1989-12-01 Calco Anstalt Syrups based on xylitol, ribitol or arabitol
GB2234171A (en) * 1989-07-27 1991-01-30 Zambon Spa Composition containing N-acetyl-cysteine of enhanced bioavailability

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102233139A (en) * 2010-04-21 2011-11-09 重庆健能医药开发有限公司 Acetylcysteine effervescent tablet and preparation method and application thereof

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UA27142C2 (en) 2000-02-28
ES2070806B1 (en) 1996-01-01
HU211912A9 (en) 1996-01-29
AU5626694A (en) 1994-06-22
FR2698545B1 (en) 1995-08-04
AU667611B2 (en) 1996-03-28
RU2108777C1 (en) 1998-04-20
ITMI922758A1 (en) 1994-06-02
FR2698545A1 (en) 1994-06-03
DK61495A (en) 1995-05-31
DE4396086B3 (en) 2013-02-28
ES2070806A1 (en) 1995-06-01
HU221484B (en) 2002-10-28
IT1256616B (en) 1995-12-12
CZ136795A3 (en) 1995-11-15
JPH08503703A (en) 1996-04-23
BE1006799A3 (en) 1994-12-13
SE520834C2 (en) 2003-09-02
ITMI922758A0 (en) 1992-12-02
CA2150462C (en) 2005-04-19
NZ258544A (en) 1996-11-26
HU9501586D0 (en) 1995-08-28
GB2288977A (en) 1995-11-08
NO952183D0 (en) 1995-06-01
SE9502001L (en) 1995-07-21
CA2150462A1 (en) 1994-06-09
NL194957B (en) 2003-05-01
HUT72668A (en) 1996-05-28
DK176247B1 (en) 2007-04-16
MD1714F2 (en) 2001-08-31
LU88618A1 (en) 1995-12-01
AT407113B (en) 2000-12-27
CH685371A5 (en) 1995-06-30
SE9502001D0 (en) 1995-06-01
DE4396086T1 (en) 1995-12-07
GB9509822D0 (en) 1995-07-19
MD1714G2 (en) 2002-03-31
NL194957C (en) 2003-09-02
CZ282550B6 (en) 1997-08-13
NO952183L (en) 1995-06-01
GB2288977B (en) 1996-09-04
ATA906093A (en) 2000-05-15
NL9320052A (en) 1995-08-01
NO314018B1 (en) 2003-01-20

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