NZ209270A - Injectable suspensions of 1-(2-hydroxyethyl)-5-nitroimidazole(metronidazole) - Google Patents
Injectable suspensions of 1-(2-hydroxyethyl)-5-nitroimidazole(metronidazole)Info
- Publication number
- NZ209270A NZ209270A NZ209270A NZ20927084A NZ209270A NZ 209270 A NZ209270 A NZ 209270A NZ 209270 A NZ209270 A NZ 209270A NZ 20927084 A NZ20927084 A NZ 20927084A NZ 209270 A NZ209270 A NZ 209270A
- Authority
- NZ
- New Zealand
- Prior art keywords
- particles
- microns
- metronidazole
- maximum dimension
- weight
- Prior art date
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
New Zealand Paient Spedficaiion for Paient Number £09270
i
209270
Priority D*t3(s)-
Mad
Complete Specification Filed: ..
C33s: .. |/+AT).^ .
Public"ition Date: ,2*9*F&B^t98® P.O. JcymaS. No:
.&3.
NEW ZEALAND N/38056
PATENTS ACT 1953 PATENTS FORM NO. 5 COMPLETE SPECIFICATION NEW INJECTABLE COMPOSITIONS
WE, MAY & BAKER LIMITED, a British company, of Dagenham, Essex, RM10 7XS, England, hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement
-1- (followed by page la)
-la -
209270
vj
DESCRIPTION
"NEW INJECTABLE COMPOSITIONS CONTAINIHG METRONIDAZOLC" This invention relates to liquid compositions comprising l-(2-hydroxyethyl)-2-methyl-5-nitroimidazole.
l-(2-Hydroxyethyl)-2-methy1-5-nitroimidazole (hereinafter referred to as 'metronidazole') is a well 5 known agent used for combatting amoebal and trichomonal infections and infections caused by anaerobic bacteria.
In order to establish effective tissue levels of metronidazole by parenteral administration which 10 are maintained for a reasonable length of time, e.g.
up to eight hours, it is frequently necessary to administer relatively large amounts of metronidazole, e.g. up to 500mg. Metronidazole is relatively insoluble in water, having a solubility of 15 approximately 0.8% w/v (weight/volume) at room temperature, necessitating the administration of 100ml of an 0.5% w/v solution to give a dose of 500mg, which requires intravenous infusion of the solution, the volume in question being much too large to be 20 administered by intramuscular or subcutaneous injection. This is relatively inconvenient and there is a need for more concentrated injectable compositions containing metronidazole, particularly for veterinary use, and more especially for a
/y c-.
2 ■* 9 DEC 1987 r,
composition which would permit the administration of a dose of metronidazole which is effective for up to 24 hours, i.e. 1500mg, in a single injection of relatively small volume, e.g. 3 to 5 ml.
Aqueous solutions containing metronidazole in very much higher concentrations, e.g. 50% w/v and above, than are obtainable using metronidazole itself, may be obtained by using salts of metronidazole which are highly soluble in water, for example potassium metronidazole phosphate. Such concentrated solutions • are, however, hypertonic, that is to say possess a high osmotic pressure relative to body fluids and cause pain and local intolerance on injection.
Satisfactory suspensions for injection containing high levels of solids, e.g. in excess of 201 w/v, are often difficult to prepare, have unsatisfactory storage lives and often cause pain and local intolerance at the site of injection.
It is, furthermore, generally recommended that solid materials for injection should be in the form of very fine particles, typically particles having a median maximum dimension of 10 microns or less, and preferably less than 5 microns.
It is also well known that it is normally necessary to include wetting and suspending agents in suspensions of fine particles for injection, in order
\ 209270
1 - 3 -
to give a suspension with sufficient mobility and, if the particles separate out from the liquid medium, resuspendability, to permit easy and accurate withdrawal of the required dose from the container 5 into the hypodermic syringe and injection into the ^ body.
Attempts to prepare injectable concentrated,
i.e. up to 50% w/v, aqueous suspensions of fine particles of metronidazole, i.e. particles having a 10 median maximum dimension of 10 microns or even 5
microns or less, have proved unsuccessful, since the suspensions have an unacceptably high viscosity, which renders them difficult to draw into or expel from a hypodermic syringe, even when wetting and suspending 15 agents commonly used in injectable suspensions are present.
It has now been found that satisfactory aqueous suspensions containing up to 80% w/v of metronidazole can be prepared by using particles of 20 metronidazole having a median maximum dimension in excess of 10 microns, the aforesaid particles having a median maximum dimension of from 15 to 30 microns, and containing not more than 10% by weight of particles of 10 microns or less maximum dimension 25 and not more than 10% by weight of particles of 80 microns, and preferably 60 microns, or more maximum dimension, percentages by weight of particles being measured by a laser 11 ?9DECJ987^
7 ^
light-scattering method. These injectable aqueous suspensions of metronidazole do not cause pain on intramuscular injection and/or local intolerance and the release rate of metronidazole from the site of injection into the body tissues is such that the required level of metronidazole in the body tissues may be maintained by a single daily injection.
It is also well known that solids in the presence of their saturated solutions undergo an increase in particle size by an Ostvald ripening or solution/recrystallisation process whereby larger particles grow at the expense of smaller particles. It has been found that this occurs with concentrated suspensions of metronidazole in water after a few, e.g. five, days. This increase in the size of the metronidazole particles in the suspension is undesirable, since excessive growth may produce large crystals, which will block the needle of a hypodermic needle or interfere with the flow of the aqueous suspension through the needle and may adversely affect the resuspendability of the metronidazole particles in the suspension medium, such that a given volume of suspension will not contain the expected amount of metronidazole. Many particle growth regulants, i.e. agents which suppress or control the growth of solid particles in contact with their saturated solutions,
/
are known, e.g. Tweens, poly(vinylpyrrolidones), lecithin, sodium carboxymethylcellulose, hydroxypropyl methylcellulose and mixtures of these regulants. Of these various particle growth regulants, hydroxypropyl methylcellulose has been found to be effective in preventing the growth of metronidazole particles in aqueous suspensions of metronidazole according to the present invention, suitably at a concentration of from 0.4 to 5.0% w/v.
Accordingly, if it is desired to prepare an injectable aqueous suspension of metronidazole according to the present invention which can be kept for a period of from a few days up to one month without unacceptable increase in the particle size of the metronidazole, this can be achieved by incorporating an effective proportion of hydroxypropyl methylcellulose and more especially hydroxypropyl-methylcellulose the viscosity of a 2% w/v aqueous solution of which is from 2 to 8 centipoises at 20°C, for example the product which is commercially available under the Trade Mark "Pharmacoat" 606, in the suspension. The hydroxypropylmethylcellulose also serves as a suspending agent retaining the metronidazole particles in suspension and facilitating the resuspension of metronidazole particles which separate out from the suspension. However, if the
injectable aqueous suspension of metronidazole is intended to be administered immediately or very soon after preparation, i.e. before growth of the metronidazole particles can occur, other suspending agents may be used which do not inhibit the growth of the metronidazole particles, e.g. products of ethoxylation of castor oil and hydrogenated castor oil, including those products which are commercially available under the Trade Narks "Cremophor" RH410, EL, RH60 and RH40, "Arlatone" 285 and 164, polypropylene oxide ethoxylated to varying degrees, including those products which are commercially available under the Trade Marks "Pluronic" L62, F68 and 108, sorbitan fatty acid ethoxylates, including those products which are commercially available under the Trade Mark "Tween", poly(vinylpyrrolidones), lecithin, sodium carboxymethylcelluloses and Carbomer BP (a synthetic high molecular weight polymer of acrylic acid cross-linked with allyl sucrose and containing 56 to 68% of carboxylic acid groups).
It will be appreciated that since the aqueous suspensions of metronidazole particles are intended to be administered by injection, they will be prepared from sterile materials or sterilised after preparation and stored under sterile conditions or contain preservatives to prevent microbial contamination.
209270
When the injectable aqueous suspension of metronidazole is to be stored in a multi-dose container from which the appropriate quantity of suspension for a single dose will be withdrawn as and 5 when required over a period of time ranging from several days to one month, a preservative should be incorporated. The preservative should be compatible with the particle growth regulant and/or suspending agent(s). Benzyl alcohol has been found to be 10 compatible with hydroxypropylmethylcellulose and is preferred as the preservative. If hydroxypropylmethylcellulose is not present and other suspending agents as hereinbefore described are used, other preservatives, e.g. cresol or ortho-chlorocresol, may 15 be used.
If desired, conventional agents, for example sodium chloride, may be incorporated in the injectable aqueous suspensions according to the present invention to render them isotonic with respect to body fluids, 20 and pharmaceutically-acceptable acids and bases, e.g.
phosphate buffers, may be added, if desired, to render the suspension substantially neutral.
Accordingly, the present invention provides sterile, substantially neutral aqueous injectable 25 suspensions comprising up to 80% w/v of metronidazole, the metronidazole being in the form
-
209270 \
of particles having a median maximum dimension of from 15 to 30 microns and containing not more than 10% by weight of particles of 10 microns or less maximum dimension and not more than 10% by weight of particles 5 of 80 microns, and preferably 60 microns, or more maximum dimension, and optionally an effective amount of a particle growth regulant, preferably hydroxypropylmethylcellulose, or suspending agent and optionally one or more agents, for example sodium 10 chloride, which render the aqueous suspension isotonic to body fluids, and optionally pharmaceutically-acceptable acids and bases, e.g. phosphate buffers, to render the suspension substantially neutral and optionally one or more 15 preservatives.
According to a preferred feature of the present invention, there are provided sterile, substantially neutral aqueous injectable suspensions which are isotonic in respect of body fluids and 20 comprise from 1 to 80%, and preferably from 1 to 60%, w/v of metronidazole, the metronidazole being in the form of particles having a median maximum dimension of from 15 to 30 microns, and containing not more than 10% by weight of particles of 10 microns or less 25 maximum dimension and not more than 10% by weight of particles of 80 microns, and preferably 60 microns, or more maximum dimension, from 0.4 to 5.0% w/v of hydroxypropylmethylcellulose,
'9DEC19&7
n,i thj.
©
209270
and more especially hydroxypropylmethylcellulose the viscosity of a 2% w/v aqueous solution of which is from 2 to 8 centipoises at 20°C, from 0.5 to 1.5% v/v (volume/volume) of benzyl alcohol, and, optionally, 5 one or more agents, for example sodium chloride, which render the aqueous suspension isotonic to body fluids ^ and optionally pharmaceutically-acceptable acids and bases, e.g. phosphate buffers, to render the suspension substantially neutral. 10 Sterile, substantially neutral aqueous injectable suspensions according to the present invention may be prepared by mixing, if necessary with agitation, the appropriate amount of sterile metronidazole in powder form of the hereinbefore 15 specified particle size with a solution in sterile water of the other hereinbefore specified ingredients or by mixing a sterile suspension as hereinbefore defined but which contains in excess of 80% w/v of metronidazole, e.g. up to 90% w/v of metronidazole, 20 and which requires dilution to give a suspension jl/ suitable for injection (such suspensions containing in excess of 80% w/v of metronidazole form a further feature of the present invention), with sterile water. The metronidazole may be sterilised by gamma 25 radiation or by passage of an aqueous solution of metronidazole through an anti-bacterial filter and
o
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'9D£Cl9S7n
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P, v ^
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209270
e
O 25
crystallisation and milling under aseptic conditions. For convenience, the metronidazole in powder form or a sterile suspension as hereinbefore defined but which contains in excess of 80% w/v of metronidazole and sterile water or a solution in sterile water of the other hereinbefore specified ingredients,
respectively, may be provided separately in suitable containers, for example glass bottles, and combined, if necessary with agitation, at the time of use. In the case of suspensions according to the present invention which contain a particle growth regulant and which may be stored for several days to about one month, for example in a multi-dose container from which single doses are removed as and when required, any metronidazole particles which separate from the suspension may be resuspended by agitation.
Metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns and containing not more than 10% by weight of particles of 10 microns or less maximum dimension and not more than 10% by weight of particles of 80 microns, and preferably 60 microns, or more maximum dimension forms a further feature of the present invention, and may be prepared by milling metronidazole powder of greater median particle dimension in a suitable mill, e.g. a pin disc mill.
The following non-limitative Examples illustrate the present invention.
a
209?
EXAMPLE 1
Metronidazole powder having a median particle size of 80 microns with 10% by weight of particles having a maximum dimension of greater than 200 microns was milled in a Minikek pin disc mill set up with 174 pins until metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns with not more than 10% by weight of particles of 10 microns or less maximum dimension and not more than about 10% by weight of particles of 60 to 80 microns or greater maximum dimension, was obtained, which was then sterilised by gamma radiation.
EXAMPLE 2
Benzyl alcohol (10ml) and Pharmacoat 606 (5g) were added, with stirring, to a solution of sodium chloride (3.5g) in sterile water (500ml). Sterile metronidazole (400g) in the form of particles having a median maximum dimension of from 15 to 30 microns with not more than about 10% by weight of particles of 10 microns or less maximum dimension and not more than about 10% by weight of particles of 60 to 80 microns or greater maximum dimension, (prepared as described in Example 1) was then added, with stirring, to the solution thus obtained. Further sterile water was then added to a final volume of 1000ml to give a sterile substantially neutral aqueous injection suspension which is isotonic is respect of body fluids containing 40% w/v of metronidazole and which is stable for up to one month.
709270
EXAMPLE 3
Benzyl alcohol (1ml) and Pharmacoat 606 (0.5g) were added, with stirring, to a solution of sodium chloride (0.35g) in sterile water (60ml). The solution thus obtained was placed under sterile 5 conditions in a 150ml glass bottle and sealed.
Sterile metronidazole (40g) in the form of particles having a median maximum dimension of from 15 to 30 microns with not more than about 10% by weight of particles of 10 microns or less maximum dimension and 10 not more than about 10% by weight of particles of 60 to 80 microns or greater maximum dimension (prepared as described in Example 1) was placed under sterile conditions in a 200ml glass bottle. The contents of the two bottles may be mixed to give 100ml of a 15 sterile substantially neutral aqueous injection suspension which is isotonic in respect of body fluids containing 40% w/v of metronidazole, which may be administered immediately or over a period of up to one month.
EXAMPLE 4
The proceedure described in Example 3 was repeated but replacing the Pharmacoat 606 by poly(vinylpyrrolidone) to give a sterile substantially neutral aqueous injection suspension which is isotonic 25 in respect of body fluids containing 40% w/v of metronidazole suitable for immediate injection.
209270
Claims (3)
1* A sterile, substantially neutral aqueous injectable suspension comprising up to 80% w/v of metronidazole, the metronidazole being in the form of 5 particles having a median maximum dimension of from 15 to 30 microns and containing not more than 10% by weight of particles having a maximum dimension of 10 microns or less and not more than 10% by weight of particles having a maximum dimension of 80 microns or 10 greater.
2. A suspension according to claim 1 which comprises not more than 10% by weight of particles having a maximum dimension of 60 microns or greater.
3. A suspension according to claim 1 or 2 which 15 comprises an effective amount of a particle growth regulant or suspending agent. A. A suspension according to claim 1 or 2 which comprises, as particle growth regulant, hydroxypropylmethylcellulose . 20 5. A suspension according to claim A in which the hydroxypropylmethylcellulose is such that a 2% w/v aqueous solution thereof has a viscosity of 2 to 8 centipoises at 20°C. 6. A suspension according to claim 1 or 2 which 25 comprises an effective amount of a suspending agent /V °-\\ :■« -r! \ I* 9 - 14 - 2 G v. which does not inhibit the growth of the metronidazole particles. 7. A suspension according to claim 6 which comprises, as suspending agent, a product of the ethoxylation of castor oil, a product of the ethoxylation of hydrogenated castor oil, ethoxylated polypropylene oxide, a sorbitan fatty acid ethoxylate, poly(vinylpyrrolidones), lecithin, a sodium carboxymethylcellulose or a synthetic high molecular weight polymer of acrylic acid cross-linked with allyl sucrose and containing 56 to 68% of carboxylic acid groups. 8. A suspension according to any one of the preceding claims which comprises one or more agents t which render the aqueous suspension isotonic to body fluids. 9. A suspension according to any one of the preceding claims which comprises pharmaceutically acceptable acids and bases to render the suspension substantially neutral. 10. A suspension according to any one of the preceding claims which comprises one or more preservatives. 11. A suspension according to claim 10 in which the preservative is benzyl alcohol. / c 209270 - 15 - 12. A sterile, substantially neutral aqueous injectable suspension which is isotonic in respect of body fluids and comprises from 1 to 80% w/v of metronidazole, the metronidazole being in the form of 5 particles having a median maximum dimension of from 15 ^ to 30 microns, and containing not more than 10% by weight of particles having a maximum dimension of 10 microns or less, and not more than 10% by weight of particles having a maximum dimension of 80 microns or 10 greater, from 0.4 to 5.0% w/v of hydroxypropylmethylcellulose and from 0.5 to 1.5% w/v of benzyl alcohol. 13. A suspension according to claim 12 which comprises not more than 10% by weight of particles 15 having a maximum dimension of 60 microns or greater. 14. A suspension according to claim 12 or 13 which comprises from 1 to 60% w/v of metronidazole. 15. A suspension according to claim 12, 13 or 14 in which the hydroxypropylmethylcellulose is such that 20 a 2% w/v aqueous solution thereof has a viscosity of 2 -'-V. ^ to 8 centipoises at 20°C. 16. A suspension according to claim 1 substantially as hereinbefore described in any one of Examples 2 to 4. o ~ 9 DEC I987Z e - 16 - 209270 r\ o 17. A sterile, substantially neutral aqueous suspension which comprises up to 90% w/v of metronidazole, the metronidazole being in the form of particles having a median maximum dimension of from 15 5 to 30 microns and containing not more than 10% by weight of particles having a maximum dimension of 10 microns or less and not more than 10% by weight of particles having a maximum dimension of 80 microns or greater. 10 18. A suspension according to claim 17 which comprises not more than 10% by weight of particles having a maximum dimension of 60 microns or greater. 19. A suspension according to claim 17 or 18 which comprises from 80% w/v to 90% w/v of 15 metronidazole. 20. Metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns and containing not more than 10% by weight of particles having a maximum dimension of 10 microns or 20 less and not more than 10% by weight of particles having a maximum dimension of 80 microns or greater. 21. Metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns and containing not more than 10% by weight of ' -A/ "A 7-V 'DEC 19875 209270 - 17 - particles having a maximum dimension of 10 microns or less and not more than 10% by weight of particles having a maximum dimension of 60 microns or greater. 22. Metronidazole according to claim 20 or 21 substantially as hereinbefore described. 23. A pack comprising metronidazole as claimed in claim 20, 21 or 22 and, separated therefrom, a sterile aqueous solution which, when added to the metronidazole, yields a sterile, substantially neutral aqueous injectable suspension as claimed in any one of claims 1 to 16. 24. A pack according to claim 23 substantially as hereinbefore described. DATED THIS *2^" DAY OF A. J. PARK & SON fer c i
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838322364A GB8322364D0 (en) | 1983-08-19 | 1983-08-19 | Compositions of matter |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ209270A true NZ209270A (en) | 1988-02-29 |
Family
ID=10547557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ209270A NZ209270A (en) | 1983-08-19 | 1984-08-17 | Injectable suspensions of 1-(2-hydroxyethyl)-5-nitroimidazole(metronidazole) |
Country Status (17)
| Country | Link |
|---|---|
| JP (1) | JPS6067468A (en) |
| AU (1) | AU577055B2 (en) |
| BE (1) | BE900381A (en) |
| CA (1) | CA1214727A (en) |
| CH (1) | CH662812A5 (en) |
| DE (1) | DE3430354A1 (en) |
| DK (1) | DK165817C (en) |
| FR (1) | FR2560043B1 (en) |
| GB (2) | GB8322364D0 (en) |
| HU (1) | HU192990B (en) |
| IL (1) | IL72714A (en) |
| IT (1) | IT1213208B (en) |
| LU (1) | LU85511A1 (en) |
| NL (1) | NL8402510A (en) |
| NZ (1) | NZ209270A (en) |
| SE (1) | SE460095B (en) |
| ZA (1) | ZA846431B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU205861B (en) * | 1986-12-19 | 1992-07-28 | Sandoz Ag | Process for producing hydrosole of pharmaceutically effective material |
| US7849856B2 (en) | 2001-06-25 | 2010-12-14 | 3M Innovative Properties Company | Respirator valve |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB213928A (en) * | 1923-04-06 | 1925-07-02 | Deutsche Werke Ag | Improvements in or relating to compensated induction motors for single or polyphase alternating current |
| US3457348A (en) * | 1966-06-27 | 1969-07-22 | American Cyanamid Co | Stable syringeable suspensions of parenteral drugs in complex floc form |
| GB1430411A (en) * | 1973-04-05 | 1976-03-31 | May & Baker Ltd | Method and compositions for combating swine dysentery |
| US4029782A (en) * | 1975-04-28 | 1977-06-14 | Eli Lilly And Company | Cefazolin suspension for parenteral administration |
| GB2000025A (en) * | 1977-05-14 | 1979-01-04 | Pfizer Ltd | Nitroimidazole formulations |
| DE2932691A1 (en) * | 1979-08-11 | 1981-04-09 | Bayer Ag, 5090 Leverkusen | Antimycotic tablets contg. micronised azole derivs. - together with acid and/or buffer |
-
1983
- 1983-08-19 GB GB838322364A patent/GB8322364D0/en active Pending
-
1984
- 1984-08-13 IT IT8422323A patent/IT1213208B/en active
- 1984-08-15 NL NL8402510A patent/NL8402510A/en not_active Application Discontinuation
- 1984-08-16 FR FR8412854A patent/FR2560043B1/en not_active Expired
- 1984-08-17 LU LU85511A patent/LU85511A1/en unknown
- 1984-08-17 JP JP59170517A patent/JPS6067468A/en active Pending
- 1984-08-17 DK DK397084A patent/DK165817C/en not_active IP Right Cessation
- 1984-08-17 IL IL72714A patent/IL72714A/en unknown
- 1984-08-17 SE SE8404130A patent/SE460095B/en not_active IP Right Cessation
- 1984-08-17 CA CA000461262A patent/CA1214727A/en not_active Expired
- 1984-08-17 NZ NZ209270A patent/NZ209270A/en unknown
- 1984-08-17 HU HU843127A patent/HU192990B/en not_active IP Right Cessation
- 1984-08-17 GB GB08420959A patent/GB2145088B/en not_active Expired
- 1984-08-17 BE BE0/213510A patent/BE900381A/en not_active IP Right Cessation
- 1984-08-17 AU AU32022/84A patent/AU577055B2/en not_active Ceased
- 1984-08-17 CH CH3960/84A patent/CH662812A5/en not_active IP Right Cessation
- 1984-08-17 DE DE19843430354 patent/DE3430354A1/en not_active Ceased
- 1984-08-17 ZA ZA846431A patent/ZA846431B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK165817B (en) | 1993-01-25 |
| NL8402510A (en) | 1985-03-18 |
| IT8422323A0 (en) | 1984-08-13 |
| AU577055B2 (en) | 1988-09-15 |
| AU3202284A (en) | 1985-02-21 |
| LU85511A1 (en) | 1985-04-24 |
| GB8420959D0 (en) | 1984-09-19 |
| BE900381A (en) | 1985-02-18 |
| ZA846431B (en) | 1985-03-27 |
| FR2560043B1 (en) | 1988-08-05 |
| DK165817C (en) | 1993-06-21 |
| JPS6067468A (en) | 1985-04-17 |
| GB8322364D0 (en) | 1983-09-21 |
| IL72714A (en) | 1988-09-30 |
| SE8404130L (en) | 1985-02-20 |
| DK397084A (en) | 1985-02-20 |
| SE460095B (en) | 1989-09-11 |
| CA1214727A (en) | 1986-12-02 |
| DK397084D0 (en) | 1984-08-17 |
| IT1213208B (en) | 1989-12-14 |
| HU192990B (en) | 1987-08-28 |
| SE8404130D0 (en) | 1984-08-17 |
| HUT35650A (en) | 1985-07-29 |
| DE3430354A1 (en) | 1985-03-07 |
| FR2560043A1 (en) | 1985-08-30 |
| GB2145088A (en) | 1985-03-20 |
| CH662812A5 (en) | 1987-10-30 |
| GB2145088B (en) | 1986-10-08 |
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