GB2145088A - Metronidazole injectable compositions - Google Patents
Metronidazole injectable compositions Download PDFInfo
- Publication number
- GB2145088A GB2145088A GB08420959A GB8420959A GB2145088A GB 2145088 A GB2145088 A GB 2145088A GB 08420959 A GB08420959 A GB 08420959A GB 8420959 A GB8420959 A GB 8420959A GB 2145088 A GB2145088 A GB 2145088A
- Authority
- GB
- United Kingdom
- Prior art keywords
- particles
- microns
- metronidazole
- maximum dimension
- weight
- 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.)
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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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
A sterile, substantially neutral aqueous injectable suspension comprises up to approximately 80% 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 about 10% by weight of particles having a maximum dimension of 10 microns or less and not more than about 10% by weight of particles having a maximum dimension of 80 microns or greater.
Description
SPECIFICATION
New injectable compositions
This invention relates to liquid compositions comprising 1-(2-hydroxyethyl)-5-nitroimida- zole.
1-(2-Hydroxyethyl)-5-nitroimidazole (hereinafter referred to as 'metronidazole') is a well 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 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 approximately 0.8% w/v (weight/volume) at room temperature, necessitating the administration of 1 OOml 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 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 composition which would permit the administration of a dose of metronidazole which is effective for up to 24 hours, i.e. 1 500mg, 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 20% 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 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 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 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 agents commonly used in injectable suspensions are present.
It has now been found that satisfactory aqueous suspensions containing up to approximately 80% w/v of metronidazole can be prepared by using particles of metronidazole having a median maximum dimension in excess of 10 microns, the aforesaid particles having a median maximum dimension of from 1 5 to 30 microns, and containing 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 80 microns, and preferbly 60 microns, or more maximum dimension, percentages by weight of particles being measured by a laser 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 Ostwald 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, hydroxypropylmethylcellulose and mixtures of these regulants. Of these various particle growth regulants, hydroxypropylmethylcellulose has been found to be effective in prevent ing 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 methyl- cellulose and more especially hydroxypropylmethylcellulose the viscosity of a 2% w/v aqueous solution of which is from 2 to 8 centipoises at 20on, 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 Marks "Cremophor" RH40, 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. 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 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). Benzyle alcohol has been found to be compatible with hydroxypropylmethylcellulose and is preferred as the preservative.If hydroxymethylcellulose is not present and other suspending agents as hereinbefore described are used, other preservatives, e.g. cresol or ortho-chlorocresol, may 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, 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 suspensions comprising up to approximately 80% w/v of metronidazole, the metronidazole being in the form of particles having a median maximum dimension of from 1 5 to 30 microns and containing 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 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 chloride, which render the aqueous suspension isotonic to body fluids, and optionally pharmaceuticallyacceptable acids and bases, e.g. phosphate buffers, to render the suspension substantially neutral and optionally one or more 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 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 1 5 to 30 microns, and containing 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 80 microns, and preferably 60 microns, or more maximum dimension, from 0.4 to 5.0% w/v of hydroxypropylmethylcellulose, 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, 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.
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 herein before 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 approximately 90% w/v of metronidazole, and which requires dilution to give a suspension 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 radiation or by passage of an aqueous solution of metronidazole through an anti-bacterial filter and 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 sepa- rately 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 1 5 to 30 microns and containing 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 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.:
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 200m microns was milled in a
Minikek pin disc mill set up with 1 74 pins until metronidazole in the form of particles having a median maximum dimension of from 1 5 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 (1 Oml) and Pharmacoat 606 (5g) were added, with stirring, to a solution of sodium chloride (3.5g) in sterile water (500ml). Sterile metronidazole (4009) in the form of particles having a median maximum dimension of from 1 5 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.
EXAMPLE 3
Benzyl alcohol (1 ml) 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 conditions in a 150ml glass bottle and sealed. Sterile metronidazole (409) 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 placed under sterile conditions in a 200ml glass bottle. The contents of the two bottles may be mixed to give 100ml of a 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 procedure 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 in respect of body fluid containing 40% w/v of metronidazole suitable for immediate injection.
Claims (24)
1. A sterile, substantially neutral aqueous injectable suspension comprising up to approximately 80% w/v of metronidazole, the metronidazole being in the form of particles having a median maximum dimension of from 1 5 to 30 microns and containing not more than about 10% by weight of particles having a maximum dimension of 10 microns or less and not more than about 10% by weight of particles having a maximum dimension of 80 microns or greater.
2. A suspension according to claim 1 which comprises not more than about 10% by weight of particles having a maximum dimension of 60 microns or greater.
2. A suspension according to claim 1 which comprises not more than about 10% by weight of particles having a maximum dimension of 60 microns or greater.
3. A suspension according to claim 1 or 2 which comprises an effective amount of a particle growth regulant or suspending agent.
4. A suspension according to claim 1 or 2 which comprises, as particle growth regulant, hydroxypropylmethylcellulose.
5. A suspension according to claim 4 in which the hydroxypropylmethylcellulise 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 claim 2 which comprises an effective amount of a suspending agent which does not inhibit the growth of the metronidazole particles.
7. A suspension according to claim 6 which comprises, as suspending agent, a pro- duct 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 ally 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 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.
12. A sterile, substantially neutral aqueous injectable suspension which is isotonic in respect of body fluids and comprises from 1 to 80K wXv 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 about 108 by weight of particles having a niaililum dimension of 10 microns or less.
and not more than about 1 0"' by weight of particles having a maximum dimension of 80 microns or greater from 0 4 to 5.096 w, v of hdroxypropylmethylcellulose and from 0.5 to 1 5iÇ^ w v of benzyl alcohol 1 z A suspension according to claim 12 which comprises not more than about 10% by weight of particles having a maximum dimension of 60 microns or greater.
14. A suspension according to claim 1 2 or 1 3 which comprises from 1 to 60% w/v of metronidazole.
1 5. A suspension according to claim 1 2, 1 3 or 14 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.
16. A suspension according to claim 1 substantially as herein before described in any one of Examples 2 to 4.
1 7. A sterile, substantially neutral aqueous suspension which comprises up to approximately 90% w/v of metronidazole, the metronidazole being in the form of particles having a median maximum dimension of from 1 5 to 30 microns and containing not more than about 10% by weight of particles having a maximum dimension of 10 microns or less and not more than about 10% by weight of particles having a maximum dimension of 80 microns or greater.
18. A suspension according to claim 1 7 which comprises not more than about 10% by weight of particles having a maximum dimension of 60 microns or greater.
19. A suspension according to claim 1 7 or 18 which comprises from 80% w/v to approximately 90% w/v of metronidazole.
20. Metronidazole in the form of particles having a median maximum dimension of from 1 5 to 30 microns and containing not more than about 10% by weight of particles having a maximum dimension of 10 microns or less and not more than about 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 1 5 to 30 microns and containing not more than about 10% by weight of particles having a maximum dimension of 10 microns or less and not more than about 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 sub stantially as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB838322364A GB8322364D0 (en) | 1983-08-19 | 1983-08-19 | Compositions of matter |
Publications (3)
Publication Number | Publication Date |
---|---|
GB8420959D0 GB8420959D0 (en) | 1984-09-19 |
GB2145088A true GB2145088A (en) | 1985-03-20 |
GB2145088B GB2145088B (en) | 1986-10-08 |
Family
ID=10547557
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB838322364A Pending GB8322364D0 (en) | 1983-08-19 | 1983-08-19 | Compositions of matter |
GB08420959A Expired GB2145088B (en) | 1983-08-19 | 1984-08-17 | Metronidazole injectable compositions |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB838322364A Pending GB8322364D0 (en) | 1983-08-19 | 1983-08-19 | Compositions of matter |
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) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2200048A (en) * | 1986-12-19 | 1988-07-27 | Sandoz Ltd | Pharmaceutical colloidal hydrosols for injection |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 DE DE19843430354 patent/DE3430354A1/en not_active Ceased
- 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 HU HU843127A patent/HU192990B/en not_active IP Right Cessation
- 1984-08-17 NZ NZ209270A patent/NZ209270A/en unknown
- 1984-08-17 GB GB08420959A patent/GB2145088B/en not_active Expired
- 1984-08-17 DK DK397084A patent/DK165817C/en not_active IP Right Cessation
- 1984-08-17 LU LU85511A patent/LU85511A1/en unknown
- 1984-08-17 AU AU32022/84A patent/AU577055B2/en not_active Ceased
- 1984-08-17 ZA ZA846431A patent/ZA846431B/en unknown
- 1984-08-17 CA CA000461262A patent/CA1214727A/en not_active Expired
- 1984-08-17 JP JP59170517A patent/JPS6067468A/en active Pending
- 1984-08-17 CH CH3960/84A patent/CH662812A5/en not_active IP Right Cessation
- 1984-08-17 BE BE0/213510A patent/BE900381A/en not_active IP Right Cessation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2200048A (en) * | 1986-12-19 | 1988-07-27 | Sandoz Ltd | Pharmaceutical colloidal hydrosols for injection |
GB2200048B (en) * | 1986-12-19 | 1991-02-06 | Sandoz Ltd | Hydrosols of pharmacologically active agents and pharmaceutical compositions comprising them |
Also Published As
Publication number | Publication date |
---|---|
DK397084D0 (en) | 1984-08-17 |
DK397084A (en) | 1985-02-20 |
JPS6067468A (en) | 1985-04-17 |
BE900381A (en) | 1985-02-18 |
DK165817B (en) | 1993-01-25 |
FR2560043B1 (en) | 1988-08-05 |
GB8420959D0 (en) | 1984-09-19 |
GB2145088B (en) | 1986-10-08 |
LU85511A1 (en) | 1985-04-24 |
SE8404130L (en) | 1985-02-20 |
IT8422323A0 (en) | 1984-08-13 |
FR2560043A1 (en) | 1985-08-30 |
ZA846431B (en) | 1985-03-27 |
CA1214727A (en) | 1986-12-02 |
SE8404130D0 (en) | 1984-08-17 |
GB8322364D0 (en) | 1983-09-21 |
DK165817C (en) | 1993-06-21 |
IT1213208B (en) | 1989-12-14 |
AU3202284A (en) | 1985-02-21 |
NL8402510A (en) | 1985-03-18 |
AU577055B2 (en) | 1988-09-15 |
NZ209270A (en) | 1988-02-29 |
DE3430354A1 (en) | 1985-03-07 |
HUT35650A (en) | 1985-07-29 |
HU192990B (en) | 1987-08-28 |
IL72714A (en) | 1988-09-30 |
SE460095B (en) | 1989-09-11 |
CH662812A5 (en) | 1987-10-30 |
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