CA1214727A - Injectable compositions comprising 1-(2-hydroxyethyl -5-nitro imidazole - Google Patents
Injectable compositions comprising 1-(2-hydroxyethyl -5-nitro imidazoleInfo
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- CA1214727A CA1214727A CA000461262A CA461262A CA1214727A CA 1214727 A CA1214727 A CA 1214727A CA 000461262 A CA000461262 A CA 000461262A CA 461262 A CA461262 A CA 461262A CA 1214727 A CA1214727 A CA 1214727A
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- microns
- metronidazole
- maximum dimension
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—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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- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
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- 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
ABSTRACT
"NEW INJECTABLE COMPOSITIONS"
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.
"NEW INJECTABLE COMPOSITIONS"
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
DESC~IPTIO~' "NEW INJECTABLE COMPOSITIONS"
This invention relates ~o liquid compositions comprising 1~(2-hydroxyethyl)-2-methyl-5-nitroimidazole.
1-(2-Hydroxyethyl~-2-methyl-5-nitroimidazole (hereinafter referred to as 'metronidazole') i6 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 100ml of an 0.5% w/v ~olution to give a dose of 500mg, which requires intravenous infusion of the solution, the volume in question being much eoo large to be administered by intramuscular or subcutaneous injection. This is relatively inconvenient and there is a need for more concentrated in~ectable 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. 1500mg, in a single injection of relatively ~mall volume, e.g. 3 to 5 ml.
Aqueous solutions contsining metronidazole in very much higher concentrations, e.g. 50~/O w/v ~nd 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 i5 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 ~f solids, e.g. in excess of 20% w~v, are often difficult to prepare, have unsatisfactory stora~e lives and often cause pain and local intolerance at the site of injection.
It is, furthermore, gener~lly recommended that solid materials for injection should be in the form of very fine particles, typically particles havin~ a median maximum dimension of 10 microns or less, and preferably less than 5 microns.
It is slso well ~nown that it is normally necessary to include wetting and suspending sgents in suspensions of fine particles for injection, in order ' ' 3L f~.
to give a suspension with sufficient mobility and, if the particles 6eparate out from the liguid medium, resuspendability, to permit easy and accurate withdrawal of the reguired dose from the container into the hypodermic ~yringe and injection into the body.
Attempts to prepare injectable concentrated, i~e. up to 50iO w/v, aqueous ~uspensions of fine particles of metronidazole, i.e. particles having a median maximum dimension of lO microns or even 5 microns or less, have proved unsuccessful, since the suspensions have an unacceptably high viscosity, which renders them dif~icult to draw into or expel from a hypodermic ~yringe, even when wetting and suspending agents commonly ~sed in injectable suspensions are present.
It has now been found that ~atisfactory aqueous suspensions containing up to approximately 80%
w/v of metronida201e ran be prepared by using particle5 of metronidazole having a median maximum dimension in excess of lO microns, the aforesaid par~icles having a median maximum dimension of from 15 to 30 microns, and containing not more than about 10%
by weight of particles of lO microns or less maximum dimension and not more thaD about 10% by weight of particles of 80 microns, and preferably 60 microns, or more maximum dimension, percentages by weight of particles bein~ measured by a laser light-scattering method. These injectable ~4ueous 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 ~uch 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 ~aturated ~olutions undergo an increase in particle ~ize by an Ostwald ripenin~ 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, ~5 e.g. five, days~ This increase in the size of the metronidazole particles in the suspension is undesirable9 since excessive growth may produce large crystals, which will block the Deedle of a hypodermic needle or interfere with the flow of the aqueous s~spension through the needle and may adversely affect the resuspendability of the metronidazole particles in the suspension medium, such that a given volume of ~uspension will not eontain the expected amount of ~etronidazole. Many particle growth regulants, i.e.
agents which suppress or control the growth of ~olid particles in contact with their saturated ~olutions, ~%~
are known, e.g. Tweens, poly(v;nylpyrrolidone~), lecithin, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose and mixtures o these regulants. Of these various par~icle growth re~ulants, hydroxypropyl-methylcellulose has been found to be effective inpreventin~ thP grow~h of metronidazole particles in aqueous ~uspensions of metronidazole according to the present invention, suitably at a concentration of from 0.4 ts 5.0% w/v.
Accordingly, if it i6 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 ~ize of the metronidazole, this csn be achieved by incorporating an effective proportion of hydroxypropyl-me~hylcellulose and more especially hydroxypropyl-methylcellulose the vi~cosity of a 2% w/v aqueous solution of which is from 2 to 8 ~entipoi6es at 20~C, for example the product which is eommercially 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 ~2~ '7 injec~able aqueous su6pension of metronidazole is intended to be administered i~mediately or very ~oon after preparation~ i.e. before growth o the metronidazole particles can occur, oeher ~uspending agen~s 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 product6 which are commercially available under the Tr~de Marks "Cremophor" RH410, EL, 10 ~H60 and RH40, "Arlatone" 285 and 164, polypropylene oxide ethoxylated to varying degrees, including those products which are commercially avail~ble under the Trade Marks "Pluronic" L62, F68 and 108, ~orbitan fatty acid ethoxylates, including those products which are commercially available under the Trade Mark "Tween"J poly(vinylpyrrolidones), lecithin, sodium carboxymethylcelluloses ~nd C~rbomer 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 ~ince the agueous suspensions of metronidazole particles are intended to be administered by injection, they will be prepared from ~terile materials ~r ~terilised after preparation ~nd 6tored 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 ~ingle dose will be withdrawn as and when required over a period of time ranging from several dsys to one month, a preservative should be incorporated~ The preservative should be compatible with the particle growth regulant and/or su6pending agent(s). Benzyl alcohol has been found to be compatible with hydroxypropylmethylcellulose and is preferred as the preservative. If hydroxypropylmethyl-cellulose is not present and other suspending agents as hercinbefore 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 eo 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 æuspension 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
This invention relates ~o liquid compositions comprising 1~(2-hydroxyethyl)-2-methyl-5-nitroimidazole.
1-(2-Hydroxyethyl~-2-methyl-5-nitroimidazole (hereinafter referred to as 'metronidazole') i6 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 100ml of an 0.5% w/v ~olution to give a dose of 500mg, which requires intravenous infusion of the solution, the volume in question being much eoo large to be administered by intramuscular or subcutaneous injection. This is relatively inconvenient and there is a need for more concentrated in~ectable 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. 1500mg, in a single injection of relatively ~mall volume, e.g. 3 to 5 ml.
Aqueous solutions contsining metronidazole in very much higher concentrations, e.g. 50~/O w/v ~nd 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 i5 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 ~f solids, e.g. in excess of 20% w~v, are often difficult to prepare, have unsatisfactory stora~e lives and often cause pain and local intolerance at the site of injection.
It is, furthermore, gener~lly recommended that solid materials for injection should be in the form of very fine particles, typically particles havin~ a median maximum dimension of 10 microns or less, and preferably less than 5 microns.
It is slso well ~nown that it is normally necessary to include wetting and suspending sgents in suspensions of fine particles for injection, in order ' ' 3L f~.
to give a suspension with sufficient mobility and, if the particles 6eparate out from the liguid medium, resuspendability, to permit easy and accurate withdrawal of the reguired dose from the container into the hypodermic ~yringe and injection into the body.
Attempts to prepare injectable concentrated, i~e. up to 50iO w/v, aqueous ~uspensions of fine particles of metronidazole, i.e. particles having a median maximum dimension of lO microns or even 5 microns or less, have proved unsuccessful, since the suspensions have an unacceptably high viscosity, which renders them dif~icult to draw into or expel from a hypodermic ~yringe, even when wetting and suspending agents commonly ~sed in injectable suspensions are present.
It has now been found that ~atisfactory aqueous suspensions containing up to approximately 80%
w/v of metronida201e ran be prepared by using particle5 of metronidazole having a median maximum dimension in excess of lO microns, the aforesaid par~icles having a median maximum dimension of from 15 to 30 microns, and containing not more than about 10%
by weight of particles of lO microns or less maximum dimension and not more thaD about 10% by weight of particles of 80 microns, and preferably 60 microns, or more maximum dimension, percentages by weight of particles bein~ measured by a laser light-scattering method. These injectable ~4ueous 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 ~uch 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 ~aturated ~olutions undergo an increase in particle ~ize by an Ostwald ripenin~ 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, ~5 e.g. five, days~ This increase in the size of the metronidazole particles in the suspension is undesirable9 since excessive growth may produce large crystals, which will block the Deedle of a hypodermic needle or interfere with the flow of the aqueous s~spension through the needle and may adversely affect the resuspendability of the metronidazole particles in the suspension medium, such that a given volume of ~uspension will not eontain the expected amount of ~etronidazole. Many particle growth regulants, i.e.
agents which suppress or control the growth of ~olid particles in contact with their saturated ~olutions, ~%~
are known, e.g. Tweens, poly(v;nylpyrrolidone~), lecithin, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose and mixtures o these regulants. Of these various par~icle growth re~ulants, hydroxypropyl-methylcellulose has been found to be effective inpreventin~ thP grow~h of metronidazole particles in aqueous ~uspensions of metronidazole according to the present invention, suitably at a concentration of from 0.4 ts 5.0% w/v.
Accordingly, if it i6 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 ~ize of the metronidazole, this csn be achieved by incorporating an effective proportion of hydroxypropyl-me~hylcellulose and more especially hydroxypropyl-methylcellulose the vi~cosity of a 2% w/v aqueous solution of which is from 2 to 8 ~entipoi6es at 20~C, for example the product which is eommercially 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 ~2~ '7 injec~able aqueous su6pension of metronidazole is intended to be administered i~mediately or very ~oon after preparation~ i.e. before growth o the metronidazole particles can occur, oeher ~uspending agen~s 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 product6 which are commercially available under the Tr~de Marks "Cremophor" RH410, EL, 10 ~H60 and RH40, "Arlatone" 285 and 164, polypropylene oxide ethoxylated to varying degrees, including those products which are commercially avail~ble under the Trade Marks "Pluronic" L62, F68 and 108, ~orbitan fatty acid ethoxylates, including those products which are commercially available under the Trade Mark "Tween"J poly(vinylpyrrolidones), lecithin, sodium carboxymethylcelluloses ~nd C~rbomer 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 ~ince the agueous suspensions of metronidazole particles are intended to be administered by injection, they will be prepared from ~terile materials ~r ~terilised after preparation ~nd 6tored 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 ~ingle dose will be withdrawn as and when required over a period of time ranging from several dsys to one month, a preservative should be incorporated~ The preservative should be compatible with the particle growth regulant and/or su6pending agent(s). Benzyl alcohol has been found to be compatible with hydroxypropylmethylcellulose and is preferred as the preservative. If hydroxypropylmethyl-cellulose is not present and other suspending agents as hercinbefore 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 eo 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 æuspension 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
2~
of particles having a median maximum dimension of from 15 to 30 microns ~nd containing not more than about 102 by weight of particles of 10 microns or les~
maximum dimension ~nd not more than about 10% by weight of particles of 80 microns, and preerably 60 microns, or more maximum dimen~ion, and optionally an effective amount of a particle growth regulant, preferably hydroxypropylmethylcellulose, or suspending agent and optionally one or more agents, for example ~o 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 and optionally one or more preservatives, According to a preferred feature of the present invention, there are provided sterile, ~ubstantially 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 ~rom 15 to 30 microns, and containing not more ~han ~bout 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 prefersbly 60 microns, or more maximum dimension, from 0.4 to 5.0~ wlv of hydroxypropylmethylcellulose, ~ 7 and more especially hydroxypropylmethylcellulose the viscosity of ~ 2h w/v aqueous ~olution of which is from 2 to 8 centipoises at 20QC, from n. 5 to 1.~% v/v ~volume/volume) of benzyl ~lcohol~ and, optionally, one or more agents, for example 60dium chloride, which render the aqueous suspension i~otonic to body fluids and optionally pharmaceutically-acceptable acids and bases, e.g. phosphate buffers, to render the suspensian sub6tantially neutral.
Sterile, ~ubstantially neutral aqueous injectable ~uspensions according to the present invention may be prepared by mixing, if necessary with agi~ation, the appropriate amount of sterile metronidazole in powder form of the hereinbefore ~pecified particle size ~ith a solution in ~terile water of the other hereinbefore specified ingredien~s or by mixing a ~terile suspension as hereinbefore defined but which contains in excess of 80% w/v of metronidazole, e.g. up to approximately 902 w/v of metronidazole, and which requires dilution to give a ~uspensi~n suitable for inject;on (~uch suspensions containin~ in excess of 80% w/v of metronidazole form a further feature of the present invention), with sterile water. The metronidazole may be ~terilised by gamma radiation or by passage of an aqueous solution of metronidazole through an ~nti-bacterial filter and crystallisation ~d milling under aseptic conditions.
For convenience, the metronidazole in powder form or a ~terile 6uspension as hereinbefore defined but which contains in excess of 80% wJv of metronidazole ~nd ~terile water or a 601ution in ~terile water of the other hereinbefore 6pecified ingredients, respectively, may be provided separately in suitable container6> for example glass bottles, and combined, if necessary with agitation, at the time of use. In the case of 6uspensions 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 reguired, any metronidazole particles which ~eparate from the ~uspensi~n may be resuspended by agitation.
Metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns ~nd 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 B0 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.~. a pin disc mill.
The following non-limitative Examples illustrate the present invention.:-72~7 Metronidazole powder having ~ median particlesize of 8D microns with 10% by weight of particles having a maximum dimension of greater than 200 microns was milled in ~ 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 lO~J~ by weight of particles of 60 to 80 mierons or greater maximum dimension9 was obtained, which was then sterilised by ga~ma radiation.
Benzyl slcohol ~lOml) 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 ~bout 10% by weight of particles of 60 to 80 microns or ~reater maximum dimension, (prepared as described in Example 1) was then added, with stirring, ~o the ~olution thus obtained. Further ~terile water was then added to a final volume of lOOOml to give a sterile substantially neutral aqueous injection su6pension which is isotonic i~ respect of body fluids containing 40% w/v of metronidazole and which is stable for up to one month.
:~L2~ 7;27 _ Benzyl slcohol (lml) end Pharmacoat 606 (0.5g) were added, with ~tirring, to ~ ~olution of sodium chloride (0.35g) in 6terile water ~60ml). The ~olution thus obtained was placed under ~terile conditions in 8 150ml glass bottle and sealed.
Sterile metronidazole ~40~) in the form of particles having a median maximum dimension of frQm 15 to 30 microns with not more than about 10h by weight of particles of 10 microns or less maximum dimension snd not more than about 10~ by weight of particles of 60 to 80 microns or greater maximum dimension (prepared as described in Example 1) W8S placed under sterile conditions in a 200ml glass bottle. The contents of the two bottles may be mixed to give lOOml of a ~5 sterile ~ubstantially neutr~l ~q~eou~ injection suspension which is isotonic in respect of body fluids containing 40V~ w~v of metronidazole, which may be ~dministered immediately or over a period of up to one month.
The proceedure described in Example 3 wa~
repeated but replacing the Pharmaco~t 606 by poly(vinylpyrrolidone) to give a ~terile ~ubstantially neutral aqueous injection ~uspension which i~ i~otonic in respect of body fluids containing 40% w/v of metronidazole suit~ble for immediate injection.
of particles having a median maximum dimension of from 15 to 30 microns ~nd containing not more than about 102 by weight of particles of 10 microns or les~
maximum dimension ~nd not more than about 10% by weight of particles of 80 microns, and preerably 60 microns, or more maximum dimen~ion, and optionally an effective amount of a particle growth regulant, preferably hydroxypropylmethylcellulose, or suspending agent and optionally one or more agents, for example ~o 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 and optionally one or more preservatives, According to a preferred feature of the present invention, there are provided sterile, ~ubstantially 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 ~rom 15 to 30 microns, and containing not more ~han ~bout 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 prefersbly 60 microns, or more maximum dimension, from 0.4 to 5.0~ wlv of hydroxypropylmethylcellulose, ~ 7 and more especially hydroxypropylmethylcellulose the viscosity of ~ 2h w/v aqueous ~olution of which is from 2 to 8 centipoises at 20QC, from n. 5 to 1.~% v/v ~volume/volume) of benzyl ~lcohol~ and, optionally, one or more agents, for example 60dium chloride, which render the aqueous suspension i~otonic to body fluids and optionally pharmaceutically-acceptable acids and bases, e.g. phosphate buffers, to render the suspensian sub6tantially neutral.
Sterile, ~ubstantially neutral aqueous injectable ~uspensions according to the present invention may be prepared by mixing, if necessary with agi~ation, the appropriate amount of sterile metronidazole in powder form of the hereinbefore ~pecified particle size ~ith a solution in ~terile water of the other hereinbefore specified ingredien~s or by mixing a ~terile suspension as hereinbefore defined but which contains in excess of 80% w/v of metronidazole, e.g. up to approximately 902 w/v of metronidazole, and which requires dilution to give a ~uspensi~n suitable for inject;on (~uch suspensions containin~ in excess of 80% w/v of metronidazole form a further feature of the present invention), with sterile water. The metronidazole may be ~terilised by gamma radiation or by passage of an aqueous solution of metronidazole through an ~nti-bacterial filter and crystallisation ~d milling under aseptic conditions.
For convenience, the metronidazole in powder form or a ~terile 6uspension as hereinbefore defined but which contains in excess of 80% wJv of metronidazole ~nd ~terile water or a 601ution in ~terile water of the other hereinbefore 6pecified ingredients, respectively, may be provided separately in suitable container6> for example glass bottles, and combined, if necessary with agitation, at the time of use. In the case of 6uspensions 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 reguired, any metronidazole particles which ~eparate from the ~uspensi~n may be resuspended by agitation.
Metronidazole in the form of particles having a median maximum dimension of from 15 to 30 microns ~nd 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 B0 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.~. a pin disc mill.
The following non-limitative Examples illustrate the present invention.:-72~7 Metronidazole powder having ~ median particlesize of 8D microns with 10% by weight of particles having a maximum dimension of greater than 200 microns was milled in ~ 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 lO~J~ by weight of particles of 60 to 80 mierons or greater maximum dimension9 was obtained, which was then sterilised by ga~ma radiation.
Benzyl slcohol ~lOml) 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 ~bout 10% by weight of particles of 60 to 80 microns or ~reater maximum dimension, (prepared as described in Example 1) was then added, with stirring, ~o the ~olution thus obtained. Further ~terile water was then added to a final volume of lOOOml to give a sterile substantially neutral aqueous injection su6pension which is isotonic i~ respect of body fluids containing 40% w/v of metronidazole and which is stable for up to one month.
:~L2~ 7;27 _ Benzyl slcohol (lml) end Pharmacoat 606 (0.5g) were added, with ~tirring, to ~ ~olution of sodium chloride (0.35g) in 6terile water ~60ml). The ~olution thus obtained was placed under ~terile conditions in 8 150ml glass bottle and sealed.
Sterile metronidazole ~40~) in the form of particles having a median maximum dimension of frQm 15 to 30 microns with not more than about 10h by weight of particles of 10 microns or less maximum dimension snd not more than about 10~ by weight of particles of 60 to 80 microns or greater maximum dimension (prepared as described in Example 1) W8S placed under sterile conditions in a 200ml glass bottle. The contents of the two bottles may be mixed to give lOOml of a ~5 sterile ~ubstantially neutr~l ~q~eou~ injection suspension which is isotonic in respect of body fluids containing 40V~ w~v of metronidazole, which may be ~dministered immediately or over a period of up to one month.
The proceedure described in Example 3 wa~
repeated but replacing the Pharmaco~t 606 by poly(vinylpyrrolidone) to give a ~terile ~ubstantially neutral aqueous injection ~uspension which i~ i~otonic in respect of body fluids containing 40% w/v of metronidazole suit~ble for immediate injection.
Claims (21)
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 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.
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 which comprises an effective amount of a particle growth regulant, said particle growth regulant being hydroxypropylmethyl-cellulose.
5. A suspension according to claim 4 in which the hydroxypropylmethylcellulose is such that a 2% w/v aqueous solution thereof has a viscosity of 2 to 8 centi-poises at 20°C.
6. A suspension according to claim 1 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 in which the suspending agent is 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 claim 1, 4 or 6 which comprises one or more agents which render the aqueous suspension isotonic to body fluids.
9. A suspension according to claim 1, 4 or 6 which comprises pharmaceutically acceptable acids and bases to render the suspension substantially neutral.
10. A suspension according to claim 1 which comprises at least one preservative.
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 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, 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 about 10% by weight of particles having a maximum dimension of 60 microns or greater.
14. A suspension according to claim 12 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 a 2% w/v aqueous solution thereof has a viscosity of 2 to 8 centipoises at 20°C.
16. 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 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.
17. A suspension according to claim 16 which comprises not more than about 10% by weight of particles having a maximum dimension of 60 microns or greater.
18. A suspension according to claim 16 or 17 which comprises from 80% w/v to approximately 90% w/v of metronidazole.
19. Metronidazole 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.
20. Metronidazole 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 60 microns or greater.
21. A pack comprising metronidazole as claimed in claim 19 or 20 and, separated therefrom, a sterile aqueous solution which, when added to the metronidazole, yields a sterile, substantially neutral aqueous injectable suspension as claimed in claim 1.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB838322364A GB8322364D0 (en) | 1983-08-19 | 1983-08-19 | Compositions of matter |
| GB8322364 | 1983-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1214727A true CA1214727A (en) | 1986-12-02 |
Family
ID=10547557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000461262A Expired CA1214727A (en) | 1983-08-19 | 1984-08-17 | Injectable compositions comprising 1-(2-hydroxyethyl -5-nitro imidazole |
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 CH CH3960/84A patent/CH662812A5/en not_active IP Right Cessation
- 1984-08-17 IL IL72714A patent/IL72714A/en unknown
- 1984-08-17 BE BE0/213510A patent/BE900381A/en not_active IP Right Cessation
- 1984-08-17 GB GB08420959A patent/GB2145088B/en not_active Expired
- 1984-08-17 HU HU843127A patent/HU192990B/en not_active IP Right Cessation
- 1984-08-17 AU AU32022/84A patent/AU577055B2/en not_active Ceased
- 1984-08-17 LU LU85511A patent/LU85511A1/en unknown
- 1984-08-17 CA CA000461262A patent/CA1214727A/en not_active Expired
- 1984-08-17 SE SE8404130A patent/SE460095B/en not_active IP Right Cessation
- 1984-08-17 DK DK397084A patent/DK165817C/en not_active IP Right Cessation
- 1984-08-17 JP JP59170517A patent/JPS6067468A/en active Pending
- 1984-08-17 DE DE19843430354 patent/DE3430354A1/en not_active Ceased
- 1984-08-17 ZA ZA846431A patent/ZA846431B/en unknown
- 1984-08-17 NZ NZ209270A patent/NZ209270A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IT8422323A0 (en) | 1984-08-13 |
| SE8404130L (en) | 1985-02-20 |
| ZA846431B (en) | 1985-03-27 |
| BE900381A (en) | 1985-02-18 |
| NL8402510A (en) | 1985-03-18 |
| JPS6067468A (en) | 1985-04-17 |
| LU85511A1 (en) | 1985-04-24 |
| HU192990B (en) | 1987-08-28 |
| FR2560043A1 (en) | 1985-08-30 |
| DK397084D0 (en) | 1984-08-17 |
| DK165817B (en) | 1993-01-25 |
| FR2560043B1 (en) | 1988-08-05 |
| IT1213208B (en) | 1989-12-14 |
| SE460095B (en) | 1989-09-11 |
| GB8322364D0 (en) | 1983-09-21 |
| NZ209270A (en) | 1988-02-29 |
| IL72714A (en) | 1988-09-30 |
| DK165817C (en) | 1993-06-21 |
| GB8420959D0 (en) | 1984-09-19 |
| GB2145088A (en) | 1985-03-20 |
| SE8404130D0 (en) | 1984-08-17 |
| DK397084A (en) | 1985-02-20 |
| AU577055B2 (en) | 1988-09-15 |
| CH662812A5 (en) | 1987-10-30 |
| DE3430354A1 (en) | 1985-03-07 |
| AU3202284A (en) | 1985-02-21 |
| GB2145088B (en) | 1986-10-08 |
| HUT35650A (en) | 1985-07-29 |
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