DK165817B - METRONIDAZOLE PARTICLES, STERILE, PRACTICALLY TAKEN NEUTRAL, Aqueous, INJECTABLE SUSPENSION THEREOF AND PACKAGE FOR PREPARATION - Google Patents

Description

in

DK 165817 B

The present invention relates to a sterile, virtually neutral, aqueous, injectable metronidazole suspension.

"Metronidazole" (1- (2-hydroxyethyl) -2-methyl-5-nitro-imidazole) is a well-known agent for use in controlling 5 amoebal and trichomonal infections and infections caused by anaerobic bacteria.

To establish, by parenteral administration, effective tissue levels of metronidazole which can be maintained for a reasonable period of time, e.g. up to 8 hours, it is often necessary to administer relatively large amounts of metronidazole, e.g. up to 500 mg. Metronidazole is relatively poorly soluble in water, having a solubility of approx. 0.8% w / v at room temperature, necessitating the administration of 100 ml of a 0.5% w / v solution to obtain a dose of 500 mg, requiring intravenous infusion of the solution, the volume in question being too large for administration by intramuscular or subcutaneous injection. This is relatively inappropriate and more concentrated injectable preparations containing metronidazole are needed, especially for veterinary use, and especially for a preparation which would allow the administration of a dose of metronidazole effective for up to 24 hours, i.e. . 1500 mg, in a single administration of a relatively small volume, e.g. 3-5 ml.

Aqueous solutions containing metronidazole at much higher concentrations, e.g. 50% w / v and above than is achievable using metronidazole as such can be obtained using salts of metronidazole which are highly soluble in water, e.g. kaliummetronidazol-phosphate. However, such concentrated solutions are hypertonic, i.e. they have a high osmotic pressure relative to body fluids and cause pain and local intolerance upon injection.

Satisfactory suspensions for injection containing high levels of solids, e.g. over 20% weight / -35 volume, are often difficult to manufacture, have unsatisfactory storage life and often cause pain and local

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2 injection site intolerance.

Furthermore, it is generally recommended that solid materials for injection should be in the form of very fine particles, typically particles having a maximum average dimension 5 of 10 µm or less, preferably less than 5 µπι.

It is also well known that it is usually necessary to include wetting and suspending agents in fine particle suspensions for injection to obtain a suspension of sufficient mobility and, if the particles separate from the liquid medium, resuspendability to allow light and high withdrawal of the required dose from the container to the hypodermic syringe and injection into the body.

Attempts at the preparation of injectable, concentrated, viz. up to 50% w / v aqueous suspensions of fine metronidazole particles, i.e. particles having a maximum average dimension of 10 μπι or even 5 μπι or less have been found to be unsuccessful as the suspensions have an unacceptably high viscosity, making it difficult to pull them into or spray them out of a hypodermic syringe, even when wetting and suspending agents, often used in injectable suspensions, are present.

It has now been found that the above problems have been solved with the present sterile, practically neutral, aqueous, injectable metronidazole suspension, which is peculiar in that it contains up to approx. 80% w / v metronidazole in the form of particles with a maximum average dimension of 15 to 30 μπι, with a maximum of approx. 10% by weight of particles have a maximum dimension of 10 μπι or less, 30 and at most approx. 10% by weight of the particles have a maximum dimension of 80 μιη, preferably 60 μιη or more.

Said weight% of the particles is measured by a laser light scattering method.

They have injectable aqueous suspensions of metronidazole not causing pain by intramuscular administration and / or local intolerance, and the release rate.

DK 165817B

The level of metronidazole from the injection site to the body tissues is such that the required level of metronidazole in the body tissues can be maintained by a single daily injection.

It is also known that solids in the presence of their saturated solutions undergo an increase in particle size by an Ostwald maturation or dissolution / recrystallization 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 10 after a few days, e.g. 5 days. This increase in the size of metronidazole particles in the suspension is undesirable, since vigorous growth can produce large crystals that will block the needle in a hypodermic syringe or interfere with the flow of the aqueous suspension through the needle, and can severely affect the resuspendability of the metronidazole particles in the suspension medium. so that a given volume of the suspension will not contain the expected amount of metronidazole.

In order to avoid this problem, it is preferred according to the invention that the present metronidazole suspension 20 contains an effective amount of a particle growth regulator or suspending agent.

Many particle growth regulators, viz. agents which suppress or control the growth of solid particles in contact with their saturated solutions are known, e.g.

25 "Tween®", poly (vinyl pyrrolidones), lecithin, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose and mixtures of these regulators. Of these various particle growth regulators, hydroxypropylmethyl cellulose has been found to be particularly suitable in effectively preventing the growth of 30 metronidazole particles in aqueous suspensions of metronidazole, conveniently at a concentration of 0.4 to 5.0% w / v.

If it is desired to prepare an injectable aqueous suspension of metronidazole of the present invention, which may be maintained for a period of a few days to a month without unacceptable increase in the particle size of the metronide.

DK 165817 B

Accordingly, it can be obtained by incorporating an effective amount of hydroxypropylmethyl cellulose, especially hydroxypropylmethylcellulose, which in the form of a 2% w / v aqueous solution has a viscosity of 2-8 cP at 20 ° C, e.g. the product commercially available under the trade name "Pharmacoat 606" in the suspension. The hydroxypropyl methylcellulose also serves as a suspending agent which holds the metronidazole particles in suspension and facilitates the resuspension of metronidazole particles which separate from the suspension.

However, if it is intended that the injectable aqueous suspension of metronidazole should be administered immediately or very quickly after preparation, i.e. before the growth of the metronidazole particles can occur, other suspending agents which do not inhibit the growth of the metronidazole particles, e.g. products of ethoxylation of castor oil and hydrogenated castor oil, including those commercially available under the trade names "Cremophore® RH410", "EL", "RH60" and "RH40", "Arlatone 285" and "164", polypropylene oxide, ethoxylated to varying degrees, including the products commercially available under the trade names "Pluronic® L62", "F68" and "108", sorbitan-fatty acid ethoxylates, including the products commercially available under the trade name "Tween®", poly (vinyl pyrrolidones), lecithin, sodium carboxymethyl cellulose and "Carbomer BP", a high molecular weight synthetic polymer of acrylic acid crosslinked with allyl sucrose and containing 56-68% carboxylic acid groups.

As the aqueous suspensions of 30 metronidazole particles are intended to be administered by injection, it will be understood that they are prepared from sterile materials or that they are sterilized after manufacture and stored under sterile conditions or contain preservatives to prevent microbial contamination.

If the injectable aqueous suspension of metronide azole is to be stored in a multi-dose container from which

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5 a suitable amount of suspension for a single dose is removed when and if necessary over a period of time ranging from a few days to a month, a preservative should be incorporated. The preservative must be compatible with the particle growth regulator and / or the suspending agent (eme). Benzyl alcohol has been found to be compatible with hydroxypropylmethyl cellulose and is preferred as a preservative.

If hydroxypropylmethyl cellulose is not present and other suspending agents are used as described above, other preservatives, e.g. cresol or ortho-chlorocresol.

If desired, conventional means, e.g. sodium chloride, is incorporated into the injectable aqueous suspensions of the present invention to render them isotonic with respect to body fluids, and if necessary, pharmaceutically acceptable acids and bases are added, e.g. phosphate buffers, to render the suspension virtually neutral.

A preferred embodiment of the sterile, virtually neutral, aqueous injectable metronidazole suspension provided by the present invention is characterized in that it is isotonic in body fluids and contains from 1 to 80%, preferably 1-60%, by weight. volume of metronidazole in the form of particles with a maximum average dimension of from 15 to 30 µm; 10% by weight of particles have a maximum dimension of 10 μιη or less, and a maximum of approx. 10 weight percent of the particles have a maximum dimension of 80 µm, preferably 60 µm or more, from 0.4-5.0% w / v hydroxypropyl methylcellulose and 0.5-1.5% w / v benzyl alcohol.

In this embodiment, the hydroxypropyl methyl cellulose in the form of a 2% w / v aqueous solution preferably has a viscosity of 2-8 cP at 20 ° c. Optionally present therein may also be one or more agents, e.g. sodium chloride which renders the aqueous suspension isotonic to body fluids and, if necessary, pharmaceutically acceptable acids and bases, e.g. phosphate buffers, to make the suspension

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6 practically neutral.

Sterile, virtually neutral, aqueous injectable suspensions of the present invention may be prepared by mixing, if necessary with stirring, an appropriate amount of powdered metronidazole in the powder form of the above specified particle size with a solution in sterile water of the other ingredients specified above. or by mixing a sterile suspension as described herein, but containing more than 80% w / v metronidazole, e.g.

10 up to approx. 90% w / v metronidazole and which requires dilution to obtain a suspension suitable for sterile water injection.

The invention also relates to such a highly concentrated metronidazole suspension which is characterized by the characterizing part of claim 8.

The metronidazole can be sterilized by gamma irradiation or by passing an aqueous solution of metronidazole through an antibacterial filter and crystallizing and formalizing under aseptic conditions.

Conveniently, the metronidazole may be in powder form or a sterile suspension as described above, but containing respectively. over 80% w / v metronidazole and sterile water, or a solution in sterile water with the other ingredients specified above, are provided separately in suitable containers, e.g. glass bottles, and, if necessary, combined with stirring, at the time of use.

Accordingly, the present invention also relates to a package which is characterized in that it contains metronidazole in particulate form with the above particle dimensions and separated therefrom by a sterile aqueous solution which, upon addition to the metronidazole, provides the sterile, practically taken herein. neutral, aqueous, injectable metronidazole suspension.

In the case of suspensions of the present invention which contain a particle growth regulator and which can be stored for a period of from a few days to approx. one

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7 months, e.g. in a multi-dose container from which single doses are removed as and when required, any metronidazole particle which is excreted from the suspension can be resuspended by stirring.

The invention finally relates to metronidazole for use in preparing the present suspensions, and this metronidazole is peculiar in that it is in the form of particles having a maximum average dimension of from 15 to 30 mm, with a maximum of approx. 10% by weight of particles has a maximum dimension of 10 µm or less, and a maximum of approx. 10 weight percent particles have a maximum dimension of 80 mm, preferably 60 mm, or more. Such particles can be prepared by grinding metronidazole powder with a larger average particle dimension in a suitable mill, e.g. a pin disk mill.

The following examples illustrate the present invention.

Example 1.

20 Metronidazole powder with an average particle size of 80 mm by 10 wt.% Particles with a maximum dimension of more than 200 mm is ground in a "Minikek" pin disk mill equipped with 174 pins until metronidazole in the form of particles with a maximum average dimension is obtained. of 25 from 15 to 30 mm, of which a maximum of 10% by weight of particles has a maximum dimension of 10 mm or less, and not more than about 10% by weight of particles have a maximum dimension of 60-80 mm or more. These particles are then sterilized by gamma radiation.

30

Example 2.

Add 10 ml of benzyl alcohol and 5 g of Pharmacoat 606 with stirring to a solution of 3.5 g of sodium chloride in 500 ml of sterile water. obtained solution.

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8

An additional amount of sterile water is then added to a final volume of 1000 ml to obtain a sterile, practically neutral, aqueous injection suspension which is isotonic with respect to body fluids containing 40% w / v metronidazole and which is stable in up to a month.

Example 3

1 ml of benzyl alcohol and 0.5 g of Pharmacoat 606 are added with stirring to a solution of 0.35 g of sodium chloride in 60 ml of sterile water. The solution thus obtained is placed under sterile conditions in a 150 ml glass bottle and sealed.

40 g of sterile metronidazole in the form of particles prepared as described in Example 1 are placed under sterile conditions in a 200 ml glass bottle. The contents of two vials are mixed to give 100 ml of a sterile, virtually neutral, aqueous injection suspension which is isotonic with body fluids containing 40% w / v metronidazole and may be administered immediately or over a period of up to a month.

20

Example 4

The procedure described in Example 3 is repeated, but "Pharmacoat 606" is replaced with poly (vinylpyrrolidone) to obtain a sterile, virtually neutral, aqueous injection suspension which is isotonic with respect to body fluids containing 40% w / v metronidazole and which is suitable for immediate administration.

Claims (10)

1. Sterile, virtually neutral, aqueous, injectable metronidazole suspension, characterized in that it contains up to approx. 80% w / v metronidazole in the form 5 of particles with a maximum average dimension of from 15 to 30 / m, with a maximum of approx. 10% by weight of particles have a maximum dimension of 10 μια or less and no more than approx. 10% by weight of the particles have a maximum dimension of 80 μια, preferably 60 μιη or more. Suspension according to claim 1, characterized in that it contains an effective amount of a particle growth regulator, preferably hydroxypropylmethylcellulose, or a suspending agent. Suspension according to claim 2, characterized in that the hydroxypropylmethyl cellulose in the form of a 2% w / v aqueous solution has a viscosity of 2-8 cP at 20 ° C. Suspension according to claim 1, characterized in that it contains an effective amount of a suspending agent which does not inhibit the growth of the metronidazole particles, preferably 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 (vinyl pyrrolidones), lecithin, a sodium carboxymethyl cellulose or a high molecular weight acrylic acid synthetic polymer crosslinked with allyl sucrose containing 56-68% carboxylic acid groups. Suspension according to any one of the preceding claims, characterized in that it contains 30 one or more agents which render the aqueous suspension isotonic to body fluids and / or pharmaceutically acceptable acids and bases to make the suspension practically neutral and / or one or more preservatives, preferably benzyl alcohol. A sterile, substantially neutral, aqueous, injectable metronidazole suspension according to claim 1, characterized in that it is isotonic with respect to body fluids and contains from 1 to 80%, preferably 1-60%, by weight / volume of metronidazole in the form of particles with a maximum average dimension of from 15 to 30 μιη, with a maximum of approx. 10 weight percent particles have a maximum dimension of 10 μιη or less, and no more than approx. 10 weight percent of the particles have a maximum dimension of 80 μπι, preferably 60 μιη or more, from 0.4-5.0% w / v hydroxypropyl methylcellulose and from 0.5-1.5% w / v benzyl alcohol. Suspension according to claim 6, characterized in that the hydroxypropylmethyl cellulose in the form of a 2% w / v aqueous solution has a viscosity of 2-8 cP at 20 ° C. 8. Sterile, virtually neutral, aqueous, injectable, 15 highly concentrated metronidazole suspension, characterized in that it contains up to approx. 90%, preferably 80-90%, w / v metronidazole in the form of particles with a maximum average dimension of from 15 to 30 μη, with a maximum of approx. 10% by weight of particles have a maximum dimension of 20 10 μη or less, and a maximum of approx. 10% by weight of particles have a maximum dimension of 80 μιη, preferably 60 μιη or more. Metronidazole for use in the preparation of a suspension according to claim 1, characterized in that it is in the form of particles having a maximum average dimension of 15 to 30 µm, with a maximum of approx. 10% by weight of particles have a maximum dimension of 10 μιη or less, and a maximum of approx. 10% by weight of particles have a maximum dimension of 80 μιη, preferably 60 μιη or more. Package characterized in that it contains metronidazole according to claim 9 and separated therefrom a sterile aqueous solution which, upon addition to the metronidazole, provides a sterile, virtually neutral, aqueous injectable suspension according to any one of claims 1- 7th