NO774315L - PROCEDURE FOR PREPARING ANTIBIOTIC FORMULATIONS - Google Patents

Description

Procedure in the manufacture of

antibiotic formulations

The present invention relates to antibiotic formulations and improvements relating to these. More specifically, the invention relates to a (3-lactam) antibiotic formulation and preparation thereof, which formulation is suitable for use in the preparation of an injectable antibiotic mixture by mixing with an aqueous solution of an aminoglycoside antibiotic. The invention also relates to the thus obtained injectable antibiotic mixture and its manufacture.Furthermore, the invention relates to equipment suitable for use in the manufacture of the injectable antibiotic suspension.

When treating infection, particularly severe infections such as those caused by pathogenic bacteria in hospital patients, it is often desirable to be able to use combinations of antibiotics.

When treating the infection caused by gram-negative bacteria, it is known to use aminoglycoside antibiotics of which gentamicin is particularly representative. Furthermore, synergism has been shown in vitro in specific combinations of an aminoglycoside antitioticum and a (3-lactam antibioticum. Thus, as early as 1963, Bulger and Kirby in Am. J. Med. Sei., 246, 717 - 726, described synergistic effect of freshly prepared mixtures of, among other things, gentamicin and certain 3-lactam antibiotics in their in vitro activity against specified gram-negative bacteria Bulger and Kirby concluded that the increased in vitro antibacterial activity was sufficient to warrant a combination therapy in certain severe or stubborn infections.

Despite the stated desirability of using combinations of aminoglycoside and (3-lactam antibiotics), their clinical use has not been fully accepted. Among other things, it has been observed that in aqueous media the 3-lactam antibiotic is capable of chemically inactivating the aminoglucoside antibiotic. This inactivation has been demonstrated in in vitro studies of mixtures of gentamicin and carbenicillin by Waitz et al., J. Antibiotics, 25(4), 219-225 (1972). Waitz et al. indicated that the effect is dependent on time, temperature and medium, and shows, for example, that in distilled water at 20° C the gentamicin potency of a gentamicin-carbenicillin mixture falls after 24 hours to about half its original level. Physico-chemical studies of the inactivation assume that this is the result of the nucleophilic opening of the (3-lactam ring in the 3-lactam antibiotic by an amino group of the aminoglycoside antibiotic with the formation of a biologically inactive amide.

Where combined clinical use of an aminoglycoside antibiotic and a (3-lactam antibiotic) has been used, it has been practice to administer the antibiotics separately and usually at relatively widely separated time intervals of several hours. Such an administration method is of course cumbersome, time-consuming and inappropriate both for patients and hospital staff.

An aim of the present invention is to provide an antibiotic combination product of an aminoglycoside antibiotic and a 3-lactam antibiotic in a form suitable for administration as a single injectable composition. It is a further object of the invention to provide such an antibiotic combination product in a form which overcomes or reduces the above-mentioned problem associated with inactivation of the aminoglycoside of the 3-lactam antibiotic.

It has now been found that a satisfactory antibiotic combination product can be obtained by using as the 3-lactam antibiotic component, a 3-lactam antibiotic in a special form and coated with a specified coating material.

According to a feature of the invention, a 3-lactam antibiotic formulation is thus provided which is suitable for use in the preparation of an injectable antibiotic mixture by mixing with an aqueous solution of an aminoglucoside antibiotic, which 3-lactam antibiotic formulation comprises a water-insoluble or very slightly soluble (3-lactam antibiotic in particulate form coated with a mixture comprising on a weight basis 1-3 parts lecithin and 0.2 - 1 part polyvinylpyrrolidone per 100 parts 3-lactam antibiotic, and where the formulation has a particle size of 74 microns or less and is mainly free of sodium chloride.

The 3-lactam antibiotic formulation enables that

a satisfactory antibiotic combination product can be obtained in a simple way by mixing the formulation on a specified basis with an aqueous solution of an aminoglycoside antibiotic.

According to another feature of the invention, an injectable antibiotic mixture is provided in the form of a suspension and use of the 3-lactam antibiotic formulation as a component thereof, which injectable antibiotic mixture comprises an aqueous solution of an aminoglycoside antibiotic which has suspended therein the 3-lactam antibiotic formulation, which suspension is essentially free of sodium chloride.

The word "injectable" as used in relation to an antibiotic mixture in the form of a suspension (whether or not it is a suspension is explicitly stated) indicates that the suspension is suitable for intramuscular injection, the suspension passing through a 20-gauge hypodermic needle, and this corresponds to a needle diameter of 0.9 mm, without clogging or

otherwise obstructing the flow through the needle.

According to another feature of the invention, a two-component device is provided for use in the preparation of the injectable antibiotic mixture, which device comprises a first container with an aqueous solution of an aminoglycoside antibiotic and a second container with the 3-lactam antibiotic formulation.

As previously stated, the current occupancy per 100 parts of the 3-lactam antibiotic, 1-3 parts by weight of lecithin and 0.2 - 1 part by weight of polyvinylpyrrolidone. The use of lecithin and polyvinylpyrrolidone for coating finely divided ampicillin is described in specific circumstances in US patent 3,634,586, where the stated intended purpose of the coating is to extend the shelf life of the powdered ampicillin. In this publication, lecithin and polyvinylpyrrolidone are used in specific amounts that lie outside the ranges used according to the present invention, and furthermore in combination with various other ingredients including, in particular, sodium chloride which constitutes an essential feature of the described coated ampicillin.

There is no description in the US patent document

3 634 586 that coating a 3-lactam antibiotic in a special way could provide a solution to the problem associated with the present invention, namely providing an antibiotic combination product which is suitable for injection. If one would further attempt to use a coating as described in the known publication, one would find that a satisfactory antibiotic combination product was not obtainable, as in strong contrast to the known publication, sodium chloride has a destructive effect on the product suspension and causes clumping in the suspended material.

In view of the destructive effect of sodium chloride, the 3-lactam antibiotic formulation and the antibiotic mixture according to the invention are essentially free of sodium chloride. By "substantially free" is meant that the concentration of each sodium chloride is below the concentration at which the resulting antibiotic mixture no longer satisfies the requirement to be an injectable antibiotic mixture.

Although the exact mechanism by which sodium chloride adversely affects the uniformity and stability of the product suspension is not known, it seems possible that the adverse effect is associated with sodium chloride being a strong electrolyte. On this basis, the use of other similarly strong electrolytes in the injectable antibiotic mixture should be avoided.

In the injectable antibiotic mixture according to the invention, the use of additives which are usually used in known intramuscular injectable compositions, other than antioxidants, should preferably be avoided. This applies whether the parenterally acceptable additive is a strong electrolyte or not, as it has been found that additives such as preservatives or surfactants adversely affect the formation of a suspension. The above-mentioned antioxidant additive can for example be any suitable metabisulphite such as potassium metabisulphite or preferably sodium metabisulphite present in usual concentrations and preferably constituting a single additional component.

The 3-lactam antibiotic formulation according to the invention is, as previously indicated, of a particle size of 74 microns or lower, with 74 microns corresponding to the size of the sieve opening in a US standard sieve no. 200 and the expression "74 microns or lower" indicates that the material passes through such a term.

The 3-lactam antibiotic itself is in a water-insoluble or very slightly soluble form, i.e. in a form capable of being suspended in an aqueous medium. The 3-lactam antibiotic may be a member of the penicillin group of antibiotics among which penicillin G, penicillin O, carbenicillin and in particular ampicillin are suitable water-insoluble agents or very sparingly soluble examples. Water-insoluble or very slightly soluble salts of the preceding compounds can also be used, e.g. procaine and. The N,N'-dibenzylethylenediamine salts. The 3-lactam antibiotic may also be any suitable member of the cephalosporin group of antibiotics of which cefoxithin, cephalothin and cephalexin may be exemplified.

The lecithin component of the 3-lactam antibiotic formulation can be any suitable pharmaceutical grade material, which also applies to the polyvinylpyrrolidone. In terms of molecular weight, a polyvinylpyrrolidone with an average molecular weight of 15,000 to 50,000 can typically be used with a preferred range of 23,000 to 33,000. A material with an average molecular weight of 25,000 has been advantageously used.

When producing the 3-lactam antibiotic formulation, the desired 3-lactam antibiotic with the required particle size can be coated with a suitable mixture of lecithin and polyvinylpyrrolidone using conventional coating techniques. For example, the coating can be applied using the methods described in US patent 3 6 34 584. Under sterile conditions and in the main absence of sodium chloride, the powdered sterile 3-lactam antibiotic can thus be triturated with a sterile solution containing appropriate amounts of lecithin and polyvinylpyrrolidone in a suitable solvent such as methylene chloride. The coated material is then dried and repulverized to form a 3-lactam antibiotic formulation with a particle size of 200 mesh or less and which is substantially free of sodium chloride. Alternatively, the coating step can be carried out using a sterile solution of lecithin and polyvinylpyrrolidone in methanol. This methanolic solution can be prepared by dispersing the lecithin in acetone, filtering off the solid material, drying it and dissolving the dried solid material in methanol. The methanol solution is then filtered, the solid is discarded and the resulting solution is added to a solution of polyvinylpyrrolidone in methanol.

The solution thus obtained is then sterilized in a known manner.

Drying of the coated material obtained by any suitable coating step can be carried out using vacuum drying on conventional drying troughs. Alternatively, the coated material can be freeze-dried using conventional freeze-drying techniques.

The entire manufacturing operation for the 3-lactam antibiotic formulation is performed under sterile conditions.

As representative examples of aminoglycoside antibiotics that can be used in the injectable antibiotic mixture according to the invention, gentamicin, sisomicin, netilmicin, kanamycin, tobramycin and amikacin can be mentioned. When preparing the aqueous solution of the aminoglycoside antibiotic, a water-soluble form of the antibiotic is used, such as a water-soluble pharmaceutically acceptable salt. Useful salts are, for example, those derived from citric acid, nitric acid and sulfuric acid. In light of its generally good solubility and stability, the sulfate salt is a particularly useful salt.

The aqueous solution of the aminoglycoside antibiotic can be prepared using conventional methods used for the preparation of injectable solutions with the exception, as previously stated, that many of the usual additives such as preservatives or surface-active agents can be omitted and are preferably omitted when the presence of such additives may adversely affect the formation of a suspension. In each particular case, one can easily determine by simple experiments whether a specific additive will adversely affect the formation of a suspension. The aqueous solution of the aminoglycoside is prepared in a known manner under conditions which give a sterile product.

In the two-component equipment for use in the preparation of the injectable antibiotic mixture according to the invention, a first container contains the sterile aqueous solution of an aminoglycoside antibiotic and a second container contains the sterile 3-lactam antibiotic formulation.

Typically, the first container is a conventional ampoule and the second container is a silicon-coated glass bottle with a permeable rubber or lingneride closure through which a needle can pass for introducing the aqueous solution of the aminoglycoside antibiotic.

In use, the injectable antibiotic mixture will be prepared by the physician or nurse by adding to the other container the required amount of the sterile aqueous solution of the aminoglycoside antibiotic followed by gentle shaking to effect a suspension.

The injectable antibiotic mixture obtained in this way is a suspension with the characteristics necessary to be able to be introduced by syringe and drip to the patient. The suspension remains stable, i.e. suitable for injection for periods of up to 36 hours and quite typically no adverse chemical inactivation of the antibiotic components is noted.

Typically, the injectable antibiotic mixture according to the invention will contain per ml suspension 5 - 250 mg, calculated as free base, of the aminoglycoside antibiotic and 50 - 500 mg of the 3-lactam antibiotic. The dose will of course depend on the particular antibiotics used in the antibiotic mixture. In a particularly preferred embodiment of the invention, a dose per ml of suspension from 10 to 40 mg, calculated as free base, of gentamicin and from 125 to 500 mg of ampicillin. Ampicillin can be in the form of the trihydrate, although it is more preferred that it is present in anhydrous form.

The two-component equipment according to the invention can also consist of a two-chamber syringe in which the two chambers form a first and second container.

It has been found in embodiments of the present invention that the release patterns in vivo of the antibiotic components in the injectable antibiotic mixture make it possible to achieve peak concentrations in the bloodstream of the antibiotics at essentially the same time. In such embodiments where the concentration of the antibiotic components reaches a peak at the same time, the synergistic effect will be particularly well demonstrated.

The invention is illustrated by the following examples, in which example 1 illustrates the production of the coated 3-lactam antibiotic formulation according to the invention.

The remaining examples illustrate the preparation of an injectable antibiotic mixture, i.e. according to the invention, in the form of an aqueous suspension comprising the coated 3-lactam antibiotic formulation and an aminoglycoside antibiotic. Also illustrated is a two-container equipment suitable for use in the preparation of the antibiotic mixture and which represents another feature of the present invention. All preparations are of course carried out under sterile conditions.

The antibiotic mixture obtained in the examples was a suspension of sufficient physical and chemical stability to permit use for intramuscular injection using a No. 20 (0.9 mm diameter) needle, and the suspension remained sterile for up to . 36 hours.

Example 1

Preparation of a coated 3-lactam antibiotic formulation

The desired sterile 3-lactam antibiotic is reduced to a particle size of 200 mesh (74 micron) or less, and is then coated in a known manner (as described in US Patent 3,634,586). The coating is typically carried out by triturating the powdered β-lactam antibiotic with a sterile solution containing the required amounts of lecithin and polyvinylpyrrolidone in a suitable solvent such as methylene chloride or methanol. The coated material is then dried and re-pulverized to form a (3-lactam antibiotic formulation) having a particle size of 200 mesh or less and which is free of sodium chloride.

The relative amounts of antibiotic, lecithin and polyvinylpyrrolidone used are chosen according to the desired composition of the formulation, this composition being specified in the examples. A typical composition is on a weight basis 98.0% (3-lactam antibiotic, 1.4% lecithin and 3.6% polyvinylpyrrolidone.

Example 2

A kit for the preparation of an antibiotic mixture suitable for intramuscular injection containing a dose of 80 mg gentamicin (calculated as free base) and 1000 mg ampicillin/2 ml is prepared from the following:

The gentamicin sulfate and sodium metabisulfate are dissolved in a small amount of water for injection. The resulting solution is brought to a volume of 2 ml by further addition of water for injection and packaged in a sterile ampoule.

The coated ampicillin is prepackaged in a 4-5 ml<1>s bottle with a sterile rubber cover.

At the time of administration to the patient, 1.6 ml of aminoglycoside antibiotic solution is withdrawn from the ampoule of the syringe and injected into the container with the coated penicillin derivative. Mixing produces an injectable suspension that delivers a dose of 40 mg/ml gentamicin and 500 mg/ml ampicillin that is stable for 36 hours.

Example 3

A device containing a pediatric dose is prepared as described in Example 2 from the following:

Mixing as described in Example 2 provides an injectable suspension which delivers a dose of 10 mg/ml gentamicin and 125 mg/ml ampicillin.

Example 4

A device was prepared as described in Example 2 from the following:

Mixing as described in Example 2 gives an injectable suspension which delivers a dose of 50 mg/ml sisomycin and 500 mg/ml ampicillin.

Example 5

A device for pediatric use was prepared as described in Example 2 from the following:

Mixing was carried out as described in Example 2 which produced an injectable suspension providing a dose of 10.0 mg/ml sisomycin and 125 mg/ml penicillin G.

Example 6

A device was prepared as described in Example 2 from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension giving a dose of 100 mg/ml netilmicin and 250 mg/ml ampicillin.

Example 7

A device was prepared as described in Example 2 from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension which gave a dose of 250 mg/ml kanamycin and 500 mg/ml ampicillin.

Example 8

A device containing a pediatric dose was prepared as described in Example 2 from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension giving a dose of 37.5 mg/ml kanamycin and 125 mg/ml ampicillin.

Example 9

A device was produced as described in example 2

from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension which delivered a dose of 40 mg/ml gentamicin and 250 mg/ml carbenicillin.

Example 10

An apparatus was prepared as detailed in

example 2 from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension which delivered a dose of 40 mg/ml gentamicin and 250 mg/ml procaine penicillin G.

Example 11

A device was produced as described ■ in the example. 2 from the following:

Mixing was carried out as described in example 2

while forming an injectable suspension that delivered a dose of

50 mg/ml tobramycin and 500 mg/ml ampicillin.

Example 12

A device was produced as described in example 2

from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension which delivered a dose of 40 mg/ml amikacin and 250 mg/ml ampicillin.

Example 13

A device for pediatric use was prepared as described in Example 2 from the following:

Mixing was carried out as described in Example 2 to form an injectable suspension which delivered a dose of

10 mg/ml amikacin and 125 mg/ml ampicillin.

Example 14

A device was prepared as described in Example 2 from the following:

Mixing was done as described in Example 2 to form an injectable suspension which delivered a dose of 40 mg/ml amikacin and 250 mg/ml cephalothin.

As previously indicated, the injectable antibiotic mixtures according to the invention are intended for intramuscular injection. Relevant pharmacological data for such administration, including in vivo activities and toxicities of the antibiotics can be obtained by consulting suitable literature.

Claims (18)

1. Method for making a 3-lactam antibiotic suitable for use in the production of an injectable antibiotic combination product of an aminoglycoside antibiotic and a 3-lactam antibiotic, characterized in that a water-insoluble or very slightly soluble 3-lactam antibiotic in particulate form of 74 micron or less is coated essentially in the absence of sodium chloride with a coating material comprising on a weight basis 1-3 parts lecithin and 0.2 to 1 part polyvinylpyrrolidone per 100 parts 3-lactam antibiotic, which coating step is followed if necessary by reducing the particle size of the formulation thus obtained to 74 microns or lower. 2. Method according to claim 1, characterized in that the 3-lactam antibiotic is a penicillin antibiotic. 3. Method according to claim 2, characterized in that the penicillin antibiotic is selected from ampicillin, carbenicillin and penicillin G. 4. Method according to claim 3, characterized in that the penicillin antibiotic is ampicillin. 5. Method according to claim 1, characterized in that the 3-lactam antibiotic is a cephalosporin antibiotic. 6. Method according to claim 5, characterized in that the cephalosporin antibiotic is cephalothin. 7. Process for producing an injectable antibiotic combination product of a 3-lactam antibiotic and an aminoglycoside antibiotic, characterized in that an aminoglycoside antibiotic, a 3-lactam antibiotic formulation comprising a water- insoluble or very slightly soluble 3-lactam antibiotic in particulate form coated with a mixture comprising on a weight basis 1-3 parts lecithin and 0.2-1 part polyvinylpyrrolidone per 100 parts 3-lactam antibiotic, and where the formulation has a particle size of 74 microns or lower and is essentially free of sodium chloride. 8. Method according to claim 7, characterized in that the aminoglycoside antibiotic is gentamicin, sisomicin, netilmicin or kanamycin in the form of a water-soluble pharmaceutically acceptable salt. 9. Method according to claim 8, characterized in that the pharmaceutically acceptable salt is a sulfate salt. 10. Method according to claim 8 or 9, karate r i s e r t in that the aminoglycoside antibiotic is gentamicin. 11. Method according to any one of claims 7-10, characterized in that the aqueous solution of the aminoglycoside also contains an anti-oxidizing agent as the only additive. 12. Method according to claim 11, characterized in that the antioxidant is the only additive. 13. Method according to any one of claims 7-12, characterized in that the 3-lactam antibiotic is a penicillin antibiotic. 14. Method according to claim 13, characterized in that the penicillin antibiotic is selected from ampicillin, carbenicillin and penicillin G. 15. Method according to claim 14, characterized in that the penicillin antibiotic is ampicillin. 16. Method according to any one of claims 7-12, characterized in that the 3-lactam antibiotic is a cephalosporin antibiotic. 17. Method according to claim 16, characterized in that the cephalosporin antibiotic is cephalothin. 18. Method according to any one of claims 7-17, characterized in that the amount of the aminoglycoside antibiotic, calculated as free base, is 5 - 250 mg per ml of aqueous solution and that the amount of the (3-lactam antibiotic formulation) is 50 - 500 mg for each ml of calculated injectable antibiotic mixture.