Antibiotic maduraphthalazin salts with delayed release of the active substance and their use

Patent description

This invention relates to antibiotic maduraphthalazin salts, which show a low solubility in water and in aqueous media and a delayed release of active substances, and the use of these salts.

Poly cyclic maduraphthalazins, 2-carboxyalkyl- and 2-carboxyaryl- substituted maduraphthalazins in form of their N-methyl-D- glucamonium salts present a new type of anti-bacterial substances that are particularly effective against Gram-positive, especially against multiresistant staphylococci (MRSA) and resistant enterococci (W. Witte, C. Cunny, E. Roemer, U. Grafe, L. Heinisch, U. Mδllmann, W. Werner: New polycyclic phthalazine compounds (madura phthalazine derivates) DE 19719522). Due to their great anti-bacterial efficacy the compounds mentioned are especially interesting for the local antibiotic therapy, in particular for the treatment of implant-associated bacterial infections. However, it is to be taken into account that the anti- bacterially effective carboxyalkylatεd or carboxyaryiated maduraphthalazin salts in form of their N-methyl-D-glucamonium salts are freely soluble compounds in water. Although this property is advantageous for the development of the anti-bacterial effect it is a disadvantage for the local application of the mentioned derivates as a depot, for example in close vicinity to an implant. In the humid milieu of the body water-soluble low-molecular compounds quickly diffuse away from the effective zone and thus they cannot develop their pharmacologic effect at the desired location or they can do it only in a weaker manner. Therefore, the available form of the mentioned freely- soluble maduraphthalzin derivates is not suited for use as a depot system.

Thus, the task of this invention is to develop, on the basis of in water soluble maduraphthalazin salts, depot forms with antibiotic effects that are able to fight successfully against a spectrum of bacterial as broad as possible and that show a controlled release of low quantities of the active

substance over a period of several days or weeks in an aqueous milieu. The depot forms shall be used in particular for the local antibiotic therapy of bacterial infections. Moreover, the depot forms to be developed shall provide an effective antibiotic protection of implants over a period of several weeks.

According to the invention, this task is fulfilled by the provision of maduraphthalazin salts that show low solubility in water and consist of an anionic component, which is formed by at least one representative of the group of carboxyalkylated or carboxyarylated maduraphthalazin salts, and of a cationic antibiotic component.

The invention is based on the surprising findings that water-soluble carboxyalkylated or carboxyarylated maduraphthalazin salts in aqueous solution and water-soluble salts of cationic antibiotics form maduraphthalazin salts with low solubility in water in form of precipitates and that in aqueous solution these precipitates exhibit a delayed release of the effective substance over a period of several weeks. The generation of maduraphthalazin salts with low solubility in water by the anionic and cationic components is based on a reciprocal salt exchange.

According to the invention, carboxylalkylated or carboxylarylated maduraphthalazin salts are used as the anionic component.

According to this invention, all the maduraphthalazin salts claimed in DE 19719522 are used as the anionic component.

The use of 2-(4-carboxyphenyl)-maduraphthalazin and/or 2- carboxymethyl-maduraphthalazin and/or 2-carbethoxymethyl- maduraphthalazin and/or 2-(D,L-α-carboxypropyl)-maduraphthalazin salts as an anionic component is particularly advantageous for this invention.

Another feature of this invention is the use of carboxylalkylated or carboxylarylated maduraphthalazin salts in form of water-soluble salts. The use of N-methyl-glucammonium salts of the carboxyalkylated or carboxyarylated maduraphthalazins is particularly preferred.

According to this invention, salts of cationic antibiotics being freely soluble in water are used as the antibiotic component.

A further feature of this invention is that the chlorides, bromides, hydrogen sulfates, sulfates, dihydrogen phosphates, hydrogen phosphates, phosphates, acetates, succinates or lactates of the cationic antibiotics are used as the freely water-soluble salts of said cationic antibiotics.

In the inventive compound, gentamicin, kanamycin, amikacin, clindamicin, neomycin, streptomycin, vancomycin, tetracycline, doxicyclin, oxytetracyclin, rolitetracyclin or mixtures of these antibiotics are used as the cationic antibiotic components.

According to this invention, 0.01 to 10 molar mass parts of the carboxyalkylated or carboxyarylated maduraphthalazins are converted with one mol mass portion of the cationic antibiotic component. Moreover, it is preferred in this invention that the carboxyalkylated or carboxyarylated maduraphthalazins and the cationic antibiotic component are converted in the stoichiometric mol mass relation according to the existing cationic and anionic groups.

The inventive use is characterized by the fact that the antibiotic maduraphthalazin salts with low solubility in water are integrated into specially shaped bodies, tablets, powder, pellets, gels, films, foils, tubes, threads, textiles, knitwear or fleeces that are used as permanent or temporary implants. These implants can be used as antibiotic depot preparations to fight against bacterial infections at a specified location and they can be used in the precaution against bacterial infections.

It is a further characteristic feature of this invention that the antibiotic maduraphthalazin salts, which have a low solubility in water, are components of coatings that can be applied onto specially shaped bodies, tablets, powder, pellets, gels, films, foils, tubes, threads, textiles, knitwear and fleeces being used as permanent or temporary implants. This refers in particular to coatings on metal implants, on ceramic, glass

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and glass-ceramic implants, on absorbable and non-absorbable plastic implants as well as on implants being composites of the just mentioned material classes.

A further characteristic feature of this invention is the use of the antibiotic maduraphthalazin salts, which have a low solubility in water, as a sole antibiotic agent or within a mixture with other antibiotics.

In the following, the invention is explained by two examples without being restricted to them.

Example 1 :

Conversion of gentamicin sulfate with the N-methyl-D-glucamonium salt of 2-carboxymethyl-maduraphthalazin

4.69 mg (0.00634 mmol) of the N-methyl-D-glucamonium salt of 2- carboxymethyl-maduraphthalazin are dissolved in 1 ml water. Then, at room temperature 0.93 mg (0.00127 mmol) gentamicin sulfate AK617 are added to this solution by stirring. A red deposit precipitates. After two hours of stirring at room temperature, this deposit is centrifuged and then washed twice with distilled water. Afterwards, the product is dried in vacuum at room temperature till the mass constant is reached. In this way, 3.6 mg of a red solid are obtained.

Wave numbers of 12 absorption-bands detectable in the FT-IR spectrum, which shows clearly marked peaks. These are in detail [I/cm]: 2946,6; 1610,1; 1587,7; 1434,5; 1407,5; 1374,7; 1351,7; 1304,2; 1265,9; 1202,9; 1051,0; 1039,3.

Example 2:

1.9 mg (0.00257 mmol) of the N-methyl-D-glucamonium salt of the 2- carboxymethyl -maduraphthalazin are converted with 0.232 mg (0.000513 mmol) gentamicin sulfate AK 628 in aqueous solution at

room temperature within two hours. The release of the active substance has been examined by adding 1.5 mg of the produced salt to 2 ml distilled water. The sample has been stored at 37°C. The excess portion has been removed daily. Then, the samples have been refilled anew with 2 ml fresh distilled water. The active substance release has been determined by means of a microbial agar-diffusion test by using the test organism Bacillus subtilis ATCC 6633 and by using a synthetic nutrient agar. The Agar plates has been incubated at 37°C over a period of 18 hours. The diameter of the inhibition zones has been measured after the incubation.

Table 1. Inhibition zone diameter of Bacillus subtilis ATCC6633 as a function of the release time.