HK1166614A - Flavouring-containing pharmaceutical formulations with improved pharmaceutical properties - Google Patents

Description

Pharmaceutical formulation with improved pharmaceutical properties containing flavouring

The present application is a divisional application of the invention patent application having application number 200480032577.5 and application date 2004, 10 and 30.

Technical Field

The present invention relates to pharmaceutical formulations containing flavouring agents with improved pharmaceutical properties, and to processes for their preparation.

Background

The use of aromatic substances (aromas) in pharmaceutical preparations is becoming increasingly important in the veterinary field. The aromatic substance should be used to assist an animal, such as a dog or cat, in taking a solid form of the drug. Commercially available fragrance materials, e.g. Trigarol Bayopal(Haarmann und Reimer GmbH, Holzminden, D) or artifical BeefFlavor (Pharma Chemie, Syracuse, Nebraska, USA) have an adverse effect on the pharmaceutical properties of the tablets. Thus, for example, tablet hardness (a measure of tablet hardness such as Bauer, Kurt h.;Karl-Heinz; fuhrer, Claus: lehrbuch der Pharmazeutischen technology, 6th reviewed and corrected edition, 1999) may decrease or tablet stability may be adversely affected due to deterioration in release or tablet hardness. These variations cause disadvantages in the quality of the pharmaceutical product.

Bottolakis, Harris and Nesbitt in pharm. res. (5, No.10, suppl. s253, 1988) and EP- ｃA-0345787 or US04910023 disclose formulations of active ingredients with an unpleasant taste and methods for their preparation. In this case, the hygroscopic active ingredient is suspended in water and dried together with the highly dispersed silica, which is an unpleasant taste. This results in a pleasant tasting, less hygroscopic tablet.

The requirements to be met by solid pharmaceutical preparations suitable for animal applications are various:

good animal acceptability, at best, ad libitum,

good storage stability, in particular a lower tendency to absorb moisture,

good mechanical properties, in particular tablet hardness,

good disintegration and release properties.

Increased acceptability is achieved by the addition of aromatic substances or flavoring agents. The problem has hitherto been that these aromatic substances lead to a deterioration in the pharmaceutical properties of the corresponding solid preparations.

Disclosure of Invention

It has now surprisingly been found that the adverse effects of flavouring or aromatic substances can be reduced or completely compensated by the addition of relatively large amounts of highly disperse silicon dioxide and that the resulting solid pharmaceutical preparations have good or very good properties on all the above-mentioned criteria. It is therefore noteworthy that the highly dispersed silica hardly influences the action of the flavouring or aromatic substance, although it is used to mask the taste in this prior art.

The invention therefore relates to a solid pharmaceutical preparation comprising a pharmaceutically active ingredient, a flavoring agent and at least 1.5% by weight of highly disperse silicon dioxide, based on the total weight of the resulting preparation.

The pharmaceutical preparation of the present invention generally contains the pharmaceutically active ingredient in an amount of 0.001 to 90% by weight.

Suitable pharmaceutically active ingredients are generally conventional pharmaceutically active ingredients in all veterinary medicine. Examples which may be mentioned are: quinolone-antibiotics and agents for treating cancer, particularly MMP inhibitors.

Quinolone antibiotics are disclosed in particular in the following documents: US4670444(Bayer AG), US4472405(Riker Labs), US 4730000(Abbott), US4861779(Pfizer), US4382892(Daiichi), US4704459(Toyama), specific examples of quinolone antibiotics to be mentioned are: ciprofloxacin (ciprofloxacin), enrofloxacin (enrofloxacin), ebafloxacin (ibafloxacin), sarafloxacin (sarafloxacin), diflufloxacin (difloxacin), binfloxacin (binfloxacin), danofloxacin (danofloxacin), marbofloxacin (marbofloxacin), benofloxacin (benofloxacin), ofloxacin (ofloxacin), orbifloxacin (orbifloxacin), tosufloxacin (tosufloxacin), temafloxacin (temafloxacin), pipemic (pipemidic acid), norfloxacin (norfloxacin), pefloxacin (pefloxacin), ofloxacin (floracin), fleroxacin (fleroxacin). Further, as more suitable quinolone antibiotics, there may be mentioned the compounds disclosed in WO97/31001, in particular, pradofloxacin of the formula (8-cyano-1-cyclopropyl-7- ((1S, 6S) -2, 8-diazabicyclo [4.3.0] non-8-yl) -6-fluoro-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acid).

Preferred quinolone-antibiotics are represented generally by the general formulae (I) and (II):

wherein

A is nitrogen or ═ C-R⁴，

R⁴Is hydrogen, fluorine, chlorine, cyano, nitro or methyl,

b is

And

R⁵hydrogen, branched or unbranched alkyl radicals having 1 to 4 carbon atoms which are optionally substituted by hydroxyl or methoxy radicals,

R⁶is hydrogen, methyl or phenyl, or a salt thereof,

R⁷is hydrogen or a methyl group,

R⁸is amino, alkylamino or dialkylamino having 1 or 2 carbon atoms in the alkyl radical, aminomethyl, alkylaminomethyl or dialkylaminomethyl having 1 or 2 carbon atoms in the alkyl radical,

R¹is alkyl containing 1-3 carbon atoms, cyclopropyl, 2-fluoroethyl, vinyl, methoxy, 4-fluorophenyl or methylamino,

R²hydrogen, alkyl having 1 to 6 carbon atoms, and cyclohexyl, benzyl, 2-oxopropyl, phenacyl and ethoxycarbonylmethyl,

R³is hydrogen, methyl or ethyl, and is,

z is oxygen, nitrogen substituted by methyl or phenyl and-CH₂-，

And pharmaceutically acceptable salts thereof.

Preferred active ingredients are quinolone carboxylic acids and their derivatives of formula (Ia),

wherein

B is

And A, R²，R⁵，R⁶And R⁷Is as defined above.

More preferred active ingredients are quinolone carboxylic acids and their derivatives as shown in formula (Ia),

wherein

R²Hydrogen, alkyl having 1 to 4 carbon atoms, and benzyl, 2-oxopropyl, phenacyl and ethoxycarbonylmethyl,

b is

R⁵Is hydrogen, methyl or ethyl, and is,

R⁶is hydrogen or a methyl group,

R⁷is hydrogen or methyl, and

a is as defined above.

Mention may be made, in particular as active ingredients, of the following quinolone carboxylic acids and their derivatives:

1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid (tendomycin), 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid, 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (4-ethyl-1-piperazinyl) quinoline-3-carboxylic acid (enrofloxacin), 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (4-methyl-1-piperazinyl) quinoline-3-carboxylic acid 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) quinoline-3-carboxylic acid, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -1, 8-Pyridine-3-carboxylic acid, 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2, 3-dihydro-7, H-pyrido- [1, 2, 3-de]-1, 4-benzoOxazine-6-carboxylic acids and their pharmaceutically acceptable salts, and the methyl and ethyl esters of these compounds.

Enrofloxacin and pradofloxacin and their pharmaceutically acceptable salts are very particularly preferably used.

The pharmaceutically acceptable salts to be mentioned are the physiologically acceptable acid addition salts and the salts with bases. These salts are known or can be prepared by methods analogous to known methods.

Examples of acids which may be mentioned are: hydrochloric acid, sulfuric acid, phosphoric acid, organic acids such as formic acid, acetic acid, lactic acid, malic acid, fumaric acid, citric acid, ascorbic acid, succinic acid, tartaric acid, malonic acid, maleic acid, embonic acid (embonic acid).

As preference, hydrochloric acid, acetic acid, lactic acid, pamoic acid may be mentioned.

Examples of salts with bases are alkali metals, alkaline earth metals, silver and alkali metal salts of the basic carboxylic acidsAnd (3) salt. Examples of suitable bases which may be mentioned are inorganic bases such as NaOH, KOH, Ca (OH)₂Ammonia, organic bases such as amines, e.g. mono-, di-, trialkylamines, substituted amines, e.g. ethanolamine, cyclic amines, e.g. morpholine, piperazine, basic amino acids, e.g. arginine, lysine, choline, N-methylglucamine.

The following bases are preferred: NaOH, KOH, ethanolamine, lysine, N-methylglucamine.

More preferred are the following bases: NaOH, KOH.

Pharmaceutically acceptable solvates, in particular hydrates, of the active ingredient or salt may likewise be used.

The active ingredients are known or can be prepared by methods analogous to known methods.

A detailed disclosure of suitable MMP inhibitors is given in WO96/15096, to which reference is expressly made. Among the compounds disclosed therein, those having a biphenyl structure are preferred; more preferred examples to be mentioned are the compounds tanomastat:

pharmaceutically acceptable salts, hydrates, and the like may be used as well.

The flavouring or aromatic substance used in the present invention relates to a mixture of protein, fat and carbohydrate obtained by a particular process. Of particular mention are Haarmann&Trigarol Bayopal from ReimerAnd Artificial Beef from Pharma Chemie, Inc. (Syracuse, Nebraska, USA)The flavoring or aromatic substances used in the pharmaceutical preparations according to the invention are present in an amount of from 1 to 40% by weight, preferably from 2.5 to 30% by weight, in particular from 4 to 20% by weight, based on the total weight of the preparation obtained.

Highly dispersed silica is as described in the european pharmacopoeia (european pharmacopoeia, silica, anhydrous colloid) or the us pharmacopoeia (us pharmacopoeia, colloidal silica). Commercial products are, for example, aerosil (Degussa), Dissolvul or Entero-Teknosal.

The solid pharmaceutical formulation of the present invention comprises at least 1.5% by weight of highly dispersed silica based on the total weight of the resulting formulation, preferably at least 2.5% by weight, more preferably at least 4% by weight of highly dispersed silica based on the total weight of the resulting formulation. Generally, the solid pharmaceutical formulations of the present invention contain no more than 15% by weight, preferably no more than 10% by weight, of highly dispersed silicon dioxide. Within the limits indicated, it has proven particularly advantageous to process the highly dispersed silica in a weight ratio of highly dispersed silica to aromatic substance of from 1: 4 to 1: 1.

Furthermore, a process for the preparation of the solid pharmaceutical preparations according to the invention has also been found, in which a flavouring agent and highly disperse silicon dioxide are granulated together with one or more auxiliaries and active substances customary in pharmacy. The preparation process of the invention may be of the following variants:

-adding flavouring and highly dispersed silica for mixing (i.e. to granules consisting of other ingredients), mixing the solid ingredients in a suitable container for 2-30 minutes, optionally after sieving, for example through a sieve with a mesh size of 0.5-2mm,

aqueous granulation of the flavour and the highly dispersed silica using a binder solution consisting of water or water and, for example, starch (maize starch, rice starch, wheat starch, potato starch), modified starch (pregelatinized starch, hydroxyethyl starch), gelatin, tragacanth, cellulose derivatives (methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose) or polyvinylpyrrolidone, addition of these granules to be mixed (i.e. to the granules consisting of the other ingredients) or further granulation,

-alcohol (e.g. ethanol) granulation of flavours and highly dispersed silica, adding/entering mixing of these granules, or further granulation,

granulating the flavouring agent and the highly dispersed silica using a further binder, adding these granules to mix or further granulate,

adding flavours and highly dispersed silica to the granulation of the active ingredient, possibly together with other adjuvants such as fillers, disintegration aids or binders.

Granulation can be carried out by means of a high-speed mixer as wet granulation (abbauende granulation) and subsequent drying, for example in a fluidized bed or tray dryer with an inlet air temperature of 40 to 120 ℃ or as aufbauend granulation, for example in a fluidized bed sizing apparatus.

The pharmaceutical preparation of the present invention is suitable for veterinary use, for example, livestock management and livestock breeding. They can be used in agriculture and for breeding livestock, zoos, laboratories and laboratory animals and pets.

Agricultural and farm animals include mammals, e.g., cattle, horses, sheep, pigs, goats, camels, buffalos, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals, e.g., mink, chinchilla, racoon, birds, e.g., chickens, geese, turkeys, ducks, pigeons, and birds raised at home or in zoos. Productive and ornamental fish are also included.

Laboratory and test animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.

Pets include dogs and cats.

The solid pharmaceutical formulation of the present invention is preferably a tablet. However, other solid formulations are also suitable, such as powders, premixes or concentrates, granules, pellets, boli, capsules, aerosols and inhalants.

The solid pharmaceutical preparation of the present invention may contain other pharmaceutically acceptable additives and auxiliaries, for example, carriers and auxiliaries as described in detail hereinafter.

Carriers which may be mentioned are all physiologically acceptable solid inert substances. Both inorganic and organic materials may be used. Examples of inorganic substances are sodium chloride, carbonates such as calcium carbonate, bicarbonates, alumina, silica, alumina, phosphates.

Examples of organic substances are sucrose, lactose, mannitol, cellulose, human or animal food such as milk powder, bone meal, ground and crushed cereals, starch.

Adjuvants are antioxidants, for example ascorbic acid, tocopherol, pigments, which are approved for use in animals and can be used in solution or suspension.

Further suitable auxiliaries are lubricants and glidants, for example magnesium stearate, stearic acid, talc, bentonite, disintegration-promoting substances such as starch and starch derivatives, crosslinked sodium carboxymethylcellulose or crosslinked polyvinylpyrrolidone, binders, for example starches (maize starch, rice starch, wheat starch, potato starch), modified starches (pregelatinized starch, hydroxyethyl starch), gelatin, tragacanth, cellulose derivatives (methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose) or polyvinylpyrrolidone, and dry binders such as microcrystalline cellulose.

Description of the drawings:

FIG. 1 shows the dependence of the crushing resistance [ N ] on the applied load [ kN ] in examples 1 to 4 as compared with the standard.

FIG. 2 shows the dependence of the crushing resistance [ N ] of examples 2, 5 and 6 and the standards on the applied load [ kN ].

FIG. 3 shows the flexural strengths [ N ] of examples 7-11.

FIG. 4 shows the water absorption [% ] during a 7-day period for examples 20-23.

Fig. 5 shows the reduction in tablet hardness [% ] of examples 20-23.

FIG. 6 is a graph showing the dependence of the crushing resistance [ N ] on the applied load [ kN ] in examples 20 and 27 to 30.

FIG. 7 is a graph showing the dependence of disintegration time [ min ] on crushing resistance [ N ] of examples 20 and 27 to 30; an upper limit for acceptable disintegration time has been shown. This time should be well below the upper limit of 15 minutes set by the european pharmacopoeia in order to ensure that all tablets can always comply with the required limits. For this reason, disintegration times of less than 10 minutes are considered acceptable.

Figure 8 shows the tablet release kinetics of examples 28 and 30 after 8 weeks of storage in a humid environment. The percentage of active ingredient released is plotted on the basis of time.

FIG. 9 shows the dependence of the crushing resistance [ N ] on the applied load [ kN ] of tablets of example 28 prepared by different methods.

FIG. 10 is a graph showing the dependence of the crushing resistance [ N ] on the applied load [ kN ] of tablets having the composition of example 30 prepared by different methods.

Detailed Description

Examples

I. Enrofloxacin tablets

TABLE 1

The formula research:

tablet composition [ mg/tablet ]

The addition of the aroma substances resulted in tablet hardness with increased flavor content, as shown in fig. 1.

Tablet hardness can be enhanced by the addition of large amounts of highly dispersed silicon dioxide (e.g. Aerosil)) And improved by the addition of other adjuvants (figure 2).

TABLE 2

The amount of the ingredients is expressed in mg/tablet

Pradofloxacin tablet

Different formulations were selected for pradofloxacin (formula) and the effect of the added fragrance on the tablet properties was tested.

TABLE 3

Mannitol-based formula:

the amount of the components is expressed in mg/tablet

The specification of the tablet is as follows: oval 14X 6r5 mm

The addition of Bayopal reduced tablet hardness (expressed as hardness yield-flexural strength/load ratio). The flexural strength of the oval tablet is reduced compared to formulations without fragrance material. Tablet hardness can be significantly increased by the addition of highly dispersed silicon dioxide, which is also advantageous for production (transport, packaging) and administration of the tablets.

An additional advantage of formulations containing highly reactive silica is represented by the storage in a humid environment. After one week storage at air humidity > 80%, all tablets with fragrance material had reduced flexural strength. This reduction can be reduced to a practically acceptable range when a large amount of highly dispersed silica is used, as shown later in fig. 3.

TABLE 4

Microcrystalline cellulose based formulations:

	example 12	Example 13	Example 14	Example 15	Example 16
						Pradofloxacin	100	100	100	100	100
Microcrystalline cellulose	152.8	152.8	152.8	152.8	152.8
						PVP25	30	30	30	30	30
Flavoring agent for artificial beef					15
						Bayopal		15	15	15
Croscarmellose Natrium	15	15	15	15	15
						Highly dispersed silica	0.9	0.9	15.9	4.65	15.9
Magnesium stearate	1.35	1.35	1.35	1.35	1.35
						Flexural Strength/load ratio	6.53×10-3	4.25×10-3	5.29×10-3	4.68×10-3	6.46×10-3

The amount of the components is expressed in mg/tablet

The specification of the tablet is as follows: oval 14X 6r5 mm

The principle of improving tablet hardness, which has been described several times, is also applied to pradofloxacin formulations based on microcrystalline cellulose. These tablets show that the addition of aroma has a particularly adverse effect on the hardness of these tablets, but this can be avoided by the addition of highly dispersed silicon dioxide.

Pradofloxacin tablets with lactose and microcrystalline cellulose:

the following mixture can be compressed into tablets of various sizes:

TABLE 5

Pradofloxacin	15.0％
		Microcrystalline cellulose	35.0％
Lactose	24.0％
		PVP25	5.0％
Flavoring agent for artificial beef	10.0％
		Croscarmellose Natrium	7.5％
Highly dispersed silica	2.5％
		Magnesium stearate	1.0％

Tablets with the following sizes and dosages are possible, for example:

pradofloxacin dosage tablet form

Example 17: 15mg 8X 4r4.5[ mm ]

Example 18: 60mg 14X 7r6[ mm ]

Example 19: 120mg 18X 8r6[ mm ]

Small tablets are particularly sensitive to humidity. The tablets of example 17 retained hardness sufficient for their size after storage outside without protective packaging, as shown below, and were confirmed and supplemented by the results of the previous pradofloxacin tablet examples.

TABLE 6

Tablet hardness after 15 days outdoor storage at 85% relative humidity:

load [ kN ]]	Tablet hardness after outdoor storage [ N ]]
		9	32
12	34
		13.5	36

Tanomastat tablets

tanomastat (structural formula) was studied in the form of various best tasting tablets.

TABLE 7

Formula containing flavoring agent of artificial beef

	Example 20	Example 21	Example 22	Example 23
					Tanomastat	200.0	200.0	200.0	200.0
Lactose	121.20	121.20	121.20	121.20
					Microcrystalline cellulose	60.8	60.80	60.80	60.80
Sodium lauryl sulfate	2.0	2.0	2.0	2.0
					Flavoring agent for artificial beef	-	40.0	40.0	20.0
Croscarmellose Natrium	12.0	12.0	12.0	12.0
					Highly dispersed silica	-	-	10.0	20.0
Magnesium stearate	4.0	4.0	4.0	4.0

The amount of the components is expressed in mg/tablet

Example 20 is a comparative formulation without flavoring. The formulations containing the flavoring agents absorbed moisture when they were stored in humid conditions, as shown later in figure 4 for the example formulations. This can be reduced by adding a large amount of highly dispersed silica.

During storage, the tablets additionally lose hardness to a significant extent, which may lead to problems in the market (consumer complaints). This problem can also be reduced by the method of the invention (see fig. 5).

Formulations corresponding to example 23 can be compressed into tablets of various sizes, as shown by the process of the following example:

TABLE 8

	Example 23	Example 24	Example 25	Example 26
					Tanomastat	200.0	50.0	300.0	400.0
Lactose	121.20	30.3	181.8	242.4
					Microcrystalline cellulose	60.80	15.2	91.2	121.6
Sodium lauryl sulfate	2.0	0.5	3.0	4.0
					Flavoring agent for artificial beef	20.0	5.0	30.0	40.0
Croscarmellose Natrium	12.0	3.0	18.0	24.0
					Highly dispersed silica	20.0	5.0	30.0	40.0
Magnesium stearate	4.0	1.0	6.0	8.0
					Tablet form	16*6r 5	9*4r 4.5	17*7r 6	18*8r 6

The amount of the components is expressed by mg/tablet; tablet size is in mm.

All these formulations exhibit the above-mentioned advantages of storage under humid conditions.

TABLE 9

Formulations containing Bayopal

	Example 20	Example 27	Example 28	Example 29	Example 30
						Tanomastat	200.0	200.0	200.0	200.0	200.0
Lactose	121.20	121.20	121.20	121.20	121.20
						Microcrystalline cellulose	60.80	60.80	60.80	60.80	60.80
Sodium lauryl sulfate	2.0	2.0	2.0	2.0	2.0
						Bayopal	-	40.0	40.0	40.0	40.0
Croscarmellose Natrium	12.0	12.0	12.0	12.0	12.0
						Highly dispersed silica	-	-	40.0	20.0	10.0
Magnesium stearate	4.0	4.0	4.0	4.0	4.0

The amount of the components is expressed in mg/tablet

The addition of Bayopal lost hardness to the formulation. This can be avoided, as already described for the other active ingredients and flavouring agents, by adding highly disperse silicon dioxide (see fig. 6).

In addition to the adverse effect on tablet hardness, flavoring agents also cause a deterioration in disintegration and release properties. These adverse effects can also be reduced by the measures according to the invention described.

The disintegration of the tablets containing highly dispersed silicon dioxide, despite the improved tablet hardness, was faster than the tablets containing the flavouring agent without highly dispersed silicon dioxide (figure 7).

If a large amount of highly dispersed silicon dioxide has been added, tablets produced e.g. with 50mg of active ingredient containing 50mg of an ingredient similar to examples 28 and 30 show an improved release after 8 weeks of storage under humid conditions (fig. 8).

Dog acceptance test

The formulations corresponding to examples 23 and 24 were used for 40 dog trials. Compared to the taste masking described in EP00345787 or US04910023, the tested formulation was voluntarily swallowed by 92.5% of the test dogs, demonstrating that the added aroma surprisingly did not lose its functionality.

Influence of the production Process

All the formulas can be selected from various production processes:

-a flavouring agent and a highly dispersed silica are added to the mixture,

aqueous granulation of flavors and highly dispersed silica, addition of these granules for post-mixing or further granulation,

-granulation of flavoring and highly dispersed silica in an alcohol (e.g. ethanol), addition of these granules for post-mixing or further granulation,

granulating the flavouring agent and the highly dispersed silica using a further binder, adding these granules for post-mixing or further granulation,

granulation of the active ingredient is carried out by adding flavours and highly dispersed silica, possibly together with other auxiliaries such as fillers, disintegrants or binders.

These production processes lead to tablets having the same properties. Figure 9 shows the hardness of tablets corresponding to the composition of example 28 produced by different granulation processes.

The selection of different production processes for the tablets according to example 30 likewise leads to tablets with virtually identical load/hardness profiles (fig. 10).

These data demonstrate the principle that the addition of large amounts of highly dispersed silicon dioxide to a formulation containing a flavoring agent results in improved tablet pharmaceutical properties, regardless of the granulation or tableting process chosen.

Claims (8)

1. A solid pharmaceutical formulation comprising:

-quinolone antibiotics as pharmaceutically active ingredients;

-4-20% by weight, based on the total weight of the final formulation, of a flavouring or aromatic substance comprising a mixture of proteins, fats and carbohydrates obtained by a particular processing; and

-1.5-15% by weight of highly dispersed silica, said highly dispersed silica being present in a weight ratio of from 1: 4 to 1: 1 with respect to the total weight of the final formulation.

2. The solid pharmaceutical preparation according to claim 1, which comprises enrofloxacin, an enrofloxacin salt, or a hydrate of enrofloxacin or a salt thereof as a pharmaceutically active ingredient.

3. A solid pharmaceutical preparation as claimed in claim 1 or 2, which contains pradofloxacin, a pradofloxacin salt or a hydrate of pradofloxacin or a salt thereof as a pharmaceutically active ingredient.

4. A solid pharmaceutical formulation according to claim 1 or 2, which contains at least 4% by weight of highly dispersed silicon dioxide, based on the total weight of the final formulation.

5. A solid pharmaceutical formulation according to claim 1 or 2, which contains not more than 10% by weight of highly dispersed silicon dioxide.

6. A process for the production of a solid pharmaceutical formulation as claimed in claim 1, wherein the flavoring agent and the highly dispersed silicon dioxide and one or more active ingredients and additives and/or auxiliaries customary in pharmacy are granulated.

7. Use of a solid pharmaceutical formulation according to any one of claims 1 to 5 in the manufacture of a medicament for use in veterinary medicine.

8. Use according to claim 7 in the manufacture of a medicament for a dog or cat.