CA2688613A1 - Formulations containing triazinones and iron - Google Patents

Abstract

The invention relates to the simultaneous application of triazines such a s toltrazuril, ponazuril or diclazuril and iron compounds in a formulation f or controlling coccidia infections and iron deficiencies in animals and huma ns.

Description

BHC 07 1 052-Foreign Countries - 1-Formulations containing triazinones and iron The invention relates to formulations containing triazinones and iron compounds (salts and complex compounds of iron) which are suitable for the simultaneous control of coccidioses and anaemic states in animals.

Economically successful meat production operations are currently distinguished by highly intensive farming, that is to say by the keeping of a large number of animals which are specifically selected in order to optimize the breeding aim. These farms are characterized for example by the use of a great deal of machinery, the additional feeding of food supplements, and the involvement of as little staff as possible. In the case of piglet rearing farms, this means that a large number of sows which are bred for a high number of piglets per litter are kept in suitably large pig houses. The optimization of the feed, and suitable selection in the breeding process, make it possible for the piglets to grow rapidly.

This type of animal keeping is frequently the cause for an increasing number of certain typical diseases and deficiencies. Besides stress, to which in particular intensively kept pigs are very susceptible, such phenomena are, in young pigs, protozoal infections (coccidioses) and anaemic states, inter alia, both of which already have to be kept under control by the prophylactic use of medicaments.
Coccidioses are frequently occurring, parasitic infectious diseases in animals.
Thus, for example, protozoans of the genera Eimeria, Isospora, Neospora, Sarcosporidia and Toxoplasma cause coccidioses all over the world. Examples of economically important coccidioses are: infections of pigs with coccidia of the genus Isospora or of cattle with coccidia of the genus Eimeria. Infections with Isospora suis have only in recent years been recognized as the cause of diarrhoea in piglets and studied intensively. As a rule, an infection proceeds from the environment to the piglets, or from piglet to piglet, via oocysts, which contain in each case two sporocysts with in each case two sporozoites. The parasitic stages multiply in the epithelial cells of the small intestine's villi. The clinical picture of the disease includes a necrotic, inflammatory destruction of the gut's epithelial cells with atrophying villi, and, as a result, impaired absorption and digestion. The characteristic of an acute disease is a liquid, whitish to yellow diarrhoea, which mostly occurs in week 2 to 3 of life. The weight gain of infected piglets is reduced.
Treatment and therapy of the disease are insufficient to date. Antibiotics are ineffective; while sulphonamides are approved for the treatment of coccidiosis, their effect is questionable, and frequently repeated administrations are in any case unsuitable for practice. Other possible treatments are questionable: the administration of, for example, monensin, amprolium or furazolidon has not been successful in preventing the disease in experimentally infected piglets. In more recent studies, Isospora suis has been identified in up to 92% of all litters in some farms, despite good hygiene. This type of disease is not limited to pigs, but also occurs in many other animal species, for example in poultry production, in calves, lambs or in small animals (rabbits).

An example of a deficiency is iron deficiency in newly-born piglets. Owing to the rapid growth in the first days after birth, the body's iron reserves are rapidly depleted and must be compensated for by external sources. Because of the large number of suckling pigs, this substitution by taking up the sow's milk cannot take place in a sufficient degree. If, moreover, the animals are kept on concrete or plastic, the piglets cannot take up iron compounds by rooting in the ground either.
The piglets become anaemic. A clinically significant anaemic state exists when the haemoglobin content of the blood has dropped to less than 80 g/1. The NRC
recommendation (National Research Council, Nutrient Requirements of Domestic Animals, No. 2, Nutrient Requirements of Swine, National Academy of Sciences, Washington DC, 1973) specifies 90 g/1 as the minimum haemoglobin value at which the piglets grow healthily and show no signs of anaemia. Noticeable symptoms such as weight loss or stunted growth are, however, only observed when the haemoglobin content of the blood has dropped to values of below 80 g/l.
Other indicators for the iron supply are the haematocrit and the number of erythrocytes per unit volume. Severe iron deficiency anaemia also leads to the young pigs' death.

Preparations are already available for controlling the abovementioned diseases and deficiencies.

Coccidiosis can be controlled successfully by administering active ingredients from the triazinone group. To this end, one distinguishes between the triazinediones - with examples of representatives being the active ingredients clazuril, diclazuril, letrazuril - and the triazinetriones with the active ingredients toltrazuril, toltrazuril sulphoxide and ponazuril. Triazines, in particular toltrazuril, ponzazuril or diclazuril, and their activity against coccidia are known from a series of publications, see, inter alia, DE-A 27 18 799 and DE-A 24 137 22.
WO 99/62519 discloses semisolid aqueous preparations of toltrazuril sulphone (ponazuril). It is also known that it is in particular toltrazuril which is suitable for treating coccidiosis (for example Isospora suis) in pigs. See, for example, also the following publications: Don't forget coccidiosis, update on Isosporosis in piglets.
Part I, Pig Progress volume 17, No. 2, 12-14; Mundt., H.-C., A. Daugschies, V.
Letkova (2001): be aware of piglet coccidiosis diagnostics. Part II, Pig Progress volume 17, No. 4, 18-20; Mundt, H.-C., G.-Pl Martineau, K. Larsen (2001):
control of coccidiosis Part III, Pig Progress volume 17, No. 6, 18-19.

Coccidioses in cattle as the result of infections with various pathogenic Eimeria spp. (for example E. bovis and E. zurnii) manifest themselves as diarrhoeas of different severity up to bloody diarrhoeas accompanied by mortality.
WO 96/38140, DE 10049468, DE 19958388, WO 00/19964, WO 99/62519 or WO 00/37063 and DE 102006038292.7 describe compositions against coccidiosis in animals. Besides other routes of administration, oral administration is also mentioned there, in general form.
DE 19603984 contains granules for oral administration. DE 19824483 describes semisolid aqueous preparations (pastes) for the treatment of animals. EP

describes solutions which can be applied orally.

In the sector of poultry rearing, preparations which are soluble in drinking water, or drinkable solutions, are frequently employed, while in farms where large animals are kept one will tend to add the active ingredients to the feed or administer it orally as a suspension, using an applicator (drench). Examples of important products on the market are diclazuril (2,6-dichloro-a-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; CAS No.
101831-37-2) (CLINACOXTM 0.5%, Janssen Animal Health; VECOXANTM, Biokema SA) for admixture to the feed and toltrazuril (1-methyl-3-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-1,3,5-triazine-2,4,6(1 H,3H,5H)trione;
CAS No. 69004-03-1). Toltrazuril is available on the market for example as a drinking water formulation for poultry and as an oral suspension formulation for, inter alia, the treatment of suckling pigs. It is recommended to administer, to the piglet, a dose of 20 mg/kg bodyweight on day 3-5 after birth.

The disadvantage in the oral administration of the abovementioned anticoccidials (sometimes also somewhat inaccurately referred to as coccidiostats) is that it is relatively laborious: the piglets must be caught and the product is administered into the throat with the aid of an applicator or a drench gun. Moreover, the method causes not inconsiderable stress for the piglets.

A series of quite different iron preparations, which differ both in the type of compound and in the mode of application and bioavailability, are available for preventing iron deficiency anaemia. One distinguishes between (I) simple inorganic Fe(2+) salts, (IIa) complex compounds of Fe(2+) with organic ligands, for example with lactic acid, or (IIb) of Fe(3+), for example with citric acid, and (III) polymer-type complex compounds of an Fe(3+) oxo-hydroxo complex (3-FeO(OH) of the akaganeite type with carbohydrates/polysaccharides, specifically with oligomeric or polymeric carbohydrate compounds, such as, for example, with dextran or with dextrin/polymaltose. Hereinbelow, polymeric carbohydrates/carbo-hydrate compounds and polysaccharides are understood as meaning both oligomeric and polymeric compounds.

Preparations of the type (I) which are to be administered orally, such as, for example, the use of iron salts as feed additives, are customary and have been known for a long time. The iron in these compounds is present in the form of iron(2+) ions, for example as iron sulphate FeSO4. These products can either be added to the breeding sow's feed or else administered directly to the piglets via the oral route. In most cases, a plurality of single doses will be administered to the piglets during the first days of their life during the growth period in order to compensate for the relatively low bioavailability. An alternative route for avoiding multiple application is to feed, at a later point in time, an extra, iron-containing ration (prestarter and starter feed). While the iron ions in the inorganic iron(2+) salts are liberated rapidly by dissociation, the release in the iron(2+) complex compounds is somewhat delayed. The absorption of free Fe(2+) ions from iron salts takes place in the upper small intestine. The solubility of Fe(2+) under the physiological conditions of the upper small intestine exceeds that of Fe(3+) by several powers of ten (Forth, W., in: Dunndarm, Handbuch der inneren Medizin, Vol. 3 Verd. Org. Part 3(A); W.F. Caspary, Ed;, Springer 1983). Moreover, free iron(3+) ions are reduced in the environment of the gut contents by cysteine, glutathione, ascorbic acid and other substances to give Fe(2+) and absorbed from the epithelial cells of the gut's mucous membrane as such. However, it is disputed whether this reduction is a necessary prerequisite for the uptake into the cells of the mucosa. The reason why Fe(2+) has a greater bioavailability is probably the concentration gradient as the result of the higher solubility of Fe(2+). The current opinion is that the Fe(2+) ions are first bound to the protein mobilferrin, on which they are reoxidized to Fe(3+) and bound the mucosal storage protein ferritin.
When the body requires iron, these Fe(3+) are released into the blood plasma, where they are again reduced by a ferrioxidase to give Fe(2+) and bound to the protein apo-transferrin, the organism's iron-binding transport protein. Whether transferrins are already present in the cells' mucosa and whether they receive the iron there at least in part is the subject of debate. With log K of approx. 30-31, transferrin's complex formation constant is so large that nowhere in the organism can free iron exist as long as transferrin's iron binding capacity is not exceeded. This is the reason for toxic effects which may occur as the result of a sudden oversupply of the iron salts, which is a disadvantage in their use. The iron is then transported via blood and lymphatic vessels to the haemoglobin synthesis sites in the bone marrow (cf.
E.
Kolb, U. Hofmann "Anwendungen von Eisenverbindungen beim Schwein" [Uses of iron compounds in pigs] Tierartzl. Umschau 60, (2005) 365-3 71 and Forth, W., "Eisen und Eisenversorgung des Warmbluterorganismus" [Iron and iron supply of the warm-blooded organism], Naturwissenschaften 74, (1987) 175-180 and John, A.; "Neue Moglichkeiten der Eisenversorgung neugeborener Ferkel unter Beachtung biochemischer Aspekte " [Novel possibilities of supplying iron to new born piglets, taking account of biochemical aspects] in: Trachtigkeit und Geburt beim Schwein [Pregnancy and birth in pigs], 8th Bernburger Biotechnology Workshop 2002, 89-94). Iron which is not required remains stored in the cells of the mucosa, but is no longer available after they have died. It is therefore understandable that the bioavailability of oral iron compounds greatly depends on other factors such as the actual iron requirement, the feeding state (colostrum) and the state of health (diarrhoea: premature loss of the upper cells of mucosa).
It is important to understand the mechanism in order to comprehend and estimate the advantages and disadvantages of certain iron preparations.

Compounds from the second group (II) of the Fe(2+) and Fe(3+) compounds which are complexed in a chelate-like manner are furthermore used. These compounds form relatively stable iron complexes which are only partly broken down into the ions by the gastric acid. In the course, the bioavailability is the result of the partial exchange of the iron with the ligands at or in the cells of the mucosa, which depends on the complexes' formation constants. Complexes which are not broken down are capable, as the result of their higher lipophilicity, of crossing the epithelium's membrane systems and must be metabolized. This explains why organic low-molecular-weight complexes have a slower bioavailability, but, in turn, a more sustained effect (H. Dietzfelbinger; "Bioavailability of Bi- and Trivalent Oral Iron Preparations"; Arzneim.-Forsch./Drug. Res 37(1), No. la, (1989) 107-112 and E.B. Kegley et al., "Iron Methionin as a Source of Iron for the Neonatal Pig", Nutrition Research 22 (2002) 1209-1217).

The third group of compounds which are applied mainly parenterally and only to a minor extent orally consists of fairly stable compounds of the poly-(3-FeO(OH) type with complex-bound polymeric carbohydrates. Commercial importance has been gained mainly, but not exclusively, by iron(III) dextran (CAS No.
9004-66-4), iron(III) hydroxide polymaltose (iron(III) hydroxide dextrin; CAS
No.
53858-86-9), iron(III) sucrose (iron(III) sucrose, iron(III) "sugar" CAS No.

67-4) and sodium/iron(III) gluconate complex in sucrose solution (CAS No.
34089-81-1). The literature reveals different names for these compounds. In this context, compounds such as iron(III) dextran, iron(III) polymaltose, iron(III) dextrin, iron(III) sucrose, iron(III) gluconate, sugar are understood as meaning complexes of the iron(3+) ion with hydroxide ions (OH), aquo groups (H20) and oxygen (0), which complexes are present in oligomeric or polymeric form and which are associated, in their coordination sphere, in the form of complexes with one or more of the abovementioned oligomeric and polymeric carbohydrate compounds. This is why the compounds are also referred to as iron(III) hydroxide polysaccharide or iron(III) oxy-hydroxy polysaccharide, where polysaccharide stands for the abovementioned oligo- and polymeric carbohydrate compounds or their derivatives or, generally, for compounds from the group of the oligomeric or polymeric carbohydrates. Polynuclear iron(III) complexes of this type are described for example in (D.S. Kudasheva et al., "Structure of Carbohydrate-bound Polynuclear Oxyhydroxide Nanoparticles in Parenteral Formulation ", J.
Inorg. Biochem. 98 (2004) 1757-1769; I. Erni et al., "Chemical Characterization of Iron(III) Hydroxide-Dextrin Complexes" Arzneim.-Forsch./Drug Res. 34 (11) (1984) 1555-1559; F. Funk et al., "Physical and Chemical Characterization of Therapeutic Iron Containing Materials ", Hyperfine Interactions 136 (2001) 73-95;
E. London "The Molecular Formula and Proposed Structure of the Iron-Dextran Complex, IMFERON", J. Pharm. Sci. 93 (2004) 1838-1846; A. John "Neue Moglichkeiten der Eisenversorgung neugeborener Ferkel unter Beachtung biochemischer Aspekte " [Novel possibilities of supplying iron to new born piglets, taking account of biochemical aspects], Trachtigkeit und Geburt beim Schwein [Pregnancy and birth in pigs]: 8th Bernburger Biotechnology Workshop, Bernburg (2002) 89-94). Since in many cases the composition of these compounds is not described in quantitative terms, and may also vary within the compounds, depending on the type of preparation, these polynuclear iron(III) polysaccharide compounds are understood as meaning all complexes of the above-described class of compounds which are known to the skilled worker.
These iron compounds are used almost exclusively in the manufacture of preparations for injection for human and veterinary medicine. In veterinary medicine, however, a few preparations for oral administration are also in use.
These complexes are generally distinguished by high stability and differ mainly with regard to their mollar weight, which may vary from 30 kDa up to 400 kDa, and in the strength of the complex binding. In aqueous solution, they are present as colloid dispersions with a particle size of 7-35 nm. What is decisive for the bioavailability in the case of oral administration is, firstly, the extent of precipitate formation and of the hydrolysis of the iron core under the influence of gastric acid, and secondly, the stability of the complexes under acidic reducing conditions.
The mechanisms of the uptake into the organism and the conversion to biological iron compounds are not fully elucidated as yet and in some cases still debated in the literature. However, some general statements on the mechanism of action can be made. The more stable the complex, the greater the portion of the compound which passes through the stomach without modification, and the smaller the portion of free iron ions. The stability of the complexes, in turn, depends on the synthetic process. High-molecular-weight iron(III) polymaltose and iron(III) dextran have proved to be fairly stable. In contrast, it is necessary to release the iron to the proteins of the transport pathway. Naturally, this transfer will become less with increasing stability of the complexes. These relationships have been confirmed by various experiments with acids, reducing agents and with complexing agents (R.
Lawrence "Development and Comparison of Iron Dextran Products "; PDA J
Pharm. Sci. Techn. 52(5) (1998) 190-197; F. Funk et al., "Physical and Chemical Characterization of Therapeutic Iron Containing Materials "; Hyperfine Interactions 136 (2001) 73-95; I. Erni et al., "Chemical Characterization of Iron(III) Hydroxide-Dextrin Complexes" Arzneim.-Forsch./Drug Res. 34(11) 11 (1984) 1555-1559).

These considerations have given rise to the doctrine that Fe(3+) compounds in general, and in particular polynuclear compounds such as iron(III) dextran, are not suitable, for oral application (H. Dietzfelbinger "Bioavailability of Bi- and Trivalent Oral Iron Preparations" Arzneim.-Forsch./Drug Res. 37(I), No. 1(a) (1987) 107-112).
A further reason for being reluctant to use polynuclear Fe(3+) complexes, in particular iron(III) dextran, orally is the specific uptake pathway of 0-FeO(OH) complexes in the intestinal tract. These compounds are taken up by pinocytosis into the gut mucosa's epithelial cells and must then be released to the organism via the lymphatic system, stored in the lymph nodes and finally transported on into the bloodstream (cf also abovementioned publications by Kolb, Hofmann; Forth;
John). Since - as explained above - they are fairly stable, the bioavailability will subsequently depend on the metabolism and the enzymatic degradation of the complexes via lysosomal enzymes. Experiments with polyvinylpyrrolidone, dextran and with dye-labelled iron(III) dextran with in each case different molecular weights have demonstrated that, in suckling pigs, these polymer complexes can be taken up by pinocytosis via the epithelial cells of the ileum and the upper small intestine in the first days of life (R.M. Clarke, R.N. Hardy "Histological Changes in the Small Intestine of the Young Pig and Their Relation to Macromolecular Uptake "; J. Anat. 108(1), (1971) 63-7; K. Thoren-Tolling, L.
Jonsson "Cellular Distribution of Orally and Intramuscularly Administered Iron Dextran in Newborn Piglets", Can. J. Comp. Med. 41 (1977) 318-325; K
Martinsson, L. Jonsson "On the Mechanism of Intestinal Absorption of Macromolecules in Piglets Studied with Dextran Blue ", Zbl. Vet. Med. A 22 (1975) 276-282). However, it is also known that this transit of high-molecular-weight compounds from the cells of the mucosa into the lymphatic system and bloodstream of the piglets is only possible without hindrance immediately after birth. This mechanism ensures that the piglets can be supplied with immunoglobulins and antibodies immediately after birth by taking up the sow's colostrum. As soon as this supply is ensured, the transport meclianism becomes defunct. This "intestinal closure" during the further course of growth is biologically meaningful in order to avoid infections with microorganisms and toxins (K. Martinsson, L. Jonsson "The Uptake of Macromolecules in the Ileum of Piglets after Intestinal Closure ", Zbl. Vet. Med. A 23 (1976) 277-282). The period between birth and intestinal closure therefore depends greatly on the piglets' nutritional status. In starving piglets, this transfer may still take place up to four days after birth (J. G. Lecce, D. O. Morgan "Effect of Dietary Regimen on Cessation of Intestinal Absorption of Large Molecules (Closure) in the Neonatal Pig and Lamb ", J. Nutrition 78 (1962) 263-268). Since, however, current keeping conditions at the breeders' naturally allow suckling, it is current knowledge and generally medically acknowledged that a sufficient supply of piglets with high-molecular-weight iron complexes via the oral route is only possible, in a meaningful manner, in the first hours after birth if multiple applications are to be avoided. Those few authors who have systematically studied the efficacy of iron(III) dextran as a function of the timing of the oral application report on a substantially reduced activity when the iron(III) dextran is administered 24-72 h after birth (L. Blomgren, N. Lanneck "Prevention ofAnaemia in Piglets by a Single Oral Dose of Iron Dextran ", Nord. Vet.-Med. 23 (1971) 529-536). Depending on the keeping and feeding conditions, however, an administration on day 2 of life will still give sufficiently good results (S. Kadis, "Relationship of Iron Administration to Susceptibility of Newborn Pigs to Enterotoxic Colibacillosis ";
Am. J. Vet. Res. 45(2), (1984) 255-259). In contrast, when administering the iron dextran 72-96 h after birth, the efficacy is already greatly reduced (Ueda H.

"Prevention of Piglet Anaemia by Oral Administration of Iron Dextran ", Nicchiku Kaiho 56(11), 1985, 872-877). This is why only few oral iron substitution products with polynuclear iron complexes have penetrated the market (Ursoferran 150 p.o.; Serumwerke Bernburg - Eisen(III)-Dextran; Ferrum Hausmann Syrup Hausmann Laboratories Inc., St. Gallen; - Eisen (III)-hydroxidpolymaltose. In modern iron dextran preparations for oral use in breeding piglets, the iron dextran is bound to the emulsifiers of microemulsion droplets 1-2 m in size in order to improve their bioavailability (Bioveyxin FeVitTM Veyx-Pharma GmbH, Schwarzenborn; SintaFerTM, Sinta GmbH, Schwarzenborn). This finely dispersed state, and the fact that they are bound to lipophilic carriers, are intended to promote the uptake into the epithelial cells and the transfer into the organism. Even with these preparations, however, the manufacturer recommends that they be used up to no more than 8-10 h after birth in order to achieve an optimal effect. This, in turn, requires the continuous monitoring of the breeding sows, which means a great deal of labour.

In general, a dosage rate of 100-200 mg of active iron per piglet and per unit dose is recommended for oral iron preparations in order to ensure a sufficiently high activity. Only the higher dose, though, makes it possible in practice to manage with a single administration.

To circumvent the above-described imponderabilities in the case of oral application, it is more conventional in pig rearing to administer polynuclear iron(III) complexes intramuscularly by means of an injection. This is carried out as a rule by injecting 100-200 mg of active iron on day 3 after birth. The transport away from the site of injection takes place via the lymphatic system and the cells of the reticulohistiocytary system. The complexes are stored in the liver and the spleen, from where they are liberated as required and metabolized enzymatically.
The free Fe(3+) is ultimately again bound to transferrin and transferred to the sites of use in the bone marrow.

However, this parenteral application form, too, has a series of disadvantages:
a pronounced disadvantage of the intramuscular application (by intramuscular injection) to young pigs is that harmful effects occur more often. Muscle bleeding, changes in the muscle fibres, inflammations and the development of oedemas are caused more frequently at the sites of injection. These are local stances of damage.
However, damage to the heart muscle is also observed, in particular when there is a simultaneous deficiency of vitamin E. In these cases, a pronounced increase in the potassium content in the blood plasma can be observed, which causes severe damage to the heart muscle and may lead to the death of the piglets. It is the current opinion that minute amounts of free Fe(2+) ions are responsible for the formation of free-radical compounds with organic molecules, for example the lipid-peroxide compounds, which are associated with the high potassium content in the blood. Vitamin E acts as a free-radical scavenger and is capable of buffering these harmful reactions in a certain manner, but this frequently exceeds the body's capacities (this is why vitamin E is also added to the oral preparations which have already been mentioned, in which the iron(III) dextran is bound to microemulsion droplets). However, there is a further disadvantage to intramuscular application in this regard: after the iron(III) dextran has been administered, a certain reduction in the immune system's performance must be expected since the macrophages in the blood are loaded with the polynuclear iron complexes. The defence against bacterial infections is reduced. An overview of the above-described disadvantages of the intramuscular administration is found in the literature (E. Kolb, U.
Hofmann "Zur Frage der zweckmaf.iigen Form der Anwendung von Fe-Dextran, seiner Verwertung sowie des Mechanismus einer moglichen Schadigung der Ferkel" [On the expedient form of administering Fe-dextran, its utilization, and the mechanism ofpotential damage to the piglets]; Mh. Vet. -Med 44 (1989) 49 7-501).

In summary, it can be said that each of the methods of anaemia prophylaxis, in suckling pigs, which are currently available on the market has a series of disadvantages:

1. According to the literature, when Fe(II) compounds of type (I) and (II) are applied orally, a markedly lower bioavailability can usually be observed. It is recommended to administer these preparations repeatedly, which, in the case of intensive animal keeping, involves a great deal of labour and is an economic disadvantage.

2. While the oral administration of polynuclear Fe(III) compounds of type (III), in particular iron(III) dextran, leads to better results, with a single dosage rate of approximately 200 mg of active iron being, as a rule, sufficient to ensure a sufficient iron supply to the piglets, the decisive disadvantage here is that a sufficient activity can, according to current doctrine, only be achieved when the iron(III) dextran can be administered to the piglets within the first 8-10 hours of life. This could only be ensured if births in the rearing farms were monitored around the clock, which is frequently not possible because it requires a great deal of labour. If this point in time is missed, substantial losses in the piglets frequently result.

3. The iron preparations to be administered intramuscularly are more advantageous on use since the administration in the period of from day 1 to day 3 after birth leads to very good results. However, the potential of damaging the piglets as the result of toxic side effects and short-term weakening of the immune system is disadvantageous. Oral preparations do not have this disadvantage.

4. Taking furthermore into account the treatment of coccidiosis, for example, with toltrazuril or similar compounds, which is frequently necessary, it becomes clear that two passes - (1) catching the piglets on day 1 after birth and the administration of, for example, iron(III) dextran, then catching the piglets again on day 3 and oral administration of a commercially available suspension formulation of toltrazuril, or (2) catching the piglets on day 3 and separate administration of the commercially available toltrazuril suspension for oral administration and a formulation for injection of iron(III) dextran (with the above-described disadvantages) - are very frequently required for successful piglet rearing.

It would therefore be very advantageous to have available preparations which would make it possible to combine the two passes without the above-described disadvantages, i.e. without harmful side effects, while being reliable and highly effective. A suitable preparation might be, for example, a formulation of the active ingredient toltrazuril and of iron(III) dextran for oral administration to piglets in the period of day 1-3 of life after birth. However, preparations which combine the two passes would have to meet a series of conditions:
= Sufficient amount of active ingredient: one unit dose must contain an anticoccidial substance in an amount sufficient for the pharmacological activity, usually 20-70 mg, for example 30 mg, 44 mg or 50 mg toltrazuril, and at least 100 mg, but better at least 150 mg, preferably 200-250 mg, of active iron (corresponding to, for example, 400-600 mg of a polynuclear iron(III) complex) for anaemia prophylaxis, which corresponds to the recommended dosage rates of 20 mg of toltrazuril/kg bodyweight and 200 mg of active iron per piglet. This corresponds to a concentration of 2-7% m/v of the anticoccidial substance and 10-25% m/v of active iron in the formulation (% m/v being understood as meaning the mass of the component in question in g per 100 ml of volume).

= Low dose volume for oral application: for example, a dose volume of approximately I ml is optimal in the case of suckling pigs since, when volumes are markedly higher, the complete uptake by the piglets is frequently not ensured. Larger amounts of fluid frequently escape from the mouth or are vomited.

= Suitable consistency: the viscosity should be in a range which makes possible the administration via drench guns or syringes, for example between 10 and 2500 mPas. If the consistency is too liquid, the preparation might escape from the animal's mouth after the application; if it is too high, a large-scale administration by means of syringes or drench guns is too demanding for the user and the animals, in particular piglets, have difficulties swallowing.

= Quality of the formulation: the physical and chemical stability, and the pharmacological activity, must be ensured. Thus, it should be ensured for example that iron ions do not adversely affect the chemical stability of the anticoccidial substance. It should furthermore be ensured that, in the case of a suspension formulation, a distribution of the active ingredient which is as finely dispersed as possible is retained, since coagulation or indeed agglomeration of the dispersed active ingredient particles is disadvantageous.
This might adversely affect for example the pharmacological activity since the dissolution rate, and thus the liberation of the active ingredient from the particles in the gut, is reduced as the result of the smaller surface area.

= Activity upon administration with a longer period of time after birth: a sufficient activity against coccidiosis and anaemia when administered in a period of from day 1 to day 3 after birth is desirable, in particular in the case of single application.

= Sufficient anaemia prophylaxis upon single application: the amount of iron to be administered in the abovementioned small dose volume of the combination preparation should be sufficiently high to suffice for covering the piglets' iron requirements under normaI keeping conditions after single application.

The combination of triazinones and iron preparations in a suitable formulation has not been described to date.

The invention relates to:

1. Composition containing triazinones of the formulae (I) or (II) R' OYN
O ~ \ N >=O
~-N\
R2 0 CH3 ~n or - CN ~--N
R s~ ~ ~H N N~O

in which Rl represents R3-SOZ- or R3-S-, R2 represents alkyl, alkoxy, halogen or SOZN(CH3)2 and R3 represents haloalkyl R4 and R5 independently of one another represent hydrogen or Cl and R6 represents fluorine or chlorine.
or their physiologically acceptable salts, and iron(2+) or iron(3+) compounds selected from among:

(a) iron(II) carboxylic acid salts, iron(II) carboxylic acid complex compounds and iron(II) chelate complexes with amino acids (b) iron(III) carboxylic acid salts, iron(III) carboxylic acid complex compounds and iron(III) chelate complexes with amino acids and (c) polynuclear iron(III) polysaccharide complex compounds.

In formulae (I) and (II), individual substituents preferably and especially preferably have the following meanings:

R2 preferably represents alkyl or alkoxy having in each case 1 to 4 carbon atoms, or represents fluorine, chlorine, bromine or SO2N(CH3)2; R2 especially preferably represents C14-alkyl.

R3 preferably represents fluoroalkyl having 1 to 4 carbon atoms, especially preferably trifluoromethyl.

The triazinones are well known per se as active ingredients against coccidial infections; the triazinetriones such as, for example, toltrazuril and ponazuril, and the triazinediones such as, for example, clazuril, diclazuril and letrazuril, may be mentioned.

The triazinediones are represented by formula (II):
Clazuril (R4 = Cl, R5 = H, R6 = Cl in formula (II)) Letrazuril (R4 = Cl, R5 = Cl, R6 = F in formula (II)) and Diclazuril (R4 = Cl, R 5 = Cl, R6 = Cl in formula (II)).

Among these 1,2,4-triazinediones, diclazuril is most preferred.

Especially preferred as active ingredients are, in accordance with the invention, the triazinetriones of the formula (I) in which R2 and R3 have the following preferred and especially preferred meanings:
R 2 preferably represents alkyl or alkoxy having in each case up to 4 carbon atoms, especially preferably methyl, ethyl, n-propyl, i-propyl.

R3 preferably represents perfluoroalkyl having 1 to 3 carbon atoms, especially preferably trifluoromethyl or pentafluoroethyl.

The preferred triazinetriones are represented by the formula (I):
Toltrazuril (RI = R3-S-, R2 = CH3, R3 = CF3) Ponazuril (RI = R3-S02-, R2 = CH3, R3 = CF3) The dosage rate of the triazinone may vary according to the animal species, as illustrated above. Conventional dosage rates are 1 to 60 mg active ingredient per kg bodyweight (mg/kg) of the animal to be treated per day, preferably 5 to 40 mg/kg and especially preferably 10 to 30 mg/kg.

In the case of oral administration, the toltrazuril dose is usually as follows:
Pigs: 20 mg/kg bodyweight Cattle: 15 mg/kg bodyweight Sheep: 20 mg/kg bodyweight Poultry: 15 mg/kg bodyweight Except for poultry, toltrazuril is only administered once per treatment, so that for example in the case of pigs, cattle and sheep the dosage rates stated apply both per day and per treatment.

Suitable iron(2+) or iron(3+) compounds are:
(a) iron(2+) carboxylic acid salts, iron(2+) carboxylic acid complex compounds and iron(2+) chelate complexes with amino acids (b) iron(3+) carboxylic acid salts, iron(3+) carboxylic acid complex compounds and iron(3+) chelate complexes with amino acids (c) polynuclear iron(3+) polysaccharide complex compounds.

Examples of iron compounds of type (a) which may be mentioned are: iron(II) lactate (FeC6HIOO6), iron(II) gluconate (FeC12H2ZO14), iron(II) fumarate (FeC4H2O4), and chelate complexes of iron with amino acids such as, for example, iron(II) bisglycinate (Fe(C2H4NO2)2), iron(II) methionate (Fe(C5H10NO2S)2) and their hydrate compounds.

Examples of iron compounds of type (b) which may be mentioned are: iron(III) citrate (FeC6H5O7), ammonium iron(III) citrate and, if appropriate, their hydrate compounds.
In the present context, iron compounds of group c) are understood as meaning complexes of the iron(3+) ion with hydroxide ions (OH-), aquo groups (H20) and oxygen (0) which are present in oligomeric or polymeric form and which are associated in their coordination sphere as complexes with one or more than one of the above oligomeric and polymeric carbohydrate compounds. This is why the compounds are also referred to as iron(III) hydroxide polysaccharide or iron(III) oxyhydroxy polysaccharide, where polysaccharide represents the corresponding oligomeric and polymeric carbohydrate compounds or their derivatives.
Polynuclear iron(III) complexes of this type are described for example in (D.S.
Kudasheva et al., "Structure of Carbohydrate-bound Polynuclear Oxyhydroxide Nanoparticles in Parenteral Formulation ", J. Inorg. Biochem. 98 (2004) 1757-1769; I. Erni et al "Chemical Characterization of Iron(III) Hydroxide-Dextrin Complexes" Arzneim.-Forsch./Drug Res. 34 (II) (1984) 1555-1559; F. Funk et al., "Physical and Chemical Characterization of Therapeutic Iron Containing Materials ", Hyperfine Interactions 136 (2001) 73-95; E. London "The Molecular Formula and Proposed Structure of the Iron-Dextran Complex, IMFERON", J.
Pharm. Sci. 93 (2004) 1838-1846; A. John "Neue Moglichkeiten der Eisenversorgung neugeborener Ferkel unter Beachtung biochemischer Aspekte "
[Novel possibilities of supplying iron to new born piglets, taking account of biochemical aspects], Trachtigkeit und Geburt beim Schwein [Pregnancy and birth in pigs]: 8th Bernburger Biotechnology Workshop, Bernburg (2002) 89-94). Since in many cases the precise composition of these compounds is not described in quantitative terms, and may also vary within the compounds, depending on the type of preparation, these polynuclear iron(III) polysaccharide compounds are understood as meaning all compounds which the skilled worker ascribes to this class of compounds.

Examples of iron compounds of type (c) which may be mentioned are: polynuclear iron(III) polysaccharide complex compounds in which a polynuclear (3-FeO(OH) nuclear complex contains polymeric carbohydrate compounds associated at the free coordination sites, for example iron(III) dextran, iron(III) hydroxy polymaltose (iron(III) dextrin), nonstoichiometric compounds of (3-FeO(OH) with saccharides and oligosaccharides "iron(III) sucrose" "iron(III) `sugar"'.
Other compounds which are preferably employed among the abovementioned iron compounds are those of type (b) and of type (c), with the latter being especially preferred. Iron(III) dextran may be mentioned as an especially preferred example.

Preparations of the formulations according to the invention which are suitable for animals are preferably solutions, suspensions or pastes, gels. Suspensions or pastes are preferred.

Solutions are prepared by dissolving the active ingredient, or active ingredients, in suitable solvents or solvent mixtures. If appropriate, further adjuvants such as solubilizers, antioxidants, preservatives, thickeners, adhesives, pH
regulators, UV
stabilizers or colorants are added.

Solvents which may be mentioned are: physiologically acceptable solvents such as water, alcohols, such as, for example, monohydric alkanols (for example ethanol or n-butanol), polyhydric alcohols such as glycols (for example ethylene glycol, propylene glycol, tetraglycol/glycofurol), polyethylene glycols, polypropylene glycols, glycerol; aromatically substituted alcohols such as benzyl alcohol, phenylethanol, phenoxyethanol; esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethyl oleate; ethers such as alkylene glycol alkyl ethers (for example dipropylene glycol monomethyl ether, diethylene glycol monobutyl ether); ketones such as acetone, methyl ethyl ketone; aromatic and/or aliphatic hydrocarbons, vegetable or synthetic oils; glycerol formal, solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane), N-methyl-pyrrolidone, 2-pyrrolidone, N,N-dimethylacetamide, glycofurol, dimethyl-isosorbitol, lauroglycol, propylene carbonate, octyldodecanol, dimethylformamide, and mixtures of the abovementioned solvents.

Solubilizers which may be mentioned are: solvents which promote the dissolution of the active ingredient in the main solvent or which prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

BHC 07 1 052-FC - 1 g-Antioxidants are sulphites or metabisulphites such as potassium metabisulphite or sodium metabisulphite, sodium disulphite or potassium disulphite, ascorbic acid, isoascorbic acid, ascorbyl palmitate, gallic acid esters, butvlhydroxytoluene, butylhydroxyanisole or tocopherols.
Synergists of these antioxidants may be: amino acids (for example alanine, arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or their salts, phosphoric acid derivatives or polyalcohols (polyethylene glycol).

Preservatives are: benzyl alcohol, benzalkonium chloride, trichlorobutanol, p-hydroxybenzoate, n-butanol, chlorocresol, cresol, phenol, benzoic acid, citric acid, tartaric acid or sorbic acid.

Thickeners are: inorganic thickeners such as bentonites, colloidal silica, aluminium stearates, organic thickeners such as cellulose derivatives, for example Hydroxypropylmethylcellulose 4000, polyvinyl alcohols and their copolymers, xanthan, acrylates and methacrylates, carboxymethylcellulose and its salts.

Adhesives are, for example, cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, gelatin.

Adhesives which also have thickening properties may likewise be employed as thickeners.
pH regulators are pharmaceutically customary acids or bases. The bases include alkali metal hydroxides or alkaline earth metal hydroxides (for example NaOH, KOH), basic salts such as, for example, ammonium chloride, basic amino acids such as, for example, arginine, choline, meglumine, ethanolamines or else buffers such as tris(hydroxy-methyl)aminomethane, citric acid buffers or phosphate buffers. The acids include, for example, hydrochloric acid, acetic acid, tartaric acid, citric acid, lactic acid, succinic acid, adipic acid, methanesulphonic acid, octanoic acid, linolenic acid, gluconolactone, and acidic amino acids such as, for example, aspartic acid.

UV stabilizers are, for example, substances from the class of the benzophenones, or novantisolic acid.

Colorants are all colorants which are approved for use on humans or animals and which may be dissolved or suspended.

Suspensions are prepared by suspending the active ingredient, or active ingredients, in a carrier liquid, if appropriate, with addition of further auxiliaries such as wetters, colorants, absorption accelerators, thickeners, adhesives, preservatives, antioxidants, UV stabilizers or antifoams.

Carrier liquids which may be mentioned are all homogeneous solvents and solvent mixtures.
The following may be mentioned as wetters (dispersants):
Surfactants (includes emulsifiers and wetters) such as 1. anionic surfactants, such as sodium lauiyl sulphate, fatty alcohol ether sulphates, the monoethanolamine salt of mono/dialkyl polyglycol ether orthophosphoric acid esters, or lignosulphonates or dioctylsulphosuccinate, 2. cationic surfactants such as cetyltrimethylammonium chloride, 3. ampholytic surfactants such as disodium N-lauryl-(3-imino-dipropionate or lecithin, 4. nonionic surfactants, for example polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, Pluronic .

Suitable antifoams are preferably those which are based on silicone, for example dimethicone or simethicone.

Further auxiliaries which may be mentioned are those detailed further above.

Preferred are suspensions and pastes, with low-viscosity pastes being preferred among the pastes. The pastes usually take the form of suspensions with a correspondingly higher viscosity. The suspensions and pastes are preferably administered orally.

The formulations according to the invention comprise the triazinone active ingredient in a concentration of from 0.1 to 30% (m/v), corresponding to 1 to 300 mg/ml, preferably 2 to 25% (m/v), corresponding to 20 to 250 mg/ml, especially preferably 3 to 15% (m/v), corresponding to 30 to 150 mg/ml, in particular 3 to 7% (m/v), corresponding to 30-70 mg of the triazinone in 1 ml.

As the result of the poor solubility of the triazinones, the latter are frequently present, in the formulations according to the invention, in finely divided form.
Here, the dispersed triazinone has a particle size (measured by laser diffraction, Malvern Mastersizer(K 2000) of d(v,90) < 30 m, preferably d(v,90) < 20 m, especially preferably d(v,90) < 10 m, and very especially preferably d(v,90) 7 m or less.

For the purposes of the present invention, d(v,90) is to be understood as meaning a volume-related particle size distribution where 90% of all particles have a dimension (diameter) of this value or less. Usually, this information is referred to as d(90), but the more precise term d(v,90) may be chosen in order to make clear that it is a volume-related particle size distribution. The names d(v,50), d(v, 10) and the like are to be understood correspondingly. The particle sizes indicated here were determined with the laser diffraction method using the Mastersizer 2000 apparatus (dispersing unit Hydro 2000G) from Malvern and using the Fraunhofer diffraction evaluation mode since the refractive indices of the active ingredient particles are not known. Here, a suitable amount of the sample solution is predispersed, with stirring, with 2-3 m1 of a dispersion medium (0.1% aqueous dioctyl sodium sulphosuccinate solution). The dispersion is then placed into the dispersing unit of the apparatus, with stirring (300 rpm) and recirculating (900 rpm), where it is measured. The evaluation software gives the particle size as d(0.5), d(0.9) values and the like.
These iron compounds in oral formulations for the treatment of iron deficiency states in large animal farms are usually applied in concentrations of from 100 mg of active iron to 200 mg of active iron per unit dose as a single or multiple administration. In drinkable solutions for supplying iron in poultry fattening operations, the dose may also amount to less than 100 mg of active iron per unit dose.

The formulations according to the invention contain the iron compounds usually in concentrations of from 10% (m/v) to 30% (m/v) of active iron, corresponding to 100 to 300 mg active iron in 1 ml, preferably 11.4% (m/v) to 25% m/v, corresponding to 114 mg to 250 mg active iron in I ml, but especially preferably from 20% rn/v to 25% m/v, corresponding to 200 mg to 250 mg active iron in 1 ml of the formulation. Active iron refers to the percentage of iron whicb is present in the formulation in the form of the iron complex. As a rule, the iron compounds are present in dissolved or colloidal form in the formulations. Finely divided iron compounds are less preferred in the formulations according to the invention.

The formulations according to the invention are preferably "water based". This means that, as a rule, they contain from 10 to 90% by weight, preferably from 20 to 80% by weight, especially preferably from 30 to 50% by weight of water. For example, the formulations as mentioned above may comprise further water-miscible solvents. Further water-miscible solvents which may be mentioned by way of example are preferably polyhydric aliphatic alcohols such as ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol and glycerol;
among these, propylene glycol is especially preferred. Such further water-miscible solvents are usually present in concentrations of from 1 to 45% by weight, preferably from 1 to 20% by weight, especially preferably from 5 to 10% by weight. The addition of such polyhydric aliphatic alcohols also has the advantage of lowering the freezing point of the formulation.

The amount of formulation to be applied per administration depends on how much triazinone and iron are to be administered in each case. One aims at relatively small volumes which can be applied readily orally and which vary depending on the animal species; for sucking pigs, for example, one aims at application volumes of from 0.3 to 2 ml, preferably from 0.5 to 1 ml.

It is advantageous when the formulations according to the invention permit an easy application, for example with the customary aids, for example a syringe, an applicator or a drench gun, and when they, for this purpose, have a fluid, slightly thickened or slightly pasty consistency which manifests itself in a viscosity -measured by forming the mean of the viscosity values measured at 20 C at shear rates 128 s1 and 256 sI with a cone-plate arrangement of a rheometer (Thermo Scientific RheoStress 600; cone diameter 35 ; cone angle 4 ; constant rate mode) -in a range of from 10 to 2500 mPas, preferably in a range of from 20 to 1500 mPas, especially preferably in a range of between 50 and 500 mPas and very especially preferably of between 20 and 250 mPas. In order to set a suitable viscosity range, the inventive formulations comprise, where appropriate, suitable substances (thickeners), as already named above.

Usually, the formulations according to the invention have a pH of from 3 to 8, preferably of from 4 to 7, especially preferably of from 4 to 6. Examples of suitable substances for regulating the pH have already been indicated further above. Substances which are preferably employed for adjusting the pH are organic acids such as, for example, citric acid or tartaric acid, mineral acids such as, for example, hydrochloric acid - preferably dilute hydrochloric acid, for example 0.1 n HCI, or bases such as, for example, sodium hydroxide solution (for example 1N
NaOH).
The formulations according to the invention as stated above can furthermore contain preservatives, if appropriate in combination with what are known as synergists. The preservatives are usually present in concentrations of from 0.01-5%
by weight and specifically of 0.05-1% by weight.
If required, antioxidants which may be employed in the formulations mentioned are, preferably, BHA or BHT. To ensure a sufficient preservation, the preservatives may be employed singly or else in combination with what are known as synergists.
Synergists such as citric acid, tartaric acid, ascorbic acid or the sodium salt of editic acid are usually present in concentrations of from 0.01-1% by weight, specifically of 0.05-0.15% by weight.

If appropriate, the formulations according to the invention may contain customary antifoams in concentrations of from 0.01 to 1% by weight.
The formulations according to the invention are preferably prepared by initially introducing the solvent, preferably water, and predissolving or dispersing therein if appropriate auxiliaries and/or additives such as, for example, cosolvents, preservatives, antioxidants and viscosity-regulating additives. In the preferred method, a second step involves introducing, into this initial solution, the triazinone, optionally in the form of a ready made dispersion concentrate, using a powerful homogenizer and homogenizing the mixture until the finely divided suspension is obtained. Then, the iron compound, preferably in the form of a powder, is introduced into this dispersion, during which process the mixture is again homogenized. In the last step, finally, the desired pH is adjusted by addition of suitable pH regulators. Individual or all auxiliaries and/or additives may, if appropriate, also be added after the last homogenization step; this may be advisable for example in the case of certain thickeners, whose structure is destroyed by the homogenization process.

The formulations according to the invention are suitable for the combined control of Coccidia and iron deficiencies, in particular in animals. Using the formulations, it is possible to administer, to the animals, the anticoccidial triazinones and the iron simultaneously in a simple manner. The formulations may be used in animal keeping and animal breeding in livestock, breeding animals, zoo animals, laboratory animals, experimental animals and pets. The spectrum of action of the triazinones is, in principle, well known. Coccidia which may be mentioned individually are:
Mastigophora (Flagellata) such as, for example, Trypanosomatidae, for example Trypanosoma brucei, T. gambiense, T. rhodesiense, T. congolense, T. cruzi, T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania brasiliensis, L. donovani, L. tropica, such as, for example, Trichomonadidae, for example Giardia lamblia, G. canis.

Sarcomastigophora (Rhizopoda) such as, for example, Entamoebidae, for example Entamoeba histolytica, Hartmanellidae, for example Acanthamoeba sp., Hartmanella sp.
Apicomplexa (Sporozoa) such as, for example, Eimeridae, for example Eimeria ascervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E.
arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E.
dispersa, E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis, E. hagani, E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E.
magna, E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix, E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani, E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E. stiedai, E.
suis, E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec., Isospora belli, I.
canis, I. felis, I. ohioensis, I. rivolta, I. spec., I. suis, Neospora caninum, N. hugesi, Cystisospora spec., Cryptosporidium spec. such as, for example, Toxoplasmadidae, for example Toxoplasma gondii, such as, for example, Sarcocystidae, for example Sarcocystis bovicanis, S. bovihominis, S. neurona, S. ovicanis, S. ovifelis, S. spec., S. suihominis such as, for example, Leucozoidae, for example Leucozytozoon simondi, such as, for example, Plasmodiidae, for example Plasmodium berghei, P.
falciparum, P. malariae, P. ovale, P. vivax, P. spec., such as, for example, Piroplasmea, for example Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec., such as, for example, Adeleina, for example Hepatozoon canis, H. spec.

Furthermore Myxospora and Microspora, for example Glugea spec., Nosema spec.
Furthermore Pneumocystis carinii, and also Ciliophora (Ciliata) such as, for example, Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis spee.
Those genera and species of protozoans which lead to subclinical or clinical infections in pigs must be very particularly emphasized, especially: Eimeria debliecki, E. suis, E. scabra, E. perminuta, E. spinosa, E. polita, E. porci, E. neodebliecki, Isospora suis, Cryptosporidium, Toxoplasma gondii, Sarcocystis miescheriana, S. suihominis, Babesia trautmanni, B. perroncitoi, Balantidium coli.
The livestock and breeding animals include mammals such as, for example, cattle, horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as, for example, mink, chinchilla, racoon, birds such as, for example, chickens, geese, turkeys, ducks, pigeons, ostriches, bird species which are kept as companion animals and as zoo animals. They furthermore include farmed fish and ornamental fish. In this context, pigs, cattle, sheep and dogs of all species, subspecies and breeds may be particularly emphasized.

Laboratory and experimental animals include mice, rats, guinea pigs, golden hamsters, dogs and cats.
The pets include dogs and cats.

The use in pigs is especially preferred.

The formulations according to the invention are preferably applied to young animals, in particular shortly after birth, preferably in sucking pigs.
Usually, the formulations according to the invention (combined iron/triazinone preparation) are only applied once. Especially preferred formulations according to the invention permit the oral treatment of piglets in such a way that a sufficient supply of the piglets with iron in the first four weeks of life can be achieved with a single oral administration of from 0.7 m1-1.3 ml, preferably from 0.7-1.0 ml, of the formulation, even on the third day after birth, where a haemoglobin value of at least S g/100 ml blood, preferably of more than 9 g/100 ml blood, may be considered the indicator for a sufficient supply. In addition, the triazinone portion is intended to successfully control coccidia.

The formulations according to the invention may contain further active ingredients or components - singly or in suitable combinations -, such as, for example, nutrients, which include, for example, vitamins, minerals, and phosphorus compounds which are suitable as metabolic and immune stimulants:

Vitamins such as, for example, vitamin E, vitamins from the B series such as, for example, vitamin B 12, vitamin C.
Minerals, preferably calcium or magnesium salts, in particular for example calcium gluconate, calcium glucoheptanoate or calcium saccharate.

Phosphorus compounds, in particular pharmacologically acceptable organic phosphonic acid derivatives which are suitable as metabolic stimulants and tonics.
Preferred examples which may be mentioned are the compounds toldimfos and, in particular, butaphosphane, which have already been known for a long time.

Subject matter and preferred embodiments of the invention:
1. Formulation containing triazinones of the formulae (I) or (II) R' ~ ~ ~--N
U N >=O
~--N
RZ O \CM3 (n or CN
&
R YN
s H N ~
N~

(1) in which R' represents R3-S02- or R3-S-, R2 represents alkyl, alkoxy, halogen or SOZN(CH3)2 and R3 represents haloalkyl R4 and R5 independently of one another represent hydrogen or Cl and R6 represents fluorine or chlorine, or their physiologically acceptable salts, and iron(2+) or iron(3+) compounds selected from among:

(a) iron(II) carboxylic acid salts, iron(II) carboxylic acid complex compounds and iron(II) chelate complexes with amino acids (b) iron(III) carboxylic acid salts, iron(III) carboxylic acid complex compounds and iron(III) chelate complexes with amino acids and (c) polynuclear iron(III) polysaccharide complex compounds.

2. Formulation according to item 1, containing from I to 30% (m/v), preferably 3-7% (m/v) of triazinone.

3. Formulation according to one of the preceding items, where the dispersed triazinone has a particle size of d(v, 90) 30 m or less, preferably d(v, 90) 20 m or less, and especially preferably d(v, 90) 10 m or less.

4. Formulation according to one of the preceding items with an iron compound concentration of from 10% (m/v) to 30% (m/v) of active iron, preferably from 11.4% (m/v) to 25% (m/v), but especially preferably from 20% m/v to 25% (m/v).

5. Formulation according to one of the preceding items with a viscosity -measured by forming the mean of the values measured at the shear rates 128 s-1 and 256 s"1 with a cone-plate arrangement of a rheometer - in a range from 10 to 2500 mPas, preferably in a range from 20 to 1500 mPas.

6. Formulation according to item 1, which is water based.

7. Formulation according to item 1, containing at least one polyhydric aliphatic alcohol.

8. Formulation according to one of the preceding items, containing a polynuclear iron(III) polysaccharide complex compound from group (c) whose polynuclear iron core consists of (3-FeO(OH) units and which contains polysaccharide molecules in the further sphere of coordination.

9. Formulation according to item 8, containing a polynuclear iron(III) polysaccharide complex compound selected from: iron(III) dextran, iron(III) hydroxy polymaltose/iron(III) dextrin and a nonstoichiometric compound consisting of polynuclear (3-FeO(OH) and sucrose and oligosaccharides.

10. Formulation according to one of items 1 to 7, containing, as iron compound of group (b), an iron citrate compound, preferably ammonium iron(III) citrate.

11. Formulation according to one of the preceding items, containing, as triazinone, a triazinetrione.

12. Formulation according to item 11, containing, as triazinetrione, toltrazuril, ponazuril or toltazuril sulphoxide.

13. Formulation according to any of items 1 to 8 and 11 to 12, wherein the triazinone is toltrazuril and the polynuclear iron(III) polysaccharide complex compound is iron(III) dextran.

14. Formulation according to one of items I to 10, containing, as triazinone, a triazinedione, in particular clazuril, diclazuril or letrazuril.

15. Use of the formulations according to one of the preceding items for the preparation of pharmaceuticals.

16. Use according to item 15 for the preparation of pharmaceuticals for the simultaneous treatment of coccidia infections and iron deficiencies.

17. Use according to item 15 or 16 for the preparation of pharmaceuticals for oral treatment.

18. Use according to item 17 for the preparation of pharmaceuticals for the oral treatment of suckling pigs.

19. Use according to one of items 17 or 18 for the preparation of pharmaceuticals for the oral treatment of piglets in the period from birth to 10 days after birth, preferably in a period from birth to 3 days after birth.

20. Formulations according to one of items 1 to 14, additionally containing one or more nutrients.

21. Formulation according to item 20, additionally containing a calcium salt or magnesium salt.

22. Formulation according to item 20 or 21, containing butaphosphan.

The examples which follow are intended to illustrate the invention, but not to limit it:

Preparation examples:

Example 1 Use of iron(III) dextran powder 38.4% m/m Batch for the preparation of 10 1 of an iron dextran/toltrazuril dispersion (22.8%
m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs Ingredient Mass/g Toltrazuril suspension concentrate (30%) 1666.67 Sodium propionate (preservative) 17.00 Sodium benzoate (preservative) 17.00 Propylene glycol 1000.00 Anhydrous citric acid 87.10 Iron(III) dextran powder 38.4% m/m 5937.50 Water to 101itres 5138.00 Viscosity regulating auxiliary/auxiliaries -Total mass 13863.27 In each case 17.00 g of the preservatives sodium propionate and sodium benzoate are, in separate vessels, weighed into 1000.00 g of the solvent propylene glycol and dissolved with stirring. All of the water is introduced into a stainless-steel vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is needed and on the desired viscosity of the end product, a viscosity-regulating auxiliary (known as a thickener) may be dissolved or incorporated into this amount of water. In Example 1, this is dispensed with. The propylene glycol premix is added to what has been introduced into the stainless-steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed amount of 1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min and simultaneously homogenized for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
The abovementioned stirring and homogenizing times may also be extended or shortened, depending on the appearance of the suspension. It is advantageous to use suitable cooling systems for keeping the temperature of the mixture at 20-C. In the next step, 6015.83 g of the iron(III) dextran powder are added to the dispersion in several portions. During the addition, the mixture must be stirred continuously and homogenized using the rotary homogenizer at 2500 rpm. The temperature is maintained at 20-30 C by activating the cooling mechanism.
After all of the iron(III) dextran powder has been added, the citric acid (85.90 g) is added to the mixture and dissolved. A pH of 4.1-4.4 establishes. After all components have been incorporated, stirring is continued for 20 minutes and a post-homogenation is carried out simultaneously at 2500 rpm. During this post-stirring phase, the temperature of the dispersion is kept at room temperature by means of cooling. The finished dispersion is transferred from the stainless-steel vessel into suitable storage containers through a 0.1 mm mesh sieve. After a certain storage period, the pH climbs to values of between 4.8 and 5.2.
To determine the quality of the dispersion, the parameters pH, particle size distribution (measured by means of laser diffraction using a Malvern Mastersizer 2000) and viscosity. The viscosity is measured using a cone/plate measuring arrangement at a shear rate of 128 and 256 s"1 (RheoStress 600; Thermo Haake).
The mean of the viscosity values measured is used as reference. These viscosity data have proved suitable for characterizing the flow resistance of such a suspension when expelled via a drench gun. In principle, one aims at a dispersion with the finest possible distribution in order to keep the bioavailability of the active ingredients at a high level. The suspension prepared as described gives the following parameters:

Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 m < 30 m m m Iron(III) 133 4.4 5.1 2.3 4.1 100% 100%
dextran powder 38.4%
m/m Example 2 Use of iron(III dextran powder 36.8% m/m Batch for the preparation of 1000 ml of an iron dextran/toltrazuril dispersion (23.6% rn/v active iron + 5.3% rn/v toltrazuril) for oral use in sucking pigs In redient Mass/g Toltrazuril suspension concentrate (30%) 177.34 Sodium propionate (preservative) 1.89 Sodium benzoate (preservative) 1.89 Propylene glycol 106.38 Anhydrous citric acid 7.59 Iron(III) dextran powder 36.8% m/m 639.98 Water 464.67 Viscosity regulating auxiliary/auxiliaries -Total mass 1399.74 In each case 1.89 g of the preservatives sodium propionate and sodium benzoate are, in separate vessels, weighed into 106.38 g of the solvent propylene glycol and dissolved with stirring. All of the water is introduced into a vessel (1 1 glass beaker). Depending on what is needed and on the desired viscosity of the end product, a viscosity-regulating auxiliary (known as a thickener) may be dissolved or incorporated into this amount of water. In Example 2, this is dispensed with.
The propylene glycol premix is added to what has been introduced into the glass beaker and homogenized with stirring (10 min). In the next step, the previously weighed amount of 177.34 g of the 30% strength toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min with the aid of a dissolver disk. The abovementioned stirring times may also be extended or shortened, depending on the appearance of the suspension. In the next step, 639.98 g of the iron(III) dextran powder are added in several portions to the dispersion, with stirring, and, when the addition is complete, the suspension is stirred for a further 20 minutes with the aid of the dissolver disk. After all of the iron(III) dextran powder has been added, the citric acid (7.59 g) is added to the mixture and dissolved. A pH of 4.1-4.4 establishes. After a certain storage period, the pH climbs to values of between 4.8 and 5.2.

Iron V iscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 m < 30 m m m Iron(III) 277 4.4 4.9 3.2 6.4 99% 100%
dextran powder 36.8%
m/m Example 3 Use of iron(III) dextran solution 27.5% m/m Batch for the preparation of 10 1 of an iron dextran/toltrazuril dispersion (21.0%
m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs Ingredient Mass/g Toltrazuril suspension concentrate (30%) 1666.67 Sodium propionate (preservative) 17.00 Sodium benzoate (preservative) 17.00 Propylene glycol 1000.00 Anhydrous citric acid 150.35 Iron(III) dextran solution 27.5% m/m 11229.00 Viscosity regulating auxiliary/auxiliaries -Total mass 14080.02 In each case 17.00 g of the preservatives sodium propionate and sodium benzoate are, in separate vessels, weighed into 1000.00 g of the solvent propylene glycol and dissolved with stirring. All of the 11229.00 g of the iron(III) dextran solution is introduced into a stainless-steel vessel (Koruma Disho; apparatus type:
DH V 100/45). Depending on what is needed and on the desired viscosity of the end product, a viscosity-regulating auxiliary (known as a thickener) may be dissolved or incorporated into what has been introduced. In Example 3, this is dispensed with. The propylene glycol premix is added to what has been introduced into the stainless-steel vessel and homogenized with stirring (20-40 min). The abovementioned stirring times may also be shortened or extended, depending on the appearance of the suspension. In the next step, the previously weighed amount of 1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min and simultaneously homogenized for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is advantageous to use suitable cooling systems for keeping the temperature of the mixture at 20-30 C. In the next step, the citric acid (150.33 g) is added and dissolved. During the addition, the homogenizer is switched on at a speed of 1800 rpm, also, the temperature is maintained at room temperature by activating the cooling mechanism. A pH of 4.1-4.4 establishes. The stirring and homogenizing times are averages and may be shortened or extended, depending on the appearance of the suspension. During this process, the cooling mechanism remains activated. The finished dispersion is transferred from the stainless-steel vessel into suitable storage containers through a 0.1 mm mesh sieve. Within a few days to weeks, the pH equilibrates to values of between 4.8-5.2.

Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage coinpound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 m < 30 m m m Iron(III) 96 4.4 4.8 2.5 4.7 100% 100%
dextran solution 27.5%
m/v Example 4 Use of iron(III) sugar powder 35.9% m/m The compound referred to as iron(III) sugar (from Dr. Paul Lohmann GmbH KG), which is an iron(III) (hydroxide) saccharate complex, was used.

Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion (22.8% m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs:

In redient Mass/g Toltrazuril suspension concentrate (30%) 1666.67 Sodium propionate ( reservative 17.00 Sodium benzoate (preservative) 17.00 Propylene glycol 1000.00 Anhydrous citric acid 400.00 Iron(III) sugar powder 35.9% m/m 6350.98 Water to 101itres 4543.73 Viscosity regulating auxiliary/auxiliaries -Total mass 13995.38 In each case 17.00 g of the preservatives sodium propionate and sodium benzoate are, in separate vessels, weighed into 1000.00 g of the solvent propylene glycol and dissolved with stirring. All of the water is introduced into a stainless-steel vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is needed and on the desired viscosity of the end product, a viscosity-regulating auxiliary (known as a thickener) may be dissolved or incorporated into this amount of water. In this Example 4, this is dispensed with. The propylene glycol premix is added to what has been introduced into the stainless-steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed amount of 1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min and simultaneously homogenized for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is advantageous to maintain the temperature of the mixture at 20-30 C by means of suitable cooling systems. In the next step, 6350.98 g of the iron(III) sugar powder are added to the dispersion in several portions. During the addition, the mixture must be stirred continuously and homogenized using the rotary homogenizer at 2500 rpm. The stirring and homogenizing times of the suspension which have been mentioned may be extended or shortened, depending on the appearance of the formulation. The temperature is maintained at 20-30 C by activating the cooling mechanism. After all of the iron(III) sugar powder has been added, the citric acid (400.00 g) is added to the mixture and dissolved with stirring. After all components have been incorporated, stirring is continued for 20 minutes and a post-homogenation is carried out at 2500 rpm. During this post-stirring phase, the temperature of the dispersion is kept at room temperature by means of cooling.
After a short time a pH of 5 is obtained. The finished dispersion is transferred from the stainless-steel vessel into suitable storage containers through a 0.1 mm mesh sieve.

Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)l d(v,90)/ < 10 m < 30 um m m Iron(III) 1312 5.0 - 2.1 4.3 100% 100%
sugar powder 35.9%
m/m Example 5 Use of iron(III) polymaltose powder 32.0% m/m Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion (22.8% m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs Ingredient Mass/g Toltrazuril suspension concentrate (30%) 1666.67 Sodium propionate (preservative) 17.00 Sodium benzoate (preservative) 17.00 Propylene glycol 1000.00 Anhydrous citric acid 604.69 Iron(III) polymaltose powder 32.0% m/m 7125.00 Water to 101itres 3927.21 Viscosity regulating auxiliary/auxiliaries -Total mass 14357.57 In each case 17.00 g of the preservatives sodium propionate and sodium benzoate are, in separate vessels, weighed into 1000.00 g of the solvent propylene glycol and dissolved with stirring. All of the water is introduced into a stainless-steel vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is needed and on the desired viscosity of the end product, a viscosity-regulating auxiliary (known as a thickener) may be dissolved or incorporated into this amount of water. In this Example 5, this is dispensed with. The propylene glycol premix is added to what has been introduced into the stainless-steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed amount of 1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min and simultaneously homogenized for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is advantageous to maintain the temperature of the mixture at 20-30 C by means of suitable cooling systems. In the next step, 7125.00 g of the iron(III) polymaltose powder are added to the dispersion in several portions. During the addition, the mixture must be stirred continuously and homogenized using the rotary homogenizer at 2500 rpm. The temperature is maintained at 20-30 C by activating the cooling mechanism. After all of the iron(III) polymaltose powder has been added, the citric acid (604.69 g) is added to the mixture and dissolved with stirring.
After all components have been incorporated, stirring is continued for 20 minutes and a post-homogenation is carried out simultaneously at 2500 rpm. Depending on the appearance of the formulation, the abovementioned stirring and homogenizing times may be extended or shortened. During this post-stirring phase, the temperature of the dispersion is kept at room temperature by means of cooling.
The finished dispersion is transferred from the stainless-steel vessel into suitable storage containers through a 0.1 mm mesh sieve. After a storage time of from a few days to weeks, the pH climbs to values of 4.8-5.2.

Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 gm < 30 gm m m Iron(III) 1226 4.4 5.0 1.9 3.3 100% 100%
polymaltose powder 3 8.4% m/m Example 6 Use of iron(III) dextran powder 37.9% m/m using a viscosity-re ug lating auxiliary Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion (22.8% m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs Ingredient Mass/g Toltrazuril suspension concentrate (30%) 1666.67 Sodium propionate (preservative) 17.00 Sodium benzoate (preservative) 17.00 Propylene glycol 1000.00 Anhydrous citric acid 70.00 Iron(III) dextran powder 37.9% m/m 6015.83 Bentonite (Veegum) as viscosity regulator 20.00 Xanthan gum as viscosity regulator 30.00 Water to 10 litres 3290.00 Total mass 12126.50 In each case 17.00 g of the preservatives sodium propionate and sodium benzoate are, in separate stainless steel vessels, weighed into 1000.00 g of the solvent propylene glycol and dissolved with stirring. When the preservatives are dissolved, 30.0 g of xanthan gum are added, and stirring is continued for approximately minutes. Thereafter, the mixture is homogenized for approximately 5 minutes at 13.500 rpm, using a rotary homogenizer (rotor/stator system; laboratory Ultra-Turrax), so that the dispersion is free from small lumps.

10 All of the water, 3290.0 g, is introduced into a stainless-steel vessel (Koruma Disho; apparatus type: DH V 100/45). Thereafter, 20 g of the bentonite are sprinkled in. This mixture is now warmed to 78 C, with gentle stirring (50 rpm of the rotary stirrer). The temperature should be maintained at 78 C for approximately 5-10 minutes and the mixture should then be cooled to 35 C with stirring and operating the cooling system. Stirring is then continued for 20-minutes, and a post-homogenization is simultaneously carried out for 20 minutes using the rotary homogenizer at 2500 rpm, with continued cooling. Thereafter, the dispersion of the xanthan gum in propylene glycol is added to the bentonite/water mixture, with constant stirring. Then, a post-homogenization of the mixture is then carried out by stirring for a further 20-40 minutes at 50 rpm and simultaneously for 10 minutes with the rotary homogenizer at 2500 rpm. Again, the abovementioned stirring and homogenization times may be extended or shortened, depending on what is required and on the appearance of the dispersion.

In the next step, the previously weighed amount of 1666.67 g of the 30%
toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min and simultaneously homogenized for 20 minutes using the rotary homogenizer at 2500 rpm. During this process, the temperature is maintained at 20-30 C by activating the cooling system. After all of the iron(III) dextran powder has been added, the citric acid (70.0 g) is added to the mixture and dissolved, with stirring and homogenizing. A pH of 4.1-4.4 establishes. After all components have been incorporated, stirring is continued for 20 minutes and a post-homogenization is carried out at 2500 rpm. During this post-stirring phase, the temperature of the dispersion is maintained at room temperature by means of cooling. The finished dispersion is transferred from the stainless-steel vessel into suitable storage containers through a 0.1 mm mesh sieve.

Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 m < 30 pm m m Iron(III) 1365 4.5 - 1.7 3.5 100% 100%
dextran powder 37.9%
m/m Example 7 Use of iron(III) dextran powder 38.6% m/m using a viscosity-re ug lating auxiliary Batch for the preparation of 1 1 of an iron dextran/toltrazuril dispersion (20% m/v active iron + 3% m/v toltrazuril) for oral use in sucking pigs Ingredient Mass/
Toltrazuril suspension concentrate (30%) 100.00 Sodium propionate (preservative) 1.80 Sodium benzoate (preservative) 1.80 Propylene glycol 100.00 Anhydrous citric acid 8.67 Iron(III) dextran powder 38.6% m/m 518.13 Bentonite (Veegum) as viscosity regulator 1.33 Xanthan gum as viscosity regulator 2.00 Water to I litre 606.42 Total mass 1340.15 In each case 1.80 g of the preservatives sodium propionate and sodium benzoate are, in a separate glass beaker, weighed into 100.00 g of the solvent propylene glycol and dissolved with stirring. When the preservatives are dissolved, 2.00 g of xanthan gum are added, and stirring is continued for approximately 10 minutes, so that the dispersion is free from small lumps.

Approximately 100 g of the water are introduced into a glass beaker and warmed to 70-80 C. Thereafter, 1.33 g of the bentonite are scattered in, and the temperature is maintained for approximately 5-10 minutes. The resulting bentonite slime is cooled with stirring, and the remainder of the water, which is 506.42 g, is subsequently added. The bentonite/water mixture is stirred at 270 rpm with the aid of a dissolver disk, and the dispersion of the xanthan gum in propylene glycol is added with constant stirring. Then, a post-homogenization of the mixture is carried out for a further 5-10 minutes, with stirring. Again, the abovementioned stirring times may be extended or shortened, depending on what is required and on the appearance of the dispersion.
In the next step, the previously weighed amount of 100.00 g of the 30%
toltrazuril dispersion concentrate is added to the mixture, and the mixture is stirred for 30-40 min at a speed of 460 rpm. Thereafter, 518.13 g of the iron(III) dextran powder are added to the dispersion in several portions, with constant stirring. After all of the iron(III) dextran powder has been added, the citric acid (8.67 g) is added to the mixture and dissolved, with stirring. A pH of 4.1-4.4 establishes.
After all components have been incorporated, a post-homogenization of the suspension is carried out for 20 minutes at 9500 rpm with the aid of a rotor stator homogenizer.
The finished dispersion is transferred into a suitable PE flask.
Iron Viscosity/ pH after pH after Particle Particle Percentage Percentage compound mPas preparation storage size size particles particles d(v,50)/ d(v,90)/ < 10 m < 30 m m m Iron(III) 108 4.2 - 1.9 3.6 100% 100%
dextran powder 38.6%
m/m The data for the dispersions of Examples 1-7 demonstrate that formulations according to the invention with a very fine solids component can be prepared.
The formation of agglomerates, which is undesired, is not observed. Moreover, the ingredients 35-44 mg toltrazuril and 200 mg active iron, which are required for use in sucking pigs, are found in 0.9 ml of the dispersion in the suspensions of the examples.

The viscosity of the dispersions of Examples 1-7 can be established over a great range of from 10-2500 mPas. A less viscous range of from 20-1500 mPas, preferably 50-500 mPas and very especially preferably 20-250 mPas is advantageous since it causes fewer problems when swallowed by, for example, the piglets.
Biological examples Results of clinical tests with formulations of Examples 2 and 3 30 breeding sows who produced a total of 270 piglets were available for a clinical experiment. The animals were divided into four groups, the litters being in each case divided and each half was assigned to different groups. Thus, as the result of slightly different litter sizes and farrowing times, between 60 and 75 piglets were assigned to one treatment group. In each case 0.9 ml of the formulations were administered orally to the piglets on day 3 after birth. On the day of administration and on day 7, 14 and 21, blood samples were taken from the piglets. The number of erythrocytes (RBC million cells/ 1), the haematocrit (Ht%), the haemoglobin value (Hb g/100 ml) and the weight of the piglets in kg were used as criteria for the efficiency of the formulations. The results were compared with those of a control group which had received a commercially available iron(III) dextran preparation for injection (Hierrox 200), applied on day 3 after birth. The results are shown in Table 5.

Both orally applied formulations of Example 2 (prepared from iron(III) dextran powder) and of Example 3 (prepared from iron(III) dextran solution) brought about a haemoglobin value of > 9 g/100 mi on days 7, 14 and 21 after birth and therefore proved effective for avoiding any anaemic deficiencies. The value of > 10 g/100 ml 14 and 21 days after birth furthermore demonstrates that the formulations were highly bioavailable. The criteria RBC, HT and weight gain, moreover, showed no disadvantages over the preparation for injection.

It can thus be demonstrated that the single oral administration of 200 mg of active iron from iron(III) dextran in combination with toltrazuril in the formulations according to the invention surprisingly - counter to doctrine and the available prior art - makes possible a good prophylaxis against anaemic deficiencies in sucking pigs even when administered on day 3 after birth.

An analysis of the piglets' faeces for oocysts gave negative findings throughout.
This demonstrates that the abovementioned formulations are just as effective against pathogens causing coccidiosis.

Moreover, no negative associated symptoms whatsoever such as, for example, diarrhoea, as can be observed more frequently in the case of the oral administration of high doses of iron compounds, were found. Thus, the formulations prepared in accordance with the invention proved to be very well tolerated.

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Claims (17)

1. claims:
   
   Formulation containing triazinones of the formulae (I) or (II) in which R1 represents R3-SO2- or R3-S-, R2 represents alkyl, alkoxy, halogen or SO2N(CH3)2 and R3 represents haloalkyl R4 and R5 independently of one another represent hydrogen or Cl and R6 represents fluorine or chlorine, or their physiologically acceptable salts, and iron(2+) or iron(3+) compounds selected from among:
   
   (a) iron(II) carboxylic acid salts, iron(II) carboxylic acid complex compounds and iron(II) chelate complexes with amino acids (b) iron(III) carboxylic acid salts, iron(III) carboxylic acid complex compounds and iron(III) chelate complexes with amino acids and (c) polynuclear iron(III) polysaccharide complex compounds.
2. 2. Formulation according to Claim 1, containing from 1 to 30% (m/v), preferably 3-7% (m/v) of triazinone.
3. 3. Formulation according to one of the preceding claims, where the dispersed triazinone has a particle size of d(v, 90) 30 µm or less, preferably d(v, 90) 20 µm or less, and especially preferably d(v, 90) 10 µm or less.
4. 4. Formulation according to one of the preceding claims with an iron compound concentration of from 10% (m/v) to 30% (m/v) of active iron, preferably from 11.4% (m/v) to 25% (m/v), but especially preferably from 20% m/v to 25%
   (m/v).
5. 5. Formulation according to one of the preceding claims with a viscosity -measured by forming the mean of the values measured at the shear rates 128 s-1 and 256 s-1 with a cone-plate arrangement of a rheometer - in a range from 10 to 2500 mPas, preferably in a range from 20 to 1500 mPas.
6. 6. Formulation according to Claim 1, which is water based.
7. 7. Formulation according to Claim 1, containing at least one polyhydric aliphatic alcohol.
8. 8. Formulation according to one of the preceding claims, containing a polynuclear iron(III) polysaccharide complex compound from group (c) whose polynuclear iron core consists of .beta.-FeO(OH) units and which contains polysaccharide molecules in the further sphere of coordination.
9. 9. Formulation according to Claim 8, containing a polynuclear iron(III) polysaccharide complex compound selected from: iron(III) dextran, iron(III) hydroxy polymaltose/iron(III) dextrin and a nonstoichiometric compound consisting of polynuclear .beta.-FeO(OH) and sucrose and oligosaccharides.
10. 10. Formulation according to one of the preceding claims, containing, as triazinone, a triazinetrione.
11. 11. Formulation according to one of the preceding claims, wherein the triazinone is toltrazuril and the polynuclear iron(III) polysaccharide complex compound is iron(III) dextran.
12. 12. Formulations according to one of Claims 1 to 11, containing one or more nutrients.
13. 13. Use of the formulations according to one of the preceding claims for the preparation of pharmaceuticals.
14. 14. Use according to Claim 13 for the preparation of pharmaceuticals for the simultaneous treatment of coccidial infections and iron deficiencies.
15. 15. Use according to Claim 13 or 14 for the preparation of pharmaceuticals for oral treatment.
16. 16. Use according to Claim 15 for the preparation of pharmaceuticals for the oral treatment of suckling pigs.
17. 17. Use according to Claim 15 for the preparation of pharmaceuticals for the oral treatment of piglets in the period from birth to 10 days after birth, preferably in a period from birth to 3 days after birth.