HK1141993A1 - Formulations containing triazinones and iron - Google Patents

Abstract

The invention relates to the simultaneous application of triazines such as toltrazuril, ponazuril or diclazuril and iron compounds in a formulation for controlling coccidia infections and iron deficiencies in animals and humans.

Description

Formulations comprising triazinones and iron

Technical Field

The invention relates to formulations containing triazineone compounds (Triazinone) and iron compounds (salts and complexes of iron) which are suitable for simultaneously controlling coccidiosis (Coccidiose) and iron-deficient states in animals

Background

An economically successful modern meat production enterprise is characterized by a highly intensive farming and animal husbandry, i.e. by raising a large number of animals specifically selected for the purpose of optimizing breeding objectives. These farms are characterized by high machine usage, supplementary feeding of nutritional supplements and involving as few staff as possible. In the case of piglet breeding enterprises, this means that a large number of sows fed for a high number of piglets per farrowing are kept in a suitably large pigpen. Suitable choices for optimizing feed and breeding processes enable piglets to grow rapidly.

Such animal feeding is often considered to be a typical disease and deficiency stateThe reason for the frequency. In particular, in addition to the pressure that pigs kept intensively are very susceptible, in piglets, such phenomena are especially protozoan infections (coccidiosis) and iron deficiency states, both of which often have to be suppressed by means of the use of prophylactic drugs.

Coccidiosis is a parasitic infectious disease that frequently occurs in animals. Thus, protozoa such as Eimeria (Eimeria), Isospora (Isospora), Neospora (Neospora), sarcocystis (sarcospora) and Toxoplasma (Toxoplasma) cause coccidiosis worldwide. Examples of economically important coccidiosis are: pigs are infected with coccidia of the genus Isospora (Isospora) or cattle are infected with coccidia of the genus Eimeria (Eimeria). Infection with porcine Isospora suis (Isospora suis) has only been recognized in recent years as a cause of diarrhea in piglets and has been studied extensively. Typically, infection will proceed from the environment to the piglets, or between piglets, by oocysts, which in each case contain two cysts (sporocysts) each having two sporozoites. The parasite phase proliferates in the epithelial cells of the small intestinal villi. The clinical manifestations of the disease include necrotic, inflammatory destruction of the intestinal epithelium with atrophic villi, and consequent disturbance of digestion and absorption. Acute disease is characterized by watery, whitish to yellowish diarrhea, most of which occurs in weeks 2-3 of life. The weight gain of the infected piglets is reduced. Currently, the treatment and therapy of this disease is still inadequate. Antibiotics are ineffective; although sulfonamides are approved for the treatment of coccidiosis. Their effectiveness is controversial and in all cases frequent repeated administration is not practical. Other possible treatments are also uncertain: for example, administration of Monensin (Monensin), Amprolium (Amprolium) or furazolidone (Furazolidon) has failed to successfully prevent the disease in experimentally infected piglets. In a recent study, in spite of good hygiene conditions, porcine isosporozoite coccidia (Isospora suis) have been identified in up to 92% of all piglets in many enterprises. This type of disease is not restricted to pigs but also occurs in many other animal species, for example in poultry breeding, in calves, in lambs or in small animals (rabbits).

An example of a deficiency is iron deficiency in newborn piglets. Endogenous iron stores are rapidly depleted due to rapid growth in the first few days after birth, and therefore must be compensated for by an external source. Because of the large number of piglets in lactation, this replacement cannot be adequately performed by taking the milk of the sow. Furthermore, if these animals are raised on concrete or plastic floors, the piglets are also unable to take up iron compounds by arching the ground. Piglets can become anaemic. Clinically significant states of anemia occur when the hemoglobin content of the blood drops below 80 g/l. The NRC recommendation (National Research Council, Nutrient Requirements of biomedical ceramics, No.2, Nutrient Requirements of Swine, National Academy of sciences, Washington DC, 1973) defines 90g/l as the lowest hemoglobin value at which piglets grow healthily and do not show signs of anemia. However, only when the hemoglobin content of the blood is reduced to a value below 80g/l, significant symptoms such as weight loss or poor growth are observed. Other indicators of iron supply are hematocrit and the number of red blood cells per unit volume. Severe iron deficiency anemia can also cause death in piglets.

Several formulations have been available for the prevention and treatment of the above mentioned diseases and conditions of deficiency.

Coccidiosis can be successfully controlled by administering active ingredients of the triazineone type. For this purpose, triazine diones (representative examples of which are the active ingredients Clazuril (Clazuril), Diclazuril (Diclazuril), Letrazuril (Letrazuril)) and triazine triketones (the active ingredients toltrazuril, toltrazuril-sulfoxide and ponazuril) are distinguished. Triazines, in particular toltrazuril, ponzazuril or diclazuril, and their activity against coccidia are known from numerous publications, see DE-OS 2718799 and DE-OS 2413722. WO99/62519 discloses semi-solid aqueous formulations of toltrazuril sulfone (ponazuril). It is also known that toltrazuril in particular is suitable for the treatment of coccidiosis in pigs (e.g. coccidia Isospora suis (Isospora suis)). For example, see also the following publications: don' tforget coccidiosis, update on isosporiosis in piglets section I, Pig Progress volume 17, No.2, 12-14; mundt, h. -c, a.daugchies, v.letkova (2001): part II of be aware of piglet coccidiosis diagnostics, 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.

Coccidiosis in cattle infected with the various pathogens Eimeria spp (e.g. Eimeria spp.) such as E.bovis and E.z ü rnii is primarily characterized by diarrhea of varying severity, up to hemorrhagic diarrhea with death.

WO 96/38140, DE 10049468, DE 19958388, WO 00/19964, WO99/62519 or WO 00/37063 and DE 102006038292.7 describe agents against coccidiosis in animals. They are mentioned in the usual form as oral administration, among other types of administration.

DE 19603984 contains granules for oral administration. DE 19824483 describes semisolid aqueous preparations (pastes) for the treatment of animals. EP 0116175 describes solutions which can be administered orally.

In the field of poultry farming, formulations or drinkable solutions are generally used which can be dissolved in drinking water, while in farms for large animals, people tend to add the active ingredient to the feed or to administer it orally as a suspension using an applicator (Drench). Examples of commercially important products are diclazuril (2, 6-dichloro-alpha- (4-chlorophenyl) -4- (4, 5-dihydro-3, 5-dioxo-1, 2, 4-triazin-2 (3H) -yl) phenylacetonitrile; CAS No.101831-37-2) (CLINACOX)^TM0.5％，Janssen Animal Health；VECOXAN^TMBiokema SA) for mixing to feed, and toltrazuril (1-methyl-3- [ 3-methyl-4- [4- [ (trifluoromethyl) thio)]Phenoxy radical]Phenyl radical]-1, 3, 5-triazine-2, 4, 6(1H, 3H, 5H) trione; CAS No. 69004-03-1). Toltrazuril is available on the market, for example as drinking water formulation for poultry, and as oral suspension formulation, especially for the treatment of suckling piglets (Saugferkeln). The piglet is recommended to be administrated at the dose of 20mg/kg body weight on 3-5 days after birth.

A disadvantage of oral administration of the above anticoccidial agents (sometimes also referred to as coccidiostats) is that they are relatively laborious: the piglets have to be grasped and the product administered to the throat by means of an applicator or a drenchistole. Moreover, this method causes considerable stress on the piglets.

A range of completely different iron preparations (both different in compound type and mode of administration and bioavailability) can be used to prevent iron deficiency anemia. People are classified into: (I) simple inorganic Fe (2+) salts; (IIa) complexes of Fe (2+) with organic ligands, for example with lactic acid, or (IIb) complexes of Fe (3+) with, for example, citric acid; and (III) tetragonal lepidocrocite-type (Akaganeit-Typ) Fe (3+) oxy-hydroxy (hydro xo-) coordinated beta-FeO (OH) polymeric coordination compounds with saccharides/polysaccharides, in particular with oligo-or polycarbohydrates, for example with dextran or with dextrin/polymaltose. In the following, polymeric carbohydrates/carbohydrate-like compounds and polysaccharides are understood to mean oligomeric and polymeric compounds.

Formulations of type (I) for oral administration, for example using iron salts as feed additives, are common and have been known for a long time. In these compounds, the iron is present in the form of iron (2+) ions, for example as ferrous sulphate FeSO₄. These products can be added to the feed of lactating sows or administered directly to piglets by oral administration. In most cases, multiple single doses are administered to piglets during the first days of their life in the growing period to compensate for the relatively low bioavailability. An alternative route to avoid multiple administrations is the late feeding of iron containing supplements (Starter diet (Prestarter) and piglet feed (Starter-Futter)). The iron ions in the inorganic iron (2+) salt are released rapidly by dissociation, whereas the release in the iron (2+) complex is somewhat delayed. Absorption of free Fe (2+) ions from iron salts occurs in the upper small intestine. Under physiological conditions in the upper small intestine, the solubility of Fe (2+) is ten times the solubility of Fe (3+) (Forth, W., in: Dunndarm, Handbuch der inneren Medizin, Vol.3 Verd.org. part 3 (A); W.F.Caspary, Ed;, Springer 1983). Furthermore, free iron (3+) ions are reduced in the environment of the intestinal contents by cysteine, glutathione, ascorbic acid and other substances to form Fe (2+) and are absorbed as Fe (2+) by the epithelial cells of the intestinal mucosa. However, there is still controversy as to whether such reduction is necessary for uptake into mucosal cells. The reason for the greater bioavailability of Fe (2+) may be due to the higher solubility of Fe (2+)The resulting concentration gradient. The current view is that the Fe (2+) ions bind first to the protein transferrin (Mobilferrin), whereupon the Fe (2+) ions are reoxidized to Fe (3+) and bind to the mucosal storage protein Ferritin (Ferritin). When the body requires iron, this Fe (3+) is released into the plasma, where it is reduced again by iron oxidase (ferrioxamase) to form Fe (2+) and binds to Apo-transferrin (the iron-binding transport protein of the organism). Whether transferrin is already present in mucosal cells and whether they at least partially accept iron is the subject of debate. The complex formation constant of transferrin is so large, about 30-31 log K, that there is no free iron in place in the organism as long as the binding capacity of transferrin has not been exceeded. This is a consequence of the toxic effects that can occur due to the sudden over-supply of iron salts, which is a disadvantage in their use. Then, iron is transported to the hemoglobin synthesis site in the bone marrow through blood and lymph vessels (see e.kolb, u.hofmann, "Anwendungen von eisenverbindung beim Schwein" [ application of iron compounds on pigs]Umschau 60, (2005)365-]Naturwissenschaften 74, (1987) 175-; "Neue" means a new form of medicineder Eisenversorgung neugebrener Ferkel unit Beachtongbiocheischer Aspekte "[ considering the biochemical field, a new possibility for the iron supply of newborn piglets]At the following stage:und Geburt beim Schwein [ conception and production of pigs]8th Bernberger Biotechnology Workshop 2002, 89-94). The unwanted iron will remain stored in the mucosal cells but will not be available after cell death. Thus, it will be appreciated that the bioavailability of oral iron compounds is largely dependent on other factors such as the actual ironDemand, feeding status (colostrum) and health status (diarrhoea: premature loss of upper mucosal cells). It is important to understand this mechanism to be able to appreciate and evaluate the advantages and disadvantages of certain iron preparations.

Furthermore, compounds from the second group (II), i.e. chelate-type coordinated Fe (2+) and Fe (3+) compounds are used. These compounds form relatively stable iron complexes which are only partially decomposed (aufbrechen) to ions by gastric acid. In this process, bioavailability is the result of partial replacement of iron with the ligand on or in mucosal cells, depending on the formation constant of the complex. Due to their higher lipophilicity, undecomposed complexes are able to cross the membrane system of epithelial cells and are necessarily metabolized. This explains why low molecular weight complexes have lower Bioavailability but longer lasting effects (H.Dietzfelbinger; "Bioavailability of Bi-and triangular Oral Iron Preparations"; Arzneim./drug. Res37(1), No.1a, (1989)107- > 112 and E.B.Kegley et al, "Iron Methionin as resource of Iron for the New Pig", Nutrition Research 22(2002)1209- > 1217).

A third class of compounds, which is administered predominantly parenterally or only rarely orally, consists of very stable poly-beta-FeO (OH) type compounds with coordinately bound polycarbohydrates. Commercial importance is primarily gained by, but not limited to, the following: iron (III) dextran (CAS No.9004-66-4), iron (III) polymaltose hydroxide (dextriniron (III) hydroxide; CAS No.53858-86-9), iron (III) sucrose (iron (III) sucrose), "iron (III) sugar" CAS No.8047-67-4) and sodium gluconate/iron (III) complex in sucrose solution (CAS No. 34089-81-1). Different names for these compounds appear in the literature. In this context, compounds such as iron (III) dextran, iron (III) polymaltose, iron (III) dextrin, iron (III) sucrose, iron (III) gluconate, iron (III) sugar are understood to mean iron (3+) ions and hydroxide ions (OH)^-) Water radical (H)₂O) and oxygen (O), which are present in oligomeric or polymeric form and which are present in oligomeric or polymeric form in association with the abovementioned oligosaccharidesAnd polysaccharide compounds are coordinately bound in their coordination sphere. This is why these compounds are also known as iron (III) hydroxide polysaccharides or iron (III) oxo-hydroxy polysaccharides, wherein the polysaccharides represent the oligomeric and polymeric carbohydrate compounds mentioned above or their derivatives, or generally represent compounds selected from oligomeric or polymeric carbohydrates. Multinuclear Iron (III) Complexes of this type are described, for example, in (D.S. Kudasheva et al, "Structure of carbohydrate-bound Polynuclear oxygen Nanoparticles in molecular formulations", J.Inorg.Biochem.98(2004)1757-1769, I.Erni et al, "Chemical modification of Iron (III) Hydroxide-Dextrin Complexes" Arzneim. -/Drug Res.34(II) (1984) 1555-1559; F.Funk et al, "Physical and Chemical modification of Therapeutic Iron binding materials", Hybride.136-95; E.Londshew.P.M.J.Thermoptical modification of molecular modification of biological Iron Complexes "John 2004-1838, John of John's et al [ J.1838 ] P.J.der Eisenversorgung neugebrener Ferkel unit Beachtongbiocheischer Aspekte "[ considering the biochemical field, a new possibility for the iron supply of newborn piglets]，und Geburt beim Schwein [ conception and production of pigs]: 8th Bernberger Biotechnology Workshop, Bernburg (2002) 89-94). Since in many cases the composition of these compounds is not described in a quantitative manner and also the compounds may vary within the compounds depending on the type of preparation, these polynuclear iron (III) polysaccharide compounds are understood to mean all complexes of the above-mentioned classes of compounds known to the person skilled in the art.

These iron compounds are almost exclusively used for the manufacture of formulations for injection by physicians (in humans) and veterinarians. However, in veterinary medicine, a few formulations for oral administration are also in use. Generally these complexes are characterized by high stability and differ mainly in their molecular weight (where the molecular weight may vary from 30kD up to 400 kDa) and in the strength of the complex binding. In aqueous solution, they are present as colloidal dispersions having a particle size of 7 to 35 nm. In the case of oral administration, the determinants of bioavailability are: first, the extent of precipitate formation under the influence of gastric acid, and the extent of iron core hydrolysis; second, the stability of the complex under acidic reducing conditions. The mechanisms of absorption into organisms and conversion into biological iron compounds have not been fully elucidated at present and in some cases are still controversial in the literature. However, some general view on the mechanism of action may be derived. The more stable the complex, the greater the proportion of compound that passes through the stomach without being altered, and the smaller the proportion of free iron ions. The stability of the complex then depends on the synthesis method. High molecular weight poly (iron (III) maltodextrins) and iron (III) dextrans have proven to be quite stable. In contrast, iron must be released to proteins in the transport pathway. Of course, this transfer will decrease as the stability of the complex increases. These relationships have been demonstrated by various experiments using acids, reducing agents, and complexing agents. (R.Lawrence "Development and company of Iron dextrose Products"; PDA J phase. Sci. Techn.52(5) (1998) 190-.

These considerations have led to the teaching: fe (3+) compounds, in particular polynuclear compounds such as Iron (III) dextran, are generally not suitable for Oral administration (H.Dietzfelbinger "Bioavailabilty of Bi-and ternary Oral Iron precursors" Arzneim. -Forsch./Drug Res.37(I), No.1(a) (1987) 107-.

Another reason why the distrust of orally administered polynuclear Fe (3+) complexes, in particular iron (III) dextran, occurs is that beta-FeO is present in the intestinal tract(OH) specific absorption pathway of the complex. These compounds can be absorbed into the epithelial cells of the intestinal mucosa by pinocytosis and have to be released into the organism via the lymphatic system (Lymphbahn), stored in the lymph nodes and finally transported into the blood circulation (see also Kolb, Hofmann; Forth; John's article, mentioned above). As explained above, since they are quite stable, bioavailability will depend on the metabolism of the complex and enzymatic degradation by lysosomal enzymes. Experiments with polyvinylpyrrolidone, dextran and iron (III) dextran labelled with dyes (in each case different molecular weights) it is known that these polymer complexes can be absorbed by the epithelial cells of the duodenum and upper Small Intestine by pinocytosis in suckling piglets during the first few days of life (R.M. Clarke, R.N.Hardy "historical Changes in the Small interest of the Young Pig and the therapy to Macromolecular Uptake"; J.Ant.108 (1), (1971) 63-7; K.Thoren-Tolling, L).“Cellular Distribution of Orallyand Intramuscularly Administered Iron Dextran in Newborn Piglets”，Can.J.Comp.Med.41(1977)318-325；K.Martinsson，L."On the mechanism of intellectual Absorption of Macromolecules in Piglets studied with Dextran Blue", Zbl. vet. Med. A22 (1975) 276-. However, it is also known that this transfer of high molecular weight compounds from mucosal cells into the lymphatic and blood circulation systems of piglets may be unhindered only shortly after birth. This mechanism ensures that piglets can be provided with immunoglobulins and antibodies immediately after birth by ingesting the colostrum of the sow. Once this supply is ensured, the transport mechanism becomes ineffective. During further growth, this mucosal Closure "Intestinal Closure" is biologically significant in order to avoid infection by microorganisms and toxins (k."The upstake of macromolecules in The Ileum of Piglets after Intelligent close", Zbl. vet. Med. A23 (1976) 277-282). The period between birth and mucosal Closure (Intestinal Closure) is strongly dependent on the nutritional status of the piglets. When starving piglets, this transfer may occur up to 4 days after birth (J.G. Lecci, D.O. Morgan "Effect of digital registration on centre of intellectual Absorption of Large Molecules (close) in the New Pig and Lamb", J.Nutrition 78(1962) 263-268). However, farm feeding conditions of course usually allow lactation, and it is therefore currently known and generally medically accepted that it is feasible to supply sufficient high molecular weight iron complexes to piglets by the oral route in a meaningful way only during the first hours of birth if multiple administrations are avoided. These authors have systematically studied the efficiency of Iron (III) Dextran as a function of time of oral administration and reported a significant decrease in activity when Iron (III) Dextran was administered 24-72 hours after birth (L.Blomagren, N.Lanbeck "preservation of Anaemia in Piglets by a Single Oraldose of Iron Dextran", Nord.vet. -Med.23(1971) 529. sub.536). However, depending on the feeding and feeding conditions, Administration on day 2 of life still provides sufficiently good results (S.Kadis, "Relationship of Iron Administration to surgery of New born pins to Enterotoxic coli"; am.J.Vet.Res.45(2), (1984) 255-. In contrast, the efficiency has been greatly reduced when Iron Dextran is administered 72 to 96 hours after birth (Ueda H. "preservation of Piglet Anaemia by Oral administration of Iron Dextran", Nicchiku Kaiho 56(11), 1985, 872-. This is why only a few oral iron substitute preparations using polynuclear iron complexes have been introduced into the market (Ursoferran 150 p.o.; Serumwerke Bernburg-Eisen (III) -Dextran; FerumHausmannHausmann Laboratories inc, st. gallen; -Eisen (III) -hydroxyid-polymaltose. In a modern iron dextran preparation for oral administration in feeding piglets, iron dextran is combined with an emulsifier of microemulsion droplets with a particle size of 1-2 μm to improve their bioavailability (Bioveyxin FeVit)^TM，Veyx-Pharma GmbH，Schwarzenborn；SintaFer^TMSinta GmbH, Schwarzenborn). This finely dispersed state, as well as binding to lipophilic carriers, is believed to promote absorption into epithelial cells and transfer into the body. However, even in the case of these formulations, manufacturers still recommend using them up to 8-10 hours after birth in order to obtain the best results. This in turn requires continuous monitoring of the breeding sows, which means a lot of labour.

Typically, for oral iron preparations, the recommended dose rate is 100-200mg of active iron per unit dose per piglet in order to ensure sufficient effectiveness. In practice, however, only higher doses are possible to control with a single administration.

In the case of oral administration, in order to avoid the above-mentioned unmeasurable factors, it is more conventional to administer the polynuclear iron (III) complex by injection when feeding pigs. Typically, this is done by injection of 100-200mg of active iron on postnatal day 3. Transport away from the injection site is by cells of the lymphatic system as well as the reticuloendothelial tissue cell system. These complexes are stored in the liver and spleen, from where they are released, if necessary, and metabolized by the action of enzymes. Free Fe (3+) will eventually re-bind to transferrin and migrate to the site of use in the bone marrow.

However, this form of parenteral administration also has a series of disadvantages: a significant disadvantage of intramuscular administration (by intramuscular injection) to piglets is the frequently occurring injurious effect. Muscle bleeding, changes in muscle fibers, inflammation, and the development of edema frequently occur at the injection site. These are local lesions. However, damage to the myocardium has also been observed, particularly in the simultaneous absence of vitamin E. In these casesIn the middle, a significant increase in the potassium content of the plasma can be observed, which causes severe damage to the myocardium and may cause death of the piglets. The current view is that minute amounts of free Fe (2+) ions are responsible for forming free radical compounds with organic compounds, such as lipo-peroxide compounds, which are associated with high potassium content of blood. Vitamin E acts as a free radical scavenger and can somehow buffer these detrimental reactions, but this often exceeds the ability to survive. (that is why vitamin E is also added to the already mentioned oral formulations, where iron (III) dextran is bound to the microemulsion droplets). However, there are other disadvantages associated with intramuscular administration as follows: after administration of iron (III) dextran, certain limitations of the immune system performance must be expected, since macrophages in the blood are loaded with polynuclear iron complexes. The defense against bacterial infections is reduced. An overview of the above-mentioned disadvantages of intramuscular administration is found in the literature (E.Kolb, U.Hofmann "Zur Frage der)Form der Anwendung von Fe-Dextran，seinerVerwertung sowie des Mechanismus einerderFerkel "[ suitable form of administration of iron dextran, its utilization and mechanism of potential damage to piglets]；Mh.Vet.-Med 44(1989)497-501)。

In summary, it can be said that the various methods available on the market today for preventing anemia in suckling piglets have a series of disadvantages:

1. according to the literature, significantly lower bioavailability is generally observed when fe (II) compounds of type (I) and type (II) are administered orally. Multiple administrations of these formulations are recommended, which involves a lot of labor and is economically disadvantageous in the case of intensive animal breeding.

2. The multinuclear fe (III) compounds of form (III), in particular iron (III) dextran, were administered orally, although better results could be obtained. A single dose rate of about 200mg of active iron is usually sufficient to ensure adequate iron supply to the piglets, but the key disadvantage is that from the present point of view, sufficient activity can only be obtained when iron (III) dextran can be administered to the piglets within the first 8-10 hours of life. This can also only be ensured by monitoring the birth time in a breeding farm around the clock, but this is often not possible because it requires a lot of labor. If this point in time is missed, it will often result in a large loss of piglets.

3. When used, the intramuscular administration of the iron preparation is more advantageous, since administration over a period of 1 to 3 days after birth gives very good results. However, possible damage to piglets due to toxic side effects and short-term impairment of the immune system is also disadvantageous. Oral formulations do not suffer from this disadvantage.

4. Furthermore, in view of the generally required treatment of coccidiosis, e.g. with toltrazuril or similar compounds, it is clear that the following two ways are generally necessary for successful feeding of piglets: (1) the piglets are caught on the first day after birth and given e.g. iron (III) dextran, followed by a recapture of the piglets on day 3 and administered orally with the commercial toltrazuril suspension formulation, or (2) the piglets are caught on day 3 and administered separately with the commercial toltrazuril suspension for oral administration and with the formulation for injection of iron (III) dextran (with the above mentioned disadvantages).

It would therefore be highly advantageous to obtain formulations which make it possible to combine these two modes of operation without the above-mentioned disadvantages, i.e. without harmful side effects, while being reliable and efficient. Suitable formulations may be, for example, formulations of the active ingredients toltrazuril and iron (III) dextran for oral administration to piglets 1 to 3 days of life after birth. However, a formulation that then combines these two modes of operation would need to satisfy the following set of conditions:

sufficient amount of active ingredient: one unit dose must contain a pharmacologically active sufficient amount of the anti-coccidiosis substance, typically 20-70mg, such as 30mg, 44mg or 50mg, toltrazuril, and at least 100mg, better at least 150mg, preferably 200-250mg of active iron (e.g. corresponding to 400-600mg of the polynuclear iron (III) complex) for the prevention of anemia, corresponding to a recommended dose rate of 20mg toltrazuril/kg body weight and 200mg of active iron per piglet. This corresponds to a concentration of the anti-coccidiosis substance in the preparation of 2-7% m/V and a concentration of active iron of 10-25% m/V, (% m/V is understood to mean the mass of the component in question per 100ml volume).

Low dose volume for oral administration: for example, in the case of suckling piglets, a dosage volume of about 1ml is optimal, and when the volume is significantly high, complete uptake by the piglets is often not ensured. A larger volume of fluid will typically flow out of the mouth or be dispensed.

Appropriate consistency: the viscosity needs to be in a range that allows administration by drenchistome or syringe, for example between 10 and 2500 mPas. If the consistency is too fluid, the formulation may flow out of the mouth of the animal after application; if the consistency is too high, large scale administration by use of a syringe or drench gun is too laborious for users with dysphagia and animals, especially piglets.

Quality of the preparation: physical and chemical stability, pharmaceutical effectiveness must be ensured. Thus, there is a need to ensure that, for example, iron ions do not adversely affect the chemical stability of the anti-coccidiosis material. Furthermore, it is necessary to ensure that, in the case of suspension formulations, the distribution of the active ingredient which is as finely divided as possible can be maintained, since coagulation or even agglomeration of the dispersed active ingredient particles is disadvantageous. This may negatively affect e.g. pharmaceutical activity, since the rate of dissolution and thus release of the active ingredient from the particles in the intestinal tract is reduced due to the smaller surface area.

Effectiveness after administration for a longer time after birth: sufficient activity against coccidiosis and anemia when administered over a period of 1-3 days after birth is desirable, especially in a single administration.

Adequate anemia prevention effect after a single administration: the amount of iron dosed with the small dose volume combination formulation described above affects the iron requirement high enough to cover piglets after a single administration under normal feeding conditions.

To date, no combination of triazineone compounds and iron preparations in a suitable formulation has been described.

The present invention relates to:

1. reagents containing triazinones of formula (I) or (II)

Wherein

R¹Represents R³-SO₂-or R³-S-，

R²Represents alkyl, alkoxy, halogen or SO₂N(CH₃)₂And

R³represents haloalkyl

R⁴And R⁵Independently of one another, represent hydrogen or Cl, and

R⁶represents fluorine or chlorine, and is selected from the group consisting of,

or a physiologically acceptable salt thereof,

and

an iron (2+) or iron (3+) compound selected from the group consisting of:

(a) iron (II) carboxylates, iron (II) carboxylic acid complex compounds and iron (II) chelate complexes with amino acids

(b) An iron (III) carboxylate, an iron (III) carboxylic acid complex compound and an iron (III) chelate complex with an amino acid, and

(c) polynuclear iron (III) polysaccharide complexes.

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

R²preferably represents alkyl or alkoxy having 1 to 4 carbon atoms in each case, or represents fluorine, chlorine, bromine or SO₂N(CH₃)₂；R²Particularly preferably represents C_1-4-an alkyl group.

R³Preferably represents a fluoroalkyl group having 1 to 4 carbon atoms, particularly preferably a trifluoromethyl group.

Triazinones are known per se as active ingredients against coccidial infections; triazinetriones such as toltrazuril and ponazuril, triazinediones such as clazuril, diclazuril and letrozuril may be mentioned.

The triazinedione compounds are represented by formula (II):

clazuril (in formula (II), R⁴＝Cl，R⁵＝H，R⁶＝Cl)

Letrozuril (in formula (II), R⁴＝Cl，R⁵＝Cl，R⁶F) and

diclazuril (in formula (II), R⁴＝Cl，R⁵＝Cl，R⁶＝Cl)。

Among them, diclazuril, which is a 1, 2, 4-triazinedione compound, is most preferable.

As active ingredients, according to the invention, triazinetriones of the formula (I) in which R is²And R³Have the following preferred and particularly preferred meanings:

R²preferably represents each havingAlkyl or alkoxy having up to 4 carbon atoms is particularly preferably methyl, ethyl, n-propyl or isopropyl.

R³Preferably represents a perfluoroalkyl group having 1 to 3 carbon atoms, particularly preferably a trifluoromethyl group or a pentafluoroethyl group.

Preferred triazinetriones are represented by formula (I):

toltrazuril (R)¹＝R³-S-，R²＝CH₃，R³＝CF₃)

Ponacuril (R)¹＝R³-SO₂-，R²＝CH₃，R³＝CF₃)。

As mentioned above, the dosage rate of triazinones can vary depending on the animal species. The conventional dosage rate is 1 to 60mg of active ingredient per kg of body weight of the animal to be treated per day (mg/kg), preferably 5 to 40mg/kg and particularly preferably 10 to 30 mg/kg.

In the case of oral administration, the toltrazuril dose is generally as follows:

a pig: 20mg/kg body weight

Cattle: 15mg/kg body weight

Sheep: 20mg/kg body weight

Poultry: 15mg/kg body weight

In addition to poultry, toltrazuril is administered only once per treatment, so that, for example in the case of pigs, cattle and sheep, the indicated dose rates apply both daily and per treatment.

Suitable iron (2+) or iron (3+) compounds are:

(a) iron (2+) carboxylate, iron (2+) carboxylic acid complex and iron (2+) chelate complex with amino acid

(b) Iron (3+) carboxylate, iron (3+) carboxylic acid complex and iron (3+) chelate complex with amino acid

(c) A polynuclear iron (3+) polysaccharide complex.

Examples of iron compounds of type (a) which may be mentioned are: iron (II) lactate (FeC)₆H₁₀O₆) Iron (II) gluconate (FeC)₁₂H₂₂O₁₄) Iron (II) fumarate (FeC)₄H₂O₄) And chelate complexes of iron with amino acids such as iron (II) bisglycinate (Fe (C)₂H₄NO₂)₂) Iron (II) methanedisulfonate (Fe (C)₅H₁₀NO₂S)₂) And their hydrated compounds.

Examples of iron compounds of type (b) which may be mentioned are: iron (III) citrate (FeC)₆H₅O₇) Iron (III) ammonium citrate and, optionally, hydrated compounds thereof.

In this context, iron compounds of group c) are understood to mean iron (3+) ions and hydroxide ions (OH)^-) Water radical (H)₂O) and oxygen (O), which are present in oligomeric or polymeric form and which are incorporated in their coordination sphere in coordination with one or more of the oligomeric and polymeric carbohydrates mentioned above. This is why these compounds are also referred to as iron (III) hydroxide polysaccharides or iron (III) oxo-hydroxy polysaccharides, where the polysaccharides represent the corresponding oligomeric and polymeric carbohydrates or their derivatives. Multinuclear Iron (III) Complexes of this type are described, for example, in (D.S. Kudasheva et al, "Structure of Carbohydrate-bound Polynuclear oxygen Hydroxide in Molecular formulations", J.Inorg.Biochem.98(2004)1757-1769, I.Erni et al, "Chemical modification of Iron (III) Hydroxide-Dextrin Compounds", Ashch./Drug Res.34(II) (1984) 1555-1559; F.Funk et al, "Physical and Chemical modification of physiological Iron Complexes", Hymenone microorganisms of Molecular modification compositions, Hy.73-95, E.Londove "Molecular and Chemical modification of physiological Iron Complexes of Molecular formulations, Hydrocarbon Complexes, Hydroquinone derivatives of Hydroquinone of strain of Hydroquinone of Molecular formulations of Hydroquinone of Escherichia of Molecular modification of Hydroquinone of strain of Hydroquinone ofERON”，J.Pharm.Sci.93(2004)1838-1846；A.John“Neueder Eisenversorgung neugeberferkel unicerbehischer Aspekte' takes into account the new possibility of iron supply to newborn piglets in the field of biochemistry]，und Geburt beim Schwein [ conception and production of pigs]: 8th Bernberger Biotechnology Workshop, Bernburg (2002) 89-94). Since in many cases the precise composition of these compounds is not described in a quantitative manner and may also vary within the compound depending on the type of production, these polynuclear iron (III) polysaccharide compounds are understood to mean all compounds of the above classes of compounds known to the person skilled in the art.

Examples of iron compounds of type (c) which may be mentioned are: a polynuclear iron (III) polysaccharide complex in which a polynuclear β -feo (oh) core complex contains a polymeric carbohydrate bound at a free coordination site, such as iron (III) dextran, iron (III) hydroxypolymaltose (dextriniron (III)), β -feo (oh) and a non-stoichiometric compound of sugars and oligosaccharides, "iron (III) sucrose".

Other compounds which are preferably used in the above-mentioned iron compounds are those of the (b) and (c) forms, the latter being particularly preferred. Iron (III) dextran is mentioned as a particularly preferred example.

Formulations according to the invention suitable for use in the formulation of an animal are preferably solutions, suspensions or pastes, gels. Preferably a suspension or paste.

Solutions are prepared by dissolving the active ingredient or ingredients in a suitable solvent or solvent mixture. Optionally, further auxiliaries (Hilfsstoff) such as solubilizers, antioxidants, preservatives, thickeners, binders, pH regulators, photoprotectors or colorants can be added.

Is mentionedSolvent(s)The method comprises the following steps: physiologically acceptable solvents such as water, alcohols, for example monohydric alkanols (e.g. ethanol or n-butanol), polyols such as glycols (e.g. ethylene glycol, propylene glycol, tetraethylene glycol/Glycofurol (Glycofurol)), polyethylene glycol, polypropylene glycol, glycerol; aromatic substituted alcohols such as benzyl alcohol, phenethyl alcohol, phenoxyethanol; esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethyl oleate; ethers such as alkylene glycol alkyl ethers (e.g., 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 form, acetonide (Soketal) (2, 2-dimethyl-4-hydroxymethyl-1, 3-dioxolane), N-methyl-pyrrolidone, 2-pyrrolidone, N-dimethylacetamide, Glycofurol (Glycofurol), dimethyl-isosorbide, Lauroglykol, propylene carbonate, octyldodecanol, dimethylformamide and mixtures of the above solvents.

Is mentionedSolubilizerThe method comprises the following steps: a solvent that promotes the dissolution of the active ingredient in the main solvent or prevents its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.

The antioxidant is sulfite or metabisulfite such as potassium or sodium metabisulfite, sodium or potassium bisulfite, ascorbic acid, isoascorbic acid, ascorbyl palmitate, gallate, butylhydroxytoluene, butylhydroxyanisole or tocopherol.

Synergists for these antioxidants may be: amino acids (e.g. alanine, arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or their salts, phosphoric acid derivatives or polyalcohols (polyethylene glycols).

The preservative is: benzyl alcohol, benzalkonium chloride, chlorobutanol, p-hydroxybenzoate, n-butanol, chlorocresol, cresol, phenol, benzoic acid, citric acid, tartaric acid or sorbic acid.

The thickening agent is: inorganic thickeners such as bentonite, colloidal silica, aluminium stearate, organic thickeners such as cellulose derivatives such as hypromellose 4000, polyvinyl alcohol and their copolymers, xanthan gum, acrylates and methacrylates, carboxymethylcellulose and salts thereof.

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

Binders having thickening properties can also be used as thickeners.

The pH adjusting agent is a pharmaceutically conventional acid or base. Mention may be made, as base, of alkali metal cassettes alkaline earth metal hydroxides (e.g. NaOH, KOH), basic salts such as ammonium chloride, basic amino acids such as arginine, choline, meglumine, ethanolamine or also buffers such as tris (hydroxymethyl) aminomethane, citric acid or phosphate buffers. Examples of the acid include hydrochloric acid, acetic acid, tartaric acid, citric acid, lactic acid, succinic acid, adipic acid, methanesulfonic acid, octanoic acid, linolenic acid, gluconolactone, and acidic amino acids such as aspartic acid.

The photo-protecting agent is, for example, from benzophenone or

Colorants are all colorants that can be used that are soluble or suspendable in animal or human applications.

By suspending the active ingredient or ingredients in a carrier liquid, optionally with the addition of other adjuvants such as wetting agents, colorants, absorption promoters, thickeners, binders, preservatives, antioxidants, photo-protecting agents or anti-foaming agents.

Carrier liquids which may be mentioned are all homogeneous solvents and solvent mixtures.

The following are mentioned as wetting agents (dispersants):

surfactants (including emulsifiers and wetting agents) such as

1. Such as sodium lauryl sulfate, fatty alcohol ether sulfate, mono/dialkyl polyglycol ether orthophosphate-monoethanolamine salt, lignosulfonate or dioctyl sulfosuccinate,

2. cationically active such as cetyltrimethylammonium chloride,

3. amphoteric active such as N-lauryl-beta-imino-dipropionic acid disodium salt or lecithin,

4. nonionic active, e.g. polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethanol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, polyoxyethylene sorbitan esters,

Suitable antifoams are preferably those based on silicones such as, for example, dimethicone (Dimethicon) or hydrated silica dimethicone (simethion).

Other auxiliaries mentioned are those described in further detail above.

Preferred are suspensions and pastes, with low viscosity pastes being preferred in pastes. Usually pastes are in the form of suspensions with a correspondingly higher viscosity. Suspensions and pastes are preferably administered orally.

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

Because of their poor solubility, triazinones are generally present in the formulations of the invention in finely divided form. Here, the triazinones dispersed thereinParticle size (measured by laser diffraction, Malvern)2000) d (v, 90) ≦ 30 μm, preferably d (v, 90) ≦ 20 μm, particularly preferably d (v, 90) ≦ 10 μm, and very particularly preferably d (v, 90) less than or equal to 7 μm.

For the purposes of the present invention, d (v, 90) is understood to mean a volume-dependent particle size distribution in which 90% of all particles have a size (diameter) which is less than or equal to this value. Typically, this data is referred to as d (90), but the more precise term d (v, 90) may be chosen to clarify that it is a volume-dependent particle size distribution. The terms d (v, 50), d (v, 10), etc. are to be understood accordingly. The particle size indicated here is determined by means of laser diffraction using a Mastersizer 2000 apparatus (scattering element Hydro 2000G) from Malvern and using a fraunhoferi diffraction (fraunhoferbeug) evaluation mode, since the refractive index of the active ingredient particles is not known. Here, the sample solution is predispersed with 2 to 3ml of dispersion medium (0.1% strength aqueous solution of dioctyl sodium sulfosuccinate) with stirring. The dispersion was then placed under stirring (300 rpm) and under reflux (Umpumpen) (900 rpm) in a scattering element of the apparatus and measured there. The evaluation software gives the granularity as d (0.5), d (0.9) values, etc.

The iron compounds in these oral formulations for the treatment of iron deficient states in large animal farms are typically administered as single or multiple administrations at a concentration of 100mg to 200mg of active iron per unit dose. In the drinkable solution for feeding iron to poultry fattening farms, the dose may also amount to less than 100mg of active iron per unit dose.

The preparation of the invention contains an iron compound, usually in a concentration of 10% (m/V) to 30% (m/V) of active iron, corresponding to 100mg of active iron in 1ml of the preparation, preferably 11.4% (m/V) to 25% (m/V), corresponding to 114mg to 250mg of active iron in 1ml of the preparation, but particularly preferably 20% (m/V) to 25% (m/V), corresponding to 200mg to 250mg of active iron in 1ml of the preparation. Active iron refers to the percentage of iron present in the formulation in the form of an iron complex. Typically, the iron compound is present in the formulation in dissolved or colloidal form. Finely divided iron compounds are less preferred in the formulations of the present invention.

The formulations of the present invention are preferably water-based. Generally this means that they contain 10 to 90% by weight, preferably 20 to 80% by weight, particularly preferably 30 to 50% by weight, of water. For example, the formulations described above may contain other water-miscible solvents. Other 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; of these, propylene glycol is particularly preferred. Such further water-miscible solvents are generally present in concentrations of from 1 to 45% by weight, preferably from 1 to 20% by weight, particularly 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 applied per administration in each case depends on how much triazineone compound and iron are to be administered in each case. Striving for relatively small volumes that can be easily administered orally, which varies according to the animal species; for example, for suckling piglets, the intended volume of administration is 0.3-2ml, preferably 0.5-1 ml.

Advantageously, when the formulation of the invention allows easy application, for example with conventional auxiliary devices such as syringes, applicators or drenching guns, and for this purpose has a liquid, slightly thickened or slightly pasty consistency, its viscosity [ using a rheometer cone/plate device (Thermo scientific rheostress 600; cone diameter 35 °; cone angle 4 °; constant speed mode), by heating at 20 ℃ for 128s^-1And 256s^-1Measured as the average value of the viscosity number measured at a shear rate of 10 to 2500mPas, preferably 20 to 1500mPas, particularly preferably 50 to 500mPas, and very particularly preferably between 20 to 250 mPas. In order to set the appropriate viscosity range, optionally, the formulation of the present invention includes the appropriate substances (thickeners) already mentioned above.

In general, the formulations of the invention have a pH of from 3 to 8, preferably from 4 to 7, particularly preferably from 4 to 6. Examples of suitable substances for adjusting the pH have already been indicated above. The substances used for adjusting the pH are preferably organic acids, such as citric acid or tartaric acid, inorganic acids, such as hydrochloric acid, preferably dilute hydrochloric acid, such as 0.1nHCl, or bases, such as aqueous sodium hydroxide solutions (e.g.1N NaOH).

As mentioned above, the formulations of the invention may furthermore contain preservatives, optionally in combination with so-called synergists. The preservative is typically present at a concentration of 0.01-5 wt% and specifically 0.05-1 wt%.

BHA or BHT may preferably be used as an antioxidant in the above formulations, if desired. In order to ensure adequate preservation, preservatives may be used alone or in combination with so-called synergists. Synergists such as citric acid, tartaric acid, ascorbic acid or edetate sodium salt are generally present in concentrations of 0.01 to 1% by weight, in particular 0.05 to 0.15% by weight.

Optionally, the formulations of the present invention may contain conventional antifoams in concentrations of from 0.01 to 1% by weight.

The formulations of the present invention are preferably prepared by: the solvent, preferably water, and optionally auxiliaries and/or additives, such as cosolvents, preservatives, antioxidants and viscosity-regulating additives, which are pre-dissolved or dispersed therein, are first introduced. In a preferred process, the second step consists in introducing the triazineone compound in the starting solution, optionally in the form of a preformed dispersion concentrate, using a powerful homogenizer, and homogenizing the mixture until a finely divided suspension is obtained. The iron compound is then introduced into the dispersion, preferably in the form of a powder, and the mixture is again homogenized during the process. In the next step, the desired pH is finally adjusted by adding a suitable pH adjusting agent. Optionally, individual or all auxiliaries and/or additives can also be added after the last homogenization step; this may be appropriate, for example, in the case of certain thickeners, the structure of which is disrupted by the homogenization process.

The formulations of the invention are suitable for the combined control of Coccidia (cocidiia) and iron deficiency states, particularly in animals. Using the preparation, the coccidiostatic triazinones and iron can be administered simultaneously to the animal in a simple manner. The preparation can be used for animal breeding and animal breeding of useful animals, farm animals, zoo animals, laboratory animals, test animals and pets. The scope of action of triazinones is known in principle. Coccidia (Coccidia) which may be mentioned are:

the class of flagellates (Mastigophora) (Flagellata) is for example Trypanosomatidae (Trypanosomatidae), such as Trypanosoma brucei (Trypanosoma brucei), Trypanosoma gambiae (t.gambiense), Trypanosoma nodosum (t.rhodesiense), Trypanosoma congolense (t.congolense), Trypanosoma cruzi (t.cruzi), Trypanosoma evanesis (t.evansi), Trypanosoma matsudanum (t.equinuum), Trypanosoma lewisi (t.lewisi), Trypanosoma punctatum (t.perca), Trypanosoma simian (t.simiae), Trypanosoma mobilis (t.vivax), leishmania brasiliensis (leishmania brasiliensis), leishmania donii (l.donovani), such as trichomonas tropicaligenes (e.g.giardia), such as Giardia), Giardia lamblia.

The subdivision of the division Sarcotina (Sarcomastigophora) (Rhizopoda) such as Entamoebaceae (Entamoebaceae) such as, for example, ameba dysenteriae (Entamoeba histolytica), Hartmanellae (Acanthamoeba sp.), Hartmanella (Hartmanella sp.).

Apical recombinator (Apicomplexa) (sporozoea (spozoea)) such as Eimeria (Eimeridae) such as Eimeria acervulina, Eimeria adenoides (e.adeneides), Eimeria alahamensis, Eimeria ducks (e.anatis), Eimeria chensinensis (e.anseriis), Eimeria niloti (e.arloingii), e.ashata, Eimeria oborena (e.auburn), Eimeria bovis (e.bovis), Eimeria brunetti (e.brunetti), Eimeria canis (e.canadensis), Eimeria nanniensis (e.chile), Eimeria kulardii (e.alnoidea), Eimeria rugosa (e.alnoidea), Eimeria maxima), Eimeria acervulina (e.alnoidea), Eimeria maxima, Eimeria necatrix, Eimeria columbigua (e), Eimeria acervulineria maxima (e), Eimeria acervulineria maxima, Eimeria acervulineria maxima (e.avina), Eimeria acervulineria acervulinea, Eimeria acervulineria, Eimeria Leicacrti, eimeria maxima (e.magna), eimeria maxima (e.maxima), eimeria mitis (e.medidia), eimeria zumi zukii (e.meleagris), eimeria meleagris (e.meleagris), eimeria mitis (e.mitis), eimeria necatrix (e.necatrix), eimeria javanica (e.ninakohlykimovae), e.ovis, eimeria miniata (e.para), eimeria meleuna (e.pavonis), eimeria perforata (e.performans), e.phasani, eimeria piriformis (e.piriformis), eimeria praecox (e.praecox), e.resiidula, eimeria (e.scabra), e.speex, eimeria stis (e.), eimeria praecox (e.), eimeria necatrix (e.e.i), eimeria necatrix (e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e.e., Coccidia canis (i.rivolta), coccidia (i.spec.), coccidia suis (i.suis), coccidia canis (Neospora caninum), n.hugesi, Cystisospora spec, Cryptosporidium (Cryptosporidium spec) such as Toxoplasma (toxoplasmiadaceae) such as Toxoplasma gondii (Toxoplasma gondii) such as Toxoplasma lagomorpha (Toxoplasma gondii), e.g. Sarcocystidae (sarcocysticanidae) such as sarcocysticeris canis (Sarcocystis boviciae), e.g. Sarcocystis canis (bovine Sarcocystis), e.g. Sarcocystis cinerea (s.bovina), e.g. Sarcocystis, e.g. oviparonychia, e.sporotrichum (s.spec sp.), pig-human Sarcocystis (s.e.e.e.g. leucomonas), e.e.g. Plasmodium (Plasmodium sp), Plasmodium falciparum (Plasmodium sp), Plasmodium sp.g. Plasmodium sp Babesia (b.spec.), Theileria (Theileria parva), Theileria (Theileria spec.), e.g. entomoriales (Adeleina) such as hamsters (hepazon canis), hepatica (h.spec.).

Furthermore, myxosporea (Myxospora) and Microspora (Microspora), such as gracilis (glugae spec.), microparticulates (Nosema spec.).

Furthermore, Pneumocystis carinii (Pneumocystis carinii) and subphylum ciliaris (Ciliata) such as marsupium colocalis (Balantidium coli), ichthyophihroiussspec, Trichodina spec, rectomy (Trichodina spec), and rectomy (Epistylis spec).

The genera and species of those protozoa that cause subclinical or clinical infections in pigs are of particular interest, in particular: eimeria dieselae (e.delphiecki), eimeria suis (e.suis), eimeria crassa (e.scabra), eimeria tenuis (e.perminuta), eimeria echinacea (e.spinosa), eimeria glabra (e.polita), eimeria suis (e.porci), eimeria neodelbrunne (e.neodelliecki), eimeria suis (Isospora suis), Cryptosporidium (Cryptosporidium), Toxoplasma gondii (Toxoplasma gondii), Sarcocystis suis (Sarcocystis miechiana), Sarcocystis suis (s.suihominisis), Babesia terrestris (Babesia trautni), Babesia arboricius (b.roncitoi), and balantidio.

Useful animals and breeding animals include mammals such as cattle, horses, sheep, pigs, goats, camels, buffalo, donkeys, rabbits, elks, reindeer, fur-bearing animals such as mink, chinchilla, raccoons, birds such as chickens, geese, turkeys, ducks, pigeons, ostriches, as companion animals and as species of birds raised in zoo animals. They also include useful and ornamental fish species. Herein, all species, subspecies and breeds of swine, cattle, sheep and dogs are particularly emphasized.

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

Pets include dogs and cats.

The use in pigs is particularly preferred.

The formulation of the invention is preferably applied to young animals, in particular shortly after birth, preferably in suckling piglets. In general, the formulations of the invention (iron/triazinone compound combination formulations are administered only once. particularly preferred formulations of the invention allow for the oral treatment of piglets in such a way that even on postnatal day 3 with a single oral administration of 0.7ml to 1.3ml, preferably 0.7ml to 1.0ml of the formulation, a sufficient iron supply to the piglets in the first 4 weeks of life can be achieved, wherein a hemoglobin value of at least 8g/100ml of blood, preferably more than 9g/100ml of blood can be considered as an indicator of a sufficient supply.

The formulations of the invention may contain other active ingredients or components-alone or in suitable combinations-such as nutrients (Aufbaustoff) which include, for example, vitamins, minerals and phosphorus compounds suitable as metabolic stimulators and immunostimulants:

vitamins, such as vitamin E, vitamins selected from the B series, such as vitamin B12, vitamin C.

The mineral is preferably a calcium or magnesium salt, such as in particular calcium gluconate, calcium Glucoheptanoate (Glucoheptanoate) or calcium saccharate.

Phosphorus compounds, in particular pharmacologically acceptable organic phosphonic acid derivatives, are suitable as metabolism stimulators and tonic drugs. Preferred examples which may be mentioned are the compounds which have been known for a long time, tolidine and in particular butafosinate (butaphosphane).

Subject and preferred embodiments of the invention:

1. formulations containing triazinones of formula (I) or (II)

Wherein the content of the first and second substances,

R¹represents R³-SO₂-or R³-S-，

R²Represents alkyl, alkoxy, halogen or SO₂N(CH₃)₂And an

R³Represents haloalkyl

R⁴And R⁵Independently of one another, represent hydrogen or Cl, and

R⁶represents fluorine or chlorine, and is selected from the group consisting of,

or a physiologically acceptable salt thereof,

and

an iron (2+) or iron (3+) compound selected from the group consisting of:

(a) iron (II) carboxylate, iron (II) carboxylic acid complex compound, and iron (II) chelate complex having amino acid

(b) Iron (III) carboxylates, iron (III) carboxylic acid complex compounds and iron (III) chelate complexes with amino acids, and

(c) polynuclear iron (III) polysaccharide complexes.

2. The preparation according to item 1, which contains 1 to 30% (m/V), preferably 3 to 7% (m/V) of the triazinone compound.

3. A formulation according to any one of the preceding items, wherein the dispersed triazineone compound has a particle size with a d (v, 90) of less than or equal to 30 μm, preferably with a d (v, 90) of less than or equal to 20 μm, and particularly preferably with a d (v, 90) of less than or equal to 10 μm.

4. A formulation according to any one of the preceding items, wherein the concentration of iron compound is from 10% (m/V) to 30% (m/V) of active iron, preferably from 11.4% (m/V) to 25% (m/V), but particularly preferably from 20% m/V to 25% (m/V).

5. A formulation according to any one of the preceding items, wherein the cone/plate apparatus of the rheometer is used to pass the sample at 128s^-1And 256s^-1The viscosity measured as the average of the viscosity values measured at shear rates of (a) is in the range of from 10 to 2500mPas, preferably in the range of from 20 to 1500 mPas.

6. The formulation according to item 1, which is water-based.

7. A preparation according to item 1, which contains at least one polyhydroxylated aliphatic alcohol.

8. A formulation according to any one of the preceding claims, comprising a polynuclear iron (III) polysaccharide complex selected from group (c), wherein the polynuclear iron core of group (c) is composed of β -feo (oh) units, and which comprises polysaccharide molecules in a further coordination sphere.

9. A formulation according to item 8, which comprises a polynuclear iron (III) polysaccharide complex compound selected from the group consisting of: iron (III) dextran, iron (III) hydroxypolymaltose/iron (III) dextrin and non-stoichiometric compounds consisting of polynuclear beta-feo (oh) and sucrose and oligosaccharides.

10. A formulation according to any of items 1 to 7, which contains an iron-citrate compound, preferably ferric ammonium citrate (III), as the iron compound of group (b).

11. A formulation according to any one of the preceding items, which contains a triazinetrione compound as the triazineone compound.

12. Formulation 1 according to item 11, which contains toltrazuril, ponazuril or toltrazuril (toltazuril) sulfoxide as the triazinetrione compound.

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

14. The formulation according to any one of items 1 to 10, which contains a triazinedione compound, particularly clazuril, diclazuril or letrozuril, as the triazineone compound.

15. Use of a formulation according to any one of the preceding items for the manufacture of a medicament.

16. The use according to item 15 for the preparation of a medicament for the simultaneous treatment of coccidial infections and iron deficiency states.

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

18. The use according to item 17 for the preparation of a medicament for the oral treatment of suckling piglets.

19. Use according to item 17 or 18 for the preparation of a medicament for the oral treatment of piglets from the time of birth to 10 days after birth, in particular from the time of birth to 3 days after birth.

20. A formulation according to any of items 1 to 14 additionally comprising one or more nutrients.

21. The formulation according to item 20, which additionally contains calcium and magnesium salts.

22. A formulation according to item 20 or 21, which contains butafosfamide (Butaphophan).

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

preparation examples:

example 1

Application of iron (III) dextran powder 38.4% m/m

Batches for the preparation of 10L iron dextran/toltrazuril dispersions (22.8% m/V active iron + 5% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	1666.67
Sodium propionate (preservative)	17.00
		Sodium benzoate (antiseptic)	17.00
Propylene glycol	1000.00
		Anhydrous citric acid	87.10
Iron (III) dextran powder 38.4% m/m	5937.50
		Adding water to 10 liters	5138.00
Viscosity-regulating adjuvant/adjuvants	-
		Total mass	13863.27

In each case, in a separate container, 17.00g of preservative sodium propionate and sodium benzoate were weighed into 1000.00g of solvent propylene glycol and dissolved with stirring. The entire amount of water was introduced into a stainless steel vessel (Koruma Disho; apparatus type: DH V100/45). Depending on the need and the desired viscosity of the final product, viscosity-regulating auxiliaries (so-called thickeners) can be dissolved or introduced into the amount of water. In embodiment 1, this is omitted. The propylene glycol premix was added to the mass which had been introduced into the stainless steel container and homogenized under stirring (20-40 min). In the next step, a previously weighed 1666.67g amount of 30% toltrazuril dispersion concentrate was added to the batch and the batch was stirred for 30-40min while being homogenized at 2500 rpm for 20 minutes using a rotary homogenizer (rotor/stator system). The stirring and homogenization times mentioned above can also be extended or shortened, depending on the appearance of the suspension. It is advantageous to maintain the temperature of the mixture at 20-30 c using a suitable cooling system. In the next step 6015.83g of iron (III) dextran powder were added in portions to the dispersion. During the addition, the mixture had to be continuously stirred and homogenized at 2500 rpm using a rotary homogenizer. The temperature was maintained at 20-30 ℃ by starting cooling. After all iron (III) dextran powder had been added, citric acid (85.90g) was added to the mixture and dissolved. Adjusting to a pH value of 4.1-4.4. After all the components have been introduced, stirring is continued for 20 minutes and simultaneously posthomogenization is carried out at 2500 rpm. During this post-stirring phase, the temperature of the dispersion was maintained at room temperature by cooling. The resulting dispersion was transferred from a stainless steel container through a 0.1mm screen into a suitable storage container. After a certain storage period, the pH rises to a value between 4.8 and 5.2.

To determine the properties of the dispersion, the parameters pH, particle size distribution (measured by laser diffraction using a Malvern Mastersizer 2000) and viscosity are mentioned. Using cone/plate measuring devicesAt 128 and 256s^-1The shear rate of (2) was measured for viscosity (RheoStress 600; Thermo Haake). The average of the measured viscosity values was used as reference. These viscosity data have proven to be useful in characterizing the flow resistance of such suspensions when emptied by a drenching gun. In principle, it is endeavoured to achieve dispersions which are as finely divided as possible in order to maintain a high level of bioavailability of the active ingredient. The suspension prepared according to the above provides the following parameters:

iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) dextran powder 38.4% m/m

133

4.4

5.1

2.3

4.1

100％

100％

Example 2

Application of iron (III) dextran powder of 36.8% m/m

Batches for the preparation of 1000ml iron dextran/toltrazuril dispersions (23.6% m/V active iron + 5.3% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	177.34
Sodium propionate (preservative)	1.89
		Sodium benzoate (antiseptic)	1.89
Propylene glycol	106.38
		Anhydrous citric acid	7.59
Iron (III) dextran powder 36.8% m/m	639.98
		Water (W)	464.67
Viscosity-regulating adjuvant/adjuvants	-
		Total mass	1399.74

In each case, in a separate container, 1.89g of preservative sodium propionate and sodium benzoate were weighed into 106.38g of solvent propylene glycol and dissolved with stirring. All water was introduced into the container (1L glass beaker). Depending on the need and the desired viscosity of the final product, viscosity-regulating auxiliaries (so-called thickeners) can be dissolved or introduced into the amount of water. In embodiment 2, this is omitted. The propylene glycol premix was added to the mass that had been introduced into the glass beaker and homogenized under stirring (10 min). In the next step, a previously weighed 177.34g amount of 30% toltrazuril dispersion concentrate was added to the batch and the mixture was stirred by means of a dissolver plate for 30-40 min. The above-mentioned stirring time can also be prolonged or shortened, depending on the appearance of the suspension. In the next step 639.98g of iron (III) dextran powder were added in portions to the dispersion under stirring, and when the addition was complete the suspension was further stirred for 20 minutes by means of a dissolver plate. After all iron (III) dextran powder had been added, citric acid (7.59g) was added to the mixture and dissolved. Adjusting to a pH value of 4.1-4.4. After a certain storage period, the pH rises to a value between 4.8 and 5.2.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) dextran powder 36.8% m/m

277

4.4

4.9

3.2

6.4

99％

100％

Example 3

Application of 27.5% m/V iron (III) dextran solution

Batches for the preparation of 10L iron dextran/toltrazuril dispersions (21.0% m/V active iron + 5% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	1666.67
Sodium propionate (preservative)	17.00
		Sodium benzoate (antiseptic)	17.00
Propylene glycol	1000.00
		Anhydrous citric acid	150.35
Dextran iron (III) solution 27.5% m/V	11229.00
		Viscosity-regulating adjuvant/adjuvants	-
Total mass	14080.02

In each case, in a separate container, 17.00g of preservative sodium propionate and sodium benzoate were weighed into 1000.00g of solvent propylene glycol and dissolved with stirring. All 11229.00g of iron (III) dextran solution were introduced into a stainless steel vessel (Koruma Disho; apparatus type: DH V100/45). Depending on the need and the desired viscosity of the end product, viscosity-regulating auxiliaries (so-called thickeners) can be dissolved or incorporated into the pre-set mass. In embodiment 3, this is omitted. The propylene glycol premix was added to the mass which had been introduced into the stainless steel container and homogenized under stirring (20-40 min). The above-mentioned stirring time can also be shortened or lengthened, depending on the appearance of the suspension. In the next step, a previously weighed 1666.67g amount of 30% toltrazuril dispersion concentrate was added to the mixture and the mixture was stirred for 30-40min and simultaneously homogenized for 20 minutes at 2500 rpm using a rotary homogenizer (rotor/stator system). It is advantageous to use a suitable cooling system for maintaining the temperature of the mixture at 20-30 ℃. In the next step, citric acid (150.33g) was added and dissolved. During the addition, the homogenizer was switched to a speed of 1800 rpm and the temperature was maintained at room temperature by activating a cooling mechanism. Adjusting to a pH value of 4.1-4.4. The stirring and homogenization times are average values and can be shortened or lengthened, depending on the appearance of the suspension. During this method, the cooling mechanism remains activated. The resulting dispersion was transferred from a stainless steel container through a 0.1mm screen into a suitable storage container. The pH rises to a value between 4.8 and 5.2 within a few days to weeks.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Dextran iron (III) solution 27.5% m/V

96

4.4

4.8

2.5

4.7

100％

100％

Example 4

Use of a ferrosaccharide (III) powder of 35.9% m/m

A compound called ferric (III) saccharide (from dr. paul Lohmann GmbH KG) was used, which is a ferric (III) hydroxide saccharide complex.

Batches for the preparation of 10L of glycoiron/toltrazuril dispersion (22.8% m/V active iron + 5% m/V toltrazuril) for oral application in suckling piglets:

composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	1666.67
Sodium propionate (preservative)	17.00
		Sodium benzoate (antiseptic)	17.00
Propylene glycol	1000.00
		Anhydrous citric acid	400.00
Iron (III) Saccharide powder 35.9% m/m	6350.98
		Adding water to 10 liters	4543.73
Viscosity-regulating adjuvant/adjuvants	-
		Total mass	13995.38

In each case, in a separate container, 17.00g of preservative sodium propionate and sodium benzoate were weighed into 1000.00g of solvent propylene glycol and dissolved with stirring. The entire amount of water was introduced into a stainless steel vessel (Koruma Disho; apparatus type: DH V100/45). Depending on the need and the desired viscosity of the final product, viscosity-regulating auxiliaries (so-called thickeners) can be dissolved or introduced into the amount of water. In this embodiment 4, this is omitted. The propylene glycol premix was added to the mass which had been introduced into the stainless steel container and homogenized under stirring (20-40 min). In the next step, a previously weighed 1666.67g amount of 30% toltrazuril dispersion concentrate was added to the batch and the batch was stirred for 30-40min while being homogenized at 2500 rpm for 20 minutes using a rotary homogenizer (rotor/stator system). It is advantageous to maintain the temperature of the mixture at 20-30 c by means of a suitable cooling system. In the next step 6350.98g of the iron (III) saccharide powder were added in portions to the dispersion. During the addition, the mixture had to be continuously stirred and homogenized at 2500 rpm using a rotary homogenizer. The stirring and homogenization times of the suspensions already mentioned can be prolonged or shortened, depending on the appearance of the formulation. The temperature was maintained at 20-30 ℃ by activating the cooling mechanism. After all of the ferric (III) sugar powder had been added, citric acid (400.00g) was added to the mixture with stirring and dissolved. After all the components have been introduced, stirring is continued for 20 minutes and simultaneously post-homogenization is carried out at 2500 rpm. During this post-stirring phase, the temperature of the dispersion was maintained at room temperature by cooling. After a short time, a pH value of 5 was obtained. The resulting dispersion was transferred from a stainless steel container through a 0.1mm screen into a suitable storage container.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) Saccharide powder 35.9% m/m

1312

5.0

-

2.1

4.3

100％

100％

Example 5

Use of iron (III) polymaltose powder at 32.0% m/m

Biorder for the preparation of 10L FeS/toltrazuril Dispersion (22.8% m/V active iron + 5% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	1666.67
Sodium propionate (preservative)	17.00
		Sodium benzoate (antiseptic)	17.00
Propylene glycol	1000.00
		Anhydrous citric acid	604.69
Iron (III) polymaltose powder 32.0% m/m	7125.00
		Adding water to 10 liters	3927.21
Viscosity-regulating adjuvant/adjuvants	-
		Total mass	14357.57

In each case, in a separate container, 17.00g of preservative sodium propionate and sodium benzoate were weighed into 1000.00g of solvent propylene glycol and dissolved with stirring. The entire amount of water was introduced into a stainless steel vessel (Koruma Disho; apparatus type: DH V100/45). Depending on the need and the desired viscosity of the final product, viscosity-regulating auxiliaries (so-called thickeners) can be dissolved or introduced into the amount of water. In this embodiment 5, this is omitted. The propylene glycol premix was added to the mass which had been introduced into the stainless steel container and homogenized under stirring (20-40 min). In the next step, a previously weighed 1666.67g amount of 30% toltrazuril dispersion concentrate was added to the batch and the batch was stirred for 30-40min while being homogenized at 2500 rpm for 20 minutes using a rotary homogenizer (rotor/stator system). It is advantageous to maintain the temperature of the mixture at 20-30 c by means of a suitable cooling system. In the next step, 7125.00g of iron (III) polymaltose powder were added in portions to the dispersion. During the addition, the mixture had to be continuously stirred using a rotary homogenizer and homogenized at 2500 rpm. The temperature was maintained at 20-30 ℃ by activating the cooling mechanism. After all the iron (III) polymaltose powder had been added, citric acid (604.69g) was added to the mixture and dissolved with stirring. After all the components have been introduced, stirring is continued for 20 minutes and simultaneously post-homogenization is carried out at 2500 rpm. Depending on the appearance of the formulation, the above-mentioned stirring and homogenization times can be extended or shortened. During this post-stirring phase, the temperature of the dispersion was maintained at room temperature by cooling. The resulting dispersion was transferred from a stainless steel container through a 0.1mm screen into a suitable storage container. After storage times of several days to several weeks, the pH rises to a value between 4.8 and 5.2.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) polymaltose powder 32.0% m/m

1226

4.4

5.0

1.9

3.3

100％

100％

Example 6

Use of iron (III) dextran powder 37.9% m/m with viscosity modifying aid

Batches for the preparation of 10L of a glycoiron/toltrazuril dispersion (22.8% m/V active iron + 5% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	1666.67
Sodium propionate (preservative)	17.00
		Sodium benzoate (antiseptic)	17.00
Propylene glycol	1000.00
		Anhydrous citric acid	70.00
Iron (III) dextran powder 37.9% m/m	6015.83
		Bentonite (magnesium aluminum silicate) as viscosity modifier	20.00
Xanthan gum as viscosity modifier	30.00
		Adding water to 10 liters	3290.00
Total mass	12126.50

In each case, 17.00g of the preservatives sodium propionate and sodium benzoate were weighed into 1000.00g of the solvent propylene glycol in a separate stainless steel container and dissolved with stirring. If the preservative is dissolved, 30.0g of xanthan gum is added and stirring is continued for about 10 minutes. Thereafter, the mixture was homogenized using a rotary homogenizer (rotor/stator system; laboratory Ultra-Turrax) at 13500 rpm for approximately 5 minutes so that the dispersion was free of lumps.

A total of 3290.0g of water were introduced into a stainless steel vessel (Koruma Disho; apparatus type: DH V100/45). Thereafter, 20g of bentonite was dispersed therein. The batch is now warmed to 78 ℃ and stirred gently there (50 rpm of the rotary stirrer). The temperature should be maintained at 78 ℃ for approximately 5-10 minutes, followed by cooling the batch to 35 ℃ with stirring and running the cooling system. Stirring was then continued for 20-40 minutes and homogenization was carried out using a rotary homogenizer at 2500 rpm for 20 minutes with continued cooling. Thereafter, a dispersion of xanthan gum in propylene glycol was added to the bentonite/water mixture with constant stirring. Homogenization of the batch is then carried out, which is post-homogenized by further stirring at 50 rpm for 20 to 40 minutes and by stirring for 10 minutes at 2500 rpm. Also, the stirring and homogenization times described above can be extended or shortened, depending on the need and on the appearance of the dispersion.

In the next step, a previously weighed 1666.67g amount of 30% toltrazuril dispersion concentrate was added to the batch and the batch was stirred for 30-40min while being homogenized at 2500 rpm for 20 minutes using a rotary homogenizer (rotor/stator system). During this treatment, the temperature is maintained at 20-30 ℃ by active cooling. In the next step, 6015.83g of iron (III) dextran powder was added in portions to the dispersion. During the addition, stirring had to be continued and homogenization was carried out with a rotary homogenizer at 2500 rpm. The temperature was maintained at 20-30 ℃ by activating the cooling device. After complete addition of iron (III) dextran powder, citric acid (70.0g) was added to the mixture with stirring and homogenization and dissolved. Adjusting to a pH value of 4.1-4.4. After all the components have been introduced, stirring is continued for 20 minutes and post-homogenization is carried out at 2500 rpm. During this post-stirring phase, the temperature of the dispersion was maintained at room temperature by cooling. The resulting dispersion was transferred from a stainless steel container through a 0.1mm screen into a suitable storage container.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) dextran powder 37.9% m/m

1365

4.5

-

1.7

3.5

100％

100％

Example 7

Use of 38.6% m/m iron (III) dextran powder with viscosity modifying aid

Batches for the preparation of 1L iron dextran/toltrazuril dispersions (20% m/V active iron + 3% m/V toltrazuril) for oral application in suckling piglets

Composition (I)	Mass/g
		Concentration of toltrazuril suspension (30%)	100.00
Sodium propionate (preservative)	1.80
		Sodium benzoate(preservatives)	1.80
Propylene glycol	100.00
		Anhydrous citric acid	8.67
Iron (III) dextran powder 38.6% m/m	518.13
		Bentonite (magnesium aluminum silicate) as viscosity modifier	1.33
Xanthan gum as viscosity modifier	2.00
		Make up water to 1 liter	606.42
Total mass	1340.15

In each case, in a separate glass beaker, 1.80g of the preservatives sodium propionate and sodium benzoate are weighed into 100.00g of the solvent propylene glycol and dissolved with stirring. If the preservative is dissolved, 2.00g of xanthan gum is added and stirring is continued for about 10 minutes so that the dispersion is free of lumps.

Approximately 100g of water was introduced into a glass beaker and warmed to 70-80 ℃. Thereafter, 1.33g of bentonite was dispersed therein and the temperature was maintained for about 5-10 minutes. The resulting bentonite slime was cooled under stirring and the remaining water (506.42g) was added. The bentonite/water mixture was stirred at 270 rpm by means of a dissolver disc and a dispersion of xanthan gum in propylene glycol was added with constant stirring. The post-homogenization of the batch is then carried out for a further 5 to 10 minutes with stirring. Also, the above-mentioned stirring time can be prolonged or shortened, depending on the need and on the appearance of the dispersion.

In the next step, a previously weighed amount of 100.00g of 30% toltrazuril dispersion concentrate was added to the batch and the mixture was stirred at 460 rpm for 30-40 min. Thereafter, 518.13g of iron (III) dextran powder were added in portions to the dispersion with constant stirring. After all the iron (III) dextran powder had been added, citric acid (8.67g) was added to the mixture and dissolved with stirring. Adjusting to a pH value of 4.1-4.4. After all the components have been introduced, homogenization of the suspension is carried out at 9500 rpm for 20 minutes by means of a rotor-stator homogenizer. The resulting dispersion was transferred to a suitable PE flask.

Iron compound

viscosity/mPas

pH after preparation

pH after storage

Particle size d (v, 50)/μm

Particle size d (v, 90)/μm

Percentage of particles < 10 μm

Percentage of particles < 30 μm

Iron (III) dextran powder 38.6% m/m

108

4.2

-

1.9

3.6

100％

100％

The measured data of the dispersions of examples 1 to 7 show that it is possible to prepare formulations of the invention having very fine solid constituents. No undesirable formation of agglomerates was observed. Furthermore, in the example suspensions, in 0.9ml of dispersion, 35-44mg toltrazuril and 200mg active iron were found as ingredients required for the administration of suckling piglets.

The viscosity of the dispersions of examples 1 to 7 can be adjusted over a wide range of 10 to 2500 mPas. A smaller viscosity range of 20-1500mPas, preferably 50-500mPas, and very particularly preferably 20-250mPas, is advantageous because it causes less problems when swallowed by e.g. piglets.

Biological examples

Results of clinical testing using the formulations of examples 2 and 3

30 breeding sows producing a total of 270 piglets were used for clinical trials. The animals were divided into four groups, in each case one litter of pup (Wurf) was divided, and each half was assigned to a different group. Thus, 60 and 75 piglets were allocated to one treatment group, since the pup size and farrowing time (Wurfzeitpunkt) were slightly different. In all cases, 0.9ml of the formulation was orally administered to piglets at postnatal day 3. Blood samples were taken from the piglets on the dosing day and on days 7, 14 and 21. The number of red blood cells (RBC million cells/μ l), hematocrit (Ht%), hemoglobin value (Hb g/100ml), and weight of piglets in kg were used as criteria for formulation efficiency. These results were compared with those of a control group that had been administered a commercially available iron (III) dextran formulation for injection (hirrrox 200) on postnatal day 3. The results are shown in table 5 below.

The formulations of example 2 (prepared from iron (III) dextran powder) and example 3 (prepared from iron (III) dextran solution) were both administered orally to give hemoglobin values > 9g/100ml at days 7, 14 and 21 after birth, thus demonstrating an effective avoidance of any anemic deficiency condition. Furthermore values of > 10g/100ml at days 14 and 21 after birth demonstrate that these formulations are highly bioavailable. Furthermore, the standard RBC, HT and weight gain all show that these formulations do not have disadvantages relative to injectable formulations.

Thus, it could be demonstrated that a single oral administration of 200mg of active iron from iron (III) dextran bound to toltrazuril in the formulation according to the invention, surprisingly (contrary to academic points and to date prior art), even when administered on postnatal day 3, could provide a good prevention against anemic deficiency states in suckling piglets.

Oocyst analysis of piglet faeces all gave negative results. These demonstrate that the above-described formulations are effective as agents against the pathogens responsible for coccidiosis.

Furthermore, no associated adverse symptoms such as diarrhea were found, which are usually observed when high doses of iron compounds are administered orally. Thus, the formulations prepared according to the invention proved to be well tolerated.

Claims (22)

1. Aqueous formulations containing triazinones of the formula (I) or (II)

Or

Wherein the content of the first and second substances,

R¹represents R³-SO₂-or R³-S-，

R²Represents alkyl, alkoxy, halogen or SO₂N(CH₃)₂And an

R³Represents haloalkyl

R⁴And R⁵Independently of one another, represent hydrogen or Cl, and

R⁶represents fluorine or chlorine, and is selected from the group consisting of,

or a physiologically acceptable salt thereof,

and

an iron (III) compound selected from the group consisting of:

(b) ammonium iron (III) citrate or hydrate thereof, and

(c) polynuclear iron (III) polysaccharide complexes.

2. The formulation according to claim 1, which contains 1 to 30% of triazinones in m/V.

3. A formulation according to claim 2, which contains from 3 to 7% of triazinones, in m/V.

4. A formulation according to any one of claims 1 to 3, wherein the dispersed triazineone compound has a particle size with a d (v, 90) of less than or equal to 30 μm.

5. A formulation according to claim 4, wherein the dispersed triazineone compound has a particle size with a d (v, 90) of less than or equal to 20 μm.

6. A formulation according to claim 4, wherein the dispersed triazineone compound has a particle size with a d (v, 90) of less than or equal to 10 μm.

7. A formulation according to any one of claims 1 to 3, wherein the concentration of the iron compound is between 10% and 30% active iron in m/V.

8. A formulation according to claim 7, wherein the concentration of iron compound is between 11.4% and 25% active iron in m/V.

9. A formulation according to claim 7, wherein the concentration of iron compound is between 20% and 25% active iron in m/V.

10. A formulation according to any one of claims 1 to 3, wherein the cone/plate set of the rheometer is used, passing at 128s^-1And 256s^-1The viscosity is in the range of 10 to 2500mPas as an average value of viscosity values measured by the shear rate of (1).

11. The formulation according to claim 10, wherein the viscosity is in the range of 20 to 1500 mPas.

12. The formulation according to claim 1, which contains at least one polyhydroxylated aliphatic alcohol.

13. The formulation according to any one of claims 1 to 3, comprising a polynuclear iron (III) polysaccharide complex from group (c), wherein the polynuclear iron core of the polynuclear iron (III) polysaccharide complex is composed of β -FeO (OH) units and the polynuclear iron (III) polysaccharide complex comprises polysaccharide molecules in a further coordination layer.

14. The formulation according to claim 13, comprising a polynuclear iron (III) polysaccharide complex compound selected from the group consisting of: iron (III) dextran, iron (III) hydroxypolymaltose/iron (III) dextrin and non-stoichiometric compounds consisting of polynuclear beta-feo (oh) and sucrose and oligosaccharides.

15. A formulation according to any one of claims 1 to 3, which contains the triazinetrione represented by the formula (I) in claim 1 as the triazineone compound.

16. The formulation according to any one of claims 1 to 3, wherein the triazineone compound is toltrazuril and the polynuclear iron (III) polysaccharide complex compound is iron (III) dextran.

17. A formulation according to any one of claims 1 to 3 which contains one or more nutrients.

18. Use of a formulation according to any one of claims 1 to 17 for the preparation of a medicament for the simultaneous treatment of coccidial infections and iron deficiency states.

19. Use according to claim 18 for the preparation of a medicament for oral treatment.

20. Use according to claim 19 for the preparation of a medicament for the oral treatment of suckling piglets.

21. Use according to claim 20 for the manufacture of a medicament for the oral treatment of piglets, in a period of time from birth up to 10 days after birth.

22. Use according to claim 21 for the manufacture of a medicament for the oral treatment of piglets, in a period from birth until 3 days after birth.