Formulations containing triazinones and iron

Description

[0001] The invention relates to formulations containing triazinones and iron compounds (salts and complex compounds of iron) that are suitable for the simultaneous control of coccidiosis and iron deficiency in animals.

[0002] Economically successful meat production farms in modern times are characterized by highly intensive management, meaning the keeping of a large number of animals specifically selected to optimize breeding goals. Key features include, for example, extensive use of machinery, supplemental feeding, and minimal labor requirements. In the case of piglet breeding farms, this means keeping a large number of sows, bred for high litter sizes, in appropriately spacious barns. Optimized feed and targeted breeding selection enable rapid piglet growth.

[0003] This type of animal husbandry often leads to an increase in certain typical diseases and deficiencies. Besides stress, to which pigs in intensive farming are particularly susceptible, these include protozoal infections (coccidiosis) and iron deficiency in young pigs, which often require prophylactic medication.

[0004] Coccidiosis is a common parasitic infectious disease in animals. For example, protozoa of the genera Eimeria, Isospora, Neospora, Sarcosporidia, and Toxoplasma cause coccidiosis, which is widespread globally. Economically significant infections include those of pigs with coccidia of the genus Isospora and of cattle with coccidia of the genus Eimeria. Infections with Isospora suis have only recently been recognized and intensively researched as a cause of diarrhea in piglets. Infection typically occurs from the environment to piglets or from piglet to piglet via oocysts, each containing two sporocysts with two sporozoites each. The parasite stages multiply in the epithelial cells of the small intestine villi. Clinically, the disease presents with necrotic, inflammatory destruction of the intestinal epithelial cells with villous atrophy, resulting in digestive and absorption disorders.A hallmark of acute coccidiosis is watery, whitish to yellow diarrhea, which usually occurs in the second to third week of life. Infected piglets exhibit reduced weight gain. Treatment and therapy for the disease are currently inadequate. Antibiotics are ineffective, and while sulfonamides are approved for coccidiosis treatment, their efficacy is questionable, and frequent administration is certainly impractical. Other treatment options are contradictory: Administering substances such as monensin, amprolium, or furazolidone failed to prevent disease in experimentally infected piglets. Recent studies have shown that, despite good hygiene practices, up to 92% of litters in some farms... Isospora suiscan be identified. This type of disease is not limited to pigs but also occurs in many other animal species, e.g. in poultry farming, in calves, lambs or in small animals (rabbits).

[0005] An example of a deficiency is iron deficiency in newborn piglets. Due to rapid growth in the first few days after birth, the body's iron stores are quickly depleted and must be replenished from external sources. Because of the large number of suckling piglets, this replacement cannot be achieved sufficiently through the intake of the sow's milk. Furthermore, if the piglets are kept on concrete or plastic floors, they cannot ingest iron compounds by rooting in the soil. The piglets become anemic. Clinically significant anemia is present when the hemoglobin level in the blood falls below 80 g / L. The NRC recommendation (National Research Council, Nutrient Requirements of Domestic Animals, No. 2, Nutrient Requirements of Swine, National Academy of Sciences, Washington DC, 1973 ) A hemoglobin level of 90 g / L is considered the minimum required for piglets to grow up healthy and show no signs of anemia. However, noticeable symptoms such as weight loss or stunted growth usually only appear when the hemoglobin content of the blood has dropped below 80 g / L. Other indicators of iron status are the hemocrist value and the number of red blood cells per unit volume. Severe iron deficiency anemia also leads to the death of piglets.

[0006] Preparations are already available to combat the aforementioned diseases and deficiencies.

[0007] Coccidiosis can be successfully treated by administering active substances from the triazinone group. A distinction is made between triazinidiones – examples of which are clazuril, diclazuril, and letrazuril – and triazintrions, including toltrazuril, toltrazuril sulfoxide, and ponazuril. Triazines, particularly toltrazuril, ponzazuril, and diclazuril, and their efficacy against coccidia are known from a number of publications, see, among others, DE-OS 27 18 799 and DE-OS 24 137 22. Semi-solid aqueous preparations of toltrazuril sulfone (ponazuril) are known from WO 99 / 62519. It is also known that toltrazuril, in particular, is suitable for treating coccidiosis (e.g., Isospora suis) in pigs. See also, for example, the following publications: Don't forget coccidiosis, update on Isosporosis in piglets. Part I, Pig Progress volume 17, No2, 12-14; Mundt., H.-C., A. Daugschies, V.Letkova (2001): be aware of piglet coccidiosis diagnoses. 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.

[0008] Coccidiosis in cattle caused by infections with various pathogenic Eimeria spp. (e.g. E. bovis and E. zürnii) manifests as diarrheal diseases of varying severity, ranging from mild to bloody diarrhea with mortality.

[0009] In WO 96 / 38140, DE 10049468, DE 19958388, WO 00 / 19964, WO 99 / 62519 or WO 00 / 37063 as well as in DE 102006038292.7, agents for the treatment of coccidiosis in animals are described. In addition to other methods of application, oral administration is also mentioned there in general terms.

[0010] DE 19603984 describes granules for oral administration. DE 19824483 describes semi-solid, aqueous preparations (pastes) for the treatment of animals. EP 0116175 describes orally administered solutions.

[0011] In poultry farming, preparations or solutions that can be dissolved in drinking water are frequently used, while in large animal operations the active ingredients are more likely to be added to the feed or administered orally as a suspension via an applicator (drench). Examples of substances of importance on the market include diclazuril (2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazine-2(3H)-yl)benzeneacetonitrile; CAS No. 101831-37-2) (CLINACOX™ < 0.5%, Janssen Animal Health; VECOXAN™ < , Biokema SA) for feed additives and toltrazuril (1-methyl-3-[3-methyl-4-[4-[(trifluoromethyl)thio]phenoxy]phenyl]-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 a drinking water formulation for poultry and as an oral suspension formulation for the treatment of piglets, among other uses. It is recommended to administer a dose of 20 mg / kg body weight to the piglet on the 3rd to 5th day after birth.The BAYER HealthCare information leaflet, "Stop coccidiosis in piglets! Baycox 5% oral suspension", 2003, XP002799547, found on the internet: URL: https: / / register.epo.org / application?documentId=E33DQJXH0457DSU&number=EP17160876&lng=en&npl=true, is an information leaflet about Baycox 5% (toltrazuril) and describes its use in piglets. Page 8 states that the simultaneous administration of Baycox 5% with commercially available iron supplements does not cause any interactions and also offers the significant advantage of treating both iron deficiency and coccidiosis at the same time.

[0012] A disadvantage is the relatively high labor cost involved in the oral administration of the aforementioned anticoccidia (sometimes also, though not entirely accurately, referred to as coccidiostats): The piglets must be caught and the product administered into their throats using an applicator or drench. This procedure also causes considerable stress for the piglets.

[0013] A number of quite different iron preparations are available for the prevention of iron deficiency anemia, differing in compound type, route of administration, and bioavailability. A distinction is made between (I) simple inorganic Fe(2+) salts, (IIa) complex compounds of Fe(2+) with organic ligands, e.g., with lactic acid, or (IIb) of Fe(3+), e.g., with citric acid, and (III) polymeric complex compounds of an Fe(3+)-oxo-hydroxo complex β-FeO(OH) of the akaganeite type with carbohydrates / polysaccharides, specifically with oligomeric or polymeric carbohydrate compounds, such as dextran or dextrin / polymaltose. In the following, the terms polymeric carbohydrates / carbohydrate compounds and polysaccharides are used to refer to both oligomeric and polymeric compounds.

[0014] Orally administered preparations of type (I), such as the use of 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, e.g., as ferrous sulfate FeSO₄. These products can be added to the sow's feed or administered directly to the piglets orally. Piglets are usually given several single doses during the first few days of life in the growth period to compensate for the relatively low bioavailability. An alternative way to avoid multiple administrations is the later administration of iron-containing supplementary feed (prestarter and starter feed). While the iron ions in inorganic iron(2+) salts are rapidly released by dissociation, the release in 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+) is many orders of magnitude greater than that of Fe(3+) under the physiological conditions of the upper small intestine (Forth, W., in: Dünndarm, Handbuch der inneren Medizin, Bd. 3 Verd.Org. Teil 3(A) ; WFCaspary, Hrsg.; Springer 1983. ).Furthermore, free iron(3+) ions are reduced to Fe(2+) in the intestinal environment by cysteine, glutathione, ascorbic acid, and other substances, and as such are absorbed by the intestinal mucosal epithelial cells. However, whether this reduction is a necessary prerequisite for absorption into the mucosal cells is controversial. The concentration gradient due to the higher solubility of Fe(2+) is likely the reason for its higher bioavailability. According to current understanding, the Fe(2+) ions initially bind to the protein mobilferrin, where they are oxidized back to Fe(3+) and bound to the mucosal storage protein ferritin. When the body requires iron, these Fe(3+) are released into the blood plasma, where they are again reduced to Fe(2+) by ferrioxidase and bound to the protein apotransferrin, the body's iron-binding transport protein.It is controversial whether transferrins are already present in the mucosal cells and whether they at least partially bind iron there. The complex formation constant of transferrin is so high (log K) of approximately 30-31 that free iron cannot exist anywhere in the organism as long as the iron-binding capacity of transferrin is not exceeded. This explains the toxic effects that can occur with a sudden overabundance of iron salts, which is a disadvantage of their use. The iron is then transported via the blood and lymphatic vessels to the sites of hemoglobin synthesis in the bone marrow (see E. Kolb, U. Hofmann, "Applications of iron compounds in pigs," Tierärtzl. Umschau 60, (2005) 365-371). and Forth, W. "Iron and iron supply of the warm-blooded organism", Naturwissenschaften 74, (1987) 175-180 as well as John, A.; "New possibilities for iron supply to newborn piglets taking biochemical aspects into account" in: Pregnancy and birth in pigs, 8th Bernburg Biotechnology Workshop 2002, 89-94 ). Unused iron remains stored in the mucosal cells but is no longer available after their death. Therefore, it is understandable that the bioavailability of oral iron compounds depends heavily on other factors such as actual iron requirements, feeding status (colostrum intake), and health status (diarrhea: premature loss of upper mucosal cells). Understanding this mechanism is important for understanding and evaluating the advantages and disadvantages of specific iron supplements.

[0015] Furthermore, compounds from the second group (II) of chelated Fe(2+) and Fe(3+) compounds are used. These form relatively stable iron complexes that are only partially broken down into ions by gastric acid. Subsequent bioavailability is determined by the fact that the iron is partially exchanged with the ligands at or within the mucosal cells, which depends on the formation constants of the complexes. Due to their higher lipophilicity, unbroken complexes can cross the membrane systems of the epithelium and must be metabolized. This explains why organic low-molecular-weight complexes have slower bioavailability but exhibit a more sustained effect (H. Dietzfelbinger; "Bioavailability of Bi- and Trivalent Oral Iron Preparations"; Arzneim.-Forsch. / Drug. Res 37(1), Nr. 1a, (1987) 107-112). and EBKegley et al., "Iron Methionine as a Source of Iron for the Neonatal Pig," Nutrition Research 22 (2002) 1209-1217).

[0016] The third group of compounds, which are mainly administered parenterally and only to a lesser extent orally, consists of relatively stable poly-β-FeO(OH) compounds with complex-bound polymeric carbohydrates. Here, 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. 8047-67-4), and sodium iron(III) gluconate complex in sucrose solution (CAS No. 34089-81-1) have achieved commercial importance, but are not limited to these. These compounds are known by various names in the literature.Compounds such as iron(III) dextran, polymaltose, dextrin, sucrose, gluconate, and sugar are understood here to be complexes of the iron(III) ion with hydroxide ions (OH⁻), aquo groups (H₂O), and oxygen (O), which exist in oligo- or polymeric form and are complexly associated in their coordination sphere with one or more of the aforementioned oligomeric and polymeric carbohydrate compounds. For this reason, the compounds are also referred to as iron(III) hydroxide polysaccharide or iron(III) oxyhydroxy polysaccharide, where polysaccharide stands for the aforementioned oligo- and polymeric carbohydrate compounds or their derivatives, or more generally for compounds from the group of oligomeric or polymeric carbohydrates. Polynuclear iron(III) complexes of this type are described, for example, in [reference missing]. (DS 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 "New possibilities for iron supply to newborn piglets taking biochemical aspects into account", Pregnancy and birth in pigs: 8th Bernburg Biotechnology Workshop, Bernburg (2002) 89-94 .).Since the composition of these compounds is not quantitatively described in many cases and can also vary within the compounds depending on the method of preparation, the term polynuclear iron(III) polysaccharide compounds shall be understood to encompass all complexes of the described class of compounds that are familiar to the person skilled in the art.

[0017] These iron compounds are used almost exclusively in the production of injectable preparations for human and veterinary medicine. However, a few orally administered preparations are also used in veterinary medicine. These complexes are generally characterized by high stability and differ mainly in their molecular weight, which can vary from 30 kDa to 400 kDa, and in the strength of the complex bond. In aqueous solution, they exist as colloidal dispersions with a particle size of 7–35 nm. Crucial for bioavailability in the case of oral administration is, firstly, the extent of precipitate formation and 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 uptake into the organism and conversion to biological iron compounds are not yet fully understood and are still partly controversial in the literature.However, some general statements can be made about the mechanism of action. The more stable the complex, the higher the proportion of the compound that survives passage through the stomach unchanged, and the lower the proportion of free iron ions. The stability of the complexes, in turn, depends on the synthesis method. High-molecular-weight iron(III) polymaltose and iron(III) dextran have proven to be quite stable. This contrasts with the necessity of transferring the iron to the proteins along the transport pathway. Naturally, this transfer is lower the more stable the complexes are. These relationships have been confirmed by various experiments with acids, reducing agents, and 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(II) 11 (1984) 1555-1559 ).

[0018] Based on these considerations, the prevailing opinion has arisen that Fe(3+) compounds in general, and especially polynuclear compounds such as iron(III) dextran, are not suitable for oral administration. ( H.Dietzfelbinger "Bioavailability of Bi- and Trivalent Oral Iron Preparations" Arzneim.-Forsch. / Drug Res. 37(I), No. 1(a) (1987) 107-112 .)

[0019] Another reason for skepticism regarding the oral use of polynuclear Fe(3+) complexes, especially iron(III) dextran, is the specific absorption pathway of β-FeO(OH) complexes in the intestinal tract. These compounds are taken up into the epithelial cells of the intestinal mucosa via pinocytosis and must then be released into the body via the lymphatic system, stored in the lymph nodes, and finally transported into the bloodstream. (See also the previously mentioned articles by Kolb, Hofmann; Forth; John).Since they are quite stable, as explained above, their subsequent bioavailability depends on the metabolism and enzymatic degradation of the complexes with lysosomal enzymes. Experiments with polyvinylpyrrolidone, dextran, and dye-labeled iron(III) dextran of varying molecular weights have shown that in suckling piglets, these polymer complexes can be absorbed via pinocytosis through the epithelial cells of the duodenum and upper small intestine during the first days of life (R. Clarke, RN 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.Jönsson "Cellular Distribution of Orally and Intramuscularly Administered Iron Dextran in Newborn Piglets", Can. J. Comp. Med. 41 (1977) 318-325 ;K. Martinsson, L.Jönsson "On the Mechanism of Intestinal Absorption of Macromolecules in Piglets Studyed with Dextran Blue", Zbl. Vet. Med. A 22 (1975) 276-282 ). However, it is also known that this transfer of high-molecular-weight compounds from the mucosal cells into the lymphatic and circulatory systems of piglets is only possible without hindrance immediately after birth. This mechanism ensures that piglets can be supplied with immunoglobulins and antibodies through the ingestion of the sow's colostrum immediately after birth. Once this supply is guaranteed, the transport mechanism ceases. This mucosal closure ("intestinal closure") during the further course of growth is biologically advantageous in order to prevent infections with microorganisms and toxins. ( K. Martinsson, L.Jönsson "The Uptake of Macromolecules in the Ileum of Piglets after Intestinal Closure" , Zbl. Vet. Med. A 23 (1976) 277-282 ).The time between birth and mucosal blockage is therefore highly dependent on the piglets' nutritional status. In starving piglets, this transfer can still occur up to four days after birth. ( JG Lecce, DO 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 the general housing conditions in breeding farms naturally allow suckling, it is currently generally accepted in medicine and considered state of knowledge that adequate oral supply of high-molecular-weight iron complexes to piglets is only practically possible in the first few hours after birth if multiple administrations are to be avoided. The few authors who have systematically investigated the efficacy of iron(III) dextran depending on the time of oral administration report a significantly reduced efficacy if the iron(III) dextran is administered 24–72 hours after birth (L. Blomgren, N. Lanneck, "Prevention of Anaemia in Piglets by a Single Oral Dose of Iron Dextran", Nord. Vet.-Med. 23 (1971) 529–536). ).Depending on husbandry and feeding conditions, administration on the second day of life can still achieve 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, the effectiveness of administering iron dextrans 72-96 hours after birth is already significantly reduced. ( Ueda H. "Prevention of Piglet Anemia by Oral Administration of Iron Dextran", Nicchiku Kaiho 56(11), 1985, 872-877 ). Therefore, only a few oral iron supplements with polynuclear iron complexes have become established on the market ( Ursoferran 150 po; Serumwerke Bernburg - iron (III) dextran; Ferrum Hausmann Syrup ®< Hausmann Laboratories Inc., St. Gallen; - Iron(III) hydroxide polymaltose. In modern iron-dextran preparations for oral use in breeding piglets, the iron-dextran is bound to the emulsifiers of 1-2µm microemulsion droplets to improve bioavailability. (Bioveyxin FeVit ™< , Veyx-Pharma GmbH, Schwarzenborn; SintaFer ™<, Sinta GmbH, Schwarzenborn)This finely dispersed state and the binding to lipophilic carriers are intended to promote uptake into epithelial cells and transfer into the organism. However, even for these preparations, the manufacturer recommends application no later than 8-10 hours after farrowing to achieve optimal efficacy. This, in turn, requires continuous monitoring of the breeding sows, which entails a considerable amount of personnel.

[0020] Generally, a dosage of 100-200 mg of active iron per piglet and dose is recommended for oral iron supplements to ensure sufficient efficacy. However, only the higher dose makes it possible in practice to manage with a single administration.

[0021] To avoid the uncertainties associated with oral administration, it is more common in pig farming to administer polynuclear iron(III) complexes intramuscularly by injection. This is usually done by injecting 100-200 mg of active iron on the third day after birth. Transport from the injection site occurs via the lymphatic system and the cells of the reticulohistiocytic system. The complexes are stored in the liver and spleen, from where they are released as needed and enzymatically metabolized. The free Fe(3+) is ultimately bound to transferrin and transported to the sites of use in the bone marrow.

[0022] However, this parenteral route of administration also has several disadvantages: A significant drawback of intramuscular injection in piglets is the higher frequency of adverse effects. Muscle hemorrhages, changes in muscle fibers, inflammation, and edema are more common at the injection sites. These are localized injuries. Furthermore, cardiac disorders are observed, particularly in cases of concurrent vitamin E deficiency. In such cases, a sharp increase in blood plasma potassium levels can be detected, which severely damages the heart muscle and can lead to the death of the piglets. Current understanding suggests that even minute amounts of free Fe²⁺ ions are responsible for the formation of radical compounds with organic molecules, such as lipid peroxide compounds, which are associated with high blood potassium levels.Vitamin E acts as a free radical scavenger and can buffer these harmful reactions to some extent, although the body's own capacity is often exceeded. (Therefore, vitamin E is added to the aforementioned oral preparations in which the iron(III) dextran is bound to microemulsion droplets.) Intramuscular administration also has another disadvantage: After administration of iron(III) dextran, a certain reduction in the effectiveness of the immune system is to be expected, as the macrophages in the blood become loaded with the polynuclear iron complexes. The ability to defend against bacterial infections is reduced. An overview of the described disadvantages of intramuscular administration can be found in the literature. ( E. Kolb, U. Hofmann "On the question of the appropriate form of application of Fe-dextran, its utilization and the mechanism of possible harm to piglets"; Mh. Vet.-Med. 44 (1989) 497-501 ).

[0023] In summary, it can be stated that the currently available methods of anemia prophylaxis in suckling piglets each have a number of disadvantages: 1. According to the literature, significantly lower bioavailability is generally observed with oral administration of Fe(II) compounds of types (I) and (II). It is recommended to administer these preparations several times, which is labor-intensive in intensive animal farming and represents an economic disadvantage. 2. Oral administration of polynuclear Fe(III) compounds of type (III), especially ferric dextran, leads to better results. A single dose of approximately 200 mg of active iron is usually sufficient to ensure adequate iron supply to piglets. However, a crucial disadvantage is that, according to current scientific opinion, sufficient efficacy can only be achieved if the ferric dextran can be administered to the piglets within the first 8–10 hours of life.This could only be guaranteed with continuous monitoring of births on breeding farms, which is often not possible due to the large number of personnel required. If this window is missed, higher mortality rates among the piglets are frequently the result. 3. Intramuscular iron preparations are more advantageous in their application, as administration between day 1 and day 3 after birth leads to very good results. However, their potential to harm the piglets through toxic side effects and temporary weakening of the immune system is a disadvantage. Oral preparations do not have this disadvantage. 4. If one also considers the frequently necessary coccidiosis treatment, for example with toltrazuril or similar compounds, it becomes clear that successful piglet breeding very often requires two steps: (1) catching the piglets on day 1 after birth and administering, for example, iron supplements.Iron(III) dextran, further capture of the piglets on day 3 and oral administration of a commercially available suspension formulation of toltrazuril or (2) capture of the piglets on day 3 and separate administration of the commercially available toltrazuril suspension for oral administration as well as an injectable formulation of iron(III) dextran (with the described disadvantages) - are necessary.

[0024] It would therefore be a great advantage if preparations were available that would allow both processes to be combined without the described disadvantages, i.e., without harmful side effects, while maintaining reliable and high efficacy. A suitable preparation could, for example, be a formulation of the active ingredient toltrazuril and ferrous dextrans for oral administration to piglets during the first three days after birth. Preparations that would have to combine both processes but meet a number of conditions would be ideal. Sufficient amount of active ingredient: Each dose unit must contain a sufficient amount of an anticocccidium for pharmacological efficacy, usually 20-70 mg, e.g., 30 mg, 44 mg, or 50 mg toltrazuril, and at least 100 mg, but preferably at least 150 mg, preferably 200-250 mg, of active iron (corresponding, for example, to 400-600 mg of a polynuclear iron(III) complex) for anemia prophylaxis – in accordance with the recommended dosages of 20 mg toltrazuril / kg body weight and 200 mg active iron per piglet. This corresponds to a concentration of 2-7% w / v of the anticocccidium and 10-25% w / v of active iron in the formulation (where % w / v refers to the mass of the component in g per 100 ml volume). Small dose volume for oral administration: For example, a dose volume of about 1ml is optimal for suckling piglets, as complete absorption by the piglets is often not guaranteed with significantly higher volumes.Larger quantities of liquid often run out of the mouth or are vomited up. Suitable consistency: The viscosity should be within a range that allows administration via drench guns or syringes, e.g., between 10 and 2500 mPas. If the consistency is too thin, the preparation could run out of the animal's mouth after application; if it is too thick, mass administration via syringes or drench guns is too strenuous for the user, and the animals, especially piglets, have difficulty swallowing. Quality of the formulation: Physical and chemical stability and pharmacological efficacy must be ensured. For example, it should be ensured that iron ions do not impair the chemical stability of the anticoccidium.Furthermore, it should be ensured that, in the case of a suspension formulation, the active ingredient is distributed as finely as possible; coagulation or even clumping of the dispersed active ingredient particles is detrimental. This could, for example, impair the pharmacological efficacy, as the dissolution rate and thus the release of the active ingredient from the particles in the intestine is reduced due to the smaller surface area. Efficacy when administered over a longer period after birth: Sufficient efficacy against coccidiosis and anemia when administered between day 1 and day 3 postpartum is desirable, especially with a single dose.Sufficient anemia prophylaxis with a single application: The amount of iron administered in the aforementioned small dose volume of the combination preparation should be sufficient to adequately cover the iron requirements of piglets after a single application under normal housing conditions.

[0025] The combination of triazinones and iron preparations in a suitable formulation has not yet been described.

[0026] The invention relates to: a formulation containing triazinones of formulas (I) or (II) or wherein R1< represents R3< -SO2- or R3< -S-, R2< represents alkyl, alkoxy, halogen or SO2N(CH3)2, and R3< represents haloalkyl, R4< and R5< independently represent hydrogen or Cl, and R6< represents fluorine or chlorine, or their physiologically acceptable salts and Polynuclear iron(III) polysaccharide complex compounds for use in the simultaneous treatment of coccidiosis infections and iron deficiency in suckling piglets, wherein the formulation is applied once.

[0027] In formulas (I) and (II), individual substituents have the following preferred and particularly preferred meanings: R2< preferably represents alkyl or alkoxy with 1 to 4 carbon atoms, or fluorine, chlorine, bromine, or SO2N(CH3)2. R2< particularly preferably represents C1-4 alkyl. R3< preferably represents fluoroalkyl with 1 to 4 carbon atoms, and particularly preferably trifluoromethyl.

[0028] Triazinones are well known as active agents against coccidiosis per se; examples include triazintriones such as toltrazuril and ponazuril, as well as triazinindiones such as clazuril, diclazuril and letrazuril.

[0029] The triazindedinions 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, R5 ≠ Cl, R6 ≠ Cl in formula (II)). Of these 1,2,4-triazinde ions, diclazuril is the most favored.

[0030] According to the invention, the triazinetriones of formula (I) are particularly preferred as active ingredients, wherein R 2< and R 3< have the following preferred and particularly preferred meanings: R 2< preferably represents alkyl or alkoxy with up to 4 carbon atoms each, particularly preferably methyl, ethyl, n-propyl, i-propyl. R 3< preferably represents perfluoroalkyl with 1 to 3 carbon atoms, particularly preferably trifluoromethyl or pentafluoroethyl.

[0031] The preferred triazinetriones are represented by formula (I): Toltrazuril (R 1< = R 3< -S-, R 2< = CH 3 , R 3< = CF 3 ) Ponazuril (R 1< = R 3< -SO 2 -, R 2< = CH 3 , R 3< = CF 3 )

[0032] The dosage of triazinone can vary depending on the animal species, as explained above. Typical dosages range from 1 to 60 mg of active ingredient per kg of body weight (mg / kg) of the animal being treated per day, preferably 5 to 40 mg / kg and particularly preferably 10 to 30 mg / kg.

[0033] When taken orally, toltrazuril is usually dosed as follows: Pig: 20 mg / kg body weight

[0034] Polynuclear iron(III) polysaccharide complexes are defined here as complexes of the iron(III) ion with hydroxide ions (OH⁻), aquo groups (H₂O), and oxygen (O), which exist in oligo- or polymeric form and are complexly associated in their coordination sphere with one or more of the aforementioned oligomeric and polymeric carbohydrate compounds. For this reason, the compounds are also referred to as iron(III) hydroxide polysaccharide or iron(III) oxyhydroxy polysaccharide, where polysaccharide denotes the respective oligo- and polymeric carbohydrate compounds or their derivatives. Polynuclear iron(III) complexes of this type are described, for example, in ( DS 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 "New possibilities for iron supply to newborn piglets taking biochemical aspects into account", Pregnancy and birth in pigs: 8th Bernburg Biotechnology Workshop, Bernburg (2002) 89-94 .). Since the exact composition of these compounds is not quantitatively described in many cases and can also vary within the compounds depending on the method of production, the term polynuclear iron(III) polysaccharide compounds shall be understood to encompass all compounds that a person skilled in the art would classify as belonging to this class of compounds.

[0035] Examples of iron compounds include: polynuclear iron(III) polysaccharide complex compounds in which a polynuclear β-FcO(OH) core complex contains polymeric carbohydrate compounds associated at the free coordination sites, e.g., iron(III) dextran, iron(III) hydroxy-polymaltose (iron(III) dextrin), non-stoichiometric compounds of β-FeO(OH) with saccharides and oligosaccharides "iron(III) sucrose" "iron(III) 'sugar'".

[0036] Iron(III) dextran is a particularly favored example.

[0037] Preparations of the formulations according to the invention that are suitable for animals are preferably solutions, suspensions or pastes, or gels. Suspensions or pastes are preferred.

[0038] Solutions are prepared by dissolving the active ingredient(s) in suitable solvent(s) or solvent mixtures. If necessary, further excipients such as solubilizers, antioxidants, preservatives, thickeners, adhesives, pH-regulating substances, light stabilizers, or dyes are added.

[0039] As solventExamples include: physiologically compatible solvents such as water; alcohols, such as monohydric alkanols (e.g., ethanol or n-butanol); polyhydric alcohols, such as glycols (e.g., 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 (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 formal, Solketal (2,2-Dimethyl-4-hydroxymethyl-1,3-dioxolane), N-Methylpyrrolidone, 2-Pyrrolidone, N,N-Dimethylacetamide, Glycofurol, Dimethyl isosorbite, Lauroglycol, Propylene carbonate, Octyldodecanol, Dimethylformamide, and mixtures of the aforementioned solvents.

[0040] As Solution mediatorExamples include solvents that promote the dissolution of the active ingredient in the main solvent or prevent its precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor oil, and polyoxyethylated sorbitan esters.

[0041] Antioxidants These include sulfites or metabisulfites such as potassium or sodium metabisulfite, sodium or potassium disulfite, ascorbic acid, iso-ascorbic acid, ascorbic palmitate, gallic acid esters, butylhydroxytoluene, butylhydroxyanisole or tocopherols.

[0042] Synergists of these antioxidants can be: amino acids (e.g., alanine, arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or their salts, phosphoric acid derivatives or polyalcohols (polyethylene glycol).

[0043] preservatives These include: benzyl alcohol, benzalkonium chloride, trichlorobutanol, p-hydroxybenzoic acid esters, n-butanol, chlorocresol, cresol, phenol, benzoic acid, citric acid, tartaric acid or sorbic acid.

[0044] ThickenerThese include: inorganic thickeners such as bentonite, colloidal silica, aluminium stearate, organic thickeners such as cellulose derivatives e.g. hydroxypropylmethylcellulose 4000, polyvinyl alcohols and their copolymers, xanthan gum, acrylates and methacrylates, carboxymethylcellulose and their salts.

[0045] Adhesive Examples include cellulose derivatives, starch derivatives, polyacrylates, natural polymers such as alginates, and gelatin.

[0046] Adhesives that also have a thickening property can also be used as thickening agents.

[0047] PH valueRegulatory substances are pharmaceutically common acids or bases. Bases include alkali or alkaline earth hydroxides (e.g., NaOH, KOH), basic salts such as ammonium chloride, basic amino acids such as arginine, choline, meglumine, ethanolamines, and buffers such as tris(hydroxymethyl)aminomethane, citric acid buffer, or phosphate buffer. Acids include, for example, 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.

[0048] sunscreen Examples include substances from the class of benzophenones or novantisolic acid.

[0049] Dyes These are all dyes approved for use on animals or humans, which may be dissolved or suspended.

[0050] Suspensions are produced by suspending the active ingredient(s) in a carrier liquid, optionally with the addition of other excipients such as wetting agents, dyes, absorption enhancers, thickeners, adhesives, preservatives, antioxidants, light protectants or defoamers.

[0051] As Carrier fluids This includes all homogeneous solvents and solvent mixtures.

[0052] As Wetting agent (dispersant) Examples include: surfactants (which include emulsifiers and wetting agents) such as 1. Anionic ethers, such as sodium lauryl sulfate, fatty alcohol ether sulfates, mono / dialkyl polyglycol ether orthophosphoric acid ester monoethanolamine salt, lignosulfonates or dioctyl sulfosuccinate; 2. Cationic ethers, such as cetytrimethylammonium chloride; 3. Ampholytic ethers, such as di-Na-N-lauryl-β-iminodipropionate or lecithin; 4. Nonionic ethers, e.g., polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, alkylphenol polyglycol ethers, Pluronic®.

[0053] Silicone-based defoamers, such as dimethicone or simethicone, are preferred.

[0054] Other auxiliary substances listed above should be mentioned.

[0055] Suspensions and pastes are preferred, with low-viscosity pastes being preferred. The pastes are typically suspensions with a correspondingly higher viscosity. The suspensions and pastes are preferably administered orally.

[0056] The formulations according to the invention contain the triazinone active ingredient in a concentration of 0.1 to 30% (w / v) corresponding to 1 to 300 mg / ml, preferably 2 to 25% (w / v) corresponding to 20 to 250 mg / ml, particularly preferably 3 to 15% (w / v) corresponding to 30 to 150 mg / ml, and in particular 3 to 7% (w / v) corresponding to 30-70 mg of the triazinone in 1 ml.

[0057] Due to the poor solubility of triazinones, they are often present in finely divided form in the formulations according to the invention. The dispersed triazinone has a particle size (measured by laser diffraction, Malvern Mastersizer® < 2000) of d(v,90) ≤ 30 µm, preferably d(v,90) ≤ 20 µm, particularly preferably d(v,90) ≤ 10 µm, and most preferably d(v,90) less than or equal to 7 µm.

[0058] For the purposes of this invention, d(v,90) is understood to be a volume-based particle size distribution in which 90% of all particles have a dimension (diameter) less than or equal to this value. This is usually denoted as d(90); however, to clarify that it is a volume-based particle size distribution, the more precise designation d(v,90) can be used. Similarly, the designations d(v,50), d(v,10), etc., are to be understood in this way. The particle sizes given here were determined using laser diffraction with the Malvern Mastersizer 2000 instrument (Hydro 2000G dispersion unit) and the Fraunhofer diffraction evaluation mode, since the refractive indices of the active ingredient particles are unknown. A suitable amount of the sample solution is pre-dispersed with 2-3 ml of a dispersion medium (0.1% aqueous dioctyl sodium sulfosuccinate solution) while stirring.The dispersion is then introduced into the device's dispersion unit while stirring (300 rpm) and pumping (900 rpm) and measured. The evaluation software outputs the particle size as d(0.5), d(0.9) values, etc.

[0059] These iron compounds are typically administered in oral formulations for the treatment of iron deficiency in large animal farms at concentrations of 100 mg to 200 mg of active iron per dose, either as a single or repeated administration. In drinking solutions for iron supplementation in poultry farms, the dose may be less than 100 mg of active iron per dose.

[0060] In the formulations according to the invention, the iron compounds are typically present in concentrations of 10% (w / v) to 30% (w / v) of active iron, corresponding to 100 to 300 mg of active iron in 1 ml, preferably 11.4% (w / v) to 25% (w / v), corresponding to 114 mg to 250 mg of active iron in 1 ml, and particularly preferably 20% (w / v) to 25% (w / v), corresponding to 200 mg to 250 mg of active iron in 1 ml of the formulation. Active iron refers to the percentage of iron contained in the formulation in the form of the iron complex. The iron compounds are generally present in the formulations in dissolved or colloidal form. Finely divided iron compounds are less preferred in the formulations according to the invention.

[0061] Preferably, the formulations according to the invention are "water-based." This means they generally contain 10 to 90 wt.%, preferably 20 to 80 wt.%, and particularly preferably 30 to 50 wt.% water. For example, the formulations as described above may contain further water-miscible solvents. Such solvents may preferably include 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 typically present in concentrations of 1 to 45 wt.%, preferably 1 to 20 wt.%, and particularly preferably 5 to 10 wt.%. The addition of such polyhydric aliphatic alcohols also has the advantage of lowering the freezing point of the formulation.

[0062] The amount of formulation to be administered per application depends on the respective amounts of triazinone and iron to be given. The aim is to use relatively small volumes that are easily administered orally, and these volumes vary depending on the animal species; for example, for suckling piglets, application volumes of 0.3 to 2 ml, preferably 0.5 to 1 ml, are targeted.

[0063] It is advantageous if the formulations according to the invention allow for easy application, e.g., with the usual aids, such as a syringe, an applicator, or a drench gun, and have a liquid, slightly thickened, or slightly pasty consistency, which manifests itself in the fact that the viscosity – measured by averaging the viscosity values ​​measured at shear rates of 128 s⁻¹ and 256 s⁻¹ with a cone / plate arrangement of a rheometer (Thermo Scientific RheoStress 600; cone diameter 35°; cone angle 4°; constant rate mode) at 20°C – lies in a range of 10 to 2500 mPas, preferably in a range of 20 to 1500 mPas, particularly preferably in a range between 50 and 500 mPas, and most preferably between 20 and 250 mPas.To achieve a suitable viscosity range, the formulations according to the invention may contain suitable substances (thickeners), as already mentioned above.

[0064] Typically, the formulations according to the invention have a pH value of 3 to 8, preferably 4 to 7, and particularly preferably 4 to 6. Examples of suitable substances for regulating the pH value have already been given above. Organic acids such as citric acid or tartaric acid, mineral acids such as hydrochloric acid – preferably dilute hydrochloric acid, e.g., 0.1 N HCl – or bases such as sodium hydroxide (e.g., 1 N NaOH) are preferably used to adjust the pH value.

[0065] Furthermore, the formulations according to the invention can contain preservatives as described above, optionally in combination with so-called synergists. The preservatives are typically present in concentrations of 0.01–5 wt.% and specifically in concentrations of 0.05–1 wt.%.

[0066] If necessary, BHA or BHT can be used as antioxidants in the aforementioned formulations. Preservatives can be used individually or in combination with synergists to ensure adequate preservation. Synergists such as citric acid, tartaric acid, ascorbic acid, or the sodium salt of edicic acid are typically present in concentrations of 0.01–1% by weight, specifically 0.05–0.15% by weight.

[0067] The formulations according to the invention may optionally contain conventional defoamers in concentrations of 0.01 to 1 wt.%.

[0068] The formulations according to the invention are preferably prepared by first supplying the solvent, preferably water, and optionally pre-dissolving or dispersing excipients and / or additives such as co-solvents, preservatives, antioxidants, and viscosity-regulating additives therein. In the preferred process, in a second step, the triazinone, optionally in the form of a pre-prepared dispersion concentrate, is introduced into this pre-solution using a high-performance homogenizer and homogenized until a finely divided suspension is obtained. Then, the iron compound, preferably in powder form, is introduced into this dispersion, and homogenization is carried out again. Finally, in the last step, the desired pH value is adjusted by adding suitable pH-regulating substances.Individual or all auxiliary and / or additive substances can also be added after the final homogenization step, if necessary; this may be advisable, for example, for certain thickeners whose structure is destroyed by homogenization.

[0069] The formulations according to the invention are suitable for the combined treatment of coccidiosis and iron deficiency, particularly in animals. With these formulations, the triazinones, which are effective against coccidiosis, and iron can be administered to the animals simultaneously in a simple manner. The formulations can be used in animal husbandry and breeding for farm animals, breeding animals, zoo animals, laboratory animals, experimental animals, and pets. The spectrum of activity of the triazinones is generally well known. The following coccidia are mentioned here in detail: Mastigophora (Flagellata) such as Trypanosomatidae e.g. 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 Trichomonadidae e.g. Giardia lamblia, G. canis.

[0070] Sarcomastigophora (Rhizopoda) such as Entamoebidae e.g. Entamoeba histolytica, Hartmanellidae e.g. Acanthamoeba sp., Hartmanella sp.

[0071] Apicomplexa (Sporozoa) wie Eimeridae zB Eimeria acervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E. arloingi, E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae, E. clupea, E. columbatore, E. columbata. 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. maxima, E. media, E. media. 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. tene, E. tene. 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 Toxoplasmadidae zB Toxoplasma gondii, such as Sarcocystidae zBSarcocystis bovicanis, S. bovihominis, S. neurona, S. ovicanis, S. ovifelis, S. spec., S. suihominis wie Leucozoidae z.B. Leucozytozoon simondi, wie Plasmodiidae z.B. Plasmodium berghei, P. falciparum, P. malariae, P. ovale, P. vivax, P. spec., wie Piroplasmea z.B. Babesia argentina, B. bovis, B. canis, B. spec., Theileria parva, Theileria spec., wie Adeleina z.B. Hepatozoon canis, H. spec.

[0072] Ferner Myxospora und Microspora z.B. Glugea spec. Nosema spec.

[0073] Ferner Pneumocystis carinii, sowie Ciliophora (Ciliata) wie z.B. Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis spec.

[0074] Of particular note are those protozoan genera and species that cause subclinical or clinical infections in pigs, 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.

[0075] The formulations according to the invention are preferably used in young animals, particularly shortly after birth, namely in suckling piglets. The formulations according to the invention are administered only once. Particularly preferred formulations according to the invention allow for oral treatment of piglets such that an adequate supply of iron to the piglets during the first four weeks of life can be achieved with a single oral dose of 0.7 ml to 1.3 ml, preferably 0.7 ml to 1.0 ml of the formulation, even on the third day after birth, whereby a hemoglobin level of at least 8 g / 100 ml of blood, preferably more than 9 g / 100 ml of blood, can be considered an indicator of adequate supply. Additionally, the triazinone component is intended to provide effective control of coccidia.

[0076] The formulations according to the invention may contain further active ingredients or components - alone or in suitable combinations - such as building blocks, which include, for example, vitamins, minerals and phosphorus compounds suitable as metabolic and immunostimulants: vitamins, such as vitamin E, B vitamins such as vitamin B12, vitamin C.

[0077] Minerals, preferably calcium or magnesium salts, in particular for example calcium gluconate, calcium glucoheptanoate or calcium saccharate.

[0078] Phosphorus compounds, especially pharmacologically compatible organic phosphonic acid derivatives, which are suitable as metabolic stimulants and tonics. Preferred examples include the long-known compounds toldimfos and, in particular, butaphosphine.

[0079] The following examples are intended to illustrate the invention. Examples of production: Example 1 Use of iron(III) dextran powder 38.4% w / w

[0080] Approach for the preparation of 10L of an iron-dextran / toltrazuril dispersion (22.8% w / v active iron + 5% w / v toltrazuril) for oral administration to suckling piglets active 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 10 liters 5138,00 Viscosity-regulating additive(s) - Total mass 13863,27

[0081] 17.00 g each of the preservatives sodium propionate and sodium benzoate are weighed into 1000.00 g of the solvent propylene glycol in a separate container and dissolved with stirring. The entire water portion is placed in a stainless steel vessel (Koruma Disho; machine type: DH V 100 / 45). Depending on the requirements and desired viscosity of the final product, a viscosity-regulating additive (a so-called thickener) can be dissolved or incorporated into this water. In this example, this is omitted. The propylene glycol premix is ​​added to the water in the stainless steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed quantity of 1666.67g of the toltrazuril dispersion concentrate 30% is added to the mixture, stirred for 30-40 minutes and simultaneously homogenized with a circulating homogenizer (rotor / stator system) at 2500 rpm for 20 minutes.The stirring and homogenization times mentioned can be lengthened or shortened depending on the appearance of the suspension. It is advantageous to maintain the temperature of the mixture at 20–30°C using suitable cooling systems. In the next step, 6015.83 g of the iron(III) dextran powder are added to the dispersion in several portions. During the addition, continuous stirring and homogenization using a circulating homogenizer at 2500 rpm are necessary. The temperature is maintained at 20–30°C by activating the cooling system. After the iron(III) dextran powder has been completely added, the citric acid (85.90 g) is added to the mixture and dissolved. The pH adjusts to 4.1–4.4. After all components have been incorporated, the mixture is stirred again for 20 minutes and simultaneously homogenized at 2500 rpm. During this post-stirring phase, the temperature of the dispersion is maintained at room temperature by cooling.The finished dispersion is transferred from the stainless steel container to suitable storage containers via a 0.1 mm mesh sieve. After some storage time, the pH value rises to between 4.8 and 5.2.

[0082] To determine the quality of the dispersion, the pH, particle size distribution (measured by laser diffraction using the Malvern Mastersizer 2000), and viscosity are used. Viscosity is measured with a cone / plate measuring setup at shear rates of 128 and 256 s⁻¹ (RheoStress 600; Thermo Haake). The mean of the measured viscosity values ​​is used as a reference value. These viscosity data have proven suitable for characterizing the flow resistance of such a suspension when dispensed through a drench gun. Ideally, a finely dispersed dispersion should be the goal to maximize the bioavailability of the active ingredients. The suspension prepared as described yields the following values: iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) dextran powder 38.4% m / m 133 4,4 5,1 2,3 4,1 100 % 100 % Example 2 Use of iron(III) dextran powder 36.8% w / w

[0083] Approach for the preparation of 1000 ml of an iron-dextran / toltrazuril dispersion (23.6% w / v active iron + 5.3% w / v toltrazuril) for oral administration to suckling piglets active ingredient 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 additive(s) - Total mass 1399,74

[0084] 1.89 g each of the preservatives sodium propionate and sodium benzoate are weighed into 106.38 g of propylene glycol in a separate container and dissolved with stirring. All of the water is placed in a 1 L beaker. Depending on the requirements and desired viscosity of the final product, a viscosity-regulating additive (a so-called thickener) can be dissolved or incorporated into this water. This is omitted in this example. The propylene glycol premix is ​​added to the water in the beaker and homogenized with stirring (10 min). In the next step, the previously weighed 177.34 g of the 30% toltrazuril dispersion concentrate is added to the mixture and stirred for 30–40 min using a dissolver disc. The stirring times mentioned can be lengthened or shortened depending on the appearance of the suspension.In the next step, 639.98 g of the iron(III) dextran powder are added to the dispersion in several portions while stirring. After complete addition, the suspension is stirred for a further 20 minutes using the dissolver disc. Once all the iron(III) dextran powder has been added, the citric acid (7.59 g) is added to the mixture and dissolved. The pH adjusts to 4.1–4.4. After some storage time, the pH value rises to between 4.8 and 5.2. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) dextran powder 36.8% m / m 277 4,4 4,9 3,2 6,4 99 % 100 % Example 3 Use of 27.5% w / v iron(III) dextran solution

[0085] Approach for the preparation of 10L of an iron-dextran / toltrazuril dispersion (21.0% w / v active iron + 5% w / v toltrazuril) for oral administration to suckling piglets active 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% w / v 11229,00 Viscosity-regulating additive(s) - Total mass 14080,02

[0086] 17.00 g each of the preservatives sodium propionate and sodium benzoate are weighed into 1000.00 g of the solvent propylene glycol in a separate container and dissolved with stirring. The entire quantity of 11229.00 g of the iron(III) dextran solution is placed in a stainless steel vessel (Koruma Disho; machine type: DH V 100 / 45). Depending on the requirements and desired viscosity of the final product, a viscosity-regulating additive (a so-called thickener) can be dissolved or incorporated into this batch. In this example 2, this is omitted. The propylene glycol premix is ​​added to the batch in the stainless steel vessel and homogenized with stirring (20-40 min). The stirring times mentioned can also be shortened or lengthened depending on the appearance of the suspension.In the next step, the previously weighed quantity of 1666.67 g of the 30% toltrazuril dispersion concentrate is added to the mixture, stirred for 30–40 minutes, 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 using suitable cooling systems. Next, the citric acid (150.35 g) is added and dissolved. During this addition, the homogenizer is switched on at a speed of 1800 rpm, and the temperature is maintained at room temperature by activating the cooling system. The pH adjusts to 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. The cooling system remains activated throughout this process. The finished dispersion is transferred from the stainless steel vessel to suitable storage containers via a 0.1 mm mesh sieve.The pH value equilibrates to 4.8-5.2 within a few days to weeks. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) dextran solution 27.5% w / v 96 4,4 4,8 2,5 4,7 100 % 100 % Example 4 Use of iron(III) sugar powder 35.9% w / w

[0087] The compound used was called iron(III) sugar (Dr. Paul Lohmann GmbH KG), which is an iron(III) (hydroxide) saccharate complex.

[0088] Approach for the preparation of 10L of an iron-sugar / toltrazuril dispersion (22.8% w / v active iron + 5% w / v toltrazuril) for oral administration to suckling piglets: active 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 400,00 Iron(III) sugar powder 35.9% w / w 6350,98 Water to 10 liters 4543,73 Viscosity-regulating additive(s) - Total mass 13995,38

[0089] 17.00 g each of the preservatives sodium propionate and sodium benzoate are weighed into 1000.00 g of the solvent propylene glycol in a separate container and dissolved with stirring. The entire water portion is placed in a stainless steel vessel (Koruma Disho; machine type: DH V 100 / 45). Depending on the requirements and desired viscosity of the final product, a viscosity-regulating additive (a so-called thickener) can be dissolved or incorporated into this water. This is omitted in this example 3. The propylene glycol premix is ​​added to the water in the stainless steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed quantity of 1666.67g of the toltrazuril dispersion concentrate 30% is added to the mixture, stirred for 30-40 minutes and simultaneously homogenized with a circulating homogenizer (rotor / stator system) at 2500 rpm for 20 minutes.It is advantageous to maintain the temperature of the mixture at 20–30°C using suitable cooling systems. In the next step, 6350.98 g of the iron(III) sugar powder are added portionwise to the dispersion. During the addition, continuous stirring and homogenization at 2500 rpm using a circulating homogenizer are necessary. The aforementioned stirring and homogenization times of the suspension can be extended or shortened depending on the desired appearance of the formulation. The temperature is maintained at 20–30°C by activating the cooling system. After the iron(III) sugar powder has been completely added, the citric acid (400.00 g) is added to the mixture and dissolved by stirring. After incorporating all components, the mixture is stirred again for 20 minutes and homogenized again at 2500 rpm. During this final stirring phase, the temperature of the dispersion is maintained at room temperature by cooling. A pH of 5 is reached shortly thereafter.The finished dispersion is transferred from the stainless steel container to suitable storage containers via a 0.1 mm mesh sieve. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) sugar powder 35.9% w / w 1312 5,0 - 2,1 4,3 100 % 100 % Example 5 Use of iron(III) polymaltose powder 32.0% w / w

[0090] Approach for the preparation of 10L of an iron-sugar / toltrazuril dispersion (22.8% w / v active iron + 5% w / v toltrazuril) for oral administration to suckling piglets active 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 10 liters 3927,21 Viscosity-regulating additive(s) - Total mass 14357,57

[0091] 17.00 g each of the preservatives sodium propionate and sodium benzoate are weighed into 1000.00 g of the solvent propylene glycol in a separate container and dissolved with stirring. The entire water portion is placed in a stainless steel vessel (Koruma Disho; machine type: DH V 100 / 45). Depending on the requirements and desired viscosity of the final product, a viscosity-regulating additive (a so-called thickener) can be dissolved or incorporated into this water. This is omitted in this example 4. The propylene glycol premix is ​​added to the water in the stainless steel vessel and homogenized with stirring (20-40 min). In the next step, the previously weighed quantity of 1666.67g of the toltrazuril dispersion concentrate 30% is added to the mixture, stirred for 30-40 minutes and simultaneously homogenized with a circulating homogenizer (rotor / stator system) at 2500 rpm for 20 minutes.It is advantageous to maintain the temperature of the mixture at 20-30°C using suitable cooling systems. In the next step, 7125.00 g of the iron(III) polymaltose powder are added portion by portion to the dispersion. During the addition, continuous stirring and homogenization using a circulating homogenizer at 2500 rpm are necessary. The temperature is maintained at 20-30°C by activating the cooling system. After the iron(III) polymaltose powder has been completely added, the citric acid (604.69 g) is added to the mixture and dissolved by stirring. After all components have been incorporated, the mixture is stirred again for 20 minutes and simultaneously homogenized at 2500 rpm. The stirring and homogenization times mentioned can be extended or shortened depending on the appearance of the formulation. During the final stirring phase, the temperature of the dispersion is maintained at room temperature by cooling. The finished dispersion is transferred from the stainless steel vessel to suitable storage containers via a 0.1 mm mesh sieve.The pH value rises to values ​​of 4.8-5.2 after a few days to weeks of storage. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) polymaltose powder 32.0% m / m 1226 4,4 5,0 1,9 3,3 100 % 100 % Example 6

[0092] Use of iron(III) dextran powder 37.9% w / w with the use of a viscosity-regulating additive

[0093] Approach for the preparation of 10L of an iron-sugar / toltrazuril dispersion (22.8% w / v active iron + 5% w / v toltrazuril) for oral administration to suckling piglets active 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) for viscosity regulation 20,00 Xanthan gum for viscosity regulation 30,00 Water to 10 liters 3290,00 Total mass 12126,50

[0094] 17.00 g each of the preservatives sodium propionate and sodium benzoate are weighed into 1000.00 g of the solvent propylene glycol in a separate stainless steel container and dissolved by stirring. Once the preservatives are dissolved, 30.0 g of xanthan gum are added and stirred again for approximately 10 minutes. The mixture is then homogenized for approximately 5 minutes using a rotary homogenizer (rotor / stator system; Ultra-Turrax laboratory system) at 13,500 rpm, ensuring the dispersion is free of lumps.

[0095] The entire water content of 3290.0 g is placed in a stainless steel vessel (Koruma Disho; machine type: DH V 100 / 45). Next, 20 g of bentonite are sprinkled in. This mixture is then heated to 78°C while being gently stirred (50 rpm of the circulating agitator). The temperature should be maintained at 78°C for approximately 5-10 minutes, then cooled to 35°C while stirring and activating the cooling system. Stirring continues for 20-40 minutes, and while cooling is ongoing, the mixture is homogenized for 20 minutes using the circulating homogenizer at 2500 rpm. Finally, the dispersion of xanthan gum in propylene glycol is added to the bentonite / water mixture while stirring continuously. The mixture is then further homogenized by stirring for another 20-40 minutes at 50 rpm and simultaneously for 10 minutes with the circulating homogenizer at 2500 rpm.Here too, the mentioned stirring and homogenization times can be lengthened or shortened depending on the requirements and appearance of the dispersion.

[0096] In the next step, the previously weighed quantity of 1666.67 g of the 30% toltrazuril dispersion concentrate is added to the mixture and stirred for 30–40 minutes while simultaneously homogenizing it with a circulating homogenizer at 2500 rpm for 20 minutes. It is advantageous to maintain the temperature of the mixture at 20–30°C during the addition by means of efficient cooling. In the next step, 6015.83 g of the ferrous dextran powder are added to the dispersion in several portions. Continuous stirring and homogenization with the circulating homogenizer at 2500 rpm must be carried out during the addition. The temperature is maintained at 20–30°C by activating the cooling system. After complete addition of the ferrous dextran powder, the citric acid (70.0 g) is added to the mixture while stirring and homogenizing until dissolved. The pH adjusts to 4.1–4.4. After all components have been incorporated, the mixture is stirred for another 20 minutes and homogenized again at 2500 rpm.During this stirring phase, the temperature of the dispersion is maintained at room temperature by cooling. The finished dispersion is transferred from the stainless steel vessel into suitable storage containers via a 0.1 mm mesh sieve. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) dextran powder 37.9% m / m 1365 4,5 - 1,7 3,5 100 % 100 % Example 7

[0097] Use of iron(III) dextran powder 38.6% w / w with the use of a viscosity-regulating additive

[0098] Approach for the preparation of 1L of an iron-dextran / toltrazuril dispersion (20% w / v active iron + 3% w / v toltrazuril) for oral administration to suckling piglets active ingredient Mass / g 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) for viscosity regulation 1,33 Xanthan gum for viscosity regulation 2,00 Water to 1 liter 606,42 Total mass 1340,15

[0099] 1.80 g each of the preservatives sodium propionate and sodium benzoate are weighed into 100.00 g of the solvent propylene glycol in a separate beaker and dissolved by stirring. Once the preservatives are dissolved, 2.00 g of xanthan gum are added and stirred again for about 10 minutes until the dispersion is free of lumps.

[0100] Approximately 100 g of the water is placed in a beaker and heated to 70–80°C. Then, 1.33 g of the bentonite is sprinkled in, and the temperature is maintained for about 5–10 minutes. The resulting bentonite slime is cooled while stirring, and then the remaining 506.42 g of water is added. The bentonite / water mixture is stirred at 270 rpm using a dissolver disc, and the dispersion of xanthan gum in propylene glycol is added while stirring continuously. The mixture is then homogenized for a further 5–10 minutes while stirring. Again, the stirring times mentioned can be lengthened or shortened depending on the requirements and the appearance of the dispersion.

[0101] In the next step, the previously weighed quantity of 100.00 g of the 30% toltrazuril dispersion concentrate is added to the mixture and stirred for 30–40 minutes at a speed of 460 rpm. Then, 518.13 g of the iron(III) dextran powder are added to the dispersion in several portions while stirring continuously. After all the iron(III) dextran powder has been added, the citric acid (8.67 g) is added to the mixture while stirring and dissolved. The pH adjusts to 4.1–4.4. After all components have been incorporated, the suspension is further homogenized for 20 minutes using a rotor-stator homogenizer at 9,500 rpm. The finished dispersion is then transferred to a suitable PE bottle. iron compound Viscosity / mPas pH after production pH after storage Particle size d(v,50) / µm Particle size d(v,90) / µm Percentage of particles < 10µm Percentage of particles < 30µm Iron(III) dextran powder 38.6% m / m 108 4,2 - 1,9 3,6 100 % 100 %

[0102] The measurement results for the dispersions of Examples 1-7 show that formulations according to the invention can be produced with a very fine solids content. Undesirable agglomerate formation is not observed. Furthermore, the suspensions of Examples contain the ingredients necessary for use in suckling piglets: 35-44 mg toltrazuril and 200 mg active iron in 0.9 ml of the dispersion.

[0103] The viscosity of the dispersions of Examples 1-7 can be adjusted over a wide range of 10-2500 mPas. A less viscous range of 20-1500 mPas is advantageous, preferably 50-500 mPas, and most preferably 20-250 mPas, as it causes fewer problems for piglets when swallowing, for example. Biological examples Results of clinical trials with formulations of examples 2 and 3

[0104] For a clinical trial, 30 breeding sows were available, producing a total of 270 piglets. The litters were divided into four groups, with each litter being split and half of each group allocated to a different group. Due to slight variations in litter size and timing, each treatment group consisted of between 60 and 75 piglets. Each piglet received 0.9 ml of the formulation orally on day 3 postpartum. Blood samples were taken from the piglets on the day of administration, as well as after 7, 14, and 21 days. The red blood cell count (million cells / µL), hemocritic value (Ht%), hemoglobin level (Hb g / 100 ml), and the piglets' weight in kg were used as criteria for assessing the efficacy of the formulations. The results were compared with those of a control group who had received a commercially available iron(III) dextran injection preparation (Hierrox 200) administered on day 3 after birth.The results are shown in Table 5.

[0105] Both orally administered formulations, as in Example 2 (prepared from iron(III) dextran powder) and Example 3 (prepared from iron(III) dextran solution), resulted in hemoglobin levels > 9 g / 100 ml on days 7, 14, and 21 postpartum, thus proving effective in preventing any anemic deficiencies. The values ​​of > 10 g / 100 ml on days 14 and 21 postpartum further demonstrate the excellent bioavailability of the formulations. Furthermore, the criteria of red blood cell count, hemoglobin concentration, and weight gain showed no disadvantages compared to the injectable preparation.

[0106] It can thus be shown that the single oral administration of 200mg of active iron from iron(III) dextran in combination with toltrazuril in the formulations according to the invention surprisingly - contrary to the prevailing opinion and the prior art - enables good prevention against anemic deficiency symptoms in suckling piglets, even when administered on day 3 after birth.

[0107] An analysis of the piglets' feces for oocysts yielded consistently negative results. This proves that the aforementioned formulations are equally effective against coccidiosis pathogens.

[0108] Furthermore, no adverse effects such as diarrhea, which is frequently observed with the oral administration of high doses of iron compounds, could be detected. The formulations produced according to the invention thus proved to be very well tolerated. Tabel: Results of the clinical trials Formulation according to example day Number of piglets N RBC [10 6< / µL] SD HT [%] SD HB [g / 100ml] SD day Number of piglets N Weight [kg] SD 2 (oral) 3 70 2,192 0,051 3 (oral) 3 74 2,116 0,050 Injection in 3 64 2,006 0,053 2 (oral) 7 67 4,29 0,24 33,71 0,72 10,05 0,18 7 70 3,154 0,084 3 (oral) 7 71 4,53 0,23 31,91 0,70 9,41 0,17 7 74 3,045 0,082 Injection in 7 62 4,18 0,25 33,22 0,75 9,75 0,19 7 64 2,955 0,084 2 (oral) 14 67 5,41 0,40 39,74 0,82 11,37 0,32 14 3 (oral) 14 72 6,09 0,39 41,85 0,78 12,16 0,31 14 Injection in 14 61 5,61 0,42 43,53 0,85 12,84 0,33 14 2 (oral) 21 64 5,48 0,11 35,66 3,33 10,78 0,36 21 68 7,061 0,146 3 (oral) 21 72 5,69 0,10 38,71 3,10 11,61 0,34 21 73 7,173 0,141 Injection in 21 60 5,96 0,11 40,32 3,44 12,51 0,37 21 63 6,974 0,152

[0109] The number of red blood cells (RBC Million Cells / µL), the hemocrit value (Ht %), the hemoglobin value (Hb g / 100ml ) and the weight of the piglets in kg were used as criteria for the efficiency of the formulations.

Claims

1. Formulation containing triazinones of the formula (I) or (II), or wherein R1 stands for R3-SO2- or R3-S-, R2 stands for alkyl, alkoxy, halogen or SO2N(CH3)2 and R3 stands for haloalkyl R4 and R5 stand independently for hydrogen or Cl and R6 stands for fluorine or chlorine or their physiologically tolerable salts and a polynuclear iron (III) polysaccharide complex compound for use in concurrent treatment of coccidial infections and iron deficiency conditions in suckling pigs, wherein the formulation is administered once.

2. Formulation for use according to claim 1, characterised in that the formulation contains 1 to 30% (m / V) triazinones of the formula (I) or (II).

3. Formulation for use according to claim 2 containing 2 to 7% (m / V) triazinones of the formula (I) or (II).

4. Formulation for use according to any of the preceding claims, characterised in that the concentration of polynuclear iron (III) polysaccharide complex compound is from 10% (m / V) to 30% (m / V) of active iron.