A formulation for the simultaneous treatment of coccidiotic infections and iron deficiency.

Abstract

This invention provides a formulation for the simultaneous treatment of coccidiotic infections and iron deficiency. [Solution] A formulation is provided which contains a triazinon such as toltrazuril and a polynuclear iron(III) polysaccharide complex compound together with a specially selected surfactant having a hydrophilic-lipophilic balance (HLB) value of 10 or more.

Description

Technical Field

[0001] The present invention relates to a preparation for the simultaneous treatment of coccidiosis and iron deficiency, comprising a triazinone such as torul ziril and a polynuclear iron(III) polysaccharide complex compound together with a specially selected surfactant.

[0002] Economically successful meat production operations are currently characterized by highly intensive rearing, i.e., rearing a large number of animals specially selected to optimize breeding purposes . These farms are characterized, for example, by the use of large amounts of machinery, additional feeding of nutritional supplements, and involvement of as few staff as possible. In the case of a piglet rearing farm, this means rearing a large number of female pigs that are bred to increase the litter size of piglets in a pigsty of appropriate size . By optimizing the feed and making appropriate selections during the rearing process, rapid growth of piglets is enabled. This type of animal rearing often causes an increase in certain typical diseases and deficiencies. Especially

[0003] in addition to the stress to which intensively reared pigs are very susceptible, such phenomena are especially protozoal infections (coccidiosis) and anemia in young pigs, and both of these must be pre-controlled by the prophylactic use of drugs.

[0004] Coccidiosis is a parasitic infection that frequently occurs in animals. For example, the genus Eimeria (Eimeria), the genus Isospora, the genus Neosp ora, the genus Sarcosporidia, and Toxoplas Protozoa of the genus Toxoplasma cause coccidiosis worldwide. An economically significant example of coccidiosis is the disease of pigs caused by coccidia of the genus Isospora. An infectious disease, or a bovine infection caused by coccidia of the genus Eimeria. (Isospora) In recent years, infection with Isospora suis has been recognized as a cause of diarrhea in piglets. This is being studied intensively. In principle, the infection is transmitted from the environment to the piglets, or from the piglets. The process progresses from the piglets through oocysts, and each oocyst is different in each case. It contains two sporocysts, each having two sporozoites. The parasitic stage is the small intestinal villi. It proliferates in epithelial cells. The clinical presentation of this disease includes necrosis of intestinal epithelial cells accompanied by atrophy of the villi and inflammation. It involves chemical damage, resulting in impaired absorption and digestion. A characteristic of acute illness is a liquid, whitish substance. The diarrhea is a light yellow to yellowish color and mainly occurs in piglets 2-3 weeks after birth. Weight gain decreases. To date, treatment and therapy for this disease have been inadequate.

[0005] Antibiotics are ineffective, and sulfonamides are approved for the treatment of coccidiosis, Its effectiveness is questionable, and in any case, frequent repeated administration is unsuitable for practical use. Other possibilities The treatment is questionable, for example, the administration of monensin, amprolium, and furazolidone. We have not been successful in preventing the disease in experimentally infected piglets. More recent research suggests that Isosu Despite good hygiene conditions, Isospora suis It has been observed in up to 92% of all littermates on the farm. This type of disease affects not only pigs. , and many other animal species, such as poultry, calves, lambs, or small animals (rabbits) This also occurs.

[0006] An example of deficiency is iron deficiency in newborn piglets. Due to rapid growth in the first few days of life, the body... Stored iron is rapidly depleted and must be replenished by external sources. Because of the large number of tadpoles, consuming sow milk is not sufficient to adequately substitute for this. This is not possible. Furthermore, if the animals are kept in concrete or plastic, Piglets cannot dig in the ground to absorb iron compounds. They become anemic.

[0007] When the hemoglobin content in the blood falls below 80 g / L, it indicates a clinically significant state of anemia. Appears. NRC recommendation (National Research Council, Nutr ient Requirements of Domestic Animals,No .6,Nutrient Requirements of Swine,Nation al Academy of Sciences,Washington DC,197 9) 90 g / m² is the minimum hemoglobin level at which piglets grow healthily and show no signs of anemia. L is specified. However, significant symptoms such as weight loss and stunted growth are present in the hemoglobin in the blood. This is only observed when the globin content drops to a value of less than 80 g / L. (Regarding iron supply) Other indicators include hematocrit and red blood cell count per unit volume. Severe iron deficiency Sexual anemia also leads to the death of young piglets.

[0008] Medications to control the aforementioned diseases and deficiencies are already available.

[0009] Coccidiosis can be effectively controlled by administering the active ingredients of the triazinon group. This is possible. For this purpose, triazinedione (a representative example is the active ingredient class clazuril, diclazuril, retazuril) is distinguished from triazinetrione containing the active ingredients toltrazuril, toltrazuril sulfoxide and ponazuril. Triazines, especially toltrazuril, ponazuril or diclazuril, and their activity against coccidia are known from a series of publications, and in particular, see German Patent Application Publication No. 2718799 (DE-A 27 18 799) and German Patent Application Publication No. 2413722 (DE-A 24 137 22). International Publication No. 99 / 62519 (WO99 / 62519) discloses a semi-solid aqueous preparation of toltrazuril sulfone (ponazuril). In particular, toltrazuril is also known to be suitable for the treatment of coccidiosis in pigs (e.g., Isospora suis).

[0010] International Publication No. 99 / 62519 (WO99 / 62519) discloses a semi-solid aqueous preparation of toltrazuril sulfone (ponazuril). In particular, toltrazuril is also known to be suitable for the treatment of coccidiosis in pigs (e.g., Isospora suis). It is also known to be suitable for the treatment of coccidiosis in pigs (e.g., Isospora suis). It is also known to be suitable for the treatment of coccidiosis in pigs (e.g., Isospora suis).

[0011] The most important products in the market for the treatment of coccidiosis are diclazuril for use in mixtures in feed (2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro -3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile ; CAS No. [101831-37-2]) 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 number 690 04-03-1).

[0012] Toltrazuril is used, for example, as a drinking water preparation for poultry, and especially for suckling pigs. Several commercially available oral suspension formulations for therapeutic use are available. For piglets, raw... It is recommended to administer 20 mg / kg body weight 3 to 5 days later.

[0013] The general concept of combining active substances with iron compounds for the treatment of coccidiosis. This is also known.

[0014] As a best example, see European Patent Application Publication No. 2164496 (EP 2 164 4 96 A1) is intended for use in the simultaneous treatment of coccidious infections and iron deficiency. Disclosure of formulations containing triazinones such as trazuril and polynuclear iron(III) complex compounds. And regarding the clinical goal of weight gain in piglet treatment with such combinations of formulations... The two compounds exhibit a synergistic effect.

[0015] European Patent Application Publication No. 2164496 (EP 2 164 496 A1) is, We discovered a formulation that can be constructed primarily from triazinon and the aforementioned polynuclear iron(III) complex compound. This also shows that it is not easy.

[0016] See European Patent Application Publication No. 2164496 (EP 2 164 496 A1) The positive correlation is described in International Publication No. 2014 / 086958 (WO 2014 / 08695 8A1) and International Publication No. 2014 / 086959 (WO 2014 / 086959A It is used for injection purposes as disclosed in 1).

[0017] The above is the specification of European Patent Application Publication No. 2164496 (EP 2 164 496 A1 ), International Publication No. 2014 / 086958 (WO 2014 / 086958A1) and International Publication No. 2014 / 086959 (WO 2014 / 086959A1) is entirely: In particular, the poly-β-FeO(OH) type iron(III) is complex-bonded polymerized into carbohydrates. To be used in combination with other substances. European Patent Application Publication No. 2164496 (EP 2 164 In 496 A1), such polynuclear iron(III) complex compounds are used as triazine compounds. In situations where these compounds are combined, it has been shown that polynuclear iron(III) polysaccharide complex compounds should be prioritized. It was done.

[0018] Its commercial importance is not monopolistic, but mainly iron(III) dextran (CAS No. 9004-66-4), iron(III) hydroxide polymaltose (iron(III) hydroxide dextrose Tran; CAS No. 53858-86-9), Iron(III) Sucrose (Iron(III) ) Sucrose, iron(III) "sugar" (CAS No. 8047-67-4) and sucrose Sodium gluconate / iron(III) complex in solution (CAS No. 34089-81 -1) is obtained by

[0019] The literature reveals different names for these compounds. In this context, Grep Toferon, iron(III) dextran, iron(III) polymaltose, iron(III) Chistrin, iron(III) sucrose, iron(III) gluconate, iron(III) sugar, etc. The compound consists of iron(3+) ions, hydroxide ions (OH-), water (H2O), and oxygen. It means a complex with (O), and these complexes exist in the form of oligomers or polymers, In the coordination sphere, one or more of the above-mentioned oligomers and polymer carbohydrate compounds are combined. It is understood that they are related by body shape.

[0020] This is because these compounds are iron(III) hydroxide polysaccharides or oxy-hydroxyiron(II) hydroxide polysaccharides. I) This is why they are also called polysaccharides, where polysaccharides refer to the oligomers and polymers mentioned above. Compound compounds or their derivatives, or generally oligomers or polymer carbohydrates Represents compounds from a group.

[0021] This type of polynuclear iron(III) complex is, for example, (DSKudasheva et al.) al.,“Structure of Carbohydrate-bound Po lynuclear Oxyhydroxide Nanoparticles in Parenteral Formulation”, J. Inorg.Bioche m.98(2004)1757-1769, similarly I.Erni et al., “Ch chemical characterization of Iron(III) Hyd roxide-Dextrin Complexes”Arzneim.-Forsch . / Drug Res. 34(II)(1984)1555-1559;F. Fun k et al., “Physical and Chemical Charact erization of Therapeutic Iron Containing Materials”,Hyperfine Interactions 136 ( 2001) 73-95;E. London “The Molecular For mula and Proposed Structure of the Iron- Dextran Complex, IMFERON”, J.Pharm. Sci. 9 3 (2004) 1838–1846 and A. John “Neue Mo:gli” neugeborene r Ferkel unter Beachtung biochemischer A spekte”[Novel possibilities of supplying iron to new born piglets,taking account of biochemical aspects], Tra:chtigkeit u nd Geburt beim Schwein [Pregnancy and bi rth in pigs]:8th Bernburger Biotechnolog This is described in y Workshop, Bernburg (2002) 89-94).

[0022] In many cases, the composition of these compounds is not quantitatively described and varies depending on the type of preparation. Because these can vary even within the compound, these polynuclear iron(III) polysaccharide complex compounds are relevant to those skilled in the art. This is understood to mean all complexes of the above types of known compounds.

[0023] These iron compounds are almost exclusively used in the manufacture of injectable formulations for human medicine and veterinary medicine. It is used. In veterinary medicine, small-dose formulations for oral administration are also used.

[0024] According to European Patent Application Publication No. 2164496 (EP 2 164 496 A1) When the initially disclosed triazine compound is combined with a polynuclear iron(III) complex compound... In addition to these advantages, the effectiveness and usefulness of the formulation used for the simultaneous treatment of coccidiosis and iron deficiency There are other potential parameters that could further influence sex.

[0025] For example, International Publication No. 2014 / 086960 (WO2014 / 086960 A1 ) discloses that foam formation is clearly an undesirable characteristic for any formulation. Therefore, International Publication No. 2014 / 086960 (WO2014 / 086960 A1) To avoid excessive foam formation, triazine, iron complex, and especially low HL are used. It is instructed that an aqueous suspension containing one or more surfactants having a B value should be used. .

[0026] International Publication No. 2014 / 086960 (WO2014 / 086960 A1) is other The surfactant can be used in combination with a low HLB value surfactant that can be added to each formulation. It is stated that this is possible, but International Publication No. 2014 / 086960 (WO2014 / 086960 A1) is International Publication No. 2014 / 086960 (WO2014 / 086 Except for those with a higher HLB value than those that reduce foam formation by 960 A1), The reasons and thresholds for the other surfactants in question have not been disclosed.

[0027] In the disclosure of International Publication No. 2014 / 086960 (WO2014 / 086960 A1) High HLB surfactants are any surfactants with an HLB value greater than 8, while also being foam-forming. Surfactants found to be advantageous in inhibiting surfactants have an HLB of up to 8. It is a sexual stimulant.

[0028] In conclusion, International Publication No. 2014 / 086960 (WO2014 / 086960 A 1) The surfactant is beneficial in inhibiting foam formation and has an HLB of 8 or less. They can be divided into two categories: those that have no such characteristic and those that can exist or not.

[0029] As described in International Publication No. 2014 / 086960 (WO2014 / 086960 A1) It has a high HLB and therefore does not contribute to the effect of inhibiting foam formation. The agents are polyethylene castor oil derivatives, polyoxyethylene alkyl ethers, and polyoxy Ethylene sorbitan fatty acid ester, polyoxyethylene stearate, sodium lauryl sulfate Thorium, docusate sodium, cetrimide, phospholipids, or cetylpyridin chloride Yes, that's correct.

[0030] However, such a list of surfactants with claimed high HLB values ​​is actually To derive an actual surfactant that would have such a high HLB value on its own It is not specific enough. For example, the polyoxyethylene mentioned and disclosed above. All of the contained compounds have a sufficiently long polyoxyethylene moiety, When it is made hydrophilic, and therefore yields a higher HLB value, it has a high HLB value. It merely conforms to that restriction.

[0031] Furthermore, the disclosed phospholipids typically do not even have a calculable HLB value, and so on. If so, it is usually well below 10. This is because lecithin (which is a phospholipid) is... In document number 014 / 086960 (WO2014 / 086960 A1), low HLB and This is also why they are mentioned as both high HLB-value surfactants.

[0032] From these structures of potential high-HLB surfactants, only two specific elements are used in later examples. See International Publication No. 2014 / 086960 (WO2014 / 086960 A1) The formulation is specifically disclosed.

[0033] These are copolymer polyoxyl 35-castor oil and sodium docusate. It is a polyethylene castor oil derivative designated as such. International Publication No. 2014 / 086 Sample 960 (WO2014 / 086960 A1) shows the effect on foam formation at different time points. There are 14 specific individual formulations, and 3 others that are not specified regarding their effect on avoiding foam formation. Two explicit formulations are disclosed (page 18, lines 13-22).

[0034] Regarding the 14 illustrated formulations, Examples 4, 5, 7, and 8 are, for example, Cremoph High HLB surfactant sold as or EL (CAS 61791-12-6) The surfactant copolymer polyoxyl 35-castor oil is included as an example, and Examples 9 to 1 4 contains sodium docusate as a surfactant.

[0035] The foam formation has not been tested, International Publication No. 2014 / 086960 (WO20 Regarding the preparations specifically described on page 18 of 14 / 086960 A1), The first two contain copolymer polyoxyl 35-castor oil, and the third formulation contains docusate It is disclosed that it contains sodium.

[0036] U.S. Patent Application Publication No. 2014 / 0127320 (US 2014 / 01273 According to 20 A1), the HLB of docusate sodium is approximately 10, but Cremo According to phor EL's supplier data, HLB is 12-14.

[0037] International Publication No. 2014 / 086960 (WO2014 / ) containing docusate sodium Considering Examples 9 to 14 of 086960 A1), none of them inhibit foam formation. It does not contain surfactants with an HLB value of 8 or less, which are claimed to be the cause of this problem. It is clear that these are comparative examples.

[0038] This is because all formulations from Examples 9 to 14 show excessive foam formation (at least t=0 This is proven by the fact that it takes minutes.

[0039] Considering Examples 4, 5, 7, and 8, these formulations are SPAN 80 (CAS It has approximately 4.6 HLB (Examples 4, 5, and 8), also known as 1338-43-8). Sorbitan monooleate, or approximately 4.3-4.5 (in accordance with the prevention of intentional foaming) Propylene glycol monolaurate (CAS27194) having the HLB value of Example 7) Includes any of the following: -74-7)

[0040] Either sorbitan monooleate or propylene glycol monolaurate, These are added as surfactants having HLB values ​​of approximately 4.6 or 4.3-4.5, respectively. Apart from the intentional effect of suppressing foam formation, copolymer poly with HLB of 12-14 Effects that may or may result from the further addition of oxyl 35-castor oil That is not mentioned.

[0041] International Publication No. 2014 / 086960 (WO2014 / 086960 A1) Another low-HLB surfactant that is claimed to be a good option is simethicone emulsion. However, the simethicone emulsion in question is published in International Publication No. 2014 / 086960 (WO In 2014 / 086960 A1), it takes ten minutes to obtain the HLB value that can be specified for it. Not specified in minutes. International Publication No. 2014 / 086960 (WO2014 / 0869 Disclosure 60 A1) also states that the simethicone emulsion is described in International Publication No. 2014 / 08 Definition of low-HLB surfactants for No. 6960 (WO2014 / 086960 A1) It is unclear whether this actually applies, but the addition of simethicone emulsion. The fact that this is beneficial in avoiding foam formation was reported in International Publication No. 2014 / 086960 (WO This is clearly instructed in 2014 / 086960 A1).

[0042] Simethicone itself is α-(trimethylsilyl)-ω-methylpoly[oxy(dimethicone) (Chillylylene) and silicon dioxide (at least WO 2014 / 086960 A1) (Regarding this) it is a mixture having an unspecified ratio of these two compounds, and is disclosed. The emulsion is also not disclosed in more detail.

[0043] α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilylene)] and dioxide There is no indication that the solvent or dispersant in the mixture with silicon forms the emulsion. The indication is that any further additives to such an emulsion will remain an emulsion. There is no incitement. This is International Publication No. 2014 / 086960 (WO2014 / 086960 The beneficial effect of having the simethicone emulsion in a formulation conforming to A1) is, Silicon dioxide or α-(trimethylsilyl)-ω-methylpoly[oxy(dimethylsilyl) It originates not from Ren itself, but from an unknown surfactant needed to stabilize the emulsion. It means to do something.

[0044] Therefore, considering particularly Examples 9 to 14, see International Publication No. 2014 / 086960 Simethicone (emulsion) to formulations disclosed in document (WO2014 / 086960 A1) The meaning of "John's addition is preferable" remains unclear.

[0045] International Publication No. 2014 / 086960 (W) includes surfactants with an HLB value exceeding 8. The specific formulations disclosed in O2014 / 086960 A1) are, more specifically, the following: It is listed below.

[0046] Example 4 contains 3.5% toltrazuril, 17.8% iron (as greptoferon), 0 0.3% sorbitan monooleate, 10% diethylene glycol monoethyl ether, 0 0.1% copolymer polyoxyl 35-castor oil and water added to make 100% This document describes a formulation consisting of [the specified ingredients].

[0047] Example 5 contains 3.5% toltrazuril, 19.4% iron (as greptoferon), 0 0.3% sorbitan monooleate, 0.1% copolymer polyoxyl 35-castor hydrogenated oil The document also describes a formulation consisting of the drug and water added to make a total concentration of 100%.

[0048] Example 7 contains 3.5% toltrazuril, 19.3% iron (as greptoferon), 0 0.3% propylene glycol monolaurate, 0.1% copolymer polyoxyl 35-H A formulation consisting of hydrogenated oil, 1% sodium chloride, and water added to make 100% It is stated.

[0049] Example 8 contains 3.5% toltrazuril, 19.4% iron (as greptoferon), 0 0.3% propylene glycol monolaurate, 0.1% copolymer polyoxyl 35-H The document describes a formulation consisting of hardened oil and water added to make a total concentration of 100%.

[0050] Example 9 contains 4.2% toltrazuril, 13.5% iron (as greptoferon), 0 0.1% sodium docusate, 0.1% silicone emulsion, 1.5% sodium chloride The description includes a formulation consisting of um and water added to make a total concentration of 100%.

[0051] Example 10 contains 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.1% sodium docusate, 5% diethylene glycol monoethyl ether, 0. 1% silicone emulsion, 1% sodium chloride, and water added to make 100%. This document describes a formulation consisting of [the specified ingredients].

[0052] Example 11 contains 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% phenol, 0.2% sodium docusate, 0.1% simethicone emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 0.5% sodium chloride The description includes a formulation consisting of um and water added to make a total concentration of 100%.

[0053] Example 12 contains 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% phenol, 0.2% sodium docusate, 0.1% simethicone emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride The document describes a formulation consisting of the compound and water added to make a total concentration of 100%.

[0054] Example 13 contains 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% phenol, 0.1% sodium docusate, 0.1% simethicone emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride The document also describes a formulation consisting of the drug and water added to make a total concentration of 100%.

[0055] Example 14 contains 2.9% toltrazuril, 18.8% iron (as greptoferon), 0.6% phenol, 0.1% sodium docusate, 0.1% simethicone emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride The description includes a formulation consisting of um and water added to make a total concentration of 100%.

[0056] Page 18 of International Publication No. 2014 / 086960 (WO2014 / 086960 A1) The three explicitly listed formulations on the page are 2.9% toltrazuril, 18.8% iron (as greptoferon), 0.3% sorbitan monooleate, 0.1 % Copolymer 15 Polyoxyl 35-Hydrogenated Castor Oil, 1.5% Sodium Chloride and Water, Alternatively, 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.3% solubil Rubitan monooleate, 0.1% copolymer polyoxyl 35-castor oil, 1.5 % sodium chloride and water, or 4.2% toltrazuryl, 13.5% iron (grapefruit) (as phenol), 1% sodium chloride, 1% polyvinylpyrrolidone, 0.6% phenol 0.5% colloidal silicon dioxide, 0.1% sodium docusate, 0.1% smethicone It consists of a con emulsion and water.

[0057] International Publication No. 2014 / 086960 (WO2014 / 086960 A1) is described as follows: It is generally known that any of the formulations being used are suitable for treating coccidiosis in animals. While this information is generally disclosed, it is also disclosed that simultaneous treatment of coccidiosis and anemia is being promoted. It is not described in Examples 4, 5, 7, 8, 9-14 and 18, and simultaneously No further disclosures have been made regarding specific formulations that may be particularly suitable for therapeutic use.

[0058] Apart from the prior art described above, appropriate concurrent treatment options for coccidiosis and anemia Several issues related to the objective of providing [something] have been addressed.

[0059] More specifically, the problem of synergistic effects between triazinon compounds and iron complex compounds. This was discovered in European Patent Application Publication No. 2164496 (EP2164496A1). The issue of foam formation has been addressed, and is described in International Publication No. 2014 / 086960 (WO201 Triazinon and iron complex with HLB values ​​less than 8, discovered in 4 / 086960 A1). This issue is addressed by adding surfactants to the compound combination.

[0060] Separately, surprisingly, European Patent Application Publication No. 2164496 (EP2 The beneficial effects observed in 164496A1) are due to certain triazinon compounds and certain iron (I II) By selecting an appropriate surfactant that promotes a synergistic effect with the complex compound. It was found that further improvements are possible.

[0061] Therefore, in the first aspect of the present invention, coccidiosis and A formulation is provided for use in the concurrent treatment of iron deficiency, and the formulation is toltrazuril or di Clazryl, polynuclear iron(III) polysaccharide complex compounds, and a small amount having an HLB value of 10 or more It contains at least one surfactant.

[0062] Any of the above prior art references include at least one with an HLB value of 10 or more This demonstrates that the addition of surfactants may be beneficial to the potency of any active substance in such formulations. I haven't done that.

[0063] It is advantageous to combine the treatments for the aforementioned anemia and coccidiosis into a single treatment. It reduces stress on animals, improves animal welfare, and reduces the labor involved in handling them on commercial farms. It reduces the need for manpower and provides economic benefits. Ultimately, European Patent Application Publication No. 2164 As first demonstrated by Specification No. 496 (EP2164496A1), This combination leads to improved weight gain in treated animals.

[0064] If a reduction in animal and environmental exposure to active substances and their metabolites can be achieved, then Furthermore, by reducing the dose without losing efficacy, the present invention can be further improved. If possible, it is even more advantageous.

[0065] In a second aspect of the present invention, coccidiosis and iron deficiency in non-human animals A formulation for use in treatment is provided. The formulation is toltrazuril or diclazuril. , polynuclear iron(III) polysaccharide complex compound, and at least one interface with an HLB value of 10 or higher Contains an activator, however, International Publication No. 2014 / 086960 (WO2014 / 08696 Excluding the formulations disclosed in Examples 4, 5, 7, and 8 of 0 A1).

[0066] In a second embodiment of the present invention, coccidiosis and iron deficiency in non-human animals Preparations for simultaneous treatment of the disease, toltrazuril or diclazuril, polynuclear iron(II) I) A polysaccharide complex compound and at least one surfactant having an HLB value of 10 or higher. (However, when using toltrazuril, the surfactant is copolymer polyoxy Preparations containing hydrogenated castor oil (excluding those containing 35-L35) are preferred.

[0067] In a third aspect of the present invention, coccidiosis and iron deficiency in non-human animals A formulation for use in treatment is provided, and the formulation is toltrazuril or diclazuril. Polynuclear iron(III) polysaccharide complex compounds, and at least one having an HLB value of 10 or more Contains surfactants, however, International Publication No. 2014 / 086960 (WO2014 / 086 Excluding the formulations disclosed in Examples 9-14 of 960 A1).

[0068] In the third aspect of the present invention, coccidiosis and iron deficiency in non-human animals Preparations for simultaneous treatment of deficiency, toltrazuril or diclazuril, polynuclear iron (I II) A polysaccharide complex compound and at least one surfactant with an HLB value of 10 or higher Preparation (however, when using toltrazuril, docusate sodium is used as the surfactant) Formulations containing (excluding) are preferred.

[0069] In a fourth aspect of the present invention, coccidiosis and iron deficiency in non-human animals A formulation for use in treatment is provided, and the formulation is toltrazuril or diclazuril. Polynuclear iron(III) polysaccharide complex compounds, and at least one having an HLB value of 10 or more Contains surfactants, International Publication No. 2014 / 086960 (WO2014 / 086960 The formulations disclosed in Examples 4, 5, 7, 8, 9-14 of A1), and International Publication No. 2 It is stated on page 18 of issue 014 / 086960 (WO2014 / 086960 A1). Excluding preparations consisting of preparations that are already in use.

[0070] As outlined above, International Publication No. 2014 / 086960 (WO2014 / 086 Formulations disclosed in 960 A1) that are excluded by that means have an HLB value of 10 or more. Unwantedly contains surfactants, but in practice, surfactants with an HLB value of less than 8 It is desirable to suppress foam formation.

[0071] In any of the above embodiments of the present invention, coccidious infections in non-human animals and Preparations for simultaneous treatment of iron deficiency, including toltrazuril or diclazuril, and polynuclear iron. (III) A compound containing a polysaccharide complex and one surfactant with an HLB value of at least 10. (However, the formulation contains 5% toltrazuril, 22.8% iron in the form of Fe(III) dextran, 0 0.2% sodium propionate, 0.2% sodium benzoate, 0.25% docusate Sodium, 0.05% simethicone emulsion USP, 30%, 10.5% propylene Glycol, 1.03% citric acid, 0.15% bentonite and to make 100% A formulation consisting of added water is preferred.

[0072] However, in the context of the present invention, the addition of the surfactant with an HLB value of 10 or more Furthermore, between toltrazuryl (or diclazuryl) and polynuclear iron(III) polysaccharide complex compounds Similarly, due to the double synergistic effect between them and surfactants with an HLB value of 10 or higher, ( It has become clear that any dose of toltrazuril (or diclazuril) may be reduced. It is.

[0073] Surprisingly, toltrazuril (or dicrazuril) is found in the HLB of 10 or higher. When administered to rats together with an surfactant, the pharmacokinetic area under the curve (AUC) and Cmax were observed. It was found that the latitudinal meter increased. The above effects on AUC and Cmax were observed in the Tor Trazuril (or diclazuril) with iron dextran or iron dextran glucohept This can also be observed when administered simultaneously with polynuclear iron(III) polysaccharide complex compounds such as nate.

[0074] Surprisingly, the unknown benefits of adding more than 10 HLB surfactants are as described above. Surfactant administration in pigs with toltrazuril or diclazuril and polynuclear iron(III) Effects on AUC and Cmax when administered in combination with sugar complex compounds. It overlaps dramatically with that.

[0075] This is because in these combination formulations, simple toltrazuril (or diclazuril) (Lu) or toltrazuril (or diclazuril) and polynuclear iron(III) polysaccharide complex compounds This offers an advantage because it shows a dramatic increase in bioavailability compared to combination formulations.

[0076] As a result, commercially available or disclosed toltrazuril (or dicrazuril) This is a combination of toltrazuril (or diclazuril) and polynuclear iron(III) polysaccharide complex compound preparations. Compared to combination therapy, a reduction in dosage may be possible.

[0077] The above advantages are independent of the route of administration. Parenteral administration (especially by injection) and Oral administration may be shown to offer the same benefits.

[0078] In the context of this invention, the HLB value is defined by the Davis method (Davies JT (1957)). ”A quantitative kinetic theory of emulsi on type,I. Physical chemistry of the emu lsifying agent",Gas / Liquid and Liquid / Li quid Interface,Proceedings of the Intern ational Congress of Surface Activity,pp. 426-38) or Griffin method (Griffin WC (1954)), "Calcu lation of HLB values ​​of non-ionic surfac tants”,Journal of the Society of Cosmeti It is determined according to c Chemists, pp. 249-56).

[0079] Both methods compare the amount of the hydrophilic portion of the molecule considered to be a surfactant with the amount of the molecule. Based on a semi-empirical equation showing the correlation with the amount of hydrophobic portion, the hydrophilic-lipophilic balance (HL B) Correlate the value with the chemical properties of the molecule.

[0080] As far as nonionic surfactants are concerned, the HLB values ​​are similar in both methods. It is not one. Typically, nonionic surfactants are assigned an HLB value based on the Griffin method. This is more common.

[0081] Therefore, in the context of the present invention, regarding the addition of surfactants with an HLB value of 10 or higher, The resulting deviation of HLB values ​​between HLB values ​​from the Ibis formula or the Griffin formula is Typically, when applied to nonionic surfactants, differences exceeding a deviation of ±1 do not occur. Therefore, it's not important.

[0082] Another type of surfactant is phospholipids. Within the above species, there are so-called zwitterionic surfactants. The herbal agent phosphatidylcholine needs to be handled individually. The HLB values ​​for each are It depends greatly on the actual composition and purity. For example, the HLB value of crude soy lecithin is 3. Yes, the HLB value of refined soy phosphatidylcholine is approximately 7 (Gunstone FD). ,“Lipid Technologies and Applications”(1 997) See p.62, Table 10).

[0083] Each HLB value is derived empirically rather than being calculated from any of the above formulas. It appears to be something that was produced.

[0084] Therefore, any HLB value mentioned in the context of the present invention is determined by the Davis method or Griffith method. It can be derived from one of the methods or measured by other means, and therefore the value is It must be understood as a value represented by ±1. In any case, it relates to the operation of the present invention. The HLB value is published in International Publication No. 2014 / 086960 (WO2014 / 086960 It is specified that the value will not overlap with the value from A1) and will only be calculated by the Davis method, and that there will be no excess This relates to avoiding the formation of bubbles.

[0085] The present invention provides at least one interface activity having a hydrophilic-lipophilic balance (HLB) value of 10 or more. The surfactant ("high HLB value surfactant") preferably has an HLB value of 10 to 18. More preferably, it is between 10 and 16.7.

[0086] A preferred surfactant with an HLB value of 10 or higher is docusate sodium (HLB 10) Polysorbate, Copolymer Polyoxyl 35-Hydrogenated Castor Oil (HLB 12- 14) Pluronic F-68 (HLB 29) and Vitamin E TPGS (H This was selected from the list of LB 13.2).

[0087] Among polysorbates, polysorbate 20 (HLB 16.7) and polysorbate A 80 (HLB 15) is preferred.

[0088] A more preferable surfactant with an HLB value of 10 or higher is docusate sodium, poly These are selected from the lists of Solvate 20 and Polysorbate 80.

[0089] A more preferred surfactant having an HLB value of 10 or higher is polysorbate 20 and po It was selected from the list of Resolve 80.

[0090] In a more preferred embodiment of all the above aspects of the present invention, the HLB value is 10 or more. Two or more surfactants are present in the formulation.

[0091] In the more preferred embodiment described above, at least two boundaries having HLB values ​​of 10 or more A surfactant is present in the formulation, and at least two of them are preferably polysorbate 2 The ratings are 0 (HLB 16.7) and polysorbate 80 (HLB 15).

[0092] In this context, polynuclear iron(III) polysaccharide complex compounds are referred to as oligomers or polymers. It exists within and as a complex with one or more of the above-mentioned oligomers and polymer carbohydrate compounds. Related to these coordination spheres are hydroxide ions (OH-), water groups (H2O), and oxygen (O). This is understood to mean a complex of iron(III) ions with iron(III) hydroxide. II) This is why it is also called polysaccharide or iron(III) oxyhydroxypolysaccharide, and polysaccharides are, This represents the corresponding oligomer and polymer carbohydrate compounds or their derivatives.

[0093] This type of polynuclear iron(III) complex is, for example, (DSKudasheva et al.) al.,“Structure of Carbohydrate-bound Po lynuclear 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. / Dru g Res.34(II)(1984)1555-1559;F.Funk et al .,“Physical and Chemical Characterization n of Therapeutic Iron Containing Materia ls”,Hyperfine Interactions 136(2001)73-9 5;E.London“The Molecular Formula and Pro posed Structure of the Iron-Dextran Comp lex,IMFERON”, J.Pharm.Sci. 93(2004)1838-1 846;A.John“Neue Mo:glichkeiten der Eisen versorgung neugeborener Ferkel unter Bea chtung biochemischer Aspekte”[Novel poss ibilities of supplying iron to new born piglets,taking account of biochemical as pects], Tra:chtigkeit und Geburt beim Sch wein[Pregnancy and birth in pigs]:8th Be rnburger Biotechnology Workshop,Bernburg It is described in (2002)89-94).

[0094] In many cases, the precise composition of these compounds is not quantitatively described, and the type of preparation is not specified. Because these can differ even within the compound, these polynuclear iron(III) polysaccharide complex compounds are It is understood that this refers to all compounds that a person skilled in the art would attribute to this type of compound.

[0095] Examples of polynuclear iron(III) polysaccharide complex compounds that can be mentioned include polynuclear β-FeO(OH) complexes. A polynuclear iron(III) polysaccharide complex containing a polymer carbohydrate compound to which is bound as a free coordination site. Compounds such as greptoferon, iron(III) dextran, and iron(III) hydroxy Polymaltose (iron(III) dextrin), β-FeO(OH), sugars and oligosaccharides These are non-stoichiometric compounds with sugars, namely "iron(III) sucrose" and "iron(III) sugar."

[0096] The formulations used in accordance with the present invention may be solutions, emulsions, or suspensions.

[0097] The solution involves dissolving an active ingredient or multiple active ingredients in a suitable solvent or solvent mixture. It is prepared by [method]. If necessary, solubilizers, antioxidants, preservatives, thickeners, adhesives, Further auxiliary agents such as pH adjusters, UV stabilizers, and colorants are added.

[0098] Solvents that may be mentioned include water, for example, monohydric alkanols (e.g., ethanol or n-but). (gol), glycol (e.g., ethylene glycol, propylene glycol, tetraglycol) Glyceryl / glycofloride, polyethylene glycol, polypropylene glycol, glycerin Alcohols such as polyhydric alcohols like rohr, benzyl alcohol, phenylethanol Aromatically substituted alcohols such as phenoxyethanol, ethyl acetate, butyl acetate, benzoyl acetate Esters such as benzyl oleate and ethyl oleate, alkylene glycol alkyl ether (Examples: dipropylene glycol monomethyl ether, diethylene glycol monobutyl) Ethers such as ether, acetone, ketones such as methyl ethyl ketone, aromatics and / or aliphatic hydrocarbons, vegetable oils or synthetic oils, glycerol formal, solketal (2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane), N-methylpyro Lidone, 2-pyrrolidone, N,N-dimethylacetamide, glycoflor, dimethyl Sosorbitol, Lauroglycol, Propylene Carbonate, Octyldodecanol, Dimethyl A physiologically acceptable solvent, such as formamide and a mixture of the above solvents.

[0099] Water is preferred as the solvent and / or suspension medium.

[0100] Solubilizers that may be mentioned are those that promote the dissolution of the active ingredient in the main solvent or their precipitation. These are agents used to prevent precipitation. An example of an agent that prevents precipitation is polyvinylpyrrolidone.

[0101] Antioxidants include sulfites, or potassium metabisulfite or sodium metabisulfite. Which metabisulfite, sodium disulfite or potassium disulfite, ascorbic acid, Ascorbic acid, ascorbyl palmitate, gallate ester, butylhydroxy acid These are luene, butylhydroxyanisole, or tocopherol.

[0102] The synergistic effect of these antioxidants is due to amino acids (e.g., alanine, arginine, methionine). , cysteine), citric acid, tartaric acid, EDTA or their salts, phosphoric acid derivatives or polyphosphates It may be a valent alcohol (polyethylene glycol).

[0103] The preservatives are benzyl alcohol, benzalkonium chloride, trichlorobutanol, p- Hydroxybenzoic acid, n-butanol, chlorocresol, cresol, phenol, benzoic acid It may be citric acid, tartaric acid, or sorbic acid.

[0104] Thickening agents include inorganic materials such as bentonite, colloidal silica, and aluminum stearate. A thickener, such as a cellulose derivative like hydroxypropylmethylcellulose 4000, Livinyl alcohol and its copolymers, xanthan, acrylates and metha These may be organic thickeners such as relate, carboxymethylcellulose, and its salts.

[0105] Adhesives include, for example, cellulose derivatives, starch derivatives, polyacrylates, and algin. These are natural polymers such as acid salts and gelatin.

[0106] Adhesives that also possess thickening properties can similarly be used as thickening agents.

[0107] pH adjusters are conventionally classified as acids or bases in pharmaceutical terms. Bases include alkali metal hydroxides. Substances or alkaline earth metal hydroxides (e.g., NaOH, KOH), e.g., ammonium chloride Basic salts such as nium, for example, arginine, choline, meglumine, ethanolamine Any basic amino acid, or tris(hydroxymethyl)aminomethane, citrate buffer Alternatively, buffers such as phosphate buffer are included. Acids include, for example, hydrochloric acid, acetic acid, tartaric acid, and chloric acid. Econic acid, lactic acid, succinic acid, adipic acid, methanesulfonic acid, octanoic acid, linolenic acid, gu This includes aluconolactones and acidic amino acids such as aspartic acid.

[0108] UV stabilizers include, for example, benzophenone species substances or novantisolic acid.

[0109] The colorants are approved for use in humans or animals and can be dissolved or suspended in all It is a coloring agent.

[0110] A suspension is formed by suspending one or more active ingredients in a carrier liquid. Depending on the application, humectants, colorants, absorption enhancers, thickeners, dispersants, adhesives, preservatives, antioxidants, Further additives such as UV stabilizers or defoamers (in addition to the aforementioned surfactants) may be added. It is prepared by [method].

[0111] The formulation used in accordance with the present invention is preferably "water-based".

[0112] This is, in principle, 10% by weight or more and up to 90% by weight, preferably 20% by weight or more and up to 80% by weight. This means that the water content is less than or equal to % by weight, and more preferably between 30% and 50% by weight.

[0113] For example, the above formulation may further contain a water-miscible solvent. Further examples may be mentioned. The water-miscible solvent is preferably ethylene glycol, diethylene glycol, or triethylene glycol. Polyhydric aliphatic alcohols such as cellulose glycol, propylene glycol, and glycerol Among these, propylene glycol is particularly preferred.

[0114] Such additional water-miscible solvents are typically present in amounts of 1% to 45% by weight, preferably. Present at a concentration of 1% by weight or more and 20% by weight or less, particularly preferably 5% by weight or more and 10% by weight or less. The addition of such polyhydric aliphatic alcohols also has the advantage of lowering the freezing point of the formulation. It has.

[0115] As described above, the formulations used in accordance with the present invention may, if necessary, be known as synergistic agents. It may be combined with other ingredients to further contain preservatives. The amount of preservatives is usually 0.01% by weight or more. It is present at a concentration of 5% by weight or less, particularly between 0.05% by weight and 1% by weight.

[0116] The antioxidants that may be used as needed in the mentioned formulations are preferably BHA or It is BHT. To ensure adequate preservation, preservatives are used alone or in combination. It can be used in combination with known substances such as citric acid, tartaric acid, and ascorbic acid. or synergistic agents such as sodium salt of EDTA are usually present in amounts of 0.01% to 1% by weight. It is present, particularly at concentrations between 0.05% by weight and 0.15% by weight.

[0117] The formulation according to the present invention first introduces a solvent, preferably water, and, if necessary, a eutectic solution. Pre-dissolve auxiliary agents and / or additives such as fertilizers, preservatives, antioxidants, and viscosity modifiers. Alternatively, it is preferable to adjust by distributing the mixture.

[0118] In a preferred method, the second step is to add a commercially available dispersion concentrate to this initial solution, if necessary. In the form of a substance, to introduce toltrazuril or diclazuril and a potent homogenizer This includes homogenizing the mixture using a hyphen until a finely divided suspension is obtained.

[0119] Next, the iron compound is introduced into the dispersion, preferably in powder form, and mixed in the process. The material is homogenized again. The final step is to add the appropriate pH adjuster. Adjust the pH to the desired level. Individual or all auxiliary agents and / or additives are also necessary. Depending on the circumstances, it may be added after the final homogenization step. This is, for example, in the homogenization process. This may be recommended in the case of certain thickeners whose structure is destroyed by this process.

[0120] As outlined in the above aspects of the present invention, the formulation according to the present invention is particularly effective in cocci in animals. It is intended for use in the combined control of diazepam and iron deficiency.

[0121] The aforementioned use involves a single dose of anticoccidial toltrazuril or diclazuril and iron. This facilitates simultaneous administration.

[0122] Use is permitted for livestock, breeding animals, animals kept in zoos, research animals, laboratory animals, and pet animals. It may be used in animal husbandry and animal breeding. The range of action of toltrazuril or dicrazuril. The following are, in principle, well-known coccidia. The coccidia that can be mentioned individually are as follows: That is correct.

[0123] Flagellates (Mastigophora (Flagellata)), for example, trypano The family Trypanosomatidae, for example, Trypanosoma bursei (T .brucei), Trypanosoma gambiens, Trypanosoma Nosoma rhodesiense, Trypanosoma congole T. congolense, Trypanosoma cruzi, Trypanosoma evansi, Trypanosoma echinanum Trypanosoma inum), Trypanosoma lewisi, Trypanosoma percae (T. percae), Trypanosoma simiae, Trypanosoma T. vivax, Leishmania brasiliensis Leishmania brasiliensis, Leishmania donova ni), Leishmania tropica, for example, Trichomonadaceae ( Trichomonadidae), for example, Giardia lambria lamblia, Giardia canis.

[0124] Sarcomastigophora (Sarcomastigophora) da)), for example, Entamoebidae, for example, Entamoebidae Entamoeba histolytica, Hartmanellaceae (ellidae), for example, the genus Acanthamoeba (Acanthamoeba sp.) Also known as the genus Hartmanella (Hartmanella sp.).

[0125] Apicomplexa (Sporozoa) For example, the Eimeriidae family, for example, Eimelia aselbrina ( Eimeria ascervulina, Eimeria adenoides (E. aden) Eimelia alabahmensis, Eimelia oides Leah Anatis, Emelia Anseris Emelia Arloingi, Emelia Ashata hata), Emelia auburnensis, Emelia E. Bovis, Emelia Brunetti, Emelia canis, Emelia chinchillae E. clupearum, E. llae E. columbae, E. ontorta, E. Emelia crandalis, Emelia debrieki (Ed E. dispersa, E. ebliecki, E. dispersa, E. E. ellipsoidales, Emelia farsiholmis (E. falciformis), E. faurei, Ey Melia flavecens, Emelia garopavonis E. gallopavonis), E. hagani, E. E. intestinalis, E. iroquoina E. iroquoina, E. irresidua, Eyesi Melia labbeana, Emelia leucartii arti), Emelia Magna, Emelia Maxima xima), Emelia Media, Emelia Meleagridis (E. meleagridis), Emelia meleagrimitis (E. meleag E. mitis, E. nekatrix E. necatrix, E. ninako hlyakimovae), Emelia Ovis, Emelia Parva (E. parva), Emelia Pavonis, Emelia Per Holance (E. perforans), Aymelia Phasani (E. phasani), Emelia piriformis, Emelia praecox (E. praecox), E. residua, E. • E. scabra, E. spec., E. scabra E. Stiedai, Emelia Suis, Emelia E. tenella, E. truncata, E. Imelia Truttae, Emelia Zuerni ii) Globidium species, Isospora belli (I Isospora belli, Isospora canis, Isospora Isospora ohioensis (Isospora ohioensis) Isospora rivolta (I. rivolta), Isospora genus (I. sp.) ec.), Isospora suis (I. suis), Neospora caninum (Neosp ora caninum), Neospora hugesi, cystoisospora Cystisospora spec, Cryptosporidium spec (Osporidium spec.), for example, the family Toxoplasma adidae), for example, Toxoplasma gondi i) For example, the Sarcocystidae family, for example, sarcosis Sarcocystis bovicanis S. bovihominis, Sarcocystis neurona (S .neurona), Sarcocystis ovicanis, Sarco Sarcocystis ovifelis, genus Sarcocystis (S. spe c.) and Sarcocystis suihominis, for example, Leucocytozoidae, for example, Leucocytozoon s Imondi (Leucocytozoon simondi), for example, Plasmodiu Plasmodiidae, for example, Plasmodium podocarpus (the parasite that causes rat malaria). berghei), Plasmodium falciparum, Plasmodium malariae, Plasmodium ovale, Plasmodium vivax, Plasmodium spp., for example, Piroplasmea, for example Babesia argentina, Babesia bovis, Babesia canis, Babesia spp., Theileria parva, Theileria spp., for example, Adeleina, for example Hepatozoon canis, Hepatozoon spp. Plasmodium malariae, Plasmodium vivax, Plasmodium spp., for example, Piroplasmea such as Babesia argentina (Babesia argentina), Babesia bovis, Babesia canis (B. canis), Babesia spp., Theileria parva (Theileria parva), Theileria spp., for example, Adeleina such as Hepatozoon canis (Hepatozoon canis), Hepatozoon spp.

[0126] Furthermore, Myxospora and Microspora, for example, Glugea spp., Nosema spp. (Glugea spec.), Nosema spec. (Nosema spec.).

[0127] Furthermore, Pneumocystis carinii, and Ciliophora (Ciliata), for example, Balantidium coli, Ichthyophthirius spec., Trichodina spec., Epistylis spec. (Pneumocystis carinii), and Ciliophora (Ciliata), for example Balantidium coli, Ichthyophthirius spec. (Ichthyophthirius spec.), Trichodina spec. (Trichodina spec.), Epistylis spec.

[0128] Genera and species of protozoa that lead to asymptomatic or clinical infections in pigs, especially Eimeria Eimeria debliecki, Eimeria 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 are not to be emphasized, unless otherwise specified.

[0129] The livestock and breeding animals for which the formulations according to the invention are particularly beneficially used include, for example, cattle, horses, sheep, pigs, goats, camels, water buffalo, donkeys, rabbits, deer, reindeer, animals with furs such as mink, chinchilla, raccoon, etc., birds such as chickens, geese, turkeys, ducks, pigeons, ostriches, etc., pets and bird species kept as zoo animals. Furthermore, farmed fish and ornamental fish are also included.

[0130] In this context, all species, subspecies, and breeds of pigs, cattle, sheep, and dogs may be particularly emphasized.

[0131] ​​​​​​​​Research and experimental animals include mice, rats, guinea pigs, golden hamsters, This includes dogs and cats. Pets include dogs and cats.

[0132] Its use in pigs is particularly preferred.

[0133] The formulations used according to the present invention are suitable as metabolic and immunostimulants, for example, as follows: Further active ingredients or components such as nutrients including vitamins, minerals, and phosphorus compounds. It may contain (either alone or in appropriate combinations).

[0134] For example, vitamin E, for example, the B series vitamins such as vitamin B12, and vitamin C. Which vitamins? Some of the above can also function as surfactants.

[0135] Minerals, preferably calcium or magnesium salts, especially calcium gluconate, for example. Um, calcium glucoheptanoate, or calcium saccharate.

[0136] Phosphorus compounds, particularly pharmacologically acceptable organic compounds suitable as metabolic stimulants and tonics. Phosphonic acid derivatives. Preferred examples that can be mentioned are the compound tolzinphos, and especially long-term He is a well-known PigHost fan.

[0137] As a result of toltrazuril or diclazuril being poorly soluble, the latter is used in accordance with the present invention. It often exists in a finely divided form within the formulations used.

[0138] Here, dispersed toltrazuril or diclazuril is preferably d(v,90) is 3 Less than 0 μm, preferably d(v,90) is less than 20 μm, particularly preferably d(v,90) is less than 10 μm, particularly preferably, the particle size (laser diffraction measurement by folding, having Malvern Mastersizer(R) 2000).

[0139] For the purposes of the present invention, d(v,90) is the dimension below which 90% of all particles have this value (diameter), and is to be understood to mean the particle size distribution with respect to volume, which is usually called d(90), but in order to make it clear that it is the particle size distribution related to volume, the more accurate term d(v,90) can also be selected. The names such as d(v,50), d( v,10), etc. are to be understood accordingly. The particle size shown here is measured by laser diffraction using a Malvern Mastersizer r 2000 device (dispersion unit Hydro 2000G) and using the Fraunhofer diffraction evaluation mode, since the refractive index of the active ingredient particles is unknown. Here, while stirring an appropriate amount of sample solution, it is pre-dispersed with 2 - 3 ml of dispersion medium (0.1% aqueous solution of dioctyl sodium sulfosuccinate). Next, the dispersion is put into the dispersion unit of the device while stirring (300 rpm) and recirculating (900 rpm) and measured there. The evaluation software

[0140] In a preferred embodiment of the present invention, the formulation is for use in a dosing schedule of 1 - 60 mg (mg / kg) of toltrazolil or diclazuril per kg of the body weight of the animal to be treated per day.

[0141] In the above-mentioned preferred embodiment, the dosing schedule is preferably 10-40 mg (mg / kg) of toltrazuril or diclazuril, more preferably 1 The recommended daily dose is 10-20 mg / kg, most preferably about 20 mg / kg.

[0142] In the most preferred embodiment, the above medication plan is used only once.

[0143] In another preferred embodiment of the present invention, the formulation contains 100 to 300 mg of polynuclear iron(III) This is intended for use in drug administration planning for polysaccharide complex compounds.

[0144] In the preferred embodiment described above, the medication schedule is preferably per kg of animal body weight It is a polynuclear iron(III) polysaccharide complex compound containing 150-250 mg (mg / kg), and is more preferably... Alternatively, it is approximately 200 mg / kg per day.

[0145] The present invention particularly involves the combination of toltrazuril or diclazuril with polynuclear iron(III) polysaccharide complex compounds. Since this concerns the combination of medications, the optional medication plan mentioned individually above will be applied on a daily basis. Approximately 20 mg / kg of toltrazuril or diclazuril and approximately 200 mg per day It is especially preferred to combine this with a dosage regimen of polynuclear iron(III) polysaccharide complex compounds at a dose of / kg. preferable.

[0146] In a very preferred embodiment, the formulation contains approximately 20 mg / kg of toltraz per day. Diclazuril or diclazuril and approximately 200 mg / kg of polynuclear iron(III) polysaccharide complex per day. It is intended for use in drug administration plans for compound compounds, and therefore, use is limited to one day only. In the aforementioned very preferred embodiment, the animal is used on the second or third day after birth. It is preferable that the animal be a piglet, and it is especially preferable that the animal be a piglet.

[0147] The amount of the preparation used with each administration is toltrazuril or diclazuril and polynuclear iron ( III) The amount of the polysaccharide complex compound administered in each case depends on the individual case.

[0148] It is easy to apply and aims for relatively small amounts, which vary depending on the animal species. For example, in suckling pigs... In this case, the target application amount is 0.3 ml to 2 ml, preferably 0.5 ml to 1 ml. To point.

[0149] In piglets aged 4 weeks, a sufficient supply of iron is preferred between 0.7 ml and 1.3 ml. Alternatively, methods that can be achieved with a single dose of a formulation of 0.7 ml to 1.0 ml, etc. A particularly preferred formulation according to the present invention, which enables parenteral treatment of the disease, is also available on the third day after birth. At least 8 g / 100 ml of blood, preferably more than 9 g / 100 ml of hemoglobin The value can be seen as an indicator of sufficient supply. Furthermore, the toltrazuril or dicrazuril portion The aim is to properly control coccidia.

[0150] The formulation used in another embodiment is 0.1% (m / v) or more and 30% (m / v) or more. The following contains toltrazuril or diclazuril. This is 1 mg / ml or more per 300 ml. This corresponds to g / ml or less. Preferably, 1.5% (m / v) or more and 25% (m / v) or less. Yes, this corresponds to 15 mg / ml to 250 mg / ml, and is particularly preferred to be 1. The concentration is between 8% (m / v) and 15% (m / v), which corresponds to 18 mg / ml to 150 mg This corresponds to less than / ml, and in particular, 1.8% (m / v) to 7% (m / v), which is This is equivalent to 18.5 mg to 70 mg of toltrazuril or diclazuril per 1 ml. ru.

[0151] In another embodiment, the formulation used is 10% (m / v) or more and 30% (m / v) or less. It contains activated iron.

[0152] The above values ​​correspond to 100-300 mg of activated iron per 1 ml. Preferably, 1 ml 11.4% (m / V) to 25% of the active iron content, corresponding to 114 mg to 250 mg of active iron. (m / V) or less, particularly preferably 200 mg to 250 mg of active ingredients in 1 ml of the formulation. It corresponds to 20% (m / V) to 25% (m / V) of iron.

[0153] In another embodiment, the formulation used is 0.01% (m / v) or more and 10% (m / v) or more. It contains at least one surfactant whose HLB value is 10 or higher.

[0154] In another embodiment, the polynuclear iron(III) polysaccharide complex compound is iron(III) dextrang Lucoheptate or iron(III) dextran, preferably iron(III) dextran It is ngulcoheptate.

[0155] A particularly preferred embodiment of the present invention is coccidious infection in non-human animals and The preparation used for the simultaneous treatment of iron deficiency is iron(III) dextran glucoheptone. Tortrazuryl iron(III) in tactile form, phenol, and polysorbate and At least one surfactant selected from the list of sodium sacrate, simethicone Emulsion, sodium chloride, water, and colloidal silicon dioxide, if necessary. It also consists of polyvinylpyrrolidone as needed.

[0156] Within the preferred embodiments described above, coccidiosis and iron deficiency in non-human animals One particularly preferred formulation for use in the simultaneous treatment of is 3-5 g / 100 ml of Tort Lazuril, in the form of iron(III) dextran glucoheptate, 10-20g / 100 Iron(III) per ml, 0.3-0.8 g / 100 ml; Phenol, 0.05-0.2 g / 100ml of docusate sodium or 0.15-0.3g / 100ml of polysorbate It consists of one of the following, where the polysorbate is 0.1-0.2g / 100ml Polysorbate 20, 0.05-0.1g / 100ml; Polysorbate 80, 0.0 Simethicone emulsion with 5-0.1g / 100ml, 0.8-1.1g / 100ml Sodium chloride, and if necessary, approximately 0.5g / 100ml of colloidal silicon dioxide. It is a mixture of polyvinylpyrrolidone and water at approximately 1g / 100ml, depending on the amount.

[0157] More preferably, the simultaneous occurrence of coccidious infection and iron deficiency in non-human animals. The preparation used for treatment consists of approximately 5g / 100ml of toltrazuril and iron(III) dextrose. 15-20g / 100ml of iron(III) in the form of strunglucoheptate, approximately 0. 5g / 100ml phenol, 0.1~0.2g / 100ml polysorbate 20 and 0.05~0.1g / 100ml Polysorbate 80, approximately 0.05g / 100ml Shimechi Con emulsion, consisting of approximately 0.9g / 100ml of sodium chloride and water, similarly, A formulation for the simultaneous treatment of coccidiotic infections and iron deficiency in non-human animals is Approximately 3g / 100ml of toltrazuril, iron(III) dextran glucoheptate Iron(III) in its form: 10-15g / 100ml, iron(III) 0.6-0.7g / 100ml Nol, 0.05-0.2g / 100ml; Docusate sodium, approximately 0.1g / 100ml ml Simethicone emulsion, approximately 1g / 100ml Sodium chloride, approximately 0.5g / 100 ml colloidal silicon dioxide, approximately 1g / 100ml polyvinylpyrrolidone, and water ru.

[0158] In the particularly preferred embodiment described above, the non-human animal is preferably from birth to birth. Piglets that are 96 hours old, and more preferably between 24 and 72 hours after birth. These are piglets that are between 24 and 96 hours old. Coccidiosis is caused by cystoisospor It is caused by Cystoisospora suis.

[0159] In another embodiment, the formulation used has a molar ratio of Ca2+ to Na+ of 0 or more and 3 or less. Yes, and more preferably 0 to 1.

[0160] In another embodiment, the formulation used has a total content of CaCl2 and NaCl of 0. The value is 1% (m / V) or more and 5% (m / V) or less. Preferably, 0.5% (m / V) or more and 4% It is less than or equal to %(m / v), and more preferably between 0.9%(m / v) and 3%(m / v). That is the case.

[0161] Surprisingly, the amounts of NaCl and CaCl2 specified in the two embodiments described above It was found that its presence increases the stability of the formulation over time.

[0162] In another embodiment, the formulation contains 3500 ppm or less, preferably 2000 ppm or less. More preferably, it has a free iron content of 1000 ppm or less.

[0163] Quantitative measurement of dissolved iron ions can be performed, for example, by dialysis of the sample followed by the removal of dialyzed free iron. It can be measured by subabsorption spectroscopy (AAS) or other appropriate methods such as polarography or photometry. This can be done by [meaning].

[0164] In another embodiment, the formulation is stored at a temperature of 20°C to 40°C for 6 months, and then 35 00 ppm or less, preferably 2000 ppm or less, more preferably 1000 ppm or less It contains dissolved free iron ions.

[0165] The formulation more preferably contains these components after 12 months of storage, and after 24 months. This is even more preferable, and 36 months is most preferable. For example, the formulation is at 20°C or higher. After storage at a temperature of 40°C or below for 36 months, the free iron ion content is 3500 ppm or less. It may have.

[0166] The measured iron ion content mainly consists of two iron ion sources. The solvent of the formulation already contains It is clear that the dissolved iron ions are part of the free iron according to the present invention.

[0167] A second source of free iron is a small complex frag known in the literature as unstable iron. It is iron that exists as free iron in the form of ment. In other words, such free iron is essential Either the polysaccharide complex compound was partially or completely decomposed, or a defect occurred. As a result, it can no longer be stably bound to the polysaccharide complex.

[0168] These complex fragments can be converted to Fe2+ and / or by appropriate sample pretreatment methods. Alternatively, it is transferred to Fe3+ ions, and together with the Fe2+ and Fe3+ ions originally present in the formulation... It is measured as described above.

[0169] Therefore, within the scope of the present invention, by AAS, polarography, or photometric methods The determined iron ion content is determined by the ions that are transferred to free dissolved ions during sample preparation. In addition, it refers to the content of Fe2+ and / or Fe3+ ions that dissolve freely in the formulation. It is understood that Fe2+ ions are not directly measured, but during sample preparation or The form of Fe3+ ions that are transferred to Fe3+ by other active means and freely dissolved in Fe3+ ions Measurable free iron is generated.

[0170] Within the scope of this invention, the term "free" iron measured by the above method is thereby By overloading the iron transport capacity of the aforementioned iron transport protein, toxicity is induced after administration. It contains all possible iron compounds.

[0171] As a result, the amount of free iron measured by any of the above methods is the same as that measured by all measurement methods The method measures the total amount of free dissolved iron and its non-functional complexes, according to the above function definition. The amount of iron is always equal to or greater than the actual amount, while only a portion of it is administered. It can actually be harmful to the target.

[0172] The above-mentioned "free" iron needs to be separated from "activated iron". For the purposes of this invention, "Activated iron" refers to the amount of iron that is stably present in a polynuclear iron(III) polysaccharide complex compound. And in the context of the present invention, activated iron cannot be Fe2+, but it must be Fe3+. It must be done.

[0173] Furthermore, in the context of the present invention, a weight percentage or ratio is disclosed with respect to the activated iron. In such cases, the amount is the respective amount / weight of the complex-forming agent (i.e., polysaccharide complex). It must be considered to always be listed.

[0174] Therefore, in the context of the present invention, any formulation used and disclosed herein Any reference made to the proportion of polynuclear iron(III) polysaccharide complex compounds that are part of the above is, In the aforementioned formulation, subsequent coordination with a polysaccharide complex results in a polynuclear iron(III) polysaccharide complex compound. This should be understood as the actual amount of activated iron(III) produced. , the actual amount of polynuclear iron(III) polysaccharide complex compounds in any formulation used and disclosed This is significantly more abundant than the actual "activated iron."

[0175] The present invention is not limited to the following embodiments, but will be further described with reference to the following embodiments. It can be done. [Examples]

[0176] Prepare the formulations to be used in Examples 1-4.

[0177] The toltrazuril preparation used in Examples 1-4 below contains the required amount of toltrazuril. It is produced by measuring it into a beaker and dissolving it in about half the volume of the main solvent.

[0178] Next, if applicable, add the specified amounts of co-solvent ethanol and surfactant. Stir the formulation until a clear solution is obtained. Transfer the formulation to a volumetric flask and allow it to cool to 20°C. Heat the mixture and fill with the main solvent up to the calibration mark (add the appropriate amount to the desired volume). Filter the mixture through a sterile filter. After heating, transfer to an injection vial and seal with a rubber stopper and crimp cap.

[0179] The list of surfactants / dispersants used is as follows:

[0180] [Table 1]

[0181] The administration and evaluation of the formulations used in Examples 1-4 are as follows.

[0182] A 1 ml / kg aliquot of the formulation was subcutaneously injected into female Wistar rats. Blood samples were then collected. The plasma was collected at various time intervals, and the plasma sample was analyzed to determine the concentration of toltrazuril in the plasma. We analyze these data. From these data, the AUC and Cmax values ​​are known targets for clinicians. It is measured according to a standard method.

[0183] (Example 1) Table 1-B shows the volume of toltrazuril formulations in the solvent dimethyl sulfoxide (DMSO). Prepare according to the composition of the formulation, expressed in mass % (%M / V) per unit. DMSO content This represents the amount added until the value reaches 100. Table 2 shows the pharmacokinetic AUC and Cmax. The data shows the percentage change compared to a reference formulation that does not contain surfactants ("ref"). (Note: "hr" = hours).

[0184] [Table 2]

[0185] [Table 3]

[0186] The data above clearly demonstrates the positive effects of adding surfactants with an HLB of 10 or higher. However, it is not an amphiphilic compound and therefore does not have an inherently calculable HLB value. The effects of the powdered drug Kollidone™17PF have been significantly reduced.

[0187] (Example 2) In glycerol formal solvent (4-hydroxymethyl-1,3-dioxolane) The lutrazuril formulation is used in the formulation composition shown in Table 3 as mass % per volume (%M / V). Prepare accordingly. The glycerol formal content refers to the amount added until it reaches 100. Table 4 shows the pharmacokinetic AUC and Cmax data, and the reference product without surfactants. This shows the percentage change compared to the agent "ref (reference)" (Note: "hr" = time).

[0188] [Table 4]

[0189] [Table 5]

[0190] The data above clearly shows the positive effects of adding surfactants with an HLB of 10 or more. This is happening. This is not so noticeable in glycerol formal solvent, however. That is also important.

[0191] (Example 3 (Comparative Example)) Glycerol formal solvent (4-hydroxymethyl-1,3-dioxolane) and The toltrazuril preparation in 10% ethanol is expressed in the mass % (%M / V) per volume shown in Table 5. Prepare according to the composition of the formulation shown. Glycerol formal and 10% ethanol The content of ru is the amount added until it reaches 100. Table 6 shows AUC and Cmax. Pharmacokinetic data and percentages compared to a surfactant-free reference formulation "ref (reference)" To indicate change. (Note: "hr" = time)

[0192] [Table 6]

[0193] [Table 7]

[0194] The above data shows that when Lipoid S100, a surfactant with an HLB of less than 10, is added... This indicates that it has an adverse effect on pharmacokinetic parameters.

[0195] (Example 4) Preparations of 2-pyrrolidone and toltrazuril in 20% ethanol solvent, in the volumes shown in Table 7. Prepare according to the composition of the formulation expressed as mass % (%M / V) per unit. 2-Pyrrolidone The 20% ethanol content refers to the amount added until it reaches 100. Table 8 shows the drug AUC and Cmax data of the pharmacokinetics, and a reference formulation that does not contain surfactants "ref(reference) This shows the percentage change compared to ) [Note: "hr" = hours].

[0196] [Table 8]

[0197] [Table 9]

[0198] The above data shows that in 2-pyrrolidone and 20% ethanol as solvents, HLB This clearly demonstrates the positive effects of adding 10 or more surfactants.

[0199] (Examples) Examples 1-4 demonstrate the individual positive effects of adding surfactants with an HLB of 10 or higher. This is done to demonstrate the combined effect of the surfactant by adding a polynuclear iron(III) polysaccharide complex. The formulations outlined in Table 9 are described in European Patent Application Publication No. 2164496 (EP2164 It was prepared in the same manner as disclosed in 496A1).

[0200] [Table 10]

[0201] A total of 21 piglets were born from two sows, and they were divided into groups of 10 and 11 piglets respectively. They were randomly assigned to two research groups. Using both formulations, each group A single oral bolus was administered to 3-day-old piglets of Loop.

[0202] After treatment, a total of 8 samples, including the pre-treatment samples, will be taken according to a predetermined schedule. Frequent blood sampling (n=22 samples per piglet) was performed over a four-day period.

[0203] The concentration of the active substance toltrazuril in plasma was determined by turbulent chromatography / tandem mass spectrometry. It was analyzed by [method / analysis method]. The limit of quantification was 10 μg / L.

[0204] The PK data in Table 10 was calculated from the collected samples.

[0205] [Table 11]

[0206] The above data shows that the surfactants with an HLB of 10 or higher, along with polynuclear iron(III) polysaccharide complexes, are suitable for use with polynuclear iron(III) polysaccharide complexes. This clearly demonstrates the beneficial combined effect achieved by adding the compound.

[0207] Examples 1 to 4 showed the positive effect of surfactants with an HLB of 10 or higher, but Table 1 The data generated for 0 indicates further improvement in the relevant pharmacokinetic parameters. They are doing it.

[0208] (Example 6) Examples 1 to 4 show the individual positive effects of adding surfactants with an HLB of more than 10. Example 5 describes the above-mentioned interface activity by adding a polynuclear iron(III) polysaccharide complex in oral application. The aphrodisiac showed a good combined effect.

[0209] To demonstrate that the overall combined effect is not affected by a specific route of administration, see Table 11. The formulation outlined was prepared for administration by injection. (See item "ref1 (reference 1)") This is the same as the "ref (reference)" item outlined in Example 5 above, and is toltrazuril. This refers to an oral formulation containing only [the specified ingredient]. Item "ref2 (reference 2)" refers to the test item for this example. This is the same as in 1, but without the addition of activated iron.

[0210] The formulation was produced in the same manner as in Example 5.

[0211] [Table 12]

[0212] In a parallel project, three test groups were prepared, each consisting of six piglets. The animals were treated for each item on the third day after birth. The preparations related to ref1 (reference 1) The piglets in the administered group received a single oral bolus (similar to the above in Example 5). The piglets in the other two groups received a single injection of the two formulations on the third day after birth.

[0213] Frequent blood draws should be performed at 0, 4, 8, 24, 32, 48, and 72 hours. The tests were performed after each procedure on the 7th, 14th, 21st, and 28th (n=11 / animal). Plasma The concentration of the active substance toltrazuril was determined by turbulent chromatography / tandem mass spectrometry. The analysis was performed. The limit of quantification was 25 μg / L for each analyte.

[0214] The PK data shown in Table 12 was calculated from the collected samples.

[0215] [Table 13]

[0216] The above data shows that surfactants with an HLB of 10 or higher and polynuclear iron (regardless of the route of administration) III) The addition of polysaccharide complex compounds clearly demonstrates a good combined effect, but the interface activity of Example 5 Surfactants with even higher HLB compared to pharmacokinetic agents have a positive impact on achieving pharmacokinetic properties. To further enhance it.

[0217] To summarize the above examples 1 to 6, surfactants with an HLB value of 10 or more are found to be Toltraz The already improved pharmacokinetic properties of the combination of lyl polynuclear iron(III) polysaccharide complex compounds are substantial To increase, and such effects are not limited to formulations which are solutions or dispersions of the active substance. And it may become clear that such effects are not due to that particular application route.

Claims

1. This formulation was intended for the simultaneous treatment of coccidiotic infections and iron deficiency in non-human animals. The preparation is toltrazuril or diclazuril, a polynuclear iron(III) polysaccharide complex compound. A formulation comprising at least one surfactant having an HLB value of 10 or higher.

2. (a) 3.5% toltrazuril, 17.8% iron (as greptoferon), 0.3% Sorbitan monooleate, 10% diethylene glycol monoethyl ether, 0.1% From copolymer polyoxyl 35-castor oil and water added to make 100% A formulation, (b) 3.5% toltrazuril, 19.4% iron (as greptoferon), 0.3% Sorbitan monooleate, 0.1% copolymer polyoxyl 35-castor oil, and A preparation consisting of water added to make a total of 100% (c) 3.5% toltrazuril, 19.3% iron (as greptoferon), 0.3% Propylene glycol monolaurate, 0.1% copolymer polyoxyl 35-castor phosphate. A preparation consisting of kerosene, 1% sodium chloride, and water added to make 100%. (d) 3.5% toltrazuril, 19.4% iron (as greptoferon), 0.3% Sorbitan monooleate, 0.1% copolymer polyoxyl 35-castor oil, and A preparation consisting of water added to make a total of 100% A formulation for use according to claim 1, excluding a formulation selected from a list consisting of the following.

3. (a) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.1% DocuSate sodium, 0.1% silicone emulsion, 1.5% sodium chloride, A preparation consisting of water added to make up 100% of the total, (b) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.1% DocuSate sodium, 5% diethylene glycol monoethyl ether, 0.1% silica Consists of a con emulsion, 1% sodium chloride, and water added to make 100%. formulation, (c) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% Phenol, 0.2% DocuSate Sodium, 0.1% Simethicone Emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 0.5% sodium chloride A preparation consisting of water added to make a total of 100% (d) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% Phenol, 0.2% DocuSate Sodium, 0.1% Simethicone Emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride and 1 A preparation consisting of water added to make a 00% solution. (e) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.6% Phenol, 0.1% DocuSate Sodium, 0.1% Simethicone Emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride and 1 A preparation consisting of water added to make a 00% solution. (f) 2.9% toltrazuril, 18.8% iron (as greptoferon), 0.6% Phenol, 0.1% DocuSate Sodium, 0.1% Simethicone Emulsion USP 30%, 0.5% colloidal silicon dioxide, 1% povidone, 1% sodium chloride and A preparation consisting of water added to make 100%. A formulation for use according to claim 1, excluding a formulation selected from a list consisting of the following.

4. (a) 2.9% toltrazuril, 18.8% iron (as greptoferon), 0.3% Sorbitan monooleate, 0.1% copolymer 15 polyoxyl 35- hydrogenated castor oil, A preparation consisting of 1.5% sodium chloride and water. (b) 4.2% toltrazuril, 13.5% iron (as greptoferon), 0.3% Sorbitan monooleate, 0.1% copolymer polyoxyl 35-castor oil, 1. A preparation consisting of 5% sodium chloride and water, and (c) 4.2% toltrazuril, 13.5% iron (as greptoferon), 1% chloride Sodium, 1% polyvinylpyrrolidone, 0.6% phenol, 0.5% colloidal diacid Silicon, 0.1% sodium docusate, 0.1% simethicone emulsion, and water A preparation consisting of, A formulation for use according to claim 1, excluding a formulation selected from a list consisting of the following.

5. Except for the formulation selected from the list described in claims 2 to 4, the use described in claim 1 Eye preparation.

6. When toltrazuril is used, copolymer polyoxyl 35-castor oil or The use described in claim 1, excluding formulations containing sodium docusate as a surfactant. A formulation for that purpose.

7. At least one of the surfactants having an HLB value of 10 or more is docusate sodium Um, polysorbate, copolymer polyoxyl 35-hydrogenated castor oil, Pluroni c Selected from the list of F-68 and Vitamin E TPGS (HLB 13.2) A formulation for use according to any one of claims 1 to 5.

8. At least one of the surfactants having an HLB value of 10 or more is polysorbate 20 and a selection from the list of polysorbate 80, as described in any one of claims 1 to 7. A formulation for use on a device.

9. At least two surfactants having an HLB value of 10 or higher are present in the formulation. A preparation for use as described in item 8.

10. At least two of the surfactants are polysorbate 20 and polysorbate 80. A formulation for use according to claim 9.

11. The use of the preparation used is a suspension, according to any one of claims 1 to 10. A formulation for this purpose.

12. The use described above is performed orally, as described in any one of claims 1 to 11. Eye preparation.

13. The use described above is performed by parenteral application, as described in any one of claims 1 to 11. A formulation for that purpose.

14. The formulation for use according to claim 13, wherein the use is performed by injection.

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