FR2946882A1 - GELIFIED VETERINARY SUSPENSION OF IRON - Google Patents

Abstract

Gelled veterinary suspensions comprising a high concentration of iron administered orally to non-human newborn mammals for the treatment and / or prevention of anemia and / or infectious diseases throughout the duration of breastfeeding.

Description

GELIFIED VETERINARY SUSPENSION OF IRON

The present invention relates to gelled veterinary suspensions comprising a high concentration of iron administered orally to non-human mammalian neonates. These suspensions will preferably be intended for the treatment and / or the prevention of anemias and / or infectious diseases for the duration of breastfeeding of these newborns. Iron deficiency anemia is quite common in newborn animals during lactation especially when reared indoors under intensive breeding conditions. Hepatic reserves of animals at birth are quite low, and the supply of iron from breast milk or colostrum is insufficient to cover the growth of farm animals. More often than not, there is no other natural source of iron available under modern intensive farming conditions whereby animals are confined to pens with concrete floors. However, the growth rate during the first weeks of life is rapid, which requires an increased iron intake to satisfy the expansion of blood volume. If the early stages of anemia are not immediately apparent, the more advanced stages of clinical anemia are generally characterized by a decrease in growth rate, intense fatigue, or even a lethargic state, and may even the appearance of dyspnoea and jerky muscular contractions of the diaphragm, and eventually the death of newborns. Iron-deficiency anemias are usually treated by oral or intramuscular iron administration to young animals. Traditional means consist in the repeated ingestion by newborns of iron supplements. These are iron salts such as iron fumarate, iron citrate, or iron sulfate. These traditional methods do not have a real feasibility in the case of farms, since they require resources of time and extra people to ensure regular administrations to each animal.

Iron-rich lining solutions are also not suitable for neonates before weaning who are not sufficiently independent. In addition, they do not guarantee that newborns can absorb enough iron to prevent the occurrence of anemia.

An indirect method is to supplement the mother during her gestation. This method increases iron transfer across the placenta and iron levels in breast milk. However, this indirect iron intake is still insufficient to eliminate deficiencies during breastfeeding. Finally, the treatments by means of iron injection have been proposed. Since iron salts are toxic at high concentrations, which can even lead to the death of newborns, iron must be complexed to a macromolecule, such as a carbohydrate or a polymer. By way of example, there may be mentioned Gleptoferron (Vétoquinol) which is a solution of iron bound to carbohydrates or Dexafer-200 (Vétoquinol) in which the iron is attached to a dextran polymer. These complexed iron solutions are generally injected intramuscularly. The active absorption of complexed iron is from the muscle to the lymphatic system and then released into the bloodstream. Some specialized liver cells absorb complexed iron from the blood, separate iron from carbohydrates or polymers. However, these compositions are very soluble in water and the iron thus complexed is therefore rapidly absorbed by the intestine: approximately within 24 hours

3 after injection, which forces the breeder to regularly renew the injections to ensure a constant supply of iron throughout the duration of breastfeeding.

Repeated injections are long and costly for breeders, and most often stressful for newborns. It is also recognized that intramuscular injections are undesirable because the iron that has not been absorbed remains fixed at the injection site, forms nodules in the muscles, thus rendering the meat unfit for consumption. .

In addition, the route of injection is known as the cause of local inflammation, septicemia, lameness and abscess related to the development and / or aggravation of arthritis Beyond the tolerance phenomenon described above, the Oral administration of iron reduces the stress of the animal related to injections and repeated manipulations, which are often the cause of immunosuppression of animals resulting in animals more susceptible to infections. administration of a sufficient quantity of iron, the quality and bioavailability of the iron which is administered, and the need to protect the newborns, in particular against anemia, throughout the duration of breastfeeding, but also to reduce the stresses for the breeder and additional stress for the animal during the curative or preventive treatments antiparasitics and / or antibiotics. The gelled iron suspensions according to the present invention aim to meet all these requirements.

The present invention relates to a gelled oral suspension comprising a high concentration of iron and a suitable gelling agent. This gelled suspension constitutes an iron matrix comprising a sufficient amount of iron, which is transformed into ferric iron as it progresses through the susceptible intestine. The ferric iron thus released continuously is then absorbed so as to cover the needs of the non-human newborn mammals throughout the period of breastfeeding until weaning.

The gelled suspensions according to the invention are therefore particularly useful as veterinary medicaments for the treatment or prevention of post-natal iron deficiency anemias. They guarantee a continuous release of bioavailable iron for several days so as to protect the newborns from iron deficiency before weaning and the administration of an enriched diet.

Advantageously, the veterinary compositions may be administered to newborns only at the same time as other postnatal care is provided, such as, for example, antibiotic treatments or antiparasitic treatments. It frees the breeder from the constraints of repeated administrations by reducing the number of animal handling. They are therefore particularly useful for treating or preventing the occurrence of post-natal iron deficiency anemias of non-human mammals before they are weaned. The present invention also relates to an apparatus adapted for oral administration, for example in the form of a feeding syringe, of a metering pump, which can be for example mounted on a bottle and on which can be adapted to a means of administration such as for example a rounded cannula.

The present invention further relates to a process for preparing a gelled oral suspension for veterinary use comprising a high concentration of free carbonyl iron. Gelled iron suspensions are likely to be stored in stable form for several months, and can be easily liquefied and homogenized by simple agitation.

Detailed description of the invention

The present invention relates to a gelled veterinary suspension comprising free iron in a high proportion of up to 30% and a gelling agent. The proportion of iron may be between 5% and 30%, or preferably between 10% and 25%. Preferably, the proportion of iron is about 20%. Free iron is iron which is not in salt form or in complexed form to a macromolecule. More specifically, it is iron carbonyl which is generally in the form of a micronized powder. The micronized ferrous iron particles may have an average size of about 3 to 7 m.

The gelling agent used in the suspensions according to the present invention confers particular rheological properties (pseudoplastic behavior), according to which the viscosity increases at rest (flow threshold) thus slowing down the sedimentation of the micronized iron particles, and the formation of cake, but decreases after simple manual agitation until the suspension becomes liquid so as to obtain a drinkable liquid suspension that can be administered orally directly into the mouth of non-human animals using for example a syringe or pump.

The gelling agents used preferably are colloidal silicas. Even more preferably, the gelling agent comprises a mixture of a colloidal silica and highly dispersed aluminum oxide in a ratio of 5: 1.

As described above, the gelled iron suspension is preferably in the form of a drinkable liquid solution. The gelling agent is then present in a proportion of between 0.25% and 5%, preferably between 0.5% and 4.5%, between 0.75% and 4%, preferably equal to 0.75%.

The gelled suspension has a viscosity of between 75 and 85 cps (centipoise) at 25 ° C after stirring at 200 s-1 with a flow threshold of 2.5 to 3.5 Pa. Alternatively, the gelled veterinary iron suspension may be in the form of a paste or a gum which is swallowed to the animal. The proportion of gelling agent is then greater than 2% and less than 10%, or between 5.5 and 7%.

According to a preferred embodiment of the present invention, the gelled iron oily suspensions further comprise at least one therapeutic agent, an oral antibiotic, and / or an oral antiparasitic agent for the treatment and / or prevention of non-human animals new -nés.

According to this embodiment, oily gel suspensions are preferably supplemented with oral antiparasitics commonly used in pig farms, such as anthelmintic antiparasitics (oxybendazole, piperazine, flubendazole), or by antibiotics also administered orally. aminoglycosides, such as neomycin, beta-lactams such as ampicillin and amoxicillin, macrolides, such as spiramycin, and tylosin, polymixins, such as colistin, as well as phenolic antibiotics. such as thiamphenicol, chloramphenicol, and florfenicol. These molecules can be associated with the oral gelled iron suspensions according to the present invention, and are particularly useful for the treatment of piglets so as to reduce the workload of the farmer and reduce the handling of piglets. This preferred embodiment is also particularly advantageous since it makes it possible to reduce the stress of the animal, which is often at the origin of immunodepression of the animals, the immunocompromised animals then being more susceptible to infections.

In addition, the oral administration of iron has a real advantage compared to the universal use of the injectable route, especially in terms of tolerance. Indeed, the route of injection is known as the cause of local inflammation, septicemia, lameness and abscess related to the development and / or aggravation of arthritis to Streptococcus suis, a real drawback of the injectable route. comparison to the oral route.

The gelled iron oily suspensions can for example comprise orally tolerated antiparasitics, capable of combating parasitic infections such as coccidiosis, such as eimeriosis or toxoplasmosis. Coccidiosis is a parasitic infection caused by coccidian protozoa that gradually invade the intestinal epithelium, preventing the absorption of nutrients, leading to weight loss in contaminated animals that may even eventually lead to death. Conventional antibiotics, ionophore compounds and other non-antibiotic synthetic products are commonly used to treat coccidiosis.

Antiparasitic agents that may be mentioned include anticoccidial antiparasitics belonging to the family of triazinones such as toltrazuril, ponazuril, or diclazuril. Preferably, the gelled iron oily veterinary suspensions are supplemented with a therapeutic amount of toltrazuril.

Among the antibiotics which may be used in oily oily iron suspensions, examples of antibiotics which may be ingested, for the treatment of infections caused by bacteria such as for example Salmonella, Staphylococcus, Pasteurella and Enterobacter, Shigella, Klebsiella, Escherichia Coli. As antibiotics, there may be mentioned preferably antibiotics belonging to the phenicolated family, such as chloramphenicol, thiamphenicol and florfenicol, or family of polymyxins, such as colistin. Preferably, the oily gel suspensions then comprise a therapeutic amount of florfenicol and / or colistin.

Veterinary gelled iron suspensions may further include other trace elements, such as calcium, magnesium, selenium, etc., vitamins, minerals, and / or nutrients that are well known to the body. skilled in the veterinary field according to the needs of each of the non-human animals treated. Advantageously, these suspensions may contain an effective amount of non-heme iron absorption promoting agents, such as vitamin C or ascorbic acid orally, ascorbic acid derivatives, such as ascorbyl palmitate, a synthetic ester composed of palmitic acid and L ascorbic acid also called vitamin C palmitate, or erythorbic acid.

When said gelled veterinary iron suspensions are supplemented with active agents such as antibiotics, antiparasitic agents, vitamins, minerals and / or other nutrients, it is then advantageous to add a so-called food oil tolerated orally. The addition of an oil makes it possible on the one hand to limit the degradation of sensitive active ingredients that one wishes to incorporate into the veterinary suspensions. In addition, it has been discovered by the Applicant that the addition of an oil makes it possible to limit the oxidation-reduction reactions which convert the Fe 2+ ions into Fe + ions, the H + ions into H 2, and lead to a release of hydrogen, when adding an active agent in aqueous solution. Such an oil may be chosen from animal food oils, such as cod liver oil, or from vegetable oils, such as, for example, soybean oil, olive oil, corn oil, peanut oil, cottonseed oil, sunflower oil, sesame oil, castor oil, almond oil, and mixtures thereof. Medium chain triglycerides, such as caprylic / capric acid triglycerides, terpene oils such as squalane and squalene, and mixtures thereof can also be used. According to the invention, it is preferred to use an oil such as medium chain triglycerides.

Advantageously, gelled iron suspensions do not include an antioxidant.

The gelled iron suspensions of the invention are useful for treating postnatal anemias of non-human mammals, such as for example piglets, lambs, calves, puppies, kittens, rabbits, and kids.

The effective therapeutic doses of the gelled suspensions according to the invention vary depending on the species treated. Those skilled in the art will know how to implement them at the required dosage. The concentration of free iron in the suspension object of the present invention will therefore be adapted so as to provide the required dose in a suspension volume acceptable for a single oral intake. In veterinary pharmacy, the dosage is usually given per kg of live weight of the animal. The dosage of these compounds ranges from 0.1 mg / kg to 1 mg / kg. The volume to be administered is of the order of 0.1 to 1 mL, depending on the type of animals for which they are intended.

They are administered during the breastfeeding period of newborns before weaning. Advantageously, the treatment of anemia is carried out by the administration in effective single therapeutic dose of the gelled veterinary suspension of iron. According to the invention, this single dose makes it possible to cover the iron needs of the newborns during the entire period of breastfeeding, while waiting for them to be able to eat a more balanced diet which will be supplemented with iron.

According to the invention, the gelled iron suspensions are not soluble in water and act as matrices or reservoirs when ingested by the newborns, thus allowing a continuous release in the intestine of carbonyl iron. , which resides longer in the intestine and thus oxidizes gradually to ferric iron. Ferric iron is thus absorbed and used by the body of newborns as and when the needs of the latter.

It was discovered by the Applicant that said suspensions thus guaranteed continuous and long-term protection throughout the duration of breastfeeding, without additional stress or stress for the breeder and the animal.

The present invention also involves the use of a gelled iron suspension as previously described for the preparation of a veterinary drug for the treatment of postnatal iron deficiency anemia of nonhuman newborn mammals.

The gelled veterinary suspensions of iron according to the invention can be administered orally, for example by means of a suitable apparatus such as a syringe or a measuring bottle by means of which the breeder can send directly to the mouth of the new breeders. born a sufficient amount of veterinary suspension. A feeding syringe or dosing pump is preferably used which can be mounted on a vial and on which is fitted a rounded cannula to facilitate administration without injuring the newborns.

Due to the low viscosity of the gelled veterinary iron suspension after shaking, it is easy to use it to administer the drug in drinkable form. Moreover, the suspension having a very good homogeneity and low viscosity after stirring, the dosage is particularly easy and accurate.

Furthermore, as demonstrated in the examples below, it is remarkable that the stability of gelled veterinary iron suspensions after several months of storage. No degradation of iron or active agent such as toltrazuril has been observed.

According to a last aspect, the subject of the present invention is a process for preparing a gelled suspension of iron for veterinary use comprising a high concentration of free iron carbonyl as previously described, stable for at least 1 year of storage, and capable of to be liquefied and homogenized after simple manual stirring. The preparation process 30 consists of adding the micronized iron powder in a proportion of up to 10

30%, and preferably up to 20%, and a gelling agent such as a colloidal silica, preferably a 5: 1 mixture of colloidal silica and a highly dispersed aluminum oxide.

EXAMPLES Example 1: Preparation of a gelled suspension of iron The suspension was prepared by the addition of the ingredients listed in Table 1 below: Table 1 INGREDIENTS QUANTITIES Iron carbonyl 25 g Colloidal silica and aluminum oxide highly dispersed 0.75 g in proportion 5: 1 1 9 Sorbitan monooleate QSP 100mI Medium chain triglycerides Example 2: Preparation of a gelled suspension of iron and toltrazuril The suspension was prepared from the ingredients listed in Table 2 below Table 2 INGREDIENTS QUANTITIES Toltrazuril 5g Iron carbonyl 20 g Example 3: Stability study of the different batches The results of the stability study after storage at 25 ° C. at 60% relative humidity (RH) for 4 months are given in Table 3 below.

Table 3 Product TOLTRAZURIL IRON 25 ° C at 60% relative humidity (RH) TO T 4 months DETERMINATIONS SPECIFICATIONS Results Results General characteristics Appearance After 1 minute Compliant Manual agitation conformation, gray suspension obtained Relative density # 1, 1.15 1.15 Identification (HPLC) Toltrazuril (HPLC) Tr identical to the Conform Conform reference substance Dosage Toltrazuril (HPLC) 4.75-5 5.25 5.00 5.00 g% ml Iron 18.0 22.0 19.1 19.2 Degradation product (HPLC%) Toltra-biuric <LOD <LOD Unknown 1.0 <LOD <LOQ Total (known + <1.0 - - unknown) <2.0 - - Colloidal silica and highly dispersed aluminum oxide in proportion 5: 1 Sorbitan monooleate Triglycerides with medium chain QSP 100mI 0.75g 1g

14 No degradation of the iron or pest control agent, toltrazuril, has been observed. The same observations were made in Table 4 below after storage at 40 ° C at 75% relative humidity (RH) or at 50 ° C.

Table 4 STORAGE TOLTRAZURIL IRON 40 ° C to 75% RH 50 ° C TO T 4 months TO T 4 months DETERMINATIONS SPECIFICATIONS Results Results Results Results General characteristics Appearance After 1 minute Conform Complies Compliant Manual agitation conformation obtained a gray suspension Density relative # 1,15 1,15 1,15 1,15 1,15 Identification (HPLC) Toltrazuril (HPLC) Tr identical to Conform Conform Conform Conform reference substance Toltrazuril Assay (HPLC) 4.75 - 5.25 5, 00 5.01 5.00 5.00 5.05 g% ml Iron 18.0-22.0 19.1 19.5 19.1 19.5 Product of degradation (HPLC%) Toltra-biuré <LOD <LOD <LOD < LOD Unknown 1.0 <LOD <LOQ <LOD <LOQ Total (known + <1.0 - - unknowns) <2.0 - -

Example 4: Effectiveness of suspensions in the preventive treatment of newborn piglets against post-natal iron deficiency anemia

The efficacy of gelled iron suspensions was tested in comparison with injectable iron dextran compositions according to the protocol shown in the following Table 5.

Group 1 comprises piglets which receive by administration (adm) single oral at 3 days of age the gelled iron suspension according to the invention (designated C629), followed by a single oral administration of iron (placebo) on the 14th day. postnatal.

Group 2 includes piglets receiving oral single administration on day 3 of the gelled iron suspension (designated C629) followed by a single injection of dextran iron at day 14 postnatal.

Group 3 comprises piglets which receive, in single oral administration, on the 3rd postnatal day, the gelled iron suspension according to the invention.

Group 4 includes piglets that receive a single injection of dextran iron and a dose of oral toltrazuril on the 3rd postnatal day.

Group 5 includes piglets that receive placebo (oral iron) as a single oral dose on day 3 and day 14 postnatal day. Iron concentrations in the blood plasma as well as hemoglobin levels are then measured throughout the duration of breastfeeding.

TABLE 5 THERAPEUTIC PROTOCOL Active Ingredient Dose Route of Administration Duration of Treatment GROUP 1 C629 0.4mL / kg b.w. Oral 1 single administration on day 3 + Placebo 0.4mL / kg b.w. Oral 1 administration (oral iron) single at day 14 GROUP 2 C629 0.4mL / kg b.w. Oral 1 single administration on day 3 + Iron dextran 10% 1-2mL / animal Injection 1 single injection (injection) on day 14 GROUP 3 C629 0.4mL / kg b.w. Oral 1 single administration on day 3 GROUP 4 Iron dextran 10% 1-2mL / animal Injection 1 injection only (injection) Day 3 + Toltrazuril 0.4mL / kg b.w. Oral 1 single administration on day 3 GROUP 5 Placebo (oral iron) 0.4mL / kg b.w. Oral 1 single administration on day 3 + Placebo (oral iron) 0.4mL / kg b.w. Oral 1 single administration on Day 14 CHECK Active Ingredient Dose Route of Administration Duration of Treatment Iron Dextran 10% 1-2mL / Intramuscular Piglet Single 3 Day Injection PETS Piglets 10 Plants of 8 Piglets Total of 80 Animals 16

Claims (15)

REVENDICATIONS1. Gelled oral veterinary suspension comprising free iron in a proportion of up to 30%, preferably up to 20% and a gelling agent in a proportion of 0.25 to 10%. 2. Suspension according to claim 1, characterized in that the gelling agent is present in a proportion of between 0.25 and 5% and the suspension is in the form of an oral suspension having a viscosity of between 75 and 85 cps. at 25 ° C after stirring, or the proportion of gelling agent is greater than 5%, and the suspension is in the form of a paste. 3. Suspension according to any one of the preceding claims, characterized in that the free iron is present in micronized carbonyl form. 4. Suspension according to any one of the preceding claims, characterized in that the gelling agent is a colloidal silica, or a mixture of colloidal silica and highly dispersed aluminum oxide in a proportion of 5: 1. 5. Suspension according to any one of the preceding claims, characterized in that it further comprises an oil and is in the form of a gelled oily suspension. 6. Suspension according to claim 5, characterized in that it further comprises at least one therapeutic agent, an antiparasitic agent, an antibiotic, and / or a promoter of nonhemic iron absorption. 17 25 30 18 7. Suspension according to claim 6, characterized in that the promoter of the absorption of non-heme iron is selected from ascorbic acid, ascorbyl palmitate, or erythorbic acid. 8. Suspension according to any one of the preceding claims, characterized in that it further comprises at least one vitamin, minerals, and / or trace elements. 9. The suspension as claimed in claim 6, wherein the antiparasitic compound belongs to the family of triazonines such as toltrazuril, ponazuril, or diclazuril, or to the family of antiparasitic anthelmintics, such as oxybendazole, piperazine, and flubendazole, and the oral antibiotic is selected from aminoglycosides, such as neomycin, beta-lactams such as ampicillin, and amoxicillin, macrolides, such as spiramycin, and tylosin, polymixins, such as colistin, or phenicolated antibiotics, such as thiamphenicol, chloramphenicol, and florfenicol. 10. Suspension according to any of the preceding claims for the treatment and / or prevention of infectious diseases and / or anemias in non-human animals during the lactation period, such as piglets, lambs, calves. puppies, kittens, rabbits, kids. 25 11. Suspension according to any one of the preceding claims, characterized in that it is administered in a single dose for the entire lactation period. 12. Suspension according to any one of claims 9-11 for the treatment of coccidiosis in piglets. 19 13. Use of a suspension according to any one of the preceding claims for the preparation of a medicament for the treatment and / or prevention of anemias and / or infectious diseases of non-human animals during the lactation period, characterized in that the suspension is administered in a single single dose throughout the breastfeeding period. 14. Process for the preparation of a gel suspension at a high concentration of free carbonyl iron according to any one of claims 1-12, stable for at least 1 year of storage, and homogeneous after stirring, characterized in that to the iron present in a proportion of up to 30%, and preferably up to 20%, a gelling agent such as a colloidal silica, preferably a 5: 1 mixture of colloidal silica and a highly aluminum oxide is added. scattered. 15. Apparatus for administering the suspension according to any of claims 1-12, in the form of a feeding syringe or dosing pump optionally mounted on a vial and adapted from a rounded cannula 20 to facilitate administration. .