Note: Descriptions are shown in the official language in which they were submitted.
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Formulations containing triazinones and iron
The invention relates to formulations containing triazinones and iron
compounds
(salts and complex compounds of iron) which are suitable for the simultaneous
control of coccidioses and anaemic states in animals.
Economically successful meat production operations are currently distinguished
by
highly intensive farming, that is to say by the keeping of a large number of
animals
which are specifically selected in order to optimize the breeding aim. These
farms
are characterized for example by the use of a great deal of machinery, the
additional feeding of food supplements, and the involvement of as little staff
as
possible. In the case of piglet rearing farms, this means that a large number
of sows
which are bred for a high number of piglets per litter are kept in suitably
large pig
houses. The optimization of the feed, and suitable selection in the breeding
process, make it possible for the piglets to grow rapidly.
This type of animal keeping is frequently the cause for an increasing number
of
certain typical diseases and deficiencies. Besides stress, to which in
particular
intensively kept pigs are very susceptible, such phenomena are, in young pigs,
protozoal infections (coccidioses) and anaemic states, inter alia, both of
which
already have to be kept under control by the prophylactic use of medicaments.
Coccidioses are frequently occurring, parasitic infectious diseases in
animals.
Thus, for example, protozoans of the genera Eimeria, Isospora, Neospora,
Sarcosporidia and Toxoplasma cause coccidioses all over the world. Examples of
economically important coccidioses are: infections of pigs with coccidia of
the
genus Isospora or of cattle with coccidia of the genus Eimeria. Infections
with
Isospora suis have only in recent years been recognized as the cause of
diarrhoea in
piglets and studied intensively. As a rule, an infection proceeds from the
environment to the piglets, or from piglet to piglet, via oocysts, which
contain in
each case two sporocysts with in each case two sporozoites. The parasitic
stages
multiply in the epithelial cells of the small intestine's villi. The clinical
picture of
the disease includes a necrotic, inflammatory destruction of the gut's
epithelial
cells with atrophying villi, and, as a result, impaired absorption and
digestion. The
characteristic of an acute disease is a liquid, whitish to yellow diarrhoea,
which
mostly occurs in week 2 to 3 of life. The weight gain of infected piglets is
reduced.
Treatment and therapy of the disease are insufficient to date. Antibiotics are
ineffective; while sulphonamides are approved for the treatment of
coccidiosis,
their effect is questionable, and frequently repeated administrations are in
any case
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unsuitable for practice. Other possible treatments are questionable: the
administration of, for example, monensin, amprolium or furazolidon has not
been
successful in preventing the disease in experimentally infected piglets. In
more
recent studies, Isospora suis has been identified in up to 92% of all litters
in some
farms, despite good hygiene. This type of disease is not limited to pigs, but
also
occurs in many other animal species, for example in poultry production, in
calves,
lambs or in small animals (rabbits).
An example of a deficiency is iron deficiency in newly-born piglets. Owing to
the
rapid growth in the first days after birth, the body's iron reserves are
rapidly
depleted and must be compensated for by external sources. Because of the large
number of suckling pigs, this substitution by taking up the sow's milk cannot
take
place in a sufficient degree. If, moreover, the animals are kept on concrete
or
plastic, the piglets cannot take up iron compounds by rooting in the ground
either.
The piglets become anaemic. A clinically significant anaemic state exists when
the
haemoglobin content of the blood has dropped to less than 80 g/1. The NRC
recommendation (National Research Council, Nutrient Requirements of Domestic
Animals, No. 2, Nutrient Requirements of Swine, National Academy of Sciences,
Washington DC, 1973) specifies 90 g/1 as the minimum haemoglobin value at
which the piglets grow healthily and show no signs of anaemia. Noticeable
symptoms such as weight loss or stunted growth are, however, only observed
when
the haemoglobin content of the blood has dropped to values of below 80 g/l.
Other
indicators for the iron supply are the haematocrit and the number of
erythrocytes
per unit volume. Severe iron deficiency anaemia also leads to the young pigs'
death.
Preparations are already available for controlling the abovementioned diseases
and
deficiencies.
Coccidiosis can be controlled successfully by administering active ingredients
from the triazinone group. To this end, one distinguishes between the
triazinediones - with examples of representatives being the active ingredients
clazuril, diclazuril, letrazuril - and the triazinetriones with the active
ingredients
toltrazuril, toltrazuril sulphoxide and ponazuril. Triazines, in particular
toltrazuril,
ponzazuril or diclazuril, and their activity against coccidia are known from a
series
of publications, see, inter alia, DE-A 27 18 799 and DE-A 24 137 22.
WO 99/62519 discloses semisolid aqueous preparations of toltrazuril sulphone
(ponazuril). It is also known that it is in particular toltrazuril which is
suitable for
treating coccidiosis (for example Isospora suis) in pigs. See, for example,
also the
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following publications: Don't forget coccidiosis, update on Isosporosis in
piglets.
Part I, Pig Progress volume 17, No. 2, 12-14; Mundt., H.-C., A. Daugschies, V.
Letkova (2001): be aware of piglet coccidiosis diagnostics. Part II, Pig
Progress
volume 17, No. 4, 18-20; Mundt, H.-C., G.-P1 Martineau, K. Larsen (2001):
control of coccidiosis Part III, Pig Progress volume 17, No. 6, 18-19.
Coccidioses in cattle as the result of infections with various pathogenic
Eimeria
spp. (for example E. bovis and E. ztimii) manifest themselves as diarrhoeas of
different severity up to bloody diarrhoeas accompanied by mortality.
W096/38140, DE 10049468, DE 19958388, W000/19964, W099/62519 or
WO 00/37063 and DE 102006038292.7 describe compositions against coccidiosis
in animals. Besides other routes of administration, oral administration is
also
mentioned there, in general form.
DE 19603984 contains granules for oral administration. DE 19824483 describes
semisolid aqueous preparations (pastes) for the treatment of animals. EP
0116175
describes solutions which can be applied orally.
In the sector of poultry rearing, preparations which are soluble in drinking
water,
or drinkable solutions, are frequently employed, while in farms where large
animals are kept one will tend to add the active ingredients to the feed or
administer it orally as a suspension, using an applicator (drench). Examples
of
important products on the market are diclazuril (2,6-dichloro-a-(4-
chloropheny1)-
4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; CAS No.
101831-37-2) (CLINACOXTM 0.5%, Janssen Animal Health; VECOXANTM,
Biokema SA) for admixture to the feed and toltrazuril (1-methy1-313-methy1-444-
[(trifluoromethypthio]phenoxy]phenyl] -1 ,3,5-triazine-2,4,6(1H,3H,5H)trione;
CAS No. 69004-03-1). Toltrazuril is available on the market for example as a
drinking water formulation for poultry and as an oral suspension formulation
for,
inter alia, the treatment of suckling pigs. It is recommended to administer,
to the
piglet, a dose of 20 mg/kg bodyweight on day 3-5 after birth.
The disadvantage in the oral administration of the abovementioned
anticoccidials
(sometimes also somewhat inaccurately referred to as coccidiostats) is that it
is
relatively laborious: the piglets must be caught and the product is
administered into
the throat with the aid of an applicator or a drench gun. Moreover, the method
causes not inconsiderable stress for the piglets.
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A series of quite different iron preparations, which differ both in the type
of
compound and in the mode of application and bioavailability, are available for
preventing iron deficiency anaemia. One distinguishes between (I) simple
inorganic Fe(2+) salts, (ha) complex compounds of Fe(2+) with organic ligands,
for example with lactic acid, or (IIb) of Fe(3+), for example with citric
acid, and
(III) polymer-type complex compounds of an Fe(3+) oxo-hydroxo complex f3-
FeO(OH) of the akaganeite type with carbohydrates/polysaccharides,
specifically
with oligomeric or polymeric carbohydrate compounds, such as, for example,
with
dextran or with dextrin/polymaltose. Hereinbelow, polymeric
carbohydrates/carbo-
hydrate compounds and polysaccharides are understood as meaning both
oligomeric and polymeric compounds.
Preparations of the type (I) which are to be administered orally, such as, for
example, the use of iron salts as feed additives, are customary and have been
known for a long time. The iron in these compounds is present in the form of
iron(2+) ions, for example as iron sulphate FeSO4. These products can either
be
added to the breeding sow's feed or else administered directly to the piglets
via the
oral route. In most cases, a plurality of single doses will be administered to
the
piglets during the first days of their life during the growth period in order
to
compensate for the relatively low bioavailability. An alternative route for
avoiding
multiple application is to feed, at a later point in time, an extra, iron-
containing
ration (prestarter and starter feed). While the iron ions in the inorganic
iron(2+)
salts are liberated rapidly by dissociation, the release in the iron(2+)
complex
compounds is somewhat delayed. The absorption of free Fe(2+) ions from iron
salts takes place in the upper small intestine. The solubility of Fe(2+) under
the
physiological conditions of the upper small intestine exceeds that of Fe(3+)
by
several powers of ten (Forth, W, in: Diinndarm, Handbuch der inneren Medizin,
Vol. 3 Verd. Org. Part 3(A); W.F. Caspary, Ed;, Springer 1983). Moreover, free
iron(3+) ions are reduced in the environment of the gut contents by cysteine,
glutathione, ascorbic acid and other substances to give Fe(2+) and absorbed
from
the epithelial cells of the gut's mucous membrane as such. However, it is
disputed
whether this reduction is a necessary prerequisite for the uptake into the
cells of the
mucosa. The reason why Fe(2+) has a greater bioavailability is probably the
concentration gradient as the result of the higher solubility of Fe(2+). The
current
opinion is that the Fe(2+) ions are first bound to the protein mobilferrin, on
which
they are reoxidized to Fe(3+) and bound the mucosal storage protein ferritin.
When
the body requires iron, these Fe(3+) are released into the blood plasma, where
they
are again reduced by a ferrioxidase to give Fe(2+) and bound to the protein
apo-
transferrin, the organism's iron-binding transport protein. Whether
transferrins are
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already present in the cells' mucosa and whether they receive the iron there
at least
in part is the subject of debate. With log K of approx. 30-31, transferrin's
complex
formation constant is so large that nowhere in the organism can free iron
exist as
long as transferrin's iron binding capacity is not exceeded. This is the
reason for
toxic effects which may occur as the result of a sudden oversupply of the iron
salts,
which is a disadvantage in their use. The iron is then transported via blood
and
lymphatic vessels to the haemoglobin synthesis sites in the bone marrow (cf.
E.
Kolb, U Hofmann "Anwendungen von Eisenverbindungen beim Schwein" [Uses
of iron compounds in pigs] Tiereirtzl. Umschau 60, (2005) 365-371 and Forth,
W,
"Eisen und Eisenversorgung des Warmblfiterorganismus" [Iron and iron supply of
the warm-blooded organism], Naturwissenschaften 74, (1987) 175-180 and John,
A.; "Neue Moglichkeiten der Eisenversorgung neugeborener Ferkel unter
Beachtung biochemischer Aspekte" [Novel possibilities of supplying iron to new
born piglets, taking account of biochemical aspects] in: Treichtigkeit und
Geburt
beim Schwein [Pregnancy and birth in pigs], 8th Bernburger Biotechnology
Workshop 2002, 89-94). Iron which is not required remains stored in the cells
of
the mucosa, but is no longer available after they have died. It is therefore
understandable that the bioavailability of oral iron compounds greatly depends
on
other factors such as the actual iron requirement, the feeding state
(colostrum) and
the state of health (diarrhoea: premature loss of the upper cells of mucosa).
It is
important to understand the mechanism in order to comprehend and estimate the
advantages and disadvantages of certain iron preparations.
Compounds from the second group (II) of the Fe(2+) and Fe(3+) compounds
which are complexed in a chelate-like manner are furthermore used. These
compounds form relatively stable iron complexes which are only partly broken
down into the ions by the gastric acid. In the course, the bioavailability is
the result
of the partial exchange of the iron with the ligands at or in the cells of the
mucosa,
which depends on the complexes' formation constants. Complexes which are not
broken down are capable, as the result of their higher lipophilicity, of
crossing the
epithelium's membrane systems and must be metabolized. This explains why
organic low-molecular-weight complexes have a slower bioavailability, but, in
turn, a more sustained effect (H. Dietzfelbinger; "Bioavailability of Bi- and
Trivalent Oral Iron Preparations"; Arzneim.-Forsch./Drug. Res 37(1), No. la,
(1989) 107-112 and E.B. Kegley et al., "Iron Methionin as a Source of Iron for
the
Neonatal Pig", Nutrition Research 22 (2002) 1209-1217).
The third group of compounds which are applied mainly parenterally and only to
a
minor extent orally consists of fairly stable compounds of the poly-3-FeO(OH)
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type with complex-bound polymeric carbohydrates. Commercial importance has
been gained mainly, but not exclusively, by iron(III) dextran (CAS No.
9004-66-4), iron(III) hydroxide polymaltose (iron(III) hydroxide dextrin; CAS
No.
53858-86-9), iron(III) sucrose (iron(III) sucrose, iron(III) "sugar" CAS No.
8047-
67-4) and sodium/iron(III) gluconate complex in sucrose solution (CAS No.
34089-81-1). The literature reveals different names for these compounds. In
this
context, compounds such as iron(III) dextran, iron(III) polymaltose, iron(III)
dextrin, iron(III) sucrose, iron(III) gluconate, sugar are understood as
meaning
complexes of the iron(3+) ion with hydroxide ions (OH), aquo groups (H20) and
oxygen (0), which complexes are present in oligomeric or polymeric form and
which are associated, in their coordination sphere, in the form of complexes
with
one or more of the abovementioned oligomeric and polymeric carbohydrate
compounds. This is why the compounds are also referred to as iron(III)
hydroxide
polysaccharide or iron(III) oxy-hydroxy polysaccharide, where polysaccharide
stands for the abovementioned oligo- and polymeric carbohydrate compounds or
their derivatives or, generally, for compounds from the group of the
oligomeric or
polymeric carbohydrates. Polynuclear iron(III) complexes of this type are
described for example in (D.S. Kudasheva et al., "Structure of Carbohydrate-
bound Polynuclear Oxyhydroxide Nanoparticles in Parenteral Formulation", J.
Inorg. Biochem. 98 (2004) 1757-1769; 1 Erni et al., "Chemical Characterization
of Iron(III) Hydroxide-Dextrin Complexes" Arzneim.-Forsch./Drug Res. 34 (II)
(1984) 1555-1559; F. Funk et al., "Physical and Chemical Characterization of
Therapeutic Iron Containing Materials", Hyperfine Interactions 136 (2001) 73-
95;
E. London "The Molecular Formula and Proposed Structure of the Iron-Dextran
Complex, IMFERON", J. Pharm. Sci. 93 (2004) 1838-1846; A. John "Neue
Moglichkeiten der Eisenversorgung neugeborener Ferkel unter Beachtung
biochemischer Aspekte" [Novel possibilities of supplying iron to new born
piglets,
taking account of biochemical aspects], Trachtigkeit und Geburt beim Schwein
[Pregnancy and birth in pigs] : 8th Bernburger Biotechnology Workshop,
Bernburg (2002) 89-94). Since in many cases the composition of these compounds
is not described in quantitative terms, and may also vary within the
compounds,
depending on the type of preparation, these polynuclear iron(III)
polysaccharide
compounds are understood as meaning all complexes of the above-described class
of compounds which are known to the skilled worker.
These iron compounds are used almost exclusively in the manufacture of
preparations for injection for human and veterinary medicine. In veterinary
medicine, however, a few preparations for oral administration are also in use.
These complexes are generally distinguished by high stability and differ
mainly
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with regard to their mollar weight, which may vary from 30 kDa up to 400 kDa,
and in the strength of the complex binding. In aqueous solution, they are
present as
colloid dispersions with a particle size of 7-35 nm. What is decisive for the
bioavailability in the case of oral administration is, firstly, the extent of
precipitate
formation and of the hydrolysis of the iron core under the influence of
gastric acid,
and secondly, the stability of the complexes under acidic reducing conditions.
The
mechanisms of the uptake into the organism and the conversion to biological
iron
compounds are not fully elucidated as yet and in some cases still debated in
the
literature. However, some general statements on the mechanism of action can be
made. The more stable the complex, the greater the portion of the compound
which
passes through the stomach without modification, and the smaller the portion
of
free iron ions. The stability of the complexes, in turn, depends on the
synthetic
process. High-molecular-weight iron(III) polymaltose and iron(III) dextran
have
proved to be fairly stable. In contrast, it is necessary to release the iron
to the
proteins of the transport pathway. Naturally, this transfer will become less
with
increasing stability of the complexes. These relationships have been confirmed
by
various experiments with acids, reducing agents and with complexing agents (R.
Lawrence "Development and Comparison of Iron Dextran Products"; PDA J
Pharm. Sci. Techn. 52(5) (1998) 190-197; F. Funk et al., "Physical and
Chemical
Characterization of Therapeutic Iron Containing Materials"; Hyperfine
Interactions 136 (2001) 73-95; I. Erni et al., "Chemical Characterization of
Iron (III) Hydroxide-Dextrin Complexes" Arzneim.-Forsch./Drug Res. 34(11) 11
(1984) 1555-1559).
These considerations have given rise to the doctrine that Fe(3+) compounds in
general, and in particular polynuclear compounds such as iron(III) dextran,
are not
suitable , for oral application (H. Dietzftlbinger "Bioavailability of ii- and
Trivalent Oral Iron Preparations" Arzneim.-Forsch./Drug Res. 37(I), No. 1(a)
(1987) 107-112).
A further reason for being reluctant to use polynuclear Fe(3+) complexes, in
particular iron(III) dextran, orally is the specific uptake pathway of 0-
FeO(OH)
complexes in the intestinal tract. These compounds are taken up by pinocytosis
into the gut mucosa's epithelial cells and must then be released to the
organism via
the lymphatic system, stored in the lymph nodes and finally transported on
into the
bloodstream (cf also abovementioned publications by Kolb, Hofmann; Forth;
John). Since - as explained above - they are fairly stable, the
bioavailability will
subsequently depend on the metabolism and the enzymatic degradation of the
complexes via lysosomal enzymes. Experiments with polyvinylpyrrolidone,
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dextran and with dye-labelled iron(III) dextran with in each case different
molecular weights have demonstrated that, in suckling pigs, these polymer
complexes can be taken up by pinocytosis via the epithelial cells of the ileum
and
the upper small intestine in the first days of life (R.M Clarke, R.N. Hardy
"Histological Changes in the Small Intestine of the Young Pig and Their
Relation
to Macromolecular Uptake"; J. Anat. 108(1), (1971) 63-7; K. Thoren-Tolling, L.
Jonsson "Cellular Distribution of Orally and Intramuscularly Administered Iron
Dextran in Newborn Piglets", Can. J. Comp. Med. 41 (1977) 318-325; K
Martinsson, L. Jonsson "On the Mechanism of Intestinal Absorption of
Macromolecules in Piglets Studied with Dextran Blue", ZbL Vet. Med. A 22
(1975)
276-282). However, it is also known that this transit of high-molecular-weight
compounds from the cells of the mucosa into the lymphatic system and
bloodstream of the piglets is only possible without hindrance immediately
after
birth. This mechanism ensures that the piglets can be supplied with
immunoglobulins and antibodies immediately after birth by taking up the sow's
colostrum. As soon as this supply is ensured, the transport mechanism becomes
defunct. This "intestinal closure" during the further course of growth is
biologically meaningful in order to avoid infections with microorganisms and
toxins (K. Martinsson, L. Jonsson "The Uptake of Macromolecules in the Ileum
of
Piglets after Intestinal Closure", ZbL Vet. Med. A 23 (1976) 277-282). The
period
between birth and intestinal closure therefore depends greatly on the piglets'
nutritional status. In starving piglets, this transfer may still take place up
to four
days after birth (J.G. Lecce, D. 0. Morgan "Effect of Dietary Regimen on
Cessation of Intestinal Absorption of Large Molecules (Closure) in the
Neonatal
Pig and Lamb", J. Nutrition 78 (1962) 263-268). Since, however, current
keeping
conditions at the breeders' naturally allow suckling, it is current knowledge
and
generally medically acknowledged that a sufficient supply of piglets with high-
molecular-weight iron complexes via the oral route is only possible, in a
meaningful manner, in the first hours after birth if multiple applications are
to be
avoided. Those few authors who have systematically studied the efficacy of
iron(III) dextran as a function of the timing of the oral application report
on a
substantially reduced activity when the iron(III) dextran is administered 24-
72 h
after birth (L. Blomgren, N. Lanneck "Prevention of Anaemia in Piglets by a
Single
Oral Dose of Iron Dextran", Nord. Vet.-Med. 23 (1971) 529-536). Depending on
the keeping and feeding conditions, however, an administration on day 2 of
life
will still give sufficiently good results (S. Kadis, "Relationship of Iron
Administration to Susceptibility of Newborn Pigs to Enterotoxic
Colibacillosis";
Am. J. Vet. Res. 45(2), (1984) 255-259). In contrast, when administering the
iron
dextran 72-96 h after birth, the efficacy is already greatly reduced (Ueda H.
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"Prevention of Piglet Anaemia by Oral Administration of Iron Dextran",
Nicchiku
Kaiho 56(11), 1985, 872-877). This is why only few oral iron substitution
products with polynuclear iron complexes have penetrated the market
(Ursoferran
150 p.o.; Serumwerke Bernburg - Eisen(III)-Dextran; Ferrum Hausmann Syrup
Hausmann Laboratories Inc., St. Gallen; - Eisen(III)-hydroxid-polymaltose. In
modern iron dextran preparations for oral use in breeding piglets, the iron
dextran
is bound to the emulsifiers of microemulsion droplets 1-2 pm in size in order
to
improve their bioavailability (Bioveyxin FeVitTm, Veyx-Pharma GmbH,
Schwarzenborn; SintaFerTM, Sinta GmbH, Schwarzenborn). This finely dispersed
state, and the fact that they are bound to lipophilic carriers, are intended
to promote
the uptake into the epithelial cells and the transfer into the organism. Even
with
these preparations, however, the manufacturer recommends that they be used up
to
no more than 8-10 h after birth in order to achieve an optimal effect. This,
in turn,
requires the continuous monitoring of the breeding sows, which means a great
deal
of labour.
In general, a dosage rate of 100-200 mg of active iron per piglet and per unit
dose
is recommended for oral iron preparations in order to ensure a sufficiently
high
activity. Only the higher dose, though, makes it possible in practice to
manage with
a single administration.
To circumvent the above-described imponderabilities in the case of oral
application, it is more conventional in pig rearing to administer polynuclear
iron(III) complexes intramuscularly by means of an injection. This is carried
out as
a rule by injecting 100-200 mg of active iron on day 3 after birth. The
transport
away from the site of injection takes place via the lymphatic system and the
cells
of the reticulohistiocytary system. The complexes are stored in the liver and
the
spleen, from where they are liberated as required and metabolized
enzymatically.
The free Fe(3+) is ultimately again bound to transferrin and transferred to
the sites
of use in the bone marrow.
However, this parenteral application form, too, has a series of disadvantages:
a
pronounced disadvantage of the intramuscular application (by intramuscular
injection) to young pigs is that harmful effects occur more often. Muscle
bleeding,
changes in the muscle fibres, inflammations and the development of oedemas are
caused more frequently at the sites of injection. These are local stances of
damage.
However, damage to the heart muscle is also observed, in particular when there
is a
simultaneous deficiency of vitamin E. In these cases, a pronounced increase in
the
potassium content in the blood plasma can be observed, which causes severe
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damage to the heart muscle and may lead to the death of the piglets. It is the
current opinion that minute amounts of free Fe(2+) ions are responsible for
the
formation of free-radical compounds with organic molecules, for example the
lipid-peroxide compounds, which are associated with the high potassium content
in
the blood. Vitamin E acts as a free-radical scavenger and is capable of
buffering
these harmful reactions in a certain manner, but this frequently exceeds the
body's
capacities (this is why vitamin E is also added to the oral preparations which
have
already been mentioned, in which the iron(III) dextran is bound to
microemulsion
droplets). However, there is a further disadvantage to intramuscular
application in
this regard: after the iron(III) dextran has been administered, a certain
reduction in
the immune system's performance must be expected since the macrophages in the
blood are loaded with the polynuclear iron complexes. The defence against
bacterial infections is reduced. An overview of the above-described
disadvantages
of the intramuscular administration is found in the literature (E. Kolb, U.
Hofmann
"Zur Frage der zweckmelfligen Form der Anwendung von Fe-Dextran, seiner
Verwertung sowie des Mechanismus einer moglichen Scheidigung der Ferkel" [On
the expedient form of administering Fe-dextran, its utilization, and the
mechanism
of potential damage to the piglets]; Mh. Vet.-Med 44 (1989) 497-501).
In summary, it can be said that each of the methods of anaemia prophylaxis, in
suckling pigs, which are currently available on the market has a series of
disadvantages:
1.
According to the literature, when Fe(II) compounds of type (I) and (II)
are applied orally, a markedly lower bioavailability can usually be
observed. It is recommended to administer these preparations
repeatedly, which, in the case of intensive animal keeping, involves a
great deal of labour and is an economic disadvantage.
2. While the oral administration of polynuclear Fe(III) compounds of
type (III), in particular iron(III) dextran, leads to better results, with a
single dosage rate of approximately 200 mg of active iron being, as a
rule, sufficient to ensure a sufficient iron supply to the piglets, the
decisive disadvantage here is that a sufficient activity can, according to
current doctrine, only be achieved when the iron(III) dextran can be
administered to the piglets within the first 8-10 hours of life. This
could only be ensured if births in the rearing farms were monitored
around the clock, which is frequently not possible because it requires a
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great deal of labour. If this point in time is missed, substantial losses in
the piglets frequently result.
3. The iron preparations to be administered intramuscularly are more
advantageous on use since the administration in the period of from day
1 to day 3 after birth leads to very good results. However, the potential
of damaging the piglets as the result of toxic side effects and short-
term weakening of the immune system is disadvantageous. Oral
preparations do not have this disadvantage.
4. Taking furthermore into account the treatment of coccidiosis, for
example, with toltrazuril or similar compounds, which is frequently
necessary, it becomes clear that two passes - (1) catching the piglets on
day 1 after birth and the administration of, for example, iron(III)
dextran, then catching the piglets again on day 3 and oral
administration of a commercially available suspension formulation of
toltrazuril, or (2) catching the piglets on day 3 and separate
administration of the commercially available toltrazuril suspension for
oral administration and a formulation for injection of iron(III) dextran
(with the above-described disadvantages) - are very frequently required
for successful piglet rearing.
It would therefore be very advantageous to have available preparations which
would make it possible to combine the two passes without the above-described
disadvantages, i.e. without harmful side effects, while being reliable and
highly
effective. A suitable preparation might be, for example, a formulation of the
active
ingredient toltrazuril and of iron(III) dextran for oral administration to
piglets in
the period of day 1-3 of life after birth. However, preparations which combine
the
two passes would have to meet a series of conditions:
= Sufficient amount of active ingredient: one unit dose must contain an
anticoccidial substance in an amount sufficient for the pharmacological
activity, usually 20-70 mg, for example 30 mg, 44 mg or 50 mg toltrazuril, and
at least 100 mg, but better at least 150 mg, preferably 200-250 mg, of active
iron (corresponding to, for example, 400-600 mg of a polynuclear iron(III)
complex) for anaemia prophylaxis, which corresponds to the recommended
dosage rates of 20 mg of toltrazuril/kg bodyweight and 200 mg of active iron
per piglet. This corresponds to a concentration of 2-7% m/v of the
anticoccidial
substance and 10-25% m/v of active iron in the formulation (% m/v being
CA 02688613 2009-11-27
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understood as meaning the mass of the component in question in g per 100 ml
of volume).
= Low dose volume for oral application: for example, a dose volume of
approximately 1 ml is optimal in the case of suckling pigs since, when volumes
are markedly higher, the complete uptake by the piglets is frequently not
ensured. Larger amounts of fluid frequently escape from the mouth or are
vomited.
= Suitable consistency: the viscosity should be in a range which makes
possible
the administration via drench guns or syringes, for example between 10 and
2500 mPas. If the consistency is too liquid, the preparation might escape from
the animal's mouth after the application; if it is too high, a large-scale
administration by means of syringes or drench guns is too demanding for the
user and the animals, in particular piglets, have difficulties swallowing.
= Quality of the formulation: the physical and chemical stability, and the
pharmacological activity, must be ensured. Thus, it should be ensured for
example that iron ions do not adversely affect the chemical stability of the
anticoccidial substance. It should furthermore be ensured that, in the case of
a
suspension formulation, a distribution of the active ingredient which is as
finely dispersed as possible is retained, since coagulation or indeed
agglomeration of the dispersed active ingredient particles is disadvantageous.
This might adversely affect for example the pharmacological activity since the
dissolution rate, and thus the liberation of the active ingredient from the
particles in the gut, is reduced as the result of the smaller surface area.
= Activity upon administration with a longer period of time after birth: a
sufficient activity against coccidiosis and anaemia when administered in a
period of from day 1 to day 3 after birth is desirable, in particular in the
case of
single application.
= Sufficient anaemia prophylaxis upon single application: the amount of
iron to
be administered in the abovementioned small dose volume of the combination
preparation should be sufficiently high to suffice for covering the piglets'
iron
requirements under normal keeping conditions after single application.
The combination of triazinones and iron preparations in a suitable formulation
has
not been described to date.
CA 02688613 2015-06-09
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The present disclosure relates to:
1. Composition containing triazinones of the formulae (I) or (H)
Ri
0
0 44I
R2 0 CH3
(I)
or
R4 0
CN
R6 441 C 4110
N
R6
in which
RI
represents R3-S02- or
R2 represents alkyl, alkoxy, halogen or SO2N(CH3)2 and
1 5 R3 represents haloalkyl
R4 and R5 independently of one another represent hydrogen or Cl and =
R6 represents fluorine or chlorine,
or their physiologically acceptable salts,
and
iron(2+) or iron(3+) compounds selected from among:
(a) iron(II) carboxylic acid salts, iron(II) carboxylic acid complex
compounds
and iron(II) chelate complexes with amino acids
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,
(b) iron(III) carboxylic acid salts, iron(III) carboxylic acid
complex compounds
and iron(III) chelate complexes with amino acids and
(c) polynuclear iron(III) polysaccharide complex compounds.
In formulae (I) and (II), individual substituents preferably and especially
preferably have the following meanings:
R2 preferably represents alkyl or alkoxy having in each case 1 to 4 carbon
atoms, or represents fluorine, chlorine, bromine or SO2N(CH3)2; R2
especially preferably represents C14-alkyl.
R3 preferably represents fluoroalkyl having 1 to 4 carbon atoms,
especially
preferably trifluoromethyl.
The triazinones are well known per se as active ingredients against coccidial
infections; the triazinetriones such as, for example, toltrazuril and
ponazuril, and
the triazinediones such as, for example, clazuril, diclazuril and letrazuril,
may be
mentioned.
The triazinediones are represented by formula (II):
Clazuril (R4 = Cl, R5 = H, R6 = Cl in formula (II))
Letrazuril (R4 = Cl, R5 = Cl, R6 = F in formula (II)) and
Diclazuril (R4 = Cl, R5 = Cl, R6 = Cl in formula (II)).
Among these 1,2,4-triazinediones, diclazuril is most preferred.
Especially preferred as active ingredients are, in accordance with the
invention, the
triazinetriones of the formula (I) in which R2 and R3 have the following
preferred
and especially preferred meanings:
R2 preferably represents alkyl or alkoxy having in each case up
to 4 carbon
atoms, especially preferably methyl, ethyl, n-propyl, i-propyl.
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R3 preferably represents perfluoroalkyl having 1 to 3 carbon atoms,
especially
preferably trifluoromethyl or pentafluoroethyl.
The preferred triazinetriones are represented by the formula (I):
Toltrazuril (RI = R3-S-, R2 = CH3, R3 = CF3)
Ponazuril (RI = R3-S02-, R2 = CH3, R3 = CF3)
The dosage rate of the triazinone may vary according to the animal species, as
illustrated above. Conventional dosage rates are 1 to 60 mg active ingredient
per
kg bodyweight (mg/kg) of the animal to be treated per day, preferably 5 to
40 mg/kg and especially preferably 10 to 30 mg/kg.
In the case of oral administration, the toltrazuril dose is usually as
follows:
Pigs: 20 mg/kg bodyweight
Cattle: 15 mg/kg bodyweight
Sheep: 20 mg/kg bodyweight
Poultry: 15 mg/kg bodyweight
Except for poultry, toltrazuril is only administered once per treatment, so
that for
example in the case of pigs, cattle and sheep the dosage rates stated apply
both per
day and per treatment.
Suitable iron(2+) or iron(3+) compounds are:
(a) iron(2+) carboxylic acid salts, iron(2+) carboxylic acid complex
compounds and iron(2+) chelate complexes with amino acids
(b) iron(3+) carboxylic acid salts, iron(3+) carboxylic acid complex
compounds and iron(3+) chelate complexes with amino acids
(c) polynuclear iron(3+) polysaccharide complex compounds.
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Examples of iron compounds of type (a) which may be mentioned are: iron(II)
lactate (FeC6H1006), iron(II) gluconate (FeCi2H22014), iron(II) fumarate
(FeC4H204), and chelate complexes of iron with amino acids such as, for
example,
iron(II) bisglycinate (Fe(C21141\102)2), iron(II) methionate (Fe(C5HI0NO2S)2)
and
their hydrate compounds.
Examples of iron compounds of type (b) which may be mentioned are: iron(III)
citrate (FeC6H507), ammonium iron(III) citrate and, if appropriate, their
hydrate
compounds.
In the present context, iron compounds of group c) are understood as meaning
complexes of the iron(3+) ion with hydroxide ions (OH), aquo groups (1120) and
oxygen (0) which are present in oligomeric or polymeric form and which are
associated in their coordination sphere as complexes with one or more than one
of
the above oligomeric and polymeric carbohydrate compounds. This is why the
compounds are also referred to as iron(III) hydroxide polysaccharide or
iron(III)
oxyhydroxy polysaccharide, where polysaccharide represents the corresponding
oligomeric and polymeric carbohydrate compounds or their derivatives.
Polynuclear iron(III) complexes of this type are described for example in
(D.S.
Kudasheva et al., "Structure of Carbohydrate-bound Polynuclear Oxyhydroxide
Nanoparticles in Parenteral Formulation", J. Inorg. Biochem. 98 (2004) 1757-
1769; I. Erni et al "Chemical Characterization of Iron (III) Hydroxide-Dextrin
Complexes" Arzneim.-Forsch./Drug Res. 34 (II) (1984) 1555-1559; F. Funk et
al.,
"Physical and Chemical Characterization of Therapeutic Iron Containing
Materials", Hyperfine Interactions 136 (2001) 73-95; E. London "The Molecular
Formula and Proposed Structure of the Iron-Dextran Complex, IMFERON",
Pharm. Sci. 93 (2004) 1838-1846; A. John "Neue Moglichkeiten der
Eisenversorgung neugeborener Ferkel unter Beachtung biochemischer Aspekte"
[Novel possibilities of supplying iron to new born piglets, taking account of
biochemical aspects], Trachtigkeit und Geburt beim Schwein [Pregnancy and
birth
in pigs] : 8th Bernburger Biotechnology Workshop, Bernburg (2002) 89-94).
Since
in many cases the precise composition of these compounds is not described in
quantitative terms, and may also vary within the compounds, depending on the
type of preparation, these polynuclear iron(III) polysaccharide compounds are
understood as meaning all compounds which the skilled worker ascribes to this
class of compounds.
Examples of iron compounds of type (c) which may be mentioned are: polynuclear
iron(III) polysaccharide complex compounds in which a polynuclear 13-Fe0(OH)
CA 02688613 2016-02-04
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- 17 -
nuclear complex contains polymeric carbohydrate compounds associated at the
free
coordination sites, for example iron(III) dextran, iron(III) hydroxy
polymaltose (iron(III)
dextrin), nonstoichiometric compounds of f3-FeO(OH) with saccharides and
oligosaccharides "iron(III) sucrose" "iron(III) 'sugar'.
Other compounds which are preferably employed among the abovementioned iron
compounds are those of type (b) and of type (c), with the latter being
especially preferred.
Iron(III) dextran may be mentioned as an especially preferred example.
The present invention relates to an oral formulation comprising a triazinone
of the
formula (I)
0
N
N\
R2 0 CH3 (I)
in which
RI represents R3-S02- or R3-S-,
R2 represents alkyl, alkoxy, halogen or SO2N(CH3)2 and
R3 represents haloalkyl
CA 02688613 2016-02-04
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- 17a -
or a physiologically acceptable salt thereof,
and
a polynuclear iron(III) polysaccharide complex compound.
In another embodiment, the invention relates to the use of the formulation as
described
above for the preparation of a pharmaceutical.
In another embodiment, the invention relates to the use as described above for
the
preparation of a pharmaceutical for the simultaneous oral treatment of
coccidial
infections and iron deficiencies.
=
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30725-719
- 17b
¨
Preparations of the formulations according to the invention which are suitable
for
animals are preferably solutions, suspensions or pastes, gels. Suspensions or
pastes =
are preferred.
=
Solutions are prepared by dissolving the active ingredient, or active
ingredients, in
= suitable solvents or solvent mixtures. If appropriate, further adjuvants
such as
solubilizers, antioxidants, preservatives, thickeners, adhesives, pH
regulators, UV
stabilizers or colorants are added.
Solvents which may be mentioned are: physiologically acceptable solvents .
such as water, alcohols, such as, for example, monohydric alkanols (for
=
example ethanol or n-butanol), polyhydric alcohols such as glycols (for
= example ethylene glycol, propylene glycol, tetraglycol/glycofurol),
polyethylene glycols, polypropylene glycols, glycerol; aromatically
substituted alcohols such as benzyl alcohol, phenylethanol,
phenoxyethanol; esters such as ethyl acetate, butyl acetate, benzyl
benzoate, ethyl oleate; ethers such as alkylene glycol alkyl ethers (for..
example dipropylene glycol monomethyl ether, diethylene glycol
=
monobutyl ether); ketones such as acetone, methyl ethyl ketone; aromatic
= and/or aliphatic hydrocarbons, vegetable or synthetic oils; glycerol
formal,
solketal (2,2-dimethy1-4-hydroxymethy1-1,3-dioxolane), N-
methyl-
pyrrolidone, 2-pyrrolidone, N,N-dimethylacetamide, glycofurol, dimethyl-
isosorbitol, lauroglycol, propylene
carbonate, octyldodecanol,
dimethylformamide, and mixtures of the abovementioned solvents. =.
Solubilizers which may be mentioned are: solvents which promote the
= dissolution of the active ingredient in the main solvent or which prevent
its
precipitation. Examples are polyvinylpyrrolidone, polyoxyethylated castor
oil, polyoxyethylated sorbitan esters.
=
=
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Antioxidants are sulphites or metabisulphites such as potassium
metabisulphite or sodium metabisulphite, sodium disulphite or potassium
disulphite, ascorbic acid, isoascorbic acid, ascorbyl palmitate, gallic acid
esters, butylhydroxytoluene, butylhydroxyanisole or tocopherols.
Synergists of these antioxidants may be: amino acids (for example alanine,
arginine, methionine, cysteine), citric acid, tartaric acid, edetic acid or
their
salts, phosphoric acid derivatives or polyalcohols (polyethylene glycol).
Preservatives are: benzyl alcohol, benzalkonium chloride, trichlorobutanol,
p-hydroxybenzoate, n-butanol, chlorocresol, cresol, phenol, benzoic acid,
citric acid, tartaric acid or sorbic acid.
Thickeners are: inorganic thickeners such as bentonites, colloidal silica,
aluminium stearates, organic thickeners such as cellulose derivatives, for
example Hydroxypropylmethylcellulose 4000, polyvinyl alcohols and their
copolymers, xanthan, acrylates and methacrylates, carboxymethylcellulose
and its salts.
Adhesives are, for example, cellulose derivatives, starch derivatives,
polyacrylates, natural polymers such as alginates, gelatin.
Adhesives which also have thickening properties may likewise be
employed as thickeners.
pH regulators are pharmaceutically customary acids or bases. The bases
include alkali metal hydroxides or alkaline earth metal hydroxides (for
example NaOH, KOH), basic salts such as, for example, ammonium
chloride, basic amino acids such as, for example, arginine, choline,
meglumine, ethanolamines or else buffers such as tris(hydroxy-
methyl)aminomethane, citric acid buffers or phosphate buffers. The acids
include, for example, hydrochloric acid, acetic acid, tartaric acid, citric
acid, lactic acid, succinic acid, adipic acid, methanesulphonic acid, octanoic
acid, linolenic acid, gluconolactone, and acidic amino acids such as, for
example, aspartic acid.
UV stabilizers are, for example, substances from the class of the
benzophenones, or novantisolic acid.
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Colorants are all colorants which are approved for use on humans or
animals and which may be dissolved or suspended.
Suspensions are prepared by suspending the active ingredient, or active
ingredients, in a carrier liquid, if appropriate, with addition of further
auxiliaries
such as wetters, colorants, absorption accelerators, thickeners, adhesives,
preservatives, antioxidants, UV stabilizers or antifoams.
Carrier liquids which may be mentioned are all homogeneous solvents and
solvent mixtures.
The following may be mentioned as wetters (dispersants):
Surfactants (includes emulsifiers and wetters) such as
1. anionic surfactants, such as sodium lauryl sulphate, fatty alcohol
ether sulphates, the monoethanolamine salt of mono/dialkyl
polyglycol ether orthophosphoric acid esters, or lignosulphonates or
dioctylsulphosuccinate,
2. cationic surfactants such as cetyltrimethylammonium chloride,
3. ampholytic surfactants such as disodium N-laury1-13-imino-
dipropionate or lecithin,
4. nonionic surfactants, for example polyoxyethylated castor oil,
polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl
alcohol, glycerol monostearate, polyoxyethylene stearate,
alkylphenol polyglycol ethers, Pluronic .
Suitable antifoams are preferably those which are based on silicone, for
example
dimethicone or simethicone.
Further auxiliaries which may be mentioned are those detailed further above.
Preferred are suspensions and pastes, with low-viscosity pastes being
preferred
among the pastes. The pastes usually take the form of suspensions with a
correspondingly higher viscosity. The suspensions and pastes are preferably
administered orally.
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The formulations according to the invention comprise the triazinone active
ingredient in a concentration of from 0.1 to 30% (m/v), corresponding to 1 to
300 mg/ml, preferably 2 to 25% (m/v), corresponding to 20 to 250 mg/ml,
especially preferably 3 to 15% (m/v), corresponding to 30 to 150 mg/ml, in
particular 3 to 7% (m/v), corresponding to 30-70 mg of the triazinone in 1 ml.
As the result of the poor solubility of the triazinones, the latter are
frequently
present, in the formulations according to the invention, in finely divided
form.
Here, the dispersed triazinone has a particle size (measured by laser
diffraction,
Malvern Mastersizere 2000) of d(v,90) < 301AM, preferably d(v,90) < 2011m,
especially preferably d(v,90) < 10 gm, and very especially preferably d(v,90)
7 ,m or less.
For the purposes of the present invention, d(v,90) is to be understood as
meaning a
volume-related particle size distribution where 90% of all particles have a
dimension (diameter) of this value or less. Usually, this information is
referred to
as d(90), but the more precise term d(v,90) may be chosen in order to make
clear
that it is a volume-related particle size distribution. The names d(v,50),
d(v,10) and
the like are to be understood correspondingly. The particle sizes indicated
here
were determined with the laser diffraction method using the Mastersizer 2000
apparatus (dispersing unit Hydro 2000G) from Malvern and using the Fraunhofer
diffraction evaluation mode since the refractive indices of the active
ingredient
particles are not known. Here, a suitable amount of the sample solution is
predispersed, with stirring, with 2-3 ml of a dispersion medium (0.1% aqueous
dioctyl sodium sulphosuccinate solution). The dispersion is then placed into
the
dispersing unit of the apparatus, with stirring (300 rpm) and recirculating
(900 rpm), where it is measured. The evaluation software gives the particle
size as
d(0.5), d(0.9) values and the like.
These iron compounds in oral formulations for the treatment of iron deficiency
states in large animal farms are usually applied in concentrations of from 100
mg
of active iron to 200 mg of active iron per unit dose as a single or multiple
administration. In drinkable solutions for supplying iron in poultry fattening
operations, the dose may also amount to less than 100 mg of active iron per
unit
dose.
The formulations according to the invention contain the iron compounds usually
in
concentrations of from 10% (m/v) to 30% (m/v) of active iron, corresponding to
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100 to 300 mg active iron in 1 ml, preferably 11.4% (m/v) to 25% m/v,
corresponding to 114 mg to 250 mg active iron in 1 ml, but especially
preferably
from 20% m/v to 25% m/v, corresponding to 200 mg to 250 mg active iron in 1 ml
of the formulation. Active iron refers to the percentage of iron which is
present in
the formulation in the form of the iron complex. As a rule, the iron compounds
are
present in dissolved or colloidal form in the formulations. Finely divided
iron
compounds are less preferred in the formulations according to the invention.
The formulations according to the invention are preferably "water based". This
means that, as a rule, they contain from 10 to 90% by weight, preferably from
20 to
80% by weight, especially preferably from 30 to 50% by weight of water. For
example, the formulations as mentioned above may comprise further water-
miscible solvents. Further water-miscible solvents which may be mentioned by
way of example are preferably polyhydric aliphatic alcohols such as ethylene
glycol, diethylene glycol, triethylene glycol, propylene glycol and glycerol;
among
these, propylene glycol is especially preferred. Such further water-miscible
solvents are usually present in concentrations of from 1 to 45% by weight,
preferably from 1 to 20% by weight, especially preferably from 5 to 10% by
weight. The addition of such polyhydric aliphatic alcohols also has the
advantage
of lowering the freezing point of the formulation.
The amount of formulation to be applied per administration depends on how much
triazinone and iron are to be administered in each case. One aims at
relatively
small volumes which can be applied readily orally and which vary depending on
the animal species; for sucking pigs, for example, one aims at application
volumes
of from 0.3 to 2 ml, preferably from 0.5 to 1 ml.
It is advantageous when the formulations according to the invention permit an
easy
application, for example with the customary aids, for example a syringe, an
applicator or a drench gun, and when they, for this purpose, have a fluid,
slightly
thickened or slightly pasty consistency which manifests itself in a viscosity -
measured by forming the mean of the viscosity values measured at 20 C at shear
rates 128 s1 and 256 s-1 with a cone-plate arrangement of a rheometer (Thermo
Scientific RheoStress 600; cone diameter 35'; cone angle 4'; constant rate
mode) -
in a range of from 10 to 2500 mPas, preferably in a range of from 20 to
1500 mPas, especially preferably in a range of between 50 and 500 mPas and
very
especially preferably of between 20 and 250 mPas. In order to set a suitable
viscosity range, the inventive formulations comprise, where appropriate,
suitable
substances (thickeners), as already named above.
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Usually, the formulations according to the invention have a pH of from 3 to 8,
preferably of from 4 to 7, especially preferably of from 4 to 6. Examples of
suitable substances for regulating the pH have already been indicated further
above. Substances which are preferably employed for adjusting the pH are
organic
acids such as, for example, citric acid or tartaric acid, mineral acids such
as, for
example, hydrochloric acid - preferably dilute hydrochloric acid, for example
0.1 n
HC1, or bases such as, for example, sodium hydroxide solution (for example 1N
NaOH).
The formulations according to the invention as stated above can furthermore
contain preservatives, if appropriate in combination with what are known as
synergists. The preservatives are usually present in concentrations of from
0.01-5%
by weight and specifically of 0.05-1% by weight.
If required, antioxidants which may be employed in the formulations mentioned
are, preferably, BHA or BHT. To ensure a sufficient preservation, the
preservatives
may be employed singly or else in combination with what are known as
synergists.
Synergists such as citric acid, tartaric acid, ascorbic acid or the sodium
salt of
editic acid are usually present in concentrations of from 0.01-1% by weight,
specifically of 0.05-0.15% by weight.
If appropriate, the formulations according to the invention may contain
customary
antifoams in concentrations of from 0.01 to 1% by weight.
The formulations according to the invention are preferably prepared by
initially
introducing the solvent, preferably water, and predissolving or dispersing
therein if
appropriate auxiliaries and/or additives such as, for example, cosolvents,
preservatives, antioxidants and viscosity-regulating additives. In the
preferred
method, a second step involves introducing, into this initial solution, the
triazinone,
optionally in the form of a ready made dispersion concentrate, using a
powerful
homogenizer and homogenizing the mixture until the finely divided suspension
is
obtained. Then, the iron compound, preferably in the form of a powder, is
introduced into this dispersion, during which process the mixture is again
homogenized. In the last step, finally, the desired pH is adjusted by addition
of
suitable pH regulators. Individual or all auxiliaries and/or additives may, if
appropriate, also be added after the last homogenization step; this may be
advisable
for example in the case of certain thickeners, whose structure is destroyed by
the
homogenization process.
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The formulations according to the invention are suitable for the combined
control
of Coccidia and iron deficiencies, in particular in animals. Using the
formulations,
it is possible to administer, to the animals, the anticoccidial triazinones
and the iron
simultaneously in a simple manner. The formulations may be used in animal
keeping and animal breeding in livestock, breeding animals, zoo animals,
laboratory animals, experimental animals and pets. The spectrum of action of
the
triazinones is, in principle, well known. Coccidia which may be mentioned
individually are:
Mastigophora (Flagellata) such as, for example, Trypanosomatidae, for example
Trypanosoma brucei, T. gambiense, T. rhodesiense, T. congolense, T. cruzi,
T. evansi, T. equinum, T. lewisi, T. percae, T. simiae, T. vivax, Leishmania
brasiliensis, L. donovani, L. tropica, such as, for example, Trichomonadidae,
for
example Giardia lamblia, G. canis.
Sarcomastigophora (Rhizopoda) such as, for example, Entamoebidae, for example
Entamoeba histolytica, Hartmanellidae, for example Acanthamoeba sp.,
Hartmanella sp.
Apicomplexa (Sporozoa) such as, for example, Eimeridae, for example Eimeria
ascervulina, E. adenoides, E. alabahmensis, E. anatis, E. anseris, E.
arloingi,
E. ashata, E. auburnensis, E. bovis, E. brunetti, E. canis, E. chinchillae,
E. clupearum, E. columbae, E. contorta, E. crandalis, E. debliecki, E.
dispersa,
E. ellipsoidales, E. falciformis, E. faurei, E. flavescens, E. gallopavonis,
E. hagani,
E. intestinalis, E. iroquoina, E. irresidua, E. labbeana, E. leucarti, E.
magna,
E. maxima, E. media, E. meleagridis, E. meleagrimitis, E. mitis, E. necatrix,
E. ninakohlyakimovae, E. ovis, E. parva, E. pavonis, E. perforans, E. phasani,
E. piriformis, E. praecox, E. residua, E. scabra, E. spec., E. stiedai, E.
suis,
E. tenella, E. truncata, E. truttae, E. zuernii, Globidium spec., Isospora
belli, I.
canis, I. felis, I. ohioensis, I. rivolta, I. spec., I. suis, Neospora
caninum, N. hugesi,
Cystisospora spec., Cryptosporidium spec. such as, for example,
Toxoplasmadidae,
for example Toxoplasma gondii, such as, for example, Sarcocystidae, for
example
Sarcocystis bovicanis, S. bovihominis, S. neurona, S. ovicanis, S. ovifelis,
S. spec.,
S. suihominis such as, for example, Leucozoidae, for example Leucozytozoon
simondi, such as, for example, Plasmodiidae, for example Plasmodium berghei,
P.
falciparum, P. malariae, P. ovale, P. vivax, P. spec., such as, for example,
Piroplasmea, for example Babesia argentina, B. bovis, B. canis, B. spec.,
Theileria
parva, Theileria spec., such as, for example, Adeleina, for example Hepatozoon
CA 02688613 2009-11-27
BHC 07 1 052-FC - 24 -
canis, H. spec.
Furthermore Myxospora and Microspora, for example Glugea spec., Nosema spec.
Furthermore Pneumocystis carinii, and also Ciliophora (Ciliata) such as, for
example, Balantidium coli, Ichthiophthirius spec., Trichodina spec., Epistylis
spec.
Those genera and species of protozoans which lead to subclinical or clinical
infections in pigs must be very particularly emphasized, especially: Eimeria
debliecki, E. suis, E. scabra, E. perminuta, E. spinosa, E. polita, E. porci,
E. neodebliecki, Isospora suis, Cryptosporidium, Toxoplasma gondii,
Sarcocystis
miescheriana, S. suihominis, Babesia trautmanni, B. perroncitoi, Balantidium
coli.
The livestock and breeding animals include mammals such as, for example,
cattle,
horses, sheep, pigs, goats, camels, water buffalos, donkeys, rabbits, fallow
deer,
reindeer, fur-bearing animals such as, for example, mink, chinchilla, racoon,
birds
such as, for example, chickens, geese, turkeys, ducks, pigeons, ostriches,
bird
species which are kept as companion animals and as zoo animals. They
furthermore include farmed fish and ornamental fish. In this context, pigs,
cattle,
sheep and dogs of all species, subspecies and breeds may be particularly
emphasized.
Laboratory and experimental animals include mice, rats, guinea pigs, golden
hamsters, dogs and cats.
The pets include dogs and cats.
The use in pigs is especially preferred.
The formulations according to the invention are preferably applied to young
animals, in particular shortly after birth, preferably in sucking pigs.
Usually, the
formulations according to the invention (combined iron/triazinone preparation)
are
only applied once. Especially preferred formulations according to the
invention
permit the oral treatment of piglets in such a way that a sufficient supply of
the
piglets with iron in the first four weeks of life can be achieved with a
single oral
administration of from 0.7 ml-1.3 ml, preferably from 0.7-1.0 ml, of the
formulation, even on the third day after birth, where a haemoglobin value of
at
least 8 g/100 ml blood, preferably of more than 9 g/100 ml blood, may be
considered the indicator for a sufficient supply. In addition, the triazinone
portion
CA 02688613 2015-06-09
30725-719
- - 25 -
is intended to successfully control coccidia.
The formulations according to the invention may contain further active
ingredients
or components - singly or in suitable combinations -, such as, for example,
nutrients, which include, for example, vitamins, minerals, and phosphorus'
compounds which are suitable as metabolic and immune stimulants:
Vitamins such as, for example, vitamin E, vitamins from the B series such as,
for
example, vitamin B12, vitamin C.
Minerals, preferably calcium or magnesium salts, in particular for example
calcium
gluconate, calcium glucoheptanoate or calcium saccharate.
Phosphorus compounds, in particular pharmacologically acceptable organic
phosphonic acid derivatives which are suitable as metabolic stimulants and
tonics.
Preferred examples which may be mentioned are the compounds toldimfos and, in
particular, butaphosphane, which have already been known for a long time.
Subject matter of this disclosure thus relates to:
1. Formulation containing triazinones of the formulae (I) or (II)
11/ 0
>¨N11
0 411 N 0
N\
R2 0 CF-I3
(I)
or
R4
CN
R6 110 ) 0
N¨
R5
in which
CA 02688613 2009-11-27
BHC 07 1 052-FC - 26 -
_
R' represents R3-S02- or
R2 represents alkyl, alkoxy, halogen or SO2N(CH3)2 and
R3 represents haloalkyl
R4 and R5 independently of one another represent hydrogen or Cl and
R6 represents fluorine or chlorine,
or their physiologically acceptable salts,
and
iron(2+) or iron(3+) compounds selected from among:
(a) iron(II) carboxylic acid salts, iron(II) carboxylic acid complex
compounds and iron(II) chelate complexes with amino acids
(b) iron(III) carboxylic acid salts, iron(III) carboxylic acid complex
compounds and iron(III) chelate complexes with amino acids and
(c) polynuclear iron(III) polysaccharide complex compounds.
2. Formulation according to item 1, containing from 1 to 30%
(m/v),
preferably 3-7% (m/v) of triazinone.
3. Formulation according to one of the preceding items, where the dispersed
triazinone has a particle size of d(v, 90) 30 pm or less, preferably d(v, 90)
20 pm or less, and especially preferably d(v, 90) 10 pm or less.
4. Formulation according to one of the preceding items with an iron
compound concentration of from 10% (m/v) to 30% (m/v) of active iron,
preferably from 11.4% (m/v) to 25% (m/v), but especially preferably from
20% m/v to 25% (m/v).
5. Formulation according to one of the preceding items with a viscosity -
CA 02688613 2009-11-27
BHC 07 1 052-FC - 27 -
measured by forming the mean of the values measured at the shear rates
128 s-1 and 256 s-1 with a cone-plate arrangement of a rheometer - in a
range from 10 to 2500 mPas, preferably in a range from 20 to 1500 mPas.
6. Formulation according to item 1, which is water based.
7. Formulation according to item 1, containing at least one polyhydric
aliphatic alcohol.
8. Formulation according to one of the preceding items, containing a
polynuclear iron(III) polysaccharide complex compound from group (c)
whose polynuclear iron core consists of 3-Fe0(OH) units and which
contains polysaccharide molecules in the further sphere of coordination.
9. Formulation according to item 8, containing a polynuclear iron(III)
polysaccharide complex compound selected from: iron(III) dextran,
iron(III) hydroxy polymaltose/iron(III) dextrin and a nonstoichiometric
compound consisting of polynuclear 3-Fe0(OH) and sucrose and
oligosaccharides.
10. Formulation according to one of items 1 to 7, containing, as iron
compound
of group (b), an iron citrate compound, preferably ammonium iron(III)
citrate.
11. Formulation according to one of the preceding items, containing, as
triazinone, a triazinetrione.
12. Formulation according to item 11, containing, as triazinetrione,
toltrazuril,
ponazuril or toltazuril sulphoxide.
13. Formulation according to any of items 1 to 8 and 11 to 12, wherein the
triazinone is toltrazuril and the polynuclear iron(III) polysaccharide
complex compound is iron(III) dextran.
14. Formulation according to one of items 1 to 10, containing, as
triazinone, a
triazinedione, in particular clazuril, diclazuril or letrazuril.
15. Use of the formulations according to one of the preceding items for
the
preparation of pharmaceuticals.
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BHC 07 1 052-FC -28-
16. Use according to item 15 for the preparation of pharmaceuticals for
the
simultaneous treatment of coccidia infections and iron deficiencies.
17. Use according to item 15 or 16 for the preparation of pharmaceuticals
for
oral treatment.
18. Use according to item 17 for the preparation of pharmaceuticals for the
oral
treatment of suckling pigs.
19. Use according to one of items 17 or 18 for the preparation of
pharmaceuticals for the oral treatment of piglets in the period from birth to
10 days after birth, preferably in a period from birth to 3 days after birth.
20. Formulations according to one of items 1 to 14, additionally containing
one
or more nutrients.
21. Formulation according to item 20, additionally containing a calcium
salt or
magnesium salt.
22. Formulation according to item 20 or 21, containing butaphosphan.
The examples which follow are intended to illustrate the invention, but not to
limit
it:
CA 02688613 2009-11-27
BHC 07 1 052-FC - 29
Preparation examples:
Example 1
Use of iron(III) dextran powder 38.4% m/m
Batch for the preparation of 10 1 of an iron dextran/toltrazuril dispersion
(22.8%
mJv active iron + 5% m/v toltrazuril) for oral use in sucking pigs
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 1666.67
Sodium propionate (preservative) 17.00
Sodium benzoate (preservative) 17.00
Propylene glycol 1000.00
Anhydrous citric acid 87.10
Iron(III) dextran powder 38.4% m/m 5937.50
Water to 10 litres 5138.00
Viscosity regulating auxiliary/auxiliaries
Total mass 13863.27
In each case 17.00 g of the preservatives sodium propionate and sodium
benzoate
are, in separate vessels, weighed into 1000.00 g of the solvent propylene
glycol
and dissolved with stirring. All of the water is introduced into a stainless-
steel
vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is
needed and on the desired viscosity of the end product, a viscosity-regulating
auxiliary (known as a thickener) may be dissolved or incorporated into this
amount
of water. In Example 1, this is dispensed with. The propylene glycol premix is
added to what has been introduced into the stainless-steel vessel and
homogenized
with stirring (20-40 min). In the next step, the previously weighed amount of
1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to
the
mixture, and the mixture is stirred for 30-40 min and simultaneously
homogenized
for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
The
abovementioned stirring and homogenizing times may also be extended or
shortened, depending on the appearance of the suspension. It is advantageous
to
use suitable cooling systems for keeping the temperature of the mixture at 20-
C. In the next step, 6015.83 g of the iron(III) dextran powder are added to
the
dispersion in several portions. During the addition, the mixture must be
stirred
continuously and homogenized using the rotary homogenizer at 2500 rpm. The
CA 02688613 2009-11-27
BHC 07 1 052-FC - 30 -
temperature is maintained at 20-30 C by activating the cooling mechanism.
After
all of the iron(III) dextran powder has been added, the citric acid (85.90 g)
is added
to the mixture and dissolved. A pH of 4.1-4.4 establishes. After all
components
have been incorporated, stirring is continued for 20 minutes and a post-
homogenation is carried out simultaneously at 2500 rpm. During this post-
stirring
phase, the temperature of the dispersion is kept at room temperature by means
of
cooling. The finished dispersion is transferred from the stainless-steel
vessel into
suitable storage containers through a 0.1 mm mesh sieve. After a certain
storage
period, the pH climbs to values of between 4.8 and 5.2.
To determine the quality of the dispersion, the parameters pH, particle size
distribution (measured by means of laser diffraction using a Malvern
Mastersizer
2000) and viscosity. The viscosity is measured using a cone/plate measuring
arrangement at a shear rate of 128 and 256 s-1 (RheoStress 600; Thermo Haake).
The mean of the viscosity values measured is used as reference. These
viscosity
data have proved suitable for characterizing the flow resistance of such a
suspension when expelled via a drench gun. In principle, one aims at a
dispersion
with the finest possible distribution in order to keep the bioavailability of
the active
ingredients at a high level. The suspension prepared as described gives the
following parameters:
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 pm <30 pm
pm pm
1ron(III) 133 4.4 5.1 2.3 4.1 100% 100%
dextran
powder
38.4%
m/m
Example 2
Use of iron(III) dextran powder 36.8% m/m
Batch for the preparation of 1000 ml of an iron dextran/toltrazuril dispersion
(23.6% m/v active iron + 5.3% m/v toltrazuril) for oral use in sucking pigs
CA 02688613 2009-11-27
BHC 07 1 052-FC - 31
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 177.34
Sodium propionate (preservative) 1.89
Sodium benzoate (preservative) 1.89
Propylene glycol 106.38
Anhydrous citric acid 7.59
Iron(III) dextran powder 36.8% m/m 639.98
Water 464.67
Viscosity regulating auxiliary/auxiliaries
Total mass 1399.74
In each case 1.89 g of the preservatives sodium propionate and sodium benzoate
are, in separate vessels, weighed into 106.38 g of the solvent propylene
glycol and
dissolved with stirring. All of the water is introduced into a vessel (11
glass
beaker). Depending on what is needed and on the desired viscosity of the end
product, a viscosity-regulating auxiliary (known as a thickener) may be
dissolved
or incorporated into this amount of water. In Example 2, this is dispensed
with.
The propylene glycol premix is added to what has been introduced into the
glass
beaker and homogenized with stirring (10 min). In the next step, the
previously
weighed amount of 177.34 g of the 30% strength toltrazuril dispersion
concentrate
is added to the mixture, and the mixture is stirred for 30-40 min with the aid
of a
dissolver disk. The abovementioned stirring times may also be extended or
shortened, depending on the appearance of the suspension. In the next step,
639.98 g of the iron(III) dextran powder are added in several portions to the
dispersion, with stirring, and, when the addition is complete, the suspension
is
stirred for a further 20 minutes with the aid of the dissolver disk. After all
of the
iron(III) dextran powder has been added, the citric acid (7.59 g) is added to
the
mixture and dissolved. A pH of 4.1-4.4 establishes. After a certain storage
period,
the pH climbs to values of between 4.8 and 5.2.
CA 02688613 2009-11-27
,
BHC 07 1 052-FC - 32 -
..
Iron Viscosity/ pH after
pH after Particle Particle Percentage Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 ttm < 301.1m
tun pill
Iron(III) 277 4.4 4.9 3.2 , 6.4 99% 100%
dextran
powder
36.8%
m/m
Example 3
Use of iron(III) dextran solution 27.5% m/m
Batch for the preparation of 10 1 of an iron dextran/toltrazuril dispersion
(21.0%
m/v active iron + 5% m/v toltrazuril) for oral use in sucking pigs
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 1666.67
Sodium propionate (preservative) 17.00
Sodium benzoate (preservative) 17.00
Propylene glycol 1000.00
Anhydrous citric acid 150.35
Iron(III) dextran solution 27.5% m/m 11229.00
Viscosity regulating auxiliary/auxiliaries -
Total mass 14080.02
In each case 17.00 g of the preservatives sodium propionate and sodium
benzoate
are, in separate vessels, weighed into 1000.00 g of the solvent propylene
glycol
and dissolved with stirring. All of the 11229.00 g of the iron(III) dextran
solution
is introduced into a stainless-steel vessel (Koruma Disho; apparatus type:
DH V 100/45). Depending on what is needed and on the desired viscosity of the
end product, a viscosity-regulating auxiliary (known as a thickener) may be
dissolved or incorporated into what has been introduced. In Example 3, this is
dispensed with. The propylene glycol premix is added to what has been
introduced
into the stainless-steel vessel and homogenized with stirring (20-40 min). The
abovementioned stirring times may also be shortened or extended, depending on
the appearance of the suspension. In the next step, the previously weighed
amount
CA 02688613 2009-11-27
WIC 07 1 052-FC - 33 -
of 1666.67 g of the 30% strength toltrazuril dispersion concentrate is added
to the
mixture, and the mixture is stirred for 30-40 min and simultaneously
homogenized
for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is
advantageous to use suitable cooling systems for keeping the temperature of
the
mixture at 20-30 C. In the next step, the citric acid (150.33 g) is added and
dissolved. During the addition, the homogenizer is switched on at a speed of
1800 rpm, also, the temperature is maintained at room temperature by
activating
the cooling mechanism. A pH of 4.1-4.4 establishes. The stirring and
homogenizing times are averages and may be shortened or extended, depending on
the appearance of the suspension. During this process, the cooling mechanism
remains activated. The finished dispersion is transferred from the stainless-
steel
vessel into suitable storage containers through a 0.1 mm mesh sieve. Within a
few
days to weeks, the pH equilibrates to values of between 4.8-5.2.
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 p.m <30 in
um p.m
Iron(III) 96 4.4 4.8 2.5 4.7 100% 100%
dextran
solution
27.5%
m/v
Example 4
Use of iron(III) sugar powder 35.9% m/m
The compound referred to as iron(III) sugar (from Dr. Paul Lohmann GmbH KG),
which is an iron(III) (hydroxide) saccharate complex, was used.
Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion
(22.8% m/v
active iron + 5% m/v toltrazuril) for oral use in sucking pigs:
CA 02688613 2009-11-27
BHC 07 1 052-FC - 34 -
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 1666.67
Sodium propionate (preservative) 17.00
Sodium benzoate (preservative) __________ 17.00
Propylene glycol 1000.00
Anhydrous citric acid 400.00
Iron(III) sugar powder 35.9% m/m 6350.98
Water to 10 litres 4543.73
Viscosity regulating auxiliary/auxiliaries
Total mass 13995.38
In each case 17.00 g of the preservatives sodium propionate and sodium
benzoate
are, in separate vessels, weighed into 1000.00 g of the solvent propylene
glycol
and dissolved with stirring. All of the water is introduced into a stainless-
steel
vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is
needed and on the desired viscosity of the end product, a viscosity-regulating
auxiliary (known as a thickener) may be dissolved or incorporated into this
amount
of water. In this Example 4, this is dispensed with. The propylene glycol
premix is
added to what has been introduced into the stainless-steel vessel and
homogenized
with stirring (20-40 min). In the next step, the previously weighed amount of
1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to
the
mixture, and the mixture is stirred for 30-40 mm and simultaneously
homogenized
for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is
advantageous to maintain the temperature of the mixture at 20-30 C by means of
suitable cooling systems. In the next step, 6350.98 g of the iron(III) sugar
powder
are added to the dispersion in several portions. During the addition, the
mixture
must be stirred continuously and homogenized using the rotary homogenizer at
2500 rpm. The stirring and homogenizing times of the suspension which have
been
mentioned may be extended or shortened, depending on the appearance of the
formulation. The temperature is maintained at 20-30 C by activating the
cooling
mechanism. After all of the iron(III) sugar powder has been added, the citric
acid
(400.00 g) is added to the mixture and dissolved with stirring. After all
components
have been incorporated, stirring is continued for 20 minutes and a post-
homogenation is carried out at 2500 rpm. During this post-stirring phase, the
temperature of the dispersion is kept at room temperature by means of cooling.
After a short time a pH of 5 is obtained. The finished dispersion is
transferred from
the stainless-steel vessel into suitable storage containers through a 0.1 mm
mesh
sieve.
CA 02688613 2009-11-27
BHC 07 1 052-FC - 35
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 gm <30 gm
gm jim
Iron(III) 1312 5.0 2.1 4.3 100% 100%
sugar
powder
35.9%
m/m
Example 5
Use of iron(III) polymaltose powder 32.0% m/m
Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion
(22.8% m/v
active iron + 5% m/v toltrazuril) for oral use in sucking pigs
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 1666.67
Sodium propionate (preservative) 17.00
Sodium benzoate (preservative) 17.00
Propylene glycol 1000.00
Anhydrous citric acid 604.69
Iron(III) polymaltose powder 32.0% m/m 7125.00
Water to 10 litres 3927.21
Viscosity regulating auxiliary/auxiliaries
Total mass 14357.57
In each case 17.00 g of the preservatives sodium propionate and sodium
benzoate
are, in separate vessels, weighed into 1000.00 g of the solvent propylene
glycol
and dissolved with stirring. All of the water is introduced into a stainless-
steel
vessel (Koruma Disho; apparatus type: DH V 100/45). Depending on what is
needed and on the desired viscosity of the end product, a viscosity-regulating
auxiliary (known as a thickener) may be dissolved or incorporated into this
amount
of water. In this Example 5, this is dispensed with. The propylene glycol
premix is
added to what has been introduced into the stainless-steel vessel and
homogenized
with stirring (20-40 min). In the next step, the previously weighed amount of
CA 02688613 2009-11-27
BHC 07 1 052-FC - 36 -
1666.67 g of the 30% strength toltrazuril dispersion concentrate is added to
the
mixture, and the mixture is stirred for 30-40 min and simultaneously
homogenized
for 20 minutes using a rotary homogenizer (rotor/stator system) at 2500 rpm.
It is
advantageous to maintain the temperature of the mixture at 20-30 C by means of
suitable cooling systems. In the next step, 7125.00 g of the iron(III)
polymaltose
powder are added to the dispersion in several portions. During the addition,
the
mixture must be stirred continuously and homogenized using the rotary
homogenizer at 2500 rpm. The temperature is maintained at 20-30 C by
activating
the cooling mechanism. After all of the iron(III) polymaltose powder has been
added, the citric acid (604.69 g) is added to the mixture and dissolved with
stirring.
After all components have been incorporated, stirring is continued for 20
minutes
and a post-homogenation is carried out simultaneously at 2500 rpm. Depending
on
the appearance of the formulation, the abovementioned stirring and
homogenizing
times may be extended or shortened. During this post-stirring phase, the
temperature of the dispersion is kept at room temperature by means of cooling.
The
finished dispersion is transferred from the stainless-steel vessel into
suitable
storage containers through a 0.1 mm mesh sieve. After a storage time of from a
few days to weeks, the pH climbs to values of 4.8-5.2.
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 gm <30 um
1-tm
Iron(III) 1226 4.4 5.0 1.9 3.3 100% 100%
polymaltose
powder
38.4% m/m
Example 6
Use of iron(III) dextran powder 37.9% m/m using a viscosity-regulating
auxiliary
Batch for the preparation of 10 1 of an iron sugar/toltrazuril dispersion
(22.8% m/v
active iron + 5% m/v toltrazuril) for oral use in sucking pigs
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 1666.67
Sodium propionate (preservative) 17.00
- -----
CA 02688613 2009-11-27
BHC 07 1 052-FC - 37 -
Sodium benzoate (preservative) 17.00
Propylene glycol 1000.00
Anhydrous citric acid 70.00
Iron(III) dextran powder 37.9% m/m 6015.83
Bentonite (Veegum) as viscosity regulator 20.00
Xanthan gum as viscosity regulator 30.00
Water to 10 litres 3290.00
Total mass 12126.50
In each case 17.00 g of the preservatives sodium propionate and sodium
benzoate
are, in separate stainless steel vessels, weighed into 1000.00 g of the
solvent
propylene glycol and dissolved with stirring. When the preservatives are
dissolved,
30.0 g of xanthan gum are added, and stirring is continued for approximately
minutes. Thereafter, the mixture is homogenized for approximately 5 minutes at
13.500 rpm, using a rotary homogenizer (rotor/stator system; laboratory Ultra-
Turrax), so that the dispersion is free from small lumps.
10 All of the water, 3290.0 g, is introduced into a stainless-steel vessel
(Koruma
Disho; apparatus type: DH V 100/45). Thereafter, 20 g of the bentonite are
sprinkled in. This mixture is now warmed to 78 C, with gentle stirring (50 rpm
of
the rotary stirrer). The temperature should be maintained at 78 C for
approximately 5-10 minutes and the mixture should then be cooled to 35 C with
stirring and operating the cooling system. Stirring is then continued for 20-
40
minutes, and a post-homogenization is simultaneously carried out for 20
minutes
using the rotary homogenizer at 2500 rpm, with continued cooling. Thereafter,
the
dispersion of the xanthan gum in propylene glycol is added to the
bentonite/water
mixture, with constant stirring. Then, a post-homogenization of the mixture is
then
carried out by stirring for a further 20-40 minutes at 50 rpm and
simultaneously for
10 minutes with the rotary homogenizer at 2500 rpm. Again, the abovementioned
stirring and homogenization times may be extended or shortened, depending on
what is required and on the appearance of the dispersion.
In the next step, the previously weighed amount of 1666.67 g of the 30%
toltrazuril
dispersion concentrate is added to the mixture, and the mixture is stirred for
30-40 min and simultaneously homogenized for 20 minutes using the rotary
homogenizer at 2500 rpm. During this process, the temperature is maintained at
20-30 C by activating the cooling system. After all of the iron(III) dextran
powder
has been added, the citric acid (70.0 g) is added to the mixture and
dissolved, with
CA 02688613 2009-11-27
BHC 07 1 052-FC - 38 -
stirring and homogenizing. A pH of 4.1-4.4 establishes. After all components
have
been incorporated, stirring is continued for 20 minutes and a post-
homogenization
is carried out at 2500 rpm. During this post-stirring phase, the temperature
of the
dispersion is maintained at room temperature by means of cooling. The finished
dispersion is transferred from the stainless-steel vessel into suitable
storage
containers through a 0.1 mm mesh sieve.
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 gm <30 gm
gm pm
Iron(III) 1365 4.5 1.7 3.5 100% 100%
dextran
powder
37.9%
m/m
Example 7
Use of iron(III) dextran powder 38.6% m/m using a viscosity-regulating
auxiliary
Batch for the preparation of 11 of an iron dextran/toltrazuril dispersion (20%
m/v
active iron + 3% m/v toltrazuril) for oral use in sucking pigs
__________________________________________________
Ingredient Mass/g
Toltrazuril suspension concentrate (30%) 100.00
Sodium propionate (preservative) 1.80
Sodium benzoate (preservative) 1.80
Propylene glycol 100.00
Anhydrous citric acid 8.67
Iron(III) dextran powder 38.6% m/m 518.13
Bentonite (Veegum) as viscosity regulator 1.33
Xanthan gum as viscosity regulator 2.00
Water to 1 litre 606.42
Total mass 1340.15
In each case 1.80 g of the preservatives sodium propionate and sodium benzoate
are, in a separate glass beaker, weighed into 100.00 g of the solvent
propylene
__-
CA 02688613 2009-11-27
BHC 07 1 052-FC - 39
glycol and dissolved with stirring. When the preservatives are dissolved, 2.00
g of
xanthan gum are added, and stirring is continued for approximately 10 minutes,
so
that the dispersion is free from small lumps.
Approximately 100 g of the water are introduced into a glass beaker and warmed
to 70-80 C. Thereafter, 1.33 g of the bentonite are scattered in, and the
temperature
is maintained for approximately 5-10 minutes. The resulting bentonite slime is
cooled with stirring, and the remainder of the water, which is 506.42 g, is
subsequently added. The bentonite/water mixture is stirred at 270 rpm with the
aid
of a dissolver disk, and the dispersion of the xanthan gum in propylene glycol
is
added with constant stirring. Then, a post-homogenization of the mixture is
carried
out for a further 5-10 minutes, with stirring. Again, the abovementioned
stirring
times may be extended or shortened, depending on what is required and on the
appearance of the dispersion.
In the next step, the previously weighed amount of 100.00 g of the 30%
toltrazuril
dispersion concentrate is added to the mixture, and the mixture is stirred for
30-40 min at a speed of 460 rpm. Thereafter, 518.13 g of the iron(III) dextran
powder are added to the dispersion in several portions, with constant
stirring. After
all of the iron(III) dextran powder has been added, the citric acid (8.67 g)
is added
to the mixture and dissolved, with stirring. A pH of 4.1-4.4 establishes.
After all
components have been incorporated, a post-homogenization of the suspension is
carried out for 20 minutes at 9500 rpm with the aid of a rotor stator
homogenizer.
The finished dispersion is transferred into a suitable PE flask.
Iron Viscosity/ pH after pH after Particle Particle Percentage
Percentage
compound mPas preparation storage size size particles
particles
d(v,50)/ d(v,90)/ <10 gm <30 gm
Iron(III) 108 4.2 1.9 3.6 100% 100%
dextran
powder
38.6%
m/m
The data for the dispersions of Examples 1-7 demonstrate that formulations
according to the invention with a very fine solids component can be prepared.
The
formation of agglomerates, which is undesired, is not observed. Moreover, the
---
CA 02688613 2009-11-27
BHC 07 1 052-FC - 40 -
ingredients 35-44 mg toltrazuril and 200 mg active iron, which are required
for use
in sucking pigs, are found in 0.9 ml of the dispersion in the suspensions of
the
examples.
The viscosity of the dispersions of Examples 1-7 can be established over a
great
range of from 10-2500 mPas. A less viscous range of from 20-1500 mPas,
preferably 50-500 mPas and very especially preferably 20-250 mPas is
advantageous since it causes fewer problems when swallowed by, for example,
the
piglets.
Biological examples
Results of clinical tests with formulations of Examples 2 and 3
30 breeding sows who produced a total of 270 piglets were available for a
clinical
experiment. The animals were divided into four groups, the litters being in
each
case divided and each half was assigned to different groups. Thus, as the
result of
slightly different litter sizes and farrowing times, between 60 and 75 piglets
were
assigned to one treatment group. In each case 0.9 ml of the formulations were
administered orally to the piglets on day 3 after birth. On the day of
administration
and on day 7, 14 and 21, blood samples were taken from the piglets. The number
of erythrocytes (RBC million cells/0), the haematocrit (Ht%), the haemoglobin
value (Hb g/100 ml) and the weight of the piglets in kg were used as criteria
for the
efficiency of the formulations. The results were compared with those of a
control
group which had received a commercially available iron(III) dextran
preparation
for injection (Hierrox 200), applied on day 3 after birth. The results are
shown in
Table 5.
Both orally applied formulations of Example 2 (prepared from iron(III) dextran
powder) and of Example 3 (prepared from iron(III) dextran solution) brought
about
a haemoglobin value of > 9 g/100 ml on days 7, 14 and 21 after birth and
therefore
proved effective for avoiding any anaemic deficiencies. The value of
> 10 g/100 ml 14 and 21 days after birth furthermore demonstrates that the
formulations were highly bioavailable. The criteria RBC, HT and weight gain,
moreover, showed no disadvantages over the preparation for injection.
It can thus be demonstrated that the single oral administration of 200 mg of
active
iron from iron(III) dextran in combination with toltrazuril in the
formulations
according to the invention surprisingly - counter to doctrine and the
available prior
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BHC 07 1 052-FC - 41 -
art - makes possible a good prophylaxis against anaemic deficiencies in
sucking
pigs even when administered on day 3 after birth.
An analysis of the piglets' faeces for oocysts gave negative findings
throughout.
This demonstrates that the abovementioned formulations are just as effective
against pathogens causing coccidiosis.
Moreover, no negative associated symptoms whatsoever such as, for example,
diarrhoea, as can be observed more frequently in the case of the oral
administration
of high doses of iron compounds, were found. Thus, the formulations prepared
in
accordance with the invention proved to be very well tolerated.
BHC 07 1052 - Foreign Countries - 42 -
=
Table: Results of the clinical tests
Formulation Day No. of RBC S.D. HT [%] S.D. Hb
S.D. Day No. of Weight S.D.
of example piglets [1064d] [g/100 ml]
piglets [kg]
N
N
-
2 (oral)
3 70 2.192 0.051
3 (oral)
3 74 2.116 0.050
i.m. injection
3 64 2.006 0.053
2 (oral) 7 67 4.29 0.24 33.71 0.72 10.05
0.18 7 70 3.154 0.084 n
3 (oral) 7 71 4.53 0.23 31.91 0.70 9.41
0.17 7 74 3.045 0.082 0
I.)
0,
i.m. injection 7 62 4.18 0.25 33.22 0.75 9.75
0.19 7 64 2.955 0.084 0
0
0,
H
2 (oral) 14 67 5.41 0.40 39.74 0.82 11.37
0.32 14 us,
I.)
0
0
3 (oral) 14 72 6.09 0.39 41.85 0.78 12.16
0.31 14 ,0
1
H
H
i.m. injection 14 61 5.61 0.42 43.53 0.85 12.84
0.33 14 1
I.)
-1
2 (oral) 21 64 5.48 0.11 35.66 3.33 10.78
0.36 21 68 7.061 0.146
3 (oral) 21 72 5.69 0.10 38.71 3.10 11.61
0.34 21 73 7.173 0.141
i.m. injection 21 60 5.96 0.11 40.32 3.44 12.51
0.37 21 63 6.974 0.152
The number of erythrocytes (RBC million cells/p.1), the haemocrit (Ht %), the
haematoglobin value (Hb g/100 ml) and the weight of the piglets in kg
were used as criteria for the efficiency of the formulations.
