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IONOPHORE ANTIBIOTIC FORMULATIONS
TECHNICAL FIELD
The present invention relates to an aqueous base suspension concentrate of an
ionophore
antibiotic or ionophore antibiotics capable with or without dilution of being
administered
to an animal.
Administration of ionophore antibiotics such as monensin to animals
(preferably
ruminants) is known to achieve in appropriate dosages advantages for a number
of
different purposes. These include the treatment or prevention of ketosis
and/or bloat, the
enhancement of milk production, enhancement of milk protein content in milk,
enhancement of mineral uptake, enhancement of weight gain, and/or enhancement
of feed
conversion efficiency (in ruminants), desirable reproduction advantages and as
a milk
replacement. See US Patent 3,829,557.
BACKGROUND ART
In this respect we refer to European Patent Specification 0,139,595 A2 of
KOFFOLK ( 1949) LTD which relates to a liquid ionophore antibiotic composition
for
ruminants and poultry where the antibiotic is dissolved in a non-toxic water-
soluble
organic solvent and in use the resulting solution is admixed with a liquid
feed, a liquid
vitamin concentrate or drinking water. There are claims for stability on
standing even for
long periods.
The composition of EP 0,139,595 indicates that because monensin and its sodium
salt is only slightly soluble in water that it is generally administered in a
dry form in an
animal feed and/or in dry liquid milk replacer compositions. The same is also
indicated
as being true for another ionophore antibiotic lasalocid which in US Patent
3,715,372 is
reported to be completely insoluble in water.
The composition of EP 0,139,595 uses as an organic solvent for the ionophore
antibiotic a solvent selected from the group comprising propylene glycol,
glycerol, ethanol
and isopropanol and mixtures thereof.
Example 1 of EP 0,139,595 indicates that 250 g of a mycelium containing 10%
monensin was mixed at room temperature with 1250 cc propylene glycol for 2
hours by
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exposing the mixture to ultrasound. There is an indication that 50% of the
monensin was
found in solution in the propylene glycol.
Monensin is usually available commercially as the sodium salt of the acid.
Monensin sodium is available in two forms, namely, a crystalline form or a
mycelial form.
The mycelial form has only about a 20% activity while the crystalline form has
greater
than 90% active monensin sodium.
Reference herein to "monensin" where the context allows encompasses all forms
thereof including monensin, alkali metal salts of monensin and monensin
esters. Likewise
for the other ionophore antibiotics.
We have found monopropylene glycol to be a poor solvent of monensin and
therefore while we refer to monopropylene glycol as being an antifreeze agent
in which
the ionophore antibiotic is sparingly soluble we do appreciate that solubility
to the extent
referred to in Example 1 of EP 0,139,595 may be achieved when induced with
ultrasound
or heating.
We have found however that it is possible to include in an aqueous suspension
system monopropylene glycol as an antifreeze agent without any significant
uptake of the
stably suspended monensin from the aqueous system into the organic antifreeze
agent.
This is despite the fact that an organic solvent, such as methanol, allows
monensin to
crash out of solution if any water is added.
An organic antifreeze agent is deemed desirable in any such aqueous base
suspension concentrate since frequently such concentrates are stored in sheds
that are
subject to extreme variations in temperature including temperatures below the
freezing
point of the aqueous system unless enhanced with a antifreeze agent.
Any freezing and thawing of the mixture is deemed undesirable as it may affect
the
uniformity of the monensin or other ionophore antibiotic distribution in the
aqueous
system. Thus the desirability of the inclusion of an antifreeze agent.
DISCLOSURE OF INVENTION
The present invention therefore in at least one aspect is directed to an
aqueous base
suspension concentrate that can stably support an ionophore antibiotic, or
mixtures
thereof, with at least the majority of the antibiotics) being within the
aqueous system and
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not in any organic inclusion that has been added in as an antifreeze agent.
We have also found (irrespective of whether or not any antifreeze agent is
present)
that an ionophore antibiotic (such as monensin) can be stably suspended in
aqueous
suspension by Xanthan Gum that (i) holds the suspension stable when not
subjected to
shear but which shear thins, (ii) does not significantly age thicken, (iii) is
capable of stably
supporting a wide range of trace elements of biological significance
(especially if in a
chelated form) and (iv) is microbiologically stable.
The present invention therefore envisages an aqueous base suspension
concentrate
that stably supports an ionophore antibiotic, or mixtures thereof, at least in
part with
Xanthan Gum.
We have also found that as a wetting agent for enabling the mixing of an
ionophore
antibiotic (especially such as monensin) was much easier using an alkyl
polyglycoside
over other wetting agents.
The present invention therefore envisages an aqueous base suspension
concentrate
that stably supports an ionophore antibiotic, or mixtures thereof, where at
least some of
the antibiotic was mixed with water in the presence of alkyl polyglycoside.
It is believed that an aqueous based suspension concentrate in accordance with
the
present invention together with its diluted form and its use will provide the
public with
a useful choice.
In a first aspect the invention consists in an aqueous base suspension
concentrate
of an ionophore antibiotic or ionophore antibiotics capable of aqueous
dilution (if
desired) and capable (with or without such aqueous dilution) of being orally
administered
to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline and/or
mycelial
form) in (II) an aqueous system containing
(i) a wetting and/or surfactant agent
(ii) an antifreeze agent or agents in which the ionophore antibiotic or
antibiotics is or are no more than sparingly soluble,
(iii) a suspension agent (preferably with rheological properties),
(iv) optionally an antifoam agent or system,
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(v) optionally a preservative
(vi) optionally a de-tittering agent,
(vii) optionally a pH buffering system, and
(viii) water.
Preferably one or anore (preferably all) of (II) (iv), (v), (vi) and (vii) are
present.
In a second aspect the invention consists in an aqueous base suspension
concentrate of an ionophore antibiotic or ionophore antibiotics capable of
aqueous
dilution (if desired) and capable (with or without such aqueous dilution) of
being orally
administered to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline and/or
mycelial
form) in (II) an aqueous system containing
(i) a wetting and/or surfactant agent
(ii) optionally an antifreeze agent or agents in which the ionophore
antibiotic or antibiotics is or are no more than sparingly soluble,
(iii) a suspension agent (preferably with rheological properties),
(iv} as an antifoam agent or system, Simethicone and a particulate carrier
therefor (preferably silicon dioxide)
(v) optionally a preservative
(vi) optionally a de-tittering agent,
(vii) optionally a pH buffering system, and
(viii) water.
Preferably one or more (preferably all) of (II) (ii), (v), (vi) and (vii) are
present.
Preferably (i) is alkyl polyglycoside.
Preferably (ii) is a glycole.
Preferably (iii) is Xanthan Gum.
In a third aspect the invention consists in an aqueous base suspension
concentrate of an ionophore antibiotic or ionophore antibiotics capable of
aqueous
dilution (if desired) and capable (with or without such aqueous dilution) of
being orally
administered to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline and/or
mycelial
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form) in (II) an aqueous system containing
(i) optionally a wetting and/or surfactant agent
(ii) optionally an antifreeze agent or agents in which the ionophore
antibiotic or antibiotics is or are no more than sparingly soluble,
(iii) a suspension agent (preferably with rheological properties),
(iv) an antifoam agent or system, (preferably Simethicone and a
particulate carrier therefor),
(v) optionally a preservative
(vi) optionally a de-tittering agent,
(vii) optionally a pH buffering system, and
(viii) water.
Preferably one or more (preferably all) of (II) (i), (ii), (v), (vi) and (vii)
are present.
Preferably (i) is alkyl polyglycocide.
Preferably (ii) is a glycol.
Preferably (iii) is Xantham Gum.
In a fourth aspect the invention consists in an aqueous base suspension
concentrate of an ionophore antibiotic or ionophore antibiotics capable of
aqueous
dilution (if desired) and capable (with or without such aqueous dilution) of
being orally
administered to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline and/or
mycelial
form) in (II) an aqueous system containing
(i) optionally a wetting and/or surfactant agent
(ii) optionally an antifreeze agent or agents in which the ionophore
antibiotic or antibiotics is or are no more than sparingly soluble,
(iii) as a suspension agent (Xanthan Gum).
(iv) an antifoam agent or system, (preferably Simethicone and
a particulate carrier therefor),
(v) optionally a preserv ative
(vi) optionally a de-tittering agent,
(vii) optionally a pH buffering system, and
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(viii) water.
Preferably said ionophore antibiotics) is (are) present in an amount (amounts)
effective
(A) in beef and dairy cattle, in the treatment or prevention of Ketosis and/or
bloat,
in the enhancement of milk production, enhancement of milk protein content in
milk,
enhancement of mineral uptake, enhancement of weight gain, and/or enhancement
of feed
conversion efficiency in the treatment or prevention of coccidiosis, and/or
in effecting reproduction advantages, and/or
(B) in calves for any of the purposes of (A) and/or
as, at least in part a milk replacer or additive, and/or
in the treatment or prevention of coccidiosis, and/or
(C) in a ruminant, for combination with and/or substantially simultaneous co-
administration with other drench components (eg; trace elements, MgO,
magnesium salts,
zinc salts, pluronics, alcohol ethoxylates, and other metabolic additives)
while exhibiting
a su~ciently effective role selected from (A) and/or (B).
Preferably said ionophore antibiotic is selected from group consisting of
Monensin,
Lonomycin, Ionomycin, Laidlomycin, Nigericin, Grisorixin, Dianemycin,
Lenoremycin,
Salinomycin, Narasin, Antibiotic X206, Alborixin, Septamycin, Antibiotic A204,
Compound 47224, Lasalocid (also including factors A, B, C, D and E),
Mutalomycin,
Isolasalocid A, Lysocellin, Tetronasin, Echeromycin, Antibiotic X-14766A,
Antibiotic
A23187, Antibiotic A32887, Compound 51532 and K41.
Preferably said ionophore antibiotic is Monensin.
Preferably said Monensin is Sodium Monensin.
Preferably the amount of the ionophore antibiotic is from 3% w/v to SO% w/v
(preferably 3 - 20% w/v and most preferably about 6% w/v).
Preferably the antifreeze agent or agents is a glycol.
Preferably said glycol is monopropylene glycol.
Preferably said glycol is not introduced into the concentrate during its
formulation
until after substantial stability of the ionophore antibiotics) has (have)
akeady been
established in the water or at least some of the water.
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In still a further aspect the invention consists in an aqueous base suspension
concentrate of an ionophore antibiotic or ionophore antibiotics capable of
aqueous
dilution (if desired) and capable (with or without such aqueous dilution) of
being orally
administered to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline non-
mycelial form) in
(II) a primarily aqueous system, the concentrate having beers prepared by
suspending the
antibiotics) in the primarily aqueous system prior to the addition of all of
an organic
(preferably glycol) antifreeze agent thereto.
In yet a still further aspect the invention consists in an aqueous base
suspension
concentrate of an ionophore antibiotic or ionophore antibiotics capable of
aqueous
dilution (if desired) and capable (with or without such aqueous dilution) of
being orally
administered to an animal (eg; by drenching), said concentrate comprising
(I) at least one ionophore antibiotic (preferably in a crystalline non-
mycelial form)
suspended in (II) a primarily aqueous system by a Xanthan Gum suspension
agent.
Preferably the primarily aqueous system includes a Simethicon (and carrier
therefor) antifoam agent.
Preferably the antifoaming agent system is Simethicone and Silicon Dioxide
(premixed together).
Preferably the aqueous system II includes a pH buffering system.
Preferably the buffering system is a phosphate buffering system.
Preferably the buffering system is Disodium Phosphate Anhydrous and
Monopotassium phosphate Dihydrate.
Preferably said ionophore antibiotics) is (are) present in an amount (amounts)
effective
(A) in beef and daisy cattle, in the treatment or prevention of ketosis and/or
bloat,
in the enhancement of milk production, enhancement of milk protein content in
milk,
enhancement of mineral uptake, enhancement of weight gain, and/or enhancement
of feed
conversion efficiency in the treatment or prevention of coccidiosis, and/or
in effecting reproduction advantages, and/or
(B) in calves for any of the purposes of (A) and/or
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as, at least in part a milk replacer or additive, and/or
in the treatment or prevention of coccidiosis, and/or
(C) in a ruminant, for combination with and/or substantially simultaneous co-
administration with other drench components while exhibiting a sufficiently
effective role
selected from (A) and/or (B).
Preferably said ionophore antibiotic is selected from group consisting of
Monensin,
Lonomycin, Ionomycin, Laidlomycin, Nigericin, Crrisorixin, Dianemycin,
Lenoremycin,
Salinomycin, Narasin, Antibiotic X206, Alborixin, Septamycin, Antibiotic A204,
Compound 47224, Lasalocid (also including factors A, B, C, D and E),
Mutalomycin,
Isolasalocid A, Lysocellin, Tetronasin, Echeromycin, Antibiotic X-14766A,
Antibiotic
A23187, Antibiotic A32887, Compound 51532 and K41.
Preferably said ionophore antibiotic is Monensin.
Preferably said Monensin is Sodium Monensin.
Preferably the amount of the ionophore antibiotic is from 3% w/v to 50% w/v
(preferably 3 - 20% w/v and most preferably about 6.2% w/v).
Preferably the aqueous system II includes an antifreeze agent or agents
(preferably
a glycol).
Preferably said glycol is monopropylene glycol.
Preferably said glycol is not fully introduced into the aqueous system until
after
substantial stability of the ionophore antibiotics) has (have) already been
established in
the water or at least some of the water of the aqueous system.
Preferably the aqueous system II includes a preservative (preferably with
wetting
properties eg; Dialkyl dimethyl ammonium bromide).
Preferably the aqueous system II includes a wetting agent/surfactant
(preferably
added to water prior to addition of the antibiotic(s)).
Preferably the concentrate is
Sodium Monensin (QA331Z) 3% - 50% w/v Ionophore antibiotic
Monopropylene glycol 1% - 20% w/v Antifreeze
Disodium Phosphate Anhydrous 0% - 1% w/v Buffer
MonoPotassium phosphate Dihydrate 0% - 0.5% w/v Buffer
Dialkyl dimethyl ammonium bromide 0% - 0.1% w/v Preservative
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Sorbitol 0% - 10% w/v Debittering agent
Xanthan Gum 0.05% - 5% w/v Suspension agent
Alkyl Polyglycoside 0.05% - 2% ~w/v Surfactant/Wetting agent
Simethicone 0.05% - 2% w/v Anti-foam
Silicon Dioxide 0.01% - 1% w/v Carrier for Simethicone
Water to 100%
and most preferably is
Sodium Monensin about 6% w/v Ionophore antibiotic
Monopropylene glycol about 10% w/v Antifreeze
Disodium Phosphate Anhydrous about 0.355% w/v Buffer
MonoPotassium phosphate Dihydrate about 0.04% w/v Buffer
Diallcyl dimethyl ammonium bromide about .0064% w/v Preservative
Sorbitol about 3.5% w/v Debittering agent
Xanthan Gum about 0.4% w/v Suspension agent
Alkyl Polyglycoside about 0.5% w/v Surfactant/Wetting agent
Simethicone about 0.333% w/v Anti-foam
Silicon Dioxide about 0.167°/~ w/v Carrier for Simethicone
Water to 100%
Depending on Sodium Monensin batch purity actual amounts required to provide
an effective 6%w/v have been 6.24%w/v and 6.33% w/v.
An alternative antifoam agent to the simethicone/silicon dioxide system is a
dimethyl polysiloxane/polyoxyalkylene system [silicone glycols]. Where such an
alternative is used quantities utilised are substantially as previously
stated.
- In still a further aspect the present invention consists in an aqueous base
suspension concentrate of an ionophore antibiotic or ionophore antibiotics
(preferably
sodium monensin) capable of aqueous dilution (if desired) and capable (with or
without
such aqueous dilution) of being orally administered to an animal (eg; by
drenching), said
concentrate comprising the at least one ionophore antibiotic (preferably in a
crystalline
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non-mycelial form) in an aqueous system which includes an organic antifreeze
agent or
agents but where most of the antibiotic is suspended in the aqueous system
rather than
dissolved in the organic antifreeze agent, the antibiotic being supported by a
suspension
agent.
Preferably said suspension agent is Xanthan Gum.
Preferably said aqueous fraction includes at least one or more of a wetting,
buffering, preservative and antifoam and debittering agent.
In still a furkher aspect the present invention consists in an aqueous base
suspension concentrate of an ionophore antibiotic or ionophore antibiotics
(preferably
sodium monensin) capable of aqueous dilution (if desired) and capable (with or
without
such aqueous dilution) of being orally administered to an animal (eg; by
drenching), said
concentrate comprising the at least one ionophore antibiotic (preferably in a
crystalline
non-mycelial form) in an aqueous system which includes an organic antifreeze
agent or
agents but where most of the antibiotic is suspended in the aqueous system
rather than
dissolved in the organic antifreeze agent, the antibiotic being supported by a
suspension
agent wherein said antibiotic has been mixed into at least some of the water
in the
presence of a wetting agent and subsequently has been supported as a
suspension by the
suspension agent.
In still a fiu~her aspect the invention consists in a method of preparing an
aqueous base suspension concentrate of an ionophore antibiotic or ionophore
antibiotics capable of aqueous dilution (if desired) and capable (with or
without such
aqueous dilution) of being orally administered to an animal (eg; by
drenching), said
concentrate comprising
(I) at least one ionophore antibiotic in (II) an aqueous system containing
(i) a wetting and/or surfactant agent
(ii) an antifreeze agent or agents in which the ionophore antibiotic or
antibiotics is or are no more than sparingly soluble,
(iii) a suspension agent,
(iv) optionally an antifoam agent or system,
(v) optionally a preservative,
i,~~ i
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(vi) optionally a de-bittering agent,
(vii) optionally a pH buffering system, and
(viii) water,
which comprises
mixing the antibiotic to an aqueous system already containing at least
some of the antifreeze agent(s), the optional preservative (if present and
having
a wetting effect), and the antifoaming agent or system, and
subsequently mixing in the balance of components (optionally with
some measure of premixing).
Preferably the method of preparation is substantially as herein after
described.
The invention also consists in a concentrate so made.
In still a further aspect the present invention consists in as a drench a
diluted version of an aqueous base suspension concentrate in accordance with
the present invention.
In yet a further aspect the present invention consists in a method of
treating an animal (preferably a ruminant animal) for any one or more of the
conditions previously set forth or for any of the purposes previously set
forth
and/or as hereinafter described which comprises administering to the animal
orally, or allowing self administration orally, of an aqueous base suspension
concentrate in accordance with the present invention or a water diluted
version
thereof.
Preferably said administration is by means of drenching, eg; preferably
using drenching apparatus.
Preferably said administration is of sodium monensin at a daily rate per
ruminant animal of from 0.4 milligrams per Kg body weight of animal to 2
milligrams per Kg body weight of animal.
Reference herein to formulations does not rule out the inclusion therein
of compatible other inclusions such as essential minerals etc that can
usefully
be administered simultaneously with the ionophore antibiotic(s). See for
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example Australian Patent Specification No. 270639 filed 6 March 1995.
In accordance with an aspect of the present invention, there is provided an
aqueous base suspension pharmaceutical composition of an ionophore antibiotic
or
ionophore antibiotics capable of aqueous dilution comprising
(I) at least one ionophore antibiotic in (II) an aqueous system containing
(i) a wetting agent and/or surfactant agent
(ii) Xanthan gum.
In accordance with another aspect of the present invention, there is provided
an aqueous base suspension formulation adapted for oral administration to a
ruminant
animal comprising:
monensin;
an alkyl polyglycoside;
monopropylene glycol;
Xanthan gum; and
water.
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BRIEF DESCRIPTION OF DRAWINGS
Preferred forms of the present invention will now be described with reference
(where appropriate) to the accompanying drawings in which Figure 1 is a flow
diagram
showing by reference to the numbers a preferred sequence of addition of
specified
componentary into one or other of two mixing containers, the numerical
sequence being
the order of addition.
Preferred forms of the present invention will be described with reference to
monensin. With particular reference to crystalline sodium monensin about a
6%w/v
inclusion is referred to. This equates to about 6.33%w/v commercially
available sodium
monensin) because of impurities. Other ionophore antibiotics have been
stabilised using
corresponding quantities of alternative ionophore antibiotics.
It has primarily been the intention however to utilise sodium monensin and
solubilising of the monensin was rejected as was the formation of a wettable
powder
formulation in favour of a very stable aqueous base suspension.
In evolving the formulations of the present invention a great number of
different
wetting agents were tried to ensure an adequate wetting of the monensin when
being
mixed with water. In this respect lecithins, sodium lauryl sulphate, sodium
dodecyl
sulphate and merlon was tried. Lecithins did not work well, sodium lauryl
sulphate and
merlon did work but were found not to be as effective as wetting agents as
alkyl
polyglycoside.
Attempts to solubilise monensin in an organic solvent such as methylated
spirits
prior to introduction to water was rejected owning to the effect that the
alcohols had on
at least some suspension agents, ie. guar gum when added was precipitated out
by the
presence of the organic solvent. Yet when monensin in methylated spirits was
added to
the water alone the monensin itself precipitated out.
Attempts were made to utilise Mg(OH)2 + Al(OH)3 but it was found that the use
thereof in conjunction with monensin led to inadequate suspension of the
monensin in the
aqueous phase.
Notwithstanding the reference above to attempts to use lecithins as wetting
agents,
lecithin type compounds such as Emulfuid E, Blendmax 322 and Yelkinol P were
used
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as wetting agents for the monensin. Some were enzyme modified compounds
utilised
with a view to modifying the Hydrophilic/Lipophilic balance (ie. HLB) of the
compounds.
Notwithstanding such attempts as indicated earlier the lecithins did not allow
for an
optimum wetting of monensin when compared with, by way of example alkyl
polyglycoside. Moreover the lecithins tended to be oily and powdered lecithins
were
expensive.
Cellulose type compounds such as methocel and cellogen were also utilised as
possible thickeners in an attempt to hold monensin in aqueous suspension. Some
separation was found with such cellulose type compounds with the monensin
settling out.
Such cellulose type compounds were prone also to age thickening as also was
the case
with guar gum.
Other suspension agents and wetting agents were utilised, for example,
liposorb.
Nothing however was located that was as effective as a wetting agent as alkyl
polyglycoside nor as effective as a suspension agent as xantham gum.
The present invention relates to an aqueous base suspension concentrate
capable
of being diluted and administered by a drench gun, such as for example, the
DRINCHMATICTM of Instrument Supplies of Corner Bryant Road and Vickery Street,
Te Rapa, Private Bag 3126, Hamilton, New Zealand or the PNEUMEDICTM Drench Gun
System of Engineering Dynamics Ltd of PO Box 30-812, Lower Hutt, New Zealand.
In each of these systems it is possible to administer a diluted version of the
aqueous
base suspension concentrate of the present invention. The present invention
relates to a
stable suspension having a shelf life sufficient to allow dilution and then
drench
administration for an extended period with a minimum of mixing difficulties at
the time
of dilution and little in the way of metering difficulties to ensure an
effective dosage of
the ionophore antibiotic is being given.
The preferred suspension in accordance with the present invention is as
follows
Sodium Monensin 6.33%(about 6%) w/v Ionophoreantibiotic
Monopropylene glycol 10% w/v Antifreeze
Disodium Phosphate Anhydrous 0.355% w/v Buffer
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MonoPotassium phosphate Dihydrate 0.04% w/v Buffer
Dialkyl dimethyl ammonium bromide .0064% w/v Preservative
Sorbitol 3.5% w/v Debittering agent
Xanthan Gum 0.4% w/v Suspension agent
Alkyl Polyglycoside 0.5% w/v Surfactant/Wetting agent -
Simethicone 0.333% w/v Anti-foam
Silicon Dioxide 0.167% w/v Carner for Simethicone
Water to 100%
Previously was set out have options for the components of the concentrate and
choices available including in respect of the antibiotic. The preferred form
of the present
invention however administers monensin and specifically sodium monensin in its
crystalline form.
Crystalline monensin can be prepared in a number of different ways. Such a
product is available from Eli Lilly & Co, Indianapolis, USA or can be prepared
by way
of the procedures set out, by way of example, in US Patent 4,213,966 (E.R.
Squibb &
Sons Inc).
For stability of the ionophore antibiotic an alkaline pH and preferably one
about
8 - 8.2 is desired. The phosphate solvent system preferably buffers for this
pH range.
The concentrates of the present invention has a stable shelf life of at least
six
months and can be decanted in metered amounts at anytime over its shelf life.
The components:
1. Ant;freezP Ag,~t (optional in some formulations)
Monoprolene glycol (MPG). It was found that it functioned adequately as an
antifreeze.
Was useful to dissolve as a "premix" with DDAB (dialkyl dimethyl ammonium -
bromide - a preservative with some wetting agent characteristics) and xanthan
gum (the
preferred aqueous suspension agent for monensin).
Monensin was only very .sparingly soluble in MPG without ultrasonic mixing
and/or heating.
Other antifreeze agents can be utilised arid it would be envisaged that in
this
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respect many glycerol derivatives or mixtures there of could equally be
chosen. Care
however must be exhibited since a gylcol (such as ethylene glycol) can be very
toxic to
monogastrics and cause kidney damage.
Since MPG works well and is safe and well known and used in the animal health
- industry, it is the antifreeze of choice.
The suspension of choice is xantham gum, (a hydrocolloid) which has the
advantage of locking the suspension when not mobilised but soon as movement is
required
it shear thins. Unlike many other gums, it also does not age thicken.
Xanthan gum was found to be far more effective than guar gum and other such
gums which tended to produce a solid lump in the bottom of the container after
a period
of time.
Xanthan gum was also very stable with respect to ions such as MGO, ZNO.
Moreover xanthan gum is microbiologically stable.
The Ionophore Antibiotic
Monensin as sodium monensin was the preferred ionophore antibiotic.
4. The Buffering~ystem
The buffers are of any effective compatible buffering system of a kind set
forth.
5. The Preservative
The preservative DDAB was preferably added into the formulation early so as to
make best use of its wetting effect in addition to its intended preservative
effect. Its
presence provides broad spectrum activity from the preservative point of view
while at the
same time providing some measure of antibloat activity due to its wetting
effect.
6. Th a Wean ~ A;gent
The preferred wetting agent was clearly alkyl polyglycoside. Its molecular
- structure was most compatible with monensin and enabled monensin to enter
the aqueous
phase easier than other agents tried. It again is a component to be added
early into the
preparative process.
The preferred anti foaming agent is preferably gensil, an emulsion of
simethicone
and silicon dioxide.
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In the examples hereinafter set out of various formulations produced, all
percentages are on a w/v basis and in each instance the formulations were of a
kind
intended to provide an about 3%w/v or about 6%w/v sodium monensin content.
Ingredients: As in each Example.
Equipment: Water deioniser
Sanitary pump and connecting hose
2250 litre SS mixing tank (high speed agitator)
50 Iitre SS vessel
Procedure {where ingredients of the Example allows):
1. Preweigh all raw materials, except water, as specified on worksheet.
2. Add approximately 90% of deionised water to stainless mixing tank and turn
on
high speed stirrer.
3. Add gensil (antifoam), rinse container with deionised water.
4. Add Agrimul 2067. Rinse container with a small amount of deionised water.
Preblend, in the 50 litre SS vessel, the DDAB at approximately 1:9 with
monopropylene glycol and add to the blender.
6. Slowly add sodium monensin allowing powder to ' wet' before adding more.
Once
wetted, rinse down sides and stirrer to remove any powder.
NB. If sodium monensin is added too quickly lumping may occur.
7. Add disodium phosphate and monopotassium phosphate and stir until
dissolved.
8. Add sorbitol and stir until well mixed in (5 minutes).
9. Add 50% of the monopropylene glycol.
10. Preblend, in the 50 litre SS vessel, Rhodigel Supra at approximately 1:3
monopropylene glycol and add to blender with remainder of MPG.
11. Add green dye.
12. Rinse sides and stirrer with deionised water and add balance of water up
to mark.
13. Continue stirring until product has thickened and free from lumps
(approximately
15-30 minutes). Turn off stirrer. NB. Product will have thickened adequately
such
that when stirrer is turned off, product will "spring back".
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Mix yuence
The mix sequence is such that preferably
(a) DDAB when present is added early but is mixed with monopropelene glycol
for
adding to the large tank.
- (b) The antifoam suspension (preferably gensil) is added early in the
sequence to
minimise excessive foam being generated by the vigourous mixing required to
wet
monensin.
The addition of monensin late in the mix sequence is to be avoided as the
concentration of monensin achieved with such late addition is far more
variable especially
when dealing with concentrations greater than 5%w/v. With concentrations of
sodium
monensin of about 10%w/v it became increasingly difficult to incorporate
monensin into
the formulation.
The preferred sequence for a composition as previously stated or as set out
in, for
example, Example 17 is as described in Figure 1.
Example 1
Sodium Monensin 3.12%
Emulfluid E (Enryme Mod. 2.50%
Lec.)
Sodium Carbonate FG 0.02~
Cellogen FSH FI 1.25~
Sorbitol 70% USP FI 14.29%
Example 2
Sodium Monensin 3.12h
Yelkinol P 2.50%
Sodium Carbonate FG 0.02%
Cellogen FSH FI 1.25%
Sorbitol 70~ USP FI 14.29~
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Example 3
Sodium Monensin 3.12%
Yelkinol P 2.50%
Sodium Carbonate FG 0.02~
Cellogen FSH FI 0.60%
Sorbitol 70% USP FI 14.29%
Example 4
Sodium Monensin 3.12
Monopropylene Glycol FI 5.00%
Centrolene S (Hydroxlated 10.00%
LEC)
Sodium Carbonate FG 0.04%
Cellogen FSH FI 1.00~
Example 5
Sodium Monensin 3.12~
Sodium Lauryl Sulphate 1.60%
Guar Gum U p,g%
Example 6
Sodium Monensin 3.12%
Sodium Lauryl Sulphate 0.12590
Sipernat 22S 0.12~
Guar Gum U 0.80%
Example 7
Sodium Monensin 3.12%
Sodium Lauryl Sulphate 0.125%
Sipernat 22S 0.12%
Guar Gum U 0.80~
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Example 8
Sodium Monensin 3.126
Sodium Lauryl Sulphate 0.125%
Monopropylene Glycol 10.00%
FI
Xanthan Gum 0.160
Example 9
Sodium Monensin 3.12%
Sodium Lauryl Sulphate 0.50~6
Monopropylene Glycol 10.00%
FI
Xanthan Gum 0.2%
Example 10
Sodium Monensin 3.12~
Sodium Lauryl Sulphate 0.50%
Monopropylene Glycol 7.50%
FI
Sorbitol 70% USP FI 5.00%
Xanthan Gum 2~ Solution 0.259
Example 11
Sodium Monensin 6.24%
Sodium Lauryl Sulphate 0.10.6
Monopropylene Glycol FI 8.00%
Sorbitol 70~ USP FI 1.00%
Xanthan Gum 2% Solufion 0.2~
Alkyl Polyglycosides 0.20%
Antifoam Powder 0.20%
Water 79.876%
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Example 12
Sodium Monensin 3.12%
Sodium Lauryl Sulphate 0.50~
Monopropylene Glycol FI 7.50%
Sorbitol 7036 USP FI 5.00~
Xantham Gum 2% Solution 0.4~
Example 13
Sodium Monensin 3.120
Sodium Lauryl Sulphate 0.50%
Monopropylene Glycol FI 7.50%
Sorbitol 70% USP FI 5.00%
Xantham Gum 2% Solution 0.3~
Example 14
Sodium Monensin 3.12~
Sodium Lauryl Sulphate 0.50%
Monopropylene Glycol FI 7.50%
Propyl Paraben FI 0.125%
Methyl Paraben FI 0.125%
Sorbitol 70% USP FI 5.00%
Xantham Gum 2% Solution 0.490
Example 15
Sodium Monensin 3.12~
Sodium Lauryl Sulphate 0.25~
Monopropylene Glycol FI 7.50%
Disodium Phosphate Anhyd FI 0.36%
Dipotassium Phosphate DI FI 0.0064%
Bromosept (DDAB 80) 0.01 ~
Sorbitol 706 USP FI 5.00~
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Example 16
Sodium Monensin 6,5%
Monopropylene Glycol FI 7.5~
Disodium Phosphate Anhyd FI 0.355%
Dipotassium Phosphate DI FI 0.046
Bromosept (DDAB 80) 0.0064%
Sorbitol 70i6 USP FI 5%
Xanthan Gum 2~ Solution 0.4%
Alkyl Polyglycosides 0.5k
Antifoam Powder 0.56
Water 79.5586%
Example 17
Sodium Monensin 6.32~
Monopropylene Glycol FI 10.0~
Disodium Phosphate Anhyd FI 0.255%
Monopotassium Phosphate DI FI 0.040%
Bromosept (DDAB 80) 0.0064%
Sorbitol 70r6 USP FI 5.0~
Xantham (Rhodigel Supra) FI 0.40~
Agrimul APG 600 0.50%
Antifoam Powder 0.50%
Water 76.8786%
REPORT ON PERFORMANCE OF 6% (NOMINAL) MONENSIN SUSPENSION
IN DRENCHING SYSTEMS
In all in vivo tests 1 litre of 6% monensin composition (as in Example 17) was
- added to 19 litres of water in the powder drenching system reservoir. This
equates to a
drenching rate of 100m1s of drench providing 300mg monensin per day. The
monensin
suspension dispersed easily with a low level of foaming even on full agitation
with the
submersible pump on full by-pass.
1. To the 20 litres of monensin suspension was added the equivalent amount of
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nonylphenol ethoxylate (Blocare 4511) for dosing 200 cows at the rate of
5mls/cow. The foam level increased dramatically but this was due to the
Blocate.
No chemical reactions were observed.
2. To another 20 litre batch of monensin suspension was added 4kg of magnesium
oxide (calmag). There was a slight increase in foam level but not more than is
'
normal for calmag on its own. No chemical reactions were observed.
3. To another 20 litre batch of monensin suspension was added 20kg of
magnesium
chloride flake. There was no significant increase in foam. There was some
sediment in the bottom of the reservoir on emptying. This was a mixture of
undissolved MgCl2 residual CALMAGTM (ie. Mg0) and rust). There did not
appear to be any chemical reactions.
General Comments
Larger particles only of sodium monensin was seen to settle out 15 to 20
minutes
after agitation cease. These particles re-suspended easily upon recommencement
of liquid
flow through the tubing (ie. agitation).
The settling out of the monensin was not considered to be a major problem
because
of
the ease of re-suspension of the monensin, once re-agitated
~ the degree of agitation provided by a power drench system
~ by emptying the drench line prior to the start of a row of animals to be
drenched
the probability of an animal receiving more than two times the required dosage
of
monensin within the 100m1 volume is very low.
Evaluation of the effectiveness of 100 ml/day of Composition of 6%w/v sodium
monensin to control bloat in milking cows on pasture
Two trials were carried out in September/October 1995 to evaluate the
effectiveness of 100 ml/day of the Example 17 composition as a drench to
control bloat '
in milking cows on pasture, firstly by drenching 50m1 twice a day, ie. before
each milking
(Trial lA), and secondly, by drenching 100m1 before each morning milking
(Trial 1B). -
There was 300mg active ingredient administered per day. In each Trial half of
the 30
cows were allocated by restricted random allocation to the untreated Control
group, and
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half to the Liquid Product ('treated') group. Animals were scored for bloat
twice daily
on white clover/ryegrass pastures or on red clover pastures (using a scale of
0, l, 1.5, 2,
2.5, 3, representing scores of increasing severity of bloat, by assessing
pressure on the
cows' left and right sides).
In Trial lA, serious bloat was recorded on 9 mornings out of 23 am and pm
recording sessions. Twelve of 15 cows from the Control group were at risk of
death from
bloat (if left untreated) on at least one day, compared with 3 of 15 in the
Treated group,
a statistically significant difference (P<O.OI). Mean scores on 8 bloating
days were
respectively 0.58 and 0.12 which was a significant difference (P<0.01). On the
most
serious four bloat days, corresponding scores were 0.94 and 0.20 (also a
significant
difference at P<0.p1).
In Trial 1B, 3 serious bloat sessions out of 9 am and pm recording sessions
led to
8/15 Control animals being at risk, compared with 1/14 Treated animals (a
statistically
significant difference, P<0.01). Mean scores on these 3 bloating days were
0.65 and 0.10
respectively, representing a statistically significant difference between
groups (P<0.01).
The composition ofExample (17) was successful in reducing the mean bloat score
and the number of animals at risk.
Trial lA 25/9 to 6/10/95 Treatment = SOmI liquid Composition of 6%w/v sodium
monensin twice a day
Table 1. Mean bloat score on days when bloat was recorded (treated and
control)
Day Mean Score Number of cows at risk
(ie. A score z 1.5)
1 0.27 4
3 0.08 1
4 0.08 1
0.09 1
8 0.18 1
9 0.70 9
0.85 11
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Day Mean Score Number of cows at risk
(ie. A score Z 1.5)
11 0.37 5
12 0.47 5
Mean/Total 0.34 15' '
Excluding Day 1, where equilibration in the rumen may not have been reached
Table 2. Treatment effects on bloat-score means from all nine days when bloat
was
recorded, and from subsets of days
Number of Non-treated Treated s.e.d. Signif.b Phenotypic
score days s.d.'
9 0.55 0.13 0.13 ** 0.60
8 (excluding 0.568 0.12 0.13 ** 0.59
first)
Best 4 0.94 0.20 0.20 ** 0.73
The Other 4 0.30 0.07 0.10 * 0.49
° Between-cow repeatability = 0.280.07 (9 days); 0.45+0.10 (best 4
days).
b * = P<0.05; ** = P<0.01.
From the cow and residual variance components combined.
Table 3. Numbers of bloated animals by treatment ( 15 per group), using
various criteria
of bloat
Criterion Non-treated Treated Chi-square Signif.b
Cows with a mean of 0 on Days 2 11 11.00 ***
9-12
Cows with a mean z on Days 9- 7 1 6.14 *
12
Cows at risk (score z 1.5) on at 12 3 10.80 **
least one day"
Excluding Day 1, where equilibration in the rumen may not have reached
b * = P<0.05; II + P<p,p l; *** = P<0.001.
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Trial 1B 24/10 TO 28/10/95 Treatment = 100m1 liquid composition of
6°/mw/v
sodium monensin per day in one dose at 0615
Table 4. Mean bloat score on days when bloat was recorded
Day Mean score Number of cows at risk
- (ie. a score Z 1.5)
3 0.29 3
4 0.56 7
0.27 3
Mean/Total 0.37 9
Table 5 Treatment effects on bloat score means from Davs 3 to 5.
Trait Non-treated Treated s.e.d. Signifa Phenotypicb
s.d.
Bloat score 0.65 0.10 0. FS *** 0.60
Number at risk 8 2 7.20°
(score z 1.5)
** = p<0.01; *** = P<0.001.
b Between-cow repeatability = 0.1810.12 (3 days); the phenotypic standard
deviation is from the cow and
residual components combined.
Chi-square, testing 8/15 against 1/14.
