NZ565548A - Stable anthelmintic veterinary formulations containing naphthalophos - Google Patents
Stable anthelmintic veterinary formulations containing naphthalophosInfo
- Publication number
- NZ565548A NZ565548A NZ565548A NZ56554808A NZ565548A NZ 565548 A NZ565548 A NZ 565548A NZ 565548 A NZ565548 A NZ 565548A NZ 56554808 A NZ56554808 A NZ 56554808A NZ 565548 A NZ565548 A NZ 565548A
- Authority
- NZ
- New Zealand
- Prior art keywords
- naphthalophos
- percentage
- formulation
- months
- white
- Prior art date
Links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
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Abstract
Disclosed is a stable veterinary formulation containing at least the active naphthalophos (Naphthalimido diethyl phosphate) wherein the liquid carrier comprises a buffered aqueous solution and the naphthalophos (preferably in micronised form) is suspended in the buffered aqueous solution having a pH in the range 2.5 to 5.5. The stable suspension is suitable for use in combination with other anthelmintics and formulations containing naphthalophos alone, or in combination with fenbendazole and/or levamisoleare. Viscosity measurements show the ready made formulations are suitable for use in drench guns.
Description
Patents Form # 5
NEW ZEALAND
Patents Act 1953
COMPLETE SPECIFICATION
Title Anthelmintic Formulations
We, VIRBAC (AUSTRALIA) PTY LIMITED, of 361 Horsley Road, Milperra, BC, New South Wales 1891, Australia, Nationality: An Australia company, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement:
20213 lNZ_Alp_20080130_2147_TDT.doc
FEE CODE - 1050
intellectual property office of n.z.
3 n JAN 2008
R F C EIV E D
2
FIELD OF THE INVENTION
This invention relates to veterinary formulations containing naphthalophos alone, or in combination with other actives.
BACKGROUND OF THE INVENTION
Naphthalophos or naftalofos are common names of Naphthalimido diethyl phosphate, its Chemical Abstracts Registry number 1491-41-4
and synonyms are listed at: "Kenneth Barbalace. Chemical Database - Naphthalimide, N-hydroxy-, diethyl phosphate. EnvironmentalChemistry.com. 1995 - 2007. 10 http://EnvironmentalChemistrv.com//vogi/chemicals/cn/Naphthalimide.%AON-hvdroxv-■%AOdiethvl%AQphosphate.html".
It is also referred to as naftalofos:
STATUS:
IUPAC:
CAS:
REG. NO.:
FORMULA:
ACTIVITY:
NOTES: STRUCTURE:
WHO INN
diethyl naphthalimidooxyphosphonate
2-[(diethoxyphosphinyl)oxy]-lif-benz[afe]isoquinoline-l,3(2.ff)-dione
1491-41-4
Ci6H16N06P
insecticides f organ ophosphorus insecticides')
There is no ISO common name for this substance; the name "naftalofos" is approved by the World Health Organization and the name "naphthalophos" was formerly approved by the British Pharmacopoeia Commission.
p ox /0-ch2-ch3
-</ X0—CH,—CHj
Naphthalophos is an anthelmintic with anti-cholistinerase activity. It is an organophosphate compound that is often referred to as a "narrow" or "mid-spectrum' treatment. It has good
202131AU CS SPEC vl 3 24 Jan.doc
3
activity against adult and immature barbers pole worm and variable efficacy against other sheep worms (generally efficacy between 70 and 90 percent depending on the worm species and stage of the lifecycle).
It is available as an insoluble wettable powder for use on farm in making up a temporary 5 suspension in water. It is difficult to formulate as it is effectively insoluble in water and other solvents used for veterinary formulations, it is difficult to retain in suspension and in liquid suspensions its potency degrades quickly to unacceptable levels. Because it is a relatively narrow spectrum product it is often combined with other actives and in particular other anthelmintics.
Where it is to be combined with other anthelmintics for use as an oral drench, it is supplied as a two component pack with the liquid drenches in one container (noting that some anthelmintics are soluble, or can be pre-formulated as a stable suspension in a liquid carrier) and the naphthalophos is supplied as a wettable powder in the other container, so that the two containers can be mixed on site by the farmer with a predetermined amount of water to make 15 up a temporary drench which should be used before the naphthalophos settles out of suspension. This is inconvenient. Supplying naphthalophos on its own or in combination with other actives, is currently disadvantageous because of the short lifetime of the product made up on site, the inconvenience of making it on site, and the fact that it must be used or discarded before the naphthalophos degrades due to its inherent instability in liquid 20 formulations.
OBJECT OF THE INVENTION
It is an object of this invention to provide an approved anthelmintic formulation, or one which will at least provide the public with a useful choice.
s\tr
AJ
STATEMENT OF INVENTION
In one aspect the invention provides a stable veterinary formulation containing at least the active naphthalophos wherein the liquid carrier comprises a buffered aqueous solution and the naphthalophos is suspended in the buffered aqueous solution having a pH in the range of 30 2.5 to 5.5.
20213! AU CS SPEC vl 3 24 Jan.doc
4
Preferably the buffer system is designed to maintain the pH range of the formulation between 2.5 and 5.0 during the useful life of the product.
Preferably the pH is at or close to 5.0 at the time of manufacture as we have found that pH of the formulations decrease over time as the naphthalophos degrades and the more acidic the 5 formulation the more likely is it to interact with the xanthan gum causing an increase in viscosity to the point that the product is no longer usable in a drench gun. We prefer to start with a pH of substantially 5.0 but in some of the examples we started with a pH of 5.12 or 5.13 (Example 3D) where the Nap is combined with Abamectin, as this starting pH drops to below 5.0, by one month after manufacture.
Preferably the viscosity is such that the product possesses the physical properties of suspendabilty and drenchability to ensure satisfactory oral delivery to animals using a conventional drenching apparatus (i.e. drench guns).
The formulation maintains the stability of the naphthalophos while in a liquid suspension for a sufficiently long period to make supply of a ready-to-use formulation for the convenience 15 of farmers. The formulation is suitable to combine one or more other veterinary compounds which increase the spectrum of activity against a range of worm parasites. In some cases, the combination may be synergistic, thereby increasing the level of efficacy of the combination relative to the efficacy of the single anthelmintics.
Preferably the pH of the formulation is in the range of 3.5 to 4.5.
Preferably the buffer includes a weak organic or inorganic acid and a conjugate organic or inorganic weak base of phosphoric, sulphuric or acetic acid or the like. More preferably the organic weak acid is citric acid. More preferably the conjugate weak base is disodium phosphate. Preferably the viscosity-imparting suspending agent is xanthan gum.
Preferably the formulation includes a combination of protective colloids for the active 25 naphthalophos. More preferably the protective coiioids are silica colloidal and povidone k-30.
Preferably the naphthalophos is micronised to 99%<20ji; and/or 90%<10ja.
More preferably the naphthalophos is micronised to 95%<10|x; and 90%<5\i.
Preferably the stable veterinary formulation also includes one or more additional actives. 30 Preferably the one or more additional actives include a benzimidazole.
202131AU CS SPEC vl 3 24 Jan.doc
Preferably the benzimidazole is suspended in the buffered viscous aqueous carrier.
Any one or more of the benzimidazoles can be used in this formulation.
More preferably the benzimidazole is fenbendazole.
Preferably the fenbendazole is micronised to 90% <20 |i
Preferably the one or more additional actives include a tetramisole. More preferably the tetramisole is levamisole.
Preferably the levamisole is dissolved in the buffered aqueous carrier.
Preferably the one or more additional actives include an avermectin or macrocyclic lactone. More preferably the avermectin is abamectin.
Preferably the formulation includes an anti-caking/dispersing agent
More preferably the anti-caking/dispersing agent is a non-ionic surfactant around 10 -12 g/L. This for example could be of the polyoxyethylene class, (Polysorbate 20, Polysorbate 60 or Polysorbate 80) or alkyl phenol ethoxylates (e.g. Teric N9).
These and other aspects will now be described with reference to the following examples. FIGURES:
Figure 1 is a graph showing the plasma concentrations of Fenbendazole and its metabolites achieved with a prior art product containing Fenbendazole and Levamisole (Phase 1 trial).
Figure 2 is a graph showing the plasma concentrations of Fenbendazole and its metabolites 20 achieved with a prior art product containing Fenbendazole and Levamisole (Phase 2 trial).
Figure 3 is a graph showing the increased plasma concentrations of Fenbendazole and its metabolites achieved with the formulation of Example 2 which also contains naphthalophos (Phase 1 trial).
Figure 4 is a similar graph showing the increased plasma concentrations of Fenbendazole 25 and its metabolites achieved with the formulation of Example 2 which also contains naphthalophos, in the Phase 2 trial.
202131 AO CS SPEC v I 3 24 Jan.doc
6
Figure 5 is a graph relating to Example 4, showing the plasma concentrations of Fenbendazole and its metabolites achieved with a prior art product containing Fenbendazole and Levamisole.
Figure 6 is a graph relating to the trial of Example 4, and shows the increased plasma 5 concentrations of Fenbendazole and its metabolites achieved with the formulation of Example 2 containing naphthalophos, fenbendazole and levamisole.
Figures 7, 9, 11, 13, 15, 17, and 19 show viscosity charts at 30C and 40C for various formulations corresponding to the stability trials of the Tables shown in Example 6.
The even numbered Figures between 8 and 20 show pH charts at 30C and 40C for various 10 formulations corresponding to the stability trials of the Tables shown in Example 6, and by comparing the odd and even numbered figures it is possible to see the effect of declining pH on the viscosity of the formulations.
Total Figures = 20.
PREFERRED EXAMPLES:
Example 1:
This is a naphthalophos only stable suspension.
Formulation of Example 1:
Ingredients
CAS No
Purpose
Concentration G/L
Naphthalophos micronised
1491-41-4
Active
150.0
Propylene glycol
Solubiliser
100.0
Xanthan gum
11138-66-2
Thickener
1.25
Teric n9
NA
r«
oui Jta^iaiii
.0
Antifoam rd
NA
Antifoam
1.0
Silica - colloidal anhydrous
112945-52-5
Protective colloid
.0
Povidone k30
Protective agent
.0
Citric acid
77-92-9
Buffer
3.0
Disodium phosphate anhyd.
7558-79-4
Buffer
1.1-5.1 qs pH 2.5 - 5.0
Methyl hydroxybenzoate
93-58-3
Preservative
1.5
Propyl hydroxybenzoate
103-65-1
Preservative
0.15
202131AU CS SPEC vl 3 24 Jan.doc
7
Benzoic acid
65-85-0
Preservative
0.15
Water purified
7732-18-5
Vehicle
TO 1.0 L
This formulation is stable and is suitable as an oral drench for sheep. Although naphthalophos is rarely used on its own. The next example shows a stable formulation of naphthalophos together with other actives leading to a more widely useful formulation.
In this formulation we maintained the pH within the range 2.5 to 5.0 as we have found that below 2.5 causes a thickening of the formulation due to the presence of Xanthan gum (which thickens at low pH). Above pH 5 reduces the stability of the active ingredients.
But as will be seen from the following example, it is preferable to narrow the pH range to 3.5 to 4.5 in most cases where other actives are present.
Example 2:
Formulation of Example 2
Ingredients
CAS No
Purpose
Concentration G/L
Naphthalophos micronised
1491-41-4
Active
150.0
Levamisole hydrochloride
5036-02-2
Active
40.0
Fenbendazole
43210-67-9
Active
.0
Propylene glycol
Solubiliser
100.0
Xanthan gum
11138-66-2
Thickener
1.25
Teric n9
NA
Surfactant
.0
Antifoam rd
NA
Antifoam
1.0
Silica - colloidal anhydrous
112945-52-5
Protective colloid
.0
Povidone k30
Protective agent
.0
Citric acid
77-92-9
Buffer
3.0
Disodium phosphate anhyd.
7558-79-4
Buffer
1.1-5.1 qs pH 3.5-4.5
Methyl hydroxybenzoate
93-58-3
Preservative
1.5
Propyl hydroxybenzoate
103-65-1
Preservative
0.15
Benzoic acid
65-85-0
Preservative
0.15
Water purified to
7732-18-5
Vehicle
1.0 L
We have found that this combined formulation is stable, whereby the active ingredients are 15 maintained within 10% of the initial concentration for the duration of the shelf life and are
202131AU CS SPEC vl 3 24 Jan.doc
8
currently testing its likely shelf life beyond 12 months. We expect from our initial tests that a practical shelf life well in excess of 18 months is possible.
The most preferred pH range for a formulation containing all 3 actives is 3.5 - 4.5; by keeping the pH within the range of 3.5 to 4.5 we are able to maintain stability and the 5 physical properties, namely, viscosity, suspendabilty, and drenchability, within acceptable limits.
Also, the product must maintain a satisfactory suspension without falling out or caking. In addition to the use of Xanthan gum, this is achieved by using an anticaking/dispersing agent (see below) and the particle size of the two actives that are in suspension, ie naphthalophos 10 and fenbendazole, which are:
naphthalophos micronised to 100%<10(x; 90%<5p.
fenbendazole micronised to 90 %< 20)u.
The levamisole is in solution and is acidic by its nature.
The buffer system maintains a balance of acid and basic components to ensure the pH is 15 correct. This is achieved by the use of citric acid at approximately 3g/L and a disodium phosphate at from 1.1 - 5.5 g/L which is applied to pH qs of 3.5 - 4.5.
In summary, the pH of the formulation has to make three active ingredients which have differing preferences for pH as comfortable as possible.
The anti-caking/dispersing agent (listed as a surfactant in the above examples) is a non-ionic 20 surfactant around 10 -12 g/L. This for example could be of the polyoxyethylene class, (Polysorbate 20, Polysorbate 60, or Polysorbate 80) or alkyl phenol ethoxylates (e.g. Teric N9).
The resulting formulation is balanced to prevent the breakdown of naphthalophos to release
Xni' jjnuopiiui JC' aviu winun luwCio un* pn cuiu xuiuiui wauujrawa uiuiv uiw-aivuu vvn kjl uio
naphthalophos. If this does occur and the pH drops to 2.5 or less, the product becomes thick and will not maintain its drenchability properties. The suspension may break and the solid material cakes on the bottom of the vessel.
The viscosity of the resulting formulation is such that it is suitable for use in a drench gun to deliver oral medication to sheep, cattle, and other animals.
202131AU CS SPEC vl 3 24 Jan.doc
9
Example 3:
This example shows 4 formulations containing Naphthalophos alone (3A) or in combination with Fenbendazole (3B) or Levamisole (3C) or Abamectin (3D). With each of the actives abbreviated in the headings as follows.
Ingredient
Nap B/N 3A g/L
Nap Fen B/N 3B
Nap Lev B/N 3C
Nap Aba B/N 3D
g/L
g/L
S/L
Naphthalophos 97.5%
150.0
150.0
150.0
150.0
Levamisole HCL
-
-
40.0
Fenbendazole
-
.0
-
Abamectin
1.0
Propylene glycol USP
100.0
100.0
100.0
100.0
Polyvinyl pyrrolidone k30
1.4
1.4
1.4
1.4
Antifoam rd
.5
.5
.5
.5
Xanthan gum
1.1
1.1
1.1
1.1
Silica - colloidal
.0
.0
.0
.0
anhydrous
Citric acid
.0
.0
.0
.0
Disodium phosphate
3.0
3.0
3.0
3.0
Teric 9
.0
.0
.0
.0
Methyl hydroxy benzoate
1.5
1.5
1.5
1.5
Propyl hydroxy benzoate
0.15
0.15
0.15
0.15
Benzoic acid
0.15
0.15
0.15
0.15
Water purified l.OL
l.OL
l.OL
l.OL
Viscosity, cps. (Brookfield DV-
471.9 (spn. 61, 6rpm)
559.9 (spn. 61, 6rpm)
397.9 (spn. 61, 6rpm)
390.9 (spn. 61, 6rpm)
11+PRO)
pH (neat)
4.85
4.86
4.62
.12
Gun Test, sec
33
36
36
Blood Studies:
iO in the foiiowing examples we tested Formulation 2 (labelled as "CRD" in the graphs, our acronym for "Combat Ready Duo") against our product Duocare made up of the two actives Fenbendazole (FBZ) and Levamisole (LEV). We have also abbreviated Naphthalophos as "NAP" in the description of these formulations and used them as shorthand notations in the following graphs.
202131AU CS SPEC vl 3 24 Jan.doc
Example 4:
The first study was a crossover study in which two groups of 6 animals were treated with either Duocare (FBZ + LEV) or CRD (FBZ + LEV + NAP). The graphs in Figures 1 to 4, show the level of fenbendazole (FBZ) and its metabolites (OFZ = oxfenbendazole or 5 FBZS02 = Fenbendazole sulphone). In the first Phase, the level of the FBZ metabolites from animals treated with CRD is greater than the same metabolites from animals treated with Duocare.
Figures 1 and 2 show the plasma concentrations achieved with the prior art product Duocare. Figures 3 and 4 show the plasma concentrations achieved with the formulation of Example 2.
In the second Phase, when the animals in the groups received the alternative treatment (ie, those getting CRD in Phase 1 (PI), received Duocare in Phase 2 (P2) and vice versa). Again, those animals receiving CRD had higher FBZ metabolites than those receiving Duocare. The high level of the FBZ metabolites was thought due to the presence of naphthalophos but the exact reason or mode of action is not known. It is tempting to speculate on competition 15 within the liver which delays the metabolism and excretion of the fenbendazole. While this is logical and intuitively comfortable it is not confirmed.
Example 5:
The results of this second study are shown in the graphs of Figures 5 and 6. It was a parallel study carried out with a formulation containing double the concentration of the three active 20 ingredients to produce a 'low volume' formulation whereby only half the required volume is needed to medicate animals. The results of Example 4 confirm the elevated plasma fenbendazole levels where naphthalophos was present in the stable formulation. These graphs show 'Total' figures which are the sum of the three individual metabolites.
The differences are also reflected in the "area under the curves" (AUC).
Example 6:
Stability Trials:
Various stability trials have been carried out at either 30°C or 40°C, and results are shown in the following Tables. The formulations shown by the batch number (abbreviated to B/N)
202131AU CS SPEC vl 3 24 Jan.doc
11
relates back to the formulations of the Examples 2 or 3. For example in Table 1 B/N 3C refers back to the formulation 3C shown in Example 3. In addition, the pH and viscosity have been plotted for each of these trials, and these graphs are shown in the attached drawings.
The later Tables show variations of the formulation of Example 2 and these variations are variously labelled B/N 2D1, 2D2, 2E and 2. The final table shows the 12 month stability trials of the formulation of Example 2.
The variations of the formulation of Example 2 have headings which show the objective, for example in formulation 2E the aim was to get a pH in the range 4.0-5.0, at the time of 10 manufacture, and to keep this pH as close as possible to pH4 during the stability trials at 30°C.
The viscosity and pH charts shown in the drawings, correspond to the pH and viscosity measurements shown in the Tables, and show the steady reduction of pH over time, and the corresponding increase in viscosity which on the whole tends to increase particularly as the 15 pH approaches pH3 at 30°C.
On the basis of our trials, we believe that the product should be formulated to ensure that the pH is kept above 2.5 during the useful life of the product.
Table 1 - Naphthalophos suspension B/N 3 A Results at 30°C
0 months
1 months
3 months
6 months
Assay
155
157
153
155
Naphthalophos
155
156
153
156
(135 -165
155
156.5
153
155.5
Or/T A
D' •—./
Percentage of
100
101
99
100
initial
Percentage of label claim
103
104
102
104
202131AU CS SPEC vl 3 24 Jan.doc
12
Specific Gravity
1.0728
1.0744
1.0743
1.0745
Viscosity (cps)
471.9
605
579
507
Percentage of initial
100
128
123
107
pH (neat)
4.85
4.79
4.69
4.66
Percentage of initial
100
98.7
96.7
96.1
Colour
Off white off white off white off white
Appearance/ colour
Suspension
Suspension
Suspension suspension
Table 2 - Naphthalophos suspension B/N 3 A Results at 40°C
0 months
1 months
3 months
6 months
Assay Naphthalophos
(135-165 g/L)
155 155
155
155 155
155
149 151
150
154 154
154
Percentage of initial
100
100
97
99
Percentage of label claim
103
103
100
103
Specific Gravity
1.0728
1.0735
1.0733
1.0735
Viscosity (cps)
471.9
608
547
426
Percentage of initial
100
128.8
115.9
90.3
pH (neat)
4.85
4.69
4.49
4.39
Percentage of initial
100
96.7
92.6
90.5
Colour
Off white off white
Off white off white
Appearance/ colour
Suspension suspension suspension suspension
Table 3 - Naphthalophos suspension B/N 3A
Time
0M
1M
3M
6M
Viscosity at 30° C
471.9
605
579
507
Viscosity at 40° C
471.9
608
547
426
202131AU CS SPEC vl 3 24 Jaii.doc
13
Table 4 - Naphthalophos suspension B/N 3A
Time
0M
1M
3M
6M
pH neat at 30° C
4.85
4.79
4.69
4.66
pH neat at 40° C
4.85
4.69
4.49
4.39
Table 5 - Naphthalophos and Fenbendazole suspension B/N 3B
Results at 30°C
0 months
1 months
3 months
6 months
Naphthalophos (135-165 g/L)
154
154
152
152
152
155
152
153
153
155
152
153
Percentage of initial
100
101
99
100
Percentage of label claim
102
103
101
102
Assay Fenbendazole (22.5-27.5 g/L)
26.2
26.0
.5
.5
26.0
26.0
.6
.5
26.1
26.0
.6
.5
Percentage of initial
100
101
100
98
Percentage of label claim
104
104
102
102
Specific gravity
1.0794
1.0816
1.0804
1.081
Viscosity (spindle 61, 6rpm)
559.9
654
594
569
Percentage of initial
100
116.8
106.1
101.6
pH (neat)
4.86
4.83
4.7
4.69
Percentage of initial
100
99.4
96.7
96.5
Appearance
Suspension suspension suspension
Suspension
202131AU CS SPEC vl 3 24 Jan.doc
• 14
Table 6 - Naphthalophos and Fenbendazole suspension B/N 3B
Results at 40°C
0 months
1 months
3 months
6 months
Naphthalophos (135-165 g/L)
154
155
152
154
152
155
151
154
153
155
152
154
Percentage of initial
100
101
99
101
Percentage of label claim
102
103
101
103
Assay Fenbendazole (22.5-27.5 g/L)
26.2
26.2
.6
26.0
26.0
26.4
.6
26.0
26.1
26.3
.6
26.0
Percentage of initial
100
101
98
100
Percentage of label claim
104
105
102
104
Specific gravity
1.0794
1.0809
1.0803
1.0815
Viscosity (spindle 61, 6rpm)
559.9
711
583
512
Percentage of initial
100
127
104.1
91.4
pH (neat)
4.86
4.72
4.51
4.42
Percentage of initial
100
97.1
92.8
90.9
Appearance
Suspension suspension suspension suspension
Table 7 - Naphthalophos and Fenbendazole suspension B/N 3B
Time
0M
1M
3M
6M
Viscosity at 30° C
559.9
654
594
569
Viscosity at 40° C
559.9
711
583
512
Table 8 - Naphthalophos and Fenbendazole suspension B/N 3B
Time
0M
1M
3M
6M
pH (neat) at 30°C
4.86
4.83
4.7
4.69
pH (neat) at 40°C
4.86
4.72
4.51
4.42
202131AU CS SPEC vl 3 24 Jan.doc
Table 9 - Naphthalophos and Levamisole suspension B/N 3C Results at 30°C
0 months
1 months
3 months
6 months
Naphthalophos (135-165 g/L)
158
159
154
156
159
158
155
159
158.5
158.5
154.5
157.5
Percentage of initial
100
100
97.48
99.4
Percentage of label claim
106
106
103.3
105.3
Levamisole
(36.0-44.0 g/L)
41.7
42
40.8
39.3
41.7
42.3
41
39.3
41.7
42.15
40.9
39.3
Percentage of initial
100
100.9677
98
94
Percentage of label claim
104.4
105
102
98
Specific gravity
1.0841
1.0846
1.0844
1.0841
pH (neat)
4.62
4.57
4.4
4.15
Percentage of initial
100
98.9
95.2
89.8
Viscosity (spindle 61, 6rpm)
397.9
592
562
543
Percentage of initial
100
148.8
141.2
136.5
Appearance
Suspension
Suspension suspension suspension
Colour
Off white
Off white off white off white
Table 10 - Naphthalophos and Levamisole suspension B/N 3C Results at 40°C
0 months
1 months
3 months
6 months
Naphthalophos
158
157
154
155
159
158
154
156
(135-165 g/L)
158.5
157.5
154
155.5
Percentage of initial
100
99
97
98
Percentage of label claim
106
105
103
104
Levamisole
41.7
41.7
40.2
37.5
41.7
41.6
40
37.8
(36.0-44.0 g/L)
41.7
41.65
40.1
37.65
202131AU CS SPEC vl 3 24 Jan.doc
16
Percentage of initial
100
100
96
99.6
Percentage of label claim
104.4
104
100
94.25
Specific gravity
1.0841
1.0844
1.0847
1.0871
pH (neat)
4.62
4.22
3.67
3.3
Percentage of initial
100
91.3
79.4
71.4
Viscosity
397.9
638
1560
1540
(spindle 61, 6rpm)
Percentage of initial
100
160.3
392
387
Appearance
Suspension
Suspension suspension
Suspension
Colour
Off white
Off white off white off white
Table 11 - Combat Ready Duo (Reduced) B/N 2D Results at 30°C
0 months
1 months
3 months
Assay
159
156
157
Naphthalophos
160
157
158
ave(135 - 165
159.5
156.5
157.5
g/L)
percentage of
100.00
98.12
98.75
initial
Percentage of
106.33
104.33
105.00
label claim
Assay
26.0
26.0
26.3
Fenbendazole
98%
(22.5-27.5g/L)
26.1
26.0
26.4
Average
26.1
26.0
26.4
percentage of
100
99.81
101.15
initial
Percentage of
104.2
104.00
105.40
label claim
202131AU CS SPEC vl 3 24 Jan.doc
17
Assay
41.1
42.2
42.1
Levamisole
41.2
42.3
41.6
HCL
(36-44 g/L)
41.2
42.3
41.9
percentage of
100.00
102.67
101.70
initial
Percentage of
102.88
105.63
104.63
label claim
Specific
1.0925
1.0942
1.0935
Gravity
Viscosity
383
465
421
(cps)
pH (neat)
4.91
4.73
4.37
Appearance suspension suspension suspension
Colour off white off white off white
Table 12 - Combat Ready Duo (Reduced) B/N 2D Results at 40°C
0 months
1 months
3 months
Assay
159
158
155
Naphthalophos
160
157
156
ave(135 -165
159.5
157.5
155.5
g/L)
percentage of
100.00
98.75
97.49
initial
Percentage of
106.33
105.00
103.67
label claim
Assay
26.0
26.3
26.4
Fenbendazole
98%
(22.5-27.5g/L)
26.1
26.4
26.2
Average
26.1
26.4
26.3
percentage of
100.00
101.15
100.96
initial
Percentage of
104.20
105.40
105.20
label claim
202! 31AU CS SPEC vl 3 24 Jan.doc
18
Assay
41.1
42.1
41.6
Levamisole
41.2
42.1
41.5
HCL
(36-44 g/L)
41.2
42.1
41.6
percentage of
100.00
102.31
100.97
initial
Percentage of
102.88
105.25
103.88
label claim
Specific
1.0925
1.0931
1.0925
Gravity
Viscosity
383
527
1610
(cps)
pH (neat)
4.91
4.34
3.71
Appearance suspension suspension
Suspension
Colour off white off white off white
Table 13 - Combat Ready Duo B/N 2E Results at 30°C
The aim here was to a pH range 4.0-5.0 by increasing the percentage of Teric9,
Antifoam RD, Xanthan Gum all increased.
0 months
1 months
3 months
6 months
9 months
Assay Naphthalophos
(135-165 g/L)
161
159
158
156
156
161
158
158
156
155
161
159
158
156
155.5
Percentage of Label Claim
107.3
105.7
105.3
104
103.667
Percentage of Initial Result
100.0
98.4
98.1
96.8944
96.9
Fenbendazole 98%
(22.5-27.5g/L)
26.8
27.0
26.9
26.3
27
26.8
27.1
26.9
26.1
26.9
26.8
27.1
26.9
26.2
26.95
Percentage of Label Claim
107.2
108.2
107.6
104.8
107.8
202131AU CS SPEC vl 3 24 Jan.doc
19
Percentage of Initial Result
100.0
100.9
100.4
97.7612
100.56
Assay
43.2
43.1
41.5
39.9
41.9
Levamisole HCL
43.2
43.2
41.5
39.9
42.3
(36-44 g/L)
43.2
43.2
41.5
39.9
42.1
Percentage of Label Claim
108.0
107.9
103.8
99.75
105.25
Percentage of Initial Result
100.0
99.9
96.1
92.3611
97.4537
Specific Gravity
1.0974
1.0981
1.0985
1.0863
1.0923
Viscosity (cps)
525.0
566.9
586
1105
2070
Percentage of Initial Result
100.0
115.5
119.3
225.051
421.589
pH (neat)
4.95
4.64
4.4
4.1
3.9
Percentage of Initial Result
100.0
93.7
87.9
82.8283
78.7879
Appearance
suspension suspension suspension suspension
Suspension
Colour off white off white off white off white off white
Table 14 - Combat Ready Duo B/N 2E Results at 40°C
The aim here was to a pH range 4.0-5.0 by increasing the percentage of Teric9,
Antifoam RD, Xanthan Gum all increased.
0
months
1 months
3 months
6 months
9 months
Assay
161
157
156
152
151
Naphthalophos
161
156
156
152
151
(135-165 g/L)
161
157
156
152
151
Percentage of Label Claim
107.3
104.3
104.0
101.333
100.667
Percentage of Initial Result
100.0
97.2
96.9
94.4099
93.7888
202131AUCS SPEC vl 3 24 Jan.doc
Fenbendazole 98%
(22.5-27.5gfl,)
26.8
27.1
27
26.5
27.3
26.8
27.1
27.1
26.6
27.3
26.8
27.1
27.1
26.55
27.3
Percentage of Label Claim
107.2
108.4
108.2
106.2
109.2
Percentage of Initial Result
100.0
101.1
100.9
99.0672
101.866
Assay Levamisole
HCL (36-44 g/L)
43.2
42.8
40.5
38.1
40.1
43.2
42.8
40.6
38.3
40.2
43.2
42.8
40.6
38.2
40.15
Percentage of Label Claim
108.0
107.0
101.4
95.5
100.375
Percentage of Initial Result
100.0
99.1
93.9
88.4259
92.9398
Specific Gravity
1.0974
1.0984
1.0957
1.0863
1.098
Viscosity (cps)
525
541
2664
2554
1225
Percentage of Initial Result
100.0
110.2
542.6
520.163
249.491
pH (neat)
4.95
4.23
3.6
3.05
2.68
Percentage of Initial Result
100.0
85.5
72.3
61.6162
54.1414
Appearance
suspensi on suspension suspension suspensio n
Suspensio n
Colour off white off white off white beige
Beige
Table 15 - Viscosity of formulation 2E
Time
0M
1M
3M
6M
9M
Viscosity at 30° C
525
567
586
1105
2070
Viscosity at 40° C
525
541
2664
2554
1225
202131AU CS SPEC vl 3 24 Jan.doc
21
Table 16 - pH of Formulation 2E
Time
0M
1M
3M
6M
9M
pH (neat) at 30°C
4.95
4.64
4.35
4.10
3.90
pH (neat) at 40°C
4.95
4.23
3.58
3.05
2.68
Table 17 - Combat Ready Duo B/N 2D1 Results at 30°C - This formulation uses a higher buffer ratio.
0 months
1 month
3 months
6 months
9 months
12 months
Assay Naphthalophos
155
156
157
158
153 153
154 154
156 156
154 154
(135-165 g/L)
155.5
157.5
153.0
154.0
156.0
154.0
Percentage of Label Claim
103.7
105.0
102.0
102.7
104.0
102.7
Percentage of Initial Result
100.0
101.3
98.4
99.0
100.3
99.0
Fenbendazole 98%
(22.5-27.5g/L)
26.3
26.4 26.4
27.1
27 27.1
26.7
26.6
26.7
27
27 27.0
26.5
26.7
26.6
26.9
26.9 26.9
Percentage of Label Claim
105.4
108.2
106.6
108.0
106.4
107.6
Percentage of Initial Result
100.0
102.7
101.1
102.5
100.9
102.1
Assay Levamisole
HCL (36-44 g/L)
42.8 43
42.9
43.4
43.5
43.5
41.6
41.7
41.7
42 41.9
42.0
40.9 41.2
41.1
41.7 41.9
41.8
Percentage of Label Claim
107.3
108.6
104.1
104.9
102.6
104.5
Percentage of Initial Result
100.0
101.3
97.1
97.8
95.7
97.4
Specific Gravity
1.0869
1.0866
1.0865
1.0879
1.0845
1.0856
202131AU CS SPEC vl 3 24 Jan.doc
22
Viscosity (cps)
438
441
401
388
596
1190
Percentage of Initial Result
100.0
100.7
91.6
88.6
136.1
271.7
pH (neat)
4.38
4.1
3.67
3.36
3.11
3.00
Percentage of Initial Result
100.0
93.6
83.8
76.7
71.0
68.5
Appearance/
suspension suspension suspension suspension suspension suspension
Colour off white off white off white off white off white off white
Table 18 - Combat Ready Duo B/N 2D1 Results at 40°C - This formulation uses a higher buffer ratio.
0 months
1 months
3 months
6 months
9 months
12
months
months month months
Months months months
Assay
155
156
151
152
152
145
Naphthalophos
156
156
151
153
153
146
(135-165 g/L)
155.5
156.0
151.0
152.5
152.5
145.5
Percentage of
103.7
104.0
100.7
101.7
101.7
97.0
Label Claim
Percentage of
100.0
100.3
97.1
98.1
98.1
93.6
Initial Result
Fenbendazole
26.3
27
26.7
27
26.7
26.3
98%
26.4
27
26.5
27.2
26.7
26.5
(22.5-27.5g/L)
26.4
27.0
26.6
27.1
26.7
26.4
Percentage of
105.4
108.0
106.4
108.4
106.8
105.6
Label Claim
Percentage of
100.0
102.5
100.9
102.8
101.3
100.2
Initial Result
Assay
42.8
43.2
41.2
40.7
39.3
40.7
Levamisole
43
43.2
41.1
41.2
39.5
40.3
HCL
(36-44 g/L)
42.9
43.2
41.2
41.0
39.4
40.5
202131AU CS SPEC vl 3 24 Jan.doc
23
Percentage of Label Claim
107.3
108.0
102.9
102.4
98.5
101.3
Percentage of Initial Result
100.0
100.7
95.9
95.5
91.8
94.4
Specific Gravity
1.0869
1.0869
1.0866
1.0886
1.0857
1.086
Viscosity (cps)
438
426
640.9
1800
1135
1225
Percentage of Initial Result
100.0
97.3
146.3
411.0
259.1
279.7
pH (neat)
4.38
3.48
2.8
2.38
2.21
2.00
Percentage of Initial Result
100.0
79.5
63.9
54.3
50.5
45.7
Appearance/
suspension suspension suspension suspension suspension suspension colour off white off white off white off white beige beige
Table 19 - pH of formulation 2D1
Time
0M
1M
3M
6M
9M
12M
pH (neat) at 30°C
4.38
4.1
3.67
3.36
3.11
3.00
pH (neat) at 40°C
4.38
3.48
2.8
2.38
2.21
2.00
Table 20 - Viscosity of formulation 2D1
Time
0M
1M
3M
6M
9M
12M
Viscosity at 30° C
438
441
401
388
596
1190
Viscosity at 40° C
438
426
640.9
1800
1135
1225
202I31AU CS SPEC vl 3 24 Jan.doc
24
Table 21 - Combat Ready Duo B/N 2D2 Results at 30°C
0 months
1
months
3
months (+18day s)
6
months
9
months
12 months
18 months
Assay
156
156
156
158
158
157
158
Naphthalophos
155
154
155
158
158
157
158
135-165 g/L
Average
156
155
156
158
158
157
158
% Initial result
100.0
99.7
100.0
101.2
101.6
101.0
101.6
% Label claim
103.7
103.3
103.7
105.3
105.3
104.7
105.3
Assay Fenbendazole
98% (22.5-27.5g/L)
26.4 26.3
26.5
26.6
26.4 26.6
27.1 27.0
26.9 27.1
27.8 27.5
27 27.1
Average
26.4
26.6
26.5
27.1
27.0
27.7
27.1
% Initial result
100.0
100.8
100.6
102.7
102.5
104.9
102.7
% Label claim
105.4
106.2
106.0
108.2
108.0
110.6
108.2
Levamisole
HCL (36-44 g/L)
42.4 42.4
42.6 42.6
43.1 43.1
42.5 42.5
42.5 42.5
43 42.7
42.1
42.2
Average
42.5
42.6
43.2
42.6
42.5
42.9
42.2
% Initial result
100.0
100.4
101.7
100.4
100.1
100.9
99.3
% Label claim
106.1
106.5
107.9
106.5
106.3
107.1
105.4
Specific Gravity i.0878
i .0873
1.0847
1.0886
1.0889
1.0863
1.0896
Viscosity (cps)
416
292
Insuffici ent
217
199
186
963
% of Initial Result
100.0
70.2
52.2
47.8
44.7
231.5
202131AU CS SPEC vl 3 24 Jan.doc
pH (neat)
2.93
2.83
2.66
2.59
2.58
2.52
2.31
% of Initial Result
100.0
96.6
90.8
88.4
88.1
86.0
78.8
Colour off white off white off white off white off white off white off white
Appearance suspensio n suspensi on
Suspensi on suspens ion suspens ion suspens ion suspens ion
Table 22 - Combat Ready Duo B/N 2D2 Results at 40°C
0
months
1 months
3 months
6 months
9 months
(+18 days)
Assay
156
155
158
156
153
Naphthalophos
155
155
157
157
153
(135-165 g/L)
Average
156
155
158
157
153
% Initial result
100.00
99.68
101.29
100.64
98.39
% Label claim
103.67
103.33
105.00
104.33
102.00
Assay Fenbendazole
98% (22.5-27.5g/L)
26.4 26.3
26.9 27.1
26.9 26.8
27.4 27.4
27 27
Average
26.35
27
26.85
27.4
27
% Initial result
100
102.47
101.20
100.18
102.47
% Label claim
105.4
108
107.4
109.6
108
Levamisole HCL (36-44g/L)
Average
42.5
42.4
42.5
42.5
42.5 42.5
43.2
42.7 43.0
41.6
41.5
41.6
40.3
40.4 40.4
202131AU CS SPEC vl 3 24 Jan.doc
26
% Initial result
100.0
100.0
101.2
97.9
95.1
% Label claim
106.1
106.3
107.4
103.9
100.9
Specific Gravity
1.0878
1.0877
1.0873
1.0885
1.0883
Viscosity (cps)
416
281
Insufficient sample
1600
1660
% Initial result
100.00
67.55
384.6
399.04
pH (neat)
2.93
2.8
2.35
2.13
1.91
% Initial result
100
95.5
80.2
72.69
65.19
Colour off white off white off white off white off white
Appearance suspension suspension
Suspension suspension suspension caking but suspensable
Table 23 - Viscosity of formulation 2D2
Time
0M
1M
6M
9M
12M
18M
Viscosity at 30° C
416
292
217
199
186
963
Viscosity at 40° C
416
281
1600
1660
Table 24 - pH of formulation 2D2
Time
0M
1M
3M
6M
9M
12M
18M
pH (neat) at 30°C
2.93
2.83
2.66
2.59
2.58
2.52
2.31
pH (neat) at 40°C
2.93
2.8
2.35
2.13
1.91
2.00
202131AU CS SPEC vl 3 24Jan.doc
27
Table 25 - Formulation 2 Results at 30°C
0 months
1
months
100 days
6 months
9
months
12 months
Assay
149
148
149
149
149
151
Naphthalophos (135-165 g/L)
148
149
148 148
148
149
150 150
149 149
149
150
Percentage of Initial result
100
99
100
100
100
101
Percentage of Label claim
99
99
99
100
99
100
Fenbendazole 98%
24.5
24.6
24.6
.2
24.9
24.5
24.8
24.4
.1
.1
24.6
(22.5-27.5g/L)
24.5
24.7
24.5
.1
.2
24.8
Percentage of Initial result
100.0
100.0
100.0
100.0
100.4
98.8
Percentage of Label claim
98.0
98.8
98.0
100.2
100.6
99.0
Assay
39.5
39.3
39.4
38.2
38.9
38.5
Levamisole HCL
39.4
39.4
39
38.3
38.9
38.1
(36-44 g/L)
39.5
39.4
39.2
38.3
38.9
38.3
Percentage of Initial result
100.0
100.0
100.0
100.0
101.7
100.1
Percentage of Label claim
98.6
98.4
98.0
95.6
97.3
95.8
Specific Gravity
1.086
1.0841
1.0854
1.0855
1.0871
1.0837
Viscosity
320
230
180
200
187
137
(cps)
Percentage of Initial result
100
71.88
56.25
62.50
58.44
73.26
pH (neat)
3
3.03
2.95
2.78
2.86
2.63
202131AU CS SPEC vl 3 24 Jan.doc
28
Percentage of Initial result
100.00
101.00
98.33
92.67
95.33
87.67
Appearance
Milky white to off white off white off white
Off white suspensi on
Suspensio n
Colour suspensio n suspensi on suspension suspension off white off white
Table 26 - Formulation 2 Results at 40°C
0 months
1 months
3 months
6 months
9 months
12 months
Assay Naphthalophos
149 148
148
149
147 149
146 146
145 144
146
147
(135-165 g/L)
149
149
148
146
145
147
Percentage of Initial result
100
100
99
98
97
98
Percentage of Label Claim
99
99
99
97
96
98
Fenbendazole 98%
(22.5-27.5g/L)
24.5
24.5 24.5
24.8
24.9 24.9
24.9
.1 25.0
24.8
24.9
.1
25.1
24.9
.1 25.0
Percentage of Initial result
100.0
101.4
102.0
101.6
102.2
102.0
Percentage of Label Claim
98.0
99.4
100.0
99.6
100.2
100.0
Assay Levamisole
HCL (36-44 g/L)
39.5
39.4
39.5
39 39.1
39.1
38.2
OO o JO. J
38.3
37.2
J/.D
37.3
37.4
t j/.I 37.3
36.2 36.4
36.3
Percentage of Initial result
100.0
99.0
97.0
94.4
94.4
92.0
Percentage of Label Claim
98.6
97.6
95.6
93.1
93.1
90.8
202131AU CS SPEC vl 3 24 Jan.doc
29
Specific Gravity
1.086
1.0845
1.0851
1.085
1.0854
1.0827
Viscosity (cps)
320
177
102
184
411
621
Percentage of Initial
100.00
55.31
31.88
57.50
128.44
194.06
pH (neat)
3
2.86
2.5
2.19
2.08
2.03
Percentage of Initial
100.00
95.33
83.33
73.00
69.33
67.67
Appearance
Milky white to off white suspension suspension suspension suspension
Suspen off white
Colour suspension
Off white off white off white off white
Table 27- Viscosity of formulation 2
Time
0M
1M
Viscosity at 30° C
320
230
Viscosity at 40° C
320
177
Table 28- pH of formulation 2
Time
0M
1M
pH (neat) at
3
3.03
°C
pH (neat) at
3
2.86
40°C
Table 29 - NapAba suspension B/N 3D Results at 30°C
0 months
1 months
3 months
6 months
Abamectin
1.00
0.99
0.97
0.97
1.02
0.98
0.97
0.96
0.90-1.10
1.01
0.98
0.97
0.97
g/L
Percentage of Initial Result
100.0
97.0
95.9
95.8
20213IAU CS SPEC vl 3 24 Jan.doc
Percentage of Label Claim
101.0
98.4
96.9
96.8
Naphthalo phos 135-165 g/L
154
155 155
151 151 151
151 151 151
152 152 152
Percentage of Initial Result
100.0
97.4
97.4
97.4
Percentage of Label Claim
103.3
100.7
100.7
101.3
Specific gravity
1.0714
1.072
1.073
1.0719
pH (neat)
.12
4.98
4.82
4.77
Percentage of Initial Result
100
97.3
94.1
93.2
Viscosity
(spindle 61, 6rpm)
390.9
462
427
391
Percentage of Initial Result
100
118.2
109.2
100
Appea ranee
Suspension suspension suspension
Suspension
Colour
Off white
Off white off white off white
Table 30 - NapAba suspension B/N 3D Results at 40°C
0 months
1 months
3
months
6 months
Abamectin
0.90-1.10 g/L
1.00 1.02
1.01
0.99 0.99 0.99
0.96 0.96 0.96
0.96 0.96 0.96
Percentage of Initial Result
100.0
98.0
95.0
95.0
Percentage of Label Claim
101.0
99.0
95.9
95.9
202131AU CS SPEC vl 3 24 Jan.doc
31
Naphthalo
154
153
149
150
phos
155
154
148
151
135-165
155
154
149
151
g/L
Percentage
100.0
99.4
96.1
97.4
of Initial
Result
Percentage
103.3
102.7
99.3
100.7
of Label
Claim
Specific
1.0714
1.0731
1.0717
1.0724
gravity
pH (neat)
.12
4.83
4.61
4.46
Percentage
100
94.3
90
87.1
of Initial
Result
Viscosity
390.9
503
438
369
(spindle 61,
6rpm)
Percentage
100
128.6
112
94.4
of Initial
Result
Appea
ranee
Suspension suspension suspension suspension
Colour
Off white off white off white off white
Table 31-
Suspension B/N 3D1 Results at 30°C
0 months
1 months
3 months
6 months
Abamectin
1.09
1.08
1.06
1.06
1.09
1.07
. 1.070
1.06
0.90-
1.10 g/L
1.09
1.08
1.07
1.06
Percentage
100.00
98.62
97.71
97.25
of Initial
Result
Percentage
109.00
107.50
106.50
106.00
of Label
Claim
Naphthalo
164
164
161
161
phos
164
162
161
161
135-165
164
163
161
161
g/L
202131AU CS SPEC vl 3 24 Jaadoc
32
Percentage of Initial Result
100.0
99.4
98.2
98.2
Percentage of Label Claim
109.3
108.7
107.3
107.3
Specific gravity
1.0766
1.0773
1.0791
1.0762
pH (neat)
.13
.05
4.92
4.86
Percentage of Initial Result
100.0
98.4
95.9
94.7
Viscosity sps Spindle 61 6rpm
502.9
608
593
512
Percentage of Initial Result
100.0
120.9
117.9
101.8
Appea ranee
Suspension suspension suspension suspension
Colour
Off white
Off white off white off white
Table 32 -
Suspension B/N 3D1 Results at 40°C
0 months
1 months
3 months
6 months
Abamectin
0.90-1.10 g/L
1.09 1.09
1.09
1.07
1.06
1.07
1.07 1.060
1.07
1.03 1.03
1.03
Percentage of Initial Result
100.00
97.71
97.71
94.50
Percentage of Label Claim
109.00
106.50
106.50
103.00
Naphthalo phos
164 164
164 162
160 160
161 161
135-165 g/L
164
163
160
161
Percentage of Initial Result
100.0
99.4
97.6
98.2
202131AUCS SPEC vl 3 24 Jan.doc
33
Percentage of Label Claim
109.3
108.7
106.7
107.3
Specific gravity
1.0766
1.0773
1.0777
1.769
pH (neat)
.13
4.94
4.67
4.51
Percentage of Initial Result
100.0
96.3
91.0
87.9
Viscosity sps Spindle 61 6rpm
502.9
656
629
493
Percentage of Initial Result
100.0
130.4
125.1
98.0
Appea ranee
Suspension suspension suspension suspension
Colour
Off white off white off white off white
Table 33 - NapAba suspension B/N3D1
Time
0M
1M
3M
6M
Viscosity at 30° C
390.9
462
427
391
Viscosity at 40° C
390.9
503
438
369
Table 34 - NapAba suspension B/N 3D1
Time
0M
1M
3M
6M
Viscosity at 30° C
502.9
608
593
512
Viscosity at 40° C
502.9
656
629
493
ADVANTAGES OF THE PREFERRED EMBODIMENTS:
A stable and convenient suspension of Naphthalophos with long shelf life enabling to be pre-formulated and sold as a suspension, either alone or in combination with other actives such as fenbendazole, levamisole, and abamectin (refer Example 3 and related stability trials).
202I31AUCS SPEC vI 3 24Jan.doc
34
The preferred formulation of Example 2 contains a stable combination of the three actives:
Naphthalophos,
Fenbendazole, and Levamisole.
'
This formulation is stable, maintaining a concentration within +/-10% or the initial concentration of active ingredients for the duration of its shelf life
Previously naphthalophos products have only been sold in a powder form and mixed on-farm. The ready to use formulation of the examples has overcome the stability problems and 10 achieved a stable liquid formulation. The other advantage of the formulation of example 2 is the increase in the level of fenbendazole and its metabolites in the formulation containing naphthalophos, fenbendazole (FBZ) and levamisole compared to that observed in a product containing only fenbendazole and levamisole. This is demonstrated by the plasma concentrations shown in the Figures and explained in Examples 4 and 5. Thus the 15 formulation of Example 2 appears to have a synergistic effect on the plasma concentration of fenbendazole and its metabolites.
Example 4 shows the results of a cross over design with two phases and two groups. Example 5 was a parallel study with just two groups and only one phase.
The formulation of Example 2 demonstrates higher blood levels of FBZ and metabolites. 20 Examples 1 and 2 demonstrate the ability to achieve a stable formulation of naphthalophos in a liquid medium with or without other anthelmintics. The stability trails and the graphs of Figures 7 onwards how the changes in pH and viscosity over time of various formulations of the invention.
202131AU CS SPEC vl 3 24 Jan.doc
Claims (11)
1. A stable veterinary formulation containing at least the active naphthalophos wherein the liquid carrier comprises a buffered aqueous solution and the naphthalophos is 5 suspended in the buffered aqueous solution having a pH in the range 2.5 to 5.5.
2. A stable veterinary formulation as claimed in claim 1 wherein the naphthalophos is micronised to 100%<10|i; and/or 90%<5|a.
3. A stable veterinary formulation as claimed in claim 1 or 2, wherein the buffer includes a weak organic or inorganic acid and a conjugate organic or inorganic weak 10 base of phosphoric, sulphuric or acetic acid or the like.
4. A stable veterinary formulation as claimed in claim 3, wherein the buffer includes citric acid and the conjugate weak base is disodium phosphate.
5. A stable veterinary formulation as claimed in any one of claims 1 to 4, wherein the buffered aqueous solution includes xanthan gum. 15
6. A stable veterinary formulation as claimed in any one of claims 1 to 5, wherein the pH of the formulation is in the range of 3.5 to 4.5.
7. A stable veterinary formulation as claimed in any one of claims 1 to 6, wherein the formulation also includes one or more additional actives.
8. A stable veterinary formulation as claimed in claim 7, wherein the one or more 20 additional actives include a benzimidazole.
9. A stable veterinary tbrmulation as claimed in claim 8, wherein the benzimidazole is fenbendazole.
10. A stable veterinary formulation as claimed in any one of claims 7 to 9, wherein the one or more additional actives include a tetramisole. 25
11. A stable veterinary formulation as claimed in claim 10, wherein the tetramisole is levamisole. 202131AU CS SPEC vl 3 24 Jan.doc intellectual property office of n.z. 3 (1 JAN 2008 RECEIVED 36 ABSTRACT A stable suspension of micronised naphthalophos in a buffered aqueous carrier having a pH in the range of 3.5 to 4.5. The stable suspension is suitable for use in combination with other anthelmintics and formulations containing naphthalophos alone, or in combination with 5 fenbendazole and/or levamisole are disclosed. Viscosity measurements show the ready made formulations are suitable for use in drench guns. 202131AU CS SPEC v 1 3 24 Jan.doc office of n.z. i I 3 o JAN 2008 | RECEIVER.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2007900463A AU2007900463A0 (en) | 2007-02-01 | Anthelmintic Formulations |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NZ565548A true NZ565548A (en) | 2009-05-31 |
Family
ID=39731372
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NZ565548A NZ565548A (en) | 2007-02-01 | 2008-01-30 | Stable anthelmintic veterinary formulations containing naphthalophos |
Country Status (3)
| Country | Link |
|---|---|
| AU (2) | AU2008200460B2 (en) |
| NZ (1) | NZ565548A (en) |
| ZA (1) | ZA200801063B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2514109C1 (en) * | 2013-02-07 | 2014-04-27 | Федеральное государственное бюджетное образовательное учреждение высшего профессионального образования Курская государственная сельскохозяйственная академия имени профессора И.И. Иванова Министерства сельского хозяйства Российской Федерации | Method of treatment of cattle with strongylatosis of gastrointestinal tract |
| RU2544165C2 (en) * | 2013-07-09 | 2015-03-10 | Александр Александрович Кролевец | Method of fenbendazole encapsulation |
| RU2552344C1 (en) * | 2014-03-18 | 2015-06-10 | Александр Александрович Кролевец | Fenbendazole encapsulation method |
| RU2552346C1 (en) * | 2014-03-26 | 2015-06-10 | Александр Александрович Кролевец | Fenbendazole encapsulation method |
-
2008
- 2008-01-30 NZ NZ565548A patent/NZ565548A/en not_active IP Right Cessation
- 2008-01-31 AU AU2008200460A patent/AU2008200460B2/en not_active Ceased
- 2008-02-01 ZA ZA200801063A patent/ZA200801063B/en unknown
- 2008-12-19 AU AU2008101247A patent/AU2008101247B4/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| AU2008200460B2 (en) | 2009-07-02 |
| AU2008200460A1 (en) | 2008-08-21 |
| AU2008101247B4 (en) | 2009-02-26 |
| AU2008101247A4 (en) | 2009-02-05 |
| ZA200801063B (en) | 2008-12-31 |
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|---|---|---|---|
| PSEA | Patent sealed | ||
| RENW | Renewal (renewal fees accepted) | ||
| LAPS | Patent lapsed |