NZ585222A - Veterinary composition comprising dicyclanil - Google Patents

Veterinary composition comprising dicyclanil

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Publication number
NZ585222A
NZ585222A NZ58522210A NZ58522210A NZ585222A NZ 585222 A NZ585222 A NZ 585222A NZ 58522210 A NZ58522210 A NZ 58522210A NZ 58522210 A NZ58522210 A NZ 58522210A NZ 585222 A NZ585222 A NZ 585222A
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NZ
New Zealand
Prior art keywords
composition according
composition
amount
dicyclanil
present
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Application number
NZ58522210A
Inventor
Kai Kin Lau
Original Assignee
Jurox Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from AU2009902058A external-priority patent/AU2009902058A0/en
Application filed by Jurox Pty Ltd filed Critical Jurox Pty Ltd
Publication of NZ585222A publication Critical patent/NZ585222A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/541,3-Diazines; Hydrogenated 1,3-diazines

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Environmental Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Agronomy & Crop Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Plant Pathology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

Disclosed is a composition comprising an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity modifier and a therapeutically acceptable carrier, wherein in Differential Scanning Calorimetry said crystal modification of dicyclanil exhibits a transformation in the temperature range of between 175 degrees C and 197 degrees C and possesses the characteristic interlattice plane distances in [Angstrom] from X-ray diffraction measurements as disclosed in the specification. Also disclosed is the use of the composition for preventing or controlling insect infestation of a non-human animal. Dicyclanil is 4,6-diamino-2-cyclopropylaminopyrimidine-5-carbonitrile.

Description

New Zealand Paient Spedficaiion for Paient Number 585222 RECEIVED at IPONZon 17 August 2011 1 NEW ZEALAND Patents Act 1953 JUROX PTY LTD COMPLETE SPECIFICATION STANDARD PATENT Invention Title: A veterinary composition for preventing and controlling insect infestation The following statement is a full description of this invention including the best method of performing it known to us:- 1485912 1.doc RECEIVED at IPONZon 17 August 2011 2 A veterinary composition for preventing and controlling insect infestation Cross-Reference to Related Applications The present application claims priority from Australian Provisional Application No. 2009902058 filed 8 May 2009, the content of which is incorporated herein by 5 reference.
Technical Field The present invention relates to compositions for external use in the prevention and control of insect infestations of animals, the compositions comprising a specific 10 crystal form of dicyclanil (4,6-diamino-2-cyclopropylaminopyrimidine-5-carbonitrile).
Background Art The morphology and polymorphology of organo-chemical active substances is of great importance to the chemical and pharmaceutical development thereof. 15 Substances are known which only appear in a single crystal form; in addition, however, there are also substances which can form two, three or even more polymorphous crystal modifications.
It is just as difficult to calculate or predict this possible morphological and structural variety and the respective physico-chemical, especially thermodynamic 20 stability respect thereof on a scientific-mathematical basis, as it is to calculate or predict their different behaviour when they are administered to an animal. The relevant polymorphism of an organo-chemical substance is always unpredictable in respect of the number of crystal modifications, the stability thereof and their therapeutic efficacy in an animal. If two, three or more crystal modifications of a substance are 25 known, then in general their absolute and relative physico-chemical stabilities may be determined. The different crystal modifications of one and the same substance may differ considerably from one another in many respects. These differences in morphology and polymorphism may have drastic effects on the development, storage stability and bio-availability of individual dosage forms.
The same also applies in respect of the physical and chemical properties of dicyclanil, a compound of formula 4,6-diamino-2-cyclopropylaminopyrimidine-5-carbonitrile with a published melting point of 249-251°C, which is disclosed in European Patent Specification EP-0 244360 B1 both as a new compound and as an agent for the control of insects pests and ectoparasites on warm-blooded animals. 1485912 1.doc 3 Dicyclanil is an insect growth regulator belonging to the group of pyrimidinamines. Dicyclanil interferes with the chitin metabolism of the insect. Treated larvae will therefore be unable to moult to the next stage. Dicyclanil is therefore used as a veterinary drug for the control of ectoparasites on domestic and 5 farm animals." The molecule shows a high specificity for Dipteran fly larvae so may be used to provide long-term protection of sheep against the widespread myasis flies such as Lucilia Sericata, Lucilia cuprina and the like.
Application is preferably effected by means of the "pour-on" process, whereby the formulation is finely dispersed to the back of the animal either directly or by a spray 10 appliance. This type of application has considerable advantages, since only the exposed places are sprayed and effects on the environment are thus minimised. It is precisely with formulations having suspended active substance, such as in the "pour-on" processes, that the different properties of the crystal modifications play a decisive role.
Several crystal modifications of dicyclanil are known. One crystal modification 15 of dicyclanil is described in EP-0 244360 Bl. Others are disclosed in W099/10333. Each of the forms are significantly distinct from one another in respect of their physio-chemical properties, their stability and, in part, their biological behaviour.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a 20 context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.
Disclosure of Invention The invention provides compositions, uses and methods as defined in the appended claims.
In work leading to the present disclosure, the inventors have surprisingly found a previously unknown crystal modification of dicyclanil and established that it is stable 30 in a pharmaceutically acceptable formulation. Further, they have also surprisingly found that such a formulation is efficacious in the control of insect infestations, particularly in the control of ectoparasite infestation.
Accordingly, disclosed herein is a composition comprising a specific crystal modification of dicyclanil which is efficacious in the control of insect infestations, 35 particularly ectoparasite infestation, and is stable in a pharmaceutically acceptable 146373Jaw_speci 4 formulation and which has not been previously used for the control of insect infestation.
Throughout this specification, and unless it is stated to the contrary, the word "comprise", or variations such as "comprises" or "comprising", will be understood to 5 imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
Disclosed herein is a composition comprising an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity modifier and a 10 therapeutically acceptable carrier, wherein in Differential Scanning Calorimetry said crystal modification of dicyclanil exhibits a transformation in the temperature range of between 175°C and 197°C and possesses the following characteristic interlattice plane distances in [A0] from X-ray diffraction measurements: 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, 5.81±0.05, 15 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60±0.05, 4.45±0.05, 4.28±0.05, 414±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05, 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05, 2.86±0.05, 2.83±0.05.
The composition disclosed herein is effective when used to prevent or control 20 insect infestation of an animal.
Accordingly, also disclosed herein is a composition comprising an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity modifier and a therapeutically acceptable carrier when used to prevent or control insect infestation of an animal, wherein in Differential Scanning Calorimetry 25 said crystal modification of dicyclanil exhibits a transformation in the temperature range of between 175°C and 197°C and possesses the following characteristic interlattice plane distances in [A0] from X-ray diffraction measurements: 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, 5.81±0.05, 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60±0.05, 4.45±0.05, 30 4.28±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05, 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05, 2.86±0.05, 2.83±0.05.
Also disclosed herein is use of a composition comprising an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity 35 modifier and a therapeutically acceptable carrier in preventing or controlling insect infestation of an animal, wherein in Differential Scanning Calorimetry said crystal 146373Jaw_speci modification of dicyclanil exhibits a transformation in the temperature range of between 175°C and 197°C and possesses the following characteristic interlattice plane distances in [A0] from X-ray diffraction measurements: 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, 5.81±0.05, 5 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60±0.05, 4.45±0.05, 4.28±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05, 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05, 2.86±0.05, 2.83±0.05.
Also disclosed herein is a method of preventing or controlling insect infestations 10 of an animal, the method comprising topically administering to the animal a composition comprising: an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity modifier and a therapeutically acceptable carrier, wherein in Differential Scanning Calorimetry said crystal modification of dicyclanil exhibits a transformation in the temperature range of between 175°C and 15 197°C and possesses the following characteristic interlattice plane distances in [A0] from X-ray diffraction measurements: 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, 5.81±0.05, 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60±0.05, 4.45±0.05, 4.28±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05,' 20 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05, 2.86±0.05, 2.83±0.05.
An "effective amount of a crystal modification of dicyclanil" is present in the composition disclosed herein. By "effective amount" it is meant that the dicyclanil is present in a concentration that is capable of controlling insects, particularly 25 ectoparasites, on an animal.
Dicyclanil is preferably present in an amount of from 1 to 20%w/v of the composition, preferably from 2 to 10 % w/v and more preferably from 4 to 6 %w/v. In one embodiment, the dicyclanil is present in an amount of about 5% w/v.
One or more surfactants are included in the composition of the invention, 30 preferably in an amount of from about 1.0 to 10%w/v. More preferably, the amount is in the range of from about 1 to 8%w/v, most preferably from about 1.5 to 5 %w/v. The surfactant may be selected from nonionic, anionic, cationic or amphoteric surfactants or mixtures thereof. Preferably a nonionic surfactant is used. Nonionic surfactants may be selected from the group consisting of Cs-Cio alkylphenol ethoxylates, C9-C17 alcohol 35 ethoxylates, C8-C20 alkyl amine ethoxylates, castor oil ethoxylates, lanolin alcohol ethoxylates, lanolin alcohol acetylates, sorbitan fatty acid ester ethoxylates, sorbitan 146373Jaw_speci 6 fatty acid esters, ethoxylated sorbitan etsers and mixtures thereof. The Cs-Cio alkylphenol ethoxylates preferably contain from 2 to 100 moles of ethylene oxide and may be selected from the commercially available Teric series products. Teric N9 ™is an alkyl phenol ethoxylate with 9 moles of ethylene oxide condensed onto nonyl rriw phenol. In one preferred embodiment, the surfactant is Teric N9 . The Teric N9 is preferably present in the composition in an amount of about 4.5%w/v. Solulan™ is a mixture of acetylated lanolin alcohol and an ethoxylated sorbitan ester. In another preferred embodiment the surfactant is Solulan™. The Solulan™ is preferably present in the composition in an amount of about 2%w/v. The sorbitan fatty acid ester 10 ethoxylates preferably contain from 4 to 20 moles of ethylene oxide and may be selected from polysorbate 60 and polysorbate 80.
One or more viscosity modifiers are included in the composition of the invention, preferably in an amount of from about 0.05 to 15%w/v. In one embodiment the viscosity modifier is present in an amount of 0.1 to 5 %w/v. Preferably, the amount 15 is in the range of from about 0.1 to 2%w/v, most preferably about 0.2%w/v. In another embodiment, the viscosity modifier is in an amount of from about 3 to 6%w/v, more preferably about 5.2% w/v. Examples of suitable viscosity modifiers include, for example, methyl cellulose, xanthum gum and colloidal silica and polymeric pyrrolidones such as povidone. In one preferred embodiment the viscosity modifier is 20 Aerosil™. Aerosil™is an example of a colloidal silica. In another preferred embodiment, the modifier is xanthum gum. In another preferred embodiment the composition of the invention includes the viscosity modifiers Aerosil™ and xanthum gum.
The viscosity of the composition shall be optimised to enable the composition to 25 provide good suspensibility of dicyclanil and ease of application of the product to the animals. Preferably the viscosity of the composition is in the range of about 100 - 1000 cps, more preferably, about 300 - 800 cps, most preferably, about 500 - 700 cps, as measured at 25°C using a Brookfield viscometer.
The compositions disclosed herein comprises a "therapeutically acceptable 30 carrier" which allows the dicylcanil to remain in crystal form in the composition. The "therapeutically acceptable carrier" may be selected from one or more of the group consisting of water and any other solvent in which the crystal modification of dicyclanil will not be dissolved or is sparingly soluble, such as, for example, propylene glycol, medium chain triglycerides and oil. In one embodiment the "therapeutically acceptable 35 carrier" may be water alone. In another embodiment the "therapeutically acceptable carrier" may be a mixture of water and one or more solvents in which the crystal 146373Jaw_speci 7 modification of dicyclanil will not be dissolved or is sparingly soluble, such as, for example, propylene glycol, medium chain triglycerides and oil. In yet another embodiment, the "therapeutically acceptable carrier" may be a mixture of one or more solvents in which the crystal modification of dicyclanil will not be dissolved or is 5 sparingly soluble, such as, for example, one or more of the solvents selected from the group consisting of propylene glycol, medium chain triglycerides and oil, wherein no water is present. It will be understood that the "therapeutically acceptable carrier" is pharmaceutically safe to administer to an animal and does not cause skin irritation. The compositions disclosed herein are made to volume with the "therapeutically acceptable 10 carrier".
In a preferred embodiment, the composition disclosed herein is an aqueous suspension composition and is made up to volume with water.
The composition optionally includes pharmaceutically acceptable excipients and adjuvants such as, for example, one or more dispersants, preservatives, buffers and 15 anti-skinning agents.
Examples of suitable dispersing agents include, for example, colloidal silica polymeric pyrrolidones such as povidone, glycerine and polyethylene glycol. It is believed that the dispersants change the density of the medium and help the dispersion of the solid phase.
It will be appreciated that one or more viscosity modifiers used in the composition disclosed herein may also function as a dispersant.
In a preferred embodiment, one or more dispersants may be included in the composition in an amount of from about 0.05 to 15 %w/v. More preferably, the amount of dispersant is in the range of from about 1 to 10 %w/v, most preferably about 25 5.2 %w/v. In a preferred embodiment the dispersant is colloidal silica. As noted above, colloidal silica may simultaneously perform the role of dispersant and viscosity modifier.
One or more preservatives may be included in the composition, such as, for example, hydroxybenzoate, benzyl alcohol, sorbic acid, sorbate salts and mixtures 30 thereof.
One or more buffers may be included in the composition disclosed herein. Preferably, the pH of the composition is in the range of about 5-9, more preferably close to neutral (about pH 7). Examples of suitable buffers include, for example, phosphate, citro-phosphate and citro- buffers.
One or more anti-skinning agent may be included in the composition disclosed herein. An anti-skinning agent is used to minimise prevent or reduce the formation of 146373Jaw_speci 8 skin on the surface of the composition due to evaporation on the surface of the liquid. Examples of suitable anti-skinning agents include, for example, polyols and silicon oil.
In Differential Scanning Calorimetry (DSC), the crystal modification of dicyclanil for use in the present invention shows a transformation in the temperature 5 range of between 175 °C and 197°C. A suitable heating rate is 2°C/minute.
The temperature range and the kinetics of this conversion is dependent both on external measurement conditions and on different properties of the respective sample of dicyclanil. The preferred characterisation of crystal modification of dicyclanil is effected by means of the interlattice plane distances d of an X-ray diffraction diagram: 10 din [A0]: 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, .81±0.05, 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60.±0.05, 4.45±0.05, 4.28±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05, 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05,2.86±0.05, 2.83±0.05.
The most intensive reflexes in the X-ray diffraction diagram thus give the following interlattice plane distances: d in [A0]: 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 5.95±0.05, 5.81±0.05, 5.73±0.05, 4.45±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.43±0.05, 3.39±0.05.
Crystal modifications, hydrates and solvates may be distinguished by their X-ray 20 powder diagrams. X-ray powder diagrams are preferably used to characterise solid forms of organic substances. In particular, X-ray diffraction (XRD) diagrams are used advantageously and with good powers of affirmation to determine the different crystal modifications of a substance. In the case of hydrates and solvates, additional methods have to be used such as thermogravimetry or thermogravimetry-Fourier-transform-25 infrared-spectroscopy (TGFTIR) and other substance-specific methods.
To characterise the crystal modification of dicyclanil included in the composition of the invention, measurements were carried out using samples of substance which were kept at room temperature. The XRD analysis was carried out using a X'Pert MPD XRD with a X'Celerator detector and the interlattice plane 30 distances of the most important lines were calculated. Results are shown in Table 1. 146373Jaw_speci 9 Table 1: X-ray diffraction diagram (interlattice plane distances and intensities of the most important lines) of the crystal modification of dicyclanil. d[A°] Intensity d[A°] Intensity 11.26 Very weak 3.58 Very weak 9.19 Very strong 3.43 Medium 8.90 Very strong 3.39 Medium 8.01 Very strong 3.33 Weak 7.70 Medium 3.27 Very weak 7.48 weak 3.19 Very weak .95 Strong 3.13 Very weak .81 medium 3.06 Very weak .73 Strong 2.96 Weak .62 Weak 2.90 Very weak .13 Very weak 2.86 Very weak 4.88 Very weak 2.83 Very weak 4.74 Very weak 4.60 Weak 4.45 Very strong 4.28 Very weak 4.14 Medium 4.00 Medium 3.72 Medium The compositions disclosed herein are effective in preventing or controlling a variety of insect infestations, particularly ectoparasites, on an animal. In a preferred embodiment the compositions disclosed herein are ectoparasiticide compositions. The phrase "preventing or controlling" will be understood to mean that the insect infestation 10 of the animal is stopped or reduced following application of the composition to the animal. The composition disclosed herein is applied topically to the animal. Without being bound by theory, the inventors believe the composition is effective in controlling insects by eradicating insect larvae, essentially by inhibiting their growth and by preventing them from maturing. The composition may be applied topically to the 146373Jaw_speci RECEIVED at IPONZ on 1 November 2011 animal in a number of ways including for example, by way of applicator, such as a gun applicator, wherein the composition is poured or sprayed onto the animal. The composition may be used as it is or further diluted with water for use in a dip or jetting race. In a preferred embodiment the composition is applied as it is onto the animal 5 without further dilution. .
The compositions disclosed herein are effective when used on a variety of animals. Examples of animals include sheep, goat, ruminants (including cattle) and camelids.
The compositions disclosed herein are effective against insects, more 10 particularly ectoparasites, including but not limited to flies such as Lucilia Seriata and Lucilia cuprina, fleas and lice. In a preferred embodiment, the composition is used to prevent or control sheep blowfly (Lucilia cuprina) infestation of a sheep.
Methods of formulation 15 To produce the compositions disclosed herein an effective amount of the crystal modification of dicyclanil disclosed herein, is dispersed in a mixture of surfactant, viscosity modifier, therapeutically acceptable carrier and optionally pharmaceutically acceptable excipients and adjuvants, followed by high speed mixing until uniform.
It will be appreciated that the dose of the composition applied to the animal will 20 be dependant upon a number of factors including, for example, if the composition is to be used for body strike, crutch strike, striking after mulesing and the weight of the animal.
Modes for Carrying Out the Invention 25 In order to better understand the nature of this invention a number of examples will be described. 11 Table 2 Quantity Function Supplier Dicyclanil -crystal modification 50 g/L %w/v Active Unisource Teric N9™ (Nonionic surfactant - alkyl phenol ethoxylate with 9 moles of ethylene oxide condensed onto nonyl phenol) 45 g/L 4.5%w/v Surfactant Huntsman Aerosil™ (Colloidal silica) 50 g/L %w/v Dispersant/ Viscosity modifier Pacific Resource Propylene glycol 50 g/L %w/v anti-skinning agent Unisource Xanthum Gum 2 g/L 0.2%w/v viscosity modifier APS Water q.s. to 1 L carrier To produce the composition according to Example 1, dicyclanil is dispersed in a 5 mixture of Teric N9™, Aerosil™, propylene glycol, xanthan gum and water followed by high speed mixing until uniform. The final volume is made up with water.
The composition according to Example 1 is readily redispersable (or has good dispersibility) and remains chemically stable after three months of storage at shown in Table 3.
Table 3 Dicyclanil Content Initial 51 g/L 3 months at 30°C 50 g/L 3 months at 40°C 50 g/L 146373Jaw_speci 12 Example 2: A composition according to the invention is shown in Table 4. Table 4: Quantity Function Supplier Dicyclanil -crystal modification 50 g/L %w/v Active Unisource Solulan ™ (Mixture of acetylated lanolin alcohol and an ethoxylated sorbitan ester.) g/L 2%w/v Surfactant Unisource Aerosil™ (Colloidal silica) 50 g/L %w/v Dispersant/ Viscosity modifier Pacific Resource Propylene glycol g/L 2.5%w/v anti-skinning agent Unisource Xanthum Gum 2 g/L 0.2%w/v viscosity modifier APS Water q.s. to 1 L carrier To produce the composition according to Example 2, dicyclanil is dispersed in a mixture of Solulan™, Aerosil™, propylene glycol, xanthan gum and water followed by high speed mixing until uniform. The final volume is made up with water.
Example 3 - Efficacy trial The efficacy of the composition according to Example 1 in preventing and controlling blowfly strike in sheep caused by the Australian blowfly Lucilia cuprina was assessed.
Seventy three mixed breed sheep including 53 adults and 20 lambs, were treated at Day 0 with a composition of Example 1. The composition was applied to each sheep by means of a spray-on applicator gun situated 15 to 25 cm above the fleece to achieve a 15 cm wide band at each pass. . Multiple passes were made to give the desired dose as shown in Table 5. At Day 0, adult sheep had 9 weeks of wool growth and lambs had 20 16 weeks of wool growth. 146373Jaw_speci 13 Blowfly pressure during the trial was confirmed by using a LuciTrap™. The LuciTrap™ system consists of a specifically designed trap and a blend of chemicals developed to attract and capture the Australian slieep blowfly {Lucilia cuprina).
Table 5 Sheep Weight (kg) Total Volume/Sheep (mL) Volume Per treatment Band (mL) Number of Bands -20 21 7 3 21-30 24 8 3 31-50 3 >50 36 12 3 The results are shown in Table 6. 10 Table 6 Strike Lucilia cuprina caught with LuciTrap™ Day 0 N/A N/A Week 6 No strike 100 Week 8 No strike 34 Week 9 No strike 23 Week 10 No strike 200 Week 11 No strike 250 The results demonstrate that the crystal modification form of dicyclanil of Example 1 is highly effective in protecting the sheep from blowfly strike even at high 15 blowfly pressure such as existed in week 10 and week 11. No adverse reactions were found during the trial indicating that the composition is non-irritant and safe for topical use. 146373Jaw_speci

Claims (50)

14 Example 4 - Efficacy Trial The efficacy of the composition according to Example 1 was compared with a marketed product in preventing and controlling blowfly strike in sheep caused by the 5 Australian blowfly Lucilia cuprina. In the test group, 101 Merino wethers, aged approximately one year, were treated with a composition of Example 1 at Day 0, while in the comparative group, 100 Merino wethers, aged approximately one year, were treated with a marketed product at Day 0. The compositions were applied to each sheep by means of a spray-on applicator gun situated 15 to 25 cm above the fleece to 10 achieve a 15 cm wide band at each pass. Multiple passes were made to give the desired dose as shown in Table 7. 29 Untreated sheep were used as a control. Table 7 15 Sheep Weight (kg) Total Volume/Sheep (mL) Volume Per treatment Band (mL) Number of Bands 10-20 21 7 3 21-30 24 8 3 31-50 30 10 3 >50 36 12 3 Results The 29 untreated sheep were struck while no strike was found or recorded for the sheep treated with the composition of Example 1 or the marketed product 13 weeks 20 post-treatment. The results confirm that crystal modification form of dicyclanil of Example 1 is highly effective and equivalent to the product in the market in protecting the sheep from blowfly strike. It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific 25 embodiments without departing from the scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive. 146373Jaw_speci 15 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:
1. A composition comprising an effective amount of a crystal modification of dicyclanil, at least one surfactant, at least one viscosity modifier and a therapeutically 5 acceptable carrier, wherein in Differential Scanning Calorimetry said crystal modification of dicyclanil exhibits a transformation in the temperature range of between 175°C and 197°C and possesses the following characteristic interlattice plane distances in [A0] from X-ray diffraction measurements: 10 11.26±0.2, 9.1±0.2, 8.9±0.2, 8.01±0.2, 7.7±0.2, 7.48±0.2, 5.95±0.05, 5.81±0.05, 5.73±0.05, 5.62±0.05, 5.13±0.05, 4.88±0.05, 4.74±0.05, 4.60±0.05, 4.45±0.05, 4.28±0.05, 4.14±0.05, 4.00±0.05, 3.72±0.05, 3.58±0.05, 3.43±0.05, 3.39±0.05, 3.33±0.05, 3.27±0.05; 3.19±0.05, 3.13±0.05, 3.06±0.05, 2.96±0.05, 2.90±0.05, 2.86±0.05, 2.83±0.05. 15
2. The composition according to claim 1 wherein the dicyclanil is present in an amount of from 1 to 20%w/v of the composition.
3. The composition according to claim 1 or 2 wherein the dicyclanil is present in 20 an amount of from 2 to 10 % w/v of the composition.
4. The composition according to any one of claims 1-3 wherein the dicyclanil is present in an amount of from 4 to 6 %w/v of the composition. 25
5. The composition according to any one of claims 1-4 wherein the dicyclanil is present in an amount of about 5%w/v of the composition.
6. The composition according to any one of claims 1-5 wherein the one or more surfactants is present in an amount of from 1.0 to 10%w/v. 30
7. The composition according to any one of claims 1-6 wherein the one or more surfactants is present in an amount of from 1.0 to 8%w/v.
8. The composition according to any one of claims 1-7 wherein the one or more 35 surfactants is present in an amount of from 1.5 to 5%w/v. 146373Jaw_speci 16
9. The composition according to any one of claims 1-8 wherein the one or more surfactants is selected from nonionic, anionic, cationic or amphoteric surfactants or mixtures thereof. 5
10. The composition according to claim 9 wherein the one or more surfactants is one or more nonionic surfactants.
11. The composition according to claim 10 wherein the nonionic surfactants are selected from the group consisting of: Cs-Cio alkylphenol ethoxylates, C9-C17 alcohol 10 ethoxylates, C8-C20 alkyl amine ethoxylates, castor oil ethoxylates, lanolin alcohol ethoxylates, lanolin alcohol acetylates, sorbitan fatty acid ester ethoxylates, sorbitan fatty acid esters, ethoxylated sorbitan etsers and mixtures thereof.
12. The composition according to claim 11 wherein the Cg-Cio alkylphenol 15 ethoxylates contain from 2 to 100 moles of ethylene oxide.
13. The composition according to any one of claims 6-12 wherein the one or more surfactants is an alkyl phenol ethoxylate with 9 moles of ethylene oxide condensed onto nonyl phenol. 20
14. The composition according to any one of claims 6-11 wherein the one or more surfactants is a mixture of acetylated lanolin alcohol and ethoxylated sorbitan ester.
15. The composition according to any one of claims 1-14 wherein the one or more 25 viscosity modifiers is present in an amount of from 0.05 to 15%w/v.
16. The composition according to any one of claims 1-15 wherein the viscosity modifier is present in an amount of from 0.1 to 5 %w/v. 30
17. The composition according to any one of claims 1-16 wherein the viscosity modifier is present in an amount of from 0.1 to 2%w/v.
18. The composition according to any one of claims 1-17 wherein the viscosity modifier is present in an amount of about 0.2%w/v. 35 146373Jaw_speci 17
19. The composition according to any one of claims 1-15 wherein the viscosity modifier is present in an amount of from 3 to 6%w/v.
20. The composition according to claim 19 wherein the viscosity modifier is present 5 in an amount of about 5.2% w/v.
21. The composition according to any one of claims 1-20 wherein the one or more viscosity modifiers is selected from the group consisting of: methyl cellulose, xanthum gum, colloidal silica and polymeric pyrrolidones. 10
22. The composition according to claim 20 wherein the polymeric pyrrolidones is povidone.
23. The composition according to any one of claims 1-22 wherein the one or more 15 viscosity modifiers is a colloidal silica and/or xanthum gum.
24. The composition according to any one of claims 1-23 wherein the composition has a viscosity in the range of 100-1000 cps at 25°C. 20
25. The composition according to any one of claims 1-24 wherein the composition has a viscosity in the range of 300-800 cps at 25°C.
26. The composition according to any one of claims 1-25 wherein the composition has a viscosity in the range of 500-700 cps at 25°C. 25
27. The composition according to any one of claims 1-26 wherein the therapeutically acceptable carrier is selected from one or more of the group consisting of: water, propylene glycol, medium chain triglycerides and oil. 30
28. The composition according to any one of claims 1-27 wherein the composition further includes one or more dispersing agents.
29. The composition according to any one of claims 1-28 wherein the composition further includes one or more dispersing agents in an amount of from 0.05 to 15 %w/v. 35 146373Jaw_speci 18
30. The composition according to any one of claims 1-29 wherein the composition further includes one or more dispersing agents in an amount of from 1 to 10 %w/v.
31. The composition according to any one of claims 1-30 wherein the composition 5 further includes one or more dispersing agents in an amount of from about 5.2 %w/v.
32. The composition according to any one of claims 1-31 wherein the composition further includes one or more dispersing agents selected from the group consisting of: colloidal silica, polymeric pyrrolidones, glycerine and polyethylene glycol. 10
33. The composition according to any one of claims 1-32 wherein the composition further includes one or more preservatives.
34. The composition according to any one of claims 1-33 wherein the composition 15 further includes one or more preservatives selected form the group consisting of: hydroxybenzoate, benzyl alcohol, sorbic acid, sorbate salts and mixtures thereof.
35. The composition according to any one of claims 1-34 wherein the composition further includes one or more buffers. 20
36. The composition according to any one of claims 1-35 wherein the composition further includes one or more buffers selected from the group consisting of phosphate, citro-phosphate and citro-buffers. 25
37. The composition according to any one of claims 1-36 wherein the composition has a pH in the range of from 5 to 9.
38. The composition according to any one of claims 1-37 wherein the composition further include one or more anti-skinning agents. 30
39. The composition according to any one of claims 1-38 wherein the composition further includes one or more anti-skinning agents selected from polyols and silicon oil and mixtures thereof. 35 40. The composition according to any one of claims 1-39 wherein the composition is an ectoparasiticide composition. 146373Jaw_speci
RECEIVED at IPONZ on 1 November 2011 19
41. The composition according to any one of claims 1-40 when used to prevent or control insect infestation of an animal.
42. Use of the composition according to any one of claims 1-40 in preventing or 5 controlling insect infestation of a non-human animal.
43. Use of a composition according to any one of claims 1-40 in the manufacture of a medicament for preventing or controlling insect infestation of a non-human animal. 10
44. A method of preventing or controlling insect infestations of a non-human animal, the method comprising topically administering to the non-human animal a composition according to any one of claims 1-40.
45. The method according to claim 44 wherein the composition is sprayed topically 15 to the non-human animal with an applicator gun.
46. The composition according to claim 41, the use according to claim 42 or 43 or the method according to claim 44 or 45 wherein the animal is selected from the group consisting of: sheep, goat, ruminants including cattle and camelids. 20
47. The composition according to claim 46, wherein the animal is a sheep.
48. The composition according to claim 41, 46 or 47, the use according to claim 42 or 43 or the method according to claim 44 or 45 wherein the insect infestation is 25 selected from one or more of the group consisting of fly infestation, flea infestation and lice infestation.
49. The composition, use or method according to claim 48 wherein the fly infestation is Lucilia cuprina infestation. 30
50. A composition according to claim 1, a method according to claim 44 or a use according to claim 42 or 43 substantially as hereinbefore described with reference to any one of the foregoing Examples.
NZ58522210A 2009-05-08 2010-05-07 Veterinary composition comprising dicyclanil NZ585222A (en)

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CN103416420B (en) * 2012-05-18 2015-10-14 陕西汤普森生物科技有限公司 A kind of Pesticidal combination containing CGA 183893
CN103880759B (en) * 2014-01-28 2016-04-20 东南大学 A kind of Dicyclanil drug crystal forms I and preparation method thereof

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US4783468A (en) * 1986-04-30 1988-11-08 Ciba-Geigy Corporation Insecticidal 5-pyrimidine carbonitriles
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