CA2237334A1 - Dry formulations of pesticides for controlling ectoparasites on animals - Google Patents

Abstract

Dry formulations of organophosphate insecticides provide effective and convenient to use treatments for protecting animals from infestation by fleas and other ectoparasites. These dry formulations are effective for periods of up to two weeks because of the controlled release of the insecticide onto the animal, they are convenient to use and most importantly, they do not cause severe adverse reaction in the treated animals.

Description

CA 02237334 1998-0~-11 DRY FOR~ ATIONS OF PESTICIDES
FOR CO~TROLLING ECTOPARASITES ON ANIMALS

This invention relates to a method ~or protecting an ~n;m~l ~rom in~estation by ~leas and other ectoparasites. Dry ~ormulations o~ organophosphate insecticides control ~leas on animals when applied to a small, limited area of the ~nim~l's coat in a high concentration, low volume, single application. These ~ormulations have unexpected properties which makes their use advantageous in comparison to liquid insecticide ~ormulations which are presently used ~or the control o~ ~leas on ~n;m~ls~

Backqround o~ the Invention Methods ~or protecting ~nim~l S ~rom in~estation by ~leas and other ectoparasites typically involve the application o~ large volumes o~ pesticide compositions which contain low concentrations o~ the insecticide.
These methods include spraying the composition onto the coat or fur o~ the ~nim~l, dipping the animal in a bath cont~ining the pesticide ~ormulation, or dusting the animal with a powder containing the insecticide.
Appllcation oI these li~uid ~r powd~red ir.s~ctlcide compositions is inconvenient, cumbersome and messy.
Domestic pets are o~ten traumatized by having their entire bodies sprayed, dipped or dusted. Signi~icant amounts o~ the insecticide never get on the animal, and much o~ what is applied o~ten ~alls o~ shortly a~ter the treatment is applied, which greatly reduces the e~ectiveness o~ the treatment and can adversely a~ect CA 02237334 1998-0~-11 WO97/18705 PCT~S96/18231 the environment. The use of dipping solutions can be upsetting to domestic animals, particularly to cats, who often have a natural aversion to water. Dip solutions are expensive, particularly when only one or a few animals are treated, and the solutions must be properly disposed of ~ollowing their use to avoid con~m;n~ting the environment. Most importantly, all of these applications of pesticide compositions must be repeated ~requently, since they are only e~fective ~or periods o~ one to two weeks.
Because cats tend to groom themselves by licking their bodies and ~ur, they are particularly susceptible to adverse reactions resulting ~rom the ingestion o~
insecticides applied to their bodies to prevent insect infestation. For example, cats may foam at the mouth or salivate excesslvely following tne appiication of certain insecticides. In more severe cases the treated animals may vomit. These adverse reactions can be due to the toxicity o~ the insecticides which are used for treatment. They also can occur under circumstances where the insecticide preparation poses no problems due to its toxicity, but the animal reacts to the bad taste or smell o~ the insecticide in an adverse way.
Insecticide impregnated collars have been used to prevent in~estation o~ domestic animals with ~leas.
Many domestic ~n;m~7 8, particularly cats, object to wearing collars around their necks, and many pet owners do not like to expose the animal or themselves to the insecticides in the collar. In addition, ~lea collars are generally less effective in preventing flea in~estation than the methods discussed previously. The owners of domestic animals often use the collars to supplement other methods involving direct application of the insecticide to the animal's body.

CA 02237334 1998-o~-11 WO97/18705 PCT~S96/18231 Many of the pesticides commonly used in agricultural and veterinary applications, including the organophosphate compounds are known to be e~ective ~or the control of ectoparasites such as ~leas. However, these compounds o~ten produce undesirable responses in domestic ~n;m~l s when applied in concentrations and in dosage ~orms needed to e~ectively control in~estation by ~leas. It is well known to those who ~ormulate pesticide compositions that their biological per~ormance in speci~ic applications is ~requently af~ected by the particular ~ormulation that is used.
Formulations which make pesticides available in solution are commonly more biologically active than dry pesticide ~ormulations. However, these li~uid ~ormulations are more toxic to those who come in contact with them, particularly the animal being treated and the person applying the pesticide to the ~n ; ~ l, since they are more readily absorbed through the skin.
Applications o~ certain ~ormulations o~ pesticides can cause adverse reactions in domestic animals. For example, domestic cats may respond to the application o~ organophosphate insecticides by salivating excessively and even vomiting. Adverse reactions also can occur even where the animal does not receive a toxic dose o~ the insecticide, but merely reacts to the unpleasant taste or smell o~ the insecticide ~ormulation used. Even though the insecticide ~ormulation poses no health risk to the animal, these responses can be extremely upsetting ~or the ~n;~l ' S
owner, particularly since owners o~ten do not realize that the animal is merely reacting to the unpleasant taste or smell o~ the preparation CA 02237334 1998-0~-11 WO97/18705 PCT~S96/18231 Thus, there continues to be a need for effective compositions for controlling fleas on animals, particularly domestic cats. Accordingly, it is an object of this invention to develop formulations of organophosphate compositions which are ef~ective for substantial periods of time and are safe, simple and convenient to use and do not cause adverse reactions in the ~ni m~l s to which the formulations are applied.

Summarv o~ the Invention The present invention relates to a method for reducing adverse reactions to an insecticide by an ~n;m~l in need of administration of insecticide ~or treating an infestation of parasites. It unexpectedly has been found that applying a dry formulation o~ an organophosphate insec~icide provides an e~~ec~ -e and convenient treatment for protecting an animal against infestation by fleas and other ectoparasites, while reducing adverse reactions by the ~n; mA 1 to the insecticide. These dry formulations include insecticide-cont~;n;ng microcapsules, which can be applied to one or more limited areas o~ an animal's body or hair coat. The formulations are e~fective in inhibiting infestation by ectoparasites for periods o~
up to two weeks as a result of the controlled release o~ the insecticide, and they do not cause severe adverse reactions in the treated animals.

~etailed Description of the Invention The invention of the present application re}ates to high concentration, low volume, substantially dry ~ormulations of insecticides which are e~fective for the control of ~1eas and other ectoparasites on animals. Ectoparasites are parasites which live on the CA 02237334 1998-o~-11 WO97/18705 PCT~S96/18231 exterior parts o~ an animal's body as distinguished ~rom endoparasites which live inside the host animal's body. Common ectoparasites include fleas, ticks, lice, mites and ~lies.
The present invention ~urther relates to methods by which these formulations are applied to the ~n;m~l being treated. Application o~ the dry ~or~u~ations of the invention provides e~ective protection against infestation by ectoparasites while m;n;m;zing the number and severity o~ adverse reactions that can occur ~ollowing treatment with topical ~ormulations o~
insecticides.
Adverse reactions include reactions which can produce prolonged or lasting toxic e~fects due to the Anlm~l's exposure to a treatment with an insecticide.
Such adverse e~ects include dermal irritation or othe~
exhibited signs o~ toxicity, such as heavy salivation or vomiting, which can last ~or hours or even days a~ter the treatment is applied. In the most severe cases, such adverse reactions can result in the animal's death.
In addition, adverse reactions include reactions which can occur even when the ~nlm~l does not receive a toxic dose o~ the insecticide, but nonetheless reacts to being exposed to the treatment. These adverse reactions include excessive salivation and even vomiting, which occur in response to the taste or smell o~ the insecticide where the preparation is o~ensive to the animal. Such adverse reactions are particularly a problem when treating cats because o~ their natural grooming ~ehavior. Topically applied substances are almost certain to be licked and ingested shortly after they are applied to the ~n;mal. When the substance is distaste~ul or unpleasant, the animal will o~ten _ CA 02237334 1998-0~-11 PCT~S96/18231 salivate immediately and, in more severe cases, it may vomit. Because such reactions generally alarm pet owner~ and lead to their not repeating treatments for controlling ectoparasites, these reactions also are considered to be adverse reactions, even though they do not result from toxic effects of the lnsecticides present in the formulations.
While not wishing to be bound by any particular theory as to why the methods of the present invention prevent or reduce adverse reactions, it does appear that the particular formulations, together with the particular methods o~ the present invention for applying the formulations, reduce the llkelihood that the treated animal will groom following the application of insecticide. This effect is most likely due to the treatment being a substantially dry ~ormulation rather than a wet formulation.
Pesticides which are useful for the dry formulations of the present invention include compounds of the group known as organophosphates. This group of compounds is known in the art to possess useful pesticidal properties, particularly in the control of fleas on animals. Suitable organophosphate pesticides can include phosphate, phosphothioate or phosphothionate compounds. Preferred pesticides suitable for use in the formulations include the organophosphate compound known as pirimiphos-methyl 0-(2-diethylamino-6-methylpyrimidin-4-yl)o,o-dimethyl phosphorothioate). Specific examples of organophosphate compounds that can be used in the formulation are listed in Table I.

SUBSTITUTE SHÉET (RULE 26) CA 02237334 1998-0~-11 TABLE I

Chloryriphos Pirimiphos-methyl Diazinon Tetrachlorovinphos In the present application the term 'Idry formulation" is used to indicate that the insecticide is prepared such that it contains no more than insignificant or negligible amounts o~ water. One way in which such a dry ~ormulation can ~e prepared is to micro-encapsulate the pesticide using organic polyisocyanate intermediates to ~orm a polyurea capsule enclosure around the water-immiscible insecticide. The amount o~ water in the ~inal preparation will be determined by the ability o~ the inert ingredients surrounding the microcapsules to hold onto water under the conditions in the drying apparatus used to dry the ~inal microencapsulated preparation. In most cases the amount o~ water adsorbed onto the inert material is very small such that the ~ormulation is substantially dry.
The microencapsulation o~ selected pesticides can be accomplished by the inter~acial polymerization o~
monomer units present in emulsion droplets, which are ~ormed when the water-immiscible pesticide is vigorously mixed with an aqueous solution cont~; n; ng additional polymerizing monomers and heated as discussed in Seaman et al., "Trends in the Formulation of Pesticides - An Overview," Pesticide Science 29 (1990) pp. 437-449. The monomers react to ~orm a polymer skin which encapsulates the pesticide and controls its release. Encapsulation can reduce the CA 02237334 1998-o~-11 WO97/18705 PCT~S96/18231 oral toxicity of the pesticide as much as 100 times over that o~ non-microencapsulated water based treatments and reduces the dermal toxicity over 10 times that o~ non-microencapsulated water based treatments.
A preferred method of encapsulation o~ pesticides for use in the treatment o~ ectoparasite in~estation in animals is that disclosed in U.S. Patent No. 4,285,720, the disclosure of which is incorporated herein by ~o reference. The water-immiscible insecticide being encapsulated is dispersed in an aqueous solution which contains suitable sur~actants and a protective colloid.
Use~ul surfactants lnclude nonionic, anionic or cationic surfactants having a hydrophile to lipophile balance (HLB) range of ~rom about 12 to about 16.
Examples o~ suitable surfactants are sodium isopropyl naphthalene sulfonate, polyoxyethylenesorbitol oleate laurate, ethoxylated nonylphenols, and polyethylene glycol ethers of linear alcohols. Preferred sur~actants are polyethylene glycol ethers of linear alcohols such as the linear alcohol ethoxylate emulsi~ier Tergitol 15-S-20. Suitable protective colloids can be selected ~rom a wide range of such materials, including polyacrylates, methyl celluloses, polyvinyl alcohol, polyacrylamide and polymethylvinyl ether/maleic anhydride. The protective colloid can be added to the microencapsulation system either prior to or a~ter the organic dispersion is made.
The dry microencapsulated ~ormulations of the invention contain ~rom about 20 to 80~ by weight o~ the active pesticide. One pre~erred embodiment is a dry microencapsulated formulation containing ~rom about 55 to 75~ pirimiphos-methyl.

CA 02237334 1998-o~-11 WO97/18705 PCT~S96/18231 Advantageously, the dry composition o~ the present application can be applied to a single, limited area on the animal to be treated. Alternatively, the treatment can be applied to two or more speci~ic sites o~ limited area on the ~nlm~l, Pre~erably, the composition is applied as a single spot to a limited area on the back of the ~n ~ ~1 between its shoulder blades at a location which the ~n;m~l iS unable to reach with his tongue, so that he is unable to lick or clean the pesticide composition ~rom his coat. This is particularly important when the composition is used to treat cats, because cats will often salivate or become nauseous after they are exposed to substances they consider distaste~ul or unpleasant, either orally or by smell.
Since the composition is applied topically, it is almost certain to be lic~eu or ingested shortly a~ter it is applied to cats because o~ thei~ grooming behavior.
The ~uantity of the dry ~ormulation to be applied to an animal is determined by the ~n; m~l ' S size and by the concentration o~ pesticide in the ~ormulation.
Generally, the compositions can be applied at a dose within a range o~ about 0.1 gram (g) to about 1.0 ~ o~
active compound per kilogram (kg) of the animal's weight. Animals weighing between 5 and 10 pounds (about 2.2 to 4.5 kg) can be treated with a single application o~ ~rom about 0.3 to about 4 g o~ the dry ~ormulation, containing ~rom 20 to 90~ organophosphate.
One pre~erred treatment comprises applying 0.3 g o~ a dry ~ormulation containing about 70-75~ pirimiphos-methyl per kg o~ the animal's weight.
The dry pesticide ~ormulations o~ the present invention are use~ul ~or controlling ~leas and other ectoparasites on animals, particularly smaller ~nl ~1 s -CA 02237334 1998-o~-11 WO97/18705 PCT~S96/18231 which are kept as pets, including dogs, cats, rabbits and rodents. The disclosed compositions and methods are particularly advantageous ~or controlling ~leas on t cats. Cats are very ine~icient at metabolizing s pesticides and are, there~ore, particularly suscepti~le r to their toxic e~ects. Additionally, because o~ their natural grooming behavior, cats are particularly susceptible to reactions due to the unpleasant taste or odor of preparations which are applied to an animals coat or ~ur. Application o~ the disclo9ed compositions by the method o~ the present in~ention is essentially non-toxic to cats, and application o~ the preparations appears to not stimulate the animal to groom immediately a~ter the application.
The disclosed methods and compositions also are use~ul ~or the control o~ other insect p~st.i, in_'~ding ~leas, lice, ticks and ~lies, on herd animals such cattle, sheep, goats, horses, donkeys, camels, pigs, reindeer, caribou, and bu~alo.

~xam~le l Preparation o~ Dry Encapsulated Pirimiphos-methyl Dry encapsulated pirimiphos-methyl was prepared by mixing 177G g o~ water with 47.0 g o~ 40~ Reax, lOOM
sodium lignosul~onate (a poly-protective colloid) and 2s 76.0 g o~ 20~ aqueous Tergitol XD emulsi~ier in an open reaction vessel with stirring. In a separate cont~; ne~
2000 g o~ technical grade pirimiphos-methyl (at least 90~ purity) was mixed with 32.0 g o~ polymethylene polyphenylisocyanate and 130.0 g o~ tolylene diisocyanate, then added to the a~ueous solution in the reaction vessel. An appropriate catalyst, such as a basic tertiary organic amine, also can be added to the _ CA 02237334 1998-o~-11 WO97/18705 ll PCT~S96/18231 water-immiscible mixture i~ desired. The mixture was vigorously stirred using a high shear stirrer to create an oil in water emulsion. A~ter the emulsion was ~ormed and particles o~ the desired size were obt~; n~, mild agitation was continued ~or the remainder o~ the reaction. The temperature of the emulsion was raised to 60~C and the pH o~ the dispersion was maint~in~ at 8.5 ~or 3 hours with stirring to allow the interfacial polymerization to proceed to completion. The resulting aqueous suspension o~ microcapsules was cooled to room temperature. l.l g of Witconate AOK (wetting agent), 15.5 g o~ colloid 225 (dispersant) and 5.9 g o~ Kaolin RC-32 (disintegrant~ were added to the aqueous suspension o~ mi~rocapsules as spray drying adjuvants, and the resulting slurry was spray dried. The dried, microencapsulated product was determined to contain 72.5 weight ~ pirimiphos-methyl.
To make the ~ormulations more pleasant to use, a ~ragrance such as Alpine Mas~ can be included in the ~ormulation by adding 0.9~ of the ~ragrance to the formulation a~ter encapsulation.

Exam~le 2 Evaluation o~ the E~icacy o~ Applications o~ Dry Formulations o~ Organophosphate Insecticides ~or Controlling Fleas on Cats The e~icacy o~ microencapsulated dry ~ormulations o~ pesticides was demonstrated in a dose titration study using a microencapsulated dry ~ormulation o~ 74 pirimiphos-methyl, which was applied to cats selected ~rom a random population o~ mixed breed, domestic animals. The animals were housed in individual cages in environmentally controlled rooms and provided with a WO97/18705 PCT~S96/18231 commercial cat ~ood and water ad libitum. For the dose titration study the An;mAls were divided into ~our groups o~ three cats each. Each group received either l) no treatment; 2) 0.2 grams o~ the dry ~ormulation o~
micro-encapsulated 74~ pirimiphos-methyl preparation prepared in accordance with the procedures o~ example l; 3) 0.3 grams o~ the preparation or 4) 0.4 grams o~
the preparation. Each cat was infected with lO0 cat ~leas, (species Ctensce~halides ~elis) one day be~ore the microencapsulated preparation was applied. The preparation was applied to the ~n;m~l's fur or coat as a single spot application to the dorsal neck area o~
each An;m~l, near the shoulder.
The e~ect of the preparation on reducing or controlling in~estation by ~leas was determined by monitoring the number o~: ~leas r~m~ining cn the bodies o~ both treated and untreated animals. The number o~
~leas remaining on the ~n;m~l S was determined by counting the number o~ dead flea6 ~ound on the pans which covered the bottom o~ each cage each day and by doing direct body counts on each animal to determine the number o~ ~leas rPmAin;ng on the An;mAl, The data obtained were used to calculate the percent reduction o~ ~leas in each group using the ~ormula given in Table II.

-WO97/18705 13 PCT~S96/18231 TABLE II

TreatmentA
Test Day 0.2 q~ 0.3 ~ 0.4 qB
3 l00~ l00~ l00 7 95~ 97~ 90 9 94~ 94~ 94~

'Cats were in~ested with l00 ~leas one day prior to treatment and again on day 5. Whole ~ody counts o~ fleas r~m~ n 1 n~ on each ~n; m~ 1 were made on days 3, 7 and 9.
bData are expressed as Percent Reduction Total Fleas on Total Fleas on o~ Fleas on Cats = Control Cat~ Tre~te~ cats x Total Fleas on Control Cats The results of the efficacy study indicate that the micro-encapsulated dry ~ormulations reduced in~estation on treated ~n;m~l S three days a~ter treatment by l00~ when compared with controls.
Additionally the one treatment, applied on day l protected ~n;m~l 9 against rein~estation for more than nine days under the conditions employed in the te~t.

~m~le 3 Response o~ Cats to a Dry Formulation o~
Microencapsulated Organophosphate Insecticides Thirty six male and female cats were randomly placed into one o~ ~our treatment groups to evaluate their response to treatment with a dry ~ormulation o~
microencapsulated pirimiphos-methyl. Each group CA 02237334 1998-0~-11 WO97tl8705 14 PCT~S96/18231 received one o~ the four ~ollowing treatments: 1) 0.3 grams o~ 72% dry microencapsulated pirimiphos-methyl, 2) 0.6 grams o~ 72~ dry pirimiphos-methyl and 3) 1 ml (milliliter) o~ 21~ pirimiphos-methyl in 79~ methyl carbitol. Treatment 3 served as a positive control ~or the study.
The cats were housed individually and provided with a commercial cat ~ood and water ad libi tum. All treatments were applied to the cat's back, on the dorsal thorax near the shoulder blades, one time on Day 0 o~ the study. The liquid composition o~ control treatment 3 was applied by pipetting 1 ml aliquots directly onto the ~n; m~l s ' skin. Treatments 1 and 2 were brie~ly rubbed into the cat's coat. The cats were observed continuously ~or the ~irst hour following the application o~ the test formulation, at hourl-~
intervals ~or the next ~our hours ~ollowing treatment, then twice daily for the next two days.
Five o~ the nine cats who received control treatment 3 (1 ml o~ 21~ pirimipho~-methyl in 79~
methyl carbitol) demonstrated an adverse salivation response within one hour following the application o~
the pesticide. One o~ these responses was mild, with the ~n i m~ 1 having mild clear drops o~ saliva on its lips. Three o~ the cats had a heavy salivation re6ponse within one hour o~ treatment and one cat had a pro~use salivation response. All o~ these responses lasted ~or 10 to 20 minutes ~ollowing the application o~ the pesticide ~ormulation and were determined to not be transient responses. One cat continued to salivate abnormally ~or ~our hours a~ter the application o~ the liquid pirimiphos-methyl ~ormulation. A sixth cat vomited twice within the ~irst hour ~ollowing treatment and again on the next day.

CA 02237334 1998-0~-11 In contrast to the ~nl m~l S receiving control treatment 3, none of cats in treatment group 1, the group treated with 0.3 grams o~ the microencapsulated dry ~ormulation o~ 72~ pirimiphos-methyl, had salivation episodes which lasted longer than two minutes. Additionally, none o~ the cats in this group vomited in response to the application of microencapsulated dry ~ormulation of pesticide. Only two of the cats demonstrated a mild sali~ation response during the first hour following treatment, and two demonstrated a heavy response. One cat exhibited a mild salivation response 3 hours following the application of the microencapsulated ~ormulation.
The animals in treatment group 2, the group treated with 0.6 grams o~ the microencapsulated dry ~ormulation o 72~~ pirimiphos-methyl, demonstrated extremely brief, transient responses which lasted no longer than two minutes. None of the cats in this group vomited in response to the application o~ the dry formulation.

Claims (19)

16

1. A method for reducing adverse reactions to an insecticide by animal in need of insecticide administration to treat an infestation of parasites which comprises topically applying to the animal an organophosphate insecticide in a dry formulation.

2. The method of claim 1 wherein the insecticide is provided in the form of microcapsules.

3. The method of claim 2 wherein the insecticide comprises pirimiphos-methyl.

4. The method of claim 2 wherein the insecticide comprises a microencapsulated dry formulation of from about 20 to 80% organophosphate.

5. The method of claim 2 wherein the insecticide comprises a microencapsulated dry formulation of from about 70 to 75% organophosphate.

6. The method of claim 1 wherein the dry formulation is applied only to a single, limited area of the animal's fur or skin.

7. The method of claim 6 wherein from about 0.1 gram to about 1.0 gram of the dry formulation per kilogram of body weight is applied to the animal,

8. The method of claim 1 wherein the parasites comprise fleas, ticks or lice.

9. The method of claim 1 wherein the animals to be treated are selected from the group consisting of cattle, sheep, goats, horses, donkeys, pigs, dogs, cats and rabbits.

10. The method of claim 1 wherein the animal to be treated is a cat.

11. The method of claim 10 wherein the dry formulation is microencapsulated pirimiphos-methyl.

12. A method for reducing adverse reactions to an insecticide by an animal in need of insecticide administration to treat an infestation of ectoparasites which comprises treating the animal by topically applying to the animal a microencapsulated dry formulation of from about 20 to about 80% pirimiphos-methyl at a dosage of about 0.1 gram to about 1.0 gram per kilogram of the animal's weight.

13. A method for protecting an animal from infestation with ectoparasites comprising topically applying a dry formulation of an organophosphate insecticide to an animal in need of such protection.

14. The method of claim 13 wherein the insecticide is provided in the form of microcapsules.

15. The method of claim 14 wherein the insecticide comprises pirimiphos-methyl.

16. The method of claim 14 wherein the insecticide comprises a microencapsulated dry formulation of from about 20 to 90% organophosphate.

17. The method of claim 14 wherein the insecticide comprises a microencapsulated dry formulation of from about 70 to 75% organophosphate.

18. The method of claim 14 wherein the animal to be treated is a cat.

19. The method of claim 13 wherein from about 0.1 gram to about 1.0 gram of the dry formulation per kilogram of body weight is applied to the animal.