NZ264936A

NZ264936A - Pour-on formulations for parasite control for homothermic animals

Info

Publication number: NZ264936A
Application number: NZ26493694A
Authority: NZ
Inventors: Irwin Boyden Wood; James Quinlan
Original assignee: American Cyanamid Co
Priority date: 1994-11-17
Filing date: 1994-11-17
Publication date: 1996-11-26

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £64936 Priority Date(s): Complete Specification Fffsd: . Class: (6) ..etoX^Sj.^:,..Bfel.feVOlofo4.Q?a.3p;( Publication Date: Jl..6...N.Q)(...t9,9.5 P.O. Journal No: no mmm 264 9 36 Patent of Addition to No 236369 Filed 6 December 1990 n.2. pfiy < optics 1 7 NOV 1994 Received NEW ZEALAND PATENTS ACT, 1953 COMPLETE SPECIFICATION POUR-ON FORMULATIONS EFFECTIVE FOR THE CONTROL OF INTERNAL AND EXTERNAL PARASITES OF HOMOTHERMIC ANIMALS We, AMERICAN CYAN AMID COMPANY a corporation organized and existing under the laws of the State of Maine, United States of America, and having its executive offices at One Cyanamid Plaza, Wayne, State of New Jersey 07470, United States of America, 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:- - 1 - (followed by page la) -la- 264 9 36 POUR-ON FORMUIiATIONS EFFECTIVE FOR THE CONTROL OF INTERNAL AMD EXTERKAL PARASITES OF HOMOTHERMIC ANIMALS BACKGROUND OF THE INVENTION Pour-on formulations are utilized by the animal industry as a means for administering certain anthelmintic agents and veterinary medicines*to animals. In practice, the medicated formulation is applied directly to the external skin or hide of the animal. As such, some practitioners have extended the term pour-on to include formulations which may be dispersed in water and applied as aqueous dips, baths or sprays. In the present specification, however, the term "pour-on" is not intended to suggest this type of application. Rather, the formulation of this invention is a non-aqueous formulation which is applied with the assistance of a suitable device such as a measuring cup, a squirt bottle or an automatic microspray device which permits directed application of a small amount of formulation onto the skin of the animal 26 4 9 3 6 being treated. While a number of anthelmintic agents and veterinary medicines such as fcetramisole, levamisole, trichlorphon and fenthion, have been successfully prepared as pour-on 5 compositions, all veterinary medicines do not lend themselves to such formulation. Moreover, those medicines that have been so formulated generally have been found to be significantly less effective as pour-on formulations than they are when administered orally or parenterally. 10 Presently, the art appears to describe no pour-on formulations which do not wash off during rainfall or which retain efficacy on wet animals. From a practical standpoint, a product which lacks efficacy on wet skin or hide is extremely inconvenient to use due to the extra 15 burden on the part of the farmer to keep the animals dry in order to effectively treat them with pour-on medicine. For successful formulation as a pour-on, a drug must be active when dissolved, dispersed or emulsified in a suitable solvent which is well tolerated by the animals 2 0 skin. The drug must be readily adsorbable through the animals skin and the composition as a whole should disperse or spread well over the animals body and be relatively non-viscous when so spread. It must also be recognized that each drug has its own chemical and 25 physical properties that require special consideration and limit the types of solvents, diluents, stabilizing agents and other formulatory agents that can be employed in the formulation of that particular drug or medicine. It is, therefore, an object of the present invention 30 to provide a non-irritating pour-on formulation which is effective on dry or wet skin and hide for the control of insects and internal and external parasitic infections and infestations of farm and companion animals and which resists wash off during normal precipitation. 3 5 It is also an object of this invention to provide an effective non-aqueous pour-on formulation that contains, as the active ingredient, an antibiotic selected from LL- 264936 -3 - F28249a, a 23-oxo or 23-imino derivative of LL-F28249a-A, a milbemycin compound or an avermectin compound, which exhibits excellent penetration of the animals hide or skin, spreads well and rapidly over the animals body, is non-malodorous, non-irritating and relatively non-viscous toward dust, dirt and foreign matter encountered by the treated 5 animals. It is a further object of this invention to provide a method for treating, controlling, preventing or protecting quadruped farm and companion animals from infestation and 10 infection by helminths, acarids and arthropod endo- and ectoparasitic insects by topically applying to said animals a pour-on formulation containing an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of the antibiotic LL-F28249a, LL-F28249(3 or a 23-oxo or 23-imino derivative of LL-F28249a, such as 23-(0-methyloxime)-LL-F28249a or 23-(O-methyloxime)-LL-F28249p. 15 New Zealand Patent Specification No. 236369 describes and claims a non-aqueous pour-on composition for combating helminth, acarid and arthropod endo- and ectoparasitic insect infestations and infections of farm and companion animals 20 characterized by an anthelmintically, acaricidally or an arthropod endo- or ectoparasitic insecticidally effective amount of a compound selected from the group consisting of LL-F28249 a-X, a 23-oxo (keto) or 23-imino derivative of LL-F28249 a-X, a milbemycin compound and an avermectin compound, dissolved or dispersed in a mixture comprising: (a) from 5.0% to 15% w/v of an aromatic solvent having a mixed aniline point of from 25 13.4°-15.4°C, a Kauri-butanol value of 92 and a specific gravity at 15.6°/15.6°C of from 0.875 to 0.899; from 2.0% w/v to 8.0% w/v of 2-[2-(tetradecyloxy)propoxy]-l-propanol propionate; from 0 w/v to 15.0% w/v of a polybutene having a number average molecular weight of from 320 to 2300 and a Cleveland open cup flash point of from 154°C to 307 °C; and quantity sufficient to 100% w/v of a pharmacologically acceptable oil; or 30 (b) from 0 w/v to 15.0% w/v of polysorbate 80 and quantity sufficient to 100% w/v of butoxyethoxyethanol. 26 493$ -3a- Summary of the Invention This invention is directed to an improvement in or modification of the invention disclosed in New Zealand Patent Specification No. 236369. 5 According to a first embodiment of the invention there is provided a non-aqueous pour-on composition for combating helminth, acarid and arthropod endo- and ectoparasitic insect infestations and infections of homothermic quadruped comprising an anthelmintically acaricidally or an arthropod endo- or ectoparasitic insecticidally effective 10 amount of a compound selected from the group consisting of LL-F28249 a-X, a 23-oxo (keto) or 23-imino derivative of LL-F28249 a-X, a milbemycin compound and an avermectin compound dissolved or dispersed in a mixture comprising: from 5.0% to 20% w/v of an aromatic solvent having a mixed aniline point of from 13.4°C to 15.4°C, a Kauri-butanol value between 90 to 96 and a specific gravity at 15.6°/15.6°C of from 15 0.872 to 0.985; from 0 w/v to 15.0% w/v of polybutenes having number average molecular weight of from 320 to 3000 and a Cleveland open cup flash point of from 154°C to 307°C; from 8.0% w/v to 15% w/v of 2-[2-(tetradecyloxy)propoxy]-l-propanol propionate and quantity sufficient to 100% w/v of a pharmacologically acceptable oil; with the proviso that the mixture contains more than 8.0% of 20 2-[2-(tetradecyloxy)propoxy]-l-propanol propionate when the mixture contains from 5.0% to 15% w/v of an aromatic solvent having a mixed aniline point of from 13.4°C to 15.4°C, a Kauri-butanol value of 92 and a specific gravity at 15.6°/15.6°C of from 0.875 to 0.899. According to a second embodiment of the invention there is provided a method for 25 treating helminth, acarid or arthropod endo- or ectoparasitic insect infection or infestation in a homothermic quadruped which is characterized by pouring onto the skin of the quadruped to be treated an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of a composition of the first embodiment. According to a third embodiment of the invention there is provided a method for 30 treating or controlling Psoroptic mange on a homothermic quadruped or preventing or protecting the quadruped from infestation by Psoroptes ovis which is characterized by pouring onto the skin of the quadruped a non-aqueous pour-on composition .0#^eTfirs^> embodiment comprising 23-(0-methyloxime) F28249a in an amount suffici^fit to provide ' t * 35 V ' 264936 -4- the quadruped with 0. lmg/kg to 5.0mg/kg of body weight of the quadruped of said 23-(O--methyloxime)-F28249a. The present invention relates to non-aqueous pour-on, water-fast compositions and the method of use thereof for treating, controlling, preventing and protecting internal and external parasites. More particularly, this invention relates to non-aqueous pour-on compositions containing as the active ingredient an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of a compound selected from compounds designated LL-F28249a-X, a 23-oxo or 23-imino derivative of LL-F28249a-X, 10 a milbemycin compound or an avermectin compound. Description of the Preferred Embodiments The compounds designated LL-F28249a-X are (collectively) isolates from the 15 fermentation broth of the microorganism Streptomvces cvaneogriseus subspecies 5 . homothermic animals, such as mammalian quadrupeds, from infestation and infection by 20 25 30 35 2649 - 5 - noncvanoaenus. deposited in the NRRL under deposit accession No. 15773. The method for preparation of the LL-F28249 compounds is disclosed in United States Patent No. 5,106,994 and is incorporated herein by reference 5 thereto. The 23-oxo (keto) and 23-imino derivatives of LL-F28249a—A. compounds, useful in the pour-on formulations of this invention, are disclosed in United States Patent No. 4,916,154, incorporated herein by reference thereto. 10 Although United States Patent No. 4,916,154 indicates that the 23-oxo (keto) and 23-imino derivatives of LL-F2&249a-X may be administered by pouring on the skin of an animal via a solution, it only suggests that the active compound may be dissolved in dimethylsulfoxide, propylene glycol or 15 the like or in a combination of solvents. These formula tions are not entirely satisfactory since the use of dimethylsulfoxide can cause instability of the 23-(oxo) or 23-imino derivatives of LL-F28249a-A. and/or leave a malodorous scent on the treated animal. The propylene 20 glycol compositions tend to be sticky and collect dust and dirt and debris from the animals' surroundings. The pour-on veterinary compositions of this invention have the following formulations: 25 % w/v Co'mpound (A) 0.1 - 5.0 Active ingredient 5.0 - 20.0 Aromatic! solvent 8.0 - 15.0 PPG—2 Myristyl ether propionate (i.e. 2-[2-30 -(tetradecyloxy)propoxy]- -1-propanol propionate) (spreader) 0 - 15.0 Polybutene (number average molecular weight range from 320 to 3000) QS to 100% Mineral or vegetable oil; o // <*■ Ar o (B) 0.1 - 5.0 Active ingredient (j^ 0 - 15.0 Polysorbate 80 ^ QS to 100% Butoxyethoxyethanol 35 264936 - 6 - These compositions may be prepared by dissolving, dispersing or emulsifying 0.1% to 5.0% w/v of the active ingredient, i.e. a compound selected from the group consisting of LL-F28249a-A, a 23-oxo or 23-imino derivative of said compound LL-F28249a-X, 5 a milbemycin compound or an avermectin compound, in a mixture consisting essentially of 5.0% to 20% w/v of an aromatic solvent having a Kauri-butanol value between 90 to 96, a mixed aniline point between 13.4°C to 15.4°C and a specific gravity at 15.6°/15.6°C of 0.872 to 0.985; 8.0% to 15.0% w/v of 10 2-[2-(tetradecyloxy)propoxy]-1-propanol propionate; if present, 1.0% w/v to 15.0% w/v of a polybutene having a number average molecular weight range of 320 to 3000 and a Cleveland open cup flash point of from 154°C to 307°C; and the remainder of the mixture a pharmacologically acceptable oil 15 such as mineral or vegetable oil. Pour-on formulations prepared as described above with LL-F28249a, LL-F282493, 23-(O--methyloxime-LL-F28249a or 23- (O-methyloxime) -LL-F28249(S , are especially effective for controlling endo- and ectoparasites on mammalian quadrupeds. 20 The pour-on compositions of the invention may also be prepared by dissolving, dispersing or emulsifying 0.1% to 5.0% w/v of a compound selected from the group consisting of LL-F28249a-X, a 23-oxo or 23-imino derivative of said antibiotic LL-F28249a-A, a milbemycin compound and an avermectin compound, 25 in butoxyethoxyethanol. Pour-on formulations prepared as described above with LL-F28249a, LL-F28249(J, 23-(O-methyloxime)--LL-F28249a or 23-(O-methyloxime) -LL-F28249(3, are especially effective for controlling endo- and ectoparasites on mammalian quadrupeds. The admixture of up to 15.0% w/v of polysorbate 80 30 with the above composition is optional. antioxidants or mixtures thereof may be included in the Excipients such as dyes, antimicrobial agents, compositions of the invention, said excipients suitable for use The amounts of 35 i; ^ 26 4 9 36 - 7 - about 0.005% to 2.0% on a weight/volume basis. Dyes suitable for use in the present invention include anthraquinone dyes, azo dyes and the like. Examples of antimicrobial agents useful in the composi-5 tions of the present invention are benzoic acid deriva tives, methylparaben, propylparaben and the like. And antioxidants suitable for use in the compositions of the invention include butylated hydroxytoluene, butylated hydroxyanisoles, tertiarybutylhydroxyquinolone, sodium 10 bisulfite, sodium metabisulfite, propyl gallate and the like and mixtures thereof. Advantageously, the compositions of the present invention are well tolerated by the animals and non-damaging to the animals' skin, hide or hair. The 15 formulations are non-malodorous. They spread well and rapidly over the animal's body and the active ingredient thereof is found to be readily absorbed through the hide or skin of the treated animals. A further benefit is that the compositions retain efficacy on wet skin or hide of 20 the animal and resist wash off during precipitation such as rain. The term "water-fast" used herein is intended to mean that the compositions resist being washed off in typical wet weather such as rainfall, snowfall, etc. The preferred active ingredients useful in the 25 preparation of the compositions/of this invention have the following structures: 264936 - 8 - and LL-F28249a The compositions of this invention are highly effective for protecting or treating farm and companion 15 animals, particularly mammalian quadrupeds such as cattle, sheep, deer, horses, swine, goats, dogs, cats and the like, against infection and infestation by helminths, nematodes, acarids and arthropod endo- and ectoparasitic insects. 20 Helminthiases is a widespread disease found in many farm and companion animals and responsible for significant economic losses throughout the world. Among the helminths most frequently encountered are the group of worms referred to as nematodes. The nematodes are found in the 25 intestinal tract, heart, lungs^ blood vessels and other body tissues of animals and are a primary cause of anemia, weight loss and malnutritibn in the infected animals. They do serious damage - to the walls of the gastrointestinal tract and the tissue of the organs in 30 which they reside and, if left untreated, may result in death to the infected animals. The nematodes most commonly found to be the infecting agents of animals include Haemonchus and Ostertagia generally found in the stomach; Cooperia. Oesphaaostomum 35 and Nematodirus generally found in the intestinal tract and Dictvocaulus found in the lungs. Treatment of animals to prevent infestation thereof by the above nematodes or 26493 & - 9 - to reduce or control the proliferation of these infecting agents in animals is thus an important and desirable advantage of the present invention. Besides controlling helminths and nematodes, the 5 present invention also controls several arthropod endo- parasitic infestations such as cattle grub infestations. It has been further found that acarid and arthropod ectoparasitic insect infestations may be controlled, prevented or eliminated by applying to said animals an 10 acaricidally or ectoparasiticidally effective amount of the above-described LL-F28249 compound or derivative thereof or milbemycin or avermectin compound. This can be achieved by applying the active compound to the skin, hide and/or hair of the animals, usually in the form of a 15 liquid formulated composition in sufficient amount to provide the treated animal with about 0.1 mg to 5.0 mg of active compound per kg of animal body weight. In practice it is found that generally 0.2 mg to 2.0 mg of LL-F28249o:, LL-F28249P, 23-(O-methyloxime)-LL-F28249a or 23-(O-methyl-20 oxime)-LL-F28249P, is sufficient to control helminths such as Ostertacria circumcincta. Haemonchus contortus and Trichostronavlus colubriformis. It has also been found that the pour-on composition disclosed in this application, which contains 23-(O-25 methyl oxime) -LL-F28249a as the active ingredient, provides excellent control of the biting louse, Damalinia ovis and Damalinia bovis. Moreover,' it has been found that this formulation which contains 23-(O-methyloxime)-LL-F28249a is unique in its ability to provide superior control of 30 Psoroptes ovis which cause psoroptic mange on animals, such as cattle and sheep. This active ingredient also finds beneficial use in treating or controlling chorioptic, sarcoptic and demodectic mange on an animal which has been caused by infestation of Chorioptes bovis. 35 Sarcoptes scabiei and the Demodex species, respective^yn^a^/ The present invention is further delineated^/fcjyc the examples set forth below which are provided simply by way t,.** - 10 - 264936 of illustration and not intended to be limitations of the invention. Example 1 Evaluation of 23-(O-Methvloxime)-LL-F28249a for Control of Psoroptic Manae. Psoroptes ovis, on Cattle The pour-on formulation of the present invention is prepared by blending together 0.5% w/v of 23-(O-methyloxime) -LL-F28249a; 10% w/v of an aromatic solvent having (1) a mixed aniline point of 15.4°C (test method ASTM D 611), (2) Kauri-butanol value 92, (3) specific gravity @ 15.6°/15.6°C of 0.899, (4) viscosity, CP @ 25°C 1.20 and (5) a mass composition aromatic C9-8% w/v, C10-74%, Cj^-15% and C12-l%; 5% w/v of the emollient ester PPG-2 myristyl ether propionate, (spreader) melting point -5°C; and 84.5% w/v of light mineral oil. Calves with naturally acquired infestations of psoroptic mange are randomly selected weighed and tagged. The calves are then treated by pouring the test formulation down the midline of the back of test animals at volumes providing 10 ml of formulation per 100 kg of live animal body weight or 0.5 mg of active ingredient per kg live weight. The treated calves are placed in pens and provided feed and water ad libitum. The calves are inspected on days 7 and 14 /after treatment for the presence of psoroptic mange live mites. Data obtained are reported below in Table l. 4 Table 1 Evaluation of 23-(0-Methyloxime)-LL-F28249a Formulation for Controlling Psoroptic Mange on Cattle Treatment 2 3-(O-methyloxime) -LL-F28249a pour-on formulation 23-(O-methyloxime) -LL-F28249a pour-on formulation 23-(O-methyloxime) -LL-F28249a pour-on formulation untreated control untreated control Initial2 Infestation +++ ++ *** + _ Live weight (kg) 170 150 17 G 150 160 Total Dose mL 17 15 17 0 0 Effect of Post-treatment Day ? mange at one site two mites no mites no changec no change Day 14 Assessment of aternal infesta'feion +++ = high ++ = moderate ± = very light b Cured c treated with commercial product to cure mange to save animal. no mites healthy skinb no mitesb healthy skin no mitesb healthy skin no change ro o> -4S CO CnI o>. - 12 - 26 4 9 3 6 Example 2 Preparation of Pour-On Formulations Containing 23-(O-Methvloyimei-i.i.-g2B249tt for Controlling Gastrointestinal Nematodes and the Biting Louse of Sheep 5 Using the procedure of Example 1, the following formulations are prepared: 1) (a) 0.5% w/v 23-(O-methyloxime)-LL-F28249a (b) 10.0% w/v aromatic solvent sp. gravity 6 15.6°/15.6°C = 0.899, mixed aniline 10 point 15.4°C and Kauri-butanol value 92 (commercially available as AROMATIC® 150, Exxon Chemical Company, Houston, Texas) (c) 5.0% w/v PPG—2 myristyl ether propionate (spreader, commercially available as 15 CRODAMOL®- PMP, Croda, Inc., Parsippany, New Jersey) (d) 84.5% w/v light mineral oil 2) (a) 0.2% w/v 23-(O-methyloxime)-LL-F28249a 20 (b) 10.0% w/v aromatic solvent sp. gravity @ 15.6°/15. 6°C = 0.899, mixed aniline point 15.4°C and Kauri-butanol value 92 (c) 5.0% w/v PPG-2 myristyl ether propionate (d) 84.8% w/v light mineral oil 25 / - 3) (a) 0.5% w/v 23-(O-methyloxime)-LL-F28249a (b) 10.0% w/v arcfmatic solvent sp. gravity § 15.6°/15.6°C = 0.899, mixed aniline point 15.4°C and Kauri-butanol value 92 30 (c) 5.0% w/v PPG—2 myristyl ether propionate (d) 74.5% w/v light mineral oil (e) 10.0% w/v polybutene H-1900 kinematic viscosity at 99°C=4069-4382 Flash point open cup = 243°C 3 5 Specific gravity at 15.5°C = 0.898-0.916 Molecular weight number average = 2300 (agent promoting adhesion and water re- - 13 264936 pellency, commercially available as INDOPOL® H—1900, Amoco Chemical Co., Chicago, Illinois) 5 4) (a) 0.2% w/v 23-(O-methyloxime)-LL-F28249ct (b) 10.0% w/v aromatic solvent sp. gravity @ 15.6°/15.6°C = 0.899, mixed aniline point 15.4°C and Kauri-butanol value 92 (c) 5.0% w/v PPG-2 myristyl ether propionate 10 (d) 74.8% light mineral oil (e) 10.0% w/v polybutene H 1900 kinematic viscosity at 99°C = 4069-4382 Flash point open cup = 243°c Specific gravity at I5.5°c = .898-.916 15 Molecular, weight member average = 2300 5) (a) 0.5% w/v 23-(O-methyloxime)-LL-F28249a (b) 99.5% w/v butoxyethoxyethanol 20 6) (a) 0.2% w/v 23-(O-methyloxime)-LL-F28249a (b) 99.8% w/v butoxyethoxyethanol 7) (a) 0.5% w/v 23-(O-methyloxime)-LL-F28249a (b) 10.0% w/v polysorbate 80, a nonionic sur-25 factant-polyoxyethylene (20) sorbitan monooleate (c) 89.5% w/v butoxyethoxyethanol 8) (a) 0.2% w/v 23-(O-methyloxime) -LL-F28249a 30 (b) 10.0% w/v polysorbate 80, a nonionic sur factant-poly oxy ethylene (20) sorbitan monooleate (c) 89.8% w/v butoxyethoxyethanol 35 9) (a) (b) 0.5% w/v 23-(O-methyloxime)-LL-F28249a 15.0% w/v aromatic solvent sp. gravity @ 15.6°/15. 6°C = 0.899, mixed aniline point (C) (d) (e) (f) (g) (a) (b) (c) (d) 20 # (e) 25 (f) (g) 10 10) 15 264936 15.4°C and Kauri-butanol value 92 10.0% w/v PPG-2 myristyl ether propionate 10.0% w/v polybutene having a molecular weight number average = 2300 0.05% w/v butylated hydroxyanisole (antioxidant) 0.1% w/v D+C Violet #2 (dye) 74.3% w/v mixed capric/caprylic glyceryl triester 0.5% w/v 23-(O-methyloxime)-LL-F28249a 15.0% w/v aromatic solvent sp. gravity § 15.6°11J3.6°C = 0.872, mixed aniline point 13.4°c and Kauri-butanol value 91 (commercially available as AROMATIC® 100, Exxon Chemical Company, Houston, Texas) 10.0% w/v PPG-2 myristyl ether propionate 10.0% w/v polybutene having a molecular weight number average = 2300 0.05% w/v mixture of 20.0% w/w butylated hydroxyanisole, 6.0% w/w tert-butylhydroquinone, 4.0% w/w citric acid and 70.0% w/w propylene glycol (an antioxidant commfercially available as TENOX®-22 from Eastman Chemical Company, Kingsport, Tdnnessee) 0.025% w/v D+C Violet #2 (dye) QS to 100% w/v mixed capric/caprylic glyceryl triester - 15 - 26 4 9 36 Example 3 Evaluation of Pour-On Formulations containing 23-(o-Methvloxime)-Lli-F28249oe for Controlling Gastrointestinal Nematodes in Sheep Merino sheep are given artificially-induced infestations of Damalinia ovis. the biting louse, and artificially-induced infections of the gastrointestinal nematodes Ostertagia circumcincta. Haemonchus contortus and Trichostronavlus colubriformis. The sheep are then sheared, weighed and placed in individual pens. The infected sheep are then treated with the selected formulation by pouring the formulation down the midline of the sheeps' back. The formulations are then applied to the weighed sheep in sufficient amount to provide from 0.2 to 1.0 mg/kg of live animal body weight. Fourteen days after treatment, three sheep from each treatment and the control group are necropsied and the nematodes recovered and counted. Data obtained are reported in Table 2 below where it can be seen that the formulations prepared in Example 2 are highly effective against the abomasal nematodes Ostertagia circumcincta and Haemonchus contortus at doses of 0.2 mg/kg and 0.5 mg/kg or 1 mg/kg when poured along the midline on the backs of off-sheared sheep. It can also be seen that doses of from 0.5 mg/kg to 1 mg/kg of the 23-(O-methyloxime) -LL-F2 82 49a provided in the above-said formulations are effective for controlling the intestinal bankrupt worm, Trichostrongvlus colubrif ormis. In these tests nematode egg counts drop to nearly zero after treatment and remain that way to the end of the trial. From Table 3 below, it can also be seen that the pour-on formulations are highly effective against the biting louse, Daisalinia ovis. throughout the six week trial period. Table 2 Efficacy of 23-(0-Methyloxime)-LL-F28249a Pour-On Against Nematodes in Sheep Dose Dosage Ostertagia Haemonchus Trichostrongvlus Formulation mg/kg mT./io icq circumcincta contortus colubriformis Control 0 0 2025* 428* % Efficacv 1375* 1 1.0 2 100 100 99.6 1 0.5 1 100 100 72 2 0.2 1 96 89 24 3 1.0 100 100 • 89 3 0.5 1 100 100 76 4 0.2 1 100 100 17 5 1.0 100 100 47 5 0.5 1 99.7 100 31 6 0.2 1 92 81 17 7 1.0 100 100 64 7 0.5 1 99 100 7 8 0.2 1 93 81 60 *Arithmetic Mean Adult Worm Count, 14 days post- -treatment The worm egg counts of the remaining sheep are markedly reduced from the initial levels at the time of treatment at the end of the six-week trial period. 1 1 2 3 3 4 5 5 6 7 7 8 8 0 0 1 0 0 1 0 0 0. 0 0. 5. Table 3 Efficacy of 23-(O-Methyloxime)-LL-F28249a Pour-On Against Biting Louse, Damalinia ovis. on Sheep Dose mq/kq 1.0 0.5 0.2 1.0 0.5 0.2 1.0 0.5 0.2 1.0 0.5 0.2 Dosage wiT./lcty 16.3 46.3 30 35 27 21 18.7 57.3 36.7 32 16.3 40.0 44.0 Average No. of Lice 2 Weeks 10.3 0.67 1.3 3.3 0.33 0.67 10.3 0 .5 1.3 .67 1.0 0 4 weeks 8.7 0 0 1 0 0 4 0 0 1 0 0.67 3.3 - 18 - 264936 Bvample 4 Evaluation of Formulations Containing 23-(O-HethvJ cwrlmei —LL—F28249a on Blood Levels in Calves Treated With Pour-on Formulations containing 23-(O-Methvloxime)-LL-F28249C In these tests four calves per treatment are used to evaluate formulations 1 and 3 reported in Example 2, above. Cattle receiving formulation 1, from Example 2, are designated Group B, cattle receiving formulation 3 are designated Group C. The pour-on formulations are applied along the backs of the animal with 2 mL per kg of animal body weight of the test formulation to provide each animal with 1 mg/kg of 23-(O-methyloxime) -LL-F28259a in the selected formulation. Blood samples are then taken from the treated animals at intervals up to 96 hours after treatment and the blood serum levels for the treated animals assayed. From the data provided in Table 4 below, it can be seen that serum levels in calves receiving the CRODAMOL® formulation 1 (Group B) show an increase in blood levels to 11, 10 and 13.5 ppb at 48, 72 and 96 hours respectively, whereas, the CRODAMOL®-INDOPOL® formulation 3 (Group C) shows enhanced blood levels to 8, 17.5 and 15.2 ppb at 48, 72 and 96 hours respectively. The higher blood levels are desirable. I Table 4 Evaluation of 23-(O-Methvloxime)-LL-F28249a Reaidues in Cattle Serum (ppb) Formulation: 0.5% w/v 23-(O-methyloxime)-LL-F28249a Pour-On Treatment Rate: 1 mg/kg body weight HOURS Group Calf No. 0 1 2 4 <? 12 24 36 48 72 96 B 1 <5 <5 <5 <5 <5 7 9 9 8 22 21 21 B 2 <5 <5 <5 <5 <5 <5 7 7 7 8 8 12 B 3 <5 <5 <5 <5 <5 <5 <5 <5 6 5 . <5 11 B 4 <5 <5 <5 <5 <5 6 7 7 8 8. 7 10 Average <5 <5 <5 <5 <5 5 7 7 7 11 10 13.! C 5 <5 <5 <5 <5 <5 <5 <5 11 16 26 19 C 6 <5 <5 <5 <5 <5 5 7 8 8 8 26 26 C 7 <5 <5 <5 <5 <5 <5 <5 <5 <5 <5 6 <5 C 8 <5 <5 <5 <5 <5 <5 <5 <5 <5 7 12 13 Average <5 <5 <5 <5 <5 <5 <5 5 7 8 17.5 15.: - 20 - 2 6 4 9 3 6 By-ample S Evaluation of Pour-on Formulations Containing 23—(O-Methy-I.li-r28249a for Controlling Endoparasites in Infected Animals Evaluation of the pour-on formulations described in Example 2 above, i.e.. Formulation 1 (Group B) and formulation 3 (Group C) , for* control of Ostertagia ostertagi. Trichostrongvlus axei. and Haemonchus placei in the abomasum of the treated animals and Cooperia punctata and Cooperia oncophora adult worms in the small intestines of the treated animals is conducted using the procedures described below. In these tests 6 calves per treatment are used. The calves are heavily infected with endoparasites and are randomly assigned to groups, each group having 3 males and 3 females. The calves are weighed and fecal egg counts made for each animal. Group 1 is then treated with the pour-on formulation B, i.e.. the CRODAMOL® formulation 1 from example 2 of the specification. Group 2 receives pour-on formulation C, formulation 3 from example 2. Fourteen days after treatment the calves are necropsied and egg counts, larval counts and adult worm counts are made. These data are reported in Table 5 where it can be seen that the fecal egg count in treated calves 14 days after treatment is zero with both formulations, but in the untreated control there are about 183 eggs per calf. The data also show' that the weight gains with treated calves is considerably better than the untreated controls. The data in Table 6 show that Ostertagia ostertagi is completely controlled with all treatments. Trichostrongvlus axei is controlled with the CRODAMOL® - INDOPOL® formulation C, but the CRODAMOL® formulation B in which INDOPOL® is omitted shows a break. With Haemonchus placei the CRODAMOL® formulation B and the CRODAMOL®-INDOPOL® formulation C give complete control of this larvae. - 21 - 264936 Finally, Table 7 shows complete control of Cooperia punctata with the CRODAMOL®-INDOPOL® formulation C, but breaks with CRODAMOL® alone, formulation B, in 3 out of 6 animals. Even more importantly, with Cooperia oncoohora 5 formulation B shows a break in 3 out of 6 animals; whereas, formulation C, CRODAMOL®-INDOPOL®, gives complete control of Cooperia oncophora. Table S 10 Fecal Egg Counts and Body Weights of Calves Used for Evaluation of Test Formulations For Control of Endoparasites in Infected Animals 15 Fecal Egg Count Calf Weights At At Formulation Group Treatment Sex Necropsy (lbs.) B-CRODAMOL® 1 F 138 0 450 500 20 Formula 1 F 88 0 460 490 from F 166 0 410 460 Example 2 M 174 0 500 585 - M 98 0 350 385 M 194 0 370 430 25 858 2,540 2,850 C-CRODAMOL®/ 2 F 98 0 400 450 INDOPOL® F 220 0 490 550 Formula 3 F 118 0 435 480 30 from M 292 0 225 270 Example 2 M 512 0 470 520 M 406 0 410 465 1,646 i 2,430 2,735 35 Untreated 3 F 104 222 475 265 Control F 170 ' 366 385 325 F 172 334 440 510 M 304 266 380 440 M 182 146 425 495 40 M 166 19 6 400 480 1,098 1,530 2,505 2,775 - 22 - 26 4 9 36 Table 6 Evaluation of Pour-On Formulations for Control 10 15 20 25 30 Formulation Ostertacria Ostertaai Tricho-stroncrvlus Axei Haemonchus Placei Total Nematode Count B CRODAMOL® - - - - - 8 - 8 C CRODAMOL®/ INDOPOL® - - - - Untreated Control 6,460 9,500 5,900 5,220 3,920 2.040 7,390 8,900 10,300 7,680 4,000 4.600 130 500 650 6 6 14,030 18,030 16,850 12,906 7,957 6.640 33,040 42,870 1,368 77,278 i i 26 4 9 - 23 - Table 7 Evaluation of Test Formulations for Control of Endoparasites in the Small Intestine of Treated Animals (Total Nematode Count) Cooperia Cooperia Formulation Punctata Oncophora 10 B 24 36 CRODAMOL® 15 20 C CRODAMOL®/ INDOPOL® 25 33 33 240 184 297 253 Untreated 2,880 5,560 3 0 Control 2,240 4,640 2,200 4,200 3,570 10,640 4,264 7,920 1.850 3.800 35 17,004 35,760 i - 24 - 26 4 9 36 revample 6 Evaluation of the Efficacy of Pour-On Formulations Containing 23-(0-Methvloxime)-LL-F28249ct During Rainfall The objective of this study is to determine the 5 potential effect of rainfall on the efficacy of a pour-on formulation of 23-(O-methyloxime)-LL—F28249a (0.5% w/v) against gastrointestinal nematodes. Formulation 10 reported in Example 2, above, is employed for the study. Forty-eight mixed beef breed heifers are ranked 10 according to the average of the day -3 and day -2 fecal nematode egg counts and randomly assigned to the following groups of 6 animals, each: Group I: Treatment with vehicle and no exposure to simulated rain (control); Group II: Treatment with 23-(O-methyloxime)-LL-F28249a pour-on and no exposure to simulated rain; Group III: Treatment with 23-(O-methyloxime)-LL-F28249a pour-on and exposure to simulated rain immediately prior to treatment; Group IV: Treatment with 2 3—( O-methyloxime) —LL— F28249a pour-on and exposure to simulated rain 2 hours posttreatment; Group V: Treatment with 23-(O-methyloxime)-LL-F28249ci£ pour-ori and exposure to simulated rain 6 hours posttreatment; Group VI: Treatment with 23-(O-methyloxime) -LL— F28249a pour-on and exposure to simulated rain 24 hours posttreatment. All cattle treated with 23-(O-methyloxime)-LL-F28249a pour-on are treated with 0.5 mg 23-(O-methyloxime)-LL-35 F28249a per kg of body weight. All animals exposed to simulated rain are sprayed with the equivalent of 1 inch of water for 3 0 minutes. 15 20 25 30 - 25 - 264 9 36 Following treatment, cattle are housed in outdoor pens which are partially covered by a three sided shed. Cattle remain outdoors during the entire posttreatment period. However, they are confined to a covered portion of the pen when it is raining or rainfall is imminent. This is done to prevent any confounding effect of natural rainfall on the interpretation of the results of this trial. The simulated rainfall apparatus used in this trial consists of a 12 feet x 12 feet pen with right angle directional spray nozzles in each corner. It is calculated that 89.75 gallons of water applied to this size pen are the equivalent of 1 inch of rain. This simulated rain is applied over a 30 minute period which is equivalent to 2 inches of rain per hour. According to the U.S. Department of Interior Geological Survey (The National Atlas of the United States of America, p. 97, Washington, D.C., 1970), 2 inches of rain per hour is the mean annual maximum hourly rainfall in the United States. The actual volumes of water applied to each of the treatment groups exposed to simulated rain are 101.3, 91, 91.4 and 91.4 for treatment Groups III, IV, V and VI, respectively. Fecal samples are taken from all animals on days 7, 14 and 21 posttreatment to evaluate nematode egg counts. The results of this study are summarized in Table 8 below. The values are expressed as number of eggs per 1 g of feces. ' - 26 - 264 9 36 Table 8 THE INFLUENCE OF SIMULATED RAIN ON THE EFFICACY OF O.S% W/V POPR-ON OF 23-(O-METHYLOXIME)-LL-F28249g IN THE REDUCTION OF NEMATODE EGG OUTPUT IN FECES IN CATTLE Geometric Means % Reduction Group Dav 7 Dav 14 Dav 21 Dav 7 Dav 14 Dav 21 I 97a 44a 82a II <lb <1° <lc >99.9 >99.9 99.8 III <lb <lbc o ja H V 99.8 98.9 98.7 IV <lb <lc <lbC 99.7 99.7 99.2 V lb 2b 4b . 98.9 94.5 94.5 VI <lb <1° <lc 99.9 99.7 99.4 a,b,c Means in the same column with different superscripts differ at P<0.05. Treatment with 23-(O-methyloxime)-LL-F28249a significantly reduces nematode egg counts at all times posttreatment regardless of exposure to simulated rainfall. Treatment with 23-(O-methyloxime)-LL-F28249a pour-on without the influence of simulated rain (Group XI) is greater than 99.8% effective in reducing fecal output of nematode eggs at all 3 posttreatment sampling times. At day 7 posttreatment, there is no effect of simulated rain either pre- (Group III) or posttreatment (Group IV, V and VI) on the reduction of fecal nematode egg output. At days 14 and 21 posttreatment' simulated rainfall prior to treatment (Group III) andt at 2 (Group IV) and 24 hours posttreatment (Group VI) has no effect on the reduction of fecal nematode egg output as compared with the positive controls (Group II). At days 14 and 21 posttreatment, simulated rain at 6 hours posttreatment (Group V) results in a significant reduction in fecal nematode egg output as compared to the untreated controls (Group I). On day 21 posttreatment, fecal samples from the eight control animals are analyzed. The results indicate that the infections include the following genera: Cooperia. Haemonchus, Ostertagia and Trichostrongvlus. No adverse §4 9 38 - 27 - effects of 23-(0-methyloxime)-LL-F28249a pour-on are observed on overall animal health at 1,2, 3, 4, 7 and 14 days posttreatment. Animals are examined at the same posttreatment times for skin reactions at the pour-on site and no reactions are observed. This study demonstrates that simulated rainfall has little, if any, effect on the 5 efficacy of 23-(0-methyloxime)-LL-F28249a pour-on. Examples 7 and 8 In Examples 7 and 8 the formulation "Moxidectin" is formulation number 10 in Example 2 hereinabove. (N:\libffl00111:ER 27 of 6 2649 36 30 - 28 - Example 7 Efficacy of Moxidectin Pour-On in Cattle Naturally Infested with psoroptes ovis Cattle were divided into two groups. Group I comprising twenty-one (21) animals and Group II comprising eighteen 5 (18) animals. In Group I ten (10) animals were found be be infested with Psoroptes ovis and in Group II, nine (9) animals were found to be infested. At the start of the trial six (6) animals were selected 10 from each experimental group according to parasitological and clinical status in order to obtain approximately similar mean parasitological and clinical scores at the start of the experiment. On Day 0, the animals of Group I were given a single dose at 0.5 mg/kg body weight of 0.5% moxidectin 15 pour-on distributed with a 20 ml disposable syringe from the withers up to the tail base. The animals of Group II remained as positive controls. There was no physical contact between the control animals and treated cattle. Skin scrapings were taken from the animals on Days -4, 2o 14, 28, 42 and 56 Posttreatment ("PT"). On Day 28 PT the control animals were treated on humane grounds with pour-on flumethrin (Bayticol, Bayer, Leverkusen, Germany) at the recommended dose and were excluded from the trial. Skin scrapings were harvested with a surgical blade by 25 collecting the scabs and epidermal layers from three 2x2 cm areas at the periphery of the lesions. On clinically unaffected animals, skin scrapings were taken from sites for which mites have a predilection: the withers, the rump and the base of the trial. The material was collected into a Petri dish containing damp cotton wool and subsequently sealed to prevent desiccation. The samples were kept at 4 C until examination which was completed within 48 hours. The samples were then maintained at 37°C for five minutes to increase mite motility and examined at x 30 magnification. 35 The mites were collected, counted and identified in terms of the stage and species. Only viable motile parasites were counted. The severity of infestation was assessed according to two criteria: 40 (a) A parasitological index for the number of mites in samples was expressed as follows: O: no live mites, 1: between 1 and 10 mites, 2: between 11 and 100 mites, 45 3: over 100 mites. - 29 - 2649 36 (b) A clinical index was calculated. For each animal, the percentage of the body with scabies lesions was determined from the proportions of total body squares within tracings. The animals were then classified into four different categories as follows: 0: no detectable lesions, l: less than 2% of body surface affected, 2: 2—10% of body surface affected, 3: more than 10% of body surface affected. Efficacy data and clinical indices are presented in Table 1. On day 14 parasitological cure was achieved in all treated animals (Group I) as no living mites were found. Furthermore, there was a marked clinical improvement: the scabs had dried and were falling off, and pruritus had disappeared. In contrast, the clinical condition of the control group (Group II)' continued to worsen rapidly and by Day 28 all animals were infested with P. ovis and some presented a very severe pyodermatitis which necessitated emergency treatment. Thus, on Day -4 PT the average clinical indices of the Group 1 moxidectin pour-on and Group II untreated control were 6.10% and 2.87%, respectively, whereas on Day 28 PT the average clinical indices were 0% and 13.05%, respectively, on Day 56, no living mites were found on any of the treated animals and clinical cure was maintained (mean clinical index: 0). No adverse reactions were recorded in any experimental animal. TABLE I Efficacy of Moxidectin Pour-on in Cattle Naturally Infested with Psoroptea ovis Group Experimental data Means .1 Means Day ' -4 Day 14 Day 28 Day 42 Day 56 P. ovis Clinical P.ovis P. ovis Clinical P. ovis P. ovis Clinical Count Index Count Count index count count index (*)2 (**)3 (*>2 (*>2 (**)3 (*>2 (*)2 (**)3 >100(3) 3.1(2) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) >100(3) 6.0(2) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) >100(3) 0.4(1) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) >100(3) 13.4(3) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) >100(3) 12.3(3) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 11(2) 1.4(1) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 6.10 0 >100(3) 2.0(3) >100(3) >100(3) 11.1(3) ND4 ND ND >100(3) 6.0(2) >100(3) >100(3) 12.6(3) ND ND ND >100(3) 0.0(0) >100(3) >100(3) 13.4(3) ND ND ND >100(3) 2.6(2) >100(3) >100(3) 24.3(3) ND ND ND >100(3) 0.6(1) 93(2) >100(3) 0.3(1) ND ND ND 85(2) 6.0(2) >100(3) >100(3) 16.6(3) ND ND ND 2.87 13.05 1Group 1: single dose of moxidectin pour-on at 0.5 mg/kg body weight. Group 2: untreated controls. { *) P. ovis score (living mites only). 3 (* *) Clinical score• 4 ND = no data (due to emergency treatment for humane reasons). 31 - 4 9 31 Example 8 Efficacy of Moxidectin Pour-on Against Experimental Infestations of Abomasal and small Xnfestine Parasites 5 Twelve six to eight month old Angus heifers, average weight 166 kg, were treated with TRAMXSOL® to remove any existing parasitic infection. In order to offset any shipping fever, calves were placed on a regimen consisting of SULMET* sodium sulfamethazine for three consecutive days 10 in drinking water at the recommended level. One injection of COMBIOTIC® waa administered to all calves at arrival. Further antibiotic treatment with LIQUAKYCIN LA-200® or COMBZOTIC was given on a need basis, as prescribed by the attending veterinarian. All calves were injected with 15 RABGUARD-TC® rabies vaccine. No further supportive medication was given after inoculation with infective larvae. The inoculum of infective larvae consisted of 27,ooo, 34,000 and 32,000 infective larvae of Cooparia oncophora/ C. surnabada, Trichostrongvlus axei and Ostertagia 20 ostertagi. respectively. All species were mixed into one volume and orally introduced (13 ml) to each calf. Group Z (six calves) were administered moxidectin pour-on formulation as a single application at 0.5 mg/kg body weight 28 days postinoculation. Moxidectin pour-on was 25 applied using a glass syringe along the back of the calf from the withers to the rump. The hair on the back of the calves was not clipped or prepared in any manner. Calves were observed closely for 8 hours after treatment and at least onoe daily until necropsy for any overt signs of 30 toxicity. The application site was observed closely for any abnormality in skin condition. TRAMISOL* - Registered trademark for levajnisole, a product of American Cyanamid Company. 35 sulmet® - Registered trademark for sodium sulfamethazine, a product of American Cyanamid Company. COMBZOTIC* - Registered trademark for penicillin and dihydrostreptomycin, a product of Pfizer Co. LIQUAMYCIN LA200® - Registered trademark for 40 oxytetracycline, a product of Pfizer Co. RABGUARD—TC® - Registered trademark for rabies vaccine, a product of Norden Labs. - 32 - 2649 3$ Fecal egg counts were made 21 and 2 6 days post-inoculation in order to determine if the experimental infections were developing properly and to ascertain the number of eggs per gram of feces (epg) and determine para-5 site burdens. Calves were assigned to replicates based on epg's. Calves were randomly assorted by drawing numbers for specific treatments within each replicate. Fecal egg counts were made to determine the post-treatment egg burden. Equal numbers of calves were killed 10 on days 14, 15 and 16 posttreatment. The dorsal area where the pour-on formulation was applied was examined for any abnormality in skin condition (flaking, irritation, loss of hair). At necropsy, three skin/backfat samples (4 x 4 x 1.5 cm) from the dorsal mid line of the back and one lobe liver 15 section (3x3x3 cm) were excised for pathological exami nation. Standard anthelmintic procedures were used to recover worms from the abomasum and small intestine. Eviscerated animals were incinerated. Formalin was added to seived (100 20 mesh) contents and scrapings and the samples were refriger ated. Adequate aliquots (5-10% of the total volume) were read to determine the numbers of specimens of each species remaining in each calf. speciation of cooperids was performed by utilizing the 25 shape and size of spicules as a characteristic for differen tiating males. Some of the female cooperids from treated calves were examined for the presence and number of eggs in the uteri and ovijector. Pre- and Posttreatment egg counts are given in Table 30 ii. The moxidectin pour-on formulation applied at 0.5 mg/kg significantly (P<.01) reduced the total eggs per gram of feces in treated calves. The total numbers of adult O. ostertagi and T. aval recovered from the abomasum are shown in Table XIX. The 35 total numbers of C. oncophora/c. snmaharia and T. colubriformia recovered from the small intestine are shown in Table IV. T. colubrif ormis. although not a part of the original inocula, was introduced as a contaminant with one of the cultures. 40 There was significant (P<.oi) treatment effect for all worm species and the control animals showed significantly higher worm counts for all species. Moxidectin pour-on treatments produced greater than 99% efficacy against all tested species (Tables XII and IV). Outstanding efficacy 45 against all abomasal and small intestinal adult parasites with the pour-on formulation at 0.5 mg moxidectin/kg of body weight was demonstrated. TABLE II Pre- and Post-treatment Egg Counts Group I Animal Number 406 416 422 413 368 419 Moxidectin mq/Kq 0.5 0.5 0.5 0.5 0.5 0.5 Mean Range Pretreatment EPG Counts 250 350 150 100 50 0 Pretreatment EPG Counts 1050 300 300 200 150 50 341.6 (50-1050) Posttreatment EPG Counts o o 0 o o 0 0 Group II 405 367 423 412 410 426 0 0 0 0 0 0 Mean Range 600 450 0 0 0 0 1550 600 300 200 100 100 475.0 (100-1550) 500 250 200 250 50 100 225.0 (50-500) 1 Epg counts at 21 days postinoculation. 3 Epg counts at 26 days postinoculation; used for assigning animals to treatments. Epg counts 14 to 16 days posttreatment. TABLE III Efficacy of Moxidectin Pour-On Formulation Against Experimentally Induced Adult Abomasal Peucasites in Calves Group I Animal Number Moxidectin mq/fcg 0. ostertagi Adults T. axei Adults 406 416 422 413 368 419 0.5 0.5 0.5 0.5 0.5 0.5 Mean 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Group II 405 367 423 412 410 426 0 0 0 0 0 0 Mean Range 12510 8770 15050 7790 3770 940 8138.3 (940-15050) 340 390 200 180 60 100 211.6 (60-390) i TABLE IV Efficacy of Moxidectin Pour-On Formulation Against Experimentally induced Adult small Intestinal Parasites in Calves Group I Group II Animal ttmnhftr 406 416 422 413 368 419 405 367 423 412 410 426 Moxidectin 0.5 0.5 0.5 0.5 0.5 0.5 Mean Range 0 0 0 o o o Mean Range C. oncophora/ C. surnabada 40 0 o 0 0 0 6.6 (0-40) 1360 1080 1500 1140 1180 1320 1263 (1080-1500) T. colubriformis o 0 o o o o 0 10500 3640 4000 300 400 1100 4373 (300-10500) </div>

Claims

<div class="application article clearfix printTableText" id="claims">



26 4 9 3 § 

- 36 - 

In the foregoing, there has been provided a detailed description of particular embodiments of the present invention for the purpose of illustration and not limitation. It is to be understood that all other modifications, ramifications and equivalents obvious to those having skill in the art based on this disclosure are intended to be included within the 5 scope of the invention as claimed. 

(N:\libH|00111 :ER 

36 of 6 

26493^ 

- 37 - 

WHAT WE CLAIM IS: 

1 . A non-aqueous pour-on composition for combating helminth, acarid and arthropod endo- and ectoparasitic 5 insect infestations and infections of homothermic quadruped comprising an anthelmintically, acaricidally or an arthropod endo- or enctoparasitic insecticidally effective amount of a compound selected from the group consisting of LL-F28249 of-A, a 23-oxo (keto) or 23-imino derivative of 10 LL-F28249 a-X, a milbemycin compound and an avermectin compound dissolved or dispersed in a mixture comprising: from 5.0% to 20% w/v of an aromatic solvent having a mixed aniline point of from 13.4°C to 15.4°C, a Kauri-butanol value between 90 to 96 and a specific gravity at 15 1 5 „ 6°/1 5.6°C of from 0.872 to 0.985; from 0 w/v to 15.0% 

w/v of polybutenes having number average molecular weight of from 320 to 3000 and a Cleveland open cup flash point of from 1 54°C to 307°C; from 8.0% w/v to 15% w/v of 2-[2--(tetradecyloxy)propoxy]-1-propanol propionate and quantity 20 sufficient to 100% w/v of a pharmacologically acceptable oil; with the proviso that the mixture contains more than 8.0% of 2-[2-(tetradecyloxy) propoxy]-1-propanol propionate when the mixture contains from 5.0% to 15% w/v of an aromatic solvent having a mixed aniline point of from 25 13.4°C to 15.4°C, a Kauri-butanol value of 92 and a specific gravity at 15.6°/15.6°C of from 0.875 to 0.899.
2. The composition according to claim 1, wherein the compound is 23-(O-methyloxime)F28249a. 

30
3. The composition according to claim 1, ^jftetein ° the compound is LL~F28249a. j! 

{ 1 r rrn
4. The composition according to any ond5,-* of 0 

XLf f t v 

35 claims 1 to 3 which comprises 1 5% to 20% w/v of an aroraan solvent. 

26493 

- 38 - 

5 - The composition according to any one of claims 1 to 4 wherein the specific gravity is 0.875 to 0.899.
5
6. The composition according to claim 1 comprising 

0.1% to 5.0% w/v of 23-(O-methyloxime) F28249a; about 15% w/v aromatic solvent; about 10% w/v 2-[2--(tetradecyloxy)propoxy]-1-propanol propionate; about 10% w/v polybutene and the pharmacologically acceptable oil is 10 capric triglycerides, caprylic triglycerides or mixtures thereof.
7. The composition of any one of claims 1 to 6 further comprising 0 to 2.0% w/v of a dye, antimicrobial 

15 agent, antioxidant or mixture thereof.
8. A method for treating helminth, acarid or arthropod endo- or ectoparasitej insect infection or infestation in a homothermic quadruped which is 

20 characterized by pouring onto the skin of the quadruped to be treated an anthelmintically, acaricidally or arthropod endo- or ectoparasiticidally effective amount of a composition according to any one of claims 1 to 7. 

25
9. The method according to claim 8, wherein the pour-on composition is applied to the quadruped in sufficient amount to provide the quadruped with from 0.2mg/kg to 1.0mg/kg of body weight of the quadruped of the compound. 

30
10. A method for treating or controlling Psoroptic mange on a homothermic quadruped or preventing or protecting the quadruped from infestation by Psoroptes ovis which is characterized by pouring onto the skin^^-35 quadruped a non-aqueous pour-on composition according to f.y i' , , 

30 

any one of claims 1 to 7 comprising 23- (O-inethyioxime) F28249a in an amount sufficient to provide the quadruped with 0.1mg/kg to 5.0mg/kg of body weight of the quadruped of said 23-(O-methyloxime) -F28249a.
11. A method according to any one of claims 8 to 10 wherein the quadruped is a cow, a sheep, a horse, a swine, a goat, a dog or a cat.
12. A non-aqueous pour-on composition for combating helminth, acarid and arthropod endo- and ectoparasitic insect infestations and infections of homothermic quadruped, which composition comprises an anthelmintically, acaricidally or an arthropod endo- or ectoparasitic insecticidally effective amount of a compound selected from the group consisting of LL-F28249 a-X, a 23-oxo (keto) or 23-imino derivative of LL-F28249 a-X, a milbemycin compound and an avermectin compound dissolved or dispersed in a mixture, which composition is substantially as herein described with reference to formulation 9 or 10 of Example 2.
13. A method for treating helminth, acarid or arthropod endo- or ectoparasitic insect infection or infestation in a homothermic quadruped, which method comprises pouring onto the skin of the quadruped to be treated a composition of claim 12 in an amount which effectively treats said infection or infestation. 



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