TOMMUNO NIUS009756852B2 UT AL ATHAR HET OM AT THE (12 ) United States Patent (10 ) Patent No. : US 9 , 756 , 852 B2 Pate et al. (45 ) Date of Patent: Sep . 12 , 2017

(54 ) TOPICAL DELIVERY FORMULATION 6 ,010 , 710 A 1 /2000 Etchegaray 6 , 797, 724 B2 9 /2004 Etchegaray 6 , 998 , 131 B2 2 / 2006 Soll et al. ( 71 ) Applicant: MERIAL INC . , Duluth , GA (US ) 2010 /0178262 A1* 7 /2010 Kergosien ...... A61K 8 / 361 ( 72 ) Inventors : James Pate , Hampton , NJ ( US) ; 424 /61 Natalya Shub , Allentown , PA (US ) FOREIGN PATENT DOCUMENTS ( 73 ) Assignee : MERIAL INC ., Duluth , GA (US ) EP 0226240 AL 11 / 1986 WO 2005 /089806 AL 9 /2005 ( * ) Notice : Subject to any disclaimer, the term of this WO 2013 /014127 A11 /2013 patent is extended or adjusted under 35 U . S .C . 154 (b ) by 60 days. OTHER PUBLICATIONS (21 ) Appl . No. : 14 /600 ,651 Volker Buhler, Chapters 1 & 4 , entitled “ Introduction and product overview ” and “ Kollicoat SR 30D ” in Functional Polymers for the (22 ) Filed : Jan . 20, 2015 Pharmaceutical Industry , Jan . 2007 , pp . 11 - 12 , and 101 - 154 , BASF , Ludwigshafen , Germany . (65 ) Prior Publication Data C . Hauser et al, “ Antimicrobial active packaging films based on sorbic acid ” in Science and Technology Against Microbial Patho US 2015 /0201611 A1 Jul. 23 , 2015 gens: Research , Development and Evaluation , Proceedings of the International Conference on Antimicrobial Research ( ICAR2010 ) , Related U . S . Application Data Valladolid , Spain , Nov . 3 - 5 , 2010 , editor A . Mendez - Vilas (60 ) Provisional application No . 61/ 929 ,371 , filed on Jan . Hackensack , NJ: World Scientific , 2011 ( ISBN : 978 - 981 - 4354 -85 - 1 20 , 2014 . & ISBN : 981 -4354 - 85 - 6 ) , pp . 131 - 134 . (51 ) Int . Cl. * cited by examiner AOIN 25 /34 ( 2006 .01 ) A01N 25 / 10 ( 2006 .01 ) Primary Examiner - Nannette Holloman AOIN 43 /56 ( 2006 .01 ) (74 ) Attorney , Agent, or Firm — Judy Jarecki- Black ; AOIN 53/ 00 ( 2006 .01 ) Katrina Bergbauer; Merial Inc . A61K 9 /00 ( 2006 .01 ) U .S . CI. (57 ) ABSTRACT CPC ...... AOIN 25/ 10 (2013 .01 ); AOIN 43/ 56 The invention is a pour- on antiparasitic formulation having (2013 .01 ); AOIN 53/ 00 ( 2013 .01 ); A61K superior water resistant properties . The pour -on formulation 9/ 0014 (2013 .01 ) utilizes one or more polymers (water insoluble with or (58 ) Field of Classification Search without water soluble ) in the range of about 5 to about 40 % CPC ...... A01N 25 /10 ; A01N 43/ 56 ; A01N 53 /00 ; w / w , one or more solvents in the range of about 50 to about A61K 9 /0014 94 % w / w , with or without additive (e . g ., isopropanol or ethanol) in the range of about 5 to about 30 % w / w , and See application file for complete search history . optionally a plasticizer in the range of about 0 . 5 to about (56 ) References Cited 25 % w / w . The pour -on antiparasitic formulation features limited spreading when applied to animals ( cattle , sheep , U . S . PATENT DOCUMENTS dogs and the like ). The pour -on antiparasitic formulation 3 ,590 , 118 A 6 / 1971 Conrady et al. further partially evaporates, leaving a water resistant poly 3 , 912 ,667 A * 10 / 1975 Spitzer ...... A61K 8 / 0208 mer matrix that diffuses at least one active ingredient to the 106 / 122 animal' s . 4 , 374 , 126 A 2 / 1983 Cardarelli 4 ,409 , 206 A 10 / 1983 Stricker 15 Claims, No Drawings US 9 , 756 ,852 B2 TOPICAL DELIVERY FORMULATION Lucilia cuprina ( known as blowfly strike in Australia , New Zealand and South Africa ) . These are flies whose CROSS -REFERENCE TO RELATED larva constitutes the animal parasite ; APPLICATIONS (b ) flies proper , namely those whose adult constitutes the 5 parasite , such as Haematobia irritans ( i . e ., horn fly ) ; This application claims priority to U . S . Provisional Patent ( c } lice such as Linognathus vitui etc. ; and Application No . 61/ 929 , 371 , filed Jan . 20 , 2014 . ( d ) mites such as Sarcoptes scabiei and Psoroptes ovis . The above list is not exhaustive and other ectoparasites are FIELD OF THE INVENTION well known in the art to be harmful to animals . 10 Protection of animals against parasites is essential to The present disclosure relates generally to topical delivery insure a healthy and safe environment for animals and their systems and their manufacture . More specifically , the dis owners . Pour- on and spot - on topical formulations are widely closure relates to topical antiparasitic delivery systems for used to deliver treatment against variety of external and animals . internal parasiticids , such as ticks , fleas, flies ,mites , worms, 15 etc . These formulations are solutions that are applied onto BACKGROUND the back of an animal and allowed to spread or penetrate . To be effective , these formulations need to retain an active in Animals such as mammals are often susceptible to para upper layers of skin or drive an active into the skin for site infestations . These parasites may be ectoparasites , such systemic absorbtion , and to be able to withstand environ as insects , and endoparasites such as filariae and worms. 20 mental stress ( e . g . , rain ) , to prevent removal of the drug . Domesticated animals , such as cats and dogs, are often Depending on the intended use , topical formulations typi infested with one or more of the following ectoparasites : cally consist of a solvent with or without a penetration fleas (Ctenocephalides felis , Ctenocephalides sp . and the enhancer ( for systemically delivered drugs ), or a solvent or like ) , co - solvents with addition of spreading agent, and various ticks (Rhipicephalus sp . , Ixodes sp ., Dermacentor sp ., 25 performance additives for delivery into upper layers of the Amblyomma sp . and the like) , skin . This is a traditional approach to formulating a topical mites ( Demodex sp ., Sarcoptes sp ., Otodectes sp. and the pour -on or spot- on solution . Currently marketed topical like ), pour -ons for production animals for protection from external lice ( Trichodectes sp ., Cheyletielfa sp ., Linognathus sp ., parasites do not have good water resistance and need to be and the like ), and 30 re - applied frequently . flies ( Hematobia sp ., Musca sp . , Stomoxys sp . , Dermato - For example , the commercial products for control of horn bia sp ., Cochliomyia sp ., mosquitoes ( family Culici- fly on cows provide limited protection lasting from several dae ) and the like ) . days to two weeks and require re - application after rain Fleas are a particular problem because not only do they throughout the fly season . This creates unnecessary stress for adversely affect the health of the animal or human , but they 35 animals resulting in significant productivity losses and addi also cause a great deal of psychological stress. Moreover , tional labor efforts for farmers . fleas are also vectors of pathogenic agents in animals , such Current commercially available topical solutions to con as dog tapeworm (Dipylidium caninum ) and may also trans trol horn fly population on cows provide limited duration of mit pathogens to humans . protection lasting from several days to about two weeks . Similarly , ticks are also harmful to the physical and 40 Current treatments further require frequent re - application psychological health of the animal or human . However , the due to a wash - off after exposure to environmental conditions most serious problem associated with ticks is that they are such as rain . the vector of pathogenic agents , which cause diseases in Extension of efficacy to one month or longer will provide both humans and animals . Major diseases which are caused continuous protection against the horn fly with less frequent by ticks include borreliosis (Lyme disease caused by Bor - 45 applications . Fewer applications will be less stressful for the relia burgdorfen ) , babesiosis (or piroplasmosis caused by animals and less time and labor consuming for the farmers . Babesia sp .) and rickettsiosis ( also known as Rocky Moun - There are several problems that contribute to the short tain spotted fever ) . Ticks also release toxins which cause duration of the active ingredient( s ) in the current pour - on inflammation or paralysis in the host . Occasionally , these nonsystemic formulations . First , the conventional solvent toxins are fatal to the host , such as in the case of the 50 system ( organic solvents ) applied topically is expected to Australian paralysis tick , Ixodes holocyclus . spread the active ingredient and retain it on the skin for the Moreover , mites and lice are particularly difficult to duration of the desired treatment period . Second , a complete combat since there are very few active substances which act dose intended to last for the duration of the treatment period on these parasites and they require frequent treatment. is applied at one time. Third , conventional solvent systems Likewise , farm animals are also susceptible to parasite 55 are not well formulated to resist some weather challenges . infestations. For example , cattle are affected by a large The active ingredient is completely exposed to environmen number of parasites ( e . g . , arthropod pests , such as fleas, lice t al conditions . The solvent carrying the active ingredient is and ticks , and mites ) . A parasite that is very prevalent among washed off during rain , rendering it non -efficacious . Fourth , farm animals is the tick genus Boophilus. especially those of the solvent system may not stay on the animal during the the species micropJus ( cattle tick ), decoloratus and anula - 60 treatment process resulting in a non -efficacious treatment. tus . Ticks, such as Boophilus microplus, are particularly Compounds that exhibit a degree of activity against a difficult to control because they live in the pasture where the wide range of ectoparasites including arthopods and insects farm animals graze . Other important parasites of cattle and are known in the art . One such class of compounds is the sheep are listed below : arylpyrazoles which are referred to , for example , in U . S . Pat . ( a ) myiases such as Dermatobia hominis (known as Berne 65 Nos. 5 , 122 ,530 ; 5 ,246 ,255 ; 5 , 576 ,429 ; 5 ,885 ,607 ; 6 ,010 , in Brazil ), Hypoderma, and Cochlyomia hominivorax 710 ; 6 , 083 ,519 ; 6 ,096 , 329; 6 ,685 ,954 ; EP 0 234 119 and EP (greenbottle ); sheep myiases such as Lucilia sericata , 0295 117 (U .S . Pat . Nos . 5 ,232 , 940 ; 5 ,547 , 974; 5 ,608 ,077 ; US 9 ,756 ,852 B2 5 ,714 , 191 ; 5 , 916 ,618 and 6 , 372, 774 ); EP 0 352 944 ( U . S . pyl alcohol or ethanol. Examples of water insoluble poly Pat. No. 4 , 963 ,575 ) ; EP 0780378 (U . S . Pat . Nos. 5 ,817 ,688 ; mers include , but are not limited to , vinyl acetate , poly 5 . 922 ,885 ; 5 , 994 , 386 ; 6 , 124 , 339 ; 6 , 180 ,798 and 6 , 395 , 906 ) ; isobutene, methacrylates, polyurethanes, styrenes and EP 0846686 ( U . S . Pat. No . 6 , 069 , 157 ) ; WO 98 /28278 , WO polyolefin elastomers . Non - limiting examples of water 08 /05489 , U . S . Pat. No . 7 ,759 ,381 and U . S . Pat. No . 8, 445 , 5 soluble polymers include povidone , polyvinylalcohol , poly 519 . All of the aforementioned patents and patent publica acrylic acid and ethyl cellulose . The optional plasticizermay tions are herein incorporated by reference . be , for example , an aliphatic ester such as acetyl tributyl The arylpyrazoles are known to possess excellent activity citrate . Other esters may function as plasticizers , for against insects , such as fleas and ticks. Fipronil is a specific example , triethyl citrate , tributyl citrate , acetyl triethyl cit type of 1 -N - arylpyrazole that is particularly effective against 10 rate , cetearyl palmitate and lanolin . Further, polymers ( e. g ., fleas and ticks and is the active ingredient in Frontline® and polybutene ) , oils (e . g ., castor oil ) , and propylene glycol and Frontline Plus® . Another arylpyrazole , 1 -( 2 -chloro -6 - propylene glycol esters may function as plasticizers . Oily fluoro - 4 - trifluoromethylphenyl) - 4 - dichlorofluoro -methyl - actives , such as pyrethroids ( e . g ., permethrin ) and growth sulfinyl- 5 -methylpyrazole - 3 -carbonitrile , has structure and regulators (e .g . , (s )- methoprene ) can also act as plasticizers . properties similar to fipronil . 15 In another aspect , the invention is a method of making a Other classes of compounds are also known in the art to topical delivery formulation using the solvents, polymers be effective parasiticides. Examples include macrocyclic and optional plasticizers described herein . lactones ( e . g ., avermectins and their derivatives ivermectin , In yet another aspect, the invention is a use of a topical eprinomectin , selamectin , doramectin and abamectin ) , ben - delivery formulation in the manufacture of a medicament for zimidazoles (e . g ., triclabendazole ), levamisole , closantel 20 the therapeutic and / or prophylactic treatment of an animal and development inhibitors such as S -methoprene . against an ectoparasite and / or an endoparasite . There is a need for a formulation that can be applied as a pour -on or a spot- on formulation but offers higher water DETAILED DESCRIPTION OF THE resistance and extended duration of efficacy . This will INVENTION decrease stress to the animals and avoid the labor and costs 25 associated with multiple pour -on applications . It will further In one aspect , the invention is a topical delivery formu avoid labor and costs associated with attaching and retriev - lation with one or more solvents to include saturated ali ing ear tags . phatic ketones, esters and alcohols . The invention further includes a water insoluble polymer alone or in combination SUMMARY OF THE INVENTION 30 with a water soluble polymer, and, optionally a plasticizer. Examples of solvents include , but are not limited to , The topical solution of the invention includes at least one methyl isobutyl ketone, butyl acetate , ethyl lactate, isopro active ingredient and a volatile solvent system that contains pyl alcohol or ethanol . A non - limiting example of a water at least one dissolved polymer. The solvent system is not insoluble polymer is vinyl acetate . Non - limiting examples of designed to maximize spreading , but instead , to have some 35 water soluble polymers include povidone, polyvinyl alcohol spreading and to evaporate shortly after dosing, leaving a or ethyl cellulose . The optional plasticizer may be an ali water- resistant film of polymer on the skin and hair . This phatic ester such as acetyl tributyl citrate . could consist of a contiguous film or a conglomerate of Veterinarily active ingredients , which include , but are not polymer particles adhering to hair and skin of an animal. limited to, acaricides , anthelmintics, antiparasitics, insecti After evaporation of the volatile solvent( s ) , the active ( s ) , 40 cides and insect repellants , may also be added to the entrapped into the polymer will diffuse out at a specified rate compositions of the invention . Antiparasitic agents can and will be carried by skin lipids of an animal. The active ( s ) include both ectoparasiticidal and endoparasiticidal agents . need to be able to dissolve not only in the volatile solvent These agents are well -known in the art ( see e . g . Plumb ' system , but also in the polymer . The rate of diffusion can be Veterinary Drug Handbook , 5th Edition , ed . Donald C . impacted by selection of solvents , their ratios , selection of 45 Plumb, Blackwell Publishing, ( 2005 ) or The Merck Veteri polymers , addition of a plasticizer ( s ) and its chemical com - nary Manual, 9th Edition , ( January 2005 ) and include but position , or by the skin lipids naturally occurring on skin . are not limited to acarbose , acepromazine maleate , acet The selection of excipients also will impact such formula - aminophen , acetazolamide , acetazolamide sodium , acetic tion properties as water resistance , run -off during dosing , acid , acetohydroxamic acid , acetyl cysteine , acitretin , acy and duration of efficacy . 50 clovir , albendazole , albuterol sulfate , alfentanil HCI, The invention provides for an increased duration of allopurinol, alprazolam , altrenogest , amantadine HCl, ami efficacy of a topical formulation through the use of a kacin sulfate , aminocaproic acid , aminopentamide hydrogen polymer dissolved in the formulation . As the formulation sulfate , aminophylline / theophylline, amiodarone HCl, ami dries on the surface ( either hair or skin ) , the active ingredient traz, amitriptyline HCl, amlodipine besylate , ammonium is entrapped in the resulting polymer matrix . The rate of 55 chloride , ammonium molybdenate, amoxicillin , amoxicillin , release of the active can be controlled by incorporating and clavulanate potassium , amphotericin B desoxycholate , adjusting the amount of a “ plasticizer ” (i . e ., a solvent that is amphotericin B lipid -based , ampicillin , amprolium HCI, fluid in the solidified polymer ) . The resultant polymer matrix antacids (oral ) , antivenin , apomorphione HCl, apramycin will then perform similarly to the traditional transdermal sulfate , ascorbic acid , asparaginase , aspiring , atenolol, ati patch or ear tag . 60 pamezole HC1, atracurium besylate , atropine sulfate , aurn In one aspect, the invention is a topical delivery formu - ofin , aurothioglucose , azaperone , azathioprine , azithromy lation with one or more solvents to include saturated ali - cin , baclofen , barbituates, benazepril HC1, betamethasone, phatic ketones, esters and alcohols . The invention further bethanechol chloride , bisacodyl, bismuth subsalicylate , includes a water insoluble polymer alone or in combination bleomycin sulfate , undecylenate , bromides , bro with a water soluble polymer, and , optionally a plasticizer. 65 mocriptine mesylate , budenoside , buprenorphine HCl, bus Examples of solvents include , but are not limited to , pirone HC1, busulfan , butorphanol tartrate , cabergoline , cal methyl isobutyl ketone, butyl acetate , ethyl lactate , isopro citonin salmon , calcitrol, saits , captopril , US 9 ,756 ,852 B2 carbenicillin indanyl sodium , , carboplatin , car - HC1, methazolamide , methenamine mandelate /hippurate , nitine, carprofen , carvedilol, cefadroxil , cefazolin sodium , methimazole , methionine , methocarbamol, methohexital cefixime , cefoperazone sodium , cefotaxime sodium , cefo - sodium , methotrexate , methoxyflurane , methylene blue , tetan disodium , cefoxitin sodium , cefpodoxime proxetil , methylphenidate, methylprednisolone , Hel , ceftazidime, ceftiofur sodium , ceftiofur HCI, ceftiaxone 5 metoprolol, metronidaxole , mexiletine HC1, mibolerlone , sodium , cephalexin , cephalosporins, cephapirin , charcoal midazolam HCl, milbemycin oxime, mineral oil, minocy (activated ), chlorambucil , chloramphenicol, chlordiazepox - cline HCl, misoprostol, mitotane , mitoxantrone Hel, mor ide , chlordiazepoxide + / - clidinium bromide , chlorothiazide , antel tartrate , morphine sulfate , moxidectin , naloxone HC1, chlorpheniramine maleate , HC1, chlorprop - mandrolone decanoate , naproxen , narcotic (opiate ) amide , chlortetracycline , chorionic (HCG ), 10 analgesics , neomycin sulfate, neostigmine , niacinamide , chromium , , ciprofloxacin , cisapride , cisplatin , nitazoxanide , nitenpyram , nitrofurantoin , nitroglycerin , citrate salts , clarithromycin , clemastine fumarate , clen - nitroprusside sodium , nizatidine , novobiocin sodium , nys buterol HC1, clindamycin , clofazimine , clomipramine HCl, tatin , octreotide acetate , olsalazine sodium , omeprozole , claonazepam , clonidine , cloprostenol sodium , clorazepate ondansetron , opiate antidiarrheals , orbifJoxacin , oxacillin dipotassium , clorsulon , cloxacillin , codeine phosphate , 15 sodium , oxazepam , oxfendazole , oxybutynin chloride , oxy colchicine , corticotropin (ACTH ) , cosyntropin , cyclophos - morphone HCI, oxytretracycline , oxytocin , pamidronate phamide , cyclosporine, HCI, cytarabine , disodium , pancreptipase , pancuronium bromide , paromo dacarbazine, dactinomycin /actinomycin D , dalteparin mycin sulfate , parozetine HCl, pencillamine , general infor sodium , , dantrolene sodium , dapsone , decoquinate , mation penicillins , penicillin G , penicillin V , potassium , deferoxamine mesylate , deracoxib , deslorelin acetate , des - 20 pentazocine , pentobarbital sodium , pentosan polysulfate mopressin acetate , desoxycorticosterone pivalate , detomi- sodium . pentoxifyiline , pergolide mesylate, phenobarbital, dine HC1, dexamethasone , dexpanthenol, dexraazoxane , phenoxybenzamine HCl, pheylbutazone , phenylephrine dextran , diazepam , diazoxide (oral ) , dichlorphenamide , HCl, phenypropanolamine HCl, sodium , phero dichlorvos, diclofenac sodium , dicloxacillin , diethylcarbam mones, parenteral phosphate , phytonadione/ vitamin K - 1 , azine citrate , (DES ), difloxacin HC1, 25 pimobendan , piperazine , pirlimycin HC1, piroxicam , poly digoxin , dihydrotachysterol (DHT ) , diltiazem HCl, dimen - sulfated glycosaminogiycan , ponazuril , potassium chloride , hydrinate , dimercaprol/ BAL , dimethyl sulfoxide , dinoprost pralidoxime chloride , praziquantel, prazosin HCl, predniso tromethamine , diphenylhydramine HC1, disopyramide phos - lone/ prednisone , primidone , procainamide HC1, procarba phate , dobutamine HC1, docusate , dolasetron mesylate , zine HC1, prochlorperazlne , propantheline bromide , propo , dopamine HC1, doramectin , doxapram HC1, 30 fol, HC1, protamine sulfate , pseudoephedrine doxepin HC1, doxorubicin HC1, doxycycline , edetate cal- HC1, psyllium hydrophilic mucilloid , pyrantel pamoate , cium disodium , calcium EDTA , edrophonium chloride, pyridostigmine bromide , pyrilamine maleate , pyrimeth enalapril , enoxaparin sodium , enrofloxacin , ephedrine sul amine, quinacrine HCl, quinidine, ranitidine HCl, rifampin , fate, epinephrine, epoetin / erythropoietin , eprinomectin , S - adenosyl- methionine (SAMe ) , saline/ hyperosmotic laxa epsiprantel, erythromycin , esmolol HC1, cypionate , 35 tive, selamectin , selegiline HCl, deprenyl , sertraline HCI, ethacrynic acid / ethacrynate sodium , ethanol ( alcohol) , sevelamer HC1, sevoflurane, silymarin /milk thistle , sodium etidronate sodium , etodolac , etomidate , euthanasia agents bicarbonate , sodium polystyrene sulfonate, sodium stibog w /pentobarbital , famotidine , fatly acids (essential / omega ), luconate , sodium sulfate , sodum thiosulfate , somatotropin , felbamate , fenbendazole , fentanyl, ferrous sulfate , fil - sotalol HCl, spectinomycin HC1, , , grastim , , fipronil, florfenicol, fluconazole, flucy - 40 streptokinase , streptozocin , succimer, succinylcholine chlo tosine , fludrocortisone acetate , flumazenil , flumethasone , ride , sucralfate, sufentanil citrate , sulfachlorpyridazine flunixin meglumine, fluorouracil ( 5 - FU ) , fluoxetine , flutica - sodium , sulfadiazine/ trimethroprim , sulfamethoxazole / sone propionate , fluvoxamine maleate, fomepizole ( 4 -MP ) , trimethoprim , sulfadimentoxine , sulfadimethoxine/ ormeto furazolidone, furosemide , gabapentin , gemcitabine HCI, prlm , sulfasalazine , taurine, tepoxaline , terbinafline HCI, gentamicin sulfate , glimepiride , glipizide, glucagon , gluco - 45 terbutaline sulfate , , tetracycline HCl, thiaben corticoid agents, glucosamine / chondroitin sulfate , gluta - dazole , thiacetarsamide sodium , thiamine HC1, thioguanine , mine , glyburide, glycerine ( oral) , glycopyrrolate , gonad thiopental sodium , thyrotropin , tiamulin , ticarcilin diso orelin , grisseofulvin , guaifenesin , halothane, hemoglobin dium , tiletamine HCl, zolazepam HCl, tilmocsin , tiopronin , glutamer - 200 (Oxyglobln ) , heparin , hetastarch , hyaluro - tobramycin sulfate , tocainide HCl, tolazoline HC1, telf nate sodium , hydrazaline HC1, hydrochlorothiazide , hydro - 50 enamic acid , topiramate , tramadol HCl, trimcinolone codone bitartrate , hydrocortisone , hydromorphone , acetonide , trientine HCl, , trimepraxine tartrate hydroxyurea , hydroxyzine, ifosfamide , imidacloprid , imido w / prednisolone , tripelennamine HCl, tylosin , urdosiol , val carb dipropinate , impenem - cilast ? ltin sodium , imipramine , proic acid , vanadium , vancomycin HCl, vasopressin , inamrinone lactate , insulin , interferon alfa - 2a ( human vecuronium bromide, verapamil HC1, vinblastine sulfate , recombinant ) , Iodide ( sodium / potassium ) , ipecac ( syrup ) , 55 vincristine sulfate , vitamin E / , warfarin sodium , , iron dextran , isoflurane , isoproterenol HCl, xylazine HCl, yohimbine HCl, zidovudine (AZT ) , isotretinoin , isoxsuprine HC1, itraconazole , ivermectin , acetate /zinc sulfate , zonisamide and mixtures thereof. kaolin / pectin , ketamine HC1, , ketoprofen , In one embodiment of the invention , pyrazole compounds ketorolac tromethamine , lactulose, leuprolide , levamisole , such as phenylpyrazoles , as described above ( e . g ., fipronil ) , levetiracetam , sodium , lidocaine HCl, linco - 60 are known in the art and are suitable actives alone or in mycin HC1, sodium , lisinopril , lomustine combination with other active compounds of the invention . (CCNU ) , lufenuron , lysine, , mannitol, marbo - Examples of such pyrazole compounds include but are not floxacin , mechlorethamine HCl, meclizine HCl, meclofe limited to those described in U . S . Pat . Nos . 6 ,001 , 384 ; namic acid ,medetomidine HCl, medium chain triglycerides , 6 ,010 , 710 ; 6 ,083 , 519 ; 6 ,096 , 329 ; 6 ,174 , 540 ; 6 ,685 , 954 medroxyprogesterone acetate , , melarsom - 65 6 , 998 , 131 ; 7 ,759 , 381 and 8 ,445 , 519 . Each is assigned to ine , melatonin , meloxican , melphalan , meperidine HC1, Merial, Ltd ., (Duluth , Ga. , USA ) and incorporated by ref mercaptopurine , meropenem , metformin HCl, methadone erence herein . (RS ) - 5 - amino - 1 - [ 2 ,6 -dichloro - 4 - (trifluorom US 9 , 756 , 852 B2 ethyl) phenyl] - 4 - (trifluoromethylsulfinyl ) - 1H - pyrazole - 3 4 ,310 , 519 to Albers - Schonberg et al. , and the 22 ,23 - dihydro carbonitrile (i . e ., fipronil ) , 1H -pyrazole -3 -carbonitrile , 1 -[ 2 , avermectin compounds are disclosed in Chabala et al ., U . S . Pat . No . 4 , 199 , 569 . Mention is also made of Kitano , U . S . 6 - dichloro - 4 - trifluoromethyl ) phenyl] - 5 -methyl - 4 Pat. No . 4 , 468, 390 , Beuvry et al. , U . S . Pat. No . 5 ,824 ,653 , [ ( trifluoromethyl )sulfinyl ] (i . e . , ML465 ), and 1- (2 -chloro -6 EP O 007 812 A1, U . K . Patent Specification 1 390 336 , EP fluoro -4 - trifluoromethylphenyl) -4 -dichlorofluoro 0 002 916 , and Ancare New Zealand Patent No . 237 086 , methylsulfinyl- 5 -methylpyrazole - 3 - carbonitrile ( 1 . e . , inter alia . Naturally occurring milbemycins are described in ML198 ) are specifically referenced . Aoki et al. , U . S . Pat . No . 3 , 950 ,360 as well as in the various In another embodiment of the invention , nodulisporic acid references cited in “ The Merck Index ” 12th ed . , S . Budavari, and its derivatives ( a class of known acaricidal, anthelmi- Ed . , Merck & Co ., Inc . Whitehouse Station , N . J . ( 1996 ) . nitic , anti - parasitic and insecticidal agents ) can be added to 10 Latidectin is described in the " International Nonproprietary the compositions of the invention . These compounds are Names for Pharmaceutical Substances ( INN ) ” , WHO Drug used to treat or prevent infections in humans and animals Information , vol. 17 , no . 4 , pp . 263 -286 , ( 2003 ) . Semisyn and are described , for example , in U . S . Pat . Nos. 5 , 399, 582 thetic derivatives of these classes of compounds are well known in the art and are described , for example , in U . S . Pat . and 5 , 962 ,499 . The composition can include one ormore of• 15 No . 5 ,077 ,308 , U . S . Pat. No. 4 ,859 ,657 , U . S . Pat. No. the known nodulisporic acid derivatives in the art , including 1 4 ,963 , 582 , U .S . Pat. No . 4 , 855 , 317 , U .S . Pat. No . 4 , 871 ,719 , all stereoisomers, such as those described in the literature U . S . Pat. No . 4 , 874 ,749 , U . S . Pat. No . 4 , 427 ,663 , U . S . Pat . cited above . No . 4 ,310 ,519 , U . S . Pat. No . 4 , 199, 569 , U . S . Pat . No . In another embodiment of the invention , one or more 5 , 055 , 596 , U . S . Pat . No . 4 , 973 ,711 , U . S . Pat. No . 4 ,978 ,677 , macrocyclic lactones , which act as an acaricide , anthel U . S . Pat. No . 4 ,920 , 148 and EP 0 667 054 . mintic agent and insecticide , can be added to the composi- 20 In another embodiment of the invention , the class of tions of the invention . The macrolides are well -known in the acaricides or insecticides known as insect growth regulators art . See e . g ., Macrolides Chemistry, pharmacology and ( IGRs) can also be added to the compositions of the inven clinical uses - edited by Bryskier et al. , published by Amette tion . Compounds belonging to this group are well known to Blackwell , ( 1993 ). Macrolides include, but are not limited the practitioner and represent a wide range of different to , 12 -membered ring macrolides ( e . g . methymycin , neom - 25 chemical classes. These compounds all act by interfering ethymycin , YC - 17 , litorin ) ; 14 -membered ring macrolides with the development or growth of the insect pests . Insect ( e . g . , erythromycin A - F , oleandomycin , sporeamicin , rox growth regulators are described , for example , in U . S . Pat. ithromycin , dirithromycin , flurithromycin , clarithromycin , No . 3 ,748 , 356 ; U . S . Pat. No . 3 , 818 ,047 ; U . S . Pat. No . 4 , 225 ,598 ; U . S . Pat. No . 4 , 798 , 837 ; U . S . Pat. No . 4 , 751, 225 , davercin ) ; 13 -membered ring macrolides ( e . g . , azithromy- EP 0179022 or UK 2140 010 as well as US Pat Nos cin ) ; 16 -membered ring macrolides (e . g ., josamycin , 6 , 096 , 329 and 6 ,685 , 954 (both assigned to Merial Ltd . , kitasamycin , spiramycin , midecamycin , rokitamycin , Duluth , Ga. ). Examples of IGRs suitable for use include but miokamicin ) and 17 -membered ring macrolides ( e . g ., are not limited to methoprene , pyriproxyfen , hydroprene , lankadicin ) . cyromazine , fluazuron , lufenuron , novaluron , pyrethroids , The macrocyclic lactones also include, but are not limited formamidines and 1 - ( 2 , 6 -difluorobenzoyl ) - 3 - ( 2 - fluoro - 4 to , avermectins , such as abamectin , dimadectin , doramectin , 3 (trifl uoromethyl) phenylurea . An anthelmintic agent that can emamectin , eprinomectin , ivermectin , latidectin , lepimectin , be combined with the compound of the invention to form a selamectin and milbemycins, such as milbemectin , milbe composition can be a benzene disulfonamide compound , mycin D , moxidectin and nemadectin . Also included are the which includes but is not limited to clorsulon ; or a cestodal 5 - oxo and 5 -oxime derivatives of said avermectins and agent, which includes but is not limited to praziquantel, milbemycins. Examples of combinations of arylpyrazole 40 pyrantel or morantel. An antiparasitic agent that can be combined with the compounds with macrocyclic lactones include but are not compound of the invention to form a composition can be a limited to those described in U .S . Pat . Nos . 6 ,426 , 333 ; biologically active peptide or protein including , but not 6 , 482, 425 ; 6 , 962, 713 and 6 , 998 ,131 - each assigned to limited to , depsipeptides, which act at the neuromuscular MerialThe, macrocyclic Ltd . (Duluth lactone , Ga. , USAcompounds ) . are known in the art 45 junction by stimulating presynaptic receptors belonging to and can easily be obtained commercially or through synthe the secretin receptor family resulting in the paralysis and sis techniques known in the art . Reference is made to the death of parasites. In one embodiment of the depsipeptide , widely available technical and commercial literature . For the depsipeptide is emodepside . avermectins , ivermectin and abamectin , reference may be An insecticidal agent that can be combined with the made, for example , to the work “ vermectin and Abamec - 50 compound of the invention to form a composition can be a tin ” . 1989 . by M . H . Fischer and H . Mrazik . William C . spinosyn ( e . g . spinosad ) or a substituted pyridylmethyl Campbell , published by Springer Verlag . , or Albers - Schon derivative compound such as imidacloprid . Agents of this berg et al. ( 1981) , “ Avermectins Structure Determination ” , class are described above and for example , in U . S . Pat . No . J . Am . Chem . Soc. , 103 , 4216 -4221 . For doramectin , “ Vet 4 , 742 ,060 or in EP 0 892 060 . It would be well within the erinary Parasitology ” , vol. 49, No . 1, July 1993 , 5 - 15 maymou hebe 3555 skill level of the practitioner to decide which individual consulted . For milbemycins, reference may be made , inter compound can be used in the inventive formulation to treat alia , to Davies H . G . et al ., 1986 , “ Avermectins and Milbe a particular infestation of an insect . mycins” , Nat. Prod . Rep . , 3 , 87 - 121 , Mrozik H . et al ., 1983 , Insect repellants , alone or in combination with the above, Synthesis of Milbemycins from Avermectins , Tetrahedron may also be considered actives in the present invention . Lett. . 24 . 5333 -5336 . U . S . Pat. No . 4 . 134 . 973 and EP 0677 60 Examples include pyrethroids such as allethrin , alphame 054 . thrin , bioresmethrin , byfenthrin , cycloprothrin , cyfluthirin , Macrocyclic lactones are either natural products or are decamethrin , cyhalothrin , cypermethrin , deJtamethrin , semi- synthetic derivatives thereof. The structure of the aver alpha -cyano - 3 - phenyl- 2 -methylbenzyl 2 , 2 -dimethyl - 3 -( 2 mectins and milbemycins are closely related , e. g ., by sharing chloro - 2 - trifluoro -methylvinyl ) cyclopropane- carboxylate , a complex 16 -membered macrocyclic lactone ring ; milbe - 65 fenpropathrin , fenfluthrin , fenvalerate, flucythrinate , flu mycins lack the glycosidic moiety of the avermectins . The methrin , fluvalinate , permethrin , resmethrin and tral avermectins are disclosed in U . S . Pat. No. omethrin . US 9 , 756 ,852 B2 10 In general, the pesticidal agent or repellant is included in polyoxyethylenated fatty acids or copolymers of eth a dose of between about 0 . 1 ug and about 10 mg. In one ylene oxide and of propylene oxide; embodiment of the invention , the pesticidal agent or repel ( f) amphoteric surfactants , such as substituted lauryl com lant is included in a dose of between about 1 ug and about pounds of betaine ; or 10 mg. In another embodiment of the invention , the pesti - 5 ( g ) a mixture of at least two of the compounds listed in cidal agent or repellant is included in a dose of about 5 to ( a ) - { f ) above . about 200 ug/ kg ofweight of animal. In yet another embodi In another embodiment of the invention , the formulation ment of the invention , the pesticidal agent or repellant is can also comprise an antioxidizing agent intended to inhibit included in a dose between about 0 . 1 to about 10 mg/ kg of oxidation in air . This agent may be present in a proportion weight of animal. In still another embodiment of the inven - 10 of about 0 . 005 to about 1 % ( w / v ) Alternatively , the antioxi tion , the pesticidal agent or repellant is included in a dose dizing agent may be present in a proportion of about 0 .01 to between about 0 . 5 to 50 mg/ kg . about 0 .05 % . Antioxidizing agents include , but are not The proportions, by weight, of the 1 - aryl - 5 - alkyl pyrazole limited to , butylated hydroxyanisole , butylated hydroxy compound and any additional pesticidal agent are, for toluene , ascorbic acid , sodium metabisulphite , propyl gal example , between about 5 / 1 and about 10 , 000 / 1 . However , 15 late , sodium thiosulphate or a mixture of not more than two one of ordinary skill in the art would be able to select the of the above . appropriate ratio of 1- aryl - 5 -alkyl pyrazole compound and Embodiments of the invention may also include colorants , the additional pesticidal agent for the intended host and use fragrances and pH stabilizers known in the art . Examples of thereof. colorants include , but are not limited to , titanium dioxide In another embodiment of the invention , the formulation 20 and iron oxide . A comprehensive list of acceptable colorants can be in ready - to - use solution form as is described in U . S . may be found at 37 CFR , Title 21, Part 74 . Colorants and pH Pat. No . 6 , 395 , 765, incorporated herein by reference . In stabilizers are conventional and known in the art. addition to the active ( s ) compound , the solution can contain The invention is also directed toward a method of treating a crystallization inhibitor. The crystallization inhibitor can an animal ( e . g . , a mammal ), against ectoparasitic infection be present in a proportion of about 1 to about 20 % ( w / v ) . 25 by administering an ectoparasiticidally effective amount of Alternatively, the crystallization inhibitor can be present in the composition of the invention . Mammals which can be a proportion of about 5 to about 15 % . In another embodi- treated include , but are not limited to , humans, cats , dogs , ment of the amount of crystallization inhibitor, the amount cattle , chickens , cows, deer, goats , horses, llamas, pigs , corresponds to the test in which 0 . 3 ml of a solution sheep and yaks . In one embodiment of the invention , the comprising 10 % ( w / v ) of 1 - aryl - 5 - alkyl pyrazole compound 30 mammals treated are humans , cats or dogs . in the liquid carrier and 10 % of the inhibitor are deposited In another embodiment for treatment against ectopara on a glass slide at 20° C . and allowed to stand for 24 hours . sites , the ectoparasite is one or more insect or arachnid The slide is then observed with the naked eye . Acceptable including those of the genera Ctenocephalides, Rhipicepha inhibitors are those whose addition provides for few ( e . g . , lus, Dermacentor , Ixodes, Boophilus, Ambylomma, Haema less than ten crystals ) or no crystal . 35 physalis , Hyalomma, Sarcoptes, Psoroptes , Otodectes , Cho Crystallization inhibitors which are useful for the inven - rioptes, Hypoderma . Damalinia , Linognathus , tion include but are not limited to : Haematopinus, Solenoptes , Trichodectes, and Felicola . ( a ) polyvinylpyrrolidone , polyvinyl alcohols , copolymers In another embodiment for the treatment against ectopara of vinyl acetate and of vinylpyrrolidone, polyethylene sites, the ectoparasite is from the genera Ctenocephalides , glycols , benzyl alcohol, mannitol, glycerol, sorbitol or 40 Rhipicephalus, Dermacentor, Ixodes and / or Boophilus . The polyoxyethylenated esters of sorbitan ; lecithin or ectoparasites treated include but are not limited to fleas , sodium carboxymethylcellulose ; or acrylic derivatives , ticks, mites mosquitoes , flies, lice , blowfly and combina such as methacrylates ; tions thereof. Specific examples include but are not limited ( b ) anionic surfactants , such as alkaline stearates ( e . g . , to cat and dog fleas ( Ctenocephalides felis, Ctenocephalides sodium , potassium or ammonium stearate ) ; calcium 45 sp . and the like ) , ticks ( Rhipicephalus sp . , Ixodes sp . , stearate or triethanolamine stearate ; sodium abietate ; Dermacentor sp . , Amblyoma sp . and the like) , and mites alkyl sulphates , which include but are not limited to (Demodex sp ., Sarcoptes sp . , Otodectes sp . and the like ), lice sodium lauryl sulphate and sodium cetyl sulphate ; ( Trichodectes sp ., Cheyletiella sp ., Lignonathus sp . , and the sodium dodecylbenzenesulphonate or sodium dioctyl like ) , mosquitoes ( Aedes sp . , Culex sp . , Anopheles sp ., and sulphosuccinate ; or fatty acids ( e . g . , coconut oil ) ; 50 the like ) and flies (Hematobia sp ., Musca sp ., Stomoxys sp . , ( c ) cationic surfactants , such as water - soluble quatemary Dematobia sp ., Cochliomyia sp . , and the like ). In yet another ammonium salts of formula N + R ' R " R "" R " " Y - , in embodiment for the treatment against ectoparasites, the which the R radicals are identical or different optionally ectoparasite is a flea and / or tick . hydroxylated hydrocarbon radicals and Y - is an anion Additional examples of ectoparasites include but are not of a strong acid , such as halide , sulphate and sulphonate 55 limited to the tick genus Boophilus , especially those of the anions , cetyltrimethylammonium bromide is one of the species microplus ( cattle tick ) , decoloratus and annulatus ; cationic surfactants which can be used ; myiases such as Dermatobia hominis (known as Berne in ( d ) amine salts of formula N + R 'R " R '" , in which the R Brazil ) and Cochliomyia hominivorax (greenbottle ) ; sheep radicals are identical or different optionally hydroxy - myiases such as Lucilia sericata , Lucilia cuprina (known as lated hydrocarbon radicals ; octadecylamine hydrochlo - 60 blowfly strike in Australia , New Zealand and South Africa ) . ride is one of the cationic surfactants which can be Flies proper, namely those whose adult constitutes the used ; paraSite , such as Haematobia irritans (horn fly ) : lice such as ( e ) non - ionic surfactants, such as optionally polyoxyeth - Linognathus vitulorum , etc . ; and mites such as Sarcoptes ylenated esters of sorbitan , e .g . , Polysorbate 80 , or scabici and Psoroptes ovis . The above list is not exhaustive polyoxyethylenated alkyl ethers ; polyethylene glycol 65 and other ectoparasites are well known in the art to be stearate , polyoxyethylenated derivatives of castor oil, harmful to animals and humans. These include , for example polyglycerol esters , polyoxyethylenated fatty alcohols , migrating dipterous larvae . US 9 , 756 ,852 B2 When an anthelmintic agent is added to the composition resistance is higher for formulations with polymers . Water of the invention , the composition can also be used to treat resistance of known solvent systems used in clinical in - vivo against endoparasites such as those helminths selected from studies A and B was evaluated and results are summarized the group consisting of Anaplocephala , Ancylostoma , in Table 1 Table 1 below shows water resistance of conven Anecator, Ascaris , Capillaria , Cooperia , Dipylidium , Diro - 5 tional pour -on formulations used in clinical studies A and B . filaria , Echinococcus, Enterobius , Fasciola , Haemonchus, Oesophagostumum , Osteriagia , Toxocara , Strongyloides, TABLE 1 Toxascaris , Trichinella , Trichuris , and Trichostrongylus. In another embodiment, the compounds of the invention in - vivo % ML465 in Duration of are administered in spot- on formulations. While not wishing 10 Efficacy Solutions, above 90 % to be bound by theory , it is believed that these formulations study w /v Solvent System efficacy (days ) work by gradual diffusion of active ( s ) encapsulated into the 3 . 0 30 % Tributyl acetyl citrate 17 polymer or blend of polymers that adhere to hair and skin Miglyol 840 AB 30 % Tributyl acetyl citrate 17 after evaporation of solvent( s ), and dissolution of the dose in 0. 5 5 % Polypropylene Glycol ( 15 ) the natural oils of the host ' s skin or fur. Thus, the polymer 15 stearyl ether becomes is a reservoir that stores and protects active ( s ) from Soybean Oil E 30 % Tributyl acetyl citrate 17 environmental stress, such as rain , for the duration of the B 3 % Polypropylene Glycol ( 15 ) treatment period , and active ( s ) continues to gradually diffuse stearyl ether from the polymer and replenish the therapeutic amounts of 8 . 5 % Isopropyl palmitate active (s ) washed off during rain or removed by other means 20 7 % Isobutene H25 ( e . g ., licking , rubbing ) . From there , the active agent( s ) Soybean Oil B 1 . 0 30 % Tributyl acetyl citrate 24 distribute around the host ' s body through the sebaceous 3 % Polypropylene Glycol ( 15 ) glands of the skin . The therapeutic agent also remains in the stearyl ether sebaceous glands. 10 % Isopropyl palmitate In one embodiment of the location of administration , a 25 7 % cetearyl octanoate single formulation containing the active agent in a substan 10 % butyl stearate tially liquid carrier and in a form which makes possible a Soybean Oil single application , ( e . g ., as a pour - on or can be applied as a spot- on at one or multiple locations of the animal' s body ) Trials A and B with traditional formulations containing will be administered to the animal over a localized region of 30 ML465 did not result in a desired duration of efficacy due to the animal, e . g . , between the two shoulders or along the the impact of water exposure during rains which occur spine . The invention is further described by the following randomly and have highly variable intensity . It can be seen non - limiting examples which further illustrate the invention , that the amount of ML465 washed off is at , or below , 10 % and are not intended , nor should they be interpreted to , limit of the applied dose , indicating a sharp decrease upon expo the scope of the invention . 35 sure to water. This was not sufficient to support thirty days In one application of the invention , Haematobia irritans efficacy duration . Thus , efficacy may depend on resistance of ( L . , i . e . , horn fly ) , is a pest of cattle that causes significant the solvent system to water exposure . economic losses estimated at more than $ 1 billion in the The in - vivo studies of Table 1 were followed with in -vitro United States annually . Horn fly infestation leads to studies conducted to assess water resistance of “ conven decreased milk production , decreased weaning weights of 40 tional” solvent systems. Conventional pour- on solvent for calves, and decreased weight gains on growing cattle . mulations described below were tested using ML465 as the (Domingues , L . N ., et al. , Discovery of the Rdl mutation in active under exposure to water for 20 and 40 minutes. association with a cyclodiene resistant population of horn flies , Haematobia irritans (Diptera : Musidae ). Vet . Parasi TABLE 2 tol. (2013 ) ) . In - lab Water Resistance ( % ML465 Current commercially available topical solutions to con Removed after Water Exposure (n = 2 )) trol horn fly population on cows provide limited duration of protection lasting from several days to about two weeks . Description of Solvent System 20 min 40 min Current treatments further require frequent re -application 30 % Tributyl acetyl citrate due to a wash -off after exposure to environmental conditions 50 Miglyol 840 2 . 4 % 5 . 2 % such as rain . Extension of efficacy to one month or longer 30 % Tributyl acetyl citrate 7 . 5 % 10 . 1 % will provide continuous protection against the horn fly with 5 % PPG - 15 stearyl ether Soybean oil less frequent applications . Fewer applications will be less 30 % Tributyl acetyl citrate 5 . 2 % 7 . 3 % stressful for the animals and less time and labor consuming 5 % PPG - 15 stearyl ether for the farmers . This may be accomplished by using active 55 6 % Isobutene H25 ingredients of superior efficacy, by using an enhanced deliv Soybean Oil 30 % Tributyl acetyl citrate 8 . 8 % 9 . 2 % ery mechanism , or both . 5 % PPG - 15 stearyl ether Although many different actives may work with the 10 % Isopropyl palmitate formulation of the invention , 1H -pyrazole - 3 - carbonitrile , 10 % ceteary octanote 1 - [ 2 , 6 -dichloro - 4 - ( trifluoromethyl) phenylbenv11] -. 5 -methyl - . 4a -. 6060 10 % butyl stearate [ (trifluoromethyl ) sulfinyl ] ( i. e ., ML465) is the compound Soybean Oil used to test topical formulations for control of horn fly on cows for a duration of one month or longer. Laboratory data indicate that ML465 is washed off after Water Resistance repeated exposure to water for all formulations tested . It In - vivo and in - vitro studies were conducted to compare 65 means that with each rainfall , of random duration and wash - off resistance of formulations prepared with lipophilic intensity , the concentration of ML465 on the skin will solvents and with polymers. Results indicate that a wash -off gradually decrease . US 9 , 756 , 852 B2 13 14 Next, the water resistance of the inventive solvent sys - adhere to hair or skin carrying an active that is entrapped in tems was tested in vitro . Table 3 shows the percentage of the polymer. The theraputic effect is achieved by diffusion of ML465 active lost upon exposure to water for 40 minutes . the active (s ) out of the polymer and blending with the lipids The formulation of the invention lowered ( i. e ., improved ) present on an animal' s skin that will carry it to cover the the percentage of ML465 removed after exposure to water 5 animal' s body . The degree of spreading of the formulation compared with the conventional solvent systems in Tables 1 can be controlled through the selection of solvents and and 2 . spreading agents . Surprisingly , the addition of isopropanol to methyl isobutyl ketone during solution preparation TABLE 3 10 resulted in an equal or even greater rate of API diffusion out In - lab Water Resistance of the API/ polymer mixture compared to API/ polymer mix Sample Solvent systems with ( % ML 465 Removed after 40 ture with addition of a plasticizer Isopropanol is not con ID 1 % w / w ML465 min . water exposure ( n = 2 ) ) sidered to be a traditional plasticizer for the polymer . It is 36 Methyl isobutyl ketone + 2 . 3 % postulated that its effectmay be on the physical structure of 10 % Polyvinyl Acetate + 15 the polymer film ( such as creating additional porosity ) . The Isopropanol concentration of isopropanol can be below , equal or greater than concentration of polymer , with the upper limit being a The entrapment of an active into the polymer and con solubility of polymer/ polymer combination in a solvent tinuous diffusion of an active out of the polymer will ensure system . Polyvinyl acetate does not dissolve in isopropanol, protection from environmental conditions such as rain , and 20 therefore isopropanol cannot replace methyl isobutyl ketone continuous replenishment and presence of an active on skin completely as there should be a sufficient amount of methyl to provide treatment for the duration of the desired treatment isobutyl ketone for polymer to dissolve . period . Lipids present on animal skin will act as a carrier and will also be continuously replenished by the animal . This approach can be utilized to topically deliver various The rate of diffusion can be controlled through the com - 25 actives to production animals such as cows, sheep , swine , position of the polymer part of the formulation , such as use horses , or companion animals, such as dogs and cats, and of a single polymer, blends of various polymers, or polymers others to protect against external parasites ( e . g . , fleas , ticks , of various molecular weights . Furthermore , the rate of mites, flies, etc . ) or internal parasites . diffusion can also be controlled by addition of a plasticizer Several embodiments of the invention are given in the in varying compositions and amounts. The plasticizer can be 30 following examples . an external agent or the sebacious lipids naturally present on the skin . This formulation for topical delivery of a pharmaceutical EXAMPLE 1 active ingredient is through the application of a liquid formulation with a solvent system consisting of a single 35 volatile solvent or a combination of volatile solvents , a Ingredients Function % w / w polymer or a combination of polymers, one or several ML465 Active 4 . 0 actives , and optionally a plasticiser or a combination of Polyvinyl acetate MW 100000 Polymer 14 . 4 plasticisers. The examples of solvent systems tested are methyl isobutyl ketone Solvent QS to 100 % presented below . It should be possible for one skilled in the 40 - art to create additional examples that would broaden the classes of materials that could be utilized . Solvents envi- Process: add methyl isobutyl ketone, in the amount of about sioned by the present invention include a saturated aliphatic 40 % of the weight to be prepared , into the container that can ketone ( e . g ., methyl isobutyl ketone ) or an ester ( e . g ., butyl be tightly closed during preparation of formulation ; add acetate or ethyl lactate ). These solvents could further be 45 polymer and mix until it dissolves , about 2 - 3 hours ; add combined with , for example , isopropyl alcohol or ethanol. ML465 , mix until dissolved ; QS 100 % with methyl isobutyl Polymers envisioned by the present invention include at ketone, mix . Make sure the container is tightly closed to least a water insoluble polymer ( e . g . , a polyvinyl acetate of prevent evaporation of solvent. varying molecular weights ) that may be combined with water soluble polymers ( e . g ., povidones , polyvinyl alcohol 50 or ethyl cellulose ). EXAMPLE 2 Optionally , the formulation of the present invention may include an external aliphatic ester plasticizer ( e . g ., acetyl tributyl citrate ), fragrances and coloring agents . It should be noted that isopropanol may be a solvent or a 55 - Ingredients Function % w / w plasticizer. Neither polymer nor ML465 dissolve in isopro ML465 Active 4 . 0 Polyvinyl acetate MW 100000 Polymer 7 . 2 panol. It was added initially to reduce the strong odor of Polyvinyl acetate MW 50000 Polymer 7 .2 methyl isobutyl ketone . Surprisingly, it was observed that methyl isobutyl ketone Solvent QS to 100 % addition of isopropanol impacts the rate of release ofML465 from the matrix , thus making isopropanol a plasticizer in this 60 case. For other actives that either can be miscible with or Process: add methyl isobutyl ketone, in the amount of about dissolve in isopropanol, it can be a solvent. 40 % of the weight to be prepared , into the container that can After dosing , the liquid formulation does not have to be tightly closed during preparation of formulation ; add spread to cover a body of an animal like a conventional polymers and mix until it dissolves , about 23 hours ; add topical formulation . À volatile solvent( s ) evaporates faster, 65 ML465 , mix until dissolved ; QS 100 % with methyl isobutyl leaving a polymer matrix patch that may not be evenly ketone , mix . Make sure the container is tightly closed to distributed around an application spot. The polymer will prevent evaporation of solvent. US 9, 756 ,852 B2 15 16 EXAMPLE 3 EXAMPLE 6

Ingredients Ingredients Function % w / w Function % w / w ML465 Active 4 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 ML465 Active 4 . 0 Isopropanol Additive 8 . 5 Polyvinyl acetate MW 100000 Polymer 14 . 4 Acetyl tributyl citrate Plasticizer 2 .0 Isopropanol Additive 25 . 0 10 methyl isobutyl ketone Solvent QS to 100 % methyl isobutyl ketone Solvent QS to 100 % Process : add methyl isobutylketone , in the amount of about 55 % of the weight to be prepared , into the container that can Process : add methyl isobutyl ketone , in the amount of about be tightly closed during preparation of formulation ; add 40 % of the weight to be prepared , into the container that can polymer and mix until it dissolves , about 2 - 3 hours ; add be tightly closed during preparation of formulation ; add ML465 , mix until dissolved ; add acetyl tributyl citrate ; polymer and mix until it dissolves, about 2 - 3 hours ; add slowly add isopropanol — whilte flakes will be formed , the ML465, mix until dissolved ; slowly add isopropanol — remaining methyl isopropyl ketone can be added at the same whilte flakes will be formed , continue to mix until flakes 2 time as addition of isopropanol, continue to mix until flakes dissolve and solution is clear , can add remaining methyl dissolve and solution is clear , can add remaining methyl isopropyl ketone and mix until solution is clear. Make sure isopropyl ketone at the time of and mix until solution is the container is tightly closed to prevent evaporation of clear. Make sure the container is tightly closed to prevent solvent. evaporation of solvent . 25 EXAMPLE 4 EXAMPLE 7

30 Ingredients Function % w / w Ingredients Function % w / w ML465 Active 4 . 0 ML465 Active 4 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 Isopropanol Additive 25 methyl isobutyl ketone Solvent QS to 100 % methyl isobutyl ketone Solvent QS to 100 % 35 – Process: add methyl isobutyl ketone, in the amount of about Process : add methyl isobutyl ketone , in the amount of 50 % of the weight to be prepared , into the container that can about 55 % of the weight to be prepared , into the container be tightly closed during preparation of formulation ; add that can be tightly closed during preparation of formulation ; 40 polymer and mix until it dissolves , about 2 - 3 hours ; add add polymer and mix until it dissolves, about 2 - 3 hours ; add ML465 , mix until dissolved ; slowly add isopropanol - white ML465 , mix until dissolved ; QS 100 % with methyl isobutyl flakes will be formed , continue to mix until flakes dissolve ketone, mix . Make sure the container is tightly closed to and solution is clear, the remaining methyl isopropyl ketone prevent evaporation of solvent. can be added at the same time as addition of isopropanol, and mix until solution is clear . Make sure the container is EXAMPLE 5 tightly closed to prevent evaporation of solvent. EXAMPLE 8 50 Ingredients Function % w / w ML465 Active 4 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 Ingredients Function % w / w Isopropanol Additive 8 . 5 methyl isobutyl ketone Solvent QS to 100 % 55 ML465 Active 4 . 0 Polyvinyl acetate MW 100000 Polymer 14 . 0 Acetyl tributyl citrate Plasticizer 3 . 0 Process : add methyl isobutyl ketone , in the amount of about methyl isobutyl ketone Solvent 100 % 55 % of the weight to be prepared , into the container that can be tightly closed during preparation of formulation ; add 60 Process : add methyl isobutyl ketone, in the amount of about polymer and mix until it dissolves, about 2 - 3 hours ; add 50 % of the weight to be prepared , into the container that can ML465 , mix until dissolved ; slowly add isopropanol be tightly closed during preparation of formulation ; add whilte flakes will be formed , continue to mix until flakes polymer and mix until it dissolves , about 2 - 3 hours ; add dissolve and solution is clear, can add remaining methyl ML465 , mix until dissolved ; add acetyl tributyl citrate and isopropyl ketone at the same time as isopropanol and mix 65 the remaining methyl isopropyl ketone and mix . Make sure until solution is clear . Make sure the container is tightly the container is tightly closed to prevent evaporation of closed to prevent evaporation of solvent. solvent. US 9, 756 ,852 B2 17 18 EXAMPLE 9 EXAMPLE 12

Ingredients Function % w / w Ingredients Function % w / w Permethrin Active 10 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 Permethrin Active 10 . 0 Tributyl acetyl citrate Plasticizer 3 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 methyl isobutyl ketone Solvent QS to 100 % methyl isobutyl ketone Solvent QS to 100 % 10 Process : add methyl isobutyl ketone , in the amount of about 50 % of the weight to be prepared , into the container that can Process : add methyl isobutyl ketone , in the amount of about be tightly closed during preparation of formulation ; add 65 % of the weight to be prepared , into the container that can polymer and mix until it dissolves , about 2 - 3 hours ; add be tightly closed during preparation of formulation : add 15 permethrin , mix ; add tributyl acetyl citrate and the remain polymer and mix until it dissolves , about 2 - 3 hours ; add ing methyl isopropyl ketone and mix . Make sure the con permethrin and mix ; QS 100 % with methyl isobutyl ketone , tainer is tightly closed to prevent evaporation of solvent. mix . Make sure the container is tightly closed to prevent EXAMPLE 13 evaporation of solvent. 20

EXAMPLE 10 Ingredients Function % w / w Permethrin Active 10 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 25 Tributyl acetyl citrate Plasticizer 1 . 5 Ingredients Function % w / w methyl isobutyl ketone Solvent QS to 100 %

Permethrin Active 10 . 0 Process: add methyl isobutyl ketone , in the amount of about Polyvinyl acetate MW 100000 Polymer 20 . 0 50 % of the weight to be prepared , into the container that can 30 be tightly closed during preparation of formulation ; add Isopropanol Additive 15 . 0 polymer and mix until it dissolves, about 2 - 3 hours ; add methyl isobutyl ketone Solvent QS to 100 % permethrin , mix ; add tributyl acetyl citrate and the remain ing methyl isopropyl ketone and mix . Make sure the con tainer is tightly closed to prevent evaporation of solvent. Process : add methyl isobutylketone , in the amount of about 35 50 % of the weight to be prepared , into the container that can EXAMPLE 14 [ DID NOT PREPARE WITH be tightly closed during preparation of formulation ; add ACTIVE , BUT PREPARED WITHOUT ACTIVE ] polymer and mix until it dissolves, about 2 - 3 hours ; add permethrin , mix ; slowly add isopropanol — white flakes will be formed , continue to mix until flakes dissolve and solution 40 Ingredients Function % w / w is clear , the remaining methyl isopropylketone can be added ML465 Active 4 . 0 at the same time as addition of isopropanol , and mix until Polyvinyl acetate MW 100000 Polymer 43. 0 solution is clear. Make sure the container is tightly closed to methyl isobutyl ketone Solvent QS to 100 % prevent evaporation of solvent. 45 Process: add methyl isobutyl ketone, in the amount of about 50 % of the weight to be prepared , into the container that can EXAMPLE 11 be tightly closed during preparation of formulation ; add polymer and mix until it dissolves , about 2 - 3 hours ; add ML465 , mix until dissolved ; add the remaining methyl 50 isopropylketone and mix . Make sure the container is tightly Ingredients Function % w / w closed to prevent evaporation of solvent. Permethrin Active 10 . 0 Polyvinyl acetate MW 100000 Polymer 15 . 0 EXAMPLE 15 Isopropanol Additive 20 . 0 methyl isobutyl ketone Solvent QS to 100 % 55 Ingredients Function Process : add methyl isobutyl ketone , in the amount of about % w / w ML465 Active 4 . 0 50 % of the weight to be prepared , into the container that can Polyvinyl acetate MW 50000 Polymer 15 . 0 be tightly closed during preparation of formulation ; add 6 Acetyl tributyl citrate Plasticizer 3 . 0 polymer and mix until it dissolves , about 2 - 3 hours ; add methyl isobutyl ketone Solvent OS to 100 % permethrin , mix ; slowly add isopropanol — white flakes will be formed , continue to mix until flakes dissolve and solution Process : add methyl isobutyl ketone, in the amount of about is clear, the remaining methyl isopropylketone can be added 50 % of the weight to be prepared , into the container that can at the same time as addition of isopropanol, and mix until 65 be tightly closed during preparation of formulation ; add solution is clear. Make sure the container is tightly closed to polymer and mix until it dissolves , about 2 -3 hours ; add prevent evaporation of solvent . ML465 , mix until dissolved ; add acetyl tributyl citrate and US 9 , 756 , 852 B2 19 20 the remaining methyl isopropyl ketone and mix . Make sure mix until solution is clear. Make sure the container is tightly the container is tightly closed to prevent evaporation of closed to prevent evaporation of solvent. solvent. EXAMPLE 19 EXAMPLE 16 (DID NOT PREPARED EXACTLY 5 WITH PVAC MW 50000 , BUT PREPARED WITH MW 100000 ) Ingredients Function % w / w ML465 Active 4 . 0 10 Polyvinyl acetate MW 100000 Polymer 13 . 0 Ingredients Function % w / w Kollidon SR Polymer 1 . 4 Isopropanol Additive 25 . 0 ML465 Active 4 . 0 methyl isobutyl ketone Solvent QS to 100 % Polyvinyl acetate MW 50000 Polymer 15 . 0 Acetyl tributyl citrate Plasticizer 3 . 0 methyl isobutyl ketone Solvent QS to 100 % 15 Process : add methyl isobutyl ketone , in the amount of about 50 % of the weight to be prepared , into the container that can be tightly closed during preparation of formulation ; add Process : add methyl isobutylketone , in the amount of about polyvinyl acetate MW 100000 and mix until it dissolves , 50 % of the weight to be prepared , into the container that can about 2 - 3 hours ; add ML465 , mix until dissolved ; slowly be tightly closed during preparation of formulation ; add 2030 add isopropanol — white flakes will be formed , continue to polymer and mix until it dissolves, about 2 - 3 hours ; add mix until flakes dissolve and solution is clear, add Kollidon ML465 , mix until dissolved ; add acetyl tributyl citrate and SR and mix until dissolved ; the remaining methyl isopropyl the remaining methyl isopropyl ketone and mix . Make sure ketone can be added at the same time as addition of Kollidon the container is tightly closed to prevent evaporation of SR , mix until solution is clear. Make sure the container is solvent . 25 tightly closed to prevent evaporation of solvent. EXAMPLE 17 EXAMPLE 20 FILM MADE FROM THIS SOLUTION CRYSTALLIZED

30 Ingredients Function % w / w Ingredients ML465 Active 4 . 0 Function % w / w Polyvinyl acetate MW 50000 Polymer 15 . 0 ML465 Active 4 . 0 Isopropanol Additive 25 . 0 Polyvinyl acetate MW 100000 Polymer 20 . 0 methyl isobutyl ketone Solvent QS to 100 % 3535 Isopropanol Additive 8 . 0 Acetyl tributyl citrate Plasticizer 12 . 5 Process : add methyl isobutyl ketone , in the amount of about methyl isobutyl ketone Solvent QS to 100 % 50 % of the weight to be prepared , into the container that can be tightly closed during preparation of formulation : add Process : add methyl isobutylketone , in the amount of about polymer and mix until it dissolves , about 2 - 3 hours : add 40 50 % of the weight to be prepared , into the container that can ML465 , mix until dissolved ; slowly add isopropanol — white be tightly closed during preparation of formulation ; add flakes will be formed , continue to mix until flakes dissolve polymer and mix until it dissolves, about 2 - 3 hours ; add and solution is clear, the remaining methyl isopropyl ketone ML465 , mix until dissolved ; add acetyl tributyl citrate and can be added at the same time as addition of isopropanol. mix ; slowly add isopropanol — white flakes will be formed , mix until solution is clear. Make sure the container is tightly 45 continue to mix until flakes dissolve and solution is clear ; the remaining methyl isopropyl ketone can be added at the same closed to prevent evaporation of solvent. time as addition of isopropanol. Make sure the container is EXAMPLE 18 tightly closed to prevent evaporation of solvent. 50 EXAMPLE 21 FILM MADE FROM THIS SOLUTION CRYSTALLIZED Ingredients Function % w / w ML465 Active 4 . 0 Polyvinyl acetate MW 50000 Polymer . 2 55 Ingredients Function % w / w Polyvinyl acetate MW 100000 Polymer 7 . 2 Isopropanol Additive 25 . 0 ML465 Active 4 . 0 methyl isobutyl ketone Solvent QS to 10000 % Polyvinyl acetate MW 100000 Polymer 14 . 4 Isopropanol Additive 22 . 0 Acetyl tributyl citrate Plasticizer 5 . 0 Process : add methyl isobutylketone , in the amount of about 60 methyl isobutyl ketone Solvent QS to 100 % 50 % of the weight to be prepared , into the container that can be tightly closed during preparation of formulation ; add Process : add methyl isobutyl ketone, in the amount of about polymers and mix until it dissolves, about 2 - 3 hours ; add 50 % of the weight to be prepared , into the container that can ML465 , mix until dissolved ; slowly add isopropanol — white be tightly closed during preparation of formulation ; add flakes will be formed , continue to mix until flakes dissolve 65 polymer and mix until it dissolves, about 2 - 3 hours ; add and solution is clear , the remaining methyl isopropyl ketone ML465 , mix until dissolved ; add acetyl tributyl citrate and can be added at the same time as addition of isopropanol, mix ; slowly add isopropanol — white flakes will be formed , US 9 , 756 , 852 B2 21 22 continue to mix until flakes dissolve and solution is clear ; the 5 . The formulation of claim 1 , wherein the polyvinyl remaining methyl isopropyl ketone can be added at the same acetate is polyvinyl acetate MW 100 , 000 . time as addition of isopropanol. Make sure the container is 6 . The formulation of claim 1, wherein the polyvinyl tightly closed to prevent evaporation of solvent. acetate is polyvinyl acetate MW 50 ,000 . What is claimed is : 1 . A topical delivery formulation in the form of a solution , 5 7. The formulation of claim 1 , wherein the water soluble which comprises: of a solution , polymer is a povidone . at least one veterinary active ingredient having ectopara 8 . The formulation of claim 1 , wherein the water soluble siticidal activity ; polymer is polyvinyl alcohol. a volatile solvent system containing at least one dissolved 10 9 . The formulation of claim 1 , wherein the water soluble polymer, polymer is ethyl cellulose . wherein said volatile solvent system comprises one or 10 . The formulation of claim 1 , wherein the optional more solvent ( s ) selected from the group consisting of plasticizer is an aliphatic ester. saturated aliphatic ketones , esters and alcohols, and 11 . The formulation of claim 10 , wherein the aliphatic wherein the volatile solvent represents from about 50 15 ester is acetyl tributyl citrate . to about 94 % w / w of the composition ; 12 . The formulation of claim 1 , wherein the water wherein said polymer comprises a water insoluble insoluble polymer is from about 5 % to about40 % w / w of the polymer that is polyvinyl acetate , alone or in com composition . bination with a water soluble polymer ; and 13. The formulation of claim 1, wherein the water soluble optionally a plasticizer ; 20 polymer is from about 5 % to about 40 % w /w of the wherein after dosing , evaporation of the volatile solvent composition . system provides a water resistant polymer matrix in which 14 . The composition of claim 1 , wherein the plasticizer is the veterinary active ingredient is entrapped . from about 0 . 5 % to about 5 % w / w of the composition . 2 . The formulation of claim 1 , wherein the solvent is methyl isobutyl ketone . 25 15 . A method for the therapeutic and/ or prophylactic 3 . The formulation of claim 1 , wherein the solvent is butyl treatment of an animal against ectoparasitic infections of acetate . said animal comprising administering to the animal a topical 4 . The formulation of claim 1 ,wherein the solvent is ethyl deliverydeli formulation according to claim 1 . lactate . * * * * *