AU595225B2 - Pyrethroid-containing parasiticidal composition - Google Patents

Description

9--AI 6 1 2 6 3 8 6 PIW WORLD INTELLECTUAL PROPERTY ORGANIZATION A International Bureau INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 A01N 25/02, A61K 31/425 AO1N 53/00, 43/90 (11 Al (43 (21) International Application Number: PCT/GB86/00356 (22) International Filing Date: (31) Priority Application Number: (32) Priority Date: (33) Priority Country: 19 June 1986 (19.06.86) 8515459 1) International Publication Number: WO 86/ 07525 3) International Publication Date: 31 December 1986 (31.12.86) (81) Designated States: AT (European patent), AU, BE (European patent), BR, CF (OAPI patent), CG (OAPI patent), CH (European patent), CM (OAPI patent), DE (European patent), DK, FI, FR (European patent), GA (OAPI patent), GB (European patent), HU, IT (European patent), JP, KP, LK, LU (European patent), MC, MG, ML (OAPI patent), MR (OAPI patent), vMW, NL (European patent), NO, RO, SE (Europein patent), SN (OAPI patent), SU, TD (OAPI paten TG (OAPI patent), US.

Published With international search report.

Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments.

19 June 1985 (19.06.85)

GB

(71)Applicant (for all designated States except US): RO- BERT YOUNG COMPANY LIMITED [GB/GB]; Cranstonhill Chemical Works, Elliot Street, Glasgow G3 8JT (GB).

(72) Inventor; and Inventor/Applicant (for US only) GALBRAITH, Andrew, Rennie [GB/GB]; 13 Lovat Avenue, Bearsden, Glasgow (GB).

(74) Agent: MARCH, Gary, Clifford; Herbert J.W. Wildbore, Wardrobe Court, 146a Queen Victoria Street, London EC4V 5AT (GB).

L FEB

I

AUSTRALIAN

NJ On 0, CL 1 3 JAN '987 PATENT OFFICE 4 (54) Title: PYRETHROID-CONTAINING PARASITICIDAL COMPOSIAfU (57) Abstract (tin 03( Pour-on compositions for simultaneously controlling ecto- and endo-parasites on e.g. sheep and cattle comprise: (i) salt of levamisole and/or tetramisole; (ii) at least one pyrethroid, in a carrier system comprising (iii) water; (iv) at least one organic water-miscible cosolvent and optionally at least one organic water-immiscible solvent. The presence of (ii) appears to synergistinally improve the performance of and by selection of (iv) and skin damage or irritation can be minimised. should be present in an anthelmintically effective amount and (ii) in an insecticidally effective amount.

595225 *i 12 WO 86/07525 PCT/GB86/00356 -1- Pyrethroid-containing Parasticidal Compositions This invention concerns pyrethroid-containing compositions for controlling ectoparasties such as lice, keds, mites, ticks, fleas and nuisance fly and endoparasites such as helminths including gut and lungworms which may infest non-human animals. More specifically the invention is concerned with aqueous compositions containing at least one synthetic (light-stable) pyrethroid insecticide and at least one anthelmintic agent* The present compositions may be provided in a form suitable for subsequent pour-on or spot-on application to the skin or fleece of a non-human animal according to well known techniques. They may, most conveniently, comprise solutions of the active ingredients.

The principal use of the compositions is for simultaneously controlling endoparasites and ectoparasites in sheep and/or cattle, As such, pour-on compositions are provided which can confer dtal control, rendering separate treatments for ecto- and endo-parasites unnecessary.

Tetramisole, 2,3,5,6 -tetrahydro-6-phenylimidazo thiazole and its laevo isomer levamisole are known to be effective Santhelmintic agents. Tetramisole is a racemic mixture of the D- and L- isomers and the activity against helminths has been shown to be derived mainly or almost entirely from levamisole. Tetramisole and levamieale are described in GB-At- 489.

GB-A-1464 552 is concerned with a method of using tetramisole and/or levamisole by application to the skin of an anik i. According to the teaching,the salts should be avoided due to reduced efficacy and water is stated tp'be an ineffective carrier for effecting passage of the i active ingredient through the skin, a pre-requisite to helmintic control.

SSUBSTITUTE

SHEET

i I 1._q II I W oo .~r WO 86/07525 PCT/GB86/o0035s .2- Anthelmintic compositions based on conventional organic solvents have caused skin irritation or damage in the treated animal.

GB-A-2 095 107 discloses anthelmintic compositions having reduced skin irritation problems.

Synthetic pyrethroids as disclosed in GB-A-1 413 491 are known to be powerful insecticides suitable for ectoparasite control on nonhuman animals.

The term "pyrethroid" as used through the description and claims is meant to include one or more compounds including geometrical and stereochemical isomers according to the formula I 0 -CH -0 (I) wherein Mis-CO- 2o CO C CH

CH

3

CH

3 CH -CH CH c

CH

3

CH

3 CH 3 CH3 II C 1 I 'X 2 X4 IV Iv or CO CH R 1 2H

CH

CH3 CH3, ii -I w INTERNATIONAL SEARCH REPORT Inlernational Applicaton No PCT/GB 86/00356 CLASSIFICATION OF SUBJECT MATTER (it several casslf1cation Symbols aoply. Indicate ail) 1 According to International Patent Classification (1PC) ar to both National Classification and IPC IPC4 A 01 N 25/02 A 61 K 31/425 A n IPC :A 01 N1 25/02: A 61 K 31142 I/A Alr hi rPnn aln r ~1 WO 86/07525 PCT/GB86/00356 -3and wherein X Ito X 4axe independently selected from halo,

(C

1

C

4 )-alkyl, halogen-substituted (C 1 C 4 )-alkyl, and halogen-substituted phenyl; X is -H or halo; R1is H or cyano; and R2is haloge'n-substituted phenyl.

Particularly preferred compounds are presented in Tables 1to 3.

TABLE 1 M CO H x 2 CH CH3 No. XI X2x3 X4 5 1 trivial namne 1 Cl Cl 1 H H permethrin 2 CH 3 CH 3 H H phenothrin 3 Br Br R CN deltamethrin 4 C1 c1 H CN cypermethrin Cl CF 3 H CN cyhalothrin 6 CI C1 F CN flumethirin 7 Cl Cl 1 F CN :'Iuthrin 8 CH CH -1 CN oyphenothrin WO 86/07525 PCT/GB86/00356 -4 TABLE 2' M MmCO -CH -x CIII) c x3 x4 C3 CH3 ITO. X 1 x 2 x 3

X

4 x 5 R tiilnm 9 Br Br Br Br H CNT tralofetb~in Cl Cl Br Br H CIT tralocythrin TABLE 3 m CO -CH -R 2

(IV)

CECH

C3 CH3 No. R2x 5 R I trivial nam L11 Cl R CN fenvalerate

T

W086/07525 PCT/GB86/00356 Combinations of known pyrethroid and anthelmintic agent are disclosed in WO-A-84/00095, GB-A-2 110 091 and GB-A-2 117 638.

Such disclosures are not concerned with aqueous compositions.

These prior art compositions rely exclusively on organic solvents which leads to increased expenditure on raw materials and environmental concerns and possible health hazards for users. As discussed earlier, there is a prejudice against using salt(s) of levamisole and/or tetramisole and (iii) water as a carrier medium, see GB-A-1 464 552.

The present invention is based on the disnvery that watercontaining pour-on compositions can be produced by incorporating at least one organic water-miscible cosolvent. Our experimentation has shown an unexpected improvement in anthelmintic skin penetration compared to levamisole or tetramisole free base alone. Furthermore, organic solvent content can be reduced whilst still maintaining acceptable or superior skin tolerance.

According to this invention there is provided a parasiticidal composition, suitable for pour-on application to a non-human animal which comprises: at least one salt of tetramisole and/or levamisole, (ii) at least one pyrethroid as herein defined, in carrier system comprising (iii) water, (iv) at least one organic water-miscible oosolvent.

The composition may include a minor proportion (less than by wei~ht) of at least one organic water-immiscible solvent.

i ul i WO 86/7523 PCT/GB86/00356 -6- Included within the scope of this invention are pour-on or spot-on compositions for controlling endo- and ectoparasites in a non-human animal and methods of controlling such parasites by use of the compositions. The term controlling is-used to mean interfering with the development and/or reproduction of the parasite(s). Prefera'bly, the compositions are solutions and they may be prepared by admixture of the relevant ingredients with when present, being added to (iv) before or after addition of (iii).

It is preferred to use salt(s) of levamisole, such as acid addition salt(s). As examples thereof levamisole hydrochloride, levamisole phosphate and levamisole citrate and levamisole oleate may be mentioned. The most preferred salt is levamisole hydrochloride.

As examples of preferred pyrethroids one or more of permethrin, cypermethrin, cyholothrin or decamethrin may be employed. It is more preferred to use permethrin and most preferred to use permethrin in high-,is form. Permethrin contains cis- and trans-isomers and it has been found that the cis-isomer is the more effective in controlling lice, keds, mites, fleas or the like, but particularly nuisance fly on cattle.

Water may be present (by weight per unit volume of solution) in an amount of 5 3f/o, preferably 10 25S, more preferably 12 20% w/v.

Examples of organic water-miscible cosolvent include one or more of the following, separately or as a mixture of two or more thereof: alkarnols, alkoxyalkanols, alkoxy-alkoxyalkanols, dipolar aprotic solvents such as dimethylsulphoxide (DMSO) or dimethylformamid and te like.

SU3STiTUT7 SHEET r I1: 7 The preferred ratio of i) to ii) is 3 to 1.

It is preferred to use one or more alcohols of the formula HO (CH 2 CH20)m R wherein m 1, 2 or 3 and R C 1 to C 6 alkyl group.

It is more preferred to use one or more alcohols wherein m 2 and most preferred to use 2-(2butoxyethoxy) ethanol, also known as diethylene glycol monobutyl ether (DGBE), which we have found well 0 10 tolerated by animal skins or 'hides. Component (iv) may comprise at least 60% by weight, preferably 80% or more of DGBE.

Provision is made for the optional presence of one or more water-immiscible organic solvents. The said solvent may itself be a mixture of solvents such as the commercial solvent comprised almost entirely of aromatic hydrocarbon fractions b.p. 186-205° sold as Shellsol AB.

This commercial solvent is preferred and comprises

C

9 -fraction, 49% 10 -fraction, 9%C 11 -fraction and 7% napthalene and methylnapthalene. The inclusion of water-immiscible solvent, such as C 9 or higher aromatic 0 0hydrocarbon(s) may enhance skir penetration of the salt(s) whilst retaining the components in solution, avoiding precipitation. Alternatively or additionally a monoterpene solvent such as eucalyptus oil may be K O 1 1 N 7 1 ii_ 7a included in the formulation.

Component when present, may be in a proportion of (by weight per unit volume of composition) 1 more preferably in the range 10-25% w/v of the carrier system.

Preferred compositions contain levamisole hydrochloride (and/or phosphate) high-cis permethrin, 2- (2-butoxyethoxy) ethanol, water with or without aromatic hydrocarbons.

We have surprisingly found that such compositions containing anthelmintically effective amount of and insecticidally effective amount of (ii) according to the invention may retain the salt(s) in solution, and improve penetration of the anthelmintic salt into the animal's circulatory system through the skin barrier.

oo go so*@ 9 9.

0999 S 9 9 9 oo II I~--L--C~UIIUIIIII~II a WO'86/07525 PCT/GB86/00356 8 Furchermore, the carrier system may be at least as acceptable as use of DGBE alone in the sense that skin irritation in the present compositions may be no worse than and possibly better than pure DGBE solvent.

In order that the invention may be illustrated the following non-limiting examples are presented together with comparative tests.

The figures correspond to grams per 100mls of composition Example 1 The following parasiticidal pour-on composition (solution) was prepared: levamisole hydrochloride 11.8 g High-cis permethrin 4.0 g water 20 g DGBE 43 g Shellsol AB 20 g This was found to control at least nuisance fly and helminths in cattle applied as a pour-on along the backline of the animals.

Example 2 The following parasiticidal pour-on composition (solution) was .0 prepared: levamisole hydrochloride 11.8 g high-cis permethrin 4.0 g wat er 15.0 g DGBE 69.0 g 1 WO 86/07515 PC/GB86/00356 HO (CH 2

CH

2 (vM wherein m 2 or 3 and 11 (C 1 6 )-alkyl.

t It is more preferred to use one or more alcohoip wherein -2 and most preferred to use 2-butoxyethoxy). ethanol, also known as diethylene glycol monobutyl ether (DGBE), which we have found well t .evated by animal skine or hides. Component (iv) may compr/ise at east 50% by weight, preferably 8(Y/n or more of DGBE.

Provision is riade for the optional pzesence o one* or more waterimmniscible organic solvents. The said solvent ty itself be a mixture of solvents such as the commercial iolvent co neied almost entirely of aromatic hydrocarbon fractions b.p. 186-205 0 sold as Shelledl AB. This commercial solvent is .preferred and compr sea 35% C 9-fraction, -fraction, 9%b C 11 -fraction and 7v/ napt. lene and methylnaphalene. The inclusion of water-immiscible solven ,such as C 9- or higher aromatic hydrocarbon(s) may enhance skin p etration of the salt(s) whilst retaining the components in sol tion, avoiding precipitation.

Alternatively or additionally a monoterpene solvent such as eucalyptus oil inay be included in the -ormulation, Coicponent wheni VZesent, may be in a proportion of (by weight per unit volume of camps.Oon) I -,3Z prkef erably 5 30/1.more preferably in the range 10 21ti w/v ot the carrier system.

Preferred co posit-ions contain levamisole hydrochloride (and/or phosphate) hi cis permethrmn, 2-(2-butoxyethoxy) ethanol, water with or without omatic hydrocarbons.@1 We h~re surprisingly found that such compositionb containing anthelmintica 4y e~tective amount of and insecticidclly effective amount of (ii) according to the invention ma retain thesat)in 5 ltoad im iove penetration of -the anthelmirntic salt into ti t anvimal's circulatory S-TTUT 11EET WO,86/07525 PCT/GB86/00356 I g It -9- Example 3 The following parasiticid l composition (solution) was prepared and effectively used on cattle levamisole hydrochloride 11.8 g high-cis permethrin 4,0 g DGBF, 48. 9 water 15. g Shellsol AB 20. g Example 4 The following parasiticidal qomposition (solution) was prepared and effectively used to control helminths and sheep lice levamisole hydrochloride 8.0 g cyrTermethrin 4.0 g DGBE 44. g8 water 12. g Shellsol AB 30. g Example 5 (Comparative) The following non-pyrethroid containing compositions were prepared and used as a pour-on for cattle

(B)

levanmiole hydrochloride 11.8 g 23.6 g vater 20. j 25. g DGBE 40. 9 58. g 1 Shellsol AB 20. g J~$I an WO 86/0752S PCT/GB86/00356 Results The pour-on compositions of examples 1 to 3 inclusive were found effective in controlling cattle nuisance fly and helminths.

The pour-on composition of Example 4 was found effective in controlling helminths in and lice on sheep. The pour-on compositions of comparative Examples 5 and 5 were not found effective in controlliig helminths in cattle despite the presence of a levamisole salt. In the absence of a pyrethroid the effect against ectoparasites was not monitored. In all of the tests no significant skin irritation or damage to the animal skin, fleece or hide was observed.

The compositions of Examples 1 to 3 showed significant improvement in anthelmintic activity whilst Example 4 was not compared. The levamisole salt component penetrates cattle skin, in in vitro testing equipment, at a rate comparable to a commercial levamisole free base product consisting of 2(o levamisole basein solvent DGBE. Comparative formulations of Example 5 and 5 (B) demonstrated little, if any, anthelmintic activity. The pyrethroid component thus appears to synergise the activity and/or penetration of the levamisole salt. By incorporating water in the compositions there are advantages of economics, environmental considerations, reduced toxicity tird flammability.

SUBSTITUTE SHEET

Claims (13)

1. Parasiticidal composition, suitable for pour-cn application to a non-human animal to control endo- and ectoparasites characterised in that it comprises a solution of at least one water soluble salt of tetramisole and/or levamisole (ii) at least one pyrethroid as herein defined in solution in a solvent system comprising (iii) water, and (iv) at least one organic water-miscible cosolvent.

2. Composition as claimed in Claim 1, characterised in that it further includes a minor proportion (less than 5.0% by weight) of at least one organic water- immisc.ible solvent.

3. Composition as claimed in Claim 1 or 2, characterised in that comprises levamisole acid addition salt.

4. Composition as claimed in Claim 3, characterised in that the acid addition salt is the hydrochloride. Composition as claimed in any preceding Claim, characterised in that the pyrethroid comprises one or more of permethrin, cypermethrin, cyhalothrin and iVNIT 0 12 decamethrin.

6. Composition as claimed in Claim 5, characterised in that the pyrethroid comprises high-cis permethrin.

7. Composition as claimed in any preceding Claim, characterised in that (iii) water is present in an amount of 5 to 30% by weight per unit volume.

8. Composition according to any preceding claim, characterised in that the ratio of to (ii) is substantially 3 to 1.

9. Composition as claimed in any preceding Claim, characterised in that (iv) comprises one or more of S alkanols, alkoxyalkanols, alkoxy-alkoxyalkanols, dipolar C S. aprotic solvents. Composition as claimed in Claim 9, characterised in that (iv) comprises one or more alcohols of the formula (v) HO (CH2 CH20)m R (v) wherein m 1, 2 or 3 and R Ci to C6 alkyl group.

11. Composition as claimed in Claim 10, characterised in that comprises 2 2(butoxyethoxy) ethanol,

12. Composition as claimed in any one of Claims 2 to 11 characterised in that comprises aromatic hydrocarbon solvent(s) and/or monoterpene solvent. 'T 'N T -13

13. Composition as claimed in any one of Claims 1 to 12 characterised in that is present in an amount of 1 to by weight per unit volume.

14. Method of controlling ecto-parasites which comprises applying to a non-human animal a composition as claimed in any preceding claim. Composition as claimed in Claim 1 substantially as herein described in any one of examples 1 to 4. Dated the 2nd day of January, 1990 9e ROBERT YOUNG CO. LIMITED By its Patent Attorneys, HALLIDAYS. A 3 o o -0r ft INTERNATIONAL SEARCH REPORT International Application No PCT/GB 86/00356 1. CLASSIFICATION OF SUBJECT MATTER (it several classification symbols apply, indicate all)I According to International Patent Clasaification (IPC) or to both National Classification and IPC 'PC 4:A 01 N 25/02; A 61 1K 31/425;//A 01 N 53/00; A 01 N 43/90

111. FIELDS SEARCHED Minimum Documentation Searched Classification System IClassification Symbols 'PC4 A 0l N; A61 K Documentation Searched other than Minimum Documentation to the Extent that such Documents ate Included In the Fields Searched a Ill. DOCUMENTS CONSIDERED ToOf RELEVANT' Category *I Citation of Document."1 with indication, where appropriate, of the relevant passage$ It Relevant to Claim No. Is X GB, A, 2117638 (WELLCOME AUSTRALIA) 19 Octo- lie 198,; page lines 434 clams2 1-6,15, bie 198,; page 1, lines 4354 clagem 2 13-15 cited in the application A 7,9,10,12 X GB, A, 2109236 (WELLCOME AUSTRALIA) 2 June 1983, see page 1, lines 15-34; page 2, 1-6,8,13-15 line 4 page 4, line 54; example 7; claims A 7,9-12 A US, A, 4439439 BALLANY ET AL.) 27 March 1984, see column 2, line 44 1-15 column 3, line 6; claims GB, A, 2095107 (JANSSEN PHARMACEUTICA) cited in the application A GB, A, 640549 (STANCO INCORP.) 19 July 1950, see page 1, line 85 -page 2, line 52; 1-15 page 2, lines 77-92; page 4, lines 58-98; claims *Special categories af cited documents: '5 I" later document publshed after the Internatlional filing date Iocument defining the general state of the art which Is not or priority date and not in conflict wit h the application but Considlored to be of particular relevance cited to understand the principle er theory underlying the invention "I earlier document but published an or siht the Internartionail X" document ot particular relevance; the claimed invention filing dale cannot be considered navel or cannot be considered to OL document which may throw doubts on priority claim(@) or Involve an invothtive step whichI is Cited to establish the publication date et another document of particular relevance: the claimed Invention citation or other special reason (as spanlfied) cannot be considered to involve an inventive step when the '0 document llrring to an oral disclosure. ue. eshibition oir document is combined with e or more other such docu. othertmoans mients, such combination being olivious to a person skilied document published prior to the International filing date but In the art later than the priority date claimed document member of the same patent tamliy IV. CERTIFICATION_______ Date of the Actual completion of the International Search iDate of Mailing of this International Search Report 2nd October 1986 1 14 NOV 1986 International Searching Authority Signature of Authorized Onf EUROPEA PATENT OFFICE M. VAN MOL Form PCTIISAIO (second sheet) IJafwrY 11M) Intefnational Application No. PCT/GB 8 6/ 00 3 56 11I. DOCUMENTS CONSIDERED TONSE RELEVANT (CONTINUED FROM THlE SECOND SWEET) Category Cttatior of Oocam ieflt, vath M0169ation, where ilpnute, of fts revnt pasages Relevant to Claim No A WO, A, 84/00095 (ROBERT YOUNG CO. .LTD.) 19 January 1984, see page 5, line 22 page 6, line 9; claims cited in the application 1-15 For r PCT 13A.211 (extra shoot) (JenU"I 1945)