PH26970A - Antiparasitic formulations - Google Patents

Description

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AUTIPARASITIC FORMULATIONS

1

This invention concerns the preparation of parenteral formulations of the compound known as ?5-cyclohexyvl-avermectin Rl} of formula (1).

OCH, - I .

MO Nr OCH, . . Vv , Iv pi CH,

Js Jeon ~~. ci, " i SS 1% HC "0 \ -

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H,C 0 [ . ot h " J 11 8 n xB H ne 1 l ~~ os O.. 0 “ly ~

OH He .

TON TET 3 na < ¢

OTL LT sm 3 CH, iol

Od (1) : This compound is a member of the avermectin family, described ‘ and claimed in European Patent publication 0214731. The 23 avermectins are highly active antiparasitic agents having particular utility as anthelmintics, ectoparasiticides, insecticides and acaricides.

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Antiparasitic agents ave mest conveniently administered to ‘ animals by using parenteral, subcutaneous or intramuscular formulations. Water is penerally a convenient liauid for injection, but avermectins have a very low eclubility in water and simple aqueous sclutions are too dilute te be usable. Certain avermectins can be cclubilized in water using surface active . agents as sviubilisers and suitable erganic co-solvente to form a { / micellar solution as described in US Patent 4389397. However, these formulations do not provide doses of active compounds sufficient to remove satisfactorily both internal and external . parasites of animals.

European Patent publication 146414 describes co-=solvent solutions of avermectins, in a mixture of glycerol formal and propylene glycol or in propylene glycol containing a minor amcunt of water, for parenteral use. However, propylene glveol is known to cause irritation en cubcttanecus or intremuscular injection.

Additionally, minor amounts of water in these formulations may cause hydrolytic degradation of the avermectin. ] Such fermulations, which comprise water-miscible organic 29 solvents for the avermectin, tend to produce unwanted local . precipitation of the avermectin at the injection site. This may result in irritation and swelling at the injection site and in * co . 3 . . : . - . B fnetfiicient and inconsistent antiparasitic efficacy. ho ) ge

Irdeed, the commercially available antiparasitic agent, t "lvomee injectable for cartle”, a co-solvent formulation of an avervectivo kvewrn as ivermectin, fe orly suitable for subeutaneons vee and may cove C0 lotion sd vetting ar the injection cite.

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An alternative method of providing an injectable solution of an avermectin is to dissolve the avermectin in a pharmaceutically acceptable oil. The vse of arachie (peanut) and cottonseed ofl, and also ethyl oleate, as solvents for certain avermectins is disclosed in British patent publication 216643. However, arachis oil and cottonseed oil do not provide a solution having ar least a 1% w/v concentration of compound T, as is generally required for a veterinary product. Veterinary formulations are commonly used or stored on farms at low temperatures, down to «°C 12 or even lower, and even if the avermectin is sufficiently soluble in the oil at normal room temperature it mav precipitate or form a supersaturated solution, on exposure to cold conditions and thus become unusable. Pure ethyl oleate, and mixtures of oils containing a major proportion of ethyl oleate, attack certain plastics or rubber components of commonly used veterinary svringes to an unacceptable extent.

Furopean Patent Application 285561 mentions pure sesame oil as a possible solvent for a different group of compounds, the milbemycins., In comparative viscosity and svringeability studies 273 it has been found that pure sesame oil has a viscosity which is too high to allow its ure as a solvent (or injection nsing conventional veterinary svringe equipment. For this reason, pure sesame oil cannnt Le used 2s an injectable solvent under practical 5 field conditions.

The present invention is intended to provide a parenteral formulation for compound (I) which is effective against hoth internal and exterual parasites, is well tolerated by animals on hoth subcutaneous and intramuscular administration and is

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em rm mmr —— —— _ . Jt 1 compatible with conventional injection equipment.

According to the invention, there is provided a solution of 25-cveleobhexvi-avermectin Rl. compound (1), in a solvent consisting of from 50 to 95% he vealume of sesame oil with the remainder ethyl]

S nleate,

The preferred solvent mixture consists of from 75 to 80% of sesame oil by volume with rhe remainder ethyl oleate.

The preferred content of avermectin for subcutaneous or intramuscular injection is from 1 to 30 mg/ml, most preferably 143 about 10 mg/ml.

The formulatiecns according to the invention are manophase snlutions and are effective in treating a variety of conditions cavsed bv endoparasites including, in particular, helminthiasis which is most frequently caused by a proup of parasitic worms described as nematodes and which can cause severe economic losses in swine. sheep, horses and cattle as well as affecting domestic animals and poultry. The compounds are also effective against other nematodes which affect various species of animals including, for example, Dirofilavia in degps and various parasites which can 23 infect humans including gastro-intestinal parasites such as

Ancylostoma, Necator. Ascaris. Strongyloides, Jvichiuvella.

Capillaria, Trichuris, Enterobius and parasites which are found in the blood or other tissues and organs such as filiarial worms and - the extra intestinal stages of Strenpvleides and Trichinella. 5 The formulations of the invention are alco of value in treating ectoparasite infections including in particular anthropod ectoparasites of animale and hirds auch as ticks, mites, lice, fleas, blowfly, hiting insects and migrating dipterous larvae

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BAD ORIGINAL 9 t ee tet ——— EE © ste eee —_ —_ ——_—_—— ——— yz . ) (1 » which can affect cattle and herses.

It has been found, unexpectedly, that formulations according the inventien show properties which are superior to the prior art formulations mentioned above, in that thev show little or no 5 irritation at the injection site when adminictered te animals bv subcutaneous or intramuscular injection, are suitable for use in commonly used standard syringes, and give consistent antiparasitic - efficacy.

A further advantage of the solutions of the invention is 13 that, as the formulation vehicle contains esters of unsaturated acide, the avermectin is protected from air oxidation during prolonged storage.

The solutions of the invention mav be prepared simply by dissolving compound (1) in the sesame oil ethyl oleate mixture and sterilising and packaging for administration in a conventional manner.

Formulations according to the invention are described by wav of illustration in the following Framples.

EXANPLES

29 Solutions of 25-cvelohexvli-avermectin RU in the oil formulations were made and tested by the methods given helow.

ESAUPLE

The following ingredients weve used to prepare an injectable solution containing 10 mgs of compound | in 1 ml of a nominal 90/10 mixture of sesame oil and ethyl nleate:

Compound | 10 me

Fthyvl oleate 0.1 ml

Sesame oil te 1.00 ml

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The ethyl oleate and secame oil were mized and heated to 8070, whilst purging with nitrogen. Compound | ie then added to the hot eile until dissolved and the resulting sclution 1apidly rooted and the volume adjusted to 1 ml with sesame oil, if required. This 3 final solution was sterilised by membrane filtration and packaged aseptically. :

Using the method of example 1, the following ingredients were used te prepare an injectable solution containing 10 mgs of compound 13 in 1 ml of a nomical 50/50 mixture of sesame oil and ethyl oleate:

Gompnund | 0 me

Fthvl oleate 0.5 ml

Sesame oil to 1.0 ml

LEAMPLE 3

Using the method of example 1, the following ingredients were used to prepare an injectable solution containing 10 mgs of compound 1 in 1 mm) of a nominal 75/25 mixture of sesame oil and ethyl oleate:

Compound | 10 me

Frhvl oleate 0.25 ml 27 Sesame oil to 1.0 ml

EEAMPLE a

The efficacy of compound 1 against ectoparasites was determined using a modification nf the method described by L 6 vramer et al., in Tet. Record. (1&8), 122. 611-612.

Cempound [ was administered to tuo groups of cattle bv subcutanenus injection at a dose of 200pp ka on dav 0. Croup A received compound Tin an aqueous micelle formulation according to

IIS Patent 4389397 containing 2.5 mg of compound 1, 120 mg of Tween

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ei 7 80 (Registered Trade Mark), 200 me of glvcerol formal, aboot 10 mp of benzyl alcohol and the remainder water per ml of formulation,

Group b were treated with compound I in the fermulation of example 1. The treated groups, together with a centrol for each treatment were then seeded with Roophilus microplus larvae on dave 0, 2 and 4 and the ticks allowed to develop inte adults. Resulting engorged adult female ticle were collected between dave 21 and 32 and the mean dailv counts recorded as shown in Table 1.

Table 1

La Mean Daily counts of female B.microplue ticks collected

Micelle Untreated Formulation Untreated bay Formulation control Ixample 1 tentrol 21 0 287 0 0 22 0 651 0 304 23 0 879 0 Gah 2a 0 733 0 1407 16 554 0 6H3 26 76 267 0 £52 23 27 85 48 0 17g 28 36 10 8 25 29 28 5 15 19 16 n 3 ] 31 0 0 3 ! 25 32 0 0 1 0

Totals 257 30% 30 aid

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Treatment with formulation example 1 both deliored the production of adult female ticks and reanlted in fewer ticks collected. e

EXAMPLE 5

The toleration of avermectin formulatinns was assessed following injection into the sewmimembraneous muscle of cattle, Animals were humanely sacrificed at 7 and 14 days post-treatment and the injection sites, with surrounding tissue, removed. Tissues were examined for gross pathology and injection site lesions were 13 evaluated using the scoring svetem described below. 0 = Nermal, no visible lesion

I = Light scar ? ~ Heavy scar 2 3 = Encapsulated debris] .0cm 4 = Tncapsulated debris>1.042. Sem” . . 3 5 = Encapsulated debris>2.5cm

Scores 0, 1 and 2 are considered acceptable. Scores greater than 2 have encapsulated debris. Compound T in formulations of examples 29 I and 2 vas administered to cattle by intramnsenlar injection at a dese of 200ug/kg. Injection site toleration was compared with that of the co-solvent formulation of the antiparasitic agent, ivermectin (Trademark; Ivomee for cattle) given at the same dose and by the same route.

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Table 2

Lomparison ef intramuscular injection site toleration scores

Mumber of Average

Treatment Day Animals Score

Formulation 7 S 0.a example 1 la 10 0.0

Formulation 7 5 0.4 example ? 14 10 0.0 14

Lvomec 7 4 1.76 la 8 2.75

Compound 1 in formulation examples 1 and 7, was well tolerated with only a few minor lesions at 7 davs pest-injection; resolving completely bv 14 davs. In contrast, Ivomee given by intramuscular injection was poorly tolerated at 7 dave with encapsulated debris still visible 14 davs post-injection. 23 -

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Claims (6)

1. Ee —————— ee ————eeeeee beep eee LN { J - 10 - Claims:

   L. An antiparasitic composition for treatment of animals by subcutaneous and intravenous injection form comprising a solution of 25-cyclohexyl-avermectin Rl of formula (1) orn, x RR on, : BT Sie os BCH, . - LL : i ee TN nz” vo | J 1 | ! ™ RT ’ H i a . He | ! A: aC Ft Ts 10 SI ~ ol Tn <7 ve A TN : A I yo |” Te” CN Lo " le bee Lo LA RR 14, C 1 1 Sel rd es Cu AC wy ‘ l I ron INST

   I. CTT a io oH 3 in seclvent consisting of from 50 to 95% by volume of sesame oil with the remainder ethvl oleate.
2. 2. An antiparasitic composition for treatment of animals comprising a solution according to claim 1, in which the solvent contains from 75% to 90% by volume of sesame oil . with the remainder ethyl oleate.
3. 3. An antiparasitic composition for treatment of animals comprising a solution according to claim 1, containing from 1 to 30 mg/ml of 25-cyclohexyl-avermectin

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4. 4. An antiparasitic composition for treatment of animals comprising a sclution according to claim 3, containing about 10 mg/ml of 25-cyclohexyl-avermectin Bl.
5. 5. An antiparasitic composition for treatment of animals comrpising a solution according to claim 1, for treating parasitic infections in animals,
6. 6. A method of treating parasitic infections in animals, which comprises administering an effective amount of a solution according to claim 1 by injection. STEPHEN RUCHARD WICKS EDWARD DAVIDSON Inventors