GB2057262A

GB2057262A - Veterinary depot preparation with prolonged release of insecticide

Info

Publication number: GB2057262A
Application number: GB8026239A
Authority: GB
Original assignee: Ciba Geigy AG
Current assignee: Novartis AG
Priority date: 1979-08-16
Filing date: 1980-08-12
Publication date: 1981-04-01
Also published as: IT8024166A0; AT367294B; NO802452L; AR225641A1; DE3030646A1; FI802543A; DK354480A; NL8004486A; FR2462910A1; SE8005760L; NZ194682A; AU6147980A; ZW18980A1; ATA332580A

Abstract

An oral sustained release depot preparation comprises a systemically active insecticidal substance and a customary auxiliary or several such auxiliaries, alkylhydroxyalkylcellulose and a higher fatty acid or a calcium or magnesium salt thereof. The active substance is a 2-cyclopropylamino- or 2 -alkylamino-4,6-diamino-s-triazine each optionally containing further substituents. The preparation is in the form of a bolus and is suitable for the long-term control of insect larvae parasitic in tissues.

Description

SPECIFICATION Depot preparation with prolonged release of active substance The present application relates to a veterinarymedicinal depot preparation in a solid compressed form giving a prolonged release of active substance, which preparation is suitable for combating tissueparasitic insect larvae, particularly those of the order Diptera, in a systemic manner, and to a process for producing the preparation.

The combating of insect larvae which live as parasites in the tissues of the host animals is of extraordinarily great importance, especially with regard to the considerable damage which can be caused by these parasites in productive-livestock production and more particularly in grazing-cattle husbandry.

The Diptera larvae can penetrate in a variety of ways into the tissues ofthe host animals. It is thus possible, after oviposition by the Diptera female, which can occur at different places on the bodies of the host animals, for the larvae, which have emerged from the eggs, to be taken up by the licking action of the host animals, and to burrow into the throat of the respective animal; or the larvae can themselves burrow from outside into the skin of the host animals.

The eggs can also be firstly deposited on gnats or flies. The larvae then develop in the eggs, and emerge as soon as the carrier insect has landed on a suitable host animal. In the case ofthe viviparous Diptera species, the larvae can be deposited by the Diptera females directly into the nose or into the eyes of the host animals.

After the larvae have found their way into the host animals, the larvae can by migration seek out the parts ofthe body most preferred by them. They can be example appearin or under the skin, in the gastro-intestinal tract or in the nasal, pharyngeal or frontal cavity of the host animal.

The various types of parasitism caused by Diptera larvae in animals are summarised by the term myiasis. Myiasis can occur in numerous species of animals, for example in cattle, horses, donkeys, mules, reindeers, sheep, pigs, dogs and cats. Infestation of the host animals by parasitic Diptera larvae can lead to a reduction of milk yield, to a loss of wool and to a loss of weight, apart from having other disadvantageous effects, and can even result in the death of the infested animal. If the host animals are infested by skin parasites which cause swellings to form in the skin, a lowering in value of the skins owing to perforation can occur since the swellings each have a small opening, and these openings are enlarged further as the larvae leave the host animals to undergo pupation.

Combating of the larvae is problematic because they can infest very varied and in some cases difficultly accessible parts ofthe animal's body. Furthermore, a possible infestation of the host animals by tissue-parasitic insect-larvae is not limited to a short, easily determinable interval of time. Thus, in particu lartheflight courses of the female insects capable of oviposition or of deposition of larvae extend, depending on environmental conditions, over long periods, factors which would necessitate, using hitherto known methods of control, in addition to continual checks of the host animals, the treatment of these animals at short intervals. A procedure of this kind under practical conditions would be extremely labour-intensive and very expensive, and in the case of free-roaming herds scarcely practicable.

For an effective and long-term control of insect larvae parasitic in animal tissues, there is therefore required a preparation which can provide a reliable and prolonged protection ofthe host animals against parasites, without the preparation having at the same time any disadvantageous effects. The producing of a preparation of this nature constitutes, by virture of the strict and varied requirements which it has to satisfy, a considerable problem. The desired properties of such preparations can be acquired only by means of a multicomponent system, with which there has to be the assurance for example that the individual components are not toxic for the host animals to be treated, and that they do not form under the influence ofthe othercompo- nents, of the gastric juices of the animals and ofthe feed taken in by them any toxic products.The effectiveness of the active substances must moreover in no way be impaired by the other constituents. Furthermore, it is necessary that, after administration of the preparation to the host animal, an effective concentration in the blood should be rapidly attained and maintained over a long period, but that at no time should there occur a concentration that is so high that it could harm the host animal. It must also be ensured that on the other hand there results no premature excretion of the active substance or of the preparation by the host animals.

By the present invention there is provided a depot preparation giving a prolonged release of active substance, which preparation, in addition to containing an active substance of the formula I

wherein R1 is hydrogen, methyl, ethyl or cyclopropyl, R2 is hydrogen or methyl, R3 is hydrogen, methyl or cyclopropyl, R4 is hydrogen or methyl, and Rs is ethyl, n-propyl, isopropyl or cyclopropyl, or an acid addition salt thereof nontoxic for ruminants, and a customary auxiliary or several such auxiliaries, also contains alkylhydroxyalkylcellulose in which the alkyl groups independently of one another each consist of 2 or 3 carbon atoms, and a higher fatty acid having 15to 18 carbon atoms in the alkyl moiety, or a calcium or magnesium salt thereof.

The active substances of the formula I exhibit a systemic action, which means that even on local administration to a part of the host animal activity against the parasitic Diptera larvae also in the untreated parts of the animals's body is achieved. The depot preparations according to the invention hence render possible an effective control ofthe parasitic Diptera larvae also in those parts of the body at which a direct administration is extremely difficult or virtually impossible.The preparations have in particular a good action against myiasis-causing larvae of insects of the order Diptera which belong to the families: Calliphoridae, Oestridae, Cuterebridae, Gasterophilidae, Sarcophagidae and Hypodermatididae, for example against larvae of Lucilia spec., Cochlyomyia hominivorax, Chrysomyia bezziana, Hypoderma lineata, Hypoderma bavis, Dermatobia hominis, Oedemagena tarandi, Gasterophilus spec., Oestrus ovis, Rhinoestrus purpureus, Wohlfahrtia vigil and Cuterebra spec.

Of the compounds of the formula 1,2 - cyclopropylamino - 4, 6 - diamino - s - triazine is especially suitable by virtue of its excellent action for combating insect larvae parasitic in tissues, particularly larvae of the order Diptera.

By the term 'acid addition salts' of compounds of the formula I are meant salts with pharmaceutically acceptable acids, for example with strong mineral acids, such as hydrochloric acid or sulfuric acid, or with organic acids, such as acetic acid, tartaric acid or citric acid.

The compounds of the formula I can be produced by processes known per se, for example a) by reacting a compound of the formula II, wherein R, R2 and R5 have the meanings given for the formula I, and Xis halogen, preferably chlorine, with ammonia or with a primary or secondary amine of the formula V, wherein R3 and R4 have the meanings given forthe formula I:

or b) by reacting a 2,4 - diamino - 6 - halogeno - s triazine of the formula Ill, wherein R1, R2, R3 and R4 have the meanings given for the formula I, and Xis halogen, preferably chlorine, with a compound of the formula VI, wherein B5 has the meaning given for the formula I::

or c) by reacting, when in the compounds of the formula I R1 has the same meaning as R3, and R2 the same meaning as R4, a compound of the formula IV, in which B5 has the meaning given under the formula I, and X is halogen, preferably chlorine, with ammonia or with a primary or secondary amine of the formula VII wherein R' has the meaning of R1 = R3, as given fortheformula I, and R'2 has the meaning of R2 = R4, as given for the formula I::

The substitution of the halogen atoms by ammonia, primary and/or secondary amines of the formulae V, VI and VII is effected by dissolving the starting materials of the formulae II, III and IV in inert solvents, for example in acetone, acetone/ water/ mixtures, methyl ethyl ketone, dioxane or dioxane/ water mixtures, and reacting these mixtures, under normal or optionally elevated pressure and at temperatures of 20-150"C, preferably 50-140"C, with ammonia or with primary and/or secondary amines.

The starting materials ofthe formulae II, Ill and IV are for the most part known, or they can be produced by processes analogous to known processes.

The production of the active substances is further illustrated by the following Examples.

Example 1 a) 2- Cyclopropylamino - 4, 6 - diamino -5- triazine A mixture of 100 g of 2 - cyclopropylamino - 4 amino - 6 - chloro - s -triazine, 51 g of ammonia and 500 ml of dioxane is heated in an autoclave for 24 hours at 140"C. After the mixture has cooled, the dioxane is filtered off in vacuo, the crystalline residue is washed with water and dried. The crude product is recrystallised from methanol; m.p. 219 222"C.

b) 2 - Cyclopropylamino - 4, 6- diamino - s - triazine, salt with 2 mols ofhydrochloric acid 25 g of 2 - cyclopropylamino - 4, 6 - diamino - s triazine are dissolved hot in 2000 ml of abs. ethanol.

This solution is cooled to 15PC; it is further cooled with ice, and then hydrochloric acid gas is introduced to saturation point, in the course of which white crystals precipitate and are filtered off. The crude salt thus obtained is washed with a large amount of ether; m.p. 195"C (decomposition).

Example 2 aJ 2 - Cyclopropylamino - 4 - methylamino - 6 - amino s-triazine A mixture of 12.7 g of 2 - cyclopropylamino - 4 methylamino - 6 - chloro - s - triazine, 17.4 g of 28% aqueous ammonia solution and 30 ml of dioxane is heated in an autoclave for 4 hours at 140"C. After the reaction mixture has cooled, it is poured into 350 ml of a solution, cooled to 0 C, of potassium carbonate in water, and extraction is performed with benzene/ether (1:1). After the drying with sodium sulfate, the solvents are removed in vacuo, and the residue is recrystallised from isopropanol/hexane; m.p. 159-162 C.

h) 2 Cyclopropylamino - 4 - methylamino -6 - aminos - triazine, salt with 2 mols ofhydrochloric acid 38 g of 2 - cyclopropylamino - 4 - methylamino - 6 amino - s - triazine are dissolved in 280 ml of chloroform. This solution is cooled with ice to 0-5"C, and hydrochloric acid gas is introduced to saturation point. White crystals precipitate, and to obtain complete precipitation 280 ml of ether are added. The crude hydrochloride is filtered off, and recrystallised from methanol; m.p. 197-199"C.

Example 3 2, 4, 6 - Tris - cyclopropylamino -5 - triazine A m ixtu re of 20 g of 2 - ch lo ro - 4, 6 - bis - cyclop- ropylamino - s - triazine, 10.1 g of cyclopropylamine and 80 ml of dioxane is heated for 22 hours at 140"C in an autoclave. The reaction mixture is concentrated by evaporation in vacuo to half its volume, and 300 ml of water are added. Extraction is performed with ethyl acetate, drying is carried out with sodium sulfate, and the solvents are removed in vacuo. The residue is recrystallised from dioxane/petroleum ether; m.p. 75-77"C.

In a manner analogous to that described in Examples 1 to 3, there can be produced for example also the following compounds of the formula I: No. Compound m.p. in C 1 2 - cyclopropylamino - 4 - amino - 6 - dimethyl- 182-184 amino - s - triazine, 2 2,4 - bis - (cyclopropylamino) - 6 - amino - s - triazine 137-140 3 2 - cyclopropylamino - 4 - methylamino - 6 - dimethyl- 164-165 amino - s - triazine dihydrochloride, 4 2 - cyclopropylamino - 4,6 - bis - (dimethyl - amino)- 140-142 s-triazine, 5 2-cyclopropylamino- 4 - amino - 6 - ethylamino- 141-145 s-triazine, 6 2 - cyclopropylamino - 4 - amino - 6 - ethylamino- 199-200 s - triazine dihydrochloride, 7 2,4 - bis - (cyclopropylamino) - 6 - dimethyl- 136-137 amino - s - triazine, 8 2 - isopropylamino - 4,6 - diamino -s-triazine, 212-213 9 2 - ethylamino - 4,6 - diamino - s - triazine, and 196-198 10 2 - isopropylamino -4,6 - diamino - s - triazine 201-203 dihydrochloride.

The depot preparations can be produced in a simple manner by firstly stirring alkylhydroxyalkylcellulose into a suitable swelling substance, for example ethanol, and allowing several hours for swelling to occur. There is formed a mass of honey-like consistency, into which is stirred the fatty acid or a calcium or magnesium salt thereof. After dry mixing, there are subsequently added the active substance and an auxiliary or several auxiliaries. The resulting mixture is worked up with stirring into the form of a plastic substance and granulated. The granulate after drying is put through a suitable sieve and compressed to obtain a solid dosage form.

Among the alkylhydroxyalkylcelluloses there is advantageously used for example ethylhydrox yethylcellulose. Water-insoluble ethylhydroxyethylcellulose having a viscosity of 10 to 250 cP (centipoises), measured in a 5% solution in 80 parts of toluene and 20 parts of 95% ethanol at 25"C proves to be particularly suitable. The ethylhydroxyethylcel- lulose designated in the following as being lowviscous has a viscosity of 20 to 35 cP measured under identical conditions.

Suitable fatty acids are for example stearic acid and palamitic acid, and also the calcium and magnesium salts thereof, especially stearic acid.

Suitable auxiliaries are in particular fillers which have a high specific weight, for example barium sulfate, bismuth subnitrate, iron(ll) salts, and especially iron powder.

Since it is in particular the alkylhydroxyalkylcellulose in interaction with the fatty acid or with salts thereof which is the controlling factor by which the rate of release of the active substance can be influenced, the regulation of the total content of active substance in the depot preparation can be advantageously effected by adjustment of the amount of filler material contained, that is to say, with an increase in the amount of active substance contained, the proportion of filler material can be reduced, and with a reduction of the amount of active substance contained, it can be increased.

The granulating media used can be customary granulating liquids, for example carbon tetrachloride, dichloromethane, or preferably ethanol.

Granulation can be performed in a manner known per se, for instance with the use of a sieve-grater, with elongated shapes being formed. The granulate obtained is advantageously dried for 24 hours at room temperature, and is subsequently put th rough a suitable sieve. The moulding of the granulate can be carried out by means of a suitable tablet compressing machine. Suitable solid dosage forms are in particular boluses.

In the production of the solid dosage forms,it is possible to mould granulates which contain the same constituents in varying proportions. By the use of mixed granulates of this kind, the process of active-substance release can be very readily adjusted to obtain the specific result required.

A further possibility of controlling the release of active substance is to provide the surface of the depot preparation partially with a coating of a water-insoluble substance, such as is customarily used in the Galenic system for the coating of preparations.

Particularly suitable depot preparations are those containing 0.1 to 60 per cent by weight of active substance of the formula 1,2 to 15 per cent by weight, preferably 3 to 8 per cent by weight, of alkylhydroxyalkylcellulose, and 0.1 to 5 per cent by weight, preferably 0.5 to 2 per cent by weight, of fatty acid or of calcium or magnesium salts thereof, relative to the total weight of the depot preparation.

The use of ethylhydroxyethylcell ulose together with stearic acid in the aforementioned amounts has proved very satisfactory.

The following Examples illustrate the production and composition of depot preparations according to the invention. There is used therein water-insoluble ethylhydroxyethylcellulose having a viscosity in the range of 20 to 35 cP.

Example 4 12.5 g of low-viscous ethylhydroxyethylcellulose are stirred into 30 ml of ethanol. The mixture is allowed to swell overnight, and 7.5 g of stearic acid powder are then stirred in. To this mixture are added, with stirring, 50.0 g of 2 - cyclopropylamino 4,6 - diamino - s - triazine and 180.0 g of iron powder, which have been thoroughly mixed together dry beforehand. There is formed a plastic mass which, to produce fine, elongated shapes, is put manually through a sieve of 6 meshes/cm. The granulate obtained in this manner is dried for 24 hours at room temperature, and is then processed, with a tablet compressing machine, into the form of 10 boluses each weighing 25 g and having a specific weight of 2.95.

Example 5 There are produced by the process described in Example 4 10 boluses, each having a weight of 25 g and a specific weight of 3.01, from 12.5 g of lowviscous ethylhydroxyethylcellulose, 30 ml of ethanol, 2.5 g of stearic acid powder, 50.0 g of 2 cyclopropylamino - 4,6 - diamino - s - triazine and 185.0 g of iron powder.

Example 6 750 ml of ethanol having a proportion of 5% of isopropyl alcohol are placed into a planetary-type mixer with oscillating agitators. 375 g of low-viscous ethylhydroxyethylcellulose are introduced with stirring into the alcohol. Stirring is continued until no further sedimentation can occur. After the mixture has been allowed to swell for several hours, for example overnight, 75 g of stearic acid powder are stirred into the formed honey-like substance. This substance is processed with stirring, in a planetarytype mixer provided with kneading hooks, with a mixture of 1500 g of 2 - cyclopropylamino - 4,6 diamino - s - triazine and 5550 g of iron powder (which ingredients have been pre-mixed dry for about 10 minutes in a planetary-type mixer fitted with stirring blades) into the form of a plastic mass.

This mass is finely granulated with a sieve-grater.

The granulate formed in this manner is dried on trays for 24 hours at room temperature, and subsequently broken down through a dry-granulating sieve having 6 meshes per cm. The finished granulate is compressed, with a suitable tablet compressing machine, into the form of boluses each 56 mm in length, 12 mm in width and at most 17 mm in height, and each having a total weight of 30 g.

Example 7 There are produced by the process described in Example 6 boluses, each having a total weight of 26.5 g, from 312.5 g of low-viscous ethylhydroxylethylcellulose, 1000 ml of ethanol having a proportion of 5% of isopropyl alcohol, 125.0 g of stearic acid powder, 1875.0 g of 2 - cyclopropyl - amino - 4,6 diamino - s - triazine and 4312.5 g of iron powder.

Example 8 By the process described in Example 6, there are obtained boluses, each having a total weight of 25 g, from 31.25 g of low-viscous ethylhyd roxyethylcel- lulose, 100 ml of ethanol having a proportion of 5% of isopropyl alcohol, 12.50 g of stearic acid powder, 187.50 g of 2 - cyclopropylamino - 4,6 - diamino - s triazine and 393.75 g of iron powder.

In a manner corresponding to that described in the preceding Examples, it is possible to also produce depot preparations having other concentrations of active substance. The content of active substance in the preparations should preferably be such that the host animals to be treated receive daily a dose within the range of 1 to 100 mg/kg of body weight. The total weight of the preparation, which is administered preferably in the form of boluses, is advantageously within the range of 10 to 100 g.

The depot preparations according to the invention can be administered by means of suitable application devices, for example by a bolus applicator, to the ruminants to be treated, particularly cattle and sheep.

The release of active substance from the depot preparations can be determined in vivo and in vitro.

In the case of in vitro tests, the liberation of active substance from the boluses is ascertained in an artificial medium at specific intervals oftime. With in vivo tests, the treated ruminants are infested with parasites in the egg- and/or larva-stages, and the time until complete destruction ofthe parasite larvae has occurred is determined.

Test 1 A bolus-applicator is used to administer to each of three sheep a bolus produced according to Example 4, and to each of another three sheep a bolus produced according to Example 5. The location of the respective boluses in the sheep is checked daily by means of an electro-iron-detector. For in vivo tests, there are applied, from 24 hours onwards after administration of the boluses, daily about 50 to 100 freshly emerged larvae and freshly deposited eggs ofLucilia sericata to the back of each sheep, and an examination is carried out 24,48,72 and 96 hours, respectively, after infestation to determine mortality (complete destruction of the parasitic larvae).

To effect infestation, the skin on the back of the test animal is scratched with a scalpel; the cut spot is then moistened by spraying with water, and the larvae and eggs, respectively, are deposited at this point on each animal. The first infestation is made on the withers of the animals, and further infestations are made at spacings of about 10 cm along the trunk of the animal. The points of infestation are indicated by means of different colour markings.

The results are summarised in the following Table:

Larvae destroyed within 48h 72h 96h Boluses Parasitic according Days after Days after Days after stage to Example application application application 4 1-32 33-46 47 eggs 5 1-32 33-38 39 4 1-31 32-46 47 larvae 5 1-29 30-37 38 The results show that over a period of about one month the parasitic larvae are destroyed within 48 hours.In the further course of the test, the boluses produced according to Example 4 prove particularly advantageous in that destruction of the larvae is ensured within 72 hours throughout a period of more than six weeks.

Test2 The release of active substance from a bolus produced according to Example 6 is examined in a test apparatus. Serving as the test apparatus is essentally the device for tablet disintegration tests, such as that described in The United States Pharmacopeia (USP) XIX, United States Pharmacopeial Convention Inc., 1975, p. 650. The device consists of a wire bas ket, a container for an immersion liquid and a suit able arrangement rendering possible the raising and lowering of the basket at constant frequency in the immersion liquid. The frequency is between 28 and 32 cycles per minute over a height difference of 5 to 6 cm.The volume of immersion liquid is such that the wire mesh of the basket is at least 2.5cm below the surface of the liquid at the highest point of the upward movement, and remains at least 2.5 cm from the bottom of the container for the liquid at the low est point of the downward movement. The length of time taken forthe upward movement is identical to that for the downward movement. The reversal of direction at top and bottom occurs smoothly and not abruptly. The device also contains a thermostatic arrangement for heating the liquid to between 35 and 39 C. The procedure differs from that described in the USP in that the bolus to be tested is placed directly into the basket and not into a small tube located in the basket.The container for the liquid is a 1000 ml beaker and this contains 750 ml of demineralised water The water is changed hourly during the first 8 hours of the test. It is subsequently changed every 12 hours, and finally every 24 hours.

The test temperature is 37"C. The quantitative determination of the content of active substance in the water specimens is carried out spectrophotomet rically at the wavelength of 207 nm.

In the attached diagram (Figure 1), the release of active substance from the bolus into the surrounding medium, expressed as a percentage of the total content of active substance in the bolus at the commencement of the test, is plotted against time.

Test 3 The release of active substance of a bolus produced according to Example 8 is examined with the test apparatus described in Test 2 over a longish period of time.

The release of active substance in the first 24 hours after commencement of the test is shown in Figure 2. During the first 2 hours, a measurement of the released amount of active substance (expressed in mg) is taken at intervals of 20 minutes. During the following 3 hours, the release is measured at halfhourly intervals, and during the subsequent 4 hours at hourly intervals. Further measurements are then made after7 hours and after8 hours.

In Figure 3 are shown the measured results from 24 hours onwards after commencement of the test up to the 10th day. There are firstly made 3 measurements per day and then 2 measurements per day.

Figure 4 shows the release of active substance, expressed as a percentage of the total content of active substance at the start of the test, over a period of 61 days, two measurements being made daily from the 4th to the 21st day, and subsequently one measurement daily.

In the case of the resultsforTests 2 and 3, the amounts of active substance are given cumulatively, that is to say, the total amount of active substance released up to the given point of time of the respective measurement is taken into account.

The results from measurements of the release of active substance show that the liberation of active substance occurs rapidly at first, then more slowly but continuously. This means that with the depot preparations according to the invention, a concentration sufficient to effect an enrichment of the active substance in the blood of the treated animals can be very rapidly attained, and that a uniform subsequent supply of active substance over a prolonged period of time is ensured.

The depot preparations according to the invention ensure an excellent long-term action of the active substance used. It is possible with these preparations to maintain an effective concentration in the blood of the treated animals over a period of about six weeks after administration.

Claims

1. Aveterinary-medicinal depot preparation in a solid compressed form giving a prolonged release of active substance, which preparation, in addition to containing an active substance ofthe formula I

wherein R1 is hydrogen, methyl, ethyl or cyclopropyl, R2 is hydrogen or methyl, R3 is hydrogen, methyl or cyclopropyl, R4 is hydrogen or methyl, and B5 is ethyl, n-propyl, isopropyl or cyclopropyl, or an acid addition salt thereof nontoxic for ruminants, and a customary auxiliary or several such auxiliaries, also contains alkylhydroxyalkylcellulose in which the alkyl groups independently of one another each consist of 2 or 3 carbon atoms, and a higher fatty acid having 15 to 18 carbon atoms in the alkyl moiety, or a calcium or magnesium salt thereof.

2. A vetennary-medicinal depot preparation according to Claim 1, which contains an active substance of the formula I wherein R1 to R4 have the meanings given in Claim 1, and Rs is cyclopropyl.

3. A veterinary-medicinal depot preparation according to Claim 2, which contains 2-cyclopropylamino-4, 6diamino-s-triazine as active substance.

4. A veterinary-medicinal depot preparation according to Claim 1, which contains an active substance of the formula I wherein R1 to R4 have the meanings given in Claim 1, and Rs is ethyl, n-propyl or isopropyl.

5. Aveterinary-medicinal depot preparation according to any one of Claims 1 to 4, which contains 0.1 to 60 per cent by weight of active substance of the formula 1, 2 to 15 per cent by weight of alkylhydroxyalkylcellulose and 0.1 to 5 per cent by weight of fatty acid or of a calcium or magnesium salt thereof, relative to the total weight of the depot preparation.

6. Aveterinary-medicinal depot preparation according to Claim 5, which contains 3 to 8 per cent by weight of alkylhydroxyalkylcellulose and 0.5 to 2 per cent by weight of fatty acid or of a calcium or magnesium salt thereof, relative to the total weight ofthe depot preparation.

7. A veterinary-medicinal depot preparation according to any one of Claims 1 to 6, in which the alkylhydroxyalkylcellulose is ethylhydroxyethylcel- lulose.

8. Aveterinary-medicinal depot preparation according to Claim 7, in which the ethylhydroxyethylcellulose is one having a low viscosity.

9. A veterinary-medicinal depot preparation according to any one of Claims 1 to 8, in which the fatty acid or a calcium or magnesium salt thereof is stearic acid or palmitic acid, or a calcium or magnesium salt thereof.

10. Aveterinary-medicinal depot preparation according to Claim 9, in which the fatty acid is stearic acid.

11. Aveterinary-medicinal depot preparation according to any one of Claims 1 to 6, which contains, besides an active substance and a customary auxiliary or several such auxiliaries, ethylhydroxyethylcellulose and stearic acid.

12. A veterinary-medicinal depot preparation according to any one of Claims 1 to 11, which contains as auxiliary a filler having a high specific weight.

13. A veterinary-medicinal depot preparation according to Claim 12, which contains as filler barium sulfate, bismuth subnitrate, iron(ll) salts or iron powder.

14. A veterinary-medicinal depot preparation according to Claim 13 which contains iron powder as filler.

15. A veterinary-medicinal depot preparation according to any one of Claims 1 to 14 for use in a process for combating insect larvae parasitic in tissues.

16. A process for producing aveterinarymedicinal depot preparation as is described in any one of Claims 1 to 15, which process comprises stirring alkylhydroxyalkylcellulose, wherein the alkyl groups independently of one another each consist of 2 or3 carbon atoms, into a swelling substance; stir ring into this mixture after swelling a higher fatty acid having 15 to 18 carbon atoms in the alkyl moi ety, or a calcium or magnesium salt thereof; adding a mixture produced by the dry mixing of an active substance of the formula I with an auxiliary or with several auxiliaries; processing the whole mixture, with stirring, into the form of a plastic mass; and granulating and compressing this.

17. A process according to Claim 16, wherein granulation is performed in the presence of a liquid granulating medium.

18. A process according to Claim 17, wherein granulation is performed in the presence of carbon tetrachloride, dichloromethane or ethanol.

19. A process according to Claim 18, wherein granulation is performed in the presence of ethanol.

20. Aveterinary-medicinal preparation according to Claim 1, substantially as hereinbefore described with reference to any one of Examples 4to 8.

21. A process according to Claim 16, substantially as hereinbefore described with reference to any one of Examples 4 to 8.