SE440449B - DEVICE FOR REGULATED AND CONTINUOUS ADMINISTRATION FOR A LONG TIME OF THE ANTHELMINTICUM MORANTEL - Google Patents

Description

ZS 40 7903973-1 administration of the medicine with a carrier which eventually decomposes by the action of the environment, for example by the action of body fluids, whereby the medicine is released. Waxes, oils, fats and soluble polymers have been used as such carriers.

It is also known to disperse the medicine in a solid matrix, through which the medicine diffuses and in this way is released or to enclose the medicine in a capsule with one or more walls of polymeric material, through which the medicine can diffuse. (U.S. Pat. No. 3,279,996).

U.S. Pat. No. 3,975,350 discloses a system comprising a hydrogel as a carrier, which hydrogel consists of polyurethane polymers for medical, pesticide, insecticide, algaecide, etc. use.

U.S. Pat. No. 1,693,890 discloses the preparation of porous membranes of cellulose acetate in the form of gels for use in dialysis. The process comprises precipitating cellulose acetate from a solution thereof in acetic acid by adding a non-solvent, for example water. If desired, the membranes can be made on a carrier. The membranes thus prepared are impregnated with water but can be freed from water by washing with alcohol, acetone or any water-miscible liquid.

Materials composed of cellulose polymer liquid (PLC) in the form of film, fibers or microspheres and containing cellulose esters, such as cellulose triacetate or cellulose nitrate or molecular mixtures thereof, serving as carriers for various substances, which are desired to be metered into controlled amounts, is described in U.S. Pat. No. 3,985,298. The substances to be released are impregnated into the cellulosic PLC material as part or all of the liquid phase (alcohol and / or water) contained in the micropores of the cellulosic material.

U.S. Pat. No. 3,846,404 discloses semipermeable membranes of gelled cellulose triacetate useful as carriers for other materials, for example, liquids having medicinal properties. The patent describes how to impregnate a fibrous fabric of polyethylene and cotton with gelled cellulose triacetate, thereby obtaining a woven cellulose-triucetal hydrogel material. It further describes the use of drug-implantable, drug-impregnated, gelled cellulose triacetate products which slowly release the impregnated medicine, as well as the casting of gelled cellulose triacetate on a woven or non-woven sheet material.

In one or more of the following patents, namely U.S. Patent Nos. 5,993,072; 3,993,073; 3,896,819; 3,948,254; 3,948,262; 3,828,777; 3,797,494; 4 060 084 and 3 995 654 describe devices for controlled delivery of medicine, which devices comprise a storage formed by a medicine and a solid or liquid medicine carrier and in contact with or surrounding this storage a wall of any of a plurality of materials, e.g. .a. a microporous material, the micropores of which contain a diffusive medium, for example a liquid phase comprising a solution, a colloidal solution, a suspension or a sol, which diffuses through the medicine.

U.S. Pat. No. 3,993,073 also discloses hydrophilic hydrogels of esters of acrylic acid and methacrylic acid and crosslinked polyvinyl alcohol as suitable wall-forming materials. The most important feature of the devices of these patents is a wall consisting at least in part of a microporous material, the pores of which contain a medium through which the medicine passes at a controlled rate, and a storage containing the medicine plus a carrier which can be penetrated by the medicine but at a higher speed than that with which the medicine can pass through the medium present in the micropores in the wall. British Patent Specification 1,318,259 discloses a suitable method of administering therapeutic agents or nutrients to ruminants by enclosing the therapeutic agent or nutrient in a thermally water-soluble material having continuous capillaries or pores and paper or fabric partially impregnated with water-insoluble polymers, for example cellulose acetate.

U.S. Pat. No. 3,594,469 discloses tablets containing magnesium and iron for prolonged administration to ruminants. According to one embodiment, each tablet consists of a cylindrical tube of magnesium alloy filled with hail and some biologically active substance and sealed at each end by means of porous discs.

U.S. Pat. No. 3,938,515 discloses a device for continuous and prolonged administration of a drug. This device comprises a container for the medicine and a solid or liquid carrier which is permeable to the medicine. Around the container is a wall of polymeric material.

This wall allows the medicine to pass through but more slowly than the carrier.

U.S. Pat. No. 3,946,734 discloses a diffusion cell which is specifically intended for implantation. This device essentially consists of a capillary, which at one end is closed with an impermeable material and at the other end is closed with a porous, neutral hydrogel. The biologically active substance is placed in the capillary against the impermeable material and the capillary is then filled with the hydrogel (agarose, polyacrylamide) through which the biologically active material diffuses.

Many of the previously described controlled release devices are referred to as zero zero delivery devices. However, these devices can maintain zero order delivery only for a short part of the calculated service life and are not practical for use for a long time, for example in ruminants. The device according to the present invention has and maintains a regulated, predetermined delivery rate of the zero order for mortar for a long time.

In addition, the prior art devices are subject to physical clogging or damage in the rumen reticulum, and this also applies to the devices which comprise a medicine container surrounded by a wall which consists at least in part of microporous material, the pores of which contain a medium which regulates drug delivery. Through the clogging is reduced and t.o.m. the drug delivery is interrupted, which of course means that the device becomes ineffective for its intended purpose.

The device of the present invention in which the pores of the porous material in contact with the present body contain a hydrogel, is substantially free of this problem and can deliver substances at a controlled and predetermined rate to an environment 4 containing an aqueous liquid for a long time.

When using the prior art devices (of the type described in U.S. Pat. Nos. 3,993,073; 3,993,072; 3,967,618; 3,948,262; 3,948,254 and 3,896,819) for controlled release of highly water-soluble drugs, it is preferred that the wall and / or the container is made of a material which is substantially water-impermeable, this in order to prevent dilution of the medicine container by absorbing body fluids into the device and reducing the speed at which the medicine is delivered. Accordingly, these devices are not suitable for delivering, especially at relatively high rates, water-soluble drugs. In addition, in most of these prior art devices, the medium that controls the rate of delivery and which is present in the pores of the wall around the container must have lower permeability to the medicine than the liquid carrier in the container. In this way, the release rate is regulated through the passage through the wall. The devices of the present invention are completely free from such restrictions. A significant difference between the device according to the invention and the previously known ones actually consists in the presence of a highly water-permeable hydrogel in the pores of the porous material, which is in contact with the container. The function of the devices is based on diffusion of water from the environment containing an aqueous liquid through pores or channels filled with liquid in the hydrogel and into the container and an outward diffusion of the medicine from the container to the environment. It has quite surprisingly been found that the concentration of the medicine dissolved in the container is not reduced, which results in a substantially constant release rate for a long time. However, the amount of dissolved medicine in the container varies continuously throughout the life of the device.

By using the anthelmintic morantine tartrate in a low content in the drinking water for calves, it has been possible to achieve that the calves had uninterrupted access to the medicinal water, as a means of endoparasitic control. This is described by Downing and co-workers, Irish Vet. J., 221, November, 1974 and in British Patent 1,530,161. Through continuous, daily anthelmintic medication on calves from early April to mid-July, it has been found that the formation of worm eggs in calves and prevent or at least minimize the development of severe larval infection in the pastures.

When mixed daily in the feed, morantel tartrate in low concentration on calves from the calves was released on the pasture until mid-July, it was found that parasitic gastroenteritis and lung machine infections could be successfully combated by reducing the contamination of the pasture. (Jones et al., Brit. Vet. J., 134, 166/1978 /).

The present invention relates to improved systems and devices for delivering the anthelmintic morantel "at a physiologically or pharmacologically effective controlled rate from a storage to an environment containing an aqueous liquid, in particular the rumen. The characteristics and features of the device according to the invention appear from the appended claims, hereinafter the terms "system" and "device" will be used without distinction of meaning.

The morantel permeable system of the present invention is valuable for the controlled release of said drug to an environment containing an aqueous liquid and is of particular value for oral administration to ruminants.

With the systems of the present invention, controlled release of morantel can be achieved over long periods of time. The devices are easy to manufacture and reliable and easy to handle in use. In addition, they are chemically and physically durable, do not clog the environment of use and are of particular value for oral use in the form of large ruminant pills. The present invention has for the first time been able to provide a practical device for controlled and uninterrupted delivery of morantel to an environment containing an aqueous liquid and the invention consequently fulfills a long-standing need, which has existed in particular in animal husbandry.

The system according to the invention comprises a barrier or shaped wall which is in contact with at least a part of a morantel supply, which barrier consists at least partly of a porous material comprising a porous tissue, the pores being filled with a hydrogel which releases by diffusion through liquid from the environment through the hydrogel's pores and morantel from the store. When the system according to the invention is used, the hydrogel contains liquid in the channels or pores of the hydrogel, through which the surrounding liquid diffuses and morantel is transported.

The systems or devices of the present invention may be designed in several different ways and in several different sizes depending on the purpose for which they are intended. Thus, for example, they may be prepared in the form of capsules for oral administration to animals, including humans, or they may be prepared in the form of cylinders for implantation. They can also be made in the form of large pills for ruminants.

A favorable embodiment of the device according to the invention comprises a porous material, the pores of which contain a hydrogel, in particular gelled cellulose triacetate, which is permeable to liquid from the environment, wherein morantel can diffuse through the pores of the hydrogel, which porous materials are in contact with at least a portion of a stock containing morantel and, if desired, a suitable water-soluble liquid excipient and optionally also a detergent. This device according to the invention has the form of a large pill intended for use for long-term and regulated administration of medicine on ruminants, in particular cattle and sheep. In particular, such pills are used for the prophylactic and therapeutic treatment of gastro-enteral infection of parasites, in particular helminths, and of lung machine infection in cattle and sheep, and they are also used for the parasitological treatment of helminth-infected pastures. In the present context, the term "large pill" includes cylindrical, spherical, spheroidal, elliptical pills or pills of another shape free of sharp edges and projecting portions.

When using prior art systems, one must consider and compromise between several factors, namely the carrier used in the storage, the solubility of the carrier in and / or the permeability of the medicine in the storage, the nature of the microporous wall surrounding the storage, the diffusive medium in the pores of the microporous wall, the relationship between the degrees of permeability of the diffuse medium and the drug carrier, the relationship between the solubility of the medicine in the diffuse medium and in the carrier and the need to maintain a substantially constant amount of dissolved medicine in the storage.

In this regard, the system of the present invention is much simpler in design and function. For a given system, the morantel release can be varied within wide limits by a simple variation of the surface area and the thickness of the porous material in contact with the supply, e.g. porous Tissue material, the pores of which are filled with hydrogel. Thus, the amount of chemical released can be controlled only by varying two parameters.

In the accompanying drawings, Figs. 1-5 illustrate various examples of systems according to the present invention. The fact that only a few examples are shown in the figures does not mean that the invention would be limited to these and many variations and equivalents are possible. Fig. 1 shows a cross section through a system 10 according to the invention. This consists of a cylindrical wall 11 in contact with a supply 12 containing morantel. The wall 1903973-1 in s-40 ll consists of a porous material, the pores 14 of which contain a hydrogel not shown in the figure, through which liquid from the environment containing an aqueous liquid diffuses into the storage 12 and morantel from the storage diffuses into the environment. through channels or pores in the hydrogel itself. The storage 12 consists of morantel 15, and a water-soluble excipient 16. The ends 17 are impermeable closures.

Fig. 2 schematically shows a system according to the invention of the same type as in Fig. 1 but with a perforated sleeve 18, for example of stainless steel, iron or plastic inserted into the system, for regulating the surface area of the porous wall impregnated with hydrogel. If the sleeve 18 is made of metal, it also serves to increase the weight of the system.

Fig. 3 shows on an enlarged scale the porous wall 11 of the system 10. The pores 14 contain a hydrogel 19 in contact with a morantel supply 12 containing morantel 15 and a water-soluble, liquid excipient 16.

Fig. 4 shows a system shaped as a capsule with only one closure 17.

Fig. 5 shows a further embodiment of the system 10 according to the invention. The porous material, the pores 14 of which contain a hydrogel not shown in the figure, constitute the closures. The cylindrical wall 18 is made of impermeable, non-porous material, in this case stainless steel, which together with the walls impregnated with hydrogel encloses a storage 12 containing mortar 15 and an excipient 16.

As stated above, the improved system according to the present invention comprises a container with morantel and in a preferred embodiment morantel and a water-soluble, liquid excipient. The water-soluble, liquid excipient has a number of important functions. Thus, for example, it eliminates air from the storage and thus enables higher "charge" in the production of the system and reinforcement of convective mixing inside the storage (which ensures constant morantel delivery). In addition, said water-soluble liquid excipient has an additional function, in that as morantel dissolves, no obvious change in volume occurs when morantel changes from solid or crystalline state to solution.

Typical water-soluble liquid excipients are monols and polyols as well as ethers thereof, such as ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and tripropylene glycol, 1,2-dimethoxyethane, mono-Cl alkyl ethers of ethylene and propylene glycols; N, N-dimethylformamide, dimethylsulfoxide and the like. The excipients must, of course, be compatible with the hydrogel.

The water-soluble liquid excipient should be a physiologically acceptable substance.

The amount of water-soluble liquid excipient used per unit weight of morantel is generally such that the morantel-excipient combination becomes a compact mass and this amount can be easily determined by simple experimentation.

To reduce the possibility of clogging during use, detergents can be added in an amount of up to 20% by weight, calculated on the total weight of the storage (morantel plus any excipient and detergent). The detergents may be organic or inorganic and representative detergents include sodium and potassium hexametaphosphate and tripolyphosphate, sodium lauryl sulfate, sodium glyceryl monolauryl sulfate, dioctyl sodium sulfosuccinate, bis (1-methylulfosyl) sodium sodium sorbitan mono-oleate and other fatty acid esters. You can also use other known detergents. The amount of detergent is not critical but should be as small as possible so as not to encroach on the amount of morantel in the store. The optimum amount of detergent is determined in the manner set forth below.

In the present context, the terms "store" and "store containing morantel" were used without any real difference in meaning.

The terms "porous material". "Porous membranes" and "porous walls" in the present context include porous tissue materials.

Representative types of such materials are described below. The porous materials used can be isotropic, ie. of homogeneous pore structure all through the cross section of the material, or they may be anisotropic, ie. do not have a homogeneous pore structure. They should, of course, be insoluble and non-reactive to the environment and to the contents of the store. In general, in the controlled release systems of the present invention, porous materials having a pore size between about 1 and about 10 μm can be used. It is necessary that the porous materials have continuous pores, i.e. pores communicating with openings on both surfaces of the porous wall. In order to facilitate the transport of morantel from the storage to the environment when using the systems according to the present invention, the pores or a part of them are filled with a hydrogel. By using a porous material, the pores of which are more or less filled with a hydrogel, a system is obtained which is not clogged or physically destroyed under conditions of normal use. By maintaining the physical integrity of the system, it can thus be used in environments and under circumstances where previously known hydrogel systems are destroyed and become ineffective for the purpose, namely controlled release of morantel for a long time. The systems according to the invention are of particular value for use on ruminants, in particular cattle and sheep. The hydrogel-containing pores allow the passage of liquid (water) through the pores of the hydrogel itself by diffusion from the environment in which the system is located during use and into the storage, where it dissolves morantel. The latter then diffuses through the liquid in the pores of the hydrogel-containing pores in the porous barrier material at a rate which depends on the morantel concentration in the solution in the storage, on the resistance offered by the barrier, i.e. the liquid in the pores of the hydrogel, and on the effective surface area of the porous part of the wall.

When morantel leaves the system, a depletion zone is eventually formed, which gives rise to a variable boundary between morantel and solution. the diffusion of the water into the system from the environment through the pores in the hydrogel-containing pores in the wall into the reservoir gives rise to convective mixing of the inflowing liquid phase and the solution in the reservoir. The driving force for this mixture is the difference between the densities of the two solutions, which is caused by their large differences in concentration. A function of the water-soluble liquid excipient is, as pointed out above, to facilitate the maintenance of this large density difference and thereby increase this critical mixing. The convective mixing results in a constant morantel concentration in the store, which in turn provides controlled release of morantel for a long time and thus ensures the release of morantel of the zero order as long as there is undissolved morantel in the system. When morantel leaves the storage and aqueous liquid from the environment diffuses into the storage, the amount of dissolved morantel in the storage continuously varies throughout the life of the system, ie. during the long period of morantel delivery. This mechanism for morantclav enabling makes it possible to arbitrarily geometrically design the system and the size and shape of the stock are not limited. This is in direct contrast to prior art systems of U.S. Pat. No. 3,993,073, which operate so (and are so manufactured that this function is achieved) that there is a substantially constant amount of dissolved medicine in the storeroom and that loose medicine diffuses in the storeroom to the wall. This system therefore has serious limitations regarding size and shape.

By "hydrogel" in the present context is meant gelled cellulose triacetate containing water; Compare U.S. Patent Nos. 1,693,890 and 3,846,404.

The water in the hydrogel pores can be easily exchanged for water-soluble liquids, such as water-soluble, liquid excipients of the type indicated above. Other water-soluble liquids can also be used instead of water, e.g. alcohols with 1-4 carbon atoms.

It is convenient to exchange the water in the hydrogel for a suitable, water-soluble liquid, which has a lower vapor pressure than water, in order to stabilize the systems of the present invention, especially when the hydrogel is gelled cellulose triacetate. Such a system can then be stored without the loss of efficiency which results from the hydrogel drying. When a water-soluble, liquid excipient-morantel combination is used in storage, it is convenient to use the same liquid to exchange the water in the hydrogel.

The hydrogels themselves are porous in that they contain areas or regions, ie. channels or pores, filled with water or other liquid. Thus, in the present context, when referring to diffusion or transport of morantel through walls "whose pores contain a hydrocele" or the like, it is meant that diffusion or transport of morantel takes place via these regions and not through the hydrogel as such. The hydrogel itself is liquid-filled. pores, which serve as diffusion pathways and are in fact considered to be permeable to the liquid and moraine of the environment in the store.

The porous wall which is in contact with the morantel-containing stock consists of polypropylene or polyethylene fabrics, in particular of the filter cloth type.

The selected fabric must, of course, be compatible with the hydrogel with which it is to be impregnated and with the intended use of the system.

The porous tissue material impregnated with the hydrogel must, of course, have sufficient strength and durability and be sufficiently inert to the morantel and the environment in which the system is intended to be used, so that it retains its physical l2> '4o_ 7903973-1 -l2-1 and chemical integrity throughout its life.

The porous material is impregnated with the hydrogel in a manner well known to those skilled in the art in the field in question. A suitable and relatively simple process for impregnating porous material with gelled cellulose triacetate comprises forcing a solution of cellulose triacetate in formic acid or acetic acid into the pores of the porous material by dipping the material in the cellulose triacetate solution in a containers, which may be subjected to a vacuum. After the impregnation, the material impregnated with cellulose triacetate can be subjected to coagulation by contact under equilibrium with a large volume of water, so that a material impregnated with hydrogel is formed. When the porous material is sintered polyethylene, acetic acid is preferred over formic acid as the solvent for the cellulose triacetate, since acetic acid better than formic acid wets the polyethylene, thereby facilitating impregnation.

For the production of systems which are storable before use, the hydrogel-filled pores are freed from water by equilibrating them in a suitable water-soluble liquid, for example one of the above-listed, water-soluble, liquid excipients. As pointed out above, it is convenient to exchange the water in the hydrogel-filled pores of the porous wall material with the same water-soluble liquid used as the excipient in the reservoir, when the reservoir contains a combination of morantel and excipient. If the supply consists only of morantel, the choice of water-soluble liquid for the exchange of the water in the hydrogel in the pore-separated pores in the porous wall is determined solely by the purpose of use of the system. Such a liquid is suitably mixed into the hydrogel at the time of preparation of the porous wall, the pores of which contain a hydrogel and before the storage is introduced into the system in the manner indicated in the present context.

The previously known systems which are most similar to that of the present invention, i.e. those described in U.S. Pat. Nos. 3,993,073 and 3,993,072 are based on the principle that the medicine in the storage has a degree of permeability in the medium in the pores of the porous wall and another in the carrier in the storage. It is claimed in these patents that the rate of release of the systems is of the zero order and to enable this it is essential that the medium in the walls has a lower permeability to the medicine than the carrier in the storage. The medium in the wall then becomes the factor which determines the release rate of the system. Dissolved medicine diffuses through the more permeable carrier to the inside of the wall at a rate sufficient for the wall to determine the rate of delivery of the system. This results in zero-order delivery rate for a short time, until the folding boundary line in the system becomes large enough to cancel the difference between the carrier and wall medium permeabilities, whereupon zero-order velocities can no longer be maintained. Due to this, the successful use of these systems is limited in practice and if they are manufactured in a practical, useful dosage form and size, they are not suitable for delivering large quantities at a zero order rate.

The systems of the present invention, in contrast to those previously known in use, have an aqueous medium in the environment, in the wall medium and in the storage. Although the permeability of the morantelle is the same in the liquid in the wall and in the storage, release rates of the zero order are achieved during large parts of the total service life of the system. In addition, it can be pointed out that the maintenance of zero order delivery does not depend on diffusion in the storage carrier and consequently there are no restrictions on geometry or dose and with these systems it is possible for the first time to deliver large amounts of morantel at zero order speeds. at the same time as the systems can be designed with practical size and shape.

In order to achieve the most efficient function of the systems according to the present invention and to reduce leakage and clogging, it is important that the porous material is impregnated with the hydrogel as completely as possible. Systems with one and the same surface area can provide different dosing rates and delivery times for morantel by varying the characteristics of the membrane wall, in particular its thickness, pore size and porosity and by varying the size of the storage charge.

As pointed out above, a preferred embodiment of the device according to the present invention is a large pill for use in the controlled delivery of morantel to ruminants, in particular cattle and sheep, for a long time. The pill is administered to the animals in such a manner, preferably orally, that it remains in the rumen reticulum for a long time, during which they continuously deliver morantel to the animal at a controlled rate. Said system thus enables, by a simple, oral administration, prophylactic and therapeutic treatment of various pharmacological and physiological conditions to which the animals are exposed.

In order for the large pill once inserted into the rumen reticulum to remain there for a long time, it is necessary that it has a density of at least 2.0 g / ml. In practice, the density can vary between 2.0 and 7 g / ml and up to be even higher. Density is of course the most important factor, which affects the retention of the pill in the rumen reticulum. The total size of the pill is a function of the required dose and the size that can be administered in practice. Once the desired size has been determined, additional weight gain can be achieved to achieve the desired average density. It is desirable, if possible, to use the maximum allowable size, because large pills with a given density are maintained better than those with a lower density. When the average density of the pillar rises above a value of about 5.0, the retention factor does not increase significantly. The preferred average density is thus between about 2.5 and about 5 mg / ml.

The size of the pill depends, of course, on the animal intended for treatment. For such ruminants as sheep and goats, the pills and weight are less than for a cattle. Maximum size is determined by practical views on the administration.

For sheep, about 1 g is the minimum weight that a pill with a density of 4 g / ml must have in order to be retained. The size of the pill varies according to the density of the pill. For administration to cattle, 5 g is the minimum weight of a pill with an average density of 4 g / ml. Also in this case, the largest size of the pill is determined by practical considerations and by the minimum average density of the pill. Thus, for example, a pill with a length of about 7.5 cm has a diameter of 2.5 cm and a density of 2.2 g / ml has a weight of young. 90 g.

Pills containing only the elements listed above generally have a density below the minimum limit indicated above.

Accordingly, it is necessary to increase the average density of the pellets by incorporating therein a suitable high density material, for example a metal (iron powder, iron or steel shot) or the like or also a mineral, such as CaSO 4.

Alternatively, the average density of the pellets can be conveniently increased by incorporating in the pellets a high density inner perforated sleeve, for example of metal, such as stainless steel, steel, in particular low carbon steel or iron, which in turn is surrounded of the porous membrane impregnated with hydrogel. The perforations in the sleeve should be large enough to allow free passage of morantel and liquid from the environment through the hydrogel impregnated porous membrane. The main functions of the sleeve are to increase the average density of the pellet to such a value that the pellet is retained in the rumen reticulum and regulates the surface area of the hydrogel-impregnated, porous material which is in contact with the morantel-containing stock. In addition, such a sleeve, although not necessary, improves the physical stability of the pill and ensures that its physical form is substantially maintained under the conditions of use.

Another and preferred alternative is a pellet with a cylinder of metal (steel or iron), which at one or both ends is closed with a porous membrane, the pores of which are impregnated with a hydrogel. Pills of this type are preferred because of their simplicity and economical manufacture and the ease with which their density can be adjusted. A low carbon steel cylinder is highly preferred. Other options are obvious to those skilled in the art.

The system of the present invention can be used for a variety of purposes and in a variety of situations for which a controlled delivery of morantel is required. It can be used for administration of morantel next to or at a distance from the system's application site. They can be applied by suitable means to suitable places in the body of the animal, where they come into contact with body fluids, for example in the stomach of domestic animals, in particular in the rumen reticulum of ruminants. They can also be implanted as depots for the administration of morantel at a regulated rate. Implants differ from other embodiments only in the shape, which of course must be adapted to the implant. Other purposes are sublingual or buccal tablets, pessaries, suppositories, bandages and pieces of skin.

As pointed out above, in a preferred embodiment of the system according to the invention, the morantel stock contains morantel and a water-soluble excipient. Systems designed in this way have the advantage of giving a larger amount of morantel per unit and longer service life to the system. However, the store can only contain morantel.

The system of the present invention is particularly valuable for long-acting pills for the therapeutic and prophylactic control of helminth infections in ruminants, in particular cattle. Pet protection becomes relatively comfortable. In temperate climates in the pastures during the early spring, the larval population (the rest from the previous season) is relatively low, but is increased by cycling through the grazing animals there, so that it increases sharply during the summer. This gives rise to clinical parasitism during the summer grazing and deterioration of the condition of the beetmmen fl nmn One can, through the uninterrupted and regulated release of morantel, in the rumen reticulum of grazing animals during the early season, when the grazing infestation is low, suppress the subsequent larval development. thereby breaking the above cycle and keeping the worm level in the pastures and in the animals low. This reduces to a minimum parasitic infection in ruminants, which graze on the same pastures during the summer. This way of controlling helminths is especially attractive and valuable for calves, as they are highly sensitive to helminths when they are first released to pasture. Continuous use of pills according to the invention reduces the amount of helminths in a given area. By using the anthelmintic pills according to the present invention in this way, the seasonal increase of the larvae is prevented or at least reduced to a minimum. on the pastures, which cause parasitic gastroenteritis and deterioration of grazing animals later in the season. When the control is carried out in this way, the time for drug delivery corresponds with the spring propagation phase and not with the period of severe grazing infection, larval infestation and machine infection that results in clinical disease and deterioration. It is for this reason that this method of control is referred to as "indirect control". In other words, if ruminants - on which one or more of the systems intended according to the present invention, which enable regulated and continuous release of morantel - are allowed, are allowed to graze on pastures early in the season, i.e. when the larval infection is at or close to its minimum, a reduction to a minimum of the usual seasonal increase in the larval infection of the pastures is made possible, whereby the animals grazing on these pastures are protected throughout the grazing season.

For "indirect control" of helminths is administered on the ruminant system according to the invention, preferably in the form of a large pill for a period of time in said epidemiological cycle of said helminths, when the grazing of the pastures with said helminths, their eggs and / or larvae is at a minimum or in close to it. In temperate zones, this corresponds to the time for the calves to be released onto the pastures in the spring. For maximum efficiency so. 7903973-1 _17 .. the pill is administered to the calves about 2-7 days before the calves are released on the pasture. In non-temperate zones, for example in semi-tropical or tropical areas, the period of least grazing infection normally occurs before the rainy season. The administration of the pills on the ruminants in such areas preferably takes place 2-14 days before the start of the rainy season. However, helminth control in non-temperate zones is best achieved through "direct control" due to the difficulty of predetermining the beginning of the rainy season.

The large pills according to the present invention also eliminate established hermint infection in ruminants and prevent the establishment of machine infection during the summer period with severe attack. This use is referred to as "direct control".

Through the direct method, ruminants are protected only during the period of the release of the anthelmintic. The indirect method, on the other hand, protects ruminants who graze on a given pasture throughout the season, as it significantly reduces the infection of the pasture. Particularly useful for such purposes are water-soluble salts of fE) -1,4,5,6-tetrahydro-1-methyl-2- [2- (3-methyl-2-thienyl) ethenyl / pyrimidine (morantel). Representative of the preferred water-soluble salts of morantel are tartrate and citrate.

The major pills of the present invention are administered orally to, for example, by intubation (balling gun). When administered to calves, the appropriate average release rate of morantel (calculated as the base) for indirect control of helminths is approximately 60-200 mg (morantel base) per day for approximately 60 days, covering the normal maximum survival time of the spring population of larvae. For direct control, longer delivery times are appropriate, namely 60-120 days, as the period of exposure to severe grazing infection normally extends from midsummer to autumn. Release rates of about 60-150 mg (calculated as morantel base) per day provide effective control of helminth infections during such '7903973-1' 40 _ 18 release periods. In larger animals, more than one pill can be administered. For indirect control of helminths using salts of pyrantel or levamisole, the desired average release rate (calculated as free base) is about 100-400 and about 100-500 mg / day, respectively, over a period of about 60 days. For direct control, release rates of about 100-300 mg (as free base) pyrantel and about 100-400 mg (as free base) levamisole per day provide effective control of helminth infections for 60-120 days of most severe attacks.

By continuous administration of low dose dosage of morantel by the helminth control system of the present invention, an effective profile is obtained which could not have been foreseen and which quite surprisingly and advantageously differs from that observed in conventional therapeutic use of helminths. morantel. Thus, for example, lung machine infection in the animals is effectively prevented during the drug delivery period by prolonged maintenance of the level of morantel tartrate or citrate (or other salt) in the digestive tract of the ruminants.

Furthermore, it can be pointed out that cattle and sheep grazing on infectious pastures and which are subjected to conventional therapeutic treatment are immediately re-infected with intestinal nematodes, whereas animals treated with the system according to the present invention are substantially freed from established infection and protected from renewed infection for a period of 60 days or longer.

Use of the system of the present invention for controlling infection in pastures, i.e. indirect control, is a unique, practical and surprising method of helminth control and protection of ruminants, in particular grazing ruminants, which method surpasses all previously known methods, and the animals are protected throughout the grazing season. The daily weight gain compared to untreated control animals during the grazing season is significantly greater than that obtained by conventional therapeutic methods.

The rate at which mOrantel departs from the storage through the walls of the system and the efficiency of a given combination of ncmanu och and / or water-soluble excipient and / or detergent in the system can be readily determined by those skilled in the art, for example by transmission methods or sorption methods. desorption methods. One technique that can be conveniently applied to select suitable porous materials and hydrogels involves the use of a selected porous material, the pores of which are filled with the selected hydrogel and which are used as a barrier between a rapidly stirred saturated solution. of morantel, from which it is desired to achieve controlled release, and a solvent bath kept under rapid agitation, the composition of which simulates the aqueous liquid environment in which the system according to the present invention is used. Each of the temperatures of the solutions is maintained at a constant value, preferably at a value which is approximately at the temperature prevailing in the environment in which the system is intended to be used. Samples are taken at predetermined intervals from the solvent bath and the mantle concentration is determined in these samples. One can also apply the standard procedures described in the Encyclopedia of Polymer Science and Technology, Vol. 5 and 9, pages 65-82 and 794-807, 1968, respectively, and references therein as well as in the Chemical Engineers Handbook, pp. 17-45, 1963, McGraw Hill, Inc.

A method which is particularly valuable for determining the rate of release from a system of the present invention and the relative mcrites of a given excipient or detergent for use in a given system, where m @ díCin @ n is morantel, can be summarized in the following method: the in vitro method is based on the release as a function of time for a water-soluble salt of morantel, for example tartrate from a system according to the present invention. A system containing morantel tartrate is placed in a one liter, conical flask, which is protected from light due to the photosensitivity of the morantel tartrate and 500 ml of a phosphate buffer with pH 7 is added. The temperature in the contents of the flask is adjusted to 37 ° C and maintained at this value. The flask containing system of the present invention is shaken at about 70 strokes (7.62 cm) per minute and 5 ml samples are taken periodically. The volume of the sample taken is replaced with an equal volume of new phosphate buffer at pH 7 and the shaking is continued. The morantel concentration in the samples is determined spectrophotometrically by measuring the absorbance at 318 nm and as a blank sample new phosphate buffer with pH 7 was used. Sampling is continued until 5 g of morantel tartrate is released, and at this time the system is transferred to another flask containing 500 ml of new phosphate buffer pH 7, after which the procedure is continued in the same manner as indicated above.

In vivo release of morantel tartrate from the system of the present invention is determined by administration of the system, for example to normal young bulls or young bulls with rumen fistula, and after a certain time, for example 30, 60, 90 or 120 days, the system is taken out via the fistula or the animals are slaughtered and the systems are taken into account to determine the remaining amount of morantel tartrate in the systems. Samples of this kind have shown that the release rate of morantel tartrate in vitro is about four times as high as the release rate in vivo.

The following examples illustrate the invention, but this is of course not limited to what is described in these examples but can be varied within the scope of the following claims.

Example 1: A large sintered polyethylene pellet with pores filled with gelled cellulose triacetate and a stock containing morantel tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate and with a perforated stainless steel sleeve was prepared on the following method: A sintered polyethylene tube with an average pore size of 10 μm, outer diameter 25.4 mm, inner diameter 22.225 ml and a length of 7.938 cm was dipped with one end (which is hereinafter referred to as end 1) in a 10% solution of cellulose acetate butyrate in methylene chloride to a depth of 4.763 mm. The tube was then dried in air and the other end (hereinafter referred to as end 2) was dipped in the cellulose acetate butyrate solution to a depth of 9.525 mm and dried. This was repeated and the end 1 was dipped again in the cellulose acetate butyrate solution for 30 seconds, allowed to air dry for 60 seconds and a cellulose acetate butyrate stopper 22.225 mm in diameter and 3.175 mm thick was inserted into the end 1 so that its outer surface was in the surface of the pipe end. The cellulose acetate butyrate stopper had been held in methylene chloride for 60 seconds before insertion at the end 1. The tube was then rolled along the table top, while finger pressure was applied to the end 1 to ensure complete attachment of the stopper to the tube. A No. 3 rubber stopper with a continuous channel and a glass tube inserted therein was inserted into the end Z of the tube. The glass tube was so long that its part projecting from the rubber stopper reached through a rubber stopper in the vacuum flask when the tube rested on the bottom of the vacuum flask. The end of the glass tube projecting from the plug of the vacuum flask was connected to a flask containing a 6% solution of cellulose triacetate in formic acid and a vacuum of approximately 150 mm Hg was established in the vacuum flask. When the cellulose triacetate solution covered the surface walls of the tube, which were not dipped in cellulose acetate butyrate, the tube was removed from the vacuum flask and the bulk of the cellulose triacetate was dried. The tube was then turned upside down so that the cellulose triacetate flowed out of the tube. The outer and inner open ends of the tube were wiped clean with a cloth. The tube was then immersed in distilled water, in which it was allowed to stand overnight to equilibrate. It was then taken out of the water, the outer surface was wiped with a cloth and excess water was shaken out of the inside of the tube. The impregnation of the pores of the tube with cellulose triacetate and equilibration in distilled water was repeated.

Equilibrium was then set in running water for 4 hours.

The tube was then tested for leaks by connecting it to a nitrogen source, then immersing the tube in water and applying a pressure of 0.28 kg / cm 2 of nitrogen for 10 seconds. If there were leaks, impregnation and equilibrium in water were repeated.

Equilibrium was then infused into the polyethylene glycol 400 tube overnight, after which the tube was removed from the polyethylene glycol 400 and allowed to drain in an upside down position for 4 hours. Excess polyethylene glycol 400 was wiped from the outside of the tube with a cloth and a perforated stainless steel sleeve having an outer diameter of 22.225 mm, an inner diameter of 18.923 mm and a length of 6.985 cm, which sleeve was provided with 16 equal parts. distance existing circular heels with a diameter of 7.114 mm were inserted into the tube so that its end was in the same plane as the closed end of the tube. Clamps of celJulosa triacetate formed upon insertion of the tight-fitting sleeve into the tube were removed. A plug of cellulose acetate-butyrate 3.175 mm was then inserted into the open end of the tube, so that it abuted against the end of the stainless steel sleeve and the tube was cleaned so that its end came to lie in the same plane as the outer surface of the plug. The plug was removed and the tube was filled with a homogeneous mixture of 63.31% morantel tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexametaphosphate all the way up to the level of the end of the stainless steel sleeve. The open end of the tube was filled with 10% cellulose acetate butyrate solution, which was then immediately drained, after which the open end of the tube was dipped in a cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. A stopper of cellulose acetate butyrate (as doppulu in menuene chloride for 60 seconds immediately before use) was then pressed into the open end of the tube with sufficient force to press the stopper against the stainless steel sleeve. The tube was then rolled over the table surface, exerting a sufficiently strong finger pressure to achieve complete fixation between the stopper and the tube. The tube was then allowed to dry for 1 hour, after which each end of the tube was dipped in a 10% cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. The weight of the pill thus obtained was about 90 g, of which 24.8 g consisted of the drug mixture. Its density was 2.2 g / ml. This pill released approximately 250 mg of morantel tartrate per day in vivo in cattle for approximately 60 days.

Example 2: Three pills prepared as described in Example 1 were tested in vitro as described above and gave an approximately constant release rate for 4-17 days with an average release rate for all three pills of 0.927 g morantel tartrate per day. gg Accumulated amount of morantel tartrate, g Try in vitro Pills 1 Pills 2 Pills 3 ilsifí i 1 0.357 0.295 0.284 2 0.804 0.723 0.66 _ 4 1.63 1.63 1.38 2.12 2.24 1.86 6 2, 61 2.96 2.4 8 4.05 6.31 3.7 11 6.55 9.0 5.76 13 8.24 11.34 7.67 11.38 13.4 9.74 19 14.52 16.2 13.2 17.99 17.4 15.4 29 17.13 17.3 15.9 Three other pills were prepared in the manner set forth in Example 1 and placed in the rumen reticulum of cattle. When the pills were taken at the end of the 30 day for these in vivo experiments, it was found that the release rate had been 0.224 g of moran tartrate per day. This means an in vitro to in vivo ratio of 4: 1.

Example 3: Two pills were prepared in the manner set forth in Example 1 and tested in vitro as indicated above. An average rate of release was obtained during the time during which the release was constant, namely between 0 and 14 days, amounting to 0.96 g of morantel tartrate per day.

Accumulated amount of moran tent - Experiment in vitro É3ÉÉ¿-g days Pills 4 2illg3_§ 1 0.51 0.59 2 1.5 2.56 3 2.4 2.2 4.9 5.4 6 5.1 5.9 7 6.5 6.1 9.7 9.7 12 11.0 11.7 14 13.5 12.6 17 14.8 13.6 19 16.4 14.6 21 17.1 17.7 24 16 , 8 14.7 26 16.9 14.8 Experiments in vivo with identical pills introduced into the rumen reticulum of cattle for a period of 30-60 days gave the following results: Pills no. Attempts at vívq, Average release date of morantel tartrate, g / day 6 so o, zzz 1 so 0.228 s 45 0.238 9 45 ogsss 1o 49 0.174 11 oo 0.198 12 60 0.171; The mean daily release was U, ¿Z4 g and the ratio between in vitro and in vivo experiments was approximately 4: 1. 10k 40 '7903973-1 _ 24 _ Example 4: Pills were made of stainless steel sleeves with outer diameter 22.225 mm, inner diameter 21.336 mm, wall thickness 0.889 mm and length 3 cm. The ends of the sleeves were threaded 0.5 mm at each end in order to be able to hold collars, which in turn were intended to hold hydrogel-impregnated sheets of porous tissue. These having an outer diameter of 22.225 mm and a thickness of 3.175 mm consisted of polypropylene felt with pores with an average size of 50 μm. They were impregnated with glazed cellulose triacetate and are prepared by immersion in a 6% solution of cellulose triacetate in formic acid in a vessel which could be placed under vacuum 25 mm Hg or less. The contents of the vessel were kept for about T0 minutes under vacuum, after which the discs were removed, dried free of excess cellulose triacetate solution, then placed in dosed water all night to achieve equilibrium. The discs were then taken out of the water, dried with a cloth and immersed in polyethylene glucol 400 overnight to equilibrate. The discs were then removed and dried with a cloth.

Impregnated boards were mounted on one end of each sleeve by layer-laminating between two washers 0.254 mm thick and with the same diameter as the steel sleeve. The washer inside the steel sleeve was made of cellulose acetate butyrate and the other of rubber cloth for dental use. The ends were then closed with stainless steel collars with an opening with a diameter of 2T, 336 mm. The sleeves were then filled with morantel tartrate (63.3%}, polyethylene glucol 400 (26.6%), sodium hexametaphosphate (T0.1%) and the other end of each of the sleeves was sealed as above.

The pills contained 21.4 g of morantel tartrate, weighed 97 g and had an average density of 30.30 g / ml.

The pills were administered to young bulls with the rumen fistula by intubation and taken via the fistula after 30, 45, 60, 75 and 90 days to determine the amount of medicine remaining in the pills.

With the help of the data thus obtained, it was possible to calculate the average daily release of moraine tartrate.

Pills Number of days in the young bull Delivery rate, mg / day 1 30 07 2 30 108 3 45 82 4 45 58 60 136 40 7903973-1 _ 25 _ (continued) Pills Number of days in the young bull Delivery rate, __ mg / day 6 60 91 7 75 71 8 75 68 9 90 67 90 106 The mean release rate was 85 mg / day with a standard deviation of 25 mg.

For each young bull, a significant reduction in the number of parasite eggs in the faeces was observed.

Example Gel 5: In the manner set forth in Example 1, Tyra pills were prepared. Each of them consisted of a tube of sintered polyethylene, the pores of which had an average size of 10 μm and were filled with gelled cellulose triacetate. The stainless steel sleeve extended only through one part of the tube, so that another part of the tube, so that another part thereof was free from the sleeve. The stock contained morantel citrate (63.3%), mixed with polyethylene glucol 400 ($ 26.6) and sodium hexametaphosphate (10.1%). Instead of the perforated stainless steel sleeve, a non-perforated sleeve with a length of 5.08 cm, 4.445 cm, 3.175 cm and 1.905 cm, respectively, was used in this case. The walls of the sleeve had a thickness of 0.165 cm. A drug mixture was introduced into each of the needles so as to obtain a drug zone over the sleeve of 6.35, 12.70, 25.4 and 38.1 mm, respectively. A stainless steel stopper with a thickness of 12.7 mm and a diameter of 22.224 mm was inserted into each of the tubes on top of the medicine mixture. The ends provided with steel plugs were cleaned so that a disc of cellulose acetate butyrate could be inserted above the plugs at the level of the pellets. The total weight of the pellets was 120.0, 115.4, 106.2 and 97.0 g, respectively. The weight of the drug mixture varied. they were between about 25.5 g and about 27.4 g / pill and the density of the pills was 3.1, 2.98, 2.75 and 2.51 g / ml, respectively.

Example Gel 6: In vitro test for the release rate of morantel citrate with the pills prepared according to Example 5, it was found that each of these gave constant release of the drug for a period of 3-21 days. The lighter of the four pills of Example 5 (with 1.905 cm long sleeve) had an average release rate of 774.8 mg of morantel citrate per day; , during the period of 3-21 days, during which the release was constant.

Example 7; Fourteen pills were prepared in the manner set forth in Example 1 and tested in vivo on bovine animals; They showed an average morantel-tartrate release rate of 238 mg / day for a period of 60 days. The standard deviation was 67 mg (28%).

Exemgelfß; The procedure described in Example 1 was repeated with the change that the length and diameter of the sintered polyethylene tubes were half of what is indicated in Example 1. The pellets thus obtained are intended for sheep and gave controlled release of anthelmintics for a long time in vivo. .

EXAMPLE 9 The procedures described in Examples 1 to 5 were repeated with the modification that instead of sintered polyethylene, sintered polypropylene was used; whereby the average porstorßr 1eken'var = l00.} um ;.

The pellets so produced gave controlled release of moran- ~~ tel during the loan period during the in vitro test: Exemgel 10; _Pills: were made? Using stainless steel sleeves supplied dimensions; namely: 225225 mm outer diameter, 2l ; 336Émm: inner: diameter; away§thick1ek * 0.889 * mm * and length 7.62 cm. The ends of the sleeves were threaded 0.5 mm at each end for attaching a collar, which in turn was intended to hold a porous, hydrogel-impregnated disc. imp * - impregnated with gelled cellulose triacetate.

The contents of the vessel were kept under vacuum for about 10 minutes, after which the slices were removed and dried free of an excess of cellulose triacetate solution. They were then left in distilled water all night for equilibration; the slices were then taken out of the water and dried. with a cloth and placed in polyethylene glycol 400 all night in order to balance. Finally, the discs were removed and dried with a cloth.

The impregnated sheets were mounted at one end of each tube by layer lamination between two trays ~ 0.254 mm thick and the same diameter as the steel sleeve. The washer next to the steel sleeve consisted of cellulose acetate butyrate and the other of rubber cloth for dental use. The ends were closed with stainless steel collars with an opening with a diameter of 21.336 mm. The tubes were then filled with the desired chemicals and the other end of each tube was sealed in the manner indicated above.

In this way, tubes with the following chemicals were prepared in the stock: morantel citrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%).

Example III: The procedure described in Example 1 was repeated with the change that the pills were filled with morantel tartrate instead of with the mixture of morantel tartrate, polyethylene glycol 400 and sodium hexametaphosphate given in said example. The pill weighed 84.0 g, of which the morantel tartrate was 18.6 g.

In the in vitro test above, the pills gave a controlled and almost constant release of morantel tartrate during the test period 8-20 days with an average release rate of 1.36 g / day.

In vitro test, days Accumulated amount of morantel tartrate, g 1.7 0.04, 7 1.03 8.7 2.74 12.7 7.63, 7 12.3 19.7 17.5 23.7 18 .3 26.7 18.6 Exemgel 12: A steel sleeve with low carbon content, length 8.77 cm, inner diameter 2.16 cm, outer diameter 2.54 cm and a 0.3 cm deep and 0.6 cm wide groove in the entire circumference of the sleeve 0.1 cm from each end intended for snapping in an aluminum cap (aluminum crimp) was closed at one end with a sheet of sintered polyethylene with ultra-high molecular weight (a polyethylene with an average molecular weight of 2-4 million made by Glasrock, Porex Division, Fairburn, GA.) The disc had an average pore size of 10 Pm and was impregnated with gelled cellulose triacetate as indicated in Example. The disc had a diameter of 2.54 cm and a thickness of 0.16 cm.

It is attached to the sleeve by means of an aluminum cap. The sleeve was then inverted and filled with a homogeneous mixture of 54.4% moraneal tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The above closure was repeated, whereby the final pill was obtained. Its total weight was 145.1 g, of which 41.4 g consisted of the drug mixture. Its density was 2.8 g / ml.

The aluminum cap at each end of the sleeve had a 3.25 cm 2 central opening, whereby the total surface area for drug delivery was 6.5 cm 2. The pills so produced gave a regulated release of morantel tartrate on cattle for about 90 days.

Example 13: This example describes a field experiment performed with 40 calves as experimental animals. The calves were of the same breed, weight (average weight 150 kg) and sex and had not previously been out grazing.

The calves were divided into 4 groups of 10 animals each according to body weight. Two of the groups were medicated replica groups and the other two control replica groups. A tracer calf was added to each of the four groups of experimental animals at the beginning of the field trial and every four weeks thereafter. Each reference calf was kept in its pasture for 2 weeks, then taken out and kept in the stable 3 weeks before slaughter for the sake of worm counting.

The experimental and reference calves were released on infected pasture, on which infected cattle grazed the previous summer and autumn. The pasture was large enough for 44 animals during the entire grazing season and was divided into 4 equally large and from each other separate pastures; On each of the calves in the medicated replica groups, a 60 day pill prepared orally as administered in Example 1 was orally administered. The pill gave continuous delivery of morantel tartrate at 250 mg / animal (equivalent to 150 mg morantel base) per day for 60 days. The animals in the medicated groups received the pills orally 2 days before they were released on the spring bed. Using a metal detector, it was confirmed that each of the experimental animals had the pill 24 hours after administration. Pill retention was checked at 2-week intervals thereafter. All the medicated animals, control animals and reference animals are weighed before placing on the pasture and at intervals of 4 weeks. Grazing samples were collected according to the method described by Taylor (Parasitology, 3l, 473, 1939) at two week intervals and starting 4 weeks before the field trial was started and the collection was continued until the end of the trial.

Stool samples were collected for McMaster eggs and lungworm larvae at the beginning of the experiment and at 2-week intervals thereafter. During the first 8 weeks, these samples consisted of rectal samples (one from each animal). Thereafter, the rectal samples were collected every four weeks, so that they coincided with the weighing of the animals. At intermediate times, samples (10 for each group) were collected from the bait (Gibson, Veterinary Bulletin No. 7, 403-410, 1065).

Total worm counts were performed in the abomasum including rucosal digestion, small intestine and the lungs of slaughtered animals. group Treatment gag Number of animals l morantel tartrate A l0 plus one reference 250 mg / day calf every four weeks 2 morantel tartrate B 10 plus one reference 250 mg / day calf every four weeks 3 Control animals C 10 plus one reference calf every four weeks 4 Control animal D 10 plus a reference calf every four weeks These data are presented graphically in Pig. 6, 7 and 8. Fig. 6 shows the weight gain during the grazing season for both the medicine-treated animals and the control animals. For all animals, the weight gain was approximately the same during the first three months. Thereafter, the weight gain of the control animals was slowed down and even led to a weight loss for a certain period of time, which coincided with an increase in the number of parasites in the pastures. The medically treated animals then continued their weight gain at almost the same rate as during the previous grazing season.

Figures 7 and 8 show the parasite population during the grazing season for the medicine-treated animals and for the control animals.

The number of eggs per gram of feces (the right ordinutun; ooh antnlef larvae per kilo of dry pasture (the left ordinate) is given as a function of time. The calves were released to pasture in mid-May. On the medically treated calves, 60-day-olds were orally administered 9039: 73 '1 _30 ... 7 pills two days before the calves were released on the pasture, which gave a treatment until mid-July ..

When the calves were released on the pasture, the number of eggs in the faeces and the number of larvae in the pastures were low. In the control group (see Fig. 7), the eggs began to appear in the faeces at the beginning of June and reached a maximum at the end of July, after which a slow decrease took place during August and September. At the end of July, these eggs gave rise to an increase in the larvae in the pastures and this increase reached its maximum in August.

In the medicine-treated animals (see Fig. 8), egg production was dramatically reduced during June and July, which was reflected in a significant reduction in the number of larvae in the pastures during July and September: Example 14: The same field samples as in Example 13 was performed but using only one group of drug-treated animals in each experiment. The data thus obtained are compiled in the following table. 7903973-1 3 3 3 _. mám S. w 1__ E E: E _. ii 3 ß Q., 3 Q 2 ._ _12 f Q å 02 m2 _. ïï ï m S 93 E; _. må I .N ä E; Z ._ QS ï m E. El 2 _, cá i NE: 3. O ä. GQ .. N. _ nß fi nßnucox anwa æw fi fåmwmä .nmhnm flfifi opucox: oo: ohs fi u m fi m fi wcwzmn fl wu mc fi c Hmucæmmm Äwwë mv .Sw ømw Û øm m> å. É flfl mxmmnnm 1222 h: xmwnwm

Claims (3)

10 15 20 '25 30 IJ. Patent claims Device for controlled and continuous administration for a long time of the anthelmintic morantel ((E) -T, 4,5,6-tetrahydro-1-methylph 2-Al 2 (3-methyl-2-thienyl) ethenyl] pyrimidine) to an environment containing an aqueous liquid and comprising the rumen reticulum of a ruminant, the device comprising: a morantel stock and a shaped wall, which consists at least in part of a porous material, which comprises sintered polyethylene or polypropylene of filter cloth type , in contact with at least a part of said stock, which porous material is insoluble in said environment and maintains its integrity for said long time, characterized in that the pores of the porous material are impregnated with a hydrogel of cellulose triacetate which allows the passage of morantel to the aqueous liquid so that the device, when introduced into said environment, continuously releases morantel from the supply to said environment at a physiologically efficient, controlled rate through the hydrogel, whereby thus dissolved dissolved morantel is replaced by uninterrupted dissolution of morantel in the store and the amount of dissolved morantel in the store continuously changes during said long time, so that the delivery of morantel to said environment is kept substantially constant for a substantial part of said long time . Device according to claim 1, characterized in that the storage contains morantel in mixture with a water-soluble excipient. Device according to claim 1, characterized in that the stock contains morantel in admixture with a water-soluble liquid excipient and a detergent;