CH643140A5 - DEVICE FOR THE CONTROLLED AND CONTINUOUS DELIVERY OF CHEMICALS DURING A LONGER PERIOD. - Google Patents

Description

The invention relates to devices which are permeable to chemicals including active ingredients and are suitable for transferring an active ingredient or other chemicals at a controlled rate from a storage container containing the active ingredient or the chemical to an environment containing an aqueous liquid, in particular to the body environment of an animal to give up a person. The invention thus relates to devices which consist of a wall or walls which at least partially consist of a porous material including a porous textile material, and whose pores contain a hydrogel and in which the porous material is in contact with an active ingredient or a Containers containing active ingredient exists. In a particular embodiment, the invention relates to so-called medicament balls or pills (bolus), which contain systems for the controlled release of active substances in ruminants and which are retained in the net stomach of the animals.

Drug delivery systems and devices for controlled release of drugs, i.e. a controlled release and a sustained and longer release,

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are known per se in the field. A variety of methods have been described in the literature, including the physiological change in absorption or excretion, the modification of the solvent, the chemical modification of the active ingredient, the adsorption of the active ingredient on an insoluble carrier, the use of suspension and the implantation of pellets, see Edkins, J. Pharm. Pharmacol., 11 (1959), 54T-66T. Other methods include mixing the active ingredient with a carrier that is gradually disintegrated by the environment, e.g. through body fluids, which causes the release of the active ingredient. Waxes, oils, fats and soluble polymers have already served as carriers.

Furthermore, it is known in the art to disperse the active ingredient within a solid matrix material, whereby the active ingredient is released by diffusion, or to enclose the active ingredient within a capsule with a wall or walls of polymeric substances through which the active ingredient can pass through diffusion , see U.S. Patent 3,279,996.

US Pat. No. 3,975,350 describes hydrogel carrier systems, which consist of polyurethane polymers, for use in medical applications, pesticide applications, insecticide applications, and in applications as anti-algae agents, etc.

US Pat. No. 1,693,890 describes the production of porous membranes from cellulose acetate in the form of jellies for use in dialysis. The method involves precipitating the cellulose acetate from a solution thereof in acetic acid by adding a non-solvent such as water. If necessary, the membrane can be formed on a carrier. Membranes made in this way are impregnated with water, but they can be freed of water by washing with alcohol, acetone or any other water-miscible liquid.

Composite materials made of cellulose-like polymer liquid (PLC materials) in film form, film form, fiber form or microsphere form including cellulose esters such as cellulose triacetate or cellulose nitrate or molecular mixtures thereof are described as carriers for the controlled release of various substances in US Pat. No. 3,985,298 . The substance to be released is impregnated into and within the cellulosic PLC material as part of the liquid phase or as a total of the liquid phase (alcohol or water or mixtures thereof) contained within the micropores of the cellulosic PLC material.

US Pat. No. 3,846,404 describes semipermeable membranes made of gelled cellulose triacetate, which are suitable as carriers for other materials such as liquids with medicinal properties. The impregnation of finished nonwoven polyethylene materials and knitted cotton materials with gelled cellulose triacetate to provide cellulose triacetate hydrogel materials on a support is described. The use of medicated products impregnated with gelled cellulose triacetate as low-release agents that can be implanted in animals has been described, for example pouring the gelled cellulose triacetate onto a film or sheet that is

woven or knitted backing material or a non-woven backing material.

In one or more of the following U.S. patents, delivery devices for the controlled release of active substances are described which have a supply formed from an active substance and a solid or liquid active substance carrier and in contact with or around the supply a wall which consists of a large variety of different materials including a microporous material whose micropores are a diffusing medium, e.g. a liquid phase consisting of a solution, a colloidal solution, a suspension or a sol and which are permeable to the passage of the active ingredient by diffusion include: US Pat. Nos. 3,993,072.3,993,073.3,896,819.3,948 254, 3 948 262.3 828 777.3 797 494.4 060 084 and 3 995 634. io In US Pat. No. 3,993,073, hydrophilic hydrogels of esters of acrylic acid and methacrylic acid and crosslinked polyvinyl alcohol are also suitable as wall-forming agents Materials described. An essential feature of the devices according to these patent specifications is the use of a wall which consists at least partially of a microporous material, the pores of which contain a medium which controls the active substance release rate and is permeable to the passage of the active substance, as well as a supply of which active substance plus a carrier 20 comprises, but this is permeable to the passage of the active ingredient at a higher rate than the permeability or permeability of the medium accommodated in the pores of the microporous wall, the rate-controlling medium. Devices suitable for the application of therapeutic sub-2s or nutrients in ruminants, which encase the substance in a permeable, water-insoluble material, which comprises capillary pores or connecting pores extending through them, and in paper or textile materials, some of which with water insoluble polymers, e.g. Cellulose acetate, impregnated, are described in British Patent 1,318,259.

US Pat. No. 3,594,469 describes pellets or tablets which contain magnesium and iron for application to ruminants in order to supply the ruminants with these metals over a relatively long period of time. According to one embodiment, the pellet or tablet consists of a tube made of magnesium alloy filled with shot and some biologically active substance, which is closed at both ends by porous disks.

US Pat. No. 3,938,515 describes some devices which are designed for the continuous application of an active ingredient for an extended period of 4 seconds and which contain a supply containing the active ingredient and a solid or liquid carrier which is permeable to the active ingredient, and a stock Include a surrounding wall of polymeric material, the wall being permeable to the active ingredient, but at a rate lower than that of the carrier.

US Pat. No. 3,946,734 describes a diffusion cell which is primarily designed for use as an implant and consists essentially of a capillary, one end of which is closed with an impermeable ss material, the rest of the tube and the other end thereof are sealed 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 60 (agarose, polyacrylamide) through which the biologically active medicament will diffuse.

Many of the prior art controlled release devices are described as zero order release devices. However, 65 such devices are capable of maintaining zero order release rates for relatively short fractions of their intended life, but are not practical for prolonged use

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tongue, for example in ruminants. The devices according to the invention, on the other hand, make it possible to achieve and maintain controlled or controlled, predictable rates of zero order release for a given active ingredient for extended periods of time. In addition, the devices according to the prior art, including the devices which comprise a supply surrounded by a shaped wall and containing the active ingredient, the wall being at least partially formed from a microporous material, the pores of which are a medium controlling the active ingredient release rate (medium with diffusivity), which is permeable to the passage of the active ingredient, is subjected to mechanical blockage or mechanical damage when used in certain environments, such as the net stomach bag of ruminants. The clogging reduces or even stops the release of the active substance, as a result of which the device is put out of operation for the intended purpose. The devices according to the invention, in which pores of the porous material contain a hydrogel in contact with the supply containing the active substance, are essentially free of this problem and they are able to achieve controlled or controlled and predictable release rates of the active substance to deliver aqueous liquid containing environment for extended periods of time.

When used for the controlled release of highly water-soluble active ingredients, it is used in devices according to the prior art - of the type as described in US Pat. Nos. 3,993,073.3,993,072.3,967,618, 3,948,262. 3,948,254 and 3,896,819 - preferred that the wall and / or the reservoir be formed from a material which is substantially impermeable to water in order to dilute the active ingredient in the reservoir by absorption of body fluids in the device as well avoid a decrease in the drug release rate. Such devices are therefore not suitable for the delivery of water-soluble active ingredients, especially at relatively high rates. Furthermore, most of the devices described in these patents require that the permeability of the medium controlling the drug release rate to the drug in the pores of the porous wall surrounding the reservoir is less than the permeability of the liquid carrier to the drug in the reservoir. In this way, the passage of the active ingredient through the wall is the speed-controlling step. There are no such restrictions in the devices according to the invention. In fact, a significant difference between the devices described here and the devices of the prior art lies in the presence of the hydrogel, which is highly permeable to water, in the pores of the porous material which is in contact with the supply. Such devices are dependent on the diffusion of water from an aqueous liquid environment into which the device is introduced, through the liquid-filled pores or channels in the hydrogel and into the reservoir, and on the outward diffusion of the active ingredient from the reservoir into the environment . Unexpectedly, the concentration of dissolved active ingredient in the supply or storage container does not decrease, which results in an essentially constant release rate for an extended period of time. However, the amount of active ingredient dissolved in the supply or storage container varies continuously during the life of the devices according to the invention.

The use of a low level of the anti-intestinal worming agent morantel tartrate in the drinking water of calves,

with the calves having continuous access to the added water, as an endoparasite control agent, was described by Downing et al., Irish Vet. J., 221 (November 1974) and British Patent 1,530,161. It has been found that the ongoing daily supply of antidermal worm medication to calves from the beginning of April to the middle of July suppresses the calf's release of worm eggs and prevents or at least minimizes the development of a strong larval infection of the plants.

Furthermore, Jones et al., Brit. Vet. J., 134 (1978), 166 found that daily application of small amounts of morantel tartrate with the feed to calves successfully controlled parasitic gastroenteritis and lungworm infections from calves to mid-July by reducing the contamination of the grazing calves accessible pasture.

The present invention thus relates to an improved device for the controlled and continuous supply of a chemical to an environment containing an aqueous liquid for an extended period of time, the device comprising a supply containing a chemical and a wall formed at least partially from a porous material, wherein the porous wall is in contact with some of the stock and is insoluble in the environment and maintains its integrity during the extended period of time, which is characterized in that the pores (14) of the porous material (11) are impregnated with a hydrogel medium, permeable to the passage of the chemical (15) and the aqueous liquid, the device (10), when placed in the environment, continuously controls the chemical from the supply (12) to the environment in a physiologically effective, controlled manner Release rate through the medium t, wherein the dissolved chemical thus released is replaced by the continuous dissolving of chemical in the supply, and the amount of the dissolved chemical in the supply changes continuously over the extended period of time, so that the rate of chemical release increases the environment remains virtually constant for a substantial portion of the extended period of time.

Furthermore, the invention relates to a method for producing the device described. This method is characterized in that the chemical is enclosed in a supply surrounded by a wall formed at least partially from a porous material, the porous material being in contact with at least part of the stock and being insoluble in the environment and its Intactness during the extended period of time maintains that the pores (14) of the porous material (11) are impregnated with a hydrogel medium permeable to the passage of the chemical (15) and the aqueous liquid, so that the device (10) when in the Environment is arranged, the chemical is continuously released from the reservoir (12) to the environment at a physiologically effective, controlled rate or speed through the medium and the thus released, dissolved chemical is replaced by the continuous dissolution of the chemical in the reservoir, wherein the amount of dissolved chemical in the supply would continue nd the extended period of time changes so that the rate of chemical release to the environment remains substantially constant during a substantial portion of the extended period of time.

The device according to the invention is particularly suitable for exposing chemicals such as active substances to the environment

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of an animal body including a human body.

The device according to the invention can be in the form of medicament balls or large pills (bolus), which contain such systems for a controlled release of active substances in ruminants and which are retained in the net stomach tract of the animals.

The improved systems and devices permeable to chemicals including active ingredients (these terms are used interchangeably hereinafter) according to the invention are valuable for the controlled release of active ingredients and other chemicals into environments containing aqueous liquids, and are particularly valuable for oral dosing in animals, including humans, and they can be used for a variety of drugs. In addition, the devices are particularly suitable for delivering highly water-soluble substances at high rates or speeds, which is not easily achievable with devices according to the prior art. The systems and devices according to the invention for the controlled release of chemicals over a longer period of time can be easily manufactured, and are reliable and easy to use. In addition, the devices described herein maintain their physical and chemical integrity, do not clog in the environment in use, and are particularly valuable for oral bolus use in ruminant animals. For the first time, they provide a practical device for the controlled and continuous release of chemicals, including active substances, to an environment containing an aqueous liquid and therefore satisfy a long-standing need, especially in animal husbandry.

The controlled rate release systems and devices of the present invention include a barrier or wall in contact with at least a portion of a chemical-containing reservoir, wherein the wall is partially or entirely made of a porous material, e.g.

a porous textile material, the pores of which contain a hydrogel which is permeable to the passage of liquid from the environment through the pores within the hydrogel itself and of chemical from the reservoir by diffusion. When the devices according to the invention are used, the hydrogel contains liquid from the environment, this liquid being contained in the areas or channels (pores) within the hydrogel itself and as diffusion paths or routes of liquid from the environment and for the transport of the active substance serve.

The systems and devices according to the invention can take a large variety of shapes and sizes, which depends on the intended use for them. For example, they can have a capsular shape for oral use in humans or animals, or a cylindrical shape as an implant for use as a bolus or medicine ball in ruminants.

The device according to the invention contains a partially porous material, the pores of which contain a hydrogel, in particular a gelled cellulose triacetate, which is permeable or permeable to the passage of liquid from the environment and of active substance by diffusion through pores within the hydrogel, this porous material is in contact with at least part of a stock containing a chemical, including an active ingredient, which contains the chemical and - if desired - a suitable, water-soluble, liquid carrier and furthermore - if desired - a detergent or surfactant, the

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Device in the form of a drug ball or a bolus for use for the controlled release of active ingredient in ruminant animals and in particular cattle and sheep is produced for an extended period of time. Such medicinal spheres are particularly used for parasitological control and in particular intestinal worm control, as a prophylactic and therapeutic agent for gastroenteral infections and lung worm infections in cattle and sheep and against intestinal worm contamination in pasture land. The term "bolus" or "drug ball" used here includes devices which are generally cylindrical, spherical, spheroidal, elliptical or of another shape and free from sharp edges and protruding parts.

The prior art devices require consideration of various factors for each application and a compromise between them, in particular with regard to the carrier used in the supply, the solubility and / or permeability of the carrier to the active ingredient contained in the supply, the type of microporous, the supply surrounding wall, the diffusion permitting medium contained in the pores of the microporous wall, the relative permeability rates of the diffusion permitting medium and the carrier to the active substance, the relative solubilities of the active substance in the diffusion permitting medium and the carrier and the Need to maintain a substantially constant amount of dissolved drug in the supply.

In contrast, the devices according to the invention are far simpler in terms of their arrangement and their operation. For a given device, the rate of release of the chemical can be varied widely by the simple means of changing the area or thickness of the porous material including a porous textile material whose pores are filled with the hydrogel and which is in contact with the supply. Therefore, manipulating only two parameters allows control of the amount of chemical released.

The invention is explained in more detail with reference to the drawings, in which FIGS. 1 to 5 show various exemplary devices according to the invention. The fact that only a few examples are shown in this way does not limit the invention, but numerous modifications and equivalents thereof are possible.

1 shows a perspective cross-sectional view of a device according to the invention, the dispensing device 10 being in contact with a supply 12 containing the chemical from a cylindrical wall 11. The wall 11 is formed from a porous material, the pores 14 of which contain a hydrogel (not shown) through which liquid diffuses from an environment containing an aqueous liquid into the reservoir 12 and a chemical from the reservoir into the environment through channels of the pores within of the hydrogel diffuses itself. The supply 12 consists of a chemical 15 and, according to a preferred embodiment of the invention, an active ingredient and a water-soluble carrier 16. The ends 17 are non-permeable caps or closures.

Fig. 2 shows a schematic representation of a device according to the invention in the form of a dispensing device of the type shown in Fig. 1, but in which a perforated sleeve 18, e.g. made of stainless steel, iron or plastic, is used as a means for controlling the surface of the hydrogel-impregnated, porous wall, which, if made of metal, increases the weight of the device.

3 shows an enlarged view of a porous

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Wall 11 of a device 10 according to the invention, the pores 14 of which contain a hydrogel 19, in contact with a reservoir 12 containing a chemical, which consists of a chemical 15 and a water-soluble, liquid carrier 16.

4 shows a dispenser shaped in the form of a capsule, which has only one closure 17.

FIG. 5 shows a further device 10 according to the invention, in which the porous material, the pores 14 of which contain a hydrogel (not shown), form the end walls of the device 10. The cylindrical wall 18 consists of a non-permeable, non-porous material, in this case made of stainless steel, which in combination with the end walls 14 impregnated with hydrogel includes a supply 12 which contains a chemical 15 and a carrier or comprises a diluent 16.

As described above, the improved delivery devices or systems according to the invention have a supply containing a chemical, preferably an active ingredient, which comprises a chemical and in a preferred embodiment chemical and a water-soluble, liquid carrier or such a diluent. The water-soluble, liquid carrier or this diluent has several essential functions, for example the removal of air from the supply, so that a greater «loading» in the manufacture of the devices and the promotion of mixing by convection within the supply (which is a constant rate chemical release) is possible. Furthermore, such a water-soluble, liquid carrier plays a further role, since it dissolves chemicals, so that no apparent volume change occurs when the chemical changes from the solid or crystalline state to the solution state.

Typical water-soluble liquid carriers or diluents include monols and polyols and ethers thereof, e.g. Ethanol, ethylene glycol, propylene glycol, glycerin, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and tripropylene glycol, 1,2-dimethoxyethane, mono-Ci-4-alkyl ether of ethylene and propylene glycols, N, N-dimethylformamide, dimethyl sulfoxide and the like . The carriers or diluents must of course be compatible with the hydrogel.

Of course, the water-soluble liquid carrier should be a physiologically acceptable substance when the devices described herein are used for animals, including humans, or in animal-containing aqueous liquid environments, e.g. in aquariums, fish ponds, in water supplies for animals or in hydroponic systems.

The amount of water-soluble liquid carrier used per unit weight of active ingredient depends on the characteristics of the active ingredient. In general, sufficient carriers are used to enable the formation of a combination of active substance carriers into a compact mass, the quantities being able to be determined by a simple experiment.

Detergents or surfactants at 20% by weight, based on the total weight of the stock (chemical including active ingredient plus the carrier and detergent or surfactant optionally used), can be used in the supply in order to prevent possible blockage of the devices when in use To minimize the minimum. Representative detergents or surfactants can be inorganic or organic substances, and they include, in particular, sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, sodium glycerol monolauryl sulfate, dioctyl sodium sulfosuccinate, bis- (l-methylamyl) -

sodium sulfosuccinate, polyoxyethylene sorbitan monooleate and other fatty acid esters and other substances known per se to the person skilled in the art. The amount of a detergent or surfactant, if this is used preferably, is not critical and is in any case kept to a minimum in order to keep the load of chemical in the stock as large as possible. The optimal amount can be determined according to the procedures described below.

In the description, the terms “stock”, “stock containing chemicals” and “stock containing active ingredients” are used interchangeably. For the sake of simplicity, the preferred devices according to the invention are those which are used for the controlled release of active substances, so that the expression “supply containing active substance” is the preferred expression

The terms "porous materials", "porous membrane" and "porous walls" as used here can include porous textile materials. Representative representatives of such materials are described below. The porous materials used can be isotropic, i.e. have a homogeneous pore structure across the cross-section of the material, or they can be anisotropic, i.e. have a non-homogeneous pore structure. Of course, they should be insoluble in the environment and the content of the stock and thus not be reactive. In general, porous materials with pore sizes from about 1 µm to about 100 µm can be used in the controlled release devices of the present invention. Porous materials with pore structures which include continuous pores, i.e. Pores which have an opening on both surfaces of the porous wall connected to them are required. In order to facilitate the transfer of active substance from the supply to the environment when using the controlled release devices according to the invention, the pores or part of the pores of the porous material are filled with a hydrogel. The result of the combination of the porous material, the pores of which are filled to a greater or lesser extent with a hydrogel, is to provide a device which resists clogging and physical or mechanical destruction under conditions of normal use and which, by maintaining it physical or mechanical integrity, can be used in environments or in cases under which previously known hydrogel devices could be destroyed or were ineffective for a controlled release of active substances over long periods of time. The devices described here have a particular value when used in ruminants, particularly in cattle and sheep. The pores containing the hydrogel allow liquid (water) to pass through the pores within the hydrogel itself by diffusion from the environment into which the controlled release device is placed in use, into the reservoir with dissolution of active ingredient. The drug then diffuses through the liquid in the pores into the hydrogel-containing pores of the porous material barrier at a rate which depends on the drug concentration in the solution in the reservoir, the resistance provided by the barrier, i.e. the liquid in the pores of the hydrogel, and the effective surface of the porous section of the wall.

When drug leaves the device, a depletion zone gradually forms, giving rise to a moving drug / solution boundary. The diffusion of water into the device from the environment through the

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Pores within the hydrogel-containing pores of the wall in the reservoir give rise to convective mixing of the incoming aqueous phase with the solution in the reservoir of the device. The motive force of this mixing is the difference in the densities of the two solutions, caused by their large differences in concentration. One function of the water-soluble, liquid carrier as previously described is to help maintain this large density difference, thereby promoting this critical mixing. The convective mixing results in a constant active ingredient concentration within the stock, which in turn provides a controlled release of active ingredient over an extended period of time and thus ensures zero-order release of active ingredient as long as undissolved active ingredient remains in the device. When drug is removed from the supply and aqueous liquid from the environment diffuses into the supply, the amount of drug dissolved within the supply varies continuously throughout the life of the device, i.e. during the extended period of drug release. This mechanism of drug release enables the use of any geometry of the device, the size and design of the stock being unlimited.

This is in direct contradiction to the devices of the prior art according to US Pat. No. 3,993,073, which are dependent on an essentially constant amount of dissolved active substance within the supply, a diffusion of dissolved active substance within the supply for supplying the wall with active substance and have been manufactured accordingly to achieve this, so that these devices are subject to severe restrictions with regard to the size and shape of the product.

The term "hydrogel" used in the description refers to a gel with water content and is described in Hackh's Chemical Dictionary, 4th edition, Grant, page 332 (1969) as a "gel produced by the coagulation of a colloid including water". Are defined. Representative hydrogels which can be used to fill the pores of the porous material are the following gels: gelled cellulose triacetate, see U.S. Patents 1,693,890 and 3,846,404, cellulose acetate hydrogels derived from cellulose acetate with an acetyl content of 20 to 40%, polymeric Hydroxyethyl methacrylate, cross-linked polyvinyl alcohol, agarose, polyacrylamide, cross-linked and partially hydrolyzed polyvinyl acetate, hydroxyethyl acrylate, diethylene glycol monoacrylate, diethylene glycol monomethacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, methacrylate, 3-hydroxypropyl acrylate, 3-methacrylate , N-propylacrylamide, N-isopropyl methacrylamide, N-methyl acrylamide, N-2-hydroxyethyl methacrylamide, polyurethane hydrogels including weakly crosslinked polymers of prepolymers terminated with isocyanates, which react the product of a poly (aIkyIenoxy) polyol with an or ganic di-isocyanate, weakly crosslinked with water or an organic polyamine, see US Pat. No. 3,939,105, copolymers of ethylene-like unsaturated monomers of hydroxyalkyl acrylates and methacrylates and of alkoxy-alkylene glycol acrylates and methacrylates, as described in US Pat. Patent 4,038,264, polyether polyurethane resins, prepared by reacting an organic diisocyanate with a mixture of at least two diols, one of which is a water-soluble polyalkylene glycol with a molecular weight of 3000 to 30.00 and the second an oxyalkylated diphenol with 2 to 20 oxyalkylene

groups, as well as other substances known per se in the field.

Advantageous hydrogels for the device according to the invention are: polyurethanes, polymeric hydroxy-lower alkyl acrylates or methacrylates, vinyl pyrrolidone, acrylamide, N-lower alkyl acrylamides and methacrylamides, in particular products crosslinked or copolymerized with a hydroxyalkyl acrylate or methacrylate in order to achieve water-insolubility of the copolymer obtained . Preferred hydrogels are gelled cellulose triacetate, polymeric hydroxyethyl methacrylate and cross-linked polyvinyl alcohol. Particularly preferred is gelled cellulose triacetate, which results in smooth and effective operation of the devices described here for the controlled release.

The water contained in the pores of the hydrogel can easily be replaced by water-soluble liquids such as the aforementioned water-soluble liquid carriers. Other water-soluble liquids can also be used to replace the water, including alcohols with 1 to 4 carbon atoms. In order to stabilize the devices according to the invention, in particular if the hydrogel is gelled cellulose triacetate, the water of the hydrogel is generally replaced for practical reasons by a suitable, water-soluble liquid which has a lower vapor pressure than water, so that the devices do not lose their effectiveness can be stored as a result of the hydrogel drying out. If a combination of water-soluble, liquid carrier active ingredient is preferably used in the supply, the use of the same liquid to replace the water in the hydrogel may be a suitable method.

The hydrogels themselves are porous in the sense that they contain areas or regions, i.e. Channels or pores, 35 filled with water or other liquid. Therefore, if reference is made here to the diffusion or transport of chemicals or active substances through the walls and the expression “whose pores contain a hydrogel” or a similar expression is used, this should mean that the diffusion or transport of the chemical or of the active ingredient takes place via these regions and not through the hydrogel per se. The hydrogel itself has liquid-filled pores which serve as diffusion paths, and in fact it is considered to be permeable to the passage of ambient liquid and chemical from the supply.

The porous wall in contact with the supply containing the active ingredient can be made of any number of materials. The porous material can thus completely surround the supply, or it can only make up part of the wall surrounding the supply. Suitable porous materials include porous metals, porous ceramics, sintered polyethylene, sintered polyvinyl chloride, sintered polypropylene, sintered polystyrene and sintered polytetrafluoroethylene, porous polymers, made from thermoplastic resins by phase separation techniques as described in Chem. Eng. News (December 11, 1978), p. 23, and other materials known to those skilled in the art.

60 Suitable porous textiles which can be used can consist of polypropylene and polyethylene, in particular textiles of the type which are usually referred to as "filter cloths", furthermore of glass, polytetrafluoroethylene, nylon, cotton, modacrylic fibers, i.e. acrylic fibers, acrylic fibers composed of a long-chain synthetic polymer with 35 to 84% acrylonitrile units, i.e. synthetic polymers with a minimum of 85% by weight acrylonitrile, polyesters, i.e. a long chain, syn

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thetic polymer, which consists of at least 85 wt .-% of an ester of a dihydric alcohol and terephthalic acid, polyvinyl acetate, polyvinyl chloride, polyvinyl acetate-co-vinyl chloride, polyvinyl alcohol, polyvinyl alcohol-co-vinyl acetate, polyvinyl alkyl ethers, polymers of vinylidene cyanide, vinylidene chloride , Vinylidene fluoride, polyureas and other materials known per se in the art, see Encyclopedia of Polymer Science and Technology, Vol. 1,342 (1964); Vol. 8,812 (1968); Vol. 9.403 (1968); Vol. 10,347,206 (1969); Vol. 6.275 (1967); Vol. 11,62,445 and 506 (1969); Vo !. 14,305,575 (1971); Interscience Publishers, New York. Metal grids or filter cloths including those made of stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel-copper, etc. are also suitable.

The particular material or textile material selected must of course be compatible with the hydrogel with which it is to be impregnated and be suitable for the end use of the device. Cotton would therefore not be used as a textile material for a device to be used as a bolus for the application of an active ingredient to ruminants for a prolonged period of time, since it would be degraded in the ruminant. Cotton can be used in a device to be used for the controlled release of a chemical from an aqueous environment such as in an aquarium or a storage container.

Nylon, i.e. a polyamide, would not be used as a textile material if gelled cellulose triacetate is to serve as the hydrogel, since it would be broken down by the formic acid or acetic acid used during the impregnation process.

The hydrogel-impregnated, porous textile materials or other materials must of course have sufficient strength, durability and sufficient inert properties with respect to the active ingredient and the environment in which they are used, so that the device for controlled release produced therewith has mechanical and chemical integrity throughout its life maintains.

The porous material can be impregnated with a suitable hydrogel according to procedures known to those skilled in the art. An advantageous and relatively simple procedure for impregnating the porous material with gelled cellulose triacetate, a preferred hydrogel, comprises injecting a solution of cellulose triacetate in formic acid or acetic acid into the pores of the porous material by immersing the material in the cellulose triacetate solution, which is in one Vacuum-retractable container is included. Following the impregnation, the plastic "loaded" with cellulose triacetate can then be coagulated by contact with a large volume of water and equilibrium with it to produce the material impregnated with hydrogel. If the porous material is preferably sintered polyethylene and the hydrogel is gelled cellulose triacetate, acetic acid as a solvent for the cellulose triacetate is preferred over formic acid because it wets the polyethylene better than formic acid and thus makes the production of the porous material impregnated with hydrogel easier.

If the hydrogel from e.g. 2-Hydroxyethyl methacrylate, crosslinked with ethylene glycol dimethacrylate, as described in US Pat. No. 3,520,949, can be used to impregnate the porous material by filling its pores with the mixture of 2-hydroxyethyl methacrylate / ethylene glycol dimethacrylate and then polymerizing the mixture within the pores by adding one free radical catalyst such as t-butyl peroctoate. Similarly, other hydrogels can be impregnated into the porous wall material using such in situ procedures from appropriate reactants. If the hydrogel e.g. cross-linked polyvinyl alcohol, the pores can be filled with a mixture of polyvinyl alcohol as a 10% aqueous solution and resorcinol (2-3%) according to the procedures described below, and the cross-linking is preferably brought about in situ. Other crosslinking agents can of course be used as is known in the art.

To produce devices that are stable in storage prior to use, the hydrogel-filled pores are usually freed of water by allowing equilibrium to be established in a suitable, water-soluble liquid, such as, for example, the water-soluble liquid carriers listed above. As previously described, it is advantageous to replace the water in the hydrogel-filled pores of the porous wall material with the same water-soluble liquid as used as a carrier in the supply if the supply comprises a combination of chemical / carrier. If the supply is chemical only in the devices described herein, the choice of water-soluble liquid used to replace the water from the hydrogel in the hydrogel-filled pores of the porous wall can only be determined by the end purpose of the device, i.e. whether a physiologically acceptable, water-soluble liquid is required. Such a liquid is suitably introduced into the hydrogel at the time of manufacture of the porous wall, the pores of which contain a hydrogel, before replenishing the supply of the device, as will be described.

The devices of the prior art closest to the devices according to the invention, i.e. the devices described in US Pat. Nos. 3,993,073 and 3,993,072 depend on the different permeability rates of active ingredient through a medium contained in the pores of the porous wall relative to that of the active ingredient in the active ingredient carrier phase in the supply. In order to achieve a zero order release rate, as attributed to the devices described in these patents, it is imperative that the medium in the walls of the devices have a lower permeability to active substance than the active substance carrier within the stock. The medium in the wall therefore becomes the portion of the device that controls the rate of exposure to the drug.

Dissolved active ingredient diffuses through the more permeable carrier to the inner wall at a sufficient rate so that the wall becomes the portion of the device controlling the active ingredient release rate. This results in zero order release rates for a certain period of time until the receding active substance limit in the device becomes sufficiently large to cancel out the difference in permeability between carrier and wall medium, in which case zero order rates are no longer achieved. As a result, successful, practical use of such devices is limited, and they are not suitable for zero order delivery of large amounts of active ingredients in practical, useful dosage form forms.

In contrast to these devices of the prior art, the devices according to the invention have an aqueous ambient medium in the wall when used

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dium as well as in the stock. Although the permeability of the active ingredient is the same in the liquid in the wall and in the reservoir, zero order release rates are achieved for large fractions of the total life of the device. Furthermore, the maintenance of the zero order release does not depend on the diffusion in the storage medium, so that there are no geometrical restrictions or dose restrictions in these devices, and it is possible for the first time to use large amounts of active substance at zero order rates or speeds in embodiments of practical sizes and deliver practical shapes.

For a particularly effective operation of the devices according to the invention for the controlled release and for the reduction of leakages and blockages, it is essential that the porous material is impregnated with a hydrogel as completely as possible. Devices of the same surface can, by varying the properties of the membrane wall, in particular its thickness, its pore size and its porosity and by changing the size of the load in the supply, deliver different dosage rates and release periods for a given active ingredient.

As already described above, a preferred form of a device according to the invention is a bolus or a medicament ball for use in the controlled release of an active substance in ruminants, in particular in cattle and sheep, over a long period of time. The bolus or the medicament ball can be in the ruminant are administered in such a way, preferably by oral administration, that it remains in the mesh stomach sac for a longer period of time, during which period he / she continuously releases active ingredient to the animal at a controlled release rate. Such devices therefore enable the control (prophylactic and therapeutic) of various pharmacological conditions to which the animals are exposed by simple oral administration of these devices to the animals.

In order for the bolus or the drug ball to remain here for an extended period of time once it has been inserted into the mesh stomach bag of cattle, it is above all necessary that the bolus or the drug ball have a density of at least 2.0 g / ml. In practice, the density can range from values as low as 2.0 to values as high as 7 or even more. The density is of course the most significant factor influencing the retention of the bolus or drug ball in the reticulum. The total size of the bolus or drug ball is a function of the dose to be delivered and the size that can be practically given. Based on this, if the desired size is determined, additional weight can be added to achieve the desired average density. If possible, the use of the maximum possible size is desirable, since a larger bolus or a larger medicine ball of a given density is retained better than those of a lower density. However, if the average bolus density increases to a value greater than about 5.0, the bolus size does not significantly affect the improvement in retention factor. The preferred average density range for the bolus or drug ball is from about 2.5 to about 5 g / ml.

The size of the bolus naturally depends on the animal to be treated with it. For ruminants such as sheep and goats, the size and weight of the bolus is less than that required for cattle. The maximum bolus size for use with any animal is, as usual, determined by the practical difficulties in applying such an article to the animal.

For the preferred application in sheep, the minimum weight of the bolus with a density of 4 that is retained is preferably about 1 g. The size of a bolus varies depending on the density of the bolus. For application to cattle, the minimum weight of a bolus with an average density, in particular of 4, is approximately 5 g. As already described above, the upper limit values for the size are in turn determined by the practical circumstances of the dosage of the animal in question and by the minimum average density of the bolus. For example, a bolus approximately 7.5 cm long and 2.5 cm in diameter with a density of 2.2 has a weight of the order of approximately 90 g.

The density of a bolus that includes only the elements listed above is generally below the lower value mentioned above. Therefore, it becomes especially necessary to increase the average density of the bolus by adding a suitable higher density material such as a metal (iron powder, iron shot, steel shot) or other density increasing agents such as minerals e.g. CaSÛ4, to increase the density to the desired value. Alternatively, the average density can be suitably determined by entering an inner sleeve, a perforated high density material, e.g. a metal (such as stainless steel, steel, especially low carbon steel or iron), which in turn is surrounded by the hydrogel impregnated porous membrane. The perforations or perforations in the sleeve should be large enough so that the active ingredient and liquid from the environment can freely pass through the porous membrane impregnated with hydrogel. The main functions of such a sleeve are to increase the average density of the bolus to such a level that the bolus is retained in the mesh stomach bag and to regulate the surface of the hydrogel-impregnated porous material in contact with the supply containing the active ingredient. In addition, although not absolutely necessary, such a sleeve improves the mechanical stability of the bolus so that its physical shape is essentially maintained under the conditions of use. A further and preferred alternative comprises a bolus which comprises a metal, steel or iron cylinder, one end or both ends of which are capped like a porous membrane, the pores of which are impregnated with a hydrogel. A bolus of this type is preferred because of its simplicity and economy of manufacture and the ease with which its density can be adjusted. A low carbon steel is very preferred as the construction material for the cylinder. Other alternatives are readily apparent to those skilled in the art.

The controlled release devices of the present invention can be used for a variety of purposes and in a variety of cases where the controlled release of an active ingredient or other chemical is desired. They can be used for the application of active substances and for the provision of chemicals in places close to or away from the application location of the device. They can be attached by means of suitable devices in suitable places within the animal body where they are in contact with body fluids, e.g. the stomach of pets, especially in the ruminants' stomach. The controlled release devices according to the invention also preferably include devices for use in

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suitable as depot implants for the purpose of applying one to ruminants and especially cattle. The

Active ingredient with a controlled speed in protecting roaming animals becomes relatively simple. In

Guest. The implants differ from the climate according to the invention, the small population of the early moderate devices for other purposes only in their spring of pasture larvae, namely the residue of the

Shape, which is of course for the implantation from contamination of the previous season. Other applications include cycle multiplied by the animals grazing on it,

Sublingual tablets or buccal tablets, pessaries, supposi- causing a strong increase in the

torias, bandages and skin patches. Still more preferred pasture land is produced. This state causes

Applications for the devices according to the invention during the pasture period in summer are clinical for controlled release, especially in land parasitism and a decrease in the performance of the

Economy for the application of fertilizers and pesticides, animals grazing on such pasture land.

in fish farming including aquariums and in fish- The continuous and controlled release of ponds, in drainage ditches, channels and tanks or tank anthelmintic agents, i.e. Anti-bowel worms e.g.

For example, for the control of algae, given by morantel, in the mesh stomach bag of grazing animals as well as in water supplies, especially for animals and is at the beginning of the season when the contaminations of the pasture

Poultry, which active ingredients for therapeutic or pro-land are still low, suppress the release of worm

need phylactic treatment. eggs and the subsequent formation of larvae, causing

The criterion for suitable substances, active substances or the aforementioned cycle is interrupted and the chemicals that are used in the devices according to the invention for worm exposure of pastureland and animals are that they are kept sufficiently low in water. Parasitic infections of soluble to a release rate of this active ingredient or ruminants that graze on the same pastureland during this chemical in the environment of use during the summer season will thereby be minimized to give the desired result. Brought from this. This method of worm control is particularly useful because active ingredients and chemicals that make acids attractive and valuable to calves, as they are more beneficial than calves or bases, desirably in the form of their phy- mers when they are first brought to pasture, very siologically or pharmacologically acceptable salts are susceptible. The consistent use of medication. The rate of release of the active ingredient or the balls (bolus) reduces the reservoir of infectious chemical from the devices described here depends on worm forms at a given location. The use of various factors, such as the thickness of the wall, the surface available from devices according to the invention, the Anthelmintica, the effective pore diameter, 30 and preferably in the form of medicament balls, can affect the porosity of the wall, the type of hydrogel, the concentration of seasonal increases the pasture larvae prevent or tration of the substance in the stock and the solubility reduces this at least to a minimum, the same of it in the surrounding liquid. The suitability also applies to parasitic gastroenteritis and a decrease in a given substance is determined in accordance with the subsequent performance in grazing animals later in the description given above. 35 season. In this type of control, the period of the active representative of active substances, which can be used in the devices described here for the multiplication phase in spring, and not the period of the strong pasture contaminants are the following substances: Anthelmintica, including the strong Larval infestation and the mass appearance of salts of morantel, pyrantel, oxantel, piperazin, diethylten of worms, which cause clinical complaints and the carbamazin, levamisole, tetramisole and hygromycin B, anti- 40 decrease in performance. For this bacterial substance, including salts of tetracy, this type of application is called “indirect control”, such as 5-oxytetracycline, chlorotetracycline, doxycycline. In other words, the grazing of Wieder and Mannich bases thereof, penicillins such as ampicillin, penicides which have one or more cillin G, aminoglycosides such as neomycin, streptomycin, of the devices described here in their reticulum, these being apramycin, bacitracin as whose zinc or methylene disali- 4s device the controlled and continuous release cylic acid derivatives, macrolides such as erythromycin, oleandozing an anti-worming agent, eg of Morantel, on these mycin and tylosin, antibacterial growth promoters enables retinal gastric sac on pastureland at an early stage such as salts of avoparicin, polymyxin, lincomycin, bamber in season, i.e. if the larval verunreini mycin and efrotomycin, hormonal growth promoters are at a minimum value or close to such including diethylstilbestrol, zearalanol, antiparasi- so minimal value, it enables the usual, seasonal means such as amprolium, nutrients such as soluble Salt nal increase in the larval contamination of the pasture to a minimum of magnesium, selenium, copper and vitamins such as thiamine and serves to protect the animals that graze thereon during hydrochloride, sulfa active ingredients such as sulfamethazine, molluscier throughout the grazing season, cide such as N -Tritylmorphin and anti-swelling agents. For the "indirect control" of worms, the agents such as alcohol ethoxylates and poly (oxyethylene) ss devices according to the invention, preferably in the form of poly (oxypropylene) poly (oxyethylene) polymers, for example of drug balls, in ruminants at one time poloxalene. applied in the epidemiological cycle of these worms

As already described above, when the pasture contamination by this stock containing them according to a preferred embodiment worms, the active substance comprises an active substance and a water-minimal value or close to, in one form of the invention, their eggs and / or their larval stages such a minimal borrowed carrier. Devices constructed in this way have the value. In the moderate zones this corresponds to

Advantage that they have a larger amount of active ingredient per device, the spring shoots, i.e. offer the first exposure and the useful life of the device of the calves in the pasture. Extends for maximum effectiveness. However, the supply can only contain the drug or bolus that is selected for the calves. 65 applied two to seven days before the shoot. In non-

The devices according to the invention are in particular temperate zones of the world, e.g. in semi-tropical or tropical

as long-acting drug balls (bolus) for therapeutic areas, the time of the least infection is

and preventive control of intestinal worm infections availability of pastureland usually before the rainy season. The

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Application of the bolus or drug balls to ruminants in such zones is advantageously carried out two to fourteen days before the start of the rainy season. Because of the unpredictability of the rainy season, worm control in non-temperate zones is best carried out using a «direct control» method.

The medication balls (bolus) described here also switch off worm infections that have already occurred in ruminants and prevent the infestation of worm infections during the summer period in the event of severe infestation. This type of application is called "direct control". The direct method of control only protects ruminants during the anti-worm delivery period. The indirect method of worm control protects ruminants that graze on a given pasture for the entire season, since it results in a significant overall reduction in pasture contamination or pasture infestation. As already stated, the devices described here result in a continuous release of active ingredients, including anthelmintics, at a controlled rate or rate. Water-soluble salts of (E) -1, 4,5,6-tetrahydro-l-methyl-2- [2- (3-methyl-2-thienyl) ethenyl] pyrimidine (morantel) are particularly useful for such purposes. (E) -1,4,5,6-tetrahydro-1-methyl-2- [2- (2-thienyl) ethenyl] pyrimidine (pyrantel) and (±) -2,3,5,6-tetrahydro -6-phenyl-imidazo- [2, lb] thiazole (tetramisole) and levamisole, the L - (-) form thereof. The tartrate and citrate salts are representative of preferred, water-soluble salts of pyrantel and morantel, and the hydrochloride salts of tetramisole and levamisole.

The preferred drug balls can be administered orally to the animals, for example with a device for administering pills to horses or cattle. For use in calves, the desired average release rate is e.g. von Morantel, calculated as base, for the indirect control of worms in the order of magnitude 60 to 200 mg of the Morantel base per day for a period of about 60 days, whereby the normal, maximum survival time of the spring population of larvae is covered. Longer release periods of 60 to 120 days are desirable in the direct control application form, since the exposure time for severe pasture contamination or pasture infestation normally ranges from the middle of summer to autumn. Release rates of about 60 to 150 mg, calculated as morantel base, provide effective control of worm infections during such release periods. For the treatment of larger animals, more than one drug ball or bolus can be given. For indirect control of worms using salts of pyrantel or levamisole, the desired average release rates for each compound thereof, calculated as free bases, are in the order of 100 to 400 mg or 100 to 200 mg / day for a period of about 60 days. For direct control, release rates of about 100 to 300 mg, as free base, of pyrantel, and of about 100 to 400 mg, as free base, of levamisole per day provide effective control of worm infections during the most infestation period, from 60 to 120 Days.

The continuous application of Morantel in small amounts using the worm control devices described here results in an effective profile which surprisingly differs from and is advantageous over the profile obtained in the conventional therapeutic use of Morantel, although this is not foreseen could be. For example, maintaining a sustained level of morantel tartrate or citrate or other salt in the gastrointestinal tract of ruminants is effective in preventing lung worm infections in such animals during the period of drug release. In addition, since cattle or sheep that graze on contaminated pasture land are exposed to immediate re-infection by intestinal nematodes after conventional therapeutic treatment, animals receiving the drug balls are essentially freed from any infection that has occurred and prior to re-infection for a period of 60 days or protected longer.

The use of the bolus to control pasture contamination, i.e. The indirect control method is a unique, practical and as yet unused method of worm control, whereby ruminants and especially grazing ruminants, which are protected according to this method, are protected during the entire grazing period and against known methods of control superior results and benefits are achieved. The increase in daily weight gain compared to untreated control animals during the grazing period is much greater than that achieved after conventional therapy. 25 The release rate of the active ingredient or the other chemicals which passes from the supply containing the active ingredient through the walls of the device for controlled release according to the invention, and the effectiveness of a predetermined combination of active ingredient 30 and / or water-soluble carrier and / or detergent or surfactant in Such devices can be determined in a simple manner by a person skilled in the art, for example by transfer methods or by methods of sorption-desorption. One technique that can be conveniently used to select 35 suitable porous materials and hydrogels involves using the selected porous material, the pores of which are filled with the selected hydrogel, as a barrier between a rapidly stirred saturated solution of an active ingredient or a 40 other chemical whose controlled release is desired and a rapidly stirred solvent bath the composition of which stimulates the aqueous liquid containing environment in which the controlled release device is to be used. The temperature of each solution is maintained at a constant value, preferably a value which approximates the average temperature of the environment in which the device is to be used. Samples are taken from the solvent bath at predetermined intervals and analyzed for the concentration of the active ingredient. Standard procedures for determining the permeability of an active ingredient or other chemical substance through the porous material, the pores of which are filled with hydrogel, can also be determined according to standard procedures, as described in Encyclopedia of Polymer Science and Technology, Volumes 5 and 9, pages 65-82 and 794-807 (1968) and the references mentioned here and in Chemical Engineers Handbook (1963), pages 17-45, published by McGraw-Hill, Inc. 60.

A procedure of particular value in determining the release rate for devices according to the invention and the relative advantages of a given carrier or detergent or surfactant for use in such a given device, in particular if the active ingredient is morantel, is summarized as follows: The procedure is one In vitro mode of operation based on the release of a water-soluble salt from Morantel,

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for example the tartrate, from a device produced according to the invention as a function of time. A device containing morantel tartrate according to the invention is placed in a 1 to 1 cone flask which is protected from light due to the photo sensitivity of morantel tartrate, and 500 ml of phosphate buffer with pH = 7 are added. The temperature of the flask and the contents are brought to 37 ° C and kept there. The flask containing the device is shaken at about 70 movements (7.62 cm) per minute and 5 ml samples are taken periodically. The volume of the withdrawn sample is replaced with an equivalent volume of fresh phosphate buffer at pH = 7 and shaking of the flask is continued. The concentration of morantel in the samples is determined spectrophotometrically by measuring the absorbency of the sample at 318 nm when reading against fresh phosphate buffer with pH = 7. The sampling process is repeated until 5 g of morantel tartrate has been released, at which point the device is transferred to another flask containing 500 ml of fresh phosphate buffer at pH = 7 and the procedure is continued as before.

The in vivo release of morantel tartrate from devices according to the invention is determined by giving the devices, for example, normal bulls or bulls with rumen fistulas, and after a certain period of time, such as 30, 60, 90 or 120 days, the devices are passed over or after the fistula removed from killing the animals and the devices are removed to determine the remaining Morantel tartrate within the device. Tests of this type showed that the rate of release of morantel tartrate in vitro is approximately four times the rate of release in vivo.

The following examples illustrate the invention, but numerous variations are readily possible.

example 1

A sintered polyethylene, the pores of which were filled with gelled cellulose triacetate, a bolus, and a supply containing mantle tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate and with a perforated stainless steel sleeve provided as follows.

One end, hereinafter referred to as End 1, of a sintered polyethylene tube with an average pore size of 10 µm and an outside diameter of 25.4 mm, an inside diameter of 22.225 mm and a length of 7.938 cm was cut in immersed a 10% solution of cellulose acetate butyrate in methylene chloride to a depth of 4.763 mm. It was then air dried and the other end of the tube, designated End 2, was immersed in the cellulose acetate butyrate solution to a depth of 9.525 mm and dried. This step was repeated. End 1 was again immersed in the cellulose acetate butyrate solution for 30 seconds, allowed to air dry for 60 seconds, and a 22.225 mm diameter and 3.175 mm diameter disc of cellulose acetate butyrate was inserted into the end of the tube so that it was flat with the end.

The cellulose acetate butyrate disk was floated on methylene chloride for 60 seconds prior to insertion into end 1 of the tube. The tube was then rolled over a workbench, finger pressure being applied to the end containing the disc so that the disc and tube were fully joined. A size 3 rubber stopper drilled with a hole, with a glass tube of sufficient length to

Protruding through the pierced rubber stopper of a vacuum bottle when the tube hit the bottom of the bottle was inserted into the tube. The protruding end of the tube was then connected to a flask containing a 6% solution of cellulose triacetate in formic acid and a vacuum of about 150 mm Hg (20 kPa) was applied. After the cellulose triacetate solution had covered the outer walls of the tube which had not been immersed in cellulose acetate butyrate, the tube was removed from the vacuum bottle and the bulk of the cellulose triacetate was wiped off. The tube was then turned over to allow the cellulose triacetate to drain from inside 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 overnight and allowed to balance. It was then removed from the water and the outside was dried with a towel and excess water was shaken out of the inside of the tube. The steps of impregnating the pores of the tube with cellulose triacetate and equilibrating them in distilled water were repeated. It was then brought into equilibrium in running water for 4 hours.

The tube was then checked for leaks by connecting it to a nitrogen source, immersing the tube in water and applying a pressure of 27.5 kPa nitrogen for 10 seconds. If there were leaks, the steps of impregnation and equilibration with water were repeated.

The tube was then equilibrated against polyethylene glycol 400 overnight, removed from the polyethylene glycol 400 and allowed to drain in an inverted position for 4 hours. Excess polyethylene glycol 400 was wiped from the outside of the tube with a towel and a perforated stainless steel tube with an outer diameter of 22.225 mm, an inner diameter of 18.923 mm and a length of 6.985 cm with sixteen evenly spaced circular Insert holes of 7.114 mm in diameter into the pipe until it was flat with the closed end. The abraded portions of cellulose triacetate resulting from the insertion of the narrow sleeve into the tube were removed. A 3.175 mm cellulose acetate butyrate disc was then inserted into the open end of the tube with the stainless steel sleeve and the tube was machined so that the end of the tube with the disc was flat. The disc was removed and the tube was filled with a homogeneous mixture containing 63.31% Morantel tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexametaphosphate, the filling being level with the end of the stainless steel sleeve was. The open end of the tube was filled with a 10% cellulose acetate butyrate solution, which was then immediately poured off, and the open end of the tube was immersed in the cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. A cellulose acetate butyrate disc which had been floated on methylene chloride for 60 seconds immediately prior to insertion was then pressed into the open end of the tube, applying sufficient pressure to press the disc against the stainless steel sleeve . The tube was then rolled along a workbench with sufficient finger pressure to ensure complete connection between the disc and the tube. The tube was allowed to dry for one hour, after which each end of the tube was soaked in 10% cellulose acetate butyrate

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dipped to a depth of 6.35 mm and allowed to dry. The weight of this bolus was approximately 90 g, of which 24.8 g consisted of a mixture of active ingredients. Its density was 2.2 g / ml. This device released approximately 250 mg / day of morantel tartrate in vivo in cattle for approximately 60 days.

Example 2

Three devices were made according to the procedure of Example 1 and tested in vitro using the previously described method. They found an approximately constant release rate over the period of 4 to 17 days with an average release rate for all three devices of 0.927 g of Morantel tartrate per day.

Days, in vitro accumulated amount (g) of morantel tartrate

Bolus 1

Bolus 2

Bolus 3

1

0.357

0.295

0.284

2nd

0.804

0.723

0.66

4th

1.63

1.63

1.38

5

2.12

2.24

1.86

6

2.61

2.96

2.4

8th

4.05

6.31

3.7

11

6.55

9.0

5.76

13

8.24

11.34

7.67

15

11.38

13.4

9.74

19th

14.52

16.2

13.2

25th

17.99

17.4

15.4

29

17.13

17.3

15.9

In vivo tests for three additional bolus preparations made according to the procedure of Example 1, which were placed in the cattle mesh stomach bag, showed a release rate of 0.224 g Morantel tartrate per day when recovered at the end of 30 days. This results in an in vitro / in vivo ratio of 4: 1.

Example 3

In vitro tests for two other bolus preparations made according to the procedure of Example 1 and examined as described above gave an average release rate during the period of constant rate, days 0 to 14, of 0.96 g of Morantel tartrate per day.

Days, in vitro accumulated amount (g) of morantel tartrate

Bolus 4

Bolus 5

1

0.51

0.59

2nd

1.5

2.16

3rd

2.4

2.2

5

4.9

5.4

6

5.1

5.9

7

6.5

6.1

10th

9.7

9.7

12

11.0

11.7

14

13.5

12.6

17th

14.8

13.6

19th

16.4

14.6

21st

17.1

14.7

24th

16.8

14.7

26

16.9

14.8

In vivo tests with identical bolus preparations placed in the cattle's gastric sac for periods of 30 to 60 days gave the following results.

Bolus number

Days in vivo mean amount (g) of morantel tartrate per day

6

30th

0.222

7

30th

0.228

8th

45

0.238

9

45

0.335

10th

49

0.174

11

60

0.198

12

60

0.178

The mean total in vivo rate is 0.224 g per day and the in vitro / in vivo ratio is approximately 4: 1.

Example 4

Bolus preparations with tubes made of stainless steel were produced with the following dimensions: outer diameter = 22.25 mm, inner diameter = 21.336 mm, wall thickness = 0.889 mm and length = 3 cm. The ends of the tubes were threaded, 0.5 mm at each end, to accommodate a collar that was used to hold a disk of porous material impregnated with a hydrogel in place. The discs, 22.225 mm in outer diameter and 3.175 mm in thickness, consisted of a polypropylene filter cloth with pores of 50 μm in average size and were impregnated with gelled cellulose triacetate. They were made by immersing them in a 6% solution of cellulose triacetate in formic acid, which was in a container that could be subjected to a vacuum of 3.33 kPa or less. The container and contents were kept under vacuum for about 10 minutes, the disks were removed and excess cellulose triacetate solution wiped free. They were then immersed in distilled water and balanced with them overnight. The slices were then removed from the water, dried with a towel and then equilibrated with polyethylene glycol 400 overnight. The panes were removed and wiped with a towel.

The impregnated washers were mounted on one end of each of the tubes by sandwiching them between two sealing rings with a thickness of 0.254 mm and the same diameters as those of the steel tube. The sealing ring adjacent to the steel tube was made of cellulose acetate butyrate and the other sealing ring was made of a dental rubber blanket. The ends were then capped with a stainless steel ring with a 21.336 mm diameter opening. The tubes were then filled with morantel tartrate (63.3%), polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) and the other end of each tube was sealed as previously described.

The bolus preparations contained 21.4 g morantel tartrate, had a weight of 97 g and an average density of 3.30 g / ml.

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The bolus preparations were administered to bulls through a rumen fistula using an appropriate delivery device, and they were removed through the fistula at 30, 45, 60, 75 and 90 day intervals to increase the amount of drug remaining in the bolus preparation determine from this the mean daily release rate of morantel tartrate was calculated.

Example 7

Fourteen bolus preparations were made according to the procedure of Example 1 and tested in vivo in cattle. They showed a mean release rate of morantel tartrate of 238 mg per day over a period of 60 days. The standard deviation was 67 mg (28%).

Bolus

Days in the bull

Release rate (mg / day)

1

30th

67

2nd

30th

108

3rd

45

82

4th

45

58

5

60

136

6

60

91

7

75

71

8th

75

68

9

90

67

10th

90

106

The mean release rate was 85 mg / day with a standard deviation of 25 mg.

A significant reduction in the number of parasite eggs in the faeces was found in each bull.

Example 5

In accordance with the procedure of Example 1, four bolus preparations were produced, which comprised sintered polyethylene with an average pore size of 10 μm, the pores of which were filled with gelled cellulose triacetate, and sleeves made of stainless steel within only a section of the total length of the bolus preparations, so that one segment of the bolus preparation was free of the sleeve and had stocks which contained morantel citrate (63.3%) mixed with polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%). Instead of the perforated stainless steel sleeve in Example 1, non-perforated sleeves of 5.08 cm, 4.445 cm, 3.175 cm and 1.905 cm were used. The walls of the sleeves were 0.165 cm thick. The active ingredient mixture was then filled into each bolus preparation, so that there was an active ingredient range of 6.35, 10.70, 25.4 and 38.1 mm above the sleeves. A stainless steel stopper, 12.7 mm thick and 22.225 mm in diameter, was inserted into each of the bolus preparations above the drug mix. The ends of the bolus preparations carrying the steel stopper were machined in such a way that it was possible to insert a cellulose acetate butyrate disc at the top of the stoppers and precisely with the ends of the bolus preparations. The total weight of the individual bolus preparations was 120.0, 115, 4, 106.2 and 97.0 g, respectively. The weight of the active ingredient mixture ranged from approximately 25.5 g to 27.4 g per bolus preparation. The densities of the bolus preparations were 3.1.2.98.2.75 and 2.51 g / ml, respectively.

Example 6

In vitro tests for the release of morantel citrate from the bolus preparations of Example 5 showed that each preparation resulted in a constant release of active ingredient over a period of 3 to 21 days. The lighter of the four bolus preparations of Example 5, i.e. the preparation with a 1.905 cm sleeve had a release rate of 774.8 mg of morantel citrate per day during the period from the 3rd to the 21st day of constant release.

Example 8

In accordance with the procedure of Example 1, bolus preparations were produced, but instead of the active substance mixture used in this example, the following chemicals were used in the supply: pyran tar tartrate (63.3%), polyethylene glycol 400 (26.6%), Sodium he is xametaphosphate (10.1%); Morantel tartrate (100%); Pyrantel hydrochloride (100%); Tetramisole hydrochloride (100%); Leva misol hydrochloride (85.0%), glycerin (15.0%); Diethyl carbamazine citrate (100%); Hydromycin-B (100%); Doxycycline hemihydro chemical alcoholate (100%); Bacitracin methylene disalicyl-20 acid (66.0%), sorbitol (22.0%), sodium lauryl sulfate (12.0%); Ampicillin, sodium salt (63.5%), polyethylene glycol (26.5%), sodium hexametaphosphate (10.0%); Sodium atrium penicillin-G (67.3%), N, N-dimethylformamide (22.2%), sodium glycerol monolauryl sulfate (10.5%); Neomycin complex (68.5%), 25 dimethyl sulfoxide (22.5%), sodium lauryl sulfate (10.0%); Streptomycin trihydrochloride (100%); Oleandomycin hydrochloride (80%), polyethylene glycol 400 (20%); Tylosinhydrochloride (100%); Polymyxin hydrochloride (79.5%), glycerin (15.0%), sodium lauryl sulfate (5.5%); Lincomycinhy-30 drochloride hemihydrate (100%); Magnesium acetate tetrahydrate (77%), sorbitol (15%), dioctyl disodium sulfosuccinate (8%).

Example 9

35 In accordance with the procedure of Example 1, a bolus preparation was prepared which comprised sintered polyethylene, the pores of which were filled with an average size of 100 .mu.m with a hydrogel made of crosslinked polyvinyl alcohol, and a stock containing morantel citrate 40 (63.3%). Polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) included, with a perforated stainless steel sleeve also provided. Instead of the cellulose triacetate-formic acid solution, the hydrogel solution consisted of an aqueous solution of 10% polyvinylal 45-alcohol (88% hydrolyzed polyvinyl acetate) with a content of 3% resorcinol. Following the vacuum treatment to fill the pores, the tube was wiped clean and kept at 0 ° C. to -10 ° C. for 5 hours to gel the polymer. It is not necessary to equilibrate the pipe in such water. The tube was then checked for leaks, equilibrated in polyethylene glycol 400, filled and sealed as described in Example 1.

In vitro tests showed that the bolus preparation resulted in a controlled release of morantel citrate.

Example 10

The procedure of Example 1 was repeated, but using pipes made of sintered polyethylene with only half 60 the length and half the diameter of the pipes used in Example 1. The bolus preparations obtained are suitable for use in sheep and result in a controlled release of the anthelmintic agent in vivo over an extended period of time.

65

Example 11

The procedures of Examples 1 and 5 were repeated, but the following microporous materials

15

643140

materials were used instead of the sintered polyethylene: porous ceramic material, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene, the average pore size of each material being 100 μm, see FIG

Each of the bolus preparations made in this way resulted in the controlled release of a chemical over an extended period of time in the test in vitro.

Example 12 io

Bolus preparations with stainless steel tubes were produced with the following dimensions: outer diameter = 22.225 mm inner diameter =

21.336 mm, wall thickness = 0.889 mm and length = 7.62 cm. The ends of the tubes were threaded (0.5 mm at each end) to accommodate a ring that was used to hold a porous hydrogel impregnated washer in place. The disks, 22.225 mm in outer diameter and 3.175 mm in thickness, were made of sintered polyethylene impregnated with gelled cellulose triacetate and were immersed in a 6% solution of cellulose triacetate in acetic acid in a container set to a vacuum of 3.33 kPa or less could be established. The container and contents were kept under vacuum for about 10 minutes, the disks were removed and excess cellulose triacetate solution was wiped free. They were then immersed in distilled water and thereby equilibrated overnight. The slices were then removed from the water, dried with a towel and then equilibrated with polyethylene glycol 400 overnight. The panes were removed and wiped with a towel.

The impregnated washers were installed on each end of the pipes, for which purpose they were placed between two sealing rings with a thickness of 0.254 mm and the same diameters as those of the steel pipe. The sealing ring adjacent to the steel tube consisted of cellulose acetate butyrate, the other sealing ring consisted of a dental rubber blanket material. The ends were then capped with stainless steel rings with an opening diameter of 21.336 mm. The tubes were then filled with the desired chemicals and the other end of each tube was closed as previously described.

In this way, tubes or bolus preparations were made with the following chemicals in stock: morantel citrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%); Oxytetracycline hydrochloride (100%); 50 pyrantel citrate (88%), glycerin (12%); Pyrantel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium lauryl sulfate (10.1%); Tetramisole hydrochloride (100%); Poloxalene (100%); Erythro-mycine hydrochloride (100%); Thiamine hydrochloride (100%).

20th

25th

30th

35

40

55

Days, in vitro accumulated amount (g) of morantel tartrate

1.7

0.04

5.7

1.03

8.7

2.74

12.7

7.63

15.7

12.3

19.7

17.5

23.7

18.3

26.7

18.6

Example 14

A low carbon steel tube with the following dimensions: length = 8.77 cm, inner diameter = 2.16 cm, outer diameter = 2.54 cm and a groove with a depth of 0.3 cm and a width of 0 , 6 cm, arranged 0.1 cm from each end thereof to receive an aluminum fold, this groove running completely around the tube, were at one end with a disc of sintered ultra-high molecular weight polyethylene, average value = 2 million to 4 million ( Product from Glasrock, Porex Division, Fairburn, GA.), Which had been impregnated with gelled cellulose triacetate as described in Example 15. The disc was 2.54 cm in diameter and 0.16 cm thick and was applied to the tube using an aluminum crimp closure. The tube was then turned over and filled with a homogeneous mixture comprising 54.4% morantel tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The process of disc closure and the application of the aluminum crimp closure were then repeated to produce a finished bolus preparation. The total weight of the bolus preparation was 145.1 g, of which 41.4 g consisted of a mixture of active substances. The density of the preparation was 2.8 g / ml.

The aluminum crimp closures at each end of the tube had an open area in the middle of 3.25 cm2, giving a total area of 6.5 cm2 available for drug delivery. The bolus preparation resulted in the controlled release of morantel tartrate in cattle over a period of approximately 90 days.

Example 13

The procedure of Example 1 was repeated with the exception that the bolus preparation was filled with Morantel tartrate instead of the mixture of Morantel tartrate-polyethylene glycol 400 sodium hexametaphosphate as in Example 1. The bolus preparation weighed 84.0 g, of which 18.6 g consisted of morantel tartrate.

In the in vitro test according to the procedure described, the bolus preparation showed a controlled and almost constant release rate of morantel tartrate during the test period of 8 to 20 days with an average release rate of 1.36 g per day.

60

Example 15

An aluminum cylinder with a length of 6 cm, an outer diameter of 2.1 cm and a wall thickness of 0.1 cm, which had a groove at the open end for receiving an aluminum bead seal, was filled with a formulation containing 70% levamisole hydrochloride and 30% polyethylene glycol 400 and was sealed with a disk of sintered high density polyethylene (0.95-0.97 g / ml) which was impregnated with gelled cellulose triacetate according to the procedure of Example 15. The bolus preparation had a density of 2.8 g / ml. The stock contained 23.46 g of the active ingredient mixture, this corresponds to 16.42 g levamisole hydrochloride.

The aluminum flanged gasket used had a circular, open area in the middle, the area being 1.1 cm in diameter, which corresponds to a transport area of 0.95 cm2.

In vitro tests at 37 ° C showed that the bolus preparation released levamisole hydrochloride at a controlled rate.

643140

16

Days, Levamisole hydrochloride released in vitro

3rd

0.815

5

1,572

6

1.805

7

2.33

8th

2.64

10th

2.79

11

2.83

14

2.87

15

4.66

18th

5.10

22

6.67

Example 16

This example describes a field test that was carried out with 40 test calves of the same breeding weight (mean = 150 kg) and 6 calves that were not in the pasture before. The calves were divided into four groups of 10 animals based on their body weight. Two of the groups were drug-treated double groups and two groups were control double groups. A worm-free calf was allocated to each of the four groups of test calves at the beginning of the field trial and every four weeks afterwards. Each "calf track" was kept in the paddock for two weeks, then removed and held in the barn three weeks before slaughter to count the worms.

The test calves and the track calves or indicator calves were exposed to infected pasture land which had been used as pasture by infected cattle in the previous summer and autumn. The pasture land was large enough to hold 44 animals that were cared for the entire pasture period and was divided into four equal and separate paddocks.

The two drug-treated double groups received orally a bolus preparation for 60 days, prepared according to the procedure of Example 1. The bolus preparations resulted in a continuous release of morantel tartrate of 250 mg / animal (equivalent to 150 mg of morantle base) per day for 60 days. The drug-receiving groups of the animals received the bolus preparations orally two days before being driven out to pasture in the spring. The presence of the bolus preparations in each of the drugged animals was determined using a metal detector 24 hours after application. The examination of the reluctance of the bolus preparations was then carried out at two-week intervals. All medicated animals, the control animals and the trace animals or indicator animals were weighed before the shoot and at four-week intervals.

Samples of the grasses were taken according to the method given by Taylor, Parasitology, 31 (1939), 473 at intervals of two weeks, starting four weeks before the start of the field trial and continued until the field trial was completed.

Faecal samples for McMaster egg counts and lung worm larval counts were collected at the start of the experiment and at two week intervals thereafter. The first eight weeks were rectal specimens, one from each animal. The rectal samples were then taken every four weeks so that there was a coincidence with the weighing of the animals. At intermediate points, samples, 10 for each group, were taken from pasture land, see Gibson, Veterinary Bulletin No. 7 (1965), 403-410.

Total worms were counted on the fat stomach including the mucous membrane accumulation, the small intestine and the lungs of the slaughtered animals.

group

treatment

Paddock

Number of animals

1

Morantel tartrate,

A

10 + 1 indicator animal

250 mg / day

every four weeks

2nd

Morantel tartrate,

B

10 + 1 indicator animal

250 mg / day

every four weeks

3rd

control

C.

10 + 1 indicator animal

every four weeks

4th

control

D

10 + 1 indicator animal

every four weeks

These values are shown graphically in FIGS. 6, 7 and 8. Figure 6 shows the weight gains during the grazing period for the two drug and control groups. It was found that both groups gained weight at almost the same net speed for the first three months. After this point in time, weight gains in the control groups slowed down and even decreased for a while, which coincided with the increase in the number of pasture parasites. On the other hand, in the medicated animals, continued growth with weight gain almost equal to that observed at the beginning of the season was observed.

Figures 7 and 8 show the parasite population during the grazing period for the medicated animals and the control animals. The number of eggs per gram of faeces (see right ordinate) and the number of larvae per kilogram of dry pasture feed (see left ordinate) are plotted against each other. The calves were driven out to pasture in mid-May. The medicated calves received the bolus preparations orally for 60 days two days before the shoot, so that treatment was given until mid-July.

At the time of sprouting, the number of eggs in the faeces and larvae in the pasture land was low. In the control group, see Fig. 7, the appearance of eggs in the faeces of the animals started at the beginning of June, peaked in late July and slowly decreased during August and September. These eggs resulted in an increase in the larvae observed in pasture in late July, peaking in August.

In the drug groups, see Figure 8, egg formation was markedly reduced during June and July, a fact that was reflected in the significant reduction in pasture larvae during July and September.

Example 17

Similar field trials were carried out according to the experiment of Example 16, except that only one drugged group and one control group were used in each field trial. The data obtained here are listed below:

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

17th

643140

attempt

Number of surplus of the mean cumulative number

Reduce

No.

Animals per

Treat the weight gain of the eggs.

tion

Group treated group

Control

Control

towards the

Group group

Control group

(kg)

(%)

1

12

17.0

0

79

100

2nd

13

9.0

33

146

77

3rd

12

32.5

67

408

84

4th

11

9.5

145

436

67

5

17th

18.2

135

886

85

6

18th

13.4

23

62

63

7

24th

17.1

34

150

77

8th

31

36.5

14

28

50

Example 18

The procedure of Example 4 was repeated, but instead of polypropylene filter cloth impregnated with gelled cellulose triacetate, the following porous materials impregnated with gelled cellulose triacetate were used:

porous material average pore

size (| im)

Polyethylene 75

10 polytetrafluoroethylene 100

Glass 60

Filter cloth made of stainless steel 80

Copper mesh 30

Modacrylic fibers (a) 10, s Nickel-copper alloy fabric (b) 50

(a) Copolymer of 40% acrylonitrile and 60% vinyl chloride (brand name Dynel by Union Carbide Corp., N.Y., USA)

(b) Commercial product with the trademark Morel from The Inter-20 national Nickel Co., Inc., N.Y., USA).

B

4 sheets of drawings

Claims (18)

643140 PATENT CLAIMS A device for controlled and continuous delivery of a chemical to an environment containing an aqueous liquid for an extended period of time, the device comprising a supply of a chemical and an at least partially formed of a porous material, the porous wall in contact with at least part of the stock and is insoluble in the environment and maintains its integrity during the extended period, characterized in that the pores (14) of the porous material (11) are impregnated with a hydrogel medium which is resistant to the passage of the chemical (15) and permeable to the aqueous liquid so that when the device (10) is placed in the environment, it continuously releases the chemical from the supply (12) to the environment at a physiologically effective, controlled rate through the medium, the dissolved , chemical released in this way by d he continuous dissolution of chemical in the supply is replaced and the amount of dissolved chemical in the supply changes continuously over the extended period of time so that the rate or rate of chemical release to the environment remains virtually constant for a substantial portion of the extended period of time . 2. Device according to claim 1, characterized in that the chemical is a medicament. 3. Device according to claim 1, characterized in that the supply (12) contains a chemical in admixture with a water-soluble carrier. 4. The device according to claim 1, characterized in that the porous material (11) either from sintered polyethylene, sintered polypropylene, sintered polytetra-fluorethylene, sintered polyvinyl chloride, sintered polystyrene or from a porous, woven, knitted or present in the form of a nonwoven material consists of polyethylene, polypropylene, polytetrafluoroethylene, glass or a modacrylic material. 5. The device according to claim 4, characterized in that the hydrogel medium is gelled cellulose triacetate. 6. The device according to claim 5, characterized in that the chemical is an anti-worming agent. 7. The device according to claim 6, characterized in that the chemical is a water-soluble acid addition salt of pyrantel, morantel or levamisole. 8. The device according to claim 7, characterized in that the water-soluble acid addition salt is levamisole hydrochloride or a tartrate or citrate salt of morantel or pyrantel. 9. The device according to claim 1, characterized in that <? "r stock (12) contains the chemical mixed with a water-soluble liquid carrier and a detergent. 10. The device according to claim 7, characterized in that the chemical is a water-soluble acid addition salt of Morantel. 11. The device according to claim 10, characterized in that the porous material (11) sintered polypropylene or sintered polyethylene and the water-soluble salt are the tartrate. 12. A method of manufacturing an apparatus according to claim 1 for the controlled and continuous delivery of a chemical to an environment containing an aqueous liquid for an extended period of time, characterized in that the chemical is enclosed in a supply of at least partially of a porous material formed wall is surrounded, wherein the porous material in contact with at least one Part of the supply stands and is insoluble in the environment and maintains its integrity during the extended period of time that the pores (14) of the porous material (11) are impregnated with a hydrogel medium which is permeable to the passage of the chemical (15) and the aqueous liquid, so that the device (10), when placed in the environment, continuously releases the chemical from the supply (12) to the environment at a physiologically effective, controlled rate through the medium and through the dissolved chemical thus released replacing the continuous dissolution of the chemical in the supply, the amount of dissolved chemical in the supply continuously changing over the extended period of time so that the rate of chemical release to the environment remains substantially constant for a substantial portion of the extended period. 13. The method according to claim 12, characterized in that the porous material is either sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered vinyl chloride, sintered polystyrene or a porous, woven, knitted or present in the form of a nonwoven material made of polyethylene, polypropylene, polytetrafluoroethylene Glass or a modacrylic material is used. 14. The method according to claim 13, characterized in that a device is produced, which is to be arranged in the net stomach bag of a ruminant, the chemical being an anthelmintic agent. 15. The method according to any one of claims 13 and 14, characterized in that gelled cellulose triacetate is used as the hydrogel medium. 16. The method according to claim 15, characterized in that a water-soluble salt of levamisole, pyrantel or morantel is used as the chemical. 17. The method according to claim 16, characterized in that sintered polypropylene or sintered polyethylene is used as the porous material. 18. The method according to claim 17, characterized in that the tartrate is used as the water-soluble salt of morantel.