DD152482A5 - METHOD OF MANUFACTURING A DEVICE FOR CONTROLLING AND CONTINUOUS CHEMICAL DISPENSING - Google Patents

Abstract

The invention relates to a method of producing a device for the controlled continuous administration of a chemical to an aqueous environment containing a liquid. The chemical is located in a container with a wall of porous material. With the device to be manufactured a chemical release over a very long period to be made possible. According to the invention, the chemical is entrapped in a reservoir surrounded by a shaped wall formed at least partially of a porous material, the porous material being in contact with at least part of the reservoir and being non-salient in the environment and being intact during the prolonged one Time span remains. The pores of the porous material are impregnated with a hydrogel medium permeable to the average of the chemical and the aqueous fluid so that the device, when placed in the environment, continues to deliver the chemical from the reservoir to the environment at a physiologically effective, controlled rate released through the medium.

Description

Manufacturing method for a device for controlled and continuous chemical delivery

Field of application of the invention :

The invention relates to a manufacturing method for systems which are permeable to chemicals, including active ingredients and are suitable, an active ingredient or other chemicals at a controlled rate from a reservoir containing the active ingredient or chemical to an aqueous liquid containing environment, in particular deliver to the body environment of an animal including a human, as well as drug delivery devices and chemicals $ which include such a system, 'particularly, the invention relates to such systems and devices, consisting of a wall or walls,

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at least partially a-.Finally consist of a porous material to a porous textile material _s and whose pores contain a hydrogel, and where there is a po- • Röse material in contact with a drug or the active substance-containing reservoir. In particular, the invention relates to so-called drug pellets or boluses containing such systems for the controlled release of active ingredients in ruminants and which are retained in the reticulum of the animals. "

Drug delivery systems and devices for controlled release of drugs, i. controlled release and sustained and prolonged release are known per se in the art. A variety of methods have been described in the literature, including physiological change of absorption or excretion, modification of the solvent, chemical modification of the active ingredient, adsorption of the active ingredient on an insoluble carrier, use of suspension and implantation of pellets, see Edkins, -J. Pharm. Pharmacol., 11 (1959), 54T-66T. Other methods include mixing the active ingredient with a carrier which is gradually degraded by the environment, e.g. by body fluids, causing the release of the drug. Waxes, oils, fats and soluble polymers 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 the active ingredient within a capsule with a wall or walls of polymeric materials.

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substance by diffusion, including U.S. Patent 3,279,996.

U.S. Patent 3,975,350 describes hydrogel carrier systems consisting of polyurethane polymers for use in medical applications, pesticide applications, insecticidal applications, and as algae control applications, and the like.

US Pat. No. 1,693,890 describes the preparation of porous membranes of cellulose acetate in the form of jellies for use in dialysis. The method comprises precipitating the cellulose acetate from a solution thereof in acetic acid by adding a light solvent such as water. Optionally, the membranes may be formed on a support. Membranes made in this manner are impregnated with water, but they can be freed from water by washing with alcohol or acetone or any other water-miscible liquid.

Film-like, sheet-like, fibrous, or microsphere-shaped composite materials including cellulose esters such as cellulose triacetate or cellulose nitrate, or molecular mixtures thereof, are shown to support cellulosic polymer liquid (PLC) materials in US Pat. No. 3,985, for the controlled release of various substances The free substance is impregnated into and within the cellulosic PIC material as part of the liquid phase or as the total amount 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 permeable membranes of gelled cellulose triacetate which

as carriers for other materials such as liquids having medicinal properties. The impregnation of as-finished plain nonwoven polyethylene materials and knitted cotton gelled cellulose triacetate materials to provide supported cellulose triacetate hydrogel materials is described. The use of drug-impregnated gelled cellulose triacetate products as low release animals implantable in animals is described. for example, casting the glazed cellulose triacetate on a woven or knitted backing sheet or web, or nonwoven backing material.

Described in one or more of the following US patents are controlled release drug delivery devices comprising a reservoir formed of an active agent and a solid or liquid drug carrier and in contact with or around the reservoir a wall consisting of a reservoir large variety of different materials including a microporous material whose micropores are a diffusing medium., eg contain a liquid phase consisting of a solution, a colloidal solution, a suspension or a sol and are permeable to the passage of the active ingredient by diffusion, U.S. Patent Nos. 3,993,072, 3,993,073, 3,896,819, 3,948,254 , 3,948,262, 3,828,777, 3,797,494, 4,006,084 and 3,995,634.

U.S. Patent 3,993,073 also describes hydrophilic hydrogels of esters of acrylic acid and methacrylic acid and cross-linked polyvinyl alcohol as suitable wall-forming materials. An essential feature of the devices according to these patents is the use of a wall which is at least partially made of a micropowder.

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porous material, whose pores contain a drug release rate controlling, against the passage of the drug pe.rmeables medium, and a stock, which comprises active ingredient plus a carrier, which, however, is permeable to the passage of the active ingredient at higher rates than the permeability or Permeability of the rate-controlling medium accommodated in the pores of the microporous wall. Devices suitable for the administration of therapeutic substances or nutrients to ruminants, which comprise a coating of the substance in a permeable, water-insoluble material, capillary pores or pores extending therethrough, and in paper or textile materials which are partially water-insoluble polymers; z "B" cellulose acetate impregnated are described in British Patent 1,318,259.

U.S. Patent 3,594,469 discloses pellets containing magnesium and iron for ruminant application to provide ruminants with these metals for a prolonged period of time. According to one embodiment, the pellet or tablet consists of a magnesium alloy tube filled with shot and any biologically active substance, which is closed at both ends by porous discs.

U.S. Patent No. 3,938,515 discloses some devices designed for continuous application of an active ingredient over a prolonged period of time and containing a supply containing the active ingredient and a solid or liquid carrier permeable to the active ingredient, as well as a reservoir surrounding it Wall of polymerera material, the wall counterparts

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permeable over the drug but at a slower rate than that of the carrier. ·.

U.S. Patent 3,946,734 discloses a diffusion cell which is primarily designed for use as an implant and consists essentially of a capillary having one end closed with an impermeable material, the remainder of the tube and the other end thereof are sealed a porous, neutral Histrogel. The biologically active substance is placed in the capillary against the impermeable material and the capillary is then filled with the hydrogel (agarose, polyacrylamide) through which the biologically active drug will diffuse.

Many of the prior art controlled release devices are described as zero order release devices. However, such devices are capable of maintaining zero order release rates for relatively short fractions of their intended life span. they are not proscopic for prolonged use, for example in ruminants.

On the other hand, the devices of the present invention make it possible to achieve and maintain controlled, predictable, zero-order release rates for a given drug for extended periods of time.

In addition, the prior art devices, including devices comprising a reservoir containing the drug contained by a molded wall, are formed at least in part from a microporous material whose

Pores have a drug release rate controlling medium (permeable medium) permeable to passage of the drug, subject to mechanical clogging or mechanical damage when used in certain environments, such as ruminant reticulum. The clogging reduces or even stops the release of the drug, thereby disabling the device for the intended purpose. The devices of the invention in which pores of the porous material in contact with the drug-containing reservoir contain a hydrogel are substantially free of this problem and are capable of delivering controlled and predictable release rates of the drug to an aqueous one To provide fluid containing environment for extended periods of time.

When used for the controlled release of highly water-soluble actives, the prior art devices of the type described in US Pat. Nos. 3,993,073, 3,993,072, 3,917,618, 3,948 262, 3,948,254 and 3,896,819 - it is preferred that the wall and / or reservoir be formed of a material which is substantially impermeable to water to permit dilution of the active ingredient in the reservoir by absorption of body fluid in the reservoir Device as well as a reduction of the drug release rate to avoid. Such devices are therefore not suitable for the delivery of water-soluble drugs, especially at relatively high rates. Furthermore, most of the devices described in these patents require that the permeability of the drug release rate controlling medium to the drug in the pores of the porous wall surrounding the reservoir be less than the permeability of the drug

liquid carrier for the Y / irkstoff in the supply or storage container. In this way, the passage of the drug through the wall is the rate controlling step. There are no such limitations with the devices of the invention. In fact, a significant difference of the devices described herein over the prior art devices is the presence of the highly permeable hydrogel in the pores of the porous material in contact with the Stock stands. Such devices are dependent upon the diffusion of water from an aqueous liquid environment into which the device is introduced, through the fluid-filled pores or channels in the hydrogel and into the reservoir, and the outward diffusion of the drug from the reservoir into the environment , Unexpectedly, the concentration of dissolved drug in the reservoir does not decrease, resulting in a substantially constant rate of release for a prolonged period of time. However, the amount of drug dissolved in the reservoir varies continuously throughout the life of the devices of the invention.

The use of a low content of the antidutrient worm agent morantel tartrate in the drinking water of calves, the calves continually having access to the mediated water, has been reported by Downing et al., Irish Vet. J., 221 (November 1974) and in British Patent 1,530,161. Calves from the beginning of April to the middle of July have been found to suppress the daily supply of antidepressant antidepressant medication to calf eggs by the calves and prevent or at least minimize the development of severe larval infection of the plants.

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Furthermore, Jones et al. Brit. Vetc J ₀ , 134 (1978,), 166 found that the daily application of low dose tartrate in the calf from the time of hatching to the middle of July successfully controlled the parasitic gastroenteritis and lungworm infections by reducing the contamination of the grazing Calves accessible pasture,

Object of the invention:

With the invention will now improved, permeable to chemicals including drugs _o permeable systems and devices which may substitute the chemicals for the release of these substances in a physiologically or pharmacologically active, controlled rate or speed of a or * containing the active substance reservoir of a a aqueous environment and in particular to the environment of an animal body including a human body are suitable to be created. More particularly, the invention relates to the manufacture of such systems and devices which comprise a container whose wall or walls comprise at least partially porous material including a porous textile material whose pores contain a hydrogel, and to devices in which this po -

, rose material is in contact with at least part of a stock of chemicals or a stock containing a chemical. In particular, the invention relates to drug pellets (bolus) containing such systems for controlled release of active ingredients in ruminants and which are retained in the animal's butchers' tract.

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The -verbesserten for chemicals including drugs (these terms are used interchangeably hereinafter) permeable ^'1 Systems and devices according to the invention are useful for the controlled release of drugs and other chemicals contained in an aqueous liquid environments valuable, and particularly valuable, they are for oral dosing in animals including humans, and they can be used for a variety of drugs. In addition, the devices are particularly well suited for delivering high water soluble substances at high rates, which is not easily achievable with prior art devices. The controlled release systems and devices of the invention for a prolonged period of time can be readily prepared they are reliable and easy to use, in addition, the devices described herein maintain their physical and chemical integrity, do not plug in DER environment in the application and are especially valuable for oral use in a bolus form in ruminant Tieren.'Sie provide for the first A practical device for the controlled and sustained release of chemicals, including active ingredients, into an environment containing an aqueous liquid, and therefore satisfies a long-felt need, particularly in the case of d he animal husbandry.

The controlled rate delivery systems and devices to be produced in accordance with the present invention comprise a barrier or wall in contact with at least a portion of a chemical containing material, wherein the wall is partially or wholly made of a porous material including a porous textile material

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Pores contain a hydrogel, which is permeable to the passage of fluid from the environment through the pores within the hydrogel itself and by chemical from the supply by diffusion. When the devices according to the invention are used, the hydrogel contains liquid from the environment, this liquid being contained in the regions or channels (pores) within the hydrogel itself, and these as diffusion paths or. routes of liquid from the environment and for the transport of the active ingredient.

For example, they may have a capsular shape for oral administration to humans or animals or a cylindrical shape as an implant for oral or human use Use as bolus or drug ball in ruminants.

 A preferred form of the device according to the invention in its most general way comprises a porous material having pores in hydrogel and in particular a gelled cellulose triacetate which is permeable to passage of liquid from the environment and from active ingredient by diffusion through pores within the hydrogel. permeable, said porous material being in contact with at least a portion of a chemical - including agent - containing stock comprising the chemical and, if desired, a suitable, water - soluble, liquid carrier / and further, if desired, a detergent or excipient Containing surfactant, wherein the device is in the form of a drug ball or a bolus for use in the controlled release of active substance in chewing animals, and in particular cattle, and

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Sheep is made for a prolonged period of time. A particular use of such drug spheres is for parasitological control, and in particular bowel worm control, as a prophylactic and therapeutic agent for gastroenteric and pulmonary infectious diseases in cattle and sheep and against intestinal worm contamination of pasture. As used herein, the term "bolus" refers to devices which are generally cylindrical, spherical, spheroidal, elliptical, or other shape and are free of sharp edges and protruding parts.

The prior art devices require the consideration of and a trade-off between different factors for each application, particularly with regard to the carrier used in the reservoir, the solubility and / or permeability of the carrier to the drug contained in the reservoir, the nature of the microporous, the wall surrounding the reservoir, the diffusion permeable medium contained in the pores of the microporous wall, the relative permeability rates of the diffusion permitting medium and the carrier to the drug, the relative solubilities of the drug in the diffusion permitting medium and the carrier, and the need to maintain a substantially constant amount of dissolved drug in the reservoir.

In contrast, the devices to be produced according to the invention are far simpler in terms of their arrangement and their operation. For a given device, the release rate of the chemical can be widely varied 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 stock. vari-

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be iert. Therefore, manipulation of only two parameters allows control of the amount of chemical released.

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The invention will be explained in more detail with reference to the drawings, wherein the Pig. I to 5 show various exemplary devices according to the invention. The fact that only a few examples are so shown is not a limitation of the invention, but numerous modifications and equivalents thereof are possible.

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

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

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The pig. Figure 3 shows an enlarged view of a porous wall 11 of a device 10 according to the invention, the pores 14 of which contain a hydrogel 19, in contact with a chemical containing supply 12 consisting of a "chemical 15 and a water-soluble liquid carrier 16. represents.

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

FIG. 5 shows another device 10 according to the invention, wherein 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 is made of a non-permeable, non-porous material, in this case stainless steel, which in combination with the hydrogel-impregnated walls 14, includes a supply 12 comprising a chemical 15 and a carrier or diluent 16.

As previously indicated, the improved dispensing devices or systems of the invention comprise a chemical-including-agent-containing reservoir comprising a chemical, and in a preferred embodiment, a chemical and a water-soluble liquid carrier or diluent, respectively. The water-soluble liquid carrier or 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 a promotion of mixing by convection within the stock (which a. constant rate of chemical release-ensures) becomes possible. Furthermore, such a water-soluble, liquid carrier plays a further role, since it dissolves chemicals, so-that no offensiebt-

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The change in volume occurs when the chemical changes from the solid or crystalline state to the solution state.

Typical water-soluble liquid carriers or diluents include monools and polyols and ethers thereof, e.g. Ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and tri-pore glycol, 1,2-dimethoxyethane, mono-C 1-4 alkyl ethers of ethylene and propylene glycols, α-dimethylformamide, dimethyl ether 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 if the devices described herein are used for animals in human or other aqueous environment-containing environments used in connection with animals, e.g. in aquariums, fish ponds, water supplies for animals or in water culture 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 carrier' is used to allow the formation of a combination of active ingredients carrier to a compact mass, wherein the determination of the amounts can be done by a simple experiment. Detergents or surfactants to 20 wt .-%, based on the total weight of the stock (chemical including active

  can be used in the supply, in order to minimize possible clogging of the devices during use. Representative detergents or surfactants may be inorganic or organic substances,

and include sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, sodium glycerol monolauryl sulfate, dioctyl sodium sulfosuccinate, bis (1-methylamyl) sodium sulfosuccinate, polyoxyethylene sorbitan monooleate, and other fatty acid esters and other substances known to those skilled in the art Detergent or surfactant, if used, is not critical and in any case it is kept to a minimum to maximize the loading of chemical in the supply. The optimum amount can be determined according to the procedures described below. «

In the description, the terms "stock", "chemical containing stock" and "active ingredient containing stock" are used interchangeably. For simplicity, the preferred devices gernäß the invention are those which are used for the controlled release of active ingredients, so that the term "active substance-containing reservoir ^1? Is the preferred term.

The terms "porous materials", "porous membranes" and "porous walls" as used in the specification include porous textile materials. Representative representatives of such materials will be described below. The porous materials used may be isotropic, i. Of course, they should be insoluble in the environment and the contents of the stock, and thus unreachable. In general, they may be anisotropic, i.e. have a non-homogeneous pore structure porous materials having pore sizes of from about 1 to about 100 to be used in the controlled release devices of the present invention. Porous materials with pore

Structures, which include continuous pores, ie pores having an opening on both surfaces of the p-ous wall connected thereto, are required. In order to facilitate the transfer of active ingredient from the supply to the environment when using the controlled release devices according to the invention, the pores or a 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 the provision of a device which resists clogging and physical or mechanical destruction under conditions of normal use and which, by maintaining its integrity physical _v or mechanical integrity, can be used in environments or in cases were among those previously known hydrogel devices destroyed or controlled release of Y / irkstoffen were ineffective over longer periods of time. The devices described herein are of particular value in use in ruminants, especially cattle and sheep. The

, the hydrogel-containing pores allow passage of liquid (water) 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 dissolving active ingredient. The active ingredient then diffuses through the fluid in the pores in the hydrogel-containing pores of the porous material barrier at a rate or rate, which is the drug concentration in the solution in the reservoir, of the resistance given by the barrier, ie the fluid in the pores of the hydrogel, and the effective surface of the porous portion of the wall is dependent.

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When drug leaves the device, a depletion zone gradually forms, causing a move-the border drug / solution. The diffusion of water into the device from the environment through the pores within the hydrogel-containing pores of the wall into the reservoir gives 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 concentration differences. One function of the water-soluble liquid carrier as described above is to help maintain this large density difference, thereby promoting this critical mixing. Convective mixing results in a constant drug concentration within the reservoir which, in turn, provides controlled release of drug over a prolonged period of time, thereby ensuring zero order release of drug as long as unresolved drug remains in the device. When drug is removed from the reservoir and aqueous fluid from the environment diffuses into the reservoir, the amount of drug dissolved within the reservoir will vary continuously over the life of the device, ie during the prolonged period of drug release. This drug release mechanism allows the use of any geometry of the device without limiting the size and design of the reservoir. This is in direct conflict with the prior art devices disclosed in U.S. Patent No. 3,993,073, which depend on a substantially constant amount of dissolved drug within the torrent, a diffusion of dissolved drug within the reservoir to supply the wall with drug and to achieve this

were made speaking so that these devices are subject to strong restrictions on the size and shape of the product.

The term "hydrogel" as used in the specification refers to a gel having a water content, and is incorporated herein by reference. Hackh's Chemical Dictionary, 4th Ed., Grant, page (1969) as a "gel made by the coagulation of a colloid with the inclusion of water". Representative hydrogels that can be used to pull the pores of the polymeric 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 having an acetyl content of 20 to 40 % , polymeric hydroxyethyl methacrylate, crosslinked polyvinyl alcohol, agarose, polyacrylamide, crosslinked and partially hydrolyzed polyvinyl acetate, hydroxyethyl acrylate, diethylene glycol monoacrylate, diethylene glycol monomethacrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monomethacrylate, vinylpyrrolidone, acrylamide, methacrylamide, N- Propylacrylamide, N-isopropylmethacrylamide, N-methylacrylamide, Ιί-2-hydroxyethylmethacrylamide, polyurethane hydrogels including slightly crosslinked prepolymers terminated with isocyanates, which is the reaction product of a poly (alkyleneoxy) polyol ro.it an organic diisocyanate, weakly crosslinked with hydrogen peroxide or an organic polyamine, see US Pat. No. 3,939,105, copolymers of ethylenically unsaturated monomers of hydroxyalkyl acrylates and methacrylates and of alkoxyalkylene glycol acrylates and methacrylates, as described in US Pat U.S. Patent 4,038,264, polyether polyurethane resins made by reacting an organic diisocyanate with a mixture of at least two

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Diols, one of which is a water-soluble polyalkylene glycol having a molecular weight of from 3.000 to 30.00 and the second is an oxyalkylated diphenol having from 2 to 20 oxyalkylene groups, and other substances known in the art.

Advantageous hydrogels for use according to the invention are:

Polyurethanes, polymeric hydroxy-lower alkyl acrylates or .methacrylates, vinylpyrrolidone, acrylamide, H-Miederalkylacrylamide and -methacrylamide, especially with a hydroxyalkyl acrylate or methacrylate cross-linked or copolymerized products to achieve a water insolubility of the resulting Copolymerisatea. Preferred hydrogels are gelled cellulose triacetate, polymeric hydroxyethyl methacrylate and crosslinked-bound polyvinyl alcohol. Especially preferred is gelled cellulose triacetate which provides a smooth and effective operation of the controlled release devices described herein.

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 may also be used to replace the water, including alcohols having from 1 to 4 carbon atoms. To stabilize the devices of the invention, especially if the hydrogel is gelled cellulose triacetate, for practical reasons, the water of the hydrogel is replaced by a suitable, water-soluble liquid which has a lower vapor pressure than water, so that the devices without loss of effectiveness as a result Drying of the hydrogel can be stored * When a combination of 'water-soluble, liquid' carrier

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Active ingredient in the stock, the use of the same liquid to replace the water in the hydrogel is a suitable method;

The hydrogels themselves are porous in the sense that they contain regions or regions, i. Channels or pores filled with water or modified liquid. Therefore, when reference is made in the specification to the diffusion or transport of chemicals or agents through the walls, and the term "whose pores contain a hydrogel" or a similar term is employed, it is intended that the diffusion or the transport of the chemical or drug across these regions occurs rather than through the hydrogel per se. The hydrogel itself has fluid-filled pores that serve as diffusion pathways, and in fact, it is considered to be permeable to the passage of ambient fluid and chemical from the reservoir.

The porous wall in contact with the stock containing the active ingredient may be any of a variety of materials. The porous material can completely surround the reservoir, or it can only * make up part of the surrounding Wans. Suitable porous materials include porous metals, porous ceramics, sintered polyethylene, sintered polyvinyl chloride, sintered polypropylene, sintered polystyrene and sintered polytetrafluoroethylene, porous polymers prepared from thermoplastic resins by phase separation techniques as described in Chem. Eng. News (December 11, 1978), "S" 23, as well as other materials known per se to the person skilled in the art,

Suitable porous textiles may consist of polypropylene and polyethylene, in particular such textiles of the type

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as commonly referred to as "filter cloths", further comprising glass, polytetrafluoroethylene, nylon, bamboo wool, modacrylic fibers, ie acrylic fibers composed of a long-chain synthetic polymer containing from 35 to 84 % of acrylonitrile units, ie synthetic polymers with a minimum of 85% by weight of acrylonitrile, polyesters, ie, a long-chain synthetic polymer comprising at least 85% by weight 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, vinylidene chloride, vinylidene chloride, vinylidene fluoride, polyurea and other materials known in the art, see Encyclopedia of Polymer Science and Technology, ¥ ol. 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 5Ο6 (1969); Vol. 14, 305, 575 (1971); Interscience Publishers, New York. Furthermore, metal grids or filter cloths including those made of stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel-copper, etc., are suitable «

The special, selected material or textile material 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. Therefore, for a device to be used as a bolus for administration of an active ingredient in ruminants for a prolonged period of time, cotton would not be used as a textile material as it would degrade in the ruminant. In a device to be used for the controlled release of a chemical to an aqueous environment, such as in an aquarium or storage tank, a tree may be used.

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Wool to be used »

Nylon, i. A polyamide would not be used as a textile material if gelled cellulose triacetate is to serve as a hydrogel as it would be degraded by the formic acid or acetic acid used in the impregnation process.

Of course, the hydrogel-impregnated porous textile materials or other materials must have sufficient strength, durability, and sufficient inert properties to the active agent and use environment so that the controlled release device manufactured therewith retains its mechanical and chemical integrity throughout its life ,

The porous material is 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 oil triacetate solution which is in a Vacuum ausse'tzbaren container is included. Following impregnation, the cellulose loaded with cellulose triacetate is then coagulated by contact with a large volume of water and equilibrated with B to produce the hydrogel-impregnated material. When the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate, acetic acid is preferred as a solvent for the cellulose triacetate over formic acid because it wets the polyethylene better than formic acid and thus facilitates the preparation of the hydrogel-impregnated porous material.

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When the hydrogel is derived from 2-hydroxyethyl methacrylate crosslinked with ethylene glycol dimethacrylate, as described in US Pat. No. 3,520,949, the impregnation of the porous material is completed by filling its pores with the. Mixture of 2 -hydroxyethyl thymate lat / ethyleneglycoldime thacry late and subsequent polymerization of the mixture within the pores is accomplished by the addition of a free-radical catalyst such as t-butyl peroctoate. Similarly, other hydrogels are impregnated into the porous wall material after such "in situ" operations from suitable reactants. When the hydrogel of crosslinked P. polyvinyl is alcohol, ¹ the pores are filled with a mixture of polyvinyl alcohol as 10% aqueous solution and resorcinol (2-3 %) according to procedures described below, and crosslinking is effected in situ, Of course, other crosslinking agents can be used, as is known per se in the art.

For the preparation of storage-stable devices before use, the hydrogel-filled pores are freed of water by adjusting an equilibrium in a suitable, water-soluble liquid such as those listed above, water-soluble, liquid. Carriers allows word. As previously described? For example, it is advantageous to exchange 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 reservoir if the reservoir comprises a combination of chemical / carrier. If the reservoir is formed solely by the chemical in the devices described herein, the selection of the water-soluble liquid used to replace the water from the hydrogel in the hydrogel-filled pores of the porous wall is determined only by the end use of the device, d , if

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a physiologically acceptable, water-soluble liquid is required. Such a liquid is suitably introduced into the hydrogel at the time of preparation of the porous wall, the pores of which contain a hydrogel, prior to refilling the reservoir of the device, as will be described.

The devices of the invention closest to the devices of the prior art, i. the devices described in US Pat. Nos. 3,993,073 and 3,993,072 are dependent upon the different permeability rates of drug through a medium contained in the pores of the porous wall relative to those of the drug in the drug-carrier phase in the reservoir. 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 be minimized. gerea permeability for drug possesses as the drug carrier within the stock. The medium in the wall therefore becomes the drug release rate controlling portion of the device.

Dissolved active diffuses through the more permeable carrier to the inner wall at an exiting rate so that the wall becomes the drug release rate controlling portion of the device. This results in zero order release rates for a period of time until the receding drug limit in the device becomes sufficiently large to cancel the difference in carrier to wall medium permeabilities, then zero-order, not long, rates are reached. As a consequence, a successful, practical application of such devices is limited, and they are for the zero-order delivery of large quantities of

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Excipients in practical, useful forms of a dosage form suitable.

In contrast to these prior art devices, the devices of the present invention, in use, have aqueous surrounding medium in the wall medium as well as in the reservoir. Although the permeability of the drug is the same in the fluid in the wall and in the reservoir, zero order release rates are achieved for large fractions of the overall life of the device. Furthermore, the maintenance of zero-order release does not depend on diffusion in the stock carrier, so that there are no geometric limitations or dose limitations in these devices, and it is possible for the first time to provide large amounts of zero-order rate drug in practical embodiments To deliver sizes and practical shapes.

For particularly efficient operation of the controlled release systems and devices of the present invention and to reduce leakage and clogging, it is essential that the porous material be impregnated with a hydrogel as completely as possible. Devices of the same surface can provide different dosage rates and release periods for a given drug by varying the characteristics of the membrane wall, particularly its thickness, pore size and porosity and by varying the size of the load in the reservoir.

As previously described, a preferred form of device of the present invention is a bolus for use in the controlled release of an active ingredient in ruminants, particularly cattle and sheep, over a long period of time.

- .26 -

The bolus bz.w «; the drug ball is applied to the ruminant in such a manner, preferably by oral administration, that it remains in the reticulum bag for an extended period of time, during which time it continuously delivers drug to the animal at a controlled release rate. Such devices therefore enabled the control (prophylactic and therapeutic) of various pharmacological conditions to which the animals are exposed, by simple oral administration of these corings to the animals,.

In order for the bolus, once inserted into the reticulum of cattle, to remain here for an extended period of time, it is necessary that the bolus or gumball have a density of at least 2.0 g / ml has. In practice, the density can range from as low as 2.0 to as high as 7 or even more. The density is, of course, the most significant factor influencing the retention of the bolus or reticulum in the reticulum. The overall size of the bolus or patch is a function of the required dose to be delivered and the size that can be given in practice. Based on this, if the desired size is once determined, additional weight may be added to achieve the desired

• to achieve average density. If possible, it is desirable to use the maximum size possible, since a larger bolus or a larger drug ball of a given density is better retained than those of a lower density. However, if the average density of the bolus increases to greater than about 5.0, the size of the bolus does not significantly affect the retention factor improvement. The preferred average density range for the bolus is from about 2.5 to about 5 grams / ml.

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

For sheep application, the minimum bolus weight with a density of 4 retained is about Ί g. The size of a bolus varies depending on the density of the bolus. For application in cattle, the minimum weight of a bolus with an average density of 4 is about 5 g. Again, as described above, the upper limits of size are determined by the practicalities of the dosage of the animal concerned and by the minimum average density of the bolus. For example, a bolus about 7.5 cm in length and 2.5 cm in diameter with a density of 2.2 has a weight of the order of about. 90 g.

The density of a bolus comprising only the elements listed above is generally below the lower, aforementioned value. Therefore, it becomes 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 enhancing agents such as minerals, e.g. CaSO ,, to increase the density to the desired value. Alternatively, the average density can be suitably determined by entering an inner sleeve, a high density perforated material, e.g. of a metal (such as stainless steel *, steel j, in particular low carbon steel or iron), which in turn are surrounded by the hydrogel impregnated porous membrane

IB

~ .28 -

is. The perforations in the sleeve should be sufficiently large so as to allow free passage of active agent and liquid from the environment through the "hydrogel impregnated" porous membrane. To increase the average density of the bolus to such a level as to retain the bolus in the Hetzmagensack, and to regulate the surface of the hydrogel-impregnated, porous material in contact with the supply containing the active ingredient.In addition, such a sleeve improves, although not absolutely necessary is the mechanical stability of the bolus, so that the retention of its physical form

.. is essentially ensured under the conditions of use. Another and preferred alternative comprises a bolus comprising a metal, steel or iron cylinder, one of which. End or both ends with a porous membrane whose pores are impregnated with a hydrogel, capped are completed. Bin bolus of this kind is due to its simplicity and economy in the manufacture and the ease with which

A low carbon steel is highly preferred as a cylinder construction material, and other alternatives will be readily apparent to those skilled in the art.

The controlled release devices of the invention may be used for a variety of purposes and in a variety of instances where the controlled release of an active agent or other chemical is desired. They can be used for the application of active ingredients and for the provision of chemicals in places close to or away from the device where the device is used

O-Pf

by appropriate means at suitable locations within the animal body where they are in contact with body fluids, e.g. the stomach of pets, especially in the reticulum of ruminants. Also included among the controlled release devices of the present invention are devices for use as depot implants for the purpose of administering an agent at a controlled rate to the host. The implants differ from the devices of the invention for other purposes only in their shape, which of course is for implantation is designed. Other applications include sublingual or buccal tablets, surgeries, suppositories, bandages, and dermal patches. Still other applications for the controlled release systems and devices of the present invention are in agriculture for application of fertilizers and pesticides, in fish farming, including aquariums and fish ponds, in drainage ditches, canals and tanks, for algae control, for example , given, and in water supplies, in particular for animals and poultry, which require active substances for the therapeutic or prophylactic treatment.

The criterion for suitable substances, agents or chemicals used in the devices of the invention is that they are sufficiently soluble in water to achieve a rate of release of this drug or chemical in the environment of use which gives the desired result. For this reason, active substances and chemicals which are acids or bases are desirably used in the form of their physiologically or pharically acceptable salts. "The rate of release" of the active ingredient or chemical from the devices described herein is dependent upon their nature.

¥ 1

various factors such as the thickness of the wall, the available surface, the effective pore diameter, the porosity of the wall, the type of hydrogel, the concentration of the substance in the reservoir, and the solubility thereof in the ambient fluid. The suitability of a given substance is determined according to the description given below.

Representative representatives of drugs used in the devices described herein are the following substances:

Anthelmintica including salts of morantel, pyrantel, oxantel, piperazine, diethylcarbamazine, levamisole, tetramisole and hygromycirt B, antibacterial agents including salts of tetracyclization such as 5-hydroxytetracycline, chlortetracycline, doxycyline and Mannich base thereof, penicillins such as ampicillin, penicillin G , Aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin as their zinc or methylenedisalicylic acid derivatives, macrolides such as erythromycin, oleandomycin and tylosin, antibacterial growth promoters such as salts of avoparicin, polymyxin, lincomycin, bambermycin and efrotomycin, hormonal growth promoters including diethylstilbestrol, zearalanol, antiparasitic Agents such as amprplium, nutrients such as soluble salts of magnesium, selenium, 'copper and vitamins' such as thiamine hydrochloride, sulfa drugs such as sulfamethazine, molluscicides such as N-tritylmorphine, and the bulge preventive agents such as alcohol ethoxylates and poly (oxyethylene) pol y (oxypropylene) -poly (oxyethylene) polymers, e.g. Poloxalene.

As already described above, according to a preferred embodiment of the invention, the stock containing the active ingredient comprises an active ingredient and a water-soluble carrier

-31.-

the advantage that they provide a larger amount of drug per device and the useful life of the device is extended. However, the stock may contain only the selected active ingredient.

The devices according to the invention are particularly suitable as long-acting medicinal balls (bolus) for the therapeutic and prophylactic control of intestinal urinary tract infections in ruminants and in particular cattle. The protection of unruly animals becomes relatively easy. In temperate climates, the low early spring population of pasture larvae, namely the backlog of previous season's contamination, is multiplied by the cycle of the animals grazing on it, which in the summer produces a strong increase in the infectivity of pastureland. This condition causes the pasture period in the summer a clinical parasitism and a decrease in the efficiency of animals grazing on such pasture land. , ,

The continuous and controlled release of anthelmintic agents, i. Antidiarrhythmic agents such as morantel, in the reticulum reticulum of grazing animals at the beginning of the season, when the contamination of the pasture is still low, suppresses the delivery of worm eggs and the subsequent formation of larvae, thus interrupting the aforementioned cycle and worm burden Rural grassland and animals are kept low. "Parasitic infections of ruminants, which graze on the same pasture during the summer season, are thereby reduced to a minimum. This method of controlling worms is particularly attractive and valuable to calves, as they are highly susceptible to worms when first placed on grazing land. The conse-

The use of drug balls (blus) reduces the reservoir of infecting worm forms at a predetermined location. The use of anthelmintica-containing medicinal spheres according to the invention in this way prevents or at least minimizes the seasonal increase in pasture larvae, which causes parasitic gastroenteritis and a decrease in grazing-animal performance later in the season. In this type of control the period of active ingredient release is that of the propagation phase in spring and not the period of strong pastureland contamination, strong larval infestation and. masses of worms that cause clinical discomfort and decreased performance. From this round, this type of application is called "indirect control". In other words, the grazing of ruminants having in their mesh stomach one or more of the devices described herein, this device allowing the controlled and continuous release of an anti-worm agent, eg morantel, to this reticulum bag on pasture land at an early stage the season, d. H. if the larval contamination is at a minimum value or near. minimally low, it helps to minimize the usual seasonal increase in larval contamination of pastureland and serves to protect the animals grazing during the entire grazing season.

For the "indirect control" of worms, the devices according to the invention, preferably in the form of medicinal spheres, are applied to ruminants at a point in the epidemiological cycle of these worms when the pasture contamination by these worms, their eggs and / or their larval stages is at one minimum value or close to such a minimum value. In the massive zones this time corresponds to the budding in the

3h

Spring, dg, the first exposure of calves to pasture land. For maximum effectiveness, the bullet or bolus is applied to the calves about two to seven days before budding. In non-temperate zones of the world, eg _t in semi-tropical or tropical areas? The time of least infestation of pastureland is usually before the rainy season. The application of the bolus or ruminant medicinal pellets in such zones is advantageously carried out two to fourteen days before the beginning of the rainy season. However, due to the predictability of the rainy season, worm control in non-temperate zones is best performed by a "direct control" method.

The bullets described here (bolus) also eliminate any worm infections that have already occurred in ruminants and they prevent the nesting of worm infections during the summer period in the case of heavy infestation. This type of application is called "direct control". The direct method of control protects ruminants only during the period of dispensing anti-worm agents. The indirect method of worm control protects ruminants grazing on a designated pastureland for the whole season, since it produces a significant overall reduction in pastureland contamination or pasture infestation. As already indicated, the devices described herein provide a sustained release of controlled rate agents including anthelmintics. Particularly useful for such purposes are water soluble salts of (E) -I, 4,5,6-tetrahy-.dro-1 -methyl-2 - / "2- (3-methl-2-thieno / l) -äthenyl7-p.yrirnidine (morantel), (E) -1,4, · 5,6-tetrahydro-1-methyl 2- / 2- (2'-thienyl) -äthenyl7-pyrimidine - (pyran el) and (-) - 2, 3, 5, 6-tetrahydro-6-phenyl-imidazo ^ ~ 2, l ~ b7-thiazole (tetramisole) and levamisole, the L (-) form thereof. "Representative of

sr

Preferred water-soluble salts of pyrantel and morantel are the tartrate and citrate salts, and of tetramisole and levamisole, the hydrochloride salts.

The medicament spheres according to the invention are administered orally to the animals, for example with a device for administering pills to horses or cattle. For calf use, the desired average release rate of morantel, calculated as base, for the indirect control of worms is about 6O to 200 mg ^r of morantel base per day for a period of time. range of about β Tagen days, thus covering the normal, maximum survival time of spring larvae larvae. Prolonged release periods of 60 to 12 days are desirable in the direct control application, since the exposure time to heavy pasture contamination usually ranges from mid-summer to fall. Release rates of about 60 to 150 mg, calculated as morantel base, per day provides effective control of worm infection during such release periods. For the treatment of larger animals, more than one drug ball or bolus may be given. For the indirect control of worms using salts of pyrantel or levamisole, the desired average release rates for each compound hereof, calculated as free bases, are on the order of 100 to 400 mg and, respectively, 100 to 500 mg per day for a period of about 60 days. For direct control, release rates of about 100 to 300 mg, as the free base, of Pvrantel and from about 100 to 400 mg, as the free base, of levamisole per day provide effective control of worm infections during the period of most severe attack of 60 to 120 days.

- 76- 36

Continuous application of morantel in small amounts using the worm control devices described herein gives an effective profile that is surprisingly different and advantageous over the profile obtained in the conventional therapeutic application of morantel, but not so could be foreseen. For example, maintenance of a protracted level of morantel tartrate or citrate or other salt in the gastrointestinal tract of ruminants is effective in preventing lungworm infections in such animals during the period of drug release. In addition, since cattle or sheep grazing on rich pastureland are subject to immediate reinjection by intestinal nematodes after conventional therapeutic treatment, animals receiving the drug pellets are essentially freed from an infection that has occurred and are prevented from re-infection for a period of time Protected for 60 days or more.

The use of the bolus to control grazing land contamination, i. The indirect control method is a unique, practical and not yet used method of controlling worms, which protects ruminants and, in particular, grazing ruminants protected by this method throughout the pasture period and provides superior results and advantages over previously known methods of control be achieved. The increase in daily weight gain compared to untreated control animals during the Weider period is significantly greater than that achieved after conventional therapy.

Jl ·

¹ ST. ·

The rate of release of the active substance or of the other chemicals resulting from the reserve containing the active substance through the walls of the device according to the invention. controlled release, and the efficacy of a given combination of active ingredient and / or water-soluble carrier and detergent in such devices can be readily determined by one skilled in the art, for example, by transfer methods or sorption-desorption methods , which can be conveniently applied to the selection of suitable porous materials and hydrogels, involves the use of 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 agent or other chemical controlled release is desired, and a r.as.ch 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 at a value which approximates the average temperature of the environment in which the device is to be used. Samples are taken from the Lösungsm'ittelbad at predetermined intervals and analyzed for concentration of the drug. Standard procedures for determining the permeability of a drug or other chemical substance through the porous materila, whose pores are filled with hydrogel, can also be determined by standard procedures as described in Encyclopedia of Polymer Science and Technology, Volumes 5 'and %. Pages 65-82 and 794-8O7 (1968) and the parts mentioned here as well as in Chemical Engineers Handbook (1963) s pages 17-45? edited by McGraw-Hill, Inc..

A procedure of particular value in determining the release rate for devices of the invention and the relative advantages of a given carrier or detergent for use in such a given device, in particular when the drug is morantel, is summarized as follows: In vitro operation and is based on the release of a water-soluble salt of Morarvtel, for example the tartrate, from a device made according to the invention as a function of time. A morantel tartrate-containing device according to the invention is used in a 1-1 conical flask exposed to light for photosensitivity protected by morantel tartrate, and 500 ml of pH 7 phosphate buffer are added. The temperature of the flask and the contents are brought to 37 ° C and held thereon. The flask containing the device is shaken with about 7O movements (7 × 62 cm) per minute, and 5 ml samples are periodically removed. The volume of sample withdrawn is replaced with an equivalent volume of pH 7 fresh phosphate buffer, and shaking of the flask is continued. The concentration of morantel in the samples is determined spectrophotometrically by measuring the absorbance of the sample at 318 nm when read against fresh phosphate buffer of pH = 7. The process of sampling is repeated until 5 g of morantel tartrate has been released, at which time the device is transferred to another flask containing 500 ml of fresh pH 7 phosphate buffer, and the procedure is continued as before. ·

The in vivo release of morantel tartrate from devices of the invention is determined by, for example, giving the devices to 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 released via the fistulas or after killing the animals.

and the devices are removed to determine the residual morethan tartrate within the device. Tests of this kind show "that the release

₍ rate of morantel tartrate in vitro is approximately four times the release rate in vivo.

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

Example. 1

A sintered polyethylene, the pores of which were filled with gelled cellulose acetate, comprising a bolus and a stock containing mixed mor tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate. and a perforated stainless steel sleeve was provided as follows.

One end, hereinafter referred to as the end 1, of a sintered polyethylene tube having an average pore size of 10 μm and an outer diameter of φ 25.4 mm, an inner diameter of 22.225 mm and a length of 7.938 cm was placed in a 10 It was then air-dried, and the other end of the tube, designated end 2, was added to the cellulose acetate butyrate solution until it reached e ^ n The depth of 9, '525 mm immersed and dried. This stage was repeated. The end 1 was again immersed in the cellulose acetate butyrate solution for 30 seconds, allowed to air dry for 60 seconds, and

-JZ-

ho

A disk of cellulose acetate butyrate having a diameter of 22.225 mm and a thickness of 3 × 175 mm was inserted into the end of the pipe 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 with finger pressure applied to the end containing the disc so that complete bonding of the disc and tube occurred. A size 3 rubber stopper pierced with a hole », which was provided with a glass tube of sufficient length for protrusion through the pierced rubber stopper of a vacuum bottle when the tube was placed on the stopper. Bottom of the bottle was used in Ääs 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 were not immersed in cellulose acetate butyrate, the tube was removed from the vacuum flask and the bulk of the cellulose triacetate was wiped off. The tube was then inverted to drain the cellulose triacetate from the interior of the tube. The outer and inner open ends of the tube were wiped clean with a cloth. The tube was then immersed in distilled water overnight and allowed to equilibrate. It was then removed from the water and the exterior was dried with a towel and excess water was shaken out of the interior of the tube. The steps of impregnating the pores of the tube with vellulosic triacetate and equilibrating them in distilled water were repeated. It was then equilibrated for 4 hours in running water.

The tube at this time was examined for leaks by connecting it with a source of nitrogen, immersing the tube in water and applying a pressure of 27.5 kPa of nitrogen for 10 seconds. Palis leaks, the stages of impregnation and insitu weighing were repeated with V / asser.

The tube was then equilibrated overnight against polyethylene glycol 400, removed from the polyethylene glycol 400 and allowed to drain in an inverted position for 4 hours. Excess polyethylene glycol 440 was wiped off the exterior of the tube with a towel and a stainless steel perforated tube with an outside diameter of 22.225 mm, an inside diameter of 18.923 mm, and a length of 6.985 cm with sixteen equally spaced, free-shaped holes of 7.115 mm diameter inserted into the pipe until it was level with the closed end. The abraded portions of cellulose triacetate resulting from the insertion of the tight fitting sleeve into the tube were removed. A cellulose acetate butyrate disc of 3.175 mm was then inserted into the open end of the tube just 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 % moraltar tartrate, 26.6 % polyethylene glycol 400 and 10.08 % sodium hexametaphosphate, the fill being flush with the end of the stainless steel sleeve , The open end of the tube was filled with 10% cellulose. acetate butyrate solution, which was then poured off immediately, and the open end of the tube was dipped in the cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. A disc of cellulose acetate butyrate which had been floated on methylene chloride for 60 seconds immediately prior to insertion

HL

was then pressed into the open end of the tube with sufficient pressure applied to press the disc against the stainless steel sleeve. The tube was then rolled along a workbench applying sufficient pressure to the pinger to ensure complete bonding between the disc and the tube. The tube was allowed to dry for one hour, after which each end of the tube was immersed in 10 % ± g of cellulose acetate butyrate to a depth of 6.35 ram and allowed to dry. The weight of this bolus was about 90 g, of which 24.8 g was an active ingredient mixture. Its density was 2.2 g / ml. This device released about 250 mg / day of morantel tartrate in vivo in cattle for about 60 days.

Example 2

Three devices were prepared according to the procedure of Example 1 and tested in vitro by the method previously described. Here they gave an approximately constant release rate over the period of 4 to 17 days at an average release rate for all three devices of 0.927 g of tartrate daily.

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

Bolus 1 Bolus 2 Bolus 3 1 0,357 0,295 0,284 IV) 0.804 0.723 0.66 4 1.63 1.63 1.38 VJL 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

HI

Days, in vitro accumulated amount (r) of moranteltartra

Bolus I Bolus 2 Bolus 3 '15 11:38. 13.4 9.74 19 14.52 16.2 13.2 25 17.99 17.4 15.4 * 20 - 17.13 17.3 15.9

In vitro tests for three more according to the labor. For example, bolus preparations made from Example 1 that were placed in cattle's last stomach sack showed a rate of 0.224 g of Morantan tartrate per day when recovered at the end of 30 days. This gives an in vitro / in vivo ratio of 4: 1.

In vitro assays for two other bolus preparations, prepared according to the procedure of Example 1 and as described above, gave an average rate of release during the. Period of constant rate, days O to 14, of 0.96 g of morale tartrate per day .. '.

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

Bolus 4 * Bolus 5 - 0 - 1 0.51 0.59 2 - 1.5 2.16 3 2.4 2.2 VJL 4.9. 5 _S 4 6 _m , 5.1 5.9 V 6.5  6.1 10 '9p7 • 9.7 .. •. 12 H ₅ O 11.7

Days, in vitro accumulated Mj3ng, e ... J, ff) to morantel tartrate

BQlus · 4 Bolus. 5 14 13.5 12.6 17 · 14.8 13.6 19 • 16.4 14.6 21 17.1 14.7 2.4 16.8 14.7 26 16.9 14.8

Bolus Hr .. Days in vivo  ; 6 30 7 30 8th 45 9 45 10 49 11 60 12 60

In vivo devices with identical Boius preparations placed in the cervical gastric pouch of cattle for periods of 30 to 60 days gave the following results.

average amount (g) of morantet tartrate · per day

0.222 0.228 0.238 0.335 0.174 0.198 0.178

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

Example 4

Bolus preparations were made with stainless steel tubes of 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 receive a collar suitable for holding a hydrogel with a hydrogel.

I ι C "

embossed disc of porous. The material was used in ^situ . The: slices with an outer diameter of 22.2 "25 ^mm and a thickness of 3.175 ^mm were made of a polypropylene ^{filter cloth} with pores of 50 / average ^size , and were ^impregnated with gelled cellulose triacetate. They had been prepared by immersing them in a 6 % solution of cellulose triacetate in formic acid which was in a container which could be exposed to a vacuum of 3300 kPa or less The container and contents were submerged for about 10 minutes Vacuumed, then the wafers removed and the excess cellulose triacetate solution wiped off, then dipped in distilled water and equilibrated overnight. The wafers were then freed of water, dried with a cloth and equilibrated overnight with polyethylene glycol 400 , allowed to warm. Subsequently, the discs were removed and dried with a cloth _i.

The impregnated discs were placed on either end of two tubes, sandwiched between two 0.254 mm (0.01 inch) thick sealing rings and the same diameter as the steel tube. The sealing ring adjacent the steel tube was composed of cellulose acetate butyrate and others, from a dental rubber blanket material. The ends were then capped with stainless steel rings with an opening diameter of 21.336 mm 2. The tubes were then washed with morantel tartrate (6 * 3.3%) _t polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) were introduced, and then the other end of each tube was sealed as described above, '.. . "- ·

The bolus preparations contained 21.4 g of mor tartrate, weighed 97 g and had a mean density of 3.30 g / ml »

LA

hb

The bolus preparations were removed from bulls with fistula fistulae via a suitable balling gum device at intervals of 30, 45, 60, 75 and 90 days to determine the amount of drug remaining in the bolus, based on the mean release rate of morantel tartrate was determined.

Bolus days in bull release rate (mg / day)

67 108

82

58. 136

68

67 106

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

In each bull, a significant reduction in parasite eggs in the faeces was noted.

Example 5

In accordance with the procedure of Example 1, four bolus preparations were prepared comprising sintered polyethylene having an average pore size of 10 μm, whose pores were filled with gelled cellulose triacetate, and stainless steel sleeves within only a portion of the total length of the bolus preparations so that a segment of the Boius preparation was free of the pod, and had supplies of which morantel citrate

1 30 2 30 3 · 45 4 45 5 60 6 60 7 75 8th 75 9 90 10 90

(63.3 %) mixed with polyethylene glycol 400 (26.6 %) and sodium hexametaphosphate (10.1 %) . Instead of the perforated stainless steel sleeve in examples' game 1 were non-perforated tubes of 5.08 cm, 4.445 crn, used 3 _S 175 cm and 1.905 cm. The walls of the * pods had a thickness of 0.165 cm. The drug mixture was then filled into each bolus preparation, so that a drug band width of 6.35, 10.70, 25j 4 or 38.1 mm was given above the pods. A 12.7 mm diameter, 22.225 mm diameter stainless steel plug was placed in each of the bolus preparations above the mixture of phosphorus. The ends of the bolus preparations carrying the steel stopper were machined to allow the insertion of a cellulose acetate butyrate disc at the top of the stopper and just at 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 drug mixture was about 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 gave a constant release of drug over a period of 3 to 21 days. The lighter of the four bolus preparations of Example 5, i. the preparation with a sleeve of 1.905 cm, had a release rate of 774.8 mg morantel citrate. per day during the period from 3rd to 21st day of constant release.

ία

Example 7

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

"B_e_beispiel 8

Bolus preparations were prepared according to the procedure of Example 1 except that instead of the active ingredient mixture used in this example, the following chemicals were used in the stock: pyrantel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate ( 1O ₅ -I%); Moranteltratrat (100%); Pyrantel hydrochloride (100%); Tetramisole hydrochloride (100%); Levamisole hydrochloride (85.0%), glycerol (15.0%); Diethylcarbamazine citrate (100%); Hydromycon-B (100%); Docyclin hemihydrate mixed alcoholate (100%); Bacitracin methylenedisalicylic acid (66.0%), sorbitol (22.0%), sodium aurylsulfate (12.0%); Ampicillin, sodium salt (63.5%), polyethylene glycol (26.5%), sodium hexametaphosphate (10.0%); Sodium penicillin-G (67.3%), N ^ T-whine thy! Formamide (22.2%), sodium glycerol monolauryl sulfate (10.5%); Neomycin complex (68.5%), dimethyl sulfoxide (22.5%), sodium lauryl sulfate (10.0%); Streptomycin trihydrochloride (100%); Oleandomycin hydrochloride (80%), polyethylene glycol 400 (20%); tylosin hydrochloride (100%); Polymyxin hydrochloride (79.5%), glycerin (15.0%), sodium lauryl sulfate (5.5%); Lincoin, cin hydrochloride hemihydrate (100%); Magnesium acetate tetrahydrate (77%), sorbitol (15 %), dioctyl disodium sulf succinate (8%). -

In accordance with the procedure of Example 1, a bolus preparation was prepared comprising sintered polyethylene, the average pore size of 100 μm of which was filled with a hydrogel of crosslinked polyvinyl alcohol, and a stock containing morantel citrate (63; 3 %) of polyethylene glycol 400 (26.6 %) and sodium hexametaphosphate (10.1 %) , with a perforated stainless steel sleeve also present. Instead of the cellulose triacetate-formic acid solution, the hydrogel solution consisted of an aqueous solution of 10% polyvinyl alcohol (88 % hydrolyzed polyvinyl acetate) containing 3 % resorcinol. The tube was wiped clean after the vacuum treatment to fill the pores and kept for 5 hours at ^{0 0} C to -10 ⁰ C to gel the polymer. It is not necessary to equilibrate the tube in water. The tube was then examined for leaks, equilibrated, filled and sealed in polyethylene glycol 400 as described in Example 1.

In vitro tests showed that the bolus preparation gave a controlled release of morantel citrate,

Example 10

The procedure of Example 1 was repeated except that "tubes of sintered polyethylene having only half the length and half the diameter of the tubes used in Example 1 were used." The obtained bolus preparations are suitable for use in sheep and give a controlled release of the anthelmintic 'agent in vivo over an extended period of time,'.

& -. * ϊ »

B EISP iel 11

The procedures of Examples 1 and 5 were repeated except that the following microporous materials were used instead of the sintered polyethylene: porous ceramic, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene, the average pore size of each material was 100 / μm.

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

Example 12

Bolus preparations were made with stainless steel tubes' 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 receive a ring which was used to hold a porous, hydrogel-impregnated disc in place, the discs having an outer diameter of 22.225 mm and 3 _S 175 ™ in thickness consisted of sintered polyethylene impregnated with gelled cellulose triacetate and were prepared by immersing it in a 6% solution of cellulose triacetate in acetic acid in a container placed at a vacuum of 3.33 kPa or less The container and contents were held under vacuum for about 10 minutes, the slices were taken out and wiped free of excess cellulose triacetate solution and were then immersed in distilled water and

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Balanced overnight, the slices were then taken out of the water, dried with a towel, and then equilibrated with polyethylene glycol 400 over power. The discs were removed and wiped with a towel.

The impregnated discs were mounted on each end of the tubes by interposing them between two sealing rings of 0.254 mm in thickness and the same diameters as the steel tube. The seal adjacent to the steel tube was cellulose acetate butyrate, the other was a den · ^ Talgurnmituchmaterial. The ends were then fitted with stainless steel rings with an opening diameter of 21 _? 336 mm cap-shaped finish. ' The tubes were then filled with the desired chemicals and the other end of each tube closed as described above.

In this way, tubes or bolus preparations were made with the following chemicals in stock: Morantel citrate (63.3 %) , '. Bolyethylene glycol 400 (26.6 %) ,. Sodium hexametaphosphate (10.1 %) oxytetracycline hydrochloride (100%); pyrantel citrate (88 %) , glycerol (12 %), pyrantel tartrate (63.3 %) , polyethylene glycol 4OO (26-6 %) , sodium lauryl sulfate (10.1 %). ); Tetramisolhydrochlorid (100%) \ poloxalene (100%); Erythromycinhydrochlorid (100%); thiamine hydrochloride (100%).

• Di # operation of example 1 was with the exception

- '*>'^;

repeated that the bolus preparation was filled with Morahteltartrat instead of the mixture of Moranteltartrat polyethylene glycol 400-liatriumhexametaphosphat as in Example 1. The bolus preparation had a weight of 84.0 g,

 Of this, 18.6 g from Moranteltartrat.

In. In the in vitro assay according to the procedure described, the bolus preparation gave a controlled and nearly constant release rate of morantel tartrate during the test period of 8 to 20 days at a mean rate of 1.36 g per day.

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 tube of low carbon steel 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, placed 0.1 cm from each end thereof to receive an aluminum rebate, this groove running completely around the pipe, was finished at one end with a disc of sintered ultrahigh molecular weight polyethylene, average = 2 million to 4 million (product of Glasrock, Porex Division, Fairburn, GA), which had been impregnated with gelled cellulose triacetate according to the instructions in Example 15, closed, The disk had a diameter of 2.54 cm and a thickness of 0, 16 cm and she was on the pipe by means of a

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Aluminum crimp closure applied. The tube vmrde then inverted and / filled with a homogeneous mixture which comprised 54 ,, _S 4% Moranteltartrarfc, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The process of closure with the disc and application of the aluminum crimp closure was then repeated to produce a finished bolus preparation. The total weight of the bolus preparation was 145 »! g> of which 41.4 g of mixtures of active substances The density of the preparation was 2.8 g / ml «

The aluminum crimp seals on each end of the tube

2 had an open area in the middle of 3 * 25 cm, giving a total area of 6.5 cm available for drug delivery. The bolus preparation resulted in the controlled release of morantel tartrate in cattle for approximately 90 days. , ,

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 was included and sealed with a sintered high density polyethylene disc (0.95 0.9 g / ml), the disc being impregnated with gelled cellulose triacetate according to the procedure of Example 15. The bolus preparation had a density of ¹ j of 2.8 g / ml. The reservoir contained 23.46 g of the active ingredient mixture, which corresponds to 16.42 g of levamisole hydrochloride.

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The aluminum flare seal used had a circular, open area in the middle, the area having a diameter of 1.1 cm, which corresponds to one

Transport area of 0.95 cm.

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

Days, in vitro released levamisole hydrochloride

3 - 0.815

5 1,572 ^

6 1.805 "7 2.33

8 2.64

10 2.79

11 2,83

14 2.87 ·

15 4,66 18 5,10

.22 6,67

example

This example describes a field trial carried out on experimental calves of the same breeding weight (mean = 150 kg) and 6 calves, which were previously not on pasture. The calves were subdivided into four groups of 10 animals each for their body weight. Two of the groups were drug-treated double groups and two groups were control double groups. A worm-free "trace calf" was added to each of the four groups of experimental calves at the beginning of the study Field trial and assigned every four weeks thereafter. Each = trace calf "was in the

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Keep paddock for two weeks, then it was removed and kept for three weeks before slaughter to count the worms in the stable. , *

The test calves and the trace calves or indicator calves were exposed to infected pastureland, which had been used as a re-infected last summer and autumn by Ridnvieh. The pasture land was of sufficient size to hold 44 animals fed for the entire grazing period and was subdivided into, _t four _rfi equal and separate paddocks.

The two drug-added duplexes were orally given a bolus preparation for 6D days, prepared according to the procedure of Example 1. The bolus preparations gave a continuous release of morantel tartrate from. 250 mg / animal (equivalent to 150 mg Mp-radellase base) per day for 60 days. The drug-containing groups of animals received the bolus preparations by oral route two days prior to expulsion to pasture in spring. The presence of the bolus preparations in each of the drug animals was determined by a metal detector 24 hours after application. The examination of the restraint of the bolus preparations was then carried out at intervals of two weeks. All medicated animals, control animals and the tracer or indicator animals were weighed before spewing and at intervals of four weeks.

Grasses samples were taken at intervals of two weeks commensurate with the method given by Taylor, Parasitology, JL (1-939), * 473, beginning four weeks prior to the start of the field trial and continuing until completion of the field trial; taken.

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Faeces samples for McMaster egg counts and lungworm larvae were at the beginning of the trial and thereafter at intervals of two weighings. collected. The first eight weeks were rectal samples, one of each animal. Thereafter, the rectal samples were taken every four weeks to give a coincidence with the weighing of the animals. At intermediate points, samples, 10 for each group, were taken from the grazing land, see Gibson, Veterinary Bulletin No. 7 (1965), 403-410.

The counts on gasworm worms were carried out on the fat stomach including the mucous membrane collection, the small intestine and the lungs of the slaughtered animals.

Group treatment

Koppel number of animals

1 morantel tartrate, A 10 -i 1 indicator animal 250 mg / day all four weeks 2 ti ti B It tt 3 control C tt ti 4 II D It tt

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-treated groups and control groups. It was found that both groups gained weight at nearly the same rate for the first three months of pregnancy. After that time, the weight gains in the control groups slowed and even decreased for a while, coinciding with the increase in the number of controls pasture parasites. On the other hand, in the medicated animals, there was a continued growth with a weight gain almost equal to that observed at the beginning of the season.

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Figures 7 and 9 show the parasite population during the grazing period for the medicated and 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 applied against each other The calves were ^: Mitt ^; e drove off to grazing land in May. »The calves treated with the drug were given the bolus preparations orally for 60 days two days before the shoot, so that they were treated until mid-July.

At the time of sprouting, the number of eggs in the faeces and larvae on the pasture was low. In the control group, see Pig. 7, the appearance of eggs began in the faeces of the animals too. Beginning of June,:. Peaked in late July and declined slowly during August and September. These eggs increased larvae observed on the pastures in late July, peaking in the Aur;

In the drugged groups, see Fig. 8 ,. egg production was markedly reduced during June and July, a fact reflected in the significant reduction in grassland larvae during July and September.

Similar field tests were carried out according to the experiment of Example 16, but only one drug-containing group and one control group were used in each field trial. The data obtained here are listed below:

58

Number of surplus of medium d. Animal weight gain No. per treated Grup group pe versus control group (kg)

cumulative reductions

Number of ornament

Handle eggs.

Contr.

Group Group (%)

r-l 12 2 13 3 12 4 11 5 17 6 18 7 24 8th '31

17.0 9.0

32.5 9.5

18.2

13.4 17.1 36.5

33

67

145

135

23

34

14

79 146 408 436 886

62 150

28

100 77 84 67 85 63 77 50

, · . example

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

porous material

Average pore size (/ um)

Polyethylene '75 ·

Polytetrafluoroethylene 100

Glass . 60

Stainless steel filter cloth 80

Copper fabric 30

Modacrylic fibers (a) ·. 10

Mackel-copper alloy fabric (b) 50

(a) Copolymer of 40 % acrylonitrile and 60 % vinyl chloride (trade name, Dynel of Union Carbide Corp., NT, USA)

(b) commercial product with the trade name Morel of The International Nickel Co., Inc., N.Y., USA)

S '3

Claims (10)

Invention claim: A process for producing a device for the controlled and continuous delivery of a chemical to an aqueous liquid-containing environment during an extended period of time, characterized in that the chemical is entrapped in a reservoir which is at least partially composed of a porous material surrounded by the porous material in contact with at least one * Teir * of the stock and is insoluble in the environment and maintains integrity during the extended period of time that the pores of the porous material with a against the passage of the Chemical and the aqueous liquid permeable hydrogel medium are impregnated, so that the device when placed in the environment, word for word releases the chemical from the supply to the environment in a physiologically effective, controlled rate or speed through the medium and thus fre When the dissolved chemical is replaced by the continuous dissolution of the chemical in the reservoir, the amount of dissolved chemical in the reservoir continuously changes over the extended period of time, so that the rate of chemical release to the environment during a substantial portion of the extended period of time remains essentially constant. 2. I ^ experience according to item 1, characterized in that the stock contains a chemical in admixture with a water-soluble carrier. 3. The method of item 1, characterized in that the stock contains a chemical in admixture with a water-soluble, liquid carrier and a detergent. ς-he _ έΰ 4. The method according to item 1 or 2, characterized in that as a porous material 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 of polyethylene, polypropylene , Polytetrafluoroethylene, glass or a modacrylic material. 5. The method according to item 1, characterized in that a device is produced, which is to be arranged in the retinal bag of a ruminant, wherein the chemical is an anthelmintic acting agent. 6. The method according to any one of the items 4 or 5, characterized in that is used as hydrogel medium gelled cellulose triacetate. 7. The method according to item 6, characterized in that a water-soluble salt of morantel is used as the chemical. 8. The method according to item 6, characterized in that the chemical is a water-soluble salt of levamisole or Pyrantel. · .. 9. The method according to item 7, characterized in that the porous material sintered polypropylene or sintered • Polyethylene is. 10. The method according to item 3, characterized in that the 'water-soluble salt is the portrait of Morantel.