DD143504A5 - DEVICE FOR CONTROLLING AND CONTINUOUS SUPPLY OF A CHEMICAL - Google Patents

Abstract

Delivery systems and devices for the controlled release of chemicals, including drugs, comprise a wall, formed in part at least, of a porous material, including a porous fabric material, pores of which contain a hydrogel, said porous wall being in contact with at least a portion of a reservoir comprised of a chemical and, if desired, a water-soluble liquid excipient and/or a detergent. Emphasis is given to said systems and devices in which the hydrogel is gelled cellulose triacetate, and to their use for controlled release of drugs to animals, especially to ruminants over prolonged periods of time.

Description

Field of application of the invention:

The invention relates to improved systems or devices which are permeable to chemicals, including active ingredients, and which are capable of delivering an active ingredient or other controlled-velocity chemicals from a reservoir containing the active agent or chemical to an aqueous fluid environment, particularly to the body environment of an animal including a human, and drug and chemical delivery devices which include such a system. More particularly, the invention relates to such systems and devices consisting of a wall or walls consisting at least in part of a porous material including a porous textile material, the pores of which contain a hydrogel, and in which the porous material is in contact with an active agent or agent containing the active substance

border reservoir exists. More particularly, the invention relates to so-called drug pellets or boluses containing such systems for the controlled release of active ingredients in ruminants

the Meztmagen of the animals are held back. '. *

Charakteris policy of beka Nnten technical solutions:

Drug delivery system and devices for controlled release of drugs, i. a 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 the physiological change of absorption or excretion, modification of the solvent, chemical modification of the drug, adsorption of the drug on a non-toxic carrier, use of suspension and implantation of pellets, see Bdkins, J. Pharm. Pharmacol., 11 (1959), 54T-66T.- Other methods involve 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 serve as carriers.

Further, 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 entrap the active ingredient within a capsule having a wall or walls of polymeric materials through which the active ingredient can pass by diffusion See U.S. Patent 3,279,996.

In US Pat. No. 3,975,350, hydrogel carrier systems consisting of polyurethane polymers are disclosed for use in medical applications, pesticide applications, insecticidal applications.

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zidanwendungen, and in applications as algae control agents, etc. described.

U.S. Patent 1,693,809 discloses the preparation of porous membranes of cellulose acetate in the form of jellies for use in dialysis. The method involves the precipitation of the cellulose acetate from a solution thereof in acetic acid by the addition of a solvent such as water. Optionally, the membranes may be formed on a support. Membranes made in this manner are impregnated with water but can be freed of water by washing with alcohol, acetone or any other water-miscible liquid. Composite materials of cellulosic polymer liquid (PLo materials) in film form, film form, fiber form or Microsphere shapes 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.

U.S. Patent 3,846,404 describes gelled cellulose triacetate semipermeable membranes useful as carriers for other materials such as fluids having medicinal properties. The impregnation of as-finished plain nonwoven polyethylene materials and knitted cotton gelled cellulose triacetate materials to provide supported cellulose triavatate hydrogel materials is described. The use of drug-impregnated glulised cellulose triacetate products in animals

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Low-release, low-release agents are described, for example, casting the gelled cellulose triacetate onto a woven or knitted backing sheet or web or nonwoven backing material.

Described in one or more of the following US patent documents are controlled release drug delivery devices which comprise a reservoir formed from an active agent and a solid or liquid drug carrier and in contact with or around the reservoir a wall from a wide variety of different materials, including a microporous material whose micropores are a diffusing medium, e.g. 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, include: U.S. Patents 3,993,023, 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.

In addition, hydrophilic hydrogels of esters of acrylic acid and methacrylic acid and crosslinked polyvinyl alcohol are described as suitable wall-forming materials in US Patent 3,983,073. An essential feature of the devices according to these patents is the use of a wall which consists at least partly of a microporous material whose pores contain a drug release rate controlling medium permeable to the passage of the drug, and a reservoir comprising active material plus a carrier, but this is permeable to the passage of the active ingredient at higher rates than the permeability of the rate-controlling medium accommodated in the pores of the microporous wall. Devices suitable for the application of therapeutic substances or nutrients in ruminants

hüllung of the substance in a permeable, -. water-insoluble material that capillary or comprises therethrough reaching communicating pores, and in paper or textile materials which are partially insoluble with water polymers z _e as cellulose acetate, are impregnated, are described in British Patent 1 318 259 described.

U.S. Patent 3,594,424 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 administration of an active agent over a prolonged period of time, and which contains a supply containing the drug and a solid or liquid carrier which is permeable to the drug surrounding wall to the polymeric material, wherein the wall is permeable to the active ingredient, but at a lower 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 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 (agarose, poly-

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, aery lamia), through which the biologically active drug will diffuse.

Numerous of the prior art controlled release devices are described as zero order release devices. However, such devices are capable of maintaining rates of zero order release for relatively short fractions of their intended life and are not practical for prolonged use, for example in ruminants. The erfindungsge-. On the other hand, devices enable it to achieve and maintain controlled predictable zero-order release rates for a given drug for extended periods of time.

Moreover, the devices according to the prior art, including the devices comprising a reservoir containing the "/" material, surrounded by a shaped wall, are at least partially formed of a microporous material whose pores are one the drug release rate controlling medium (permeable medium) which is permeable to passage of the drug is subject to mechanical clogging or mechanical damage when used in certain environments, such as the rumen of ruminant animals, clogging reduces the release of the drug or The devices according to the invention, in which pores of the porous material in contact with the supply containing the active substance contain a hydrogen radical, are substantially free of this problem and they are capable of providing controlled and predictable release rates of the active agent to an aqueous fluid containing

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To deliver environment for extended periods of time.

When used for the controlled release of highly water-soluble drugs, in prior art devices, it will be of the type disclosed in U.S. Patents 3,993,073, 3,993,072, 3,967,618, 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 device as well as a reduction of the drug delivery 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 liquid carrier for the drug in the reservoir , 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 reservoir. Such devices are of 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 in the supply and the outward diffusion of the active ingredient from the supply into the environment dependent. Unexpectedly, the concentration of dissolved increases

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Active ingredient · in the supply or reservoir does not decrease, resulting in a viesentlichen constant release rate 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 level of antidiarrhythmic agent morantetartartrate in the drinking water of calves, which calves have constant access to the mediated water, as a means of endoparasite. Control was described by Downing et al., Irish Vet. J., 221 (Nobember 1974) and British Patent Specification 1,530. It has been found that the continuous daily antiarrhythmic drug supply in calves from the beginning of April to the middle of July suppresses the delivery of worm eggs by the calves and prevents or at least minimizes the development of severe larval infection of the plants. , '

Further, by Jones et al., Boit. Vet. J., Y ^ s. (1978), 166 found that the daily administration of moranteltar in a small amount with the putter in calves from sprouting to the middle of July successfully controlled the parasitic detroenteritis and lungworm infections by reducing the contamination of the grazing calves' accessible pasture.

Object of the invention;

The invention is now to be improved, permeable to chemicals and drugs permeable systems and devices, which for the release of Dieeer substances in a physiologically or pharmacologically effective, controlled rate or speed of a chemical or drug-containing stock

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in an aqueous liquid environment and, in particular, to the environment of an animal body including a human body. More particularly, the invention relates to such systems and apparatus comprising a container whose walls or walls at least partially comprise a porous material including a porous textile material, the pores of which contain a hydrogel, and devices in which this porous material contacts at least part of a stock of chemicals or of a chemical containing In particular, the invention relates to drug pellets (bolus) containing such systems for the controlled release of drugs in ruminants and which are retained in the animal's IT mesh.

Presentation ; the We sen 3 of the invention

The improved systems and devices permeable to chemicals, including drugs (these terms are used interchangeably hereinafter) are valuable for the controlled release of active ingredients and other chemicals into aqueous fluid containing environments, and are particularly valuable for oral Dosage in animals including humans, and they can be used for a variety of drugs. In addition, the devices are particularly suitable for delivering high-solubility substances at high rates, which is not easily achievable with prior art devices. The systems and devices for the controlled release of chemicals according to the invention for a prolonged period of time can be easily prepared and are reliable and easy to use. In addition, the devices described herein maintain their physical and chemical integrity,

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Do not clog in the environment during use and _: are especially valuable for oral use in a bolus form in v / ruminant animals. They provide, for the first time, a practical device for the controlled and sustained release of chemicals, including active ingredients, to an environment containing an aqueous fluid and, therefore, meet a long-felt need, particularly in animal husbandry.

The Freisetzungssys.teme ^x according to the invention and apparatus at a controlled rate comprise a barrier or wall in contact with at least a portion of a chemical-containing supply, wherein the wall is made of a porous material including a porous textile material partially or completely, the pores of which a hydrogel which is permeable to the passage of fluid from the environment through the pores within the hydrogel itself and to chemical from the supply by diffusion. When the devices of the present invention are used, the hydrogel contains environmental fluid, which fluid is contained in the regions or channels (pores) within the hydrogel itself, and these as diffusion paths or pathways of fluid from the environment and for transport of the drug serve.

The systems and devices of the present invention may take on a wide variety of shapes and sizes, depending on the intended application. For example, they may have a capsular shape for oral administration to humans or animals, or a cylindrical shape as an implant for use as a bolus in ruminants.

A preferred form of the device according to the invention in its most general way comprises a porous material whose

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Pores contain a hydrogel and in particular a gelled cellulose triacetate which is permeable to the passage of liquid from the environment and active ingredient by diffusion through pores within the hydrogel, this porous material in contact with at least a portion of a Containing a chemical including an active ingredient containing the chemical and, if desired, a suitable, water soluble, liquid carrier and further, if desired, a detergent or surfactant, the device being in the form of a drug bolus or bolus for use in the art controlled release of active substance in ruminating animals, and especially cattle and sheep, for a prolonged period of time. A particular use of such pharmaceutical spheres is for parasitological control, and in particular bowel worm control, as a prophylactic and therapeutic agent for gastroenteritis and lungworm infections in cattle and sheep and against intestinal contamination of pastureland. As used herein, the term "bolus" includes devices that are generally cylindrical, spherical, spheroidal, elliptical, or other shape, and are free of sharp edges and protruding portions.

The prior art devices require consideration of various factors for each application and a compromise therebetween, 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 device microporous wall surrounding the reservoir, diffusion permeable medium contained within the pores of the microporous wall, the relative permeability rates of the diffusion permitting medium and the support to the active agent, the relative solubilities of the drug in the diffusion permitting

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Medium and the carrier and the need to maintain a substantially constant amount of dissolved drug in the reservoir.

In contrast, the devices of the present invention are far simpler in their arrangement and operation. A given device can greatly increase the release rate of the chemical by the simple means of changing the area or thickness of the porous material including a porous textile material having its pores with the Therefore, a manipulation of only two parameters allows control of the amount of released chemical.

The invention will be 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 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 ₅ 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 17 are non-permeable caps or closures.

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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, for example * of stainless steel, iron or plastic, as a means for controlling the surface of the hydrogel impregnated porous wall, which, if made of metal, still increases the weight of the device.

Fig. 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 is, dar.

Fig. 4 shows a shaped in the form of a capsule dispenser having only a closure 17.

FIG. 5 shows another device 10 according to the invention, wherein the porous material whose pores 14 contain a hydrogel (not shown) form the end walls of the device 10. The cylindrical belt 18 is made of a non-permeable, non-porous material, in this case stainless steel, which in combination with the hydrogel-impregnated end 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 include a supply of chemical including an active ingredient which comprises a chemical and in a preferred embodiment a chemical and a water-soluble liquid carrier or diluent. The water-soluble, liquid carrier or diluent

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It has several important functions, such as the removal of air from the supply, so that there is a greater "load" in the manufacture of the devices and a promotion of mixing by convection within the reservoir which has a constant rate of chemical release. assuring) becomes possible. Furthermore, such a water-soluble liquid carrier plays a more important role because it dissolves chemicals so that no apparent volume change occurs as the chemical moves from the solid or crystalline state to the solution state. , ·

Typical water-soluble liquid carriers or diluents include mono-ols and polyols and ethers thereof, e.g. Ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and Tripropylengl ^ kol, 1,2-Dimethoxyäthanj mono-Cj ^ alkyl ethers of ethylene and propylene glycols, ^!, ^ - dimethylformamide, dimethyl sulfoxide and the same. 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 environments including animals used in animals, including humans, or aquatic fluid, e.g. in aquariums, fish ponds, water supplies for animals or in water culture systems.

The amount of water-soluble, liquid carrier used per sines weight of active ingredient depends on the characteristics of the active ingredient. In general, sufficient support is used to allow for the formation of a combination of drug carriers into a "compact" mass, which can be determined by a simple experiment.

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Detergents or surfactants at up to 20 wt .-%, based on the total weight of the stock (chemical including active ingredient plus the carrier and detergent or surfactant, if used) can be used in the supply to a possible blockage of the devices in use Representative detergents or surfactants may be inorganic or organic, and include sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, IT sodium glycerol monolauryl sulfate, dioctyl sodium sulfosuccinate, bis (1-methylamyl) sodium sulfosuccinate, polyoxyethylene sorbitan monooleate, and others Fatty acid esters and other substances known to those skilled in the art The amount of detergent, if used, is not critical and is kept to a minimum in each batch in order to minimize the loading of chemical into the supply big to keep «The optimal amount can be na the methods of operation described below

In the description, the terms "stock", "stock containing chemicals" and "stock containing active ingredient" 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 term "active ingredient supply" is the preferred expression »

The terms "porous materials", "porous membranes" and "porous walls" as they are described in the specification include porous textile materials. Representative representatives of such materials will be described below. The porous materials used may be isotropic, i. have a homogeneous pore structure across the cross section of the material, or they may be anisotropic, i. have a non-homogeneous pore structure. Of course, they should be in the environment and the in-

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hold the .Version insoluble and hereby not be reactive. In general, porous materials having pore sizes of about 1 to about 100 microns can be used in the controlled release devices of this invention. Porous materials having pore structures, including continuous pores, i. Pores having an opening on both surfaces of the porous wall connected thereto are required. In order to facilitate the transfer of active material from the supply to the environment when using the controlled release device 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 any Verstofpen and physical or mechanical destruction under conditions of normal use and, by maintaining their physical or mechanical integrity, in environments or cases in which hitherto known hydrogel devices could be destroyed or were ineffective for a controlled release of .Werstoffen over long periods of time. The devices described herein are of particular value for use in ruminants, especially cattle and sheep. 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 liquid in the pores in the hydrogel-containing pores of the barrier of porous material at a rate which depends on the concentration of active ingredient in the solution in the supply, on the resistance given by the barrier.

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stood, i. the fluid in the pores of the hydrogel, and the effective surface of the porous portion of the wall is dependent.

As the active ingredient leaves the process, a depletion zone gradually forms, giving rise to a moving border of drug / solution. The dissipation 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 corrective 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. The 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 gives a constant concentration of drug 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 treachery 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, i. during the prolonged period of drug release. This mechanism of drug release allows the application of any geometry of the device, the size and the design of the stock are not limited. 3 is in direct contradiction to the prior art devices disclosed in US Pat. No. 3,993,073 which discloses a substantially constant amount of dissolved drug within the reservoir, a diffusion of dissolved drug within the reservoir to supply the drug

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Wall are dependent on active ingredient and have been prepared to obtain thereof, so that these devices are subject to severe restrictions on the size and shape of the product. "

The term "hydrogel" used in the specification refers to a water-containing gel and is described in Hackh's Chemical Dictionary, 4th Ed., Grant, p. 332 (1969) as a gel prepared by the coagulation of a colloid with the inclusion of water " Are defined. Representative hydrogels that can be used to pull the pores of the porous material are the following

Cellulose triacetate gelled, see US Patents 1,693,890 and 3,846,404, cellulose acetate] derivatives derived from cellulose acetate having an acetyl content of 20 to 40 % , polymeric hydroxyethyl acrylate, cross-linked polyvinyl alcohol, agarose, polyacrylamide, cross-linked and partially hydrolyzed Polyvinyl acetate, hydroxyethyl acrylate, diethylene glycol monoacrylate, diethylene glycol monomethyl acrylate, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol monomethacrylate, vinyl pyrrolidone, acrylamide, methacrylamide, α-propyl acrylamide, IT-isopropyl methacrylamide, H-propyl Methylacrylamide, IT-2-hydroxyethylmethacrylamide, polyurethane hydrogels including weakly crosslinked polyisocyanates of isocyanate-terminated prepolymers containing the reaction product of a poly-r (alkyleneoxy) -polyol with an organic diisocyanate, slightly crosslinked with Y. / asser or an organic pglyamine, 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. No. 4,038,264, polyether polyurethane resins prepared by reacting an organic diisocyanate with a mixture of at least two diols, one of which

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water-soluble polyalkylene glycol having a molecular weight of 3,000 to 30,000, and the second is an oxyalkylated dipheno having 2 to 20 oxyalkylene groups, as well as other substances known in the art per se.

Advantageous hydrogels for use according to the invention are:

Polyurethanes, polymeric hydroxy-lower alkyl acrylates or methacrylates, vinylpyrrolidone, acrylamide, N-lower alkylacrylamides and -methacrylamides, in particular products cross-linked or copolymerized with a hydroxyalkyl acrylate or methacrylate to obtain a water-insolubility of the resulting copolymer. Preferred hydrogels are gelled cellulose triacetate, polymeric hydroxyethyl methacrylate and cross-linked polyvinyl alcohol. Particularly 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 be easily 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. In order 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 having a lower vapor pressure than water, so that the devices can be used without loss of effectiveness Result of drying out of the hydrogel can be stored. When a combination of water-soluble liquid carrier active ingredient is used in the stock, the use of the same liquid to replace the water in the hydrogel is a suitable method.

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The hydrogels themselves are porous in the sense that they contain regions or regions, i. Channels or pores filled with water or other liquid. Therefore, in the description, when reference is made to the diffusion or transport of chemicals or active ingredients through the walls, and the expression = the pores of which contain a hydrogel, or a similar term is used, this shall mean that the diffusion or transport of the 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 may completely surround the reservoir, or it may only make up a portion of the Y / and surrounding the reservoir. 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. Hews (December 11, 1973), p. 23, as well as other materials known to those skilled in the art.

Suitable porous textiles may consist of polypropylene and polyethylene, in particular those of the type commonly referred to as "filter cloths", further comprising glass, polytetrafluoroethylene, hylon, cotton, modacrylic fibers, ie 35 to 84 % long-chain synthetic polymer. Acrylonitrile units composed acrylic fibers, Acrylfafaaern, ie

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synthetic polymers having a minimum of 85% by weight / acrylonitrile, polyesters, ie. a long-chain synthetic polymer which consists of 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, polymers of vinylidene cyanide, vinylidene chloride, vinylidene fluoride, polyureas and other materials known in the art, see Encyclopedia of Polymer Science and Tedhology, Vol. I ₅ 342 (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); Vol. 14, 305 * 575 (1971); Interscience Publishers, jtfew York. Furthermore, metal mesh or filter cloth including those that. made of stainless steel, carbon steel, brass, copper, aluminum, various alloys such as Mckel copper, etc., suitable.

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The particular, selected 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 that was too much used as a bolus for application of an active ingredient in ruminants for a prolonged period of time, cotton would not be used as a textile because it would degrade in the ruminant. Cotton can be used 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.

Nylon, i. a polyamide would not be used as a fabric if gelled cellulose triacetate was to serve as a hydrogel as it would be degraded by the formic acid or acetic acid used during the impregnation process.

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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 made thereby 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 cellulose triacetate solution which is exposed to a vacuum Container is included. Following impregnation, the plastic "loaded" with cellulose triacetate is then coagulated by contact with a large volume of water and equilibrated 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 the solvent for the cellulose triacetate over formic acid because it wets the polyethylene better than formic acid and thus makes it easier to produce the hydrogel-impregnated porous material.

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 accomplished by filling its pores with the mixture of 2-hydroxyethyl methacrylate / ethylene glycol dimethacrylate and then polymerizing the mixture internally. .

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half of the pores accomplished by the addition of a free radical catalyst such as t-butyl peroctoate. Likewise, other hydrogels are impregnated into the porous wall material after such "in situ" operations from suitable reactants. When the hydrogel is cross-linked polyvinyl alcohol, the pores are filled with a mixture of polyvinyl alcohol as a 10% aqueous solution and resorcinol (2-3 %) according to procedures described below, and cross-linking 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 prior to use, the hydrogel-filled pores are freed from water by allowing the equilibrium to be established in a suitable water-soluble liquid, such as the water-soluble liquid carriers listed above. As previously described, it is advantageous to replace the vessel in the hydrogel-filled pores of the porous wall material with the same water-soluble liquid as used as a carrier in the pool if the pool comprises a combination of chemical / carrier. If the reservoir is formed solely of the chemical 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 is determined only by the end use of the device, i. whether a physiologically acceptable, water-soluble liquid is required. Such a liquid will suitably be incorporated in the hydrogel at the time of preparation of the porous wall whose pores contain a hydrogel, prior to filling the reservoir of the device as will be described.

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The closest prior art devices of the invention, d, h. U.S. Patent Nos. 3,993,073 and 3,993,072 disclose the different permeability rates of active agent through a medium contained in the pores of the porous Y / and relative to those of the drug in the drug-carrier phase in the reservoir dependent. 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 drug than the drug carrier within the reservoir in the wall, therefore, becomes the drug release rate controlling portion of the device.

Dissolved drug diffuses through the more permeable carrier to the inner wall at a rate sufficient to become the Y / and drug release rate controlling portion of the device. "This results in zero-order release arrays for a certain period of time until the receding drug limit in the device becomes sufficiently large to cancel the difference in carrier to wall medium permeabilities, and then zero-order rates can not be achieved any longer this limits a successful, practical application of such devices, and they are not suitable for zero-order delivery of large quantities of drugs in practical, useful forms of a dosage form.

The devices of the present invention, in contrast to these prior art devices, have aqueous surrounding medium in use in the wall reticulum as well as in the reservoir during use. Although the permeability or permeability of the active substance is the same in the liquid in the wall

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and in the reservoir, zero order release rates are achieved for large burrs throughout the life of the device. Furthermore, the maintenance of zero order release does not depend on the diffusion in the Yorratsbehälzer so that no geometric limitations or Dosiereinschränkungen are given in these devices, and it is now possible, large amounts of active compound at rates or speeds zero-order in embodiments of practical sizes and 'practical shapes to deliver.

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 properties of the membrane, in particular 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 according to the present invention is a bolus for use in the controlled release of an active ingredient in ruminants, especially in cattle and sheep for a long period of time. The bolus or bullet is applied to the ruminant in such a manner, preferably by oral administration, that it remains in the rash pouch for a prolonged period of time, continuously administering active ingredient to the animal at a controlled release rate during this period Such devices thus allow the control (prophylactic and therapeutic) of various pharmacological conditions to which the animals are exposed,

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by simple oral administration of these devices to the animals.

In order for the bolus (s), once inserted into the reticulum mesh of cattle, to remain here for an extended period of time, it is necessary that the bolus or gumule have a density of at least 2.0 g / ml , In practice, the density may range from as low as four out of 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 bullet in the iliac stomach. The overall size of the bolu3 or the medicinal bullet is a puncture of the required dose to be dispensed and the size which can be practically given , Based on this, if the desired size is determined once, additional weight may be added to achieve the desired average density. Palis possible the use of the maximum size is desired because a larger bolus or a larger drug ball of a given density better retained than those of a lower density. However, if the average density of the bolus increases to a value greater than about 5.0, the size of the bolus does not significantly affect the improvement in the retention factor. The preferred average density range for the bolus or the 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. For pure 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 such an article to the animal.

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The application in sheep is the minimum weight of the bolus with a density of 4, which is retained, about 1 g. The size of a bolus varies depending on the density of the bolus. Purely the application in cattle is the minimum weight of a bolus with an average density of 4 about 5 g · As previously described, the upper limits of the size in turn by the practical circumstances of the dosage of the relevant, the animal and by the minimum average density of the bolus certainly. 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 the addition of a suitable higher density material such as a metal (iron powder, ¹ iron shot, steel shot) or other density increasing agents such as minerals, eg CaCO 2, to the density to increase the desired value. Alternatively, the average density can be conveniently increased by inserting an inner sleeve, a high density perforated material, eg, a metal (such as stainless steel, steel, especially low carbon steel or iron), these in turn being impregnated with the hydrogel, surrounded by porous membrane. The perforations or, Durchborhungen in the sleeve should be large enough so that a free passage of drug and fluid from the environment through the hydrogel impregnated porous membrane is possible. The main functions of such a sheath are to increase the average density of the bolus to such a level as to retain the bolus in the retinal pouch and to maintain the surface of the hydrogel-impregnated porous material in contact with the drug containing the bolus.

- 28 - '

- 28 - £ 1 Z / Z

to regulate supply. In addition, although not strictly required, such a sheath improves the mechanical stability of the bolus so as to substantially ensure the maintenance of its physical shape under the conditions of use. A further and preferred alternative comprises a bolus comprising a metal, steel or iron cylinder having one end or both ends capped with a porous membrane whose pores are impregnated with a hydrogel. A bolus of this kind is due to its simplicity and economy in the production and the. Ease with which its density can be adjusted, preferred. A low carbon steel is much preferred as a cylinder material. Other alternatives are readily apparent to one 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 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 at sites close to or remote from the device's site of use. They may be attached by suitable means to suitable locations within the animal body where they are in contact with body fluids, e.g. the stomach of pets, especially in the barking of ruminants. Also contemplated among the controlled release devices of the present invention are devices for use as depot implants for the purpose of administering an active agent at a controlled rate to the guest. The implants differ from the devices according to the invention for other purposes only in their shape, which of course, is designed for implantation. Other

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Phrases include sublingual tablets or buccal tablets, pessaries, suppositories, bandages, and dermal patches. Still further applications for the controlled release systems and devices of the present invention are in agriculture for the application of fertilizers and pesticides, in fish farming, including aquariums and fish ponds, in drainage ditches, canals and tanks, for example for control of algae, given in the case of water supplies, in particular for animals and poultry, which require active substances for therapeutic or prophylactic treatment.

The raven of suitable substances, agents or chemicals used in the devices of the present invention is that they are sufficiently soluble in water to achieve a rate of release of this active ingredient or chemical in the environment of use giving the desired result , For this reason, active ingredients and chemicals which are acids or bases are desirably used in the form of their physiologically or pharmacologically acceptable salts. The rate of release of the drug or chemical from the devices described herein depends on various factors such as wall thickness, available surface area, effective pore diameter, porosity of the wall, type of hydrogel, concentration of the substance in the reservoir, and solubility thereof in the surrounding liquid. The suitability of a given substance is determined according to the description given below.

Representative agents for agents that may be used in the devices described herein are the following substances:

Anthelmintica including salts of morantel, pyrantel, oxantel; Piperazine, diethylcarbamazine, levamisole, tetramisole

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and hygromycin B, antibacterial substances including salts of tetracyclines such as 5-oxytetracycline, chlororetracycline, doxycycline and Mannich base thereof, penicillins such as ampicillin, penicillin G, aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin ala their zinc or methylenedisalicylic acid derivatives, macrolides such as erythromycin , Oil andomyein and tylosin, antibacterial growth promoters, such as salts of. Avoparicin, polymyxin, lincomycin, bambermycin and efrotomycin, hormonal growth promoters including diethylstilbestanol, hormonal wax activators including diethylstilbestrol, zearalanol, antiparasitic agents such as amprolium, nutrients such as soluble salts of magnesium, selenium, copper and vitamins such as thiamine hydrochloride, sulfavikricides such as sulfamethaine , Mollsuciciäe v / ie IT tritylmorphine and the bulge-preventing agents such as alcohol ethoxylates and poly- (oxyäthylen) -poly- (ox: ypropylene) -poly (oxyäthylen) -polymerisate, eg Poloxalene.

In accordance with a preferred embodiment of the invention, the drug-containing reservoir "comprises an active agent and a water-soluble carrier." Devices thus constructed have the advantage of providing a greater amount of drug per device and extending the useful life of the device 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 roaming animals becomes relatively easy. In temperate climates, the small population of early spring grassland larvae, namely the backlog of contamination of the previous season, is affected by the cycle through the

- 31 - ·

multiplied on grazing animals, which in the summer produces a strong increase in the infectious capacity of pastureland. "This condition induces clinical parasitism and a decrease in the performance of animals grazing on such pasture during the pasture period in summer.

Me continuous and controlled release of anthelmintic agents, i. Antidiarrheal drugs, e.g. of morantel, in the reticulum of grazing animals at the beginning of the season, when the contamination of the rangelands is still low, suppresses the delivery of worm eggs and the subsequent formation of larvae, thus interrupting the aforementioned cycle and the willow burden of pastureland and animals are kept at a low level. Parasitic infections of ruminants grazing on the same farm during the summer season are thereby minimized. This method of controlling worms is particularly attractive and valuable for calves, as they are highly susceptible to yaws when first placed on grazing land. "The consistent use of bolus reduces the reservoir of infecting worm forms in a given location. The use of anthelmintica-containing medicinal spheres in accordance with the invention in this manner prevents or at least minimizes the seasonal increase in pastureland larvae, which causes parasitic gastroenteritis and a decline in grazing-animal performance later in the season. In this type of control, the period of drug release is that of the proliferative phase in spring rather than the period of high pasture contamination, larval larvae and masses of worms which cause clinical discomfort and decreased performance. For this reason, this type of application is called "indirect control". In other words, that

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Grazing ruminants having in their carcass sac one or more of the devices described herein, this device providing the controlled and continuous release of anti-worm agent, e.g. by Morantel, made possible at this net magnesia, on pasture land in the Saoson at an early date, i. when the larval contamination is at or near a minimum Y value, it minimizes the usual seasonal increase in larval contamination of the pasture and serves as a means of grazing during the entire Yielding season Protect animals.

For "indirect control" of worms, the devices of the present invention, preferably in the form of drug pellets, are applied to ruminants at a time in the epidemiological cycle of these worms when the residual contamination by these worms, their eggs and / or their larval stages is minimized or close to such a minimum value. In the moderate zones, this time corresponds to the expulsion in the grout, ie the first exposure of the calves on the yard. For maximum effectiveness, the drug pellet or bolus is applied to the calves about two to seven days before budding. In non-temperate zones of the world, e.g. 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 the drug balls in ruminants in such zones is advantageously carried out two to fourteen days before the start of the rainy season. However, due to the rain forecast of the rainy season, worm control in non-temperate zones is best performed by a "direct control" method. ·

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The medicine balls (bolus) described here also switch off already occurred worm infections in ruminants and they prevent the nesting of worm infections during the Sominer period in 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 controlling worms protects Y / ruminants grazing on designated pasture land for the entire season, as it results in a significant overall reduction of pasture contamination or pasture infestation. As stated previously, the devices described herein provide a sustained release of drugs including anthelmintics at a controlled rate. Particularly useful for such purposes are water-soluble salts of (E) -I, 4,5,6-tetrahydro-1-methyl-2- / 2- (3-methyl-2-thienyl) -athenyl-7-pyridine (MorantBl ) _A (E) -l, 4i5,6-tetrahydro-1-niethyl-2 - ^ "" 2- (2-thienyl) -ae'fhenyl / pyrimidine, (pyrantel) and (-) - 2,3, 5> 6-tetrahydro-6-phenyl-imidazo / ~ 2, l-b7-thiazole (tetramisole) and levamisole, the L- (-) -3 -orah thereof. Representative of preferred water-soluble salts of pyrantel and morantel are the tartrate and citrate salts and tetramisole and levamisole the hydrochloride salts.

The pharmaceutical spherules according to the invention are administered orally to the animals, for example with a device for administering. Pills .an horses or cattle, for use in calves is the desired average release rate of morantel, calculated as the base for the indirect control of worms on the order of 60 to 200 mg of morantel base per day for a period of about SO days, whereby the normal, maximum survival time of the spring polarization of larvae is covered. Longer release periods of 60 to 120 days are desirable in the direct control embodiment

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the exposure time for heavy grazing land contamination or heavy pasture infestation usually ranges from mid-summer to fall. Release rates of about 60 to 15P mg, calculated as morantel base, per day provides effective control of worm infections 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 free range of menthol agarates for each compound thereof, calculated as free bases, is of the order of 100 to 400 mg or 100 to 500 mg per day for one Period of about 60 days. For direct control, release rates of about 100 to 300 mg, as the free base, of pyrantel 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. , ,

Continuous application of morantel in small amounts using the worm control devices described herein gives an effective profile that is surprisingly different from and advantageous over the profile obtained in the conventional therapeutic application of morantel, although not anticipated could, could. For example, maintaining 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, as cattle or sheep grazing on contaminated pasture undergo immediate re-infection by intestinal nematodes after conventional therapeutic treatment, the animals receiving the granules are essentially

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infection and protected from Y / re-infection for a period of 60 days or longer.

The use of the Bolua to control grazing land contamination, i. Indirect control method is a unique, practical and unused method of control of worms, which protects ruminants and, in particular, grazing ruminants protected by this method, throughout the growing period and provides superior results and advantages over previously known methods of control The increase in daily weight gain compared to untreated control animals during the grazing period is significantly greater than that achieved after conventional therapy.

The rate of release of the active ingredient or other chemicals passing through the supply containing the active ingredient, the walls of the controlled release device of the present invention, and the efficacy of a predetermined combination of active ingredient and / or water soluble carrier and / or detergent and / or detergent Surfactant in such devices can be readily determined by one skilled in the art, for example by transfer methods or sorption-desorption methods. One technique which can be conveniently employed to select suitable porous materials and rydrogels 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 a another chemical whose controlled release is desired, and a rapidly stirred solvent bath the composition of which stimulates the aqueous fluid-containing environment in which the controlled release device is to be used. The temperature

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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. Bs samples are taken from the solvent bath 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 material, the pores of which are filled with hydrogel, can also be determined by standard procedures, as described in Encyclopedia of Polymer Science and Technology, Volumes 5 and 9, pages S5-32 and 794-8O7 (I968) and the references cited herein, as well as in Chemical Engineers Handbook (I963), pages 17-45, edited by McGraw-Hill, Inc.

A procedure of particular value in determining the release rate of the devices of the invention and the relative advantages of a given carrier or detergent for use in such a given device, especially when the drug is morantel, is summarized as follows: The procedure is an In Vitro mode of operation and is based on the release of a water-soluble salt 3 of morantel, for example the tartrate, from a device made according to the invention as puncture of time. "A morantel tartrate-containing device according to the invention is used in a 1-1 conical flask exposed to light of the photosensitivity of morantel tartrate, and 500 ml of phosphate buffer of pH = 7 are added. The temperature of the flask and the contents are brought to 37 G and held thereon. The flask containing the device is shaken with about 70 movements (7.62 cm) per minute and 5 ml samples are periodically withdrawn. The volume of sample withdrawn is replaced with an equivalent volume of pH 7 fresh phosphate buffer, and shaking of the flask is continued.

- 37 -

The concentration of morantel in the samples is determined spectrophotometrically by measuring the absorbance of the sample at 318 iam read against fresh phosphate buffer of pH = 7. The process of sampling is repeated; until 5 g of morantel tartrate have been released, at which time the apparatus is transferred to another flask containing 500 ml of fresh phosphate buffer of pH ss 7, and the procedure is continued as before,

The in vivo release of morantel tartrate from devices of the present 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 passed over the fistulas or after killing the animals, and the devices are removed to determine the remainder of the mantle 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.

Examples of embodiments;

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

example 1

A sintered polyethylene whose pores were filled with gelled cellulose triacetate, comprising a bolus and a stock containing morantel tartrate mixed with polyethylene glycol 400 and iatrium hexametaphosphate and having a perforated stainless steel sleeve were prepared as follows;

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One end, hereinafter referred to as the end 1, of a sintered polyethylene tube having 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 placed in a 10 % solution of cellulose acetate butyrate in methylene chloride to a depth of 4.763 J ™. immersed. 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 stage was repeated. The. End i was again immersed in the cellulose acetate butyrate solution for 30 seconds, allowed to air dry for 60 seconds, and a disk of cellulose acetate butyrate having a diameter of 22.225 ram and a thickness of 3.175 mm was inserted into the end of the tube so that it could with the end was just. 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 the pinger 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 and provided with a glass tube of sufficient length to pass 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 flask and the bulk of the cellulose triacetate was wiped off. The tube was then inverted to drain the cellulose triacetate from inside the tube

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to let. 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 out of the. Water was removed 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 cellulose triacetate and equilibrating them in distilled water were performed. the repeated. It was then equilibrated for 4 hours in flowing water.

The tube at this time was inspected for leaks by connecting it with a nitrogen source, immersing the tube in water and applying a pressure of 27.5 kPa of nitrogen for 10 seconds. Palis leaks, the steps of impregnation and insufflating with water were repeated.

The tube was then equilibrated overnight against polyethylene glycol 400, removed from the polyethylene glycol 400 and allowed to drain in the reverse position for 4 hours. Excess polyethylene glycol 400 was wiped from the exterior of the tube with a towel and a perforated tube was made. stainless steel with an outer diameter of 22.225 mm, an inner diameter of 18.923 mm and a length of 6.985 cm with sixteen equally spaced, circular holes of 7.114 mm diameter inserted into the tube until it is flush with the closed end. The abraded portions of cellulose triacetate resulting from the insertion of the close fitting sleeve into the tube were removed. A 3.755 mm cellulose acetate butyrate disk was then inserted into the open end of the pipe, just with the stainless steel sleeve, and the pipe was so machined.

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2127 2 5

The wafer was removed and the tube was filled with a homogeneous mixture containing 63.31 % mor tar tartrate, 26.61 % polyethylene glycol 400, and 10.08 % sodium hexa-naphthoate 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 added to the oil cellulose acetate butyrate solution A disk of celulose acetate butyrate, which had been allowed to float on methylene chloride for 60 seconds immediately before insertion, was then forced into the open end of the tube with sufficient pressure applied to allow it to dry Pressing the disc against the stainless steel sleeve The tube was then rolled along a workbench with sufficient pressure was applied to the finger 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 immersed in 10% cellulose acetate butyrate to a depth of 6.35 mm and allowed to dry. The weight of this bolus was approximately 90g, of which 24.8g was a mixture of the raw material. 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 4 to 17 day period at a medium release rate for all three devices of 0.927 g of tartrate daily.

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Days, in vitro accumulated amount (p;) of morantel tartrate

Bolus I Bolus 2 Bolus 3 1 0,357 , 0,295 0,284 2 0.804 0.723 0.66 4 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 19 14.52 16.2 13.2. 25 17.99 17.4 15.4 29 17.13 17.3 15.9

In vivo assays for three further bolus preparations prepared according to the procedure of Example 1, placed in the cattle's denim bag, showed a freeze rate of 0.224 g of tartrate tartrate per day when recovered at the end of 30 days. This gives an in vitro / in vivo ratio of 4: 1.

Example 3

In vitro assays for two other bolus preparations, prepared according to the procedure of Example 1 and 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

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Days, in vitro accumulated amount (p;) of morantel tartrate

Bolus 4 Bolus 5 1 0.51 0.59 2 1.5 : 2,1-b 3 2.4 2.2 5. 4.9 5.4 6 5.1 5.9 6.5 6.1 10 9.7 9.7 12 11.0 11.7 14 13.5 12.6 17 14.8 13.6 19 16.4 14.6 21 17.1 14.7 24 16.8 14.7 2 B 16.9 , 14.8

In vivo tests with individual bolus preparations, placed in cattle retinal pouches for periods of 30 to days, gave the following results:

Days in vivo average amount (g) of morantel

Tartrat 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 g per day, and the ratio of in vitro / in vivo is close to

4. * 1 , 43 "

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

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 which served to hold a hydrogel-impregnated washer of porous material in place. The disks having an outer diameter of 22.225 mm and a thickness of 3.175 mm consisted of a polypropylene filter cloth having pores of 50 / μm average size and were impregnated with gelled cellulose triacetate. They had been prepared by immersing them in a yellow solution of cellulose triacetate in 'formic acid, which was in a container that could be exposed to a bakuum of 3.33 kPa or less. The container and the contents were kept under vacuum for about 10 min, 'then the discs removed, and the excess wiped _e cellulose triacetate · They were then immersed in distilled ater Y / and hereby equilibrated overnight. The slices were then freed from water, dried with a cloth and allowed to equilibrate overnight with polyethylene glycol 4-00. The slices were then removed and dried with a cloth. The impregnated discs were placed on each end of two tubes, sandwiched between two 0.2 / 4mm (0.01 inch) thick sealing rings and the same diameter as the steel tube. The sealing ring adjacent to the steel pipe was made of cellulose acetate butyrate and the other of a dental rubber blanket material. The ends were then capped with stainless steel rings with an opening diameter of 21.336 mm.

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closed. The tubes were then filled with morantel tartrate (63.3 %)% polyethylene glycol 400 (26.6 %) and sodium hexametaphosphate (10.1 %) , and then the other end of each tube was closed as described above.

The bolus preparations contained 21.4 g of tartrate tartrate, weighed 97 6 and had a mean density of 30 3 g / l.

The bolus preparations were removed from bulls with rumen fistulas by a suitable balling gun introduced at 30, 45, 60, 75, and 90 day intervals to determine the amount of drug remaining in the bolus, from which the mean release rate of morantel tartrate was determined «

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Bolus Days in the Taurus Pricing Schedule (mg / day)

1 30 ⁶ 7

2 30 108

'3 45 82

4 ' 45 .58

5 60 136

6 60 91

7 75 71

8 75 68

9 90 67 10 90 10b

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

In each bull, a significant reduction in parasitic numbers in the faeces was noted.

Example 5

In accordance with the procedure of Example 1, four bolus preparations were prepared comprising sintered polyethylene having a mean pore size of ΙΟ / μm whose pores were filled with gelled cellulose triacetate, as well as stainless steel sleeves within only a portion of the total length of the bolus preparations so that one segment of the bolus preparation was free of the pod and had stocks containing morantel citrate (63.3%) "mixed with polyethylene glycol 400 (26.6 %) and efatrium hexametaphosphate (10.1 %) " perforated stainless steel sleeve in example 1, non-perforated tubes of 5.08 cm, 4.445 cm, ₅ cm and 3.175 cm 1.905 used "the walls of the sleeves had a thickness of 0.165 cm. The drug mixture was then added to each bolus

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Preparation filled so that a drug bandwidth of 6.35> 10.70, 25.4 and 38.1 mm was given above the sleeves. A stainless steel stopper of 12.7 mm thickness and 22.225 mm diameter was placed in each of the bolus preparations above the drug mixture. The ends of the bolus slides bearing the steel stopper were machined to allow the insertion of a slice of cellulose acetate butyrate at the top of the plugs 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 ranged from 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 3 "to 21st day of constant release"

Example 7

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

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Example 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: pyrantel tartrate (63.3%), polyethylene glycol 400 (2b, 6%), sodium hexaraetaphosphate (10 ,1 %); Morantel tartrate (100%) ; Pyrantel hydrochloride (100%); Tetramine hydrochloride (100%); Levarnisol hydrochloride (85.0%), glycerol (15.0%); Diethylcarbamazine citrate (100 %) ; Hydromycin B (100 %) ; Dosycyclin hemihydrate mixed alcoholate (100 %) ; Bacitracin methylenedisalicylic acid (66.0%), sorbitol (22.0%), sodium lauryl sulfate (12.0 %), j ampicillin, sodium salt (63.5 %) , polyethylene glycol (26.5 %), sodium hexametaphosphate (10.0 %) ; Hatriumpenicillin-G (b7.3%), Ν, Ν-dimethylformamide (22.2 %) , sodium glycerol monolauryl sulfate (10.5%); Neomycin spike (68.5%), dimethyl sulfoxide (22.5%), sodium lauryl sulfate (10.0%); Streptomycin trihydrochloride (100%); Oleandomycin hydrochloride (80%), poly (ethylene glycol) 400 (20 %) ; TyIosine hydrochloride (100%); Polymyxin hydrochloride (79.5%) j ¹ glycerol (15.0%), sodium lauryl sulfate (5.5%); Lincomycin hydrochloride hemihydrate (100%); Magnesium acetate tetrahydrate (77%), sorbitol (15%), dioctyl disodium sulfosuccinate (8%).

Example 9 '·

In accordance with the procedure of Example 1, a bolus preparation was prepared comprising sintered polyethylene, the average size pores of which were 100 / μm filled with a cross-linked polyvinyl alcohol hydrogel, and a stock, the morantel citrate (63.3 %) . Polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) were included, with a perforated stainless steel sleeve also being present. Instead of the cellulose

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triacetate-formic acid solution consisted of the hydrogel solution of an aqueous solution of 10 % polyvinyl alcohol (88 % h ^ drolyzed 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. The equilibration of the tube in water is not required. The tube was then examined for leaks, placed in polyethylene glycol 400 in the same manner, filled and sealed 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, but using sintered polyethylene tubes of only half the length and one-half the diameter of the tubes used in Example 1. The bolus preparations obtained are suitable for sheep application and give a controlled release of the anthelmintic agent in vivo over an extended period of time.

Example 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 material, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene, wherein the average pore size of each material was 100 / μm,

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Each of the bolus preparations prepared in this way gave 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 of 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 anneal a ring which served to hold a porous hydrogel-impregnated disc in place. The disks having an outer diameter of 22.225 mm and a thickness of 3> 175 mm were made of sintered polyethylene impregnated with gelled cellulose triacetate, and they were prepared by immersing them in a 6% solution of cellulose triacetate in acetic acid in a container containing a vacuum of 3 _} 33 kPa or less could be set. The container and contents were held under vacuum for about 10 minutes, the slices were removed and washed free of excess cellulose triacetate solution. They were then dipped in distilled water and equilibrated overnight Towel dried and then equilibrated over polyethylene with polyethylene glycol 400. The slices were removed and wiped with a towel.

The impregnated discs were mounted on each end of the tubes, for which they were placed 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 consisted of cellulose acetate = butyrate, the other sealing ring consisted of a dental rubber.

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cloth 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 described above.

In this way, tubes or bolus preparations were made in stock with the following chemicals: Morantel Citrate (63.3 %), Polyethylene Glycol 400 (26, b #), Sodium Hexametaphosphate (10.1 $); Ixytetracycline hydrochloride (100 %) i pyrantel citrate (38%), glycerin (12 %) ; Pyrantel tartrate (63.3%); Polyethylene glycol 4OO (2b, 6 '%) , sodium lauryl sulfate (10.1%); Tetramisolhydrochlorid (100%) - Po loxalen (100%); Erythromycin hydrochloride (100 %) ; Thiamine hydrochloride (100 %) .

The procedure of Example 1 was repeated except that the bolus preparation was filled with moraltetartrate instead of the mixture of moraltetartrate-polyethylene glycol 4OO-sodium hexametaphosphate as in Example 1. The bolus preparation had a weight of 84.0g, of which 18.6g was morantel tartrate.

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

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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, each 0.1 cm from each end thereof, for receiving an aluminum salt, this groove running completely around the tube, was placed at one end with a sintered polyethylene disc of ultra-high molecular weight, average = 2 million to 4 million ( Product of Glasrock, Porex Division, Fairburn, GA.), Which had been impregnated with gelled cellulose triacetate as described in Example 15, sealed. The disk had a diameter of 2.54 cm and a thickness of 0.16 cm and was applied to the pipe by means of an aluminum crimp seal. The tube was then inverted and filled with a homogeneous mixture comprising 54.4 % moraltar tartrate, 35-6 % polyethylene glycol 400 and 1 % sodium hexametaphosphate. The process of sealing with the disc and applying the aluminum crimp seal was 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 Y / irkstoffgemisch. The density of the preparation was 2.8 g / ml.

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The aluminum linkage allows conclusions to be drawn at each end of the tube.

sat an open area in the middle of .3 "25 cm, giving a total area available for drug delivery

.of 6.5 om . The bolus preparation provided controlled release of morantel tartrate in cattle for approximately 90 days.

Example 15

An aluminum cylinder of 6 inches in length, 2.1 cm in outer diameter and 0.1 cm in wall thickness, with a groove at the open end to receive an aluminum flare seal, was filled with a formulation containing 70 % levamisole hydrochloride and 30 % polyethyleneglycol 400 and sealed with a sintered high density polyethylene disc (0.95-0.97 g / ml), the disc being 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 Ib, 42 g levamisole hydrochloride.

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

2 transport area of 0.95 cm.

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

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212725

in vitro released Levamisollzydrochlorid

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 16 . ·

This example describes a field trial that was carried out with Yersuchskälbern of the same breeding weight (average = 150 kg) and 6 calves, which were previously not on the pasture. The calves were divided 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 free of worms "track calf ¹¹ was allotted after each of the four groups of trial calves at the start of the field trial and every four weeks. Each" track calf "was held in the paddock for two week, then it was removed and three weeks before slaughter to Counting the worms kept in the stable.

The test calves and the calves of the indicator calves were exposed to infected grazing land used as pasture by infected cattle in the previous summer and autumn. The pasture was of sufficient size to hold 44 animals fed for the whole grazing period. and it has been divided into four equal and separate couplers.

212725

The two drug-added duplexes were orally given a bolus preparation for b0 days, prepared according to the procedure of Example 1. The bolus preparations gave a continuous release of morantel tartrate of 250 mg / animal (equivalent to 150 mg morantel base) per day during 60 days. The drugs provided with groups of animals received the bolus preparations orally two days before the expulsion of the meadow _r country in the spring. The presence of the bolus preparations on each of the drugged animals was measured 24 hours after application by means of a metal detector. 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 animals were weighed before sprouting and at intervals of four weeks.

Samples of the grasses were taken according to the method given by Taylor, Paraeitology, J31 (1939), 473 at intervals of two weeks starting four weeks before the start of the field trial and continuing until the completion of the field trial.

Fecal samples for McMaster egg counts and lungworm larvae were collected at the beginning of the experiment and thereafter at two-week intervals. The first eight weeks were rectal samples, one from each animal. Thereafter, the rectal samples were taken every four weeks to coincide with the weighing of the animals. At intermediate points, samples, 10 for each group, were taken from the grazing land, see Gibson, Veterinary Bulletin Ur. "7 (1965), 403-410.

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

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Group Treatment paddock Number of animals

1 Morantel tartrate, 250 mg / day A 10 + all 1 indicator animal four weeks It 2 It's it B It Il Il 3 control 0 It It It 4 ti Il D It U

These values are graphically illustrated in the _Pig} 6, 7 and 8. FIG. Pigur 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 net speed for the first three months. After this time, weight gains slowed in the control groups and even decreased for a while, coinciding with the increase in the number of pasture parasites. On the other hand, in the medicated animals, there was a continued growth with a weight gain nearly equal to that observed at the beginning of the season.

The pigs 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 paeces (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 were given the bolus preparations orally for two days before sprouting for 60 days, so they were on treatment until mid-July.

At the time of sprouting, the number of eggs in the paeces and larvae on the pasture was low. In the control group, see Pig. 7, the appearance of eggs began in the Paeces of the animals at the beginning of June, reached one

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Peak in late July and slowly decreased during August and September. These eggs increased the number of larvae observed in the late July on pastureland, peaking in August. ' ^:

For drug-containing groups, see Pig. 8, the formation of eggs was markedly reduced during June and July, a fact that was reflected in the significant reduction in grassland larva; a during July and September.

Example 17

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 are listed below: ...- · '

Number of excess of the average cumulative reductions

such animals per weight increase of the number of

No. group acted group counter-egg

over the control group.

(kg) group group

1 12 17.0 0 79 100 ' 2 13 9.0 33 146 77 3 12 32.5 67 408 84 4 11 9.5 145 436 67 5 17 18.2 135 886 85 6 18 13.4 23 62 63 7 • 24 17.1 34 150 77 8th 31 36.5 14 28 50

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Example 18-

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

porous material average pores

size (/ um)

Polyethylene '. 75

Polytetrafluoroethylene 100

Glass . * 60

Stainless steel filter cloth 80

Copper fabric 30

Modacrylic · !! (a) 10

Nickel-copper alloy fabric (b) 50

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

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

Claims (3)

-st- 212725 Erfindungsanspruchj An apparatus for the controlled and continuous delivery of a chemical to an aqueous liquid-containing environment for a prolonged period of time, the apparatus comprising a chemical-containing supply and a molded wall at least partially formed of a porous material, the porous wall in contact is at least part of the stock and is insoluble in the environment and maintains its integrity during the extended period of time, 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 the aqueous liquid is permeable so that the device (10), when placed in the environment, continuously releases the chemical from the reservoir (12) to the environment at a physiologically effective, controlled rate through the medium , being resolved, this way e released chemical is replaced by the continuous dissolution of chemical rd η the stock and wherein the amount of dissolved chemical in the supply varies continuously during the extended period of time, so that the rate or rate of chyric release to the environment during a substantial portion of the extended period of time remains practically constant. .- "- 212725 Device according to item 1, characterized in that the porous material is sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride or sintered polystyrene. 3. Device according to item 1, characterized in that the porous material is a porous fabric material of polyethylene, polypropylene, polytetrafluoroethylene, glass or modacrylic. A device according to any one of the preceding claims, characterized in that the container contains a chemical in admixture with a water-soluble carrier. 5e device according to items 1 to 4, characterized in that the container contains a chemical in admixture with a water-soluble, liquid carrier and a detergent. 6 - device according to item 1 to 5 »characterized in that the hydrogel medium is gelled cellulose triacetate» 7 · Device according to "one of the preceding pancakes" characterized in that the chemical is an anti-clogging agent. 8 * Device according to one of the preceding points _s characterized in that the device includes a high density material in an amount such that the device has a density of at least 2.0 has " Device according to item 8, characterized in that the material of high density consists of steel, and in that the shaped wall comprises a cylinder of this steel, the ends of which are sealed with sintered polyethylene, the pores of which contain gelled cellulose triacetate. -6ο- 21272 5 Apparatus according to item 8, characterized in that the high density material is present as a perforated steel or ferrule sleeve within the device between the reservoir and the porous material. Device according to item 10, characterized in that the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate. 12. Device according to one of the items 1 to 11, characterized in that the chemical is a water-soluble acid addition salt of morantel · Device according to one of the preceding points, characterized in that the water-soluble acid addition salt, the tartrate or ootrat of morantel is Device according to any one of the preceding points, characterized in that the chemical is a water-soluble acid addition salt of pyrantel or levamisole. The device according to item 14 »characterized in that the water-soluble acid addition salt is levamisole hydrochloride or a tartrate or citrate salt of pyrantel · l6. Device according to item 14, characterized in that the porous material is sintered polypropylene or sintered polyethylene and the water-soluble salt is the tartrate of morantel · Rierzu._A_Seiien drawings