NO147902B - PROCEDURE FOR MANUFACTURING A DEVICE FOR REGULATED, CONTINUOUS ADMINISTRATION OF CHEMICALS - Google Patents

Description

The invention relates to a method for producing a device for long-term and physiologically effective, regulated, continuous administration of chemicals to aqueous, liquid-containing environments, e.g. for placement in the rumeno-reticular sac of a ruminant, whereby a chemical is enclosed in a reservoir surrounded by a shaped wall, at least partially made of a porous material which is in contact with at least part of said reservoir and is insoluble in said surroundings and maintains its integrity during the period of administration. The method is characterized by the pores in the porous material being impregnated with a hydrogel medium which is permeable to the passage of said chemical and to the aqueous liquid, gelled cellulose triacetate being used as the hydrogel medium.

Devices manufactured according to the invention can be used in the body of animals, including humans. In particular, such devices can include large pills (so-called boluses) for regulated administration to ruminants.

Administration systems for medicines and devices

for regulated delivery of medicinal products, i.e. regulated delivery and maintained or extended delivery, is well known in the field. Many different methods are described in the literature, including physiological modification of absorption or excretion, modification of the solvent, chemical modification of the drug, adsorption of the drug on an insoluble carrier, use of suspensions, and implantation pellets (Edkins, J. Pharm. Pharmacol., 11, 54T-66T, 1959). Other methods include mixing the drug with a carrier that is gradually degraded by the environment, e.g. of the body fluids, resulting in delivery of the drug. Growing, ol-

ers, fats and soluble polymers have served as carriers.

It is also known in the art to disperse the drug

in a solid matrix material through which the drug is delivered by diffusion, or to enclose the drug in a capsule

with one or more polymer walls through which the drug can pass by diffusion (US patent 3,279,996).

US patent 3,975,350 describes the hydrogel carrier system consisting of polyurethane polymers for use in medical, pesticide, insecticidal, algicidal and similar purposes.

US patent 1,693,890 describes the production of porous membranes of cellulose acetate in the form of gels for use in dialysis. The method comprises precipitation of the cellulose acetate from a solution thereof in acetic acid by adding a non-solvent such as e.g. water. If desired, the membranes can be formed on a substrate. The membranes produced in this way are impregnated with water, but can be freed from water by washing with alcohol, acetone or another water-miscible liquid.

Materials of cellulose-polymer-liquid compositions (PLC) in film, fiber or microspherical form, comprising cellulose esters such as e.g. cellulose triacetate or cellulose nitrate, or molecular mixtures thereof, as a carrier for the regulated delivery of various substances is described in US patent 3,985,298. The substance to be delivered is impregnated into and inside the PLC cellulose material, as part of or as the whole of the liquid phase (alcohol or water or mixtures thereof) contained in the micropores of the cellulosic PLC.

US patent 3,846,404 describes semipermeable membranes of gelled cellulose triacetate which are usable as carriers for other materials such as e.g. liquids with medical properties, the impregnation of non-woven polyethylene fabric with a smooth finish and plain cotton cloth with gelled cellulose triacetate to provide supported cellulose triacetate hydrogel materials is described. The use of medication-impregnated gelled cellulose triacetate products as slow-release agents for implantation in animals is described, as is the casting of gelled cellulose triacetate onto a woven or non-woven carrier sheet material.

Devices for the controlled administration of drugs comprising a reservoir formed of a drug and a solid or liquid drug carrier and, in contact with or surrounding the reservoir, a wall formed of one of a variety of materials, comprising a microporous material whose micropores contain a diffusible medium ( e.g., a liquid phase consisting of a solution, a colloidal solution, a suspension, or a sol) that can be permeated by drugs by diffusion is described in one or more of the following US patents: 3,993,072, 3,993,073, 3,896,819, 3,948. 254, 3,948,262, 3,828,777, 3,797,494, 4,060,084 and 3,995,634.

US 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. A key feature of the devices in these patents is the use of a wall that is at least partially composed of microporous material whose pores contain a drug delivery rate control medium that can be permeated by the drug, and a reservoir comprising drug and a carrier that can be permeated by the drug, but at a greater speed than the permeability of the speed-regulating medium located in the pores of the microporous wall. Devices suitable for administering therapeutic or nutritive substances to ruminants and comprising surrounding the substance in a permeable, water-insoluble material having capillaries or interconnected pores passing therethrough, and paper or cloth partially impregnated with water-insoluble polymers, e.g. cellulose acetate, is described in British patent 1,318,259.

US Patent 3,594,469 describes pellets containing magnesium and iron for administration to ruminants to supply said metals to the ruminants over a long period of time. In one embodiment, the pellet consists of a cylindrical tube of magnesium alloy filled with shot and some biologically active substances, and the tube is sealed at both ends with porous plates.

US patent 3,938,515 makes known devices intended for the continuous administration of a drug over a long period, which comprises a reservoir containing the drug and a solid or liquid carrier that can be penetrated by the drug, and a polymer wall that surrounds the reservoir and that can penetrated by the drug, but at a lower rate than through the carrier.

US patent 3,946,734 describes a diffusion cell. intended primarily for use as an implant and which is essentially a capillary whose one end is sealed with an impermeable material and where the rest of the tube and its other end are sealed with a porous, neutral hydrogel. The biologically active substance is placed in the capillary close to the impermeable material, and the capillary is then filled with the hydrogel (agarose, polyacrylamide) again.

nom which the biologically active drug will diffuse.

Many of the known devices for regulated delivery are described as zero-order delivery devices. Said devices are, however, able to maintain zero-order delivery rates for only relatively short parts of their projected lifespan and cannot be used for extended use such as e.g. in ruminants. The devices described herein, on the other hand, achieve and maintain regulated, predictable, zero-order delivery rates for a given drug over extended periods of time. In addition, known devices, including those comprising a drug-containing reservoir surrounded by a shaped wall formed at least in part of a microporous material whose pores have a drug delivery rate-regulating medium (diffusible medium) permeable to the drug, are physically sealed or undergo physical destruction in certain application environments, such as e.g. rumeno-reticular sac of ruminants. The clogging decreases and even stops delivery of the medicine and makes the devices unusable for their intended purpose. Devices described here, where the pores in it

porous material in contact with the drug-containing reservoir containing a hydrogel is essentially free of this problem and can provide controlled and predictable delivery rates of drug into an aqueous, fluid-containing environment for long periods of time.

When used for controlled delivery of highly water-soluble drugs, it is preferred for known devices (of the type described in US patents 3,993,073, 3,993,072, 3,967,618, 3,948,262, 3,948,254 and 3,896 .819) that the wall and/or the reservoir is made of a material that is essentially impermeable to water, in order to prevent dilution of the medicine in the reservoir by absorption of body fluids in the device and reduce the delivery rate of the medicine. They are therefore not suitable for the administration of water-soluble drugs, especially at relatively high speeds. Furthermore, the devices described in most of these patents require that the permeability of the drug to the drug delivery rate regulating medium in the pores of the porous wall surrounding the reservoir be less than the permeability of the liquid carrier in the reservoir of the drug. In this measure, passage through the wall is the rate-regulating step for the drug. The devices described here are completely free of such limitations.

A significant difference between the devices described here compared to known devices is the presence of highly water-permeable hydrogel in the pores of the porous material which is in contact with the reservoir. Said devices depend on water diffusing from an aqueous-liquid environment where the device is placed, through liquid-filled pores or channels in the hydrogel and into the reservoir, and outward diffusion of the medicine from the reservoir to the environment. Unexpectedly, the concentration of dissolved drug in the reservoir does not decrease, resulting in an essentially constant delivery rate for a long period of time. The amount of solution

however, the gene in the reservoir varies continuously throughout the lifetime of the devices manufactured according to the invention.

The use of a small amount of the anthelmintic agent morantel tartrate in the drinking water of calves, where the calves have continuous access to the medicated water, as a means of endoparasite control has been reported by Downing et al., Irish Vet. J., 221, November, 1974 and in British Patent 1,530,161. Continuous daily anthelmintic medication of calves from early April to mid-July was found to suppress the production of worm eggs in the calves and to prevent, or at least reduce, the development of heavy larval infestation on plants.

Daily low-level administration of morantel tartrate to calves from weaning to mid-July was by Jones et al., Brit. Know. J., 134,166 (1978) found success in controlling parasitic gastroenteritis and lungworm infections by reducing contamination of the pasture available to the grazing calves.

By means of the invention, improved chemical, including medical, permeable systems and devices are provided which are designed to release said substances at a physiologically or pharmaceutically effective, controlled rate from a chemical-containing reservoir into an aqueous, liquid-containing environment, especially into surrounding body fluids in animals and humans". In particular, it applies to such systems and devices which comprise a container, whose walls or parts of walls at least comprise a porous material, including a porous fabric material, the pores of which contain■a hydrogel, and devices in which said porous material is in contact with at least a part of a chemical or chemical-containing reservoir. More particularly, it applies to large pills comprising said systems for regulated drug delivery to ruminants and which are retained in the animals' rumeno-reticular sac.

The improved permeable chemical comprehensive medical (the terms are used interchangeably herein) systems and devices described herein are of value for controlled delivery of drugs and other chemicals to aqueous, fluid-containing environments and are of particular value for oral dosing to animals, including humans, and can be used for different medicines. In addition, the devices are particularly well suited for delivering very water-soluble substances at high speed, which was not easy to achieve with known devices. The systems and devices described here enable regulated delivery of chemicals for long periods of time, are easy to manufacture and are reliable and easy to use. Furthermore, the devices described retain their physical and chemical integrity, do not clog in the environments in which they are used and are particularly valuable for oral use in pill form for ruminants. For the first time, they provide a practical device for the regulated and continuous delivery of chemicals, including pharmaceuticals, to an aqueous liquid-containing environment and therefore fulfill a long-standing need, especially in livestock farming.

The delivery cisterns and devices described here with a regulated delivery rate comprise a barrier or wall in contact with at least a part of a chemical-containing reservoir and in which the wall partly or entirely consists of a porous material, comprising a porous fabric material, the pores of which contain a hydrogel that is permeable to the passage of liquid from the environment through pores within the hydrogel itself and to chemicals from the reservoir by diffusion. When such devices are in use, the hydrogel contains liquid from the surroundings, said liquid being contained in areas or channels (pores) inside the hydrogel itself and which serve as pathways for diffusion of ambient liquid and transport of medicine.

The systems and facilities can

assume a wide variety of different shapes and sizes depending on the purpose for which they are to be used. They can, for example, be capsule-shaped for oral use in humans and animals or cylindrical for implantation or for use as a large pill in ruminants.

A preferred form of the device which

produced comprises a porous material whose pores contain

holds a hydroqel, specifically gelled cellulose triacetate.,

which is permeable for the passage of liquid from the surroundings and for drug by diffusion through pores inside the hydrogel, said porous material being in contact with at least part of a chemical, including drug, containing reservoir comprising chemicals and, if desired, a suitable water-soluble, liquid binding agent and also, if desired, a detergent, as said device is made in the form of a large pill for use in regulated delivery of drugs to ruminants, especially cattle and sheep over a long period of time. A particular application of such large pills is for the control of parasites and helminths, prophylactically and therapeutically, gastroenteral and lungworm infections in cattle and sheep and helminth contamination of pasture. The term "large pill" as used herein includes devices that are generally cylindrical, spherical, spheroidal, elliptical, or of any other shape, free of sharp edges and protrusions.

Known devices require consideration and compromise of many factors in each application; the solubility and/or permeability of the drug carrier in the reservoir; the nature of the microporous wall surrounding the reservoir; the diffusible medium in the pores of the microporous wall; the relative permeability rates of the diffusible medium and the drug carrier; the relative solubilities of the drug in the diffusible medium and in the carrier; and the need to maintain a substantially constant amount of dissolved drug in the reservoir.

The devices described here are on the other

side far simpler in design and application. For a given device, the rate of delivery of a chemical can be greatly varied by the simple measure of varying the area or thickness of the porous material, comprising porous fabric material whose pores are filled with hydrogel, in contact with the reservoir. Manipulation of just two parameters thus enables regulation of the released chemicals.

Figures 1-5 illustrate various examples of embodiments of the invention. The fact that few examples are illustrated should not be regarded as a limitation of the invention, of which it is possible to produce many variations and equivalents. Figure 1 shows a cross-section in perspective of a device as described here, where the delivery device 10 consists of a cylindrical wall 11 in contact with a chemical-containing reservoir 12. The wall 11 is made of a porous material whose pores 14 contain a hydrogel (not indicated) through which liquid from an aqueous, liquid-containing environment diffuses into the reservoir 12 and chemicals from the reservoir diffuse into the environment through channels or pores within the hydrogel itself. The reservoir 12 consists of a chemical 15 and, in a preferred embodiment of the invention, of a drug and a water-soluble binder 16. The ends 17 are non-permeable caps or closures.

Figure 2, a schematic drawing of

. a delivery device of the type shown in Figure 1 but in which a perforated sleeve is inserted, e.g. of stainless steel, iron or plastic, 18 as a means of regulating the surface area of the hydrogel-impregnated porous wall 14, and if it is of metal to increase the weight of the device.

Figure 3 shows an enlarged image of a porous wall

11 in a device 10 whose pores 14 contain a hydrogel 19, in contact with a chemical-containing reservoir 12 consisting of a chemical 15 and a water-soluble, liquid binder 16. Figure 4 illustrates a delivery device which is shaped like a capsule and with only one closing 17.

Figure 5 shows a further device 10

in which the porous material, whose pores 14 contain

a hydrogel (not illustrated), comprises the end walls of the device 10. The cylindrical wall 18 consists of a non-permeable, non-porous material, in this case of stainless steel, which in combination with the hydrogel-impregnated end walls 14 encloses a reservoir 12 comprising a chemical 15 and a binder 16.

As illustrated above, the improved delivery systems or devices have a chemical, including drug, containing reservoir comprising chemicals, and in a preferred form, chemicals and a water-soluble, liquid binder. The water-soluble, liquid binder has several important functions, such as e.g. elimination of air from the reservoir, thereby enabling greater "charge" in the manufacture of the devices, and increasing convective mixing within the reservoir (which ensures a constant delivery rate of chemicals). In addition, said water-soluble, liquid binder has another role in that, as the chemicals dissolve, there is no visible change in volume when the chemicals change from a solid or crystalline state to a dissolved state.

Typical water-soluble, liquid binders include mono-ols and polyols, and ethers thereof, such as e.g. ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and tri-ethylene glycol, di- and tri-propylene glycol, 1,2-dimethoxyethane, mono-C 1 -alkyl ethers of ethylene and propylene glycols; N,N-dimethylformamide, dimethylsulfoxide, and the like. The binders must of course be compatible with the hydrogel.

When the devices described here are to be used for animals, including humans, or in aqueous liquid-containing environments used by animals, e.g. aquariums, fish ponds, water supplies for animals and poultry, hydroponic systems, the water-soluble, liquid binding agent must naturally be a physiologically acceptable substance.

The amount of water-soluble, liquid binder used per unit weight of the medicine depends on the properties of the medicine. In general, sufficient binder is used to form the drug-binder combination into a compact mass, and this is easily determined by experiment.

Detergents up to 20% by weight based on the total weight

of the reservoir (chemicals, including pharmaceuticals and possibly binders and detergents) can be used in the reservoir to minimize possible clogging of the devices when they are in use. Representative detergents may be inorganic or organic in nature and include sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, sodium glyceryl monolauryl sulfate, dioctyl sodium sulfosuccinate, bis(1-methylamyl) sodium sulfosuccinate, polyoxyethylene sorbitan mono-oleate and other fatty acid- Estonians, and others known to the person skilled in the art. The amount of detergent, when used, is not critical and, in any case, is kept to a minimum so as not to take up space for chemicals in the reservoir. The optimal amount is determined by methods described below.

In the present description and the accompanying claims, the terms "reservoir", "chemical-containing reservoir" and "drug-containing reservoir" are used interchangeably. Since the preferred devices described here <are those used for regulated delivery of drugs, for reasons of expediency the term "drug-containing reservoir" is the preferred one.

The terms "porous materials", "porous membranes" or "porous walls" as used herein include porous fabric materials. Representative types of such materials are described below. The porous material used can be isotropic, i.e. of homogeneous pore structure across the material's cross-section, or can be anisotropic, i.e. of inhomogeneous pore structure. Naturally, they must be insoluble and non-reactive with the surroundings and with the contents of the reservoir. Porous materials with pore sizes of from approx. sl st to approx. 100 jum can generally be used in devices for regulated delivery as described here. Porous materials with pore structures that comprise continuous pores, that is, pores that have an effective opening on both sides of the porous wall associated with it, are required. In order to facilitate passage of the drug from the reservoir to the environment when devices for regulated delivery are used,

the pores, or part of the pores, in the porous material are filled with a hydrogel. The net result of the combination of the porous material, the pores of which are filled to a greater or lesser extent with a hydrogel, is to provide a device that can resist clogging and physical destruction under normal conditions of use and, by maintaining its physical integrity, a device that can be used in environments and situations under which previously known hydrogel devices would be destroyed and be ineffective for controlled drug delivery for extended periods of time. The devices described here are of particular value for use in ruminants, especially cattle and sheep. The hydrogel-like pores allow the passage of liquid (water) through the pores in the hydrogel itself by diffusion from the surroundings where the device for regulated delivery is placed, into the reservoir for dissolution of the drug. The drug then diffuses through the liquid in the pores of the hydrogen-containing pores in the porous material barrier at a rate that depends on the drug concentration in the solution in the reservoir, on the resistance offered by the barrier, i.e. liquid in the pores of the hydrogel, and the effective surface area of the porous part of the wall.

As drug leaves the device, a depletion zone is gradually formed causing a moving drug/dissolution boundary. The diffusion of water into the device from the environment through pores within the hydrogel-containing pores in the wall into the reservoir causes convective mixing of the incoming aqueous phase with the solution in the device's reservoir. The driving force for this mixture is the difference in densities in the two solutions caused by their large concentration differences. One function of the water-soluble liquid binder, as noted above, is to help maintain this large density difference, thus increasing this critical mixing. The convection mixture results in a constant drug concentration inside the reservoir, which in turn provides regulated drug release for an extended period of time, thus ensuring zero-order drug release as long as undissolved drug remains in the device. When drug is removed from the reservoir, and aqueous liquid from the surroundings diffuses into the reservoir, the amount of dissolved drug inside the reservoir varies continuously throughout the life of the device, i.e. during the extended time period of drug release. This drug delivery mechanism allows any geometric shape of the device to be used, and the size and shape of the reservoir is not limited. This is in direct contrast to devices known from US Patent 3,993,073 which depend on, and are designed to achieve a substantially constant amount of dissolved drug within the reservoir, diffusion of dissolved drug within the reservoir to supply drug to the wall, and therefore have serious product limitations both in terms of size and shape.

The term "hydrogel" as used herein refers to a gel containing water and is defined in Hackh's chemical Dictionary, 4th ed., Grant, page 332, 1969, as "a gel produced by coagulation of a colloid containing water ". Representative hydrogels that can be used to fill the pores of the porous material are the following: gelled cellulose triacetate, see US Patent 1,693,890

and 3,846,404; cellulose acetate hydrogels obtained from cellulose acetate with an acetyl content of from 20 to 40%; polymeric hydroxyethyl methacrylate; cross-linked polyvinyl alcohol; agarose; polyacrylamide; crosslinked, 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-propyl-

acrylamide, N-isopropyl methacrylamide, N-methylacrylamide, N-2-hydroxyethyl methacrylamide; polyurethane hydrogels comprising weakly cross-linked polymers of isocyanate-terminated prepolymers which are reaction products of a poly(alkyleneoxy)polyol and an organic diisocyanate which is lightly cross-linked with water or an organic polyamine, as described in US Patent 3,939,105; copolymers of ethylenically unsaturated monomers of hydroxyalkyl acrylates and methacrylates, and of alkoxyalkylene glycol acrylates and methacrylates, as described in US Patent 4,038,264; polyether polyurethane resins prepared by reaction between an organic diisocyanate and a mixture of at least 2 diols, one of which is a water-soluble polyalkylene glycol with a molecular weight of from 3,000 to 30,000 and the other is an oxyalkylated diphenol with from 2 to 20 oxyalkylene groups, and others known for the professional.

Preferred hydrogels for use in the present invention are polyurethanes; polymeric hydroxy-lower alkyl acrylates or

-methacrylates, vinylpyrrolidone, acrylamide, N-lower alkylacrylamides and -methacrylamides, especially those cross-linked or copolymerized with a hydroxyalkyl acrylate or -methacrylate to render the resulting copolymer water-insoluble. The preferred hydrogels are gelled cellulose triacetate, polymeric hydroxyethyl methacrylate and

crosslinked polyvinyl alcohol. Particularly preferred is gelled cellulose triacetate, which provides smooth and efficient operation of the controlled delivery devices described here.

The water present in the hydrogel's pores can easily be replaced by water-soluble liquids such as e.g. the water-soluble binders described above. Other water-soluble liquids can also be used to replace the water, including alcohols of one to four carbon atoms. For practical reasons to stabilize the device according to the invention, especially when the hydrogel is gelled cellulose triacetate, the water in the hydrogel is replaced with a suitable water-soluble liquid that has a lower vapor pressure than water so that the devices can be stored without loss of efficiency as a result of drying out the hydrogel. When a water-soluble, liquid binder-drug combination is used in the reservoir, it is convenient to use the same liquid to replace the water in the hydrogel.

The hydrogels themselves are porous in the sense that they contain areas or regions, i.e. channels or pores, filled with water or another liquid. It is therefore intended in the description when reference is made to diffusion or transport of chemicals or drugs through walls, "pores containing a hydrogel", or similar expressions to indicate that diffusion or transport of chemicals or drugs takes place via these regions rather than through the hydrogel per see. The hydrogel itself has fluid-filled pores that serve as diffusion pathways and are considered permeable to the passage of ambient fluids and chemicals from the reservoir.

The porous wall which is in contact with the drug-containing reservoir may be made of a different type of material. The porous material may completely surround the reservoir or may form only part of the wall 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. Meadow. News, December 11, 1978, p. 23, and others known to those skilled in the art.

Suitable porous materials are polypropylene and polyethylene, particularly those materials of each type commonly referred to as "filter cloth", glass, polytetrafluoroethylene, nylon, cotton, modacrylic fibers, i.e. acrylic fibers consisting of a long-chain synthetic polymer containing 35-85% acrylonitrile units; acrylic fibers, i.e. synthetic polymers with a minimum of 85% by weight of acrylonitrile; polyesters, i.e. a long-chain, synthetic polymer consisting of at least 85% by weight of an ester of a dihydric alcohol and terephthalic acid; polyvinyl acetate, polyvinyl chloride, poly(vinyl acetate-co-vinyl chloride), polyvinyl alcohol, poly(vinyl alcohol-co-vinyl acetate), polyvinyl alkyl ethers; polymers of vinylidene cyanide, vinylidene chloride, vinylidene fluoride; polyurea and others known to those skilled in the art (see Encyclopedia of Polymer Science and Technology, Vol. 1, 342 (1964); Vol. 8, 812 (1968); Vol. 9, 403 (1968); Vol. 10, 347, 206 (1969) ; Vol. 6, 275 (1967); Vol. 11, 62, 445 and 506 (1969); Vol. 14, 305, 575 (1971) , Interscience Publishers, New York). In addition, metal cloths or filter cloths include those made from stainless steel, carbon steel, brass, copper, aluminium, various alloys such as e.g. nod1-copper, etc. suitable.

The particular substance chosen must of course be compatible with the hydrogel with which it is to be impregnated and with the end use for the device. Thus, for a device to be used as a large pill for administering medicine to ruminants for extended periods of time, cotton could not be used as a fabric since it would undergo degradation in the ruminant.

In a facility that is to be used for regulated release of chemicals to aqueous environments such as e.g. an aquarium or reservoir, cotton can be used.

Nylon will not be able to be used as a material when gelled cellulose triacetate is to serve as a hydrogel, since it would be broken down by the formic acid or acetic acid used during the impregnation process.

The hydrogel-impregnated, porous fabric materials must of course have sufficient strength, durability and inertness towards medicinal products and the environment of use so that the device for regulated release produced from them retains its physical and chemical integrity throughout its lifetime.

The porous material is impregnated with a suitable hydrogel using methods known to those skilled in the art. A favored and relatively simple method of impregnating the porous material with gelled cellulose triacetate, a preferred hydrogel, involves pressing a solution of cellulose triacetate in formic or acetic acid into the pores of the porous material by immersing the material in the cellulose triacetate solution in a vessel which can be exposed to vacuum. After impregnation, the cellulose triacetate "charged" plastic is coagulated by contact with and equilibration with a large volume of water 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, since it wets the polyethylene better than formic acid and thus facilitates the production of the hydrogel-impregnated, porous material.

When the hydrogel is obtained from 2-hydroxyethyl methacrylate cross-linked with ethylene glycol dimethacrylate as described in US patent 3,520,949, the impregnation of the porous material is carried out by filling its pores with the 2-hydroxyethyl methacrylate-ethylene glycol dimethacrylate mixture and then polymerizing the mixture inside in the pores by adding a free radical catalyst such as t-butyl peroctoate. In the same way, other hydrogels are impregnated in the porous wall material by such in situ methods from suitable reactants. When the hydrogel is cross-linked polyvinyl alcohol, the pores are filled with polyvinyl alcohol (10% aqueous solution)-resorcinol (2-3%) mixture using methods described here, and the cross-linking is carried out in situ. Other cross-linking agents known to the person skilled in the art can of course be used.

For the production of devices that are stable during storage before use, the hydrogel-filled pores are freed from water by

allow equilibrium to be established in a suitable water-soluble liquid such as e.g. the water-soluble binders mentioned above. It is, as noted, appropriate to replace the water in the hydrogel-filled pores with the same water-soluble liquids that are used as binders in the reservoir, when the reservoir comprises a chemical-binder combination. If the chemical alone comprises the reservoir in the devices described here, the choice of water-soluble liquid to be used to replace the water in the hydrogel in the hydrogel-filled pores in the porous wall is determined only by the final application of the device, i.e. whether a physiologically acceptable, water soluble liquid. Such a liquid is conveniently placed in the hydrogel when the porous wall is produced and whose pores contain a hydrogel, before the reservoir in the device is filled, as illustrated here.

The previously known devices which are most closely related to those produced by the invention, i.e. those according to US patents 3,993,073 and 3,993,072, depend on different permeability rates for drug through a medium contained in the pores of the porous wall in relation to the velocity of the drug in the drug carrier phase in the reservoir. In order to achieve zero-order delivery rates as specified for the devices described in the aforementioned patents, it is crucial that the medium in the walls of the device has a lower permeability to the medicine than the medicine carrier inside the reservoir has. The medium in the wall thus becomes the drug release rate-regulating part of the device.

Dissolved medicine diffuses through the more permeable carrier to the inner wall quickly enough so that the wall becomes the drug release rate-regulating part of the device. This results in zero-order delivery rates for some time until the backward drug limit in the device becomes large enough to offset the difference in permeabilities between the carrier and the wall medium, and then zero-order rates are no longer achieved. Because of this, successful practical use of these devices is limited and they are not suitable for zero-order delivery of large amounts of medicine in practical, usable dosage forms.

In contrast to known hard devices produced by the invention when in use, aqueous ambient medium in the wall medium as well as in the reservoir. Although the permeability to the medication is the same in the fluid in the wall and the reservoir, zero-order delivery rates are achieved for large parts of the device's lifetime. In addition, maintenance of zero-order delivery does not depend on diffusion in the reservoir carrier, and thus there are no geometric or dose restrictions for these devices, and for the first time, large amounts of drug can be delivered at zero-order rates in embodiments of practical sizes and shapes.

In order to achieve the most efficient function of the regulated delivery systems and devices described here and to reduce sealing and leakage, it is important that the porous material is impregnated as completely as possible with hydrogel. Devices with the same surface area can, by varying the properties of the membrane wall, especially its thickness, pore size and porosity, and by varying the size of the charge in the reservoir, give different dosage rates and delivery periods for a given drug.

As noted above, a preferred form of the device described here is a large pill for use in regulated delivery of a drug to ruminants, primarily to cattle and sheep, for an extended period of time. The large pill is administered to the ruminant in such a way, preferably by oral administration, that it remains in the rumeno-reticular sac for an extended period of time, during which time it continuously delivers medicine to the animal at a controlled rate of delivery. Said devices thus make it possible to combat (prophylactically and therapeutically) various pharmacological and physiological conditions to which the animal is exposed by simple oral administration of said devices to the animals.

In order for the large pill, when introduced into the rumeno-reticular sac in cattle, to remain there for an extended period of time, it is necessary that the pill has a density of at least 2.0 g/ml. In practice, the density can vary between as little as 2.0 to as much as 7, or even higher. The density is of course the most significant factor affecting retention of the pill in the rumeno-reticular sac. The overall size of the pill is a function of the dose required and the size that can be conveniently administered. Based on this, once the desired size is determined, additional weight can be added to achieve the desired average density. If possible, it is desirable to use the maximum acceptable size since larger pellets with a given density are better retained than those with a lower density. When the average density of the pill increases to a value greater than approx.

5, however, increasing the size of the pill does not significantly improve the retention factor. The preferred average density range for the pill is from approx. 2.5 to approx. 5 g/ml.

The size of the pill naturally depends on the animal to be treated. For ruminants such as e.g. sheep and goats, the pill size and weight will be smaller than for cattle. The maximum size of the pill for application to an animal is determined by the practical difficulties of administering such an object to the animal.

For administration to sheep, the minimum weight for pellets with a density of 4 that will be retained is approx. 1 gram. The size of the pill will vary depending on the pill's density. For administration to cattle, the minimum weight for a pill with an average density of 4 is approx. 5 grams. As noted above, the upper limits of the size will again be determined by the practical expediency of dosing to the animal in question and by the minimum average density of the pill. A pill of approx. 7.5 cm length and 2.5 cm diameter and with a density of 2.2 will, for example, have a weight in the order of approx. 90 grams.

The density of large pellets comprising only the elements indicated above is generally below the lowest level indicated above. It therefore becomes necessary to increase the average density of the pill by introducing a suitable, high-density material such as e.g. a metal (iron powder, iron shot, steel shot) or other density enhancers, such as minerals such as CaSO^, to increase the density to the desired value. Alternatively, the average density can be increased in a conventional manner by introducing into the pill, as an inner sleeve, a perforated material of high density, e.g. of metal (such as stainless steel, steel, especially low-carbon steel, or iron) which in turn is surrounded by the hydrogel-impregnated, porous membrane. The perforations in the sleeve must be sufficiently large to enable the free passage of medicine and liquid from the environment, through the hydrogel-impregnated, porous membrane. The main functions of such a sleeve are to increase the average density of the pill to a value such that the pill is retained in the rumeno-reticular sac and to regulate the surface area of the hydrogel-impregnated porous material in contact with the drug-containing reservoir. In addition, such a sleeve, although not necessary, also improves the physical stability of the pill and ensures that its physical shape is maintained under the conditions of use. A further and preferred alternative comprises a large pill comprising a metal, steel or iron cylinder, one or both ends of which are covered with a porous membrane, the pores of which are impregnated with a hydrogel. Pills of this type are preferred because of their simple and economical manufacture and the ease with which their density can be adjusted.

A low carbon steel is highly favored as a construction material for the cylinder. Other alternatives will be obvious to the person skilled in the art.

The devices manufactured according to the invention

The solution can be used for various purposes and situations where regulated delivery of medicines or other chemicals is desirable. They can be used for the administration of medicines and

provide chemicals at locations close to or far from the location for application of the device. They can be placed by suitable means in suitable places in the animal's body where they are in contact with the body fluids, e.g. the stomach of domestic animals, especially the rumeno-reticular sac of ruminants. Also included among the controlled delivery devices are those used for depot implantation for the purpose of administering a drug at a controlled rate to the host. The implants differ from the devices described here only by their shape, which ■ is naturally adapted for implantation. Other uses include sublingual or buccal tablets, pessaries, suppositories, bandages and skin patches. Additional applications for the regulated delivery systems and devices

occurs in agriculture for the administration of fertilizers and pesticides, in fish farming including aquariums and fish ponds; in drainage ditches, canals and tanks for algae control; and in water

supplies, especially for animals and poultry that need drugs for prophylactic or therapeutic treatment.

The criterion for suitable substances, medicines or chemicals to be used in the devices described here,

is that they are sufficiently soluble in water to achieve a delivery rate of said medicine or chemicals in the application environment that will give the desired result. For this reason, medicines and chemicals that are acids or bases are often used in the form of their physiologically or pharmacologically acceptable salts. The delivery rate for medicines or chemicals from the devices described here depends on many factors such as e.g. the wall thickness, available surface area, effective pore diameter, wall porosity, the nature of the hydrogel, the concentration of the substance in the reservoir and its solubility in the surrounding liquid. The suitability for a given substance is determined as described below.

Representative of drugs that can be used in the devices described herein are the following: anthelmintics, including salts of morantel, pyrantel, oxantel, piperazine, diethylcarbamazine, levamisole, tetramisole and hygromycin B; antibacterial substances comprising salts of tetracyclines, such as e.g. 5-oxytetracycline, chlortetracycline, doxycycline and Mannich bases thereof; penicillins such as ampicillin, and penicillin G; aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin as its zinc or methylene-disalicylic acid derivative; macrolides such as erythromycin, oleandomycin and tylosin; antibacterial growth-promoting substances such as salts of avoparicin, polymyxin, lincomycin, bambermycin and efrotomycin; hormonal growth promoting agents including diethylstilbestrol and zearalanol; antiparasitic agents such as amprolium; nourishing agents such as e.g. soluble salts of magnesium, selenium, copper, and vitamins such as thiamine hydrochloride; sulfa drugs such as sulfamethazine; molluscicides such as N-tritylmorphine; and anti-swelling agents such as e.g. alcohol ethoxylates and poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) polymers, e.g. the polo hall.

As noted above, the drug-containing reservoir in a preferred form according to the invention comprises a drug and a water-soluble binder. Devices that are constructed in this way have the advantage that they provide a larger amount of medicine per device and that they extend the useful life of the device. However, the reservoir can only contain the selected drug.

The devices described here are particularly valuable as long-acting pills for combating (therapeutic and prophylactic) helminth infections in ruminants, especially cattle. Protection of stray animals becomes relatively appropriate. In temperate climates, the low, early spring population of pasture larvae, the remainder of the previous season's contamination, is multiplied by circulation through animals that graze on them so that in the summer there is a strong increase in the infection on the pasture. During the summer grazing season, this condition is the cause of clinical parasitism and a reduction in the performance of animals that graze on said pasture.

The continuous and regulated release of anthelmintic agents, e.g. morantel, in the rumeno-reticular sac of grazing animals early in the season when pasture contamination is low, suppresses helminth eggs and subsequent larval formation and thus breaks the above cycle and keeps the worm load on pasture and animals at a low level. Parasite infections of ruminants that graze on the same pasture during the summer season are thus minimized. This method of helminth control is particularly attractive and valuable for calves since they are very susceptible to helminths when they first go to pasture. Constant use of large pills reduces the reservoir of infectious helminth forms in a given locality. Application of anthelminth-containing pills according to the invention in this way prevents, or at least reduces, the seasonal increase of larvae on the pasture which causes parasitic gastroenteritis and performance reduction in grazing animals later in the season. In this control method, the period of drug release is the spring multiplication phase, not the period of heavy pasture contamination, larval challenge and worm infestation that cause clinical disease and performance reduction. For this reason, this method of use is called "indirect combat". To put it another way, the grazing of ruminants which have in their rumeno-reticular sac one or more of the devices described here, which device allows regulated and continuous release of anthelmintic agent, e.g. morantel, to said sack, on pasture early in the season, i.e. when larval infestation is at or near a minimum level, enables minimization of the usual seasonal increase in larval infestation of the pasture and serves to protect animals that graze there throughout the grazing season.

For "indirect control" of helminths, the devices described here are administered, preferably in the form of large pills, to ruminants at a time in the epidemiological cycle of said helminths, when pasture contamination by said helminths, their

■eggs and/or larvae, are at or close to a minimum level. In temperate zones, this corresponds to the time of spring calving, i.e. the first placement of calves on pasture. To achieve maximum effectiveness, the pills are administered to the calves approx. 2 or 3 days before they are released. In non-temperate regions of the earth, e.g. in semi-tropical and tropical areas, the period of lowest contamination of the pasture normally occurs before the rainy season. Administration of pills to ruminants in such areas is preferably carried out between 2 and 14 days before the start of the rainy season. However, due to the difficulty of predicting when the rainy season will begin, helminth control in the non-temperate zones is best achieved by the "direct control" method.

The large pills described here also eliminate established helminth infections from ruminants and prevent the establishment of worm infections during the large attack in the summer period. This method of use is called "direct combat". The direct method of control protects ruminants only during the period in which the anthelmintic agent is released. The indirect method of helminth control protects ruminants that graze on a given pasture throughout the season because it results in a significant, total reduction of pasture contamination. As noted, the devices described herein provide continuous, controlled-rate delivery of drugs, including anthelmintic agents. Particularly useful for such purposes are water-soluble salts of (E)-1,4,5,6-tetrahydro-1-methyl-2-[2-(3-methyl-2-thienyl)ethenylpyrimidine (morantel), (E)- 1,4,5,6-tetrahydro-l-phiethyl-2-[2-(2-thienyl)ethenyl]pyrimidine (pyrantel) and (+)-2,3,5,6-tetrahydro-6-phenylimidazo[2,i-b ]thiazole (tetramisole) and levamisole, the L-(-) form thereof. Representative of preferred water-soluble salts of pyrantel and morantel are the tartrate and citrate salts; and of tetramisole and levamisole, the hydrochloride salts are preferred.

The large pills are administered orally to the animals, for example with a balling gun. For bruk.hes calves, the desirable average release rate of morantel (calculated as base) for indirect control of helminths is of the order of 60-200 mg (morantel base) per day for a period of approx. 60 days, which covers the normal maximum survival time for the spring population of larvae. Longer delivery periods of 60-120 days are desirable for direct control of helminths since the exposure period for heavy pasture contamination extends from midsummer to the end of August. Release rates of approx. 60-150 mg (calculated as morantel base) per day effectively combats helminth infections in such delivery periods. For dosing to larger animals, more than one large pill can be administered. For indirect control of helminths using salts of pyrantel or levamisole, the desirable delivery rates for each (calculated as free base) are of the order of 100-400 mg and 100-500 mg per day, respectively for an approximate 60 day period, for direct combat, release rates of approx. 100-300 mg (as free base of pyrantel) and of approx. 100-400 mg (free base) of levamisole per day effectively fight helminth infections in the 60-120 day period with the strongest attack.

Continuous low-level administration of morantel using the devices for helminth control described herein gives rise to an efficacy profile that is surprisingly different from and advantageous to that observed with conventional therapeutic use of morantel and which could not be predicted. Maintenance of a prolonged level of morantel tartrate or citrate (or other salt) in the gastrointestinal tract of ruminants is, for example, effective in preventing lungworm infections in said animals during the period of delivery of the medicine. While cattle or sheep grazing on contaminated pasture are further exposed to immediate reinfection of intestinal nematodes after conventional therapeutic dosing, animals receiving the big pill are essentially freed from established infection and protected from reinfection for a period of 60 days or more.

The use of large pellets for the control of pasture infestation, i.e. the indirect control method, is a unique, practical and not previously used method of helminth control, which protects ruminants, and especially grazing ruminants, treated by this method throughout the grazing season and provides performance benefits which is superior compared to known combat methods. The increase in daily weight gain compared to untreated control animals during the grazing season is significantly greater than that achieved with conventional therapy.

The rate of drug release, or release

of other chemicals, from the drug-containing reservoir through the walls of the devices for controlled release according to the invention, and the effectiveness of a given drug and/or water-soluble binder and/or a detergent combination in said devices, can be easily determined by the person skilled in the art, for example by transmission methods, or by sorption/desorption methods. A technique that can be conveniently used to select suitable porous materials and hydrogels involves using the selected porous material, the pores of which are to be filled with the selected hydrogel, as a barrier between a rapidly stirred, saturated solution of a drug or other chemical, the controlled release of which is desired, and a rapidly stirred solvent bath, the composition of which stimulates the aqueous, liquid-containing environment in which the controlled release device is to be used. The temperature of each solution is maintained at a constant value, preferably at a value close to the average temperature of the environment the said device is to be used in. Samples are taken at predetermined intervals from the solvent bath, and these are analyzed for drug concentration. The permeability of a drug, or other chemical substances, through the porous material whose pores are filled with hydrogel can also be determined by standard methods described in the Encyclopedia of Polymer Science and Technology, Volumes 5 and 9, pp.65-82 and 794 respectively -807, 1968; and references cited therein; and in Chemical Engineers Handbook, pp. 17-45, 1963, published by McGraw-Hill, Inc.

A method of particular value in determining release rates for devices as described herein and the relative merits of a given binder or a given detergent for use in a given device, especially when the drug is morantel, is summarized as follows: The method, an in vitro method, is based on the release of a water-soluble salt of morantel, for example the tartrate, from a device made according to the invention, as a function of time. Such a device,

containing morantel tartrate is placed in a one-liter conical flask protected from light due to the photosensitivity of morantel tartrate, 500 ml of phosphate buffer pH 7 is added, and the temperature of flask and contents adjusted to and maintained at 37°C . The flask containing the device is shaken with approx. 70 strokes (7.62 cm) per minute, and 5 ml samples are taken periodically. The volume of it

removed sample is replaced with an equivalent volume of new phosphate buffer with pH 7, 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 read against new phosphate buffer with pH 7. The sampling process is repeated until 5 grams of morantel tartrate has been released, at which point the device is transferred to another flask containing 500 ml new phosphate buffer with pH 7 and the procedure continues as before.

In vivo release of morantel tartrate from the devices described here is determined by administering the devices to, for example, normal young bulls or young cows with a rumen fistula and, after a certain period of time such as e.g. 30, 60, 90 or 120 days, to remove the devices via fistula or by killing the animals and removing the devices to determine the residual amount of morantel tartrate inside the devices. Tests of this type have shown that the release rate for morantel tartrate in vitro is approx. four times as great as the release rate in vivo..

The following examples shall illustrate the present invention.

Example 1.

A large pellet comprising sintered polyethylene, the pores of which are filled with gelled cellulose triacetate, and a reservoir containing morantel tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate, and with a perforated stainless steel sleeve, was prepared as follows: One end (referred to as end 1) of a sintered polyethylene pipe with a mean pore size of 10y-m, an outer diameter of 2 5.4 mm, an inner diameter of 2 2.2 mm and a length of 7.94 cm was dipped in a 10% solution of cellulose acetate butyrate in methylene chloride to a depth of 4.8 mm. It was then dried in air and the other end (referred to as end 2) of the tube <?. dipped in the cellulose acetate butyrate solution to a depth of 9.5 mm and dried. This step was repeated. End 1 was again dipped in the cellulose acetate butyrate solution for 30 seconds, allowed to dry in air for 60 seconds, and a cellulose acetate butyrate disc with a diameter of 22.2 mm and a thickness of 3.2 mm inserted into the end of the tube so that there', became in flight with said end. The cellulose acetate butyrate disk was allowed to float on methyl chloride for 60 seconds before being introduced into end 1 of the tube. The tube was then rolled over the bench, finger pressure being applied to the end containing the disc to ensure complete bond between disc and tube. 1 A No. 3 one-hole rubber stopper fitted with a glass tube of sufficient length to pass through the one-hole rubber stopper in a vacuum flask when the tube rests on the bottom of the flask 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 approx. 150 mm Hg applied. When the cellulose triacetate solution covered the outer walls of the tube that was not dipped in cellulose acetate butyrate, the tube was removed from the vacuum flask and the bulk of the cellulose triacetate was dried off. The tube was then turned upside down to drain the cellulose triacetate from the interior of the tube. The outer and inner ends of the tube were wiped clean with a towel. The tube was then immersed in and allowed to equilibrate in distilled water overnight. It was then removed from the water, the outside dried with a towel, and excess water shaken off from the inside of the tube. The steps for impregnating the tube's pores with cellulose triacetate and to equilibrate in distilled water was repeated.It was then equilibrated in running water for 4 hours.

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

The tube was then brought to equilibrium in polyethylene glycol

400 overnight, removed from polyethylene glycol 400 and allowed to drain upside down for 4 hours. Excess polyethylene glycol 400 was wiped from the outside of the tube with a towel and a stainless steel tube 22.2 mm outer diameter, 18.9 mm inner diameter, 6.99 cm long and with 16 evenly spaced, circular holes (7, 1 mm diameter) inserted into the tube until it was flush with the sealed end. Cellulose triacetate chips resulting from the insertion of the tight-fitting sleeve into the tube were removed. A cellulose acetate butyrate disc (3.2 mm) was then inserted into the open end of the tube flush with the stainless steel sleeve and the tube trimmed so that the end of the tube was flush with the disc. The disc was removed and the tube filled with a homogeneous mixture comprising 63.31% morantel tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexametaphosphate flush with the end of the stainless steel sleeve. 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 dipped into the cellulose butyrate solution to a depth of 6.4 mm and allowed to dry. A cellulose acetate butyrate disc (floated on methylene chloride for 60 seconds just prior to use) was then pressed into the open end of the tube, applying sufficient pressure to press the disc against the stainless steel sleeve. The tube was then rolled on the benchtop, and sufficient finger pressure was applied to ensure complete bond between disc and tube. The tube was allowed to dry for one hour, after which each end of the tube was dipped in 10% cellulose acetate butyrate to a depth of 6.4 mm and allowed to dry. The weight of the pill was approx. 90 g, of which 24.8 g was medicinal mixture. Its density was 2.2 g/ml. This facility emitted approx. 250 mg per day of morantel tartrate in vivo in cattle for approx. 60 days.

Example 2.

Three devices prepared according to Example 1 tested in vitro by the method described herein provided an approximately constant release rate over a period of 4-17 days, with a mean release rate for all three pills of 0.927 g of morantel tartrate per . day.

In vivo tests with 3 other pills prepared according to example 1 and placed in the rumeno-retical sac in cattle showed a release rate of 0.224 g morantel tartrate per day, when they were recovered at the end of a 30 day period. This is an in vitro/in vivo ratio of 4:1.

Example 3

In vitro tests with two other pills prepared according to Example 1 and tested as described herein gave a mean release rate during the constant rate period, 0-14 days, of 0.96 morantel tartrate per day.

In vivo tests with identical pellets placed in the rumeno-reticular sac in cattle for a period of 30-60 days gave the following results:

Overall, mean in vivo rate is 0.224 g per day and the ratio in vitro/in vivo is approx. 4:1.

Example 4.

Pellets were prepared from stainless steel tubing with the following dimensions: 22.2 mm y.d., 21.3 mm i.d.

and 3 cm length. The tube ends were threaded (0.5 mm at each end) to receive a collar that serves to hold a hydrogel-impregnated porous fabric disc in place. The plates (22.2 mm y.d. and 3.2 mm thickness) of polypropylene filter cloth with pores of 50 f* > .m average size and impregnated with gelled cellulose triacetate, were prepared by immersing them in a 6% solution of cellulose triacetate in formic acid in a vessel that could be exposed to a vacuum of 25 mm of mercury or less. The flask and contents were kept under vacuum for approx. 10 minutes, the discs removed and dried free of excess cellulose triacetate solution. They were then immersed in and allowed to equilibrate with distilled water overnight. The discs were then removed from the water, dried with a towel and then equilibrated with polyethylene glycol 400 overnight. The discs were removed and dried with a towel.

Impregnated washers were fitted to one end of each

of the pipes by placing them between two sealing washers which are 0.254

mm thick and of the same diameter as the steel pipe. The sealing disc closest to the steel tube was of cellulose acetate butyrate and the other of dental dam gum rubber. The ends were closed with stainless steel sleeves with an opening of 21.3 mm diameter. The tubes were then filled with morantel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%) and the other end of each tube was sealed as described above.

The pills contained 21.4 g of morantel tartrate, weighing 9 7

g and had a mean density of 3.30 g/ml.

The pills were administered to young bulls with a rumen fistula and removed via the same fistula at intervals of 30, 40,

60, 75 and 90 days to determine the amount of drug remaining in the pill, from which the mean daily release rate of morantel tartrate was calculated.

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

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

Example 5.

Four large pills comprising sintered polyethylene, (average pore size 10 µm) the pores of which are filled with gelled cellulose triacetate, and with sleeves of stainless steel for only part of the total length of the pill (so that a piece of the bolus is left free of sleeve), and reservoirs containing morantel citrate (63.3%), mixed with polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) were prepared according to the procedure of Example 1 instead of the perforated stainless steel sleeve used however, imperforate sleeves of 5.08, 4.45, 3.18 and 1.91 cm were used here. The walls of the sleeves were 0.17 cm thick. The drug mixture was then introduced into each pill so that a drug band width of 6.35, 12.70, 25.4 and 38.1 mm across the sleeve was obtained, respectively. A stainless steel plug, 12.7 mm thick and 22.2 mm in diameter was inserted into each of the pills above the drug mixture. The ends of the pills with the steel plug were trimmed so that it was possible to insert a cellulose acetate butyrate disc on top of the plugs, flush with the ends of the pills. The total weight of each individual pill was respectively 120.0, 115.4, 106.2 and 97.0 g. The weight of the medicinal mixtures varied from approx. 25.5 to 27.4 g per pill. The densities of the pills were respectively 3.1, 2.98, 2.75 and 2.51 g/ml.

Example 6.

In vitro tests on the release rate of morantel citrate for the pills of Example 5 showed that each provides a constant release of drug over a period of 3-21 days. The lightest of the four pills from Example 5 (the one with the 1.91 cm sleeve) had a mean release rate of 774.8 mg morantel citrate per day in the period of 3-21 days with constant release.

Example 7.

14 pills prepared according to example 1 were tested in vivo in cattle and showed a mean release rate of morantel tartrate of 238 mg per day in a 60 day period. The standard deviation 1 was 6 7 mg (28%).

Example 8.

A large pellet comprising sintered polyethylene, whose pores (average size 100 µm) are filled with a cross-linked polyvinyl alcohol hydrogel, and a reservoir containing morantel citrate (63.3%), polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) ), and with a sleeve of perforated, stainless steel is prepared in accordance with the method from example 1. Instead of cellulose triacetate-formic acid solution, however, the hydrogel solution comprises an aqueous solution of 10% polyvinyl alcohol (88% hydrolyzed polyvinyl acetate) containing 3% resorcinol. After vacuum treatment to fill the pores, the tube is dried clean and kept at 0 to -10°C for 5 hours to gel the polymer. Equilibrium treatment of the pipe in water is unnecessary. The pipe is then tested for leaks, balanced in polyethylene glycol 400, filled and sealed as in example 1.

In vitro tests showed that it produced regulated release

of morantel citrate.

Example 9.

The procedure from Example 1 is repeated, but using sintered polyethylene tubing half the length and half the diameter of those used in Example 1. The resulting pellets are intended for use in sheep and provide controlled release of anthelmintic agents over an extended period of time in vivo.

Example 10.

The procedure from Examples 1 and 5 is repeated, but using the following microporous materials instead of sintered polyethylene: porous ceramic, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene (average pore size of each material was 100 µm).

Each of the pills produced in this way produced controlled release of chemicals for an extended period of time when tested in vitro.

Example H •

Pills are produced from stainless steel tubes with the following dimensions: 22.2 mm outer diameter, 21.3 mm inner diameter

and length 7.62 cm. The ends of the tubes are threaded (0.5 mm at each end) to receive a sleeve that serves to hold a porous, hydrogel-impregnated disk in place. The disks (22.2 mm outer diameter and 3.2 mm thick) of sintered polyethylene impregnated with gelled cellulose triacetate are prepared by immersing them in a 6% solution of cellulose triacetate in acetic acid in a vessel - which can be subjected to a vacuum of 2 5 mm Hg or less. The flask and contents are kept under vacuum for approx. 10 minutes, the slices are removed and dried free of excess cellulose triacetate solution. They are then immersed in and allowed to equilibrate with distilled water overnight. The slices are then removed from the water, dried with a towel and then brought to equilibrium with polyethylene glycol 400 overnight. The discs are removed and dried with a towel.

Impregnated washers are fitted to one end of each of the pipes by clamping them between two sealing washers which are 0.25 mm thick and have the same diameter as the steel pipe. The sealing disc closest to the steel tube is of cellulose acetate butyrate and the other of dental damming rubber. The ends are then fitted with stainless steel sleeves with an opening of 21.3 mm in diameter. The tubes are then filled with the desired chemicals and the other end of each tube is sealed as described above.

The tubes (pills) are made with the following chemicals: morantel citrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%); oxytetracycline hydrochloride (100%); pyrantel citrate (88%), glycerol (12%); pyrantel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium lauryl sulfate (10.1%); tetramisole hydrochloride (100%); poloxalen (100%) erythromycin hydrochloride (100%);

thiamine hydrochloride (100%).

Example 12.

The procedure from example 1 was repeated with the exception that the pill was filled with morantel tartrate instead of the morantel polyethylene glycol 400 sodium hexametaphosphate mixture in the aforementioned example. The pill weighed 84.0 g of which 18.6 g was morantel tartrate.

The pill, when tested in vitro according to the method described herein, provided a controlled and near constant release rate of morantel tartrate during the test period of 8-20 days with a mean release rate of 1.36 g per day.

Example 13.

A low carbon steel tube with the following dimensions: length - 8.77 cm, inner diameter -2.16 cm, outer diameter - 2.54 cm and a groove 0.3 cm deep and 0.6 cm wide located 0.1 cm from each end thereof to receive an aluminum crimp, and which completely encircles the pipe, was sealed at one end with an ultra-high molecular weight sintered polyethylene disc (average = 2-3 million, available from Glasrock, Porex Division, Fairburn, Ga) with medium partial pore size of 10 µm, impregnated with gelled cellulose triacetate as described in Example 15. The disk, 2.54 cm in diameter and 0.16 cm thick, was sealed to the tube with an aluminum crimp. The tube was then set upside down and filled with a homogeneous mixture comprising 54.4% morantel tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The slice/shrink seal process was repeated to complete the pill. The total weight of the pill was 145.1

g of which 41.4 g was medicinal mixture. Its density was 2.8 g/ml.

The aluminum crimps at each end of the tube had an open center area of o 3.25 cm 2 , resulting in a total area of 6.5 cm 2 available for drug delivery. The pill provided regulated release of morantel tartrate to cattle for a period of approx. 90 days.

Example 14.

An aluminum cylinder, 6 cm long with an outer diameter of 2.1 cm and a wall thickness of 0.1 cm, and with a groove at the open end to receive an aluminum shrink seal, was filled with a composition comprising 70% levamisole hydrochloride , 30% polyethylene glycol 400 and sealed with a sintered, high-density (0.95-0.97 g/ml) polyethylene disk impregnated with gelled cellulose triacetate according to the method in Example 15. The pill had a density of 2.8 g/ml. The reservoir contained 23.46 g of the drug mixture, equivalent to 16.42 g of levamisole hydrochloride.

The aluminum crimp used had a circular, open area in its center, said area having a diameter of 1.1 cm, giving a transport area of 0.95 cm 2 .

In vitro tests at 37°C showed that the pill released levamisol hydrochloride at a controlled rate.

Example 15.

This example describes a field experiment carried out with 40 test calves of uniform pedigree, weight (average = 150 kg) and sex, which had not previously grazed. The calves were divided into four groups of 10 each on the basis of body weight. Two of the groups were parallel drug-treated groups and two were parallel control groups. A worm-free track calf was added to each of the four groups of test calves at the start of the field trial and every four weeks thereafter. Each tracked calf was kept in its pen for two weeks, then removed and housed for three weeks before slaughter for worm counting.

The test and track calves were taken out onto infected pasture that had been used for grazing last summer and autumn by infected cattle. The pasture was of sufficient size to keep 44 animals for the entire grazing season and was divided into four equal and separate enclosures.

The two drug-treated parallel groups were orally administered a 60-day pill prepared according to the method in example 1. The pills provided a continuous release of morantel tartrate of 250 mg/animal (equivalent to 150 mg morantel base) per day for 60 days. The drug-treated animal groups received the pills orally two days before they were released to pasture in the spring. The presence of the pill in each drug-treated animal was determined with a metal detector 24 hours after administration. Control of pill retention was carried out at two-week intervals thereafter. All animals, drug-treated, control animals and tracer animals, were weighed before going out to pasture and at 4-week intervals.

Plant samples were collected according to the method described by Taylor (Parasitology, 31, 473, 1939) at 2-week intervals beginning 4 weeks before the start of the field experiment and continuing until the end of the experiment.

Fecal samples for McMaster egg counts and lungworm larval counts were collected at the start of the experiment and at 2-week intervals thereafter. In the first 8 weeks, these were rectal samples (one from each animal). Thereafter, rectal samples were collected every 4 weeks so that it coincided with weighing the animals. At intermediate points, samples, 10 for each group, were collected from the pasture (Gibson, Veterinary Bulletin No. 7, 403-410, 1965).

Total worm counts were performed on the abomasum, including mucosa, small intestine and lungs of slaughtered animals.

These data are shown graphically in Figures 6, 7 and 8. Figure 6 shows weight gain during the grazing season for both drug-treated and control groups. Both groups were found to gain weight with almost the same net gain in approximately the first 3 months. Subsequently, weight gain in the control groups slowed down and even decreased for a certain period of time, consistent with an increase in the number of grazing parasites. Medicated animals, on the other hand, continued to gain weight at a weight almost the same as early in the season. Figures 7 and 8 show the parasite population throughout the grazing season for drug-treated and control animals. Number of eggs per grams of faeces (right ordinate) and the number of larvae per kg dry pasture plants (left ordinate) are deposited. The calves were released to pasture in mid-May; the medicated calves were given the 60-day pills orally 2 days before release, giving them treatment until mid-July.

At the time of discharge, the number of eggs in faeces and larvae in the grass was low. In the control group, Figure 7, eggs began to appear in the animals' faeces in early June, peaked in late July and slowly declined in August and September. These eggs lead to the increase in larvae in the grass that was observed in late July and peaked in August.

In the drug-treated groups, figure 8, the production of eggs in June and July was dramatically reduced, a fact that was reflected by the significant reduction of larvae in the grass in July and September.

Example 16.

Similar field trials were conducted consistent with the pattern of Example 15, but using only one drug-treated and one control group in each trial. Current data is listed in the table below:

Average weight gain

Advantage at Kumulativ

Experiments Number of animals treated against egg count % Reduction

Example 17.

The procedure from example 4 is repeated, but instead of polypropylene filter cloth impregnated with gelled cellulose triacetate, the following porous substances gelled with cellulose triacetate are used:

a) copolymer of acrylonitrile (40%) and vinyl chloride (60%), sold under the trade name "Dynel" by Union Carbide Corp., New York. b) sold under the trade name "Morel" by the International Nickel Co., Inc., New York.

Claims (8)

1. Process for manufacturing a device for long-term and physiologically effective, regulated, continuous administration discharge of chemicals into aqueous, liquid-containing environments, e.g. for placement in the rumeno-reticular sac of a ruminant, whereby a chemical is enclosed in a reservoir surrounded by a shaped wall, at least partly made of a porous material which is in contact with at least part of said reservoir and is insoluble in said surroundings and maintains its integrity during the administration period, characterized in that the pores in the porous material are impregnated with a hydrogel medium which is permeable to the passage of said chemical and to the aqueous liquid, gelled cellulose triacetate being used as the hydrogel medium. 2. Method according to claim 1, characterized in that a drug is added to the reservoir in mixture with a water-soluble drug carrier. 3. Method according to claim 1, characterized in that the drug is added to the reservoir in a mixture with a water-soluble, liquid drug carrier and a synthetic detergent. 4. Method according to claims 1 or 2, characterized in that the porous wall is made of a porous material selected from a first group consisting of sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride or sintered polystyrene; and a second group consisting of porous cloth of material selected from polyethylene, polypropylene, polytetrafluoroethylene, glass or modacryi polymers. 5. Method according to claim 1, characterized in that an anthelmintic agent is enclosed in the reservoir. 6. Method according to claim 1, characterized in that a water-soluble salt of levamisole, pyrantel or morantel is enclosed in the reservoir. 7. Method according to claim 4, characterized in that the porous wall is produced from sintered polypropylene or sintered polyethylene. 8. Method according to claim 6, characterized in that the tartrate is used as a water-soluble salt of morantel.