DK153917B - PROCEDURE FOR MANUFACTURING A DEVICE FOR REGULATED, CONTINUOUS ADMINISTRATION OF ACTIVE SUBSTANCES - Google Patents

Description

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The present invention relates to a method for preparing a device for long-lasting and physiologically effective controlled, continuous administration of active substances to aqueous, liquid-containing environments, e.g. for placement in the rumeno-reticular sack of a ruminant, wherein an active substance is enclosed in a reservoir surrounded by a shaped wall formed at least in part by a porous material which contacts at least one part 10 of the reservoir and is insoluble in said environment and retains its integrity during the administration time. The process is characterized in that the pores in the pores of the porous material are impregnated with a hydrogel medium which is permeable for passage of the active substance and for the aqueous liquid, using as a hydrogel medium, gelled cellulose triacetate.

Devices made according to the invention can be used in the body for animals and humans. In particular, such devices may comprise 20 large pills (so-called boli) for controlled administration to ruminants.

Administration systems for drugs and devices for controlled release of drugs (hereinafter referred to as drugs), ie. controlled release and prolonged or extended release are well known. The literature describes several different methods, 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 which is gradually disintegrated by the environment, e.g. body fluids so that the drug is released. Waxes, oils, fats and soluble polymers have served as carriers.

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It is also known to disperse the drug completely through a solid matrix material through which the drug is released by diffusion, or to enclose the drug in a capsule with a wall or walls of polymeric material through which the drug can pass through diffusion (U.S. Pat. No. 3,279,996).

U.S. Patent No. 3,975,350 discloses hydrogel support systems consisting of polyurethane polymers for use in medicinal, pesticide, insecticidal, and algicidal applications.

U.S. Patent No. 1,693,890 discloses the preparation of cellulose acetate porous membranes in the form of gelatinous material for use in dialysis. The process comprises precipitating the cellulose residue from a solution thereof in acetic acid by adding a non-solvent such as water. If desired, the membranes can be formed on a carrier. The membranes thus prepared are impregnated with water, but can be liberated from water by washing with alcohol, acetone or a 20 Hg water-miscible liquid condition.

Cellulose polymer and liquid composite materials (PLCs) in the form of films, fibers or microspheres, including cellulose esters such as cellulose acetate or cellulose nitrate, or molecular mixtures thereof, as carriers for the controlled release of various substances are disclosed in U.S. Patent No. 3,985,298. The substance to be released is impregnated in and within the cellulose-based PLC material as part or all of the liquid phase (alcohol 30 or water or mixtures thereof) contained in the micropores of the cellulose-based PLC material.

U.S. Patent No. 3,846,404 discloses semipermeable membranes of gelled cellulose triacetate which are useful as carriers for other materials such as 35 liquids having medicinal properties. The impregnation of finished, smooth, non-woven polyethylene textile material and plain cotton cloth with gelled cellulose triacetate to provide the support

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3 cellulose triacetate hydrogel materials are described. The use of drug-impregnated gelled cellulose triacetate products as slow release implants for animals is described, and likewise, the casting of gelled cellulose triacetate on a woven or non-woven foil carrier material is described.

Devices for controlled release of medicaments comprising a reservoir formed by a medicament 10 and a solid or liquid drug carrier and, in contact with or surrounding the reservoir, a wall formed of any of a variety of materials, including a microporous material whose micropores contain a diffusive medium (e.g., a liquid phase consisting of a solution, a colloid solution, a suspension, or a sol) permeable to drug passage by diffusion is disclosed in one or more of the following United States 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.

In U.S. Pat. No. 3,993,073, hydrophilic hydrogels of esters of acrylic acid and methacrylic acid and cross-linked polyvinyl alcohol have also been described as suitable wall forming materials. A feature of the devices 25 of these patents is the use of a wall which is at least partially comprised of a microporous material whose pores contain a drug release rate regulating medium which is permeable to drug passage and a reservoir comprising drug plus a carrier, which is permeable to drug passage, but at a rate greater than the permeability of the rate-regulating medium contained in the pores of the microporous wall. Devices suitable for the administration of therapeutic or nutritional substances to ruminants and in which the substance is contained in a permeable, water-insoluble material with capillary or interconnected pores extending through them and paper or cloth partially impregnated with water-insoluble poly 4

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more, e.g. cellulose acetate, is described in British Patent Specification No. 1,318,259.

U.S. Patent 3,594,469 discloses pellets containing magnesium and iron for administration to ruminants to supply ruminants with these metals over a prolonged period of time. In one embodiment, this pellet consists of a cylindrical tube of magnesium alloy filled with hail and some biologically active substance and closed at both ends with porous discs.

10 It should be noted that the term "organ" in the following is often used synonymously with the word "device".

Pra U.S. Patent No. 3,938,515 discloses means adapted for continuous administration of a drug for a prolonged period of time and comprising a reservoir containing the drug and a solid or liquid carrier permeable to the drug and a the reservoir surrounding polymer wall which is permeable to the drug but at a slower rate than the carrier.

U.S. Patent No. 3,946,734 discloses a diffusion cell which is primarily designed for use as an implant member, and which is essentially a capillary tube, one end of which is closed with an impervious material, and the remainder of the tube 25 and the other end thereof are closed with a porous neutral hydrogel. The biologically active substance is placed in the capillary tube against the impermeable material and the capillary tube is then filled with the hydrogel (agarose, polyacrylamide) through which the biologically active drug will diffuse.

Many of the known controlled release organs are described as zero-order release organs. However, these bodies are only capable of maintaining zero-order release rates for relatively short fractions of their intended lifespan and are not practical for long-term use, e.g.

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By contrast, with the device manufactured according to the invention, controlled, predictable zero order release rates are obtained and maintained for a given drug for prolonged periods of time. The known means, including those comprising a drug-containing reservoir surrounded by a shaped wall formed at least in part by a microporous material whose pores contain a drug release rate regulating medium (diffusive medium) which is permeable to medium. In addition, there is also a possibility of physical blockage or physical damage in certain application environments, such as the rumen reticular sac in ruminants. The clog even slows or stops the release of the drug, thereby rendering the organs inactive for the intended purpose. The device made according to the invention, wherein pores in the porous material in contact with the drug-containing reservoir contain a hydrogel, are substantially free of this problem and capable of providing controlled and predictable release rates of the drug to an environment containing an aqueous fluid, for extended periods of time.

When used for controlled release of highly water-soluble drugs, it is preferred for the known organs (of the U.S. Pat. Nos. 3,993,073, 3,993,072, 3,967,618, 3,948,262, 3,948,254, and 3,896 .819 described) that the wall and / or reservoir is formed of a material which is substantially impervious to water to prevent dilution of the drug in the reservoir by absorbing body fluids into the organ and decreasing the drug release rate. Therefore, they are not suitable for delivering water-soluble drugs, especially at relatively high rates. The bodies described in most of these patents further require that the drug permeability of the drug release rate regulating medium in the pores of the porous wall surrounding the reservoir is 6

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less than the permeability of the liquid carrier in the reservoir with respect to the drug. By this agent, the drug passage through the wall is the rate-controlling step. The device made according to the invention is completely free of such limitations.

Indeed, a significant difference between the device of the present invention and the known means lies in the presence of highly water-permeable hydrogel in the pores of the porous material in contact with the reservoir. The present device is dependent on the diffusion of water from an aqueous liquid containing environment into which the device is placed, through liquid filled pores or channels in the hydrogel and into the reservoir, and the outward diffusion of drug from the reservoir into the environment. Unexpectedly, the concentration of dissolved drug in the reservoir does not decrease, which restarts at a substantially 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 device.

The use of a low concentration of the anthelmintic morantel tartrate in the drinking water for calves, the calves having sustained access to the drug-containing water, as a means of endoparasite control, has been reported by Downing et al., Irish Vet.

J., 221, November 1974, and in British Patent Specification No. 1,530,161. Sustained daily administration of anthelmintic drug to calves from early April to mid-July was found to suppress the calf's delivery of worm eggs 30 and to prevent or at least reduce the development of severe larval infections on herbs and grasses.

Jones et al., Brit.Vet. J., 134, 166 (1978), found that by daily administration in low concentration in the feed of morantel tartrate to calves from the time when they were put on grass, until mid-July successfully fight parasitic gastroenteritis and pulmonary worm infections by reducing contamination

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7 the ring of the pasture available to the grazing calf.

The present invention provides improved devices which are permeable to active substances, including drugs, and adapted to release these substances at a physiologically or pharmacologically effective controlled rate from a reservoir containing the active substance to aqueous liquid containing environment, especially to surrounding body fluids 10 in animals or humans. The invention relates in particular to such devices comprising a container in which at least a portion of the wall or walls comprises a porous material, including a porous textile material whose pores contain a hydrogel, and devices in which said porous material is in contact with at least part of an active substance or reservoir containing an active substance. More particularly, the invention relates to boli which comprises said device for controlled release of drugs for ruminants, which is retained in the rumen reticular sac of the animals.

The present improved devices, which are permeable to active substances, including drugs (the terms are used interchangeably herein), are of value 25 for controlled release of drugs and other active substances into aqueous, liquid environments, and are of particular value for oral dosing in animals. and humans and can be used for several different medications.

Furthermore, the devices are particularly well suited for the delivery of highly water-soluble substances at high speeds, which is not easily achieved with the known devices. The devices in question allow for controlled release of active substances over a long period of time and are easy to manufacture and reliable and easy to use. In addition, the devices described herein preserve their physical and chemical integrity, do not become clogged in the application environment, and are particularly valuable for oral use in a bolus.

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shaped shape for ruminant animals. This provides, for the first time, a practical device for the controlled and continuous release of active substances, including drugs, for aqueous, liquid environments, and thus meets a long-standing need, especially in animal husbandry.

The disclosed controlled rate devices comprise a barrier or wall in contact with at least a portion of a reservoir containing an active substance, the wall consisting wholly or partially of a porous material including a porous textile material whose pores contain a hydrogel which is permeable for passage of liquid from the surrounding environment through pores within the hydrogel itself and for active substance from the reservoir by diffusion. When the present device is in use, the hydrogel contains fluid from the surrounding environment, which fluid is contained within areas or channels (pores) within the hydrogel itself, which serve as pathways for diffusion of fluid from the surrounding environment and drug transport.

The devices in question can take many different shapes and sizes depending on the purpose for which they are to be used. For example, they can be capsule-shaped for oral use in humans or 25 animals or cylindrical for implantation or for use as a bolus in ruminants.

Various convenient embodiments of the method according to the invention may be used as set forth in claims 2-8.

A device made in accordance with the invention wherein the reservoir is supplied with a drug, if desired in admixture with a water-soluble liquid drug carrier, and furthermore, if desired, a detergent, may be in the form of a bolus for use in controlled delivery of drug for ruminant animals, especially cattle and sheep, for a long period of time. Such boli are used in particular for parasitological, especially helminthic, control, prophylactic and therapeutic, gastrointestinal disorders.

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real infections and lung worm infections in cattle and sheep and by helminth contamination of pastures.

The term "bolus" as used herein includes means which are generally cylindrical, spherical, spheroidal, elliptical, or of other shape, free of sharp edges and projections.

The known means require consideration and compromise between several factors for each use, namely the carrier used in the reservoir, the solubility of the carrier 10 and / or permeability with respect to the drug contained in the reservoir, the nature of the reservoir surrounding microporous wall, the microporous wall. wall pores contained diffusive medium, the relative permeability rates of the diffusive medium and the carrier with respect to the drug, the relative solubilities of the drug in the diffusive medium and the carrier, and the need to maintain a substantially constant amount of dissolved drug in the drug. reservoir.

The device in question, on the other hand, is far simpler in design and operation. According to the device, the release rate of the active substance can be varied within wide limits by simply varying the area or thickness of the porous material in contact with the reservoir, including porous textile material whose pores are filled with hydrogel. Thus, manipulation of only two parameters allows control of the released amount of active substance.

FIG. 1-5 of the drawings show various exemplary embodiments of the present device. The fact that only a few examples are shown should not be construed as a limitation of the invention, since many variants and equivalent embodiments thereof are possible.

In FIG. 1, which shows a perspective cross-sectional view of a friend device as disclosed, a dispensing means 10 comprises a cylindrical wall 11 in contact with a reservoir 12 containing an active substance.

The wall 11 is formed of a porous material, if any

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pores 14 contain a hydrogel (not shown) through which liquid from a surrounding environment containing aqueous liquid diffuses into the reservoir 12, and active substance from the reservoir diffuses into the surrounding environment through channels or pores within the hydrogel. The reservoir 12 comprises an active substance 15 and, in accordance with a preferred embodiment of the invention, a medicament and a water-soluble carrier 16. End portions 17 are non-permeable caps or closures.

FIG. 2 schematically shows a dispensing means of the embodiment of FIG. 1 in which a perforated casing 18 of e.g. stainless steel, iron or plastic is inserted as a means to regulate the surface area 15 of the hydrogel impregnated porous wall 14 and, if metal, to increase the weight of the member.

FIG. 3 shows on a larger scale a porous wall 11 in a member 10, whose pores 14 contain a hydrogel 19, in contact with a reservoir 12 containing an active substance, comprising an active substance 15 and a water-soluble liquid excipient. 16th

FIG. 4 shows a dispensing means shaped like a capsule and having only one closure means 17.

FIG. 5 shows a further member 10 in which the porous material whose pores 14 contain a hydrogel (not shown) constitutes the end walls of the member 10.

The cylindrical wall 18 consists of a non-permeable, non-porous material, in the present case of stainless steel, which, in combination with the hydrogel 30 impregnated end walls 14, encloses a reservoir 12 comprising an active substance 15 and an auxiliary substance 16.

As illustrated above, the present improved dispensing devices have a reservoir containing an active substance, including a drug, and, in a preferred form, an active substance and a water-soluble liquid excipient. The water-soluble liquid excipient has several important functions, such as elimination of air from the reservoir, which allows greater

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In addition, the water-soluble liquid excipient 5 plays another role in that, as the active substance dissolves, it does not play a role in the preparation of the devices for increasing mixing by convection within the reservoir (which ensures constant release rate of the active substance). any visible volume change occurs when the active substance goes from the solid or crystalline state to the dissolved state.

Typical water-soluble liquid excipients may be mentioned monols and polyols and ethers thereof, such as ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and tripropylene glycol, 1,2-dimethoxyethane, mono-C β-alkyl ethers of ethylene and propylene glycol, N, N-15 dimethylformamide, dimethyl sulfoxide and the like. Of course, the excipients must be compatible with the hydrogel.

When the organs described herein are to be used for animals or humans, or in aqueous liquid environments used by animals, e.g. aquariums, fish ponds, 20 water supplies for animals and poultry and hydroponic systems, the water-soluble liquid excipient must of course be a physiologically acceptable substance.

The amount of water-soluble liquid excipient used per weight unit drug depends on the properties of the drug. Generally, sufficient adjuvant is used to enable the drug-adjuvant combination to form a compact mass, and this amount is readily determined by simple experiments. Detergents, up to 20% by weight based on the total weight of the reservoir (active substance, including drug, plus, if used, excipient and detergent), can be used in the reservoir to minimize any clogging of the organs when is applicable. Representative detergents may be inorganic or organic, including sodium and potassium hexametaphosphates and tripolyphosphates, sodium lauryl sulfate, sodium glyceryl monolauryl sulfate, dioctyl sodium sulfosuccinate, bis- (1-methylamyl)

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12 succinate, polyoxyethylene sorbitan monooleate and other fatty acid esters, as well as other known detergents.

The amount of detergent when used is not substantial and in any case it is kept to a minimum so as not to sacrifice the amount of active substance filled into the reservoir. The optimum amount is determined by the methods described below.

In the present specification of claims, the terms "reservoir", "reservoir containing active substance" and "reservoir containing drug" are used interchangeably. For convenience, since the preferred organs of the present invention are those used for controlled release of drugs, the term "drug-containing reservoir" is the preferred term.

The term "porous materials", "porous membranes" or "porous walls" includes porous textile materials. Representative types of such materials are described below. The porous materials used may be isotropic, i.e. with homogeneous pore structure throughout the cross-section of the material, or they may be anisotropic, i.e. with non-homogeneous pore structure. Of course, they must be insoluble and non-reactive to the surrounding environment and the contents of the reservoir.

Generally, porous materials having pore sizes of from ca. 1 micron to approx. 100 microns in the subject controlled release organs. Porous materials with pore structures are needed which include continuous pores, i.e. pores which effectively have an aperture on both surfaces of the associated porous wall. In order to facilitate the transfer of drug from the reservoir to the surrounding environment when the controlled release organs are used, the pores or part of the pores in the porous material are filled with a hydrogel. The overall result of the combination of the porous material, whose pores are filled to a greater or lesser extent with a hydrogel, is the provision of a means capable of withstanding

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13, clogging and physical destruction under normal conditions of use, and, because it retains its physical integrity, can be used in environments and situations where previously known hydrogel 5 organs would be damaged and ineffective for controlled release of drugs over prolonged periods of time. The organs described herein are of particular value for use in ruminants, especially in cattle and sheep. The hydrogel-containing pores allow passage of liquid (water) 10 through pores within the hydrogel even by diffusion from the environment in which the controlled-release organ is placed in use and into the reservoir for dissolving the drug. The drug then diffuses through liquid into pores of the hydrogel contained in the pores 15 of the porous material barrier at a rate which depends on the drug concentration in the solution in the reservoir and the resistance provided by the barrier, i.e. the liquid in the pores of the hydrogel and the effective surface area of the porous portion of the wall.

As the drug exits the organ, a depletion zone gradually develops, giving rise to a moving drug / solution limit. The diffusion of water into the organ from the surrounding environment through pores inside the hydrogel-containing pores in the wall and into the reservoir gives rise to convective mixing of the incoming aqueous phase with the solution in the reservoir in the organ. The driving force for this mixture is the difference in density between the two solutions caused by their large concentration differences. A function of the water-soluble liquid excipient is, as stated above, to help preserve this large density difference and thus increase this critical mixture. The convective mixture results in a constant drug concentration within the reservoir, which in turn provides for controlled release of the drug over a prolonged period of time, thus ensuring zero order release of drug as long as unresolved drug remains in the organ.

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As drug is removed from the reservoir and aqueous fluid from the surrounding environment diffuses into the reservoir, the amount of dissolved drug within the reservoir varies continuously throughout the life of the organ, i.e. throughout the prolonged drug release period. This drug release mechanism allows one to select any geometric shape of the organ, and the size and shape of the reservoir is not limited. This is in direct contrast to the 10 known US patents which rely on and are made to obtain a substantially constant amount of dissolved drug within the reservoir and diffusion of dissolved drug within in the reservoir for delivery of drug to the wall gene and therefore have serious product limitations in 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, pages 332, 20, 1969, as "a gel prepared by coagulation of a colloid while enclosing water. ". In the process of the present invention, as mentioned, gelled cellulose triacetate is used as hydrogel medium, see United States Patent Nos. 1,693,890 and 3,846,404.

Gelled cellulose triacetate provides a smooth and effective operation of the controlled release organs herein. The water present in the pores of the hydrogel can easily be replaced by water-soluble liquids, such as the water-soluble liquid excipients listed above. Other 30 water-soluble liquids can also be used to replace the water, including alcohols having 1-4 carbon atoms. As a practical measure to stabilize the aforementioned organs, the water in the hydrogel is replaced with a suitable water-soluble liquid having a lower vapor pressure than 35, so that the organs can be stored without loss in efficiency due to dehydration of the hydrogel. When using a combination of water-soluble liquid

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As an excipient and drug in the reservoir, it is convenient to use the same fluid to replace the water in the hydrogel.

The hydrogel itself is porous in the sense that it contains regions or regions, ie. channels or pores, filled with water or other liquid. In the present specification, reference is made to the diffusion or transport of active substances or drugs through walls, "whose pores contain a hydrogel," or similar terms are used, this means that the diffusion or transport of the active substance or drug occurs through these regions rather than through the hydrogel itself. The hydrogel itself has liquid-filled pores that serve as diffusion pathways, and it is actually considered permeable to passage of fluid from the surrounding environment and from active substance from the reservoir.

The porous wall in contact with the drug-containing reservoir may consist of any of several different materials. The porous material may completely surround the reservoir or it may constitute only a portion 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 made from thermoplastic resins by phase separation methods as described in Chem. Meadow. News, December 11, 1978, page 23, as well as other expertly known porous materials.

Suitable porous textile materials are of polypropylene and polyethylene, in particular those textile materials of each type commonly referred to as "filter cloth", and furthermore of glass, polytetrafluoroethylene, cotton, modacrylic fibers, ie. acrylic fibers consisting of a 35 long chain synthetic polymer containing 35-85% acrylonitrile units, acrylic fibers, i.e. synthetic polymers having a minimum of 85 wt.% acrylonitrile, polyesters, ie. a long chain synthetic polymer consisting of at least

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16 85% by weight of an ester of a divalent alcohol and terephthalic acid, polyvinyl acetate, polyvinyl chloride, polyivinyl acetate co-vinyl chloride), polyvinyl alcohol, poly (vinyl alcohol co-vinyl acetate), polyvinyl alkyl ether, polymer of vinylidene chloride, vinylidene and vinylidene fluoride, polyureas and other known materials [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]. Also suitable are metal mesh or filter cloth including those made from stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel copper, etc.

The particular textile material chosen must, of course, be compatible with the hydrogel with which it is to be impregnated and with the end-use conditions of the body. Thus, for a device to be used as a bolus 20 for administering a drug to ruminants over a prolonged period of time, cotton should not be used as a textile material as it will be degraded by the ruminant. In a device to be used for controlled release of an active substance into an aqueous environment, such as an aquarium or reservoir, cotton may be used.

Nylon cannot be used as a textile material when gelled cellulose triacetate is used as the hydrogel as it will be degraded by the formic acid or acetic acid used during the impregnation process.

The hydrogel impregnated porous textile materials must, of course, have sufficient strength, durability and inertness to the drug and the environment of application, so that the controlled release means 35 thus produced maintains its physical and chemical overall appearance throughout its lifetime.

The porous material is impregnated with a suitable hydrogel by the known methods. A fore-

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17, a relatively simple method of impregnating the porous material with gelled cellulose triacetate consists in forcing 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 contained in a container. which can be subjected to a vacuum. After impregnation, cellulose triacetate "filled" plastic coagulation is subjected to contact with and equilibration. with a large volume of water to form the hydrogel impregnated material. When the porous material is sintered polyethylene, acetic acid is preferred as a solvent for the cellulose triacetate rather than formic acid, as it wets the polyethylene better than formic acid and thus facilitates the preparation of the hydrogel impregnated porous material.

For the preparation of bodies that are stock resistant before use, the hydrogel-filled pores for water are equilibrated by an appropriate water-soluble liquid, such as the water-soluble liquid excipients listed above. As stated, it is convenient to replace the water in the hydrogel-filled pores of the porous wall material with the same water-soluble liquid used as an adjuvant in the reservoir when the reservoir comprises a combination of active substance and adjuvant.

If the active substance alone constitutes the reservoir of the organs herein, the choice of water-soluble liquid used to replace the water in the hydrogel of the hydrogel-filled pores of the porous wall is determined only by the end use of the organ, i. of whether a physiologically acceptable water-soluble liquid is necessary.

Such a liquid is conveniently placed in the hydrogel at the time of preparing the porous wall whose pores contain a hydrogel before filling the reservoir of the organ.

35 The known organs which are closely related to the organs in question, viz. US Patent Nos. 3,993,073 and 3,993,072, based on, 18

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a different degree of permeability of the drug through a medium contained in the pores of the porous wall relative to the degree of permeability of the drug in the drug carrier phase of the reservoir. In order to obtain the claimed zero order release rate for the organs described in said patents, it is essential that the medium in the walls of the organs has a lower permeability to the drug than the drug carrier within the reservoir has. Thus, the medium in the wall becomes the regulating part of the organ with respect to the drug release rate.

Dissolved drug diffuses through the more permeable carrier to the inner wall quickly enough for the wall to become the regulating part of the organ with respect to the drug release rate. This results in zero order release rates for some time until the receding drug limit in the organ becomes large enough to offset the difference in permeabilities between the carrier and the wall medium, and then zero order rates are no longer obtained. As a result, the successful practical use of these organs is limited and they are not suitable for zero-order delivery of large amounts of drug in practical and useful dosage forms.

In use, in contrast to the known means, the present means has an aqueous surrounding medium in both the wall medium and the reservoir. Although the permeability of the drug is the same in the fluid in the wall and the reservoir, zero order release rates are obtained for a large part of the total life of the organ. In addition, maintaining the zero-order release does not depend on diffusion in the reservoir carrier, and thus there are no geometric or dose limitations for these organs, and for the first time 35 large quantities of drugs can be delivered at zero-order rates in organ embodiments of a practical size and shape.

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For the most efficient operation of the disclosed controlled release systems and organs, it is important to reduce leakage and clogging that the porous material is impregnated with hydrogel as completely as possible. With organs of the same surface area, by varying the properties of the membrane wall, in particular its thickness, pore size and porosity, and by varying the size of the filling in the reservoir, different dosage rates and release times 10 for a given drug can be obtained.

As indicated above, a preferred form of the organ of the invention is a bolus for use in the controlled release of a drug for ruminant animals, mainly for cattle and sheep, for an extended period of time. This bolus is administered to the ruminant in such a way, preferably by oral administration, that it remains in the rumenreticular sac for a longer period of time during which it continuously releases the drug to the animal at a controlled release rate. Said organs thus enable the control (prophylactic and therapeutic) of various pharmacological and physiological conditions to which the animals are exposed, by simple oral administration of said organs to the animals.

In order for the bolus to remain in the rumen reticular sac of cattle, once inserted therein, for a prolonged period of time, it is necessary that the bolus has a density of at least 2.0 g / ml. In practice, the density can range from as low as 2.0 to as high as 7 30 or even greater. Density is, of course, the most significant factor affecting the retention of the bolus in the rumeno-reticular sac. The total size of the bolus is a function of the required dose to be given and the size that can be administered in 3 ^ practice. Based on this, once the desired size is determined, additional weight can be added to achieve the desired average density. Whose

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Where possible, it is desirable to use the maximum allowable size, as larger bolts of a given density are retained better than those of lower density. When the average density of bolus 5 is increased to a value greater than ca. However, an increase in the size of the bolus will not significantly improve the retention factor. The preferred range for the average density of the bolus is from approx. 2.5 to approx. 5 g / ml.

10 The size of the bolus obviously depends on the animal to be treated with it. For ruminants, such as sheep and goats, the size and weight of the bolus will be smaller than that required for cattle. The maximum bolus size for use in any animal is determined by the practical difficulties in administering such an object to the animal.

For administration to sheep, the minimum weight of a bolus with a density of 4 which will be withheld is approx. The size of a bolus will vary 20 depending on the density of the bolus. For administration to cattle, the smallest weight of a bolus with an average density of 4 is approx. As indicated above, the upper size limits are again determined by what is convenient in practice for dosing the animal concerned and by the minimum average density of the bolus. Eg. will a bolus of approx. 7.5 cm in length and 2.5 cm in diameter and with a density of 2.2 have a weight of the order of approx. 90 g.

The density of boli comprising only the elements listed above is generally below the lower level indicated above. Therefore, it becomes necessary to increase the average density of the bolus by incorporating a suitable high density material such as a metal (iron powder, iron hail, steel-33 shotgun) or other density enhancing agents, or minerals such as CaSO 2, to increase the density to the desired value. Alternatively, it can average- 21

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equal density is conveniently increased by incorporating in the bolus as an inner sheath a perforated material of high density, e.g. a metal (such as stainless steel, steel, especially low carbon steel, or iron), which in turn is surrounded by the hydrogel impregnated porous membrane. The perforations in the sheath must be sufficiently large to allow free passage of the drug, and of fluid from the surrounding environment, through the hydrogel impregnated porous membrane. The main effects of such a casing are to increase the mean density of the bolus to such a value that the bolus 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. Such a casing, although not necessary, further improves the physical stability of the bolus, ensuring that its physical form is substantially preserved under the conditions of use. A further and preferred alternative 20 consists of a bolus comprising a metal cylinder such as a steel or iron cylinder having one or both ends covered by a porous membrane whose pores are impregnated with a hydrogel. Boli of this type is preferred because of their simple and economical preparation 25 and the ease with which their density can be adjusted.

A low carbon steel is highly preferred as a construction material for the cylinder. Other alternatives will be obvious to the expert.

The disclosed controlled release organs 30 can be used for a variety of purposes and situations where controlled release of a drug or other active substance is desirable. They can be used for the administration of medications and for the supply of active substances at sites located near or far from the point of application of the organ. They may, by appropriate means, be placed at appropriate locations within the animal body where they are in contact with the body.

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22 liquids, e.g. in the stomach of domestic animals, especially in the rumeno-reticular sac of ruminants. The disclosed controlled organs also include those for use as depot implantation agents for the purpose of administering a drug at a controlled rate to a host individual. The implants differ only from the implants in question for other purposes in their shape, which is of course adapted for implantation. Other uses include sublingual or buccal tablets, pessaries, suppositories, bandages, and skin patches. Still other uses of the said controlled release systems and organs are in agriculture for the administration of fertilizers and pesticides, in fish breeding, including in aquariums and fish ponds, in drainage ditches, channels and tanks such as for the control of algae, and in water supplies, especially for animals and poultry in need of medications for therapeutic and prophylactic treatment.

The criterion for suitable active substances, including 20 drugs, for use in the disclosed organs is that they are sufficiently soluble in water to achieve a release rate of said drug or other active substance for the application environment which will produce the desired result. For this reason, drugs 25 and active substances which are acids or bases are suitably used in the form of their physiologically or pharmacologically acceptable salts. The release rate of the drug or active substance from the organs described herein depends on several factors such as the thickness of the wall, available surface area, effective pore diameter, porosity of the wall, the nature of the hydrogel, the concentration of the substance in the reservoir and the solubility thereof in the surrounding liquid. The suitability of a given substance is determined as described below.

Representative examples of the drugs which may be used in the organs described herein are the following: anthelmintics, including salts of morantel, pyrantel, oxanthel, piperazine, diethylcarbamazine, levamisole, tetrahydrocarbon.

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23 misol and hygromycin B, antibacterial agents including salts of tetracyclines such as 5-oxytetracycline, chloro-tetracycline, doxycycline and Mannich bases thereof, penicillins such as ampicillin and penicillin G, aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin as its zinc or methylenedisalicylic acid derivative, macrolides such as erythromycin, oleandomycin and tylosin, antibacterial growth promoters such as salts of avoparcin, polymyxin, lincomycin, bambermycin and efrotomycin, nutrients such as soluble salts of magnesium, selenium and copper, and vitamins such as thiamine hydrochloride, sulfamide drugs such as sulfamethazine, molluscicides such as N-trityl morphine, and antipyretic agents such as alcohol ethoxylates and poly (oxyethylene) poly (oxypropylene) -poly (oxyethylene) polymers, e.g. poloxalene.

As indicated above, in a preferred embodiment of the invention, the drug-containing reservoir comprises a medicament and a water-soluble carrier. The means so constructed have the advantage of providing a greater amount of drug per day. organ, and that they extend the useful life of the organ. However, the reservoir can contain only the drug of choice.

The organs in question are particularly valuable as long-acting drugs for the control (therapeutic and prophylactic) of helminth infections in ruminants, especially cattle. Protecting animals on pastures is relatively convenient. In temperate climates, the low population in early spring of grazing larvae, scm is the remainder of the previous season's contamination, multiplied by circulation through animals grazing on these pastures, to produce a steep rise 35 in the summer in pasture infectivity. During the summer grazing season, this condition gives rise to clinical parasitism and lowering of performance in animals grazing on these pastures.

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24

The continuous and controlled release of anthelmintic agent, e.g. morantel, in the rumeno-reticular sack of grazing animals early in the season, when contamination of pastures is low, suppresses 5 helminth herd production and then larval production, thus breaking the aforementioned circuit and keeping worm propagation on the pastures and animals at a low level. Thus, parasitic infections in ruminants grazing on the same pastures during the summer season 10 are reduced to a minimum. This helminth control method is particularly attractive and valuable to calves as they are highly susceptible to helminths once applied to grass. Completed use of boli reduces the inventory of infectious helminth forms at a given site. The use of anthelmintic containing boli produced by the method of the invention in this way prevents, or at least minimizes, the seasonal increase in the number of larvae on the pastures causing parasitic gastroenteritis and the lowering of performance in grazing animals later in the season.

In this mode of control, the time of drug release is the time of the spring multiplication phase and not the time of severe contamination of the pastures, larval and worm infestations causing 25 clinical disease and benefit lowering. It is for this reason that this approach is called "indirect control".

Put another way, grazing in ruminants having in their rumeno-reticular sacs one or more of the organs described herein will allow for regulated and continuous release of anthelmintic agent, e.g. morantel, for said sack, on pastures early in the season, viz. when larval contamination is at or near a minimal level, allow the usual seasonal increase of larval contamination 35 of pastures to be minimized and serve to protect animals grazing on these pastures throughout the grazing season.

25

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For "indirect control" of helminths, the subject organs, preferably in the form of a bolus, are administered to ruminants at a time during the epidemiological cycle of said helminths, where the contamination of the pasture with said helminther, their eggs and / or larval stages is at or near a minimal level. In temperate zones, this time corresponds to the spring exposure, ie. the first placement (put on grass) of the calves on the pastures. For maximum effect, the bolus is administered to the calves 2-7 days before being put on grass. In non-temperate zones of the world, e.g. semitropical and tropical areas, the period with the lowest infectivity of the pastures usually occurs before the rainy season. The administration of the ruminant to ruminants in such areas is conveniently performed within 2-14 days before the start of the rainy season. However, because of the unpredictability of the rainy season, helminth combat in the non-temperate zones is best accomplished by the 20 "direct combat" approach.

The boli described herein also eliminates helminth infections from ruminants and prevents worm infections during the summer season with severe attacks. This method is called "direct combat". The direct control method only protects the ruminants during the anthelminthic release period. The indirect method of full-mint control protects ruminants grazing on a given pasture throughout the season as it results in a total significant reduction in pasture contamination. As noted, the organs described herein provide continuous, controlled rate release of drugs, including anthelmintics. Particularly useful for such purposes are water-soluble salts of (E) -1,4,5,6-tetrahydro-1- methyl-2- [2- (3-methyl-2-thienyl) ethenyl] pyrimidine (morantel), (E) - 1,4,5,6-tetrahydro-1-methyl-2- [2- (2-thienyl) ethenyl] pyrimidine (pyrantel) and (i) -2,3,5,6-tetrahydro-6 phenyl-imidazo [2, lb] thiazole

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26 (tetramisole) and levamisole, the L - (-) form thereof. Representative examples of preferred water-thawing salts of pyrantel and morantel are the tartrate and citrate, and of tetramisole and levamisole, the hydrochloride.

The boli in question are administered orally to animals by e.g. a bullet gun. For use in calves, the desirable average release rate of morantel (calculated as base) for indirect control of helminths is of the order of 60-200 mg 10 (of morantel base). day for a period of approx. 60 days, covering the normal maximum survival time of the spring population of larvae. Longer release times of 60-120 days are desirable in the direct control mode of application, as the period of exposure to severe grazing contamination usually extends from midsummer and through the fall. Release rates of 60-150 mg (calculated as morantel base) per Today provides effective control of helminth infections over such release periods. For dosing of larger 2q animals, more than 1 bolus can be administered. For indirect control of helminths using pyrantel or levamisole salts, the desirable average release rates for each (calculated as free base) are of the order of 100-25 400 mg and 100-500 mg, respectively. day for approx. a 60-day period.

For direct control, release rates of 100-300 mg (as free base) of pyrantel and of 100-400 mg (as free base) of levamisole per day an effective fight against helminth infections over the period of 30 to 60-120 days with the most severe attacks.

Continuous low-concentration administration of morantel using the helminth control means 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. Eg. is the maintenance of a prolonged concentration of morantel tartrate or citrate

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27 (or other salt) in the gastrointestinal tract of ruminants effective in preventing lungworm infections in said animals during the drug release period. Furthermore, while cattle or sheep grazing on contaminated pastures 5 are subjected to immediate reinfection of intestinal nematodes after conventional therapeutic dosing, animals receiving the bolus are also essentially freed of an emergent infection and protected from reinfection over a period of 60 years. days or long-10 re.

The use of the bolus for controlling pasture contamination, ie. the indirect control method is a unique, practical and novel method of helminth control which protects ruminants and especially grazing ruminants treated in this way throughout the grazing season and provides benefits that are superior to the known ones. control methods. The increase in daily weight gain over untreated control animals over pasture season 20 is substantially greater than that achieved after conventional therapy.

The release rate of drug or other active substance passing from the drug-containing reservoir through the walls of the subject controlled release organs and the effectiveness of a given combination of drug and / or water-soluble excipient and / or detergent in said organs can be readily determined by the experts, e.g. by transfer methods or by sorption-desorption methods. One method that can be conveniently used to select suitable porous materials and hydrogels is to use the selected porous material whose pores are filled with the selected hydrogel as a barrier between a rapidly stirred saturated solution of a drug or another 35 chemical substance to be used for controlled release and a rapidly stirred solvent bath whose composition simulates the aqueous liquid containing environment in which the controlled release organ is to be

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28 is used. The temperature of each solution is kept at a constant value, preferably at a value that is approximately the average temperature in the environment in which said member is to be used. Samples are taken at 5 predetermined intervals from the solvent bath and analyzed for drug concentration. The permeability of a drug or other chemical substance through the porous material whose pores are filled with hydrogel can also be determined by standard methods as described in Encyclopedia, of Polymer Science and Technology, Vol. 5 and 9, respectively, pages 65 to 82 and 794-807, 1968, and references therein, and in the Chemical Engineers Handbook, pages 17-45, 1963, published by McGraw-Hill,

Inc.

A method of particular value for determining the release rate of organs prepared by the method of the invention and the relative advantages of a given adjuvant or detergent for use in a given organ, especially when the drug is morantel, are summarized as follows. The method, which is an in vitro method, is based on the release of a water-soluble salt of morantel, e.g. the tartrate, from a device made in accordance with the present invention as a function of time.

A morantel tartrate containing means according to the invention is placed in a 1 liter conical flask which is protected from light by light sensitivity of morantel tartrate, 500 ml pH 7 phosphate buffer is added and the temperature of the flask and its contents is adjusted to and maintained at 37 ° C. The body containing the flask is shaken with approx. 70 fluctuations (7.62 cm) per 5 ml samples are taken at intervals. The volume of the sample taken is replaced by an equal volume of fresh pH 7 phosphate buffer and the shaking of the flask is continued. The concentration of morantelle in the samples is determined spectrophotometrically by measuring the absorbance of the sample at 318 nm determined against fresh phosphate buffer of pH 7. Sampling is repeated until

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29, 5 g of morantel tartrate were released, at which time the organ was transferred to another flask containing 500 ml of fresh pH 7 phosphate buffer and the process was continued as; before.

The in vivo release of morantel tartrate from organs readily prepared by the method of the invention is determined by administering the organs to e.g. normal mumps or mumps with rumen fistula, and after a certain period of time, such as 30, 60, 90 or 120 days, remove the organs through fistula 10 or euthanize the animals and withdraw the organs again to determine the remaining amount of morantel tartrate in the organ. Tests of this type have shown that the in vitro rate of morantel tartrate release is approximately 4 times that of the in vivo release rate.

The invention is further illustrated by the following examples.

Example 1 20 A bolus comprising sintered polyethylene, whose pores are filled with gelled cellulose triacetate, and a reservoir containing morantel tartrate mixed with polyethylene glycol 400 and sodium hexamethaphosphate, and with a perforated stainless steel sheath were prepared as follows.

One end (designated as end 1) of a sintered polyethylene tube having an average pore size of 10 microns, an outside diameter of 25.4 mm, an inside diameter of 22.2 mm, and a length of 7.9 cm 30 pedes 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 of the tube (referred to as end 2) dipped in the cellulose acetate butyrate solution to a depth of 9.5 mm and dried. This step was repeated. The end 1 was again dipped in the cellulose acetate butyrate solution for 30 seconds and allowed to dry in air for 60 seconds. and inserted a cellulose acetate butyrate disk of 30

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22.2 mm in diameter at the end of the tube so that it flared with said end. The cellulose acetate butyrate disk was allowed to float, on methylene chloride for 60 seconds, before inserting it into the end of the tube 1. The tube was then rolled 5 along the bench, applying finger pressure to the end thereof containing the disk to ensure complete bonding of the washer and tube. A one-hole No. 3 rubber stopper provided with a glass tube of sufficient length to protrude through a one-hole rubber stopper in a vacuum flask 10 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 mmHg. When the cellulose triacetate solution covered the outer walls of the tube which had not been dipped in cellulose acetate butyrate, the tube was removed from the vacuum flask and the bulk of the cellulose triacetate was dried. The tube was then inverted to drain the cellulose triacetate from the tube interior. The outer and inner open ends of the tube 20 were wiped clean with a cloth.

The tube was then immersed in and allowed to equilibrate in distilled water overnight. It was then removed from the water and dried externally with a cloth, and excess water was shaken from the interior of the tube.

The steps were repeated to impregnate the pores of the tube with cellulose triacetate and equilibrate it in distilled water. It was then equilibrated in running water for 4 hours.

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

The tube was then equilibrated in polyethylene-glycol 400 overnight and removed from this polyethylene glycol 400 and allowed to run in reverse for 4 hours. Excess polyethylene glycol 400 was

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31 wiped from the exterior of the tube with a cloth and inserted into the tube a perforated stainless steel tube of 22.2 mm in outside diameter, 18.9 mm in internal diameter, 7.0 cm in length and 16 at a regular distance from each other 5 placed circular holes (7.1 mm in diameter) until it aligned with the sealed end. The cellulose triacetate chips obtained by inserting the tight fitting casing into the tube were removed. A cellulose acetate butyrate disk (3.2 mm) was then inserted into the open end of the tube "in alignment with the stainless steel casing, and the tube was trimmed so that its end flush with the disk. The disk was removed and the tube filled with a homogeneous mixture of 63.31% morantel tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexamethaphosphate for flushing with the end of the stainless steel casing.

At the open end of the tube was filled a 10% cellulose acetate butyrate solution, which was then immediately poured off again, and the open end of the tube was dipped into the cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. A slice of cellulose acetate butyrate (which was allowed to float on methylene chloride for 60 seconds immediately prior to use) was then forced into the open end of the tube, using sufficient pressure to force the slice against the stainless steel sheath.

The tube was then rolled along the bench top, using sufficient finger pressure to ensure complete bonding between the washer and tube. The tube was then allowed to dry for 1 hour, after which each end of the tube was dipped in 10% cellulose acetate butyrate to a depth of 6.35 mm and allowed to dry. The weight of the bolus was approx. 90 g, of which 24.8 g was drug mixture. Its density was 2.2 g / ml. This organ released approx. 250 mg per day of morantel tartrate in vivo in cattle for approx.

60 days.

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32

Example 2 3 Organs prepared according to Example 1 and tested in vitro by the method described herein gave 5 an approximately constant release rate for a period of 4-17 days, with an average release rate for all 3 bolis of 0.927 g of morantel tartrate per day. day.

Accumulated g morantel tartrate 10 Days in vitro Bolus 1 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 15 6 2.61 2.96 2.4 8 '4.05 6.31 3.7 11 6.55 9.0 5.76 13 8.24 11.34 7.67 15 11.38 13.4 9.74 20 19 14 , 52 16.2 13.2 25 17.99 17.4 15.4 29 17.13 17.3 15.9

In vivo samples of 3 other bolis prepared according to Example 1 and placed in the rumen reticular sac in cattle showed a release rate of 0.224 g of morantel tartrate per ml. per day, when they were withdrawn after 30 days. This gives an in vitro / in vivo ratio of 4: 1.

30

Example 3

In vitro samples of 2 other boli prepared according to Example 1 and tested as described herein gave an average release rate over a period of 35 hours.

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33 constant rate of 0-14 days of 0.96 g of morantel tartrate per day. day.

Accumulated g morantel tartrate Days in vitro Bolus 4 Bolus 5 5 1 0.51 0.59 2 1.5 2.16 3 2.4 2.2 5 4.9 5.4 6 5.1 5.9 10 7 6.5 6.1 10 9.7 9.7 12 11.0 11.7 14 13.5 12.6 17 14.8 13.6 15 19 16.4 14.6 21 17.1 14.7 24 16.8 14.7 26 16.9 14.8

In-vivo samples with exactly the same boli placed in the rumeno-reticular sac of bovine animals for a period of 30-60 days yielded the following results:

Days Average g & rantel

Bolus No. in vivo tartrate per day_ 6 30 0.222 25 7 30 0.228 8 45 0.238 9 45 0.335 10 49 0.174 11 60 0.198 30 12 60 0.178

The total average in vivo rate is 0.224 g / ml. per day, and the in vitro / in vivo ratio is approx.

4: 1.

Example 4 35 Boli were made from stainless steel pipes with

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34 the following dimensions: 22.2 mm outside diameter, 21.3 mm inside diameter (wall thickness = 0.9 mm) and 3 cm long. The ends of the tubes were threaded (0.5 mm at each end) to receive a collar which serves to hold a hydrogel impregnated porous textile sheet. The washers (22.2 mm outside diameter and 3.2 mm thick), polypropylene filter cloth with an average pore size of 50 microns and impregnated. with gelled cellulose triacetate, 10 was prepared by immersing them in a 6% solution of cellulose triacetate in formic acid contained in a container which could be subjected to a vacuum of 25 mmHg or less. The flask and its contents were kept under vacuum for approx. 10 min, and the slices were removed and dried to excess cellulose triacetate solution. They were then immersed in and allowed to equilibrate in distilled water overnight. The slices were then removed from the water, dried with a cloth and then equilibrated with polyethylene glycol 400 overnight. The slices were removed and wiped with a cloth.

Impregnated washers were mounted on one end of each of the tubes by pressing them in between two packing washers, 0.25 mm thick and of the same diameter as the steel tube. The packing disk adjacent to the steel tube was 25 of cellulose acetate butyrate and the other of dental "dam gum" rubber. The ends were then closed with stainless steel sheaths with an opening of 21.3 mm in diameter.

The tubes were then filled with morantel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexamethaphosphate 30 (10.1%), and the other end of each tube was sealed as described above.

The resulting boli contained 21.4 g of morantel tartrate, weighed 97 g and had an average density of 3.30 g / ml.

These boluses were administered to the rumen fistula using a bullet gun and removed through the fistula at 30, 45, 60, 75 and 90 day intervals to determine the residual bolus.

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35 amount of drug from which to calculate the average daily release rate of morantel-tar-trat.

Bolus Days in stud Release rate 5 ......... (xtig / day ·) .........

1 30 67 2 30 108 3 45 82 4 45 58 10 5 60 136 6 60 91 7 75 71 8 75 68 9 90 67 15 10 90 106

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

At each stud, a significant decrease in fscale parasitic count was observed.

Example 5

Four boli comprising sintered polyethylene (average pore size 10 μ), whose pores are filled with gelled cellulose triacetate, and with stainless steel casings within only a portion of the total Length of bolus 25 (leaving a casing free bolus segment) and reservoirs containing morantel citrate (63.3%) mixed with polyethylene glycol 400 (26.6%) and sodium hexamethaphosphate (10.1%) was prepared by the procedure of Example 1. Instead of the perforated stainless steel casing used there, however, unperforated casings were used. of 5.1 cm, 4.4 cm, 3.2 cm and 1.9 cm respectively. The walls of the casing were 0.165 cm thick.

Drug mixture was then loaded into each bolus to provide a drug bandwidth of 6.35, 12.7, 25.4 and 38.1 mm, respectively, over the casings. A stainless steel plug, 12.7 mm thick and 22.2 mm in diameter, was inserted into each bolus over the drug mixture. The \ 36

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ends of the bolies which carried the steel plugs / were trimmed to allow insertion of a cellulose acetate butyrate disk on top of the plugs and flush with the ends of the bolies. The total weight of each boli 5 was 120.0, 115.4, 106.2 and 97.0 g, respectively. The weight of drug mixtures ranges from approx. 25.5 g to 27.4 g per bolus. The bulk densities of the bolies were 3.1, 2.98, 2.75 and 2.51 g / ml, respectively.

Example 6 10 In vitro samples for the release rate of morantel citrate from the bolies of Example 5 showed that each of them provided a constant drug release over a period of 3-21 days. The lightest of the four boli of Example 5 (the one with a 1.9 cm sheath) had an average release rate of 774.8 mg of morantel citrate per day. day over the 3-21 day period of constant release.

Example 7 14 Boli prepared according to Example 1, when 20 were tested in vivo in cattle, showed an average release rate of morantel tartrate of 238 mg per day. per day over a period of 60 days. The standard deviation was 67 mg (28%).

Example 8

The procedure of Example 1 is repeated, however, using sintered polyethylene tubes that are half the length and half the diameter of the ones used in Example 1. The obtained boli are designed for use 35

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37 and provides controlled release of anthelmintic over a longer period of time in vivo.

Example 9

The procedures of Examples 1 and 5 are repeated, however, the following microporous materials are used instead of sintered polyethylene: porous ceramics, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene (average pore size for each material 10). is 100 microns).

Each of the boli thus produced provides controlled release of active substance over a prolonged period of time when tested in vitro.

Example 10 15 Boli are made from stainless steel pipes with the following dimensions: 22.2 mm outside diameter, 21.3 mm inside diameter (wall thickness = 0.9 mm) and length 7.62 cm. The ends of the tubes are threaded (0.5 mm at each end) to receive a collar which serves to hold a porous hydrogel impregnated disc in place. The discs (22.2 mm outside diameter and 3.2 mm thick), sintered polyethylene impregnated with gelled cellulose triacetate, are prepared by immersing them in a 6% solution of cellulose triacetate in acetic acid 25 contained in a vacuum-capable container of 25 mm Hg or less. The flask and its contents are kept under vacuum for approx. 10 minutes and the slices are removed and dried free of excess cellulose triacetate solution.

They are then immersed in and allowed to equilibrate 30 in distilled water overnight. The slices are then stripped from the water, dried with a cloth and then equilibrated with polyethylene glycol 400 overnight. The slices are removed and wiped with a cloth.

Impregnated washers are mounted at one end of each of the tubes by pressing them in between two packing washers, 0.25 mm thick and of the same diameter as steel.

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38 tube. The packing disc adjacent to the steel pipe is made of cellulose acetate butyrate and the other is of dental "dam gum" rubber. The ends are then closed with stainless steel collars with an opening of 21.3 mm in diameter. The tubes 5 are then filled with the desired active substances and the other end of each tube is sealed as described above.

Thus, tubes (boli) with the following active substances are prepared in the reservoir: morantel citrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate 10 (10.1%); oxytetracycline hydrochloride (100%); pyrantel citrate (88%), glycerol (12%); pyranthel tartrate (63.3%), polyethylene glycol 400 (26.6%), sodium lauryl sulfate (10.1%); tetramisole hydrochloride (100%); poloxalene (100%); erythromycin hydrochloride (100%); thiamine-hy-hydrochloride (100%).

Example 11

The procedure of Example 1 was repeated with the difference that the bolus was filled with morantel tartrate instead of the mixture of morantel tartrate, polyethylene glycol 400 and sodium hexametaphosphate according to the above example. The bolus weighed 84.0 g, of which 18.6 g was morantel tartrate.

The bolus, when tested in vitro by the method described herein, gave a controlled and nearly 25 constant release rate of morantel tartrate during the trial period of 8-20 days, with an average release rate of 1.36 g / ml. day.

Days. in vitro Accumulated gmorantel tartrate 1.7 0.04 5.7 1.03 8.7 2.74 12.7 7.63 15.7 12.3 35 19.7 17.5 23.7 18.3 26.7 18.6

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39

Example 12

A low carbon steel pipe having the following dimensions: length 8.77 cm, inner diameter 2.16 cm, outside diameter 2.54 cm, and with a groove 0.3 5 cm deep and 0.6 cm wide placed 0 1 cm from each end thereof to receive an aluminum clamp, which extends all the way around the tube, is sealed at one end with a disc of ultra high molecular weight sintered polyethylene (average = 2 million to 4 million, 10 available from Glasrock , Porex Division, Fairburn, GA.), Average pore size 10 microns, impregnated with gelled cellulose triacetate as described in Example 10.

The disc that was. 2.54 cm in diameter and 0.16 cm thick, sealed to the tube with an aluminum clamp. The tube was then inverted and filled with a homogeneous mixture comprising 54.4% moranthel tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The washer / clamp sealing process was repeated to provide the finished bolus. The total weight of the bolus was 145.1 g, of which 41.4 g was drug mixture. Its density was 2.8 g / ml.

The aluminum clamps at each end of the tube had a 2 open center area of 3.25 cm, giving a total available area of 6.5 cm for drug delivery.

The bolus provides controlled release of morantel tartrate to cattle over a period of approx. 90 days.

Example 13

An aluminum cylinder 6 cm long with an outside diameter of 2.1 cm and a wall thickness of 0.1 cm, 30 and provided with an open end groove for receiving an aluminum clamp closure was filled with a composition comprising 70 % levamisole hydrochloride and 30% polyethylene glycol 400 and sealed with a high density sintered polyethylene disc (0.95-0.97 g / ml) impregnated with gelled cellulose triacetate in the procedure of Example 10 · The bolus had a density of 2.8 g / ml. The reservoir contained 23.46 g of I (

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The drug mixture is equivalent to 16.42 g of levamisole hydrochloride.

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

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

Days In Vitro Levamisole Hydrochloride 10 Release 3 0.815 5 1,572 6 1,805 7 2.33 15 8 2.64 10 2.79 11 2.83 14 2.87 15 4.66 20 18 5.10 22 6.67

Example 14

This example describes a field trial conducted with 40 uniform calves of uniform breed, weight 25 (mean = 150 kg) and genders that had not previously grazed. The calves are divided into four groups of 10 each based on body weight. Two of the groups were dual groups who had been given medication and two were double control groups. A worm-free spore calf was added to 30 each of the four groups of experimental calves at the start of the field trial and every four weeks thereafter. Each track calf was kept in its enclosure for two weeks, after which it was removed and housed for three weeks before being slaughtered for counting the worm count.

35 The experimental calves and the track calves were put on grass on an infected pasture, after which infected cattle had grazed the previous summer and autumn. The pasture was off

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41 a sufficient size to hold 44 animals with sufficient fodder throughout the grazing season, and it is divided into four equally sized and separate enclosures.

The two drug groups receiving double 5 were orally administered a 60 day bolus prepared according to the procedure of Example 1. The bolies provided a continuous release of 250 mg / animal morantel tartrate (equivalent to 150 mg morantel base) per day. day for 60 days. The two drug groups that received medication received the bolies 10 orally two days before being put on grass in the spring. The presence of the bolus in each drug given animal was confirmed with a metal detector 24 hours after administration. Bolus retention was then checked every two weeks. All the 15 animals that had been given medication and all the control and tracking animals were weighed before being put on grass and at 4 week intervals.

The samples of herbs and grass were collected following the procedure described by Taylor (Parasito-20 logy, 1/473, 1939) at two-week intervals beginning four weeks before the start of the field trial and continuing until the end of the experiment.

Faeces samples for McMaster egg count and lungworm larvae were collected at the beginning of the experiment and at two week intervals thereafter. For the first 8 weeks, these samples were rectal samples (one from each animal). Then rectal samples were collected every four weeks to coincide with the weighing of the animals. At intervals, samples, ten for each 30 group, were collected from the pasture (Gibson, Veterinary Bulletin No.

7, 403-410, 1965).

Counting the total number of worms was performed on the caloon, including mucosa, small intestine and lungs of slaughtered animals.

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42

Group ........ Treatment_Fence Number of animals 1 Morantel tartrate A 10 and one tracer 250 mg / day every four weeks 2 Morantel tartrate B 10 and one tracer 5 260 mg / day every four weeks 3 Control C 10 and one track animal every four weeks 4 Check D 10 and one track animal every four weeks

The data is graphically depicted in FIG. 6, 7 and 8.

FIG. Figure 6 shows the weight gain during the grazing season for both drug-treated and control groups.

Both groups were found to gain weight at almost the same net rate for approx. the first 3 months. After this time, the weight gain in the control groups 15 decreased, and the weight was even diminished for a period of time, coinciding with the increase in the number of parasites on the pasture. The drug-treated animals, on the other hand, continued their growth with a weight gain almost equal to that observed early in the season.

FIG. 7 and 8 show the parasite population throughout the grazing season for drug-treated and control animals. The number of eggs per g faeces (right ordinate) and number of larvae per kg of dry pasture grass (left ordinate) is deposited. The calves were put on grass in mid-May, 25 with the drug-treated calves given the 60-day boli administered orally two days before being put on grass, giving them treatment until mid-July.

At the time the animals were put on grass, the number of eggs in faeces and the number of larvae on the 30 pasture was low. In the control group, fig. 7, the eggs began to appear in the faeces of the animals only in June, reaching a peak at the end of July and slowly decreasing in numbers through August and September. These eggs led to the increase in the number of larvae on the pasture, which was ob-35 served in late July, which reached its maximum in August.

In the drug-treated groups, fig. 8, egg production decreased dramatically in June and July,

DK 153917 B

43, which was reflected in the significant decrease in the number of larvae in the pasture in July and September.

Example 15 5 Similar field tests were performed following the pattern of Example 14, however, using only one drug-treated group and one control group in each trial. The relevant data are given in the table below:

Experiment Number of animals Through- Cumulative% Prod. group average number of eggs min- weight loss- Treated control increase

Advantage for treated versus _ control_ 15 1 12 17.0 kg 0 79 100 2 13 9.0 33 146 '77 3 12 32.5 67 408 84 4 11 9.5 145 436 87 5 17 18.2 135 886 85 20 6 18 13.4 23 62 63 7 24 17.1 34 150 77 8 31 36.5 14 28 50

Example 16

The procedure of Example 4 is repeated, however, instead of polypropylene filter cloth impregnated with gelled cellulose triacetate, the following porous textile gelled cellulose triacetate was used:

Porous textile material Average pore size __ size _ 30 polyethylene 75 μ polytetrafluoroethylene 100 μ glass 60 μ stainless steel filter cloth 80 μ copper mesh 30 μ 33 modacrylic fiber ^ 10 μ nickel-copper alloy mesh '' 50 μ 44 3

DK 153917 B

^ copolymer of acrylonitrile (40%) and vinyl chloride (60%), sold under the trade name "Dynel" by Union Carbide Corp. # N.Y.

'' negotiated under the trade name "Morel" by The 5 International Nickel Co., Inc., N.Y.

Claims (8)

A method of preparing a device for long-lasting and physiologically effective, controlled, continuous administration of active substances to aqueous, liquid-containing environments, e.g. for placing 5. the rumeno-reticular sack of a ruminant in which an active substance is enclosed in a reservoir surrounded by a shaped wall formed at least in part by a porous material which contacts at least a portion of the reservoir and is insoluble in said environment and retains its integrity during the administration time, characterized in that the pores in the pores of the porous material are impregnated with a hydrogel medium which is permeable to the passage of the active substance and to the aqueous liquid, hydrogel medium, gelled cellulose triacetate is used. Process according to claim 1, characterized in that a drug is supplied to the reservoir in admixture with a water-soluble drug carrier. Process according to claim 1, characterized in that the drug is supplied to the reservoir in admixture with a water-soluble liquid drug carrier and a synthetic detergent. Process according to claim 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 and sintered polystyrene, and a second group. consisting of porous tablecloth of material selected from polyethylene, polypropylene, polytetrafluoroethylene, glass and modacrylic polymers. Method according to claim 1, characterized in that an anthelmintic agent is included in the reservoir. 6. A process according to claim 1, characterized in that a water-soluble salt of levamisole, pyrantel or in DK 153917B is included in the reservoir. Process according to claim 4, characterized in that the porous wall is made of sintered polypropylene or sintered polyethylene. Process according to claim 6, characterized in that as the water-soluble salt of morantel the tartrate is used.