FI75735C - Device for continuous dosing of chemical. - Google Patents

Description

7755 ^ 71 ANNOUNCEMENT

jsffe [β] n1) UTLÄGGNINGSSKRIFT 7 57 35 (51) Kv.lk.Vlnt.CI.4 A 61 K 9/00, 9/70, A 61 M 31/00

SUOMI FINLAND

(Fl) (21) Patent application - Patentansökning 791452 (22) Application date - Ansökningsdag 07 · 05-79

National Board of Patents and Registration (23) Start date-Giltighetsdag 07.05.79

Patent * och registerstyrelsen (4-1) Has become public - Bhvit offentiig 09.11.79 (44) Date of dispatch and of publication. - 29 04 88

Ansökan utlagd och utl.skriften publicerad J * (86) Kv. application - Int. ansökan (32) (33) (31) Privilege claimed - Begärd priority 08.05.78 08.05.78, 22.02.79, 22.02.79 USA 904078, 904049, 014387, 014388 (71) Pfizer Inc., 235 East 42nd Street, New York, New York, USA (72) David Samuel Dresback, Groton, Connecticut, USA (74) Oy Kolster Ab (54) Device for continuous chemical dosing -

This invention relates to devices adapted to deliver a drug or other chemical from a container containing a drug at a controlled rate to an aqueous, liquid environment, particularly to the animal or human body. The device according to the invention has a wall made at least in part of a porous material, the pores of which contain a hydrogel and which are in contact with the medicament or the container containing the medicament. A preferred embodiment of the invention is a bolus tablet that can be used for controlled delivery of drugs to ruminants and is retained in the retina of an animal. Drug delivery systems and devices for controlled release of drugs, i. for controlled release or for delayed or extended release are well known in the art. Numerous methods have been reported in the literature, including physiological modifications of absorption and secretion, solvent modifications, chemical modification of the drug, absorption of the drug in an insoluble carrier, use of suspensions, and implanted drug tablets (Edkins, J. Pharm. Pharmacol. 66, 11.5). , 1959). Other methods include mixing the drug with a carrier that degrades slowly under the influence of the environment, such as body fluids, releasing the drug. Waxes, oils, fats and soluble polymers act as carriers.

It is also known in the art to thoroughly disperse a drug in a solid matrix through which the drug is released by diffusion, or to encapsulate the drug in a capsule whose wall or walls are a polymer through which the drug can pass by diffusion (U.S. Patent 3,279,996).

U.S. Patent 3,975,350 discloses a hydrogel carrier system consisting of polyurethane polymers for use in medical, phytosanitary, insecticidal, fungicidal, etc. applications.

U.S. Patent 1,693,890 discloses the preparation of cellulose acetate porous membranes as a gel for use in dialysis. The method comprises precipitating cellulose acetate from its solution in acetic acid by adding a non-solvent such as water. If desired, membranes can be formed on a support. Thus, the preparations membranes are impregnated with water, but can be freed from water by washing with alcohol, acetone, or some other water-miscible liquid.

The use of cellulosic polymer-liquid (PLC) compositions in films, fibers, or microspheres, including cellulose esters such as cellulose triacetate or cellulose nitrate, or molecular mixtures thereof as carriers for controlled release of various substances is disclosed in U.S. Patent 3,985,298. or entirely from the liquid phase (as its alcoholic or aqueous mixtures) and contained in the micropores of the PLC material.

U.S. Patent 3,846,404 discloses semipermeable membranes of gelled cellulose triacetate that can be used as carriers for other materials such as liquids with medicinal properties. It shows the impregnation of flat, non-woven polyethylene fabrics and cotton fabric alone into a gel

II

75735 for obtaining cellulose triacetate-supported hydrogel materials supported with 3 cellulose triacetate. The use of drug-impregnated, gelled cellulose triacetate products as slow-release implants in animal tissue and the casting of gelled cellulose triacetate on woven and nonwoven backing materials are disclosed.

Controlled drug delivery devices comprising a container of a drug and a solid or liquid carrier and made of or in contact with a wall of the container made of a plurality of materials, including a microporous material having a microporous solution (e.g., a liquid phase consisting of a colloidal solution). , suspension or sol) capable of permeation through a drug by diffusion is disclosed in one or more of the following U.S. Patents: 3,993,072; 3,993,073; 3,896,919; 3,948,254; 3,828,777; 3,797,494; 4,060,084 and 3,995,634.

U.S. Patent 3,993,073 also discloses hydrophilic hydrogels of acrylic acid and methacrylic acid esters and crosslinked polyvinyl alcohol as suitable wall-forming materials. The devices of these patents are characterized by the use of a wall consisting at least in part of a microporous material whose pores contain a drug rate-controlling medium permeable to the drug and a container comprising a drug and carrier permeable to the drug and at an even higher rate than the microporous wall. the rate of the drug release rate regulating medium is. Devices suitable for the administration of therapeutic or nutrient substances to ruminants, encapsulated in a permeable, water-insoluble material with capillaries or interconnected pores through the material, and paper or fabric partially impregnated8 with water-insoluble polymers such as 259.

U.S. Patent 3,594,469 discloses magnesium and iron containing pellets for administration to ruminants over an extended period of time. In one embodiment, the pellets consist of a cylindrical tube of magnesium alloy filled with sieves and 4,757,355 of a biologically active agent and closed at both ends by porous plates.

U.S. Patent 3,938,515 discloses devices designed for continuous delivery of a drug over an extended period of time, comprising a reservoir containing the drug and a drug-permeable solid or liquid carrier and a wall surrounding the reservoir that permeates the drug but at a lower rate than the carrier.

U.S. Patent 3,946,734 discloses a diffusion cell designed primarily for use implanted in tissue and is in fact a capillary having one end sealed with an impermeable material and filled at the other end with a porous neutral hydrogel. The biologically active substance is placed in the capillary against an impermeable material and the capillary is then filled with a hydrogel (agarose, polyacrylamide) through which the biologically active drug diffuses.

Several of the prior art controlled release devices in the industry have been classified as zero degree release devices. However, said devices are able to maintain zero-degree release rates for a relatively short time from their intended operating times and are not practical for long-term use, for example for ruminants. The devices of this invention, on the other hand, achieve and maintain controlled, predictable, zero-order release rates for a given drug for extended periods of time. In addition, prior art devices, including those comprising a drug-containing container surrounded at least in part by a microporous material-shaped wall with pores containing a drug-rate-regulating drug-permeable agent (diffusing medium), are susceptible to physical occlusion, obstruction, or obstruction. in the rumen of ruminants. Blockage reduces or even stops the release of the drug, rendering the device unusable for its original purpose. In the devices of the present invention, in which the pores of the porous material in contact with the drug-containing container contain a hydrogel, this difficulty is substantially absent and capable of

II

5,75735 to provide controlled and predictable drug release rates to the aqueous-liquid environment for extended periods of time.

In the case of controlled release of highly water-soluble drugs, it is recommended that prior art devices (of the type disclosed in U.S. Patents 3,993,073; 3,993,072; 3,967,618; 3,948,262; 3,948,254 and 3,896,819) the wall and / or container is formed of a material that is substantially impermeable to water to prevent dilution of the drug in the container due to absorption of body fluids into the device and a decrease in the rate of drug release. They are thus not suitable for dispensing water-soluble drugs, especially at high rates. In addition, the devices disclosed in most of these patents require that the drug permeability of the drug release rate controlling medium in the pores of the wall surrounding the container be less than the drug permeability of the liquid carrier in the container. This means that the passage of the drug through the wall is the determining step in the rate of release. The devices of the present invention are completely free of such limitations.

In fact, the significant difference between the devices disclosed herein and prior devices in the art is based on the use of a highly water-permeable hydrogel in the pores of the porous material in contact with the container. The operation of said devices is based on the diffusion of water from the water-liquid environment in which the device is placed, through the liquid-filled pores or channels in the hydrogel into the container and on the outward diffusion of the drug from the container to the environment. Surprisingly, the concentration of dissolved drug in the container does not decrease, resulting in a substantially constant release rate for a relatively long time. However, the amount of drug dissolved in the container is constantly changing during use of the device of this invention.

The use of the anti-gut agent, morantel tartrate, as a low concentration in calves' drinking water, in which calves are continuously treated with drug-treated water, as an endoparasitic treatment has been proposed by Downing et al. Irish Vet. J. 221, November 1974 and also disclosed in British Patent 1,530,161.

Continuous daily anthelmintic treatment of calves from the beginning of April to mid-July was found to reduce the secretion of worm eggs in calves and to prevent or at least minimize the development of severe larval infection during grazing.

In the context of a daily, low-dose dietary dose of morantel tartrate from calves to pasture until mid-July, Jones et al. Brit. Vet. J., 134, 166, 1978) have been found to be effective in the treatment of inflammatory infections caused by parasitic gastroenteritis and pulmonary worms by reducing contamination of the food provided by the grazing calf.

This invention relates to an improved device for the continuous administration of a chemical, such as a drug, over an extended period of time at a physiologically or pharmacologically effective rate from a container containing the chemical to an aqueous liquid-containing environment, particularly an animal or human body. In the device according to the invention, the chemical is enclosed in a container, the surrounding wall of which is formed by at least a portion of a porous material insoluble in the liquid-containing environment, and this porous material is at least partially in contact with the chemical-containing container, and the pores of the porous material are saturated. with a medium that allows the chemical and the aqueous liquid in the environment to pass through. The porous material used in the wall of the container may be, for example, a porous fabric material. A preferred embodiment of the invention are bolus tablets which: are placed in the retina of a ruminant for the controlled administration of drugs to ruminants.

The permeable devices of the present invention, such as drugs (these terms are used interchangeably herein), are useful for the controlled release of drugs and other chemicals into an aqueous, liquid environment and are particularly valuable for oral administration to animals and humans and can be used with a variety of drugs. . In addition, the devices are particularly well suited for the dosing of very strongly water-soluble substances at high speeds, which cannot easily be realized with prior art devices. The devices of this invention provide

II

7 75735 controlled release of chemicals over a long period of time, they are easy to manufacture and are reliable and easy to use. In addition, the devices disclosed herein retain their physical and chemical integrity, do not clog in the environment of use, and are particularly suitable for administration orally as bolus tablets to ruminants. They form, for the first time, a useful device for the controlled and continuous dosing of chemicals, such as drugs, in an aqueous liquid-containing environment and thus meet a long-term need, especially in animal husbandry.

The controlled release devices of this invention comprise a barrier layer, i.e., a wall in contact with at least a portion of the chemical-containing container, the wall being formed in part or in whole of a porous material, including a porous fabric, the pores of which contain a hydrogel to allow liquid to pass through the environment. through the pores, and the passage of the chemical from the reservoir by diffusion. When using the devices of the present invention, the hydrogel contains a fluid obtained from the environment, said fluid being contained in the channels or pores in the hydrogel itself, which act as conduits for the diffusion of the ambient fluid and drug transfer.

The devices according to the present invention can be of different shapes and sizes, adapted to the particular application. For example, they may be capsule-like for oral administration to humans and animals, or cylindrical for implantation in tissue, or when used as bolus tablets for ruminants.

In the preferred form of the device according to the invention, in the most general sense, a porous material is used, the pores of which contain a hydrogel, in particular gelled cellulose triacetate, which allows the liquid to pass from the environment and diffuse through the pores in the hydrogel, said porous material being in contact with at least part of a chemical such as a drug, 8 75735 and, if desired, a suitable water-soluble liquid extender and also, if desired, a surfactant, said device being formulated as a bolus tablet for controlled release of the drug to ruminants, especially cattle, and sheep, over a long period of time. These bolus tablets can be used in particular for the control of parasites, in particular internal worms, prophylactically and therapeutically, for the treatment of infections caused by gastroenteral and pulmonary worms in cattle and sheep, and for the treatment of pastures contaminated with internal worms. The term "bolus tablet" as used herein means devices that are generally cylindrical, spherical, ellipsoidal, or other, and do not have sharp edges and protrusions.

Prior art devices require a number of factors to be considered and coordinated for each application; namely, the relative permeation rates of the carrier used in the container, the carrier's solubility and / or permeability to the drug in the container, the microporous wall surrounding the container, the diffusing agent in the pores of the microporous wall, the diffusing medium and the carrier to maintain a substantially constant amount in the container.

The devices according to the invention, on the other hand, are considerably simpler in structure and operation. For a given device, the rate of chemical release can be varied widely by simply changing the surface area and thickness of the porous material in contact with the container, wherein the porous material also includes a porous fabric-like material and its pores are filled with a hydrogel. Thus, processing only two parameters controls the amount of chemical released.

Figures 1-5 show various examples of devices according to the present invention. The fact that only a few examples are given is not to be construed as limiting the invention, but rather: several modifications and equivalents thereof are possible. Pictured. 1, which is a perspective cross-section of the device according to the present invention.

II

9 75735 sectional view, the dosing device 10 consists of a cylindrical wall 11 in contact with a container 12 containing a chemical. The wall 11 is formed of a porous material having pores 14 containing a hydrogel (not shown) through which liquid from the aqueous, liquid-containing environment diffuses into the container 12 and chemical from the container diffuses into the environment through channels or pores in the hydrogel. The container 12 contains a chemical 15 and, in a preferred embodiment of the present invention, a drug and a water-soluble extender 16. The ends 17 are impermeable lids or stoppers.

Figure 2 is a schematic drawing of a device according to the present invention, a dosing device of the type shown in Figure 1, in which a perforated sheath, e.g. stainless steel, iron, plastic, 18 is placed as a means for adjusting the surface area of a hydrogel impregnated porous wall 14 and if it is iron, a device for lifting the weight of the device.

Figure 3 is an enlarged view of a porous wall 11 of a device 10 according to the present invention, the pores 14 of which contain a hydrogel 19, in contact with a chemical-containing container 12 containing a chemical 15 and a water-soluble liquid carrier 16.

Figure 4 shows a dispensing device in the form of a capsule with only one closure body 17.

Figure 5 further shows a device 10 according to the present invention, in which a porous material having pores 14 containing a hydrogel (not shown) forms the outer walls of the device 10. The cylindrical wall 18 consists of an impermeable, non-porous material, in this case stainless steel, which together with the hydrogel impregnated end walls 14 form a container 12 containing the chemical 15 and the carrier 16.

As indicated above, the improved dosing devices of the present invention comprise a container containing a chemical, including drugs, and, in a preferred embodiment, a container containing the chemical and a water-soluble liquid carrier. The water-soluble, liquid carrier performs a number of important functions, such as ίο 75735 deaeration from the tank, thus allowing greater filling in the manufacture of equipment and improving flow mixing in the tank (ensuring chemical release at a constant rate. It also has the task of ensuring that there is no significant volume transfer during chemical dissolution). from a solid or crystalline state to a liquid state.

Typical water-soluble liquid carriers include monools and polyols and their ethers, such as ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di- and triethylene glycol, di- and tripropylene glycol, ethylene-ethylene, 1,2-dimethoxyethane. mono-C 1-4 alkyl ethers, Ν, Ν-dimethylformamide, dimethyl sulfoxide and the like. The carrier must, of course, be compatible with the hydrogel.

Of course, if the devices disclosed herein are used for animals or humans or in an aqueous, liquid environment used for animals, such as aquariums, fish ponds, animal or poultry drinking water systems, plant aquaculture systems, the water-soluble liquid carrier must be a physiologically acceptable substance.

The amount of water-soluble liquid carrier to be used per unit of drug depends on the properties of the drug. Generally, sufficient carrier is used to form a drug / carrier combination into a uniform mass and this can be readily determined by a simple experiment.

Surfactants may be used in the container up to 20% by weight of the total weight of the container (chemical, including drugs and, if used, carrier and surfactant) to prevent possible clogging of the device during use. Suitable surfactants may be inorganic or organic in nature and include sodium and potassium metaphosphate and tripolyphosphate, sodium lauryl sulfate, sodium glyceryl monolauryl sulfate and dioctyl sodium sulfosuccinate (sodium) sulfate succinate (bis (1-methyl) other 11,75735 substances known in the art. The amount of surfactant, if used, is not critical and in all cases is kept to a minimum so as not to reduce the placement of the chemical in the container. The optimum amount is determined using the following procedures.

In this specification and the appended claims, the terms "container", "chemical-containing container" and "drug-containing container" are used interchangeably. Since the preferred device of the present invention is intended for the controlled release of a drug, the term "drug-containing container" is preferred for convenience.

The terms "porous material", "porous membrane" or "porous wall" as used herein include porous fabric materials. Representative types of these materials are presented below. The porous material used may be isotropic, i.e. its pore structure is homogeneous over the entire cross-section of the material or may be anisotropic, i. its pore structure is inhomogeneous. They must, of course, be insoluble and unreactive with the environment and the contents of the container. In general, porous materials having a pore size of about 1 to 100 micrometers can be used in the controlled release devices of this invention. Porous materials include continuous pore pore structures; this means that pores with openings on both sides of the associated porous wall are necessary. To effect drug delivery from the reservoir to the environment when using the controlled release devices of this invention, the pores of the porous material are filled with a hydrogel. The result obtained with a porous material whose pores are filled with a hydrogel is a prerequisite for the device to be able to resist clogging and physical breakage in normal use and, while maintaining physical integrity, to be used in environments and situations where previously known hydrogel devices have been destroyed and destroyed. for release over a long period of time. The devices presented here are particularly valuable for use in ruminants, especially cattle and sheep. The pores containing the hydrogel allow liquid (water) to pass through the pores in the hydrogel itself due to diffusion from the environment in which the controlled release device, when used, is placed in the container in which it dissolves the drug. The drug then diffuses through the liquid in the hydrogel-containing pores of the porous material at a rate that depends on the drug content of the solution in the container, the resistance formed by the barrier layer, i. the liquid in the pores of the hydrogel, and the effective surface area of the porous portion of the wall.

As the drug leaves the device, a depleted area gradually forms with it, causing the drug / solution interface to shift. The diffusion of water into the device from the environment through the hydrogel-containing pores of the wall into the tank causes the incoming water phase to mix with the solution in the tank of the device due to the flow. The force causing this mixing is the difference in density between the two solutions due to their large differences in concentration. The function of the water-soluble liquid carrier, as mentioned above, is to help maintain this large density difference, thus improving this critical mixing. The flow mixing causes a constant concentration of drug in the container, which in turn allows for controlled release of the drug over a long period of time, thus ensuring zero order drug release as long as insoluble drug is present in the device. As the drug exits the reservoir and the aqueous liquid diffuses into the reservoir, the amount of drug dissolved in the reservoir changes continuously over the life of the device; i. throughout the duration of drug release. This drug release mechanism allows all shapes to be used for the device, the size and shape of the container are not limited. This is in stark contrast to prior art devices based on U.S. Pat. No. 3,993,073, which are based on and thus manufactured to provide a substantially constant amount of dissolved drug in a container, with diffusion of dissolved drug in the container transferring the drug to the wall and thus having adverse product size and size limitations. .

Il 13 757 35

The term "hydrogel" as used herein means an aqueous gel and is defined in Hackh's "Chemical Dictionary", Fourth Edition, Grant, page 332, 1969 as "a gel prepared by coagulating a colloid with aqueous inclusions." Representative hydrogels that can be used to fill the pores of the porous material include: gelled cellulose triacetate, see U.S. Patents 1,693,890 and 3,846,404, cellulose acetate t-hydrogels derived from cellulose acetate having an acetyl content of 20-40 %, the polymeric hydroxyethyl methacrylate, equipped polyvinvylialkoholi-crosslinking, agarose, poly-acrylamide, crosslinked, partially-hydrolyzed polyvinyyliasetaat acetate, hydroxyethyl acrylate, dietyleeniglykolimonoakrylaatti, di-etyleeniglykolimonometakrylaatti, 2-hydroxypropyl acrylate, 2-hydroxypropyl methacrylate, 3-hydroksipropvyliakrylaatti, 3-hydroxypropyl methacrylate, dipropyleeniglykolimonometakrylaatti , vinylpyrrolidone, acrylamide, methacrylamide, N-propylacrylamide, N-isopropylmethacrylamide, N-methacrylamide, N-2-hydroxyethylmethylacrylamide, polyurethane hydrogels containing weakly crosslinked isocyanate endocyanate ends polymers, the prepolymers being reaction products of poly (alkyleneoxy) polyols with an organic diisocyanate weakly crosslinked with water or an organic polyamine, as disclosed in U.S. Pat. No. 3,939,105, and methacrylates, as disclosed in U.S. Patent 4,083,264, polyether-polyurethane resins prepared by the reaction of an organic diisocyanate with a mixture of at least two diols, one of which is a water-soluble polyalkylene glycol having a molecular weight of 3,000 to 30,000 and the other of an oxyalkylated diphenol , having 2 to 20 oxyalkylene groups and other substances known to those skilled in the art.

Preferred hydrogels for use in this invention include polyurethanes; polymeric lower alkyl acrylates or methacrylates, vinylpyrrolidone, acrylamide, N-lower alkyl acrylamides and methacrylamides, especially those crosslinked or copolymerized with a copolymer of hydroxyalkyl acrylate or methacrylate obtained without uncoating. Preferred hydrogels include gelled cellulose triacetate, polymeric hydroxyethyl methacrylate, and cross-linked polyvinyl alcohol. Particularly preferred is gelled cellulose triacetate, which allows for the smooth and efficient operation of the controlled release devices disclosed herein.

The water in the pores of the hydrogel can be easily replaced by water-soluble liquids, such as the above-mentioned water-soluble liquid carriers. Other water-soluble liquids can also be used to replace water, including alcohols having 1 to 4 carbon atoms. For practical reasons, to stabilize the devices of this invention, especially if the hydrogel is gelled cellulose triacetate, the water in the hydrogel is replaced with a suitable water-soluble liquid having a lower vapor pressure than water so that the devices can be stored without loss of efficiency due to hydrogel drying. If a water-soluble liquid carrier combination is used in the container, it is preferable to use the same liquid to replace the water in the hydrogel.

The hydrogels themselves are porous in the sense that they contain regions, i. channels or pores, filled with water or other liquid. Thus, throughout this specification, reference to the diffusion of chemicals or drugs through a wall "having pores containing a hydrogel," or the like, means that the diffusion or migration of a chemical or drug occurs through these regions rather than through the hydrogel per se. The hydrogel itself has liquid-filled pores that act as diffusion pathways and by its function it can be considered permeable to the surrounding liquid and the drug in the container.

The porous wall in contact with the drug-containing container may be any of a number of materials. The porous material may completely surround the container or may form only a portion of the wall surrounding the container. Suitable porous materials include porous metals, porous ceramics, sintered polyethylene, sintered poly (vinyl chloride), sintered polypropylene, sintered polystyrene, and sintered poly (tetrafluoroethylene), porous polymers made from thermoplastics.

II

15,75735 resins by phase separation methods as described in Chem. Eng. News, December 11, 1978 page 23 and other materials known to those skilled in the art.

Suitable porous fabrics include polypropylene and polyethylene, especially fabrics of both types, commonly referred to as "filter fabric", glass, poly (tetrafluoroethylene), nylon, cotton, modacrylic fibers, i. acrylic fibers consisting of a long chain synthetic polymer containing 35-85% acrylonitrile units, acrylic fibers, i.e. synthetic polymers containing 85% by weight or more of acrylonitrile, polyesters, i.e. long chain synthetic polymers containing at least 85% by weight of a dihydric alcohol and terephthalic acid ester, polyvinyl acetate, polyvinyl chloride, polyvinyl acetate-co-vinylidene chloride, polyvinyl alcohol, polyvinyl alcohol, polyvinyl alcohol co-vinyl, other substances 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 screens and filter fabrics, including those made of stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel-copper, etc., are suitable.

The particular tissue selected must, of course, be compatible with the hydrogel with which it is impregnated and suitable for the intended use of the device. Thus, in a device used as a bolus tablet to deliver a drug to ruminants over a relatively long period of time, cotton cannot be used as a tissue because it disintegrates during ruminating. In a device used for the controlled release of a chemical into an aqueous environment such as an aquarium or tank, cotton can be used.

Nylon cannot be used as a tissue if the hydrogel is cellulose triacetate because it decomposes under the action of formic acid or acetic acid used in the impregnation treatment.

16 75735

The hydrogel-impregnated porous tissue must, of course, be sufficiently strong, abrasion resistant, and ineffective with respect to the drug and the environment of use so that the controlled release device made therefrom retains its physical and chemical integrity throughout its life.

The porous material is impregnated with the hydrogel by methods known to those skilled in the art. A preferred and relatively simple procedure for impregnating a porous material with gelled cellulose triacetate, which is the preferred hydrogel, comprises forcing a solution of cellulose triacetate in formic acid or acetic acid to migrate into the pores of the porous material by immersing the material in a cellulose triacetate solution. After impregnation, the plastic "loaded" with cellulose triacetate is then coagulated by contacting and equilibrating with a large volume of water to form a hydrogel impregnated material. If the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate, acetic acid is the preferred solvent for cellulose triacetate instead of formic acid because it wets polyethylene better than formic acid and thus facilitates hydrogel impregnation.

If the hydrogel is derived from 2-hydroxyethyl methacrylate crosslinked with ethylene glycol dimethacrylate, as disclosed in U.S. Patent 3,520,949, impregnation of the porous material is accomplished by filling its pores with 2-hydroxyethyl methacrylate-ethylene glycol , such as t-butyl peroctoate. Similarly, other hydrogels are impregnated into the porous wall material by similar "in situ" methods from appropriate reactants. If the hydrogel is a cross-linked polyvinyl alcohol, the pores are filled with a mixture of polyvinyl alcohol (10% aqueous solution) resorcinol (2-3%) by the methods set forth herein and crosslinking is performed in situ. Of course, other crosslinking agents known to those skilled in the art may be used.

Il 17 75735

In the manufacture of devices that can withstand storage prior to use, the hydrogel-filled pores are dewatered by allowing them to equilibrate in a suitable water-soluble liquid, such as the water-soluble liquid carriers described above. As mentioned above, it is desirable to exchange water in the hydrogel-filled pores of the porous wall material for the same water-soluble liquid used as a carrier in the container when the container contains a chemical-carrier combination. If the containers of the devices presented here contain only a chemical, the choice of water-soluble liquid used to replace water in the hydrogel in the pores of the porous wall hydrogel-filled pores is determined only by the intended use of the device, i. whether a physiologically acceptable water-soluble fluid is required. Such a liquid is suitably placed in the hydrogel in connection with the manufacture of the porous wall, the pores of which contain the hydrogel, before filling the container of the device as described herein.

Prior art devices that most closely correspond to the devices of this invention, i. U.S. Patents 3,993,073 and 3,993,072 are based on a different rate of drug permeation through the porous wall pore medium compared to the rate of drug permeation through the drug carrier in the container. In order to obtain a zero-order release rate, which is claimed to be achieved with the devices disclosed in said patents, it is essential that the permeability of the wall of the device to the drug be lower than the permeation rate of the drug carrier in the container. The medium in the wall is thus a component that determines the rate of drug release in the device.

The dissolved drug diffuses more strongly through the permeable carrier onto the inner wall sufficiently rapidly that the wall is part of the device that determines the rate of drug release. This results in a zero order release rate for some time until the reversible drug interface in the device becomes large enough to eliminate the difference in permeabilities between the carrier and the wall medium, thereby no longer reaching zero order rates. For this reason, the successful use of these devices is limited and they are no longer suitable for zero-volume administration of large amounts of drugs in useful dosage forms.

__- I- ie 75735

Unlike previous devices in the art, the devices of the present invention use an aqueous environmental medium in both the wall and the tank medium. Although the permeability of the drug is the same in both the wall and the liquid in the container, zero-order release rates are achieved for most of the total life of the device. In addition, maintaining a zero-order release rate does not depend on diffusion in the reservoir carrier, so these devices have no geometric or dose-limited constraints and, for the first time, large amounts of drugs can be delivered at zero-order rates in practical sized and shaped implementations.

For the most effective operation of the controlled release devices of this invention, to reduce leakage and blockages, it is important that the porous material be impregnated with the hydrogel as completely as possible. Devices with the same surface area can be made to provide different dosing rates and dosing times for a given drug by altering the properties of the membrane wall, in particular its thickness, pore size and porosity, and by changing the amount of charge in the container.

As mentioned above, the preferred form of the device of the present invention is a bolus tablet for use in the controlled release of a drug for ruminants, mainly cattle and sheep, during an extended dosing period. The bolus tablet is administered to the ruminant in such a way (preferably orally) that it remains in the retina for a relatively long time, during which time it continuously releases the drug to the animal at a controlled release rate. Said devices thus allow the monitoring of the various pharmacological and physiological conditions (prophylactic and therapeutic) which occur in animals by means of a simple oral administration of said devices to the animals.

In order to ensure that the bolus tablet administered to the bovine retina lasts for a long time, it is necessary that the bolus tablet has a density of at least 2.0 g / ml. In practice, the duct may be as small as 2.0 g / ml or as large as 7 g / ml or even greater. Density is, of course, the most significant factor influencing the survival of a bolus tablet in the retina. The size of the bolus tablet 19,75735 female size depends on the dose required and the size that can be practically administered. Based on this, once the desired size is determined, additional weight can be added to obtain the desired, average density. If possible, it is preferable to use the largest possible size because large bolus tablets with a given density remain better in place than those with a low density. However, if the average density of the bolus tablets increases to greater than about 5.0 g / ml, the increase in bolus tablet size does not significantly improve the retention factor. The recommended average density range for a bolus tablet is about 2.5-5 g / ml.

The size of the bolus tablet will, of course, depend on the animal being treated. For sheep and goats, the size and weight of the bolus tablet are smaller than for cattle. The maximum size of a bolus tablet for each animal is determined by the practical difficulties encountered in administering it to the animal.

When administered to a sheep, the minimum weight of the bolus tablet at a density of 4 g / ml and the tablet is stationary is about 1 gram. The size of the bolus may vary depending on the density of the bolus. When administered to cattle, a bolus having a density of about 4 g / ml has a minimum weight of about 5 grams. Again, as mentioned above, the upper size limit is determined by practical reasons when administered to the animal in question and by the average minimum bolus density. For example, a bolus having a length of about 7.5 cm and a diameter of 2.5 cm and a density of 2.2 g / ml weighs about 90 grams.

The density of boluses containing only the above ingredients is generally below the aforementioned lower limit. Thus, it is necessary to increase the average density of the bolus by adding a suitable high density material such as metal (iron flour, iron shot, steel shot) or other density enhancing agents such as minerals such as CaSO 4 to increase the density to the desired value. Alternatively, the average density may be suitably increased by adding a high density perforated material, such as a metal (such as stainless steel, steel, especially low carbon steel, or iron) to the bolus liner, which in turn is surrounded by a hydrogel impregnated porous membrane. The perforation in the sheath must be large enough to allow the free passage of the drug 20 7 5 7 3 5 and the fluid from the environment through the hydrogen impregnated porous membrane. The main function of such a sheath is to increase the average density of the bolus to such an extent that the bolus remains in the retina and adjusts the surface area of the hydrogel-saturated soluble material in contact with the drug-containing container. In addition, such a sheath, although not necessarily, also improves the physical stability of the bolus, ensuring that its physical form remains substantially unchanged under the conditions of use. Yet another and preferred alternative comprises a bolus consisting of a metal, iron or steel cylinder, one or both ends of which are closed by a porous membrane whose pores are impregnated with a hydrogel. These types of boluses are recommended because they are simple and economical to manufacture and their density can be easily adjusted. Low carbon steel is a highly recommended construction material for the cylinder. Experts in the field may use other alternatives known to them.

The controlled release devices of this invention can be used for a variety of purposes and situations where controlled release of a drug or other chemical is desired. They can be used to dispense drugs and direct chemicals to locations near or far from the location of the device. They can be suitably placed in appropriate places in the body of the animal where they are in contact with body fluids, for example in the stomach of livestock, especially in the rumen of ruminants. Controlled delivery devices of this invention also include those used when implanted in tissue to deliver a drug at a controlled rate to a carrier animal. The implants placed in the tissues differ from the devices used for other purposes according to the present invention only in their shape, which is, of course, adapted to the implant purposes. Other uses include sublingual or oral tablets, suppositories, pessaries, bandages, and skin patches. Still other uses for the controlled delivery devices of this invention include the dosing of fertilizers and pesticides in agriculture, use in fish farming, including aquariums and fish ponds, use in sewers, canals and tanks for the control of algae, and for feeding or for prophylactic purposes.

A requirement for suitable agents, drugs or chemicals to be used in the devices of this invention is that they be sufficiently soluble in water to provide a rate of release of said drug or chemical such that the desired result is achieved in the environment of use. For this reason, drugs or chemicals which are acids or bases are preferably used as their physiologically or pharmacologically acceptable salts. The rate of drug or chemical release from the devices disclosed herein depends on several factors, such as wall thickness, available surface area, effective pore diameter, wall porosity, the nature of the hydrogel, the concentration of the substance in the container, and its solubility in the ambient fluid. The suitability of a given substance is determined as follows.

Representative drugs that can be used in the devices disclosed herein include: anthelmintic drugs including salts of morantel, pyrantel, oxantel, piperazine, diethylcarbamazine, levamisole, tetramisole, and hydromycin B; antibacterial agents including salts of tetracyclines such as 5-oxytetracycline, chlorotetracycline, doxycycline and their Mannich bases; penicillins such as ampicillin, penicillin G; aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin as its zinc or methylenedisalicyl acid derivative, oleandomycin and tylosin; antibacterial growth promoters such as salts of avoparicin, polymyxin, lir.co-mycin, bambermycin and efrotomycin; hormone growth promoters including diethylstilbestrol, zearalanol; Antiparasitic agents such as amprolium, nutrients such as magnesium, selenium, copper and soluble salts of vitamins such as thiamine hydrochloride; sulfa drugs such as sulfamethazine, molluscicides such as N-tritylmorphine; and anti-swelling agents such as alcohol ethoxylates and polyoxyethylene-polyoxypropylene-polyoxyethylene polymers e.g. poloxalene.

As mentioned above, the drug-containing container of the present invention in its preferred form contains a drug and a water-soluble carrier. The devices thus formed have the advantage that a larger amount of drug is obtained per device and the service life of the device can be extended. However, the container may contain only the desired drug.

The devices of this invention are particularly valuable as long-acting bolus tablets for the treatment (inflammatory and prophylactic) of inflammation caused by wormwood in ruminants, especially cattle. Protecting grazing animals is relatively simple. In temperate zones, the small, early spring number of grazing larvae as a remnant of contamination from the previous grazing season multiplies in circulation through the animals as they graze, resulting in a sharp increase in pasture morbidity in summer. This condition causes, during the summer grazing season, a decrease in clinical parasitism and the ability of the animals grazing on said pasture.

Continuous and controlled application of an anthelmintic agent, such as morantel, to the retina of grazing animals at the beginning of the season when pasture contamination is low, reduces the formation of internal worm eggs and subsequent larvae, thus interrupting the aforementioned cycle and keeping pasture and animal worm load low. The parasitic infections of ruminants grazing on the same pasture during the summer are thus also reduced. This method of controlling gnats is particularly pleasant and valuable for calves, as they are very susceptible to gnats when they are first grazed. Continuous use of bolus tablets reduces the number of disease-causing guts in a given area. The use of bolus tablets containing an anthelmintic according to the present invention in this way prevents, or at least reduces, the growth of grazing larvae during the grazing season, which would otherwise lead to parasitic gastroenteritis and reduced performance in grazing animals at a later stage of the season. With this method of control, the release time of the drug is during the spring growing season and not during the high contamination of the pasture, where the growth of larvae and the growth of worms cause clinical illness and decreased performance. For this reason, this approach is called "indirect control". That is, grazing animals with one or more of the devices described herein that allow the controlled and sustained release of an anti-worm agent, e.g., morantel, into said web in the pasture at the beginning of the season, i. when larval contamination is at or near its minimum, it allows the seasonal growth of normal larval contamination to be minimized on pastures and protects animals throughout their grazing season.

For the "indirect control" of worms, the devices of this invention, preferably in the form of bolus tablets, are administered to ruminants during the epidemiological period of said worms, with contamination of pastures by or near their eggs and / or larvae. In temperate zones, this time corresponds to the arrival of spring; i. when releasing calves for the first time out to pasture. For maximum efficacy, bolus tablets are administered to calves for about two to seven days before being placed on pasture. In the hot zones of the world, i.e. in semi-tropical and tropical areas, the lowest contamination of pastures usually occurs before the start of the rainy season. Dosing of bolus to ruminants in these areas is preferably performed two to fourteen days before the start of the rainy season. However, due to the unpredictability of the rainy season, the control of indoor worms in hot zones is best performed according to the "direct control" method.

The bolus tablets presented here also eliminate infections caused by intestinal worms in ruminants and prevent worm infections during the intense summer of growth. This use is called "direct control". The direct control method protects ruminants only during the release period of the anthelmintic. An indirect method of controlling indoor worms protects ruminants when grazing on a given pasture throughout the season, as it achieves a significant reduction in pasture contamination throughout. As mentioned, the devices presented herein provide a waste of drugs, including anthelmintics.

24 75735 image release at controlled speed. Particularly suitable for these purposes are (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-thienyl) ethenyl) pyrimidine (pyrantel) and (+) - 2,3,5,6-tetrahydro-6-phenylimidazo (2,1- (b) water-soluble salts of thiazole (tetramisole) and levimisol, its L - (-) form. Representative and preferred water-soluble salts of pyrantel and morantel include tartrate and citrate salts; and the hydrochloride salts of tetramisole and levamisole.

The bolus tablets of this invention are administered to animals orally, for example, by means of a ball gun. For calves, the recommended average rate of release of morantel (calculated as a base) for indirect control of intestinal worms is on the order of 60-200 mg (morantel base) per day for approximately 60 days, covering the normal longest spring growth period for larvae. Longer release times of about 60-120 days are recommended for direct control, as the exposure time to severe pasture contamination usually extends from mid-summer to autumn. Approximately 60-150 mg (calculated as morantel base na) per day of release rate is effective in controlling glandular infections during these release periods. More than one bolus may be administered to large animals. When using salts of pyrantel or levamisole for indirect control of intestinal worms, the average release rates of both (calculated as free bases) are in the order of 100-400 mg and 100-500 mg per day for about 60 days, respectively. For direct control, release rates of about 100-300 mg (free base) pyrantel and about 100-400 mg (free base) levamisole per day are effective in controlling intestinal worm infections in 60-120 days for the strongest growth.

Continuous, low-dose dosing of morantel using the visceral control devices disclosed herein provides an effective effect that surprisingly and effectively differs from the exchange achieved with conventional therapeutic use of morantel. For example, long-term maintenance of morantel tartrate or citrate (or other salt) levels in the rumen of the ruminant effectively protects said animals from lungworm infections during drug release. Furthermore, when cattle or sheep grazing on a contaminated pasture are susceptible to re-infection with intestinal nematodes after conventional therapeutic treatment, animals administered bolus tablets are substantially free of detectable infections and protected against re-infection for more than 60 days.

Use of bolus tablets to control pasture contamination, i.e. indirect control method, is a unique, practical and new method of controlling internal worms, protecting ruminants and especially grazing ruminants treated in this way throughout the grazing period and enabling efficiencies that are superior to previous control methods in the field. The daily increase in weight gain compared to untreated control animals during grazing time is significantly greater than that achieved with conventional therapy.

The rate of release of a drug or other chemical transferred from a drug-containing container through a wall in a controlled release device of this invention and the effectiveness of a particular drug and / or water-soluble carrier and / or surfactant combination in said devices can be readily determined by those skilled in the art. using desorption methods. A method that can be suitably used to select a suitable porous material and hydrogel comprises using a selected porous material having pores filled with the selected hydrogel as a barrier layer between a rapidly mixed saturated solution of a drug or other chemical whose controlled release is desired and a rapidly stirred solvent bath having a composition corresponding to the aqueous liquid environment in which the controlled release device is intended to be used. The temperature of both solutions is kept constant, preferably at a value corresponding to the average temperature of the environment in which said device will be used. At predetermined intervals, samples are taken from the solvent bath and analyzed for drug concentration. Normal procedures for determining the permeability of a drug or other chemical through a porous material whose pores are filled with a hydrogel can also be used, which standard procedures are set forth in 26 7 5 7 3 5 Encyclopedia of Polymer Science and Technology, parts 5 and 9, pages 65 -82 and 794-807, 1968, respectively and in the references cited herein, and in the book Chemical Engineers Handbook, pages 17-45, 1963, published by McGraw-Hill, Inc.

A particularly valuable procedure for determining the rate of release for the devices of this invention and determining the relative importance of a given carrier or surfactant, especially if the drug is morantel, is summarized as follows. The procedure, the in vitro procedure, is based on the release of a water-soluble salt of morantel, for example tartrate, from the device according to the invention as a function of time. The device according to the present invention containing monantel tartrate is placed in a one liter conical flask which is protected from light because morantel tartrate is photosensitive, 500 ml of phosphate buffer pH 7 is added and the temperature of the flask and its contents is adjusted to 37 ° C and maintained at this value. . The flask containing the device is shaken about 70 times per minute (deviation 7.62 cm) and samples are taken from time to time. The volume of the removed sample is replaced with an equivalent volume of fresh phosphate buffer 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 and read relative to fresh phosphate buffer pH 7. The sampling procedure is continued until 5 grams of morantel tartrate is released, in which case the apparatus is transferred to another flask containing 500 ml of fresh pH 7 phosphate buffer and the procedure is continued as above.

The in vivo release of morantel tartrate from the devices of this invention is determined by administering the devices to, for example, normal young bulls or bulls with reticulum fistula, and after a period of time such as 30, 60, 90 or 120 days, removing the device via fistula or slaughtering the animals and recovering morantel tartrate. as appropriate. Experiments of this kind have shown that the in vitro release rate of morantel tartrate is approximately four times higher than the in vivo release rate.

The following examples merely illustrate the present invention.

27 75735

They are not to be construed as limiting the scope of the present invention, and many possible variations will be apparent to those skilled in the art.

. Example 1

A bolus consisting of sintered polyethylene having pores filled with gelled cellulose triacetate and a container containing morantel tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate and having a perforated stainless steel jacket was prepared as follows.

The other end (referred to as head 1) of a sintered polyethylene tube having an average pore size of 10 micrometers and an outer diameter of 25.4 mm, an inner diameter of 22.225 mm and a length of 7.938 cm was dipped in a 10% solution of cellulose acetate butyrate in methylene chloride to a depth of 4.763 mm. The tubes were then air dried and one end (called end 2) was dipped in cellulose acetate butyrate solution to a depth of 9.525 mm and dried. This step was repeated. Head 1 was re-dipped in cellulose acetate butyrate solution for 30 seconds, allowed to air dry for 60 seconds, and a 22.225 mm diameter cellulose acetate butyrate plate (thickness 3.175 mm) was placed at the end of the tube so as to be flush with said end. The cellulose acetate butyrate plate was rinsed in methylene chloride for 60 seconds before being placed on the end of the tube 1. The tube was then rotated along the table with the finger pressing the end containing the plate so that the plate and the tube were completely connected. One-hole no. 3 A rubber stopper attached to a glass tube of sufficient length to extend through a single-hole rubber stopper of the vacuum bottle with the tube at the bottom of the bottle was placed in the tube. The present end of the tube was then connected to a flask containing a 6% solution of cellulose triacetate in formic acid and a vacuum of about 150 mmHg was formed. When the cellulose triacetate solution covered the outer wall of the tube that had not been immersed in cellulose acetate butyrate, the tube was removed from the vacuum flask and the excess cellulose triacetate was wiped off. The tubes were then inverted to drain the cellulose triacetate from inside the tube. The open end of the tube was wiped on the outside and inside with a towel. The tubes were then immersed in distilled water and allowed to stand there overnight. It was then removed from the water, the outside was dried with a towel and the excess water was removed by shaking the inside of the tube. The steps of impregnating the pores of the tube with cellulose triacetate and equilibrating it in distilled water were repeated. It was then treated with running water for 4 hours.

The leaks in the tube were examined at this stage by connecting it to 2 nitrogen sources, immersing the tube in water to form a nitrogen pressure of 0.28 kp / cm for 10 seconds. If leaks were observed, the impregnation and equilibration steps in water were repeated.

The tube was then allowed to equilibrate in polyethylene glycol 400 overnight, removed from polyethylene glycol 400 and allowed to drain in the up position for 4 hours. Excess polyethylene glycol 400 was wiped off the outside of the tube with a towel and a perforated stainless steel tube, outer diameter 22.225 mm, inner diameter 18.923 mm, length 6.985 cm and equipped with 16 evenly spaced round holes (diameter 7.114 mm) was placed in the tube. Cellulose triacetate chips formed by tightly inserting a suitable jacket into the tube were removed. A cellulose acetate butyrate plate (3.175 mm) was then placed at the open end of the tube flush with the stainless steel sheath and the tube was finished so that the end of the tube was flush with the plate. The plate was removed and the tube was filled with a homogeneous mixture of 63.31% Moran batch tartrate, 26.61% polyethylene glycol 400 and 10.08% sodium hexametaphosphate to the end of the stainless steel jacket. The open end of the tube was filled with 10% cellulose acetate butyrate solution, which was then immediately poured off, and the open end of the tube was immersed in the cellulose acetate butyrate solution to a depth of 6.35 mm and allowed to dry. The cellulose acetate butyrate plate (rinsed in methylene chloride for 60 seconds immediately before use) was then inserted into the open end of the tube using sufficient pressure to force the plate against the stainless steel sheath. The tube was then rotated on a table with sufficient finger pressure to form a tight connection between the plate and the tube. The tube was allowed to dry for one hour, after which both ends of the tube were immersed in 10% cellulose acetate butyrate solution to a depth of 6.35 mm and the tube was allowed to dry. The weight of the bolus was about 29 7 5 7 3 5 90 g, of which 24.8 g was a drug mixture. Its density was 2.2 g / ml. This device released approximately 250 mg of morantel tartrate per day in vivo in calves for approximately 60 days.

Example 2

Three devices prepared according to Example 1 were tested in vitro according to the procedure set forth therein and gave an approximately constant release rate over 4-17 days with an average release rate for all three boluses of 0.927 g morantel tartrate per day.

Accumulation of morantel tartrate, grams

D. 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 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 19 14.52 16, 2 13.2 25 17, 99 17.4 15, 4 29 17.13 17.3 15.9

In vivo tests of the other three boluses prepared according to Example 1 showed that the release rate of morantel tartrate when bolus was placed in the bovine retina was 0.224 g per day removed after 30 days.

Thus, the in vitro / in vivo ratio is 4: 1.

Example 3

In the other two in vitro bolus assays, in which the boluses were prepared according to Example 1 and tested as described above, the average release rate over a constant release rate of 0-14 days was 0.96 g of morantel tartrate per day.

30 7 5 7 3 5

Accumulation of morantel tartrate, grams ...... Bolus 4 Bolus 5

D. in vitro ---— -f 0.51 0 * 59 2 1.5 2'16 3 2, 4 2, 2 5 4.9 5.4 6 5.1 5.1 5.9 7 6, 5 6 '1 10 9.7 9'7 12 11.0 11.7 14 13.5 12'6 17 14.8 I3.6 19 16.4 I4.6 21 17.1 14'7 24 16, 8 14, 7.

26 16.9 I4 '®

With identical boluses placed in the bovine retina in in vivo tests, the following results were obtained in 30-60 days.

Mprantel tartrate average

Bolus Vrk. in vivo per day, grams 6 30 0.222 7 30 0.228 8 45 0.238 9 45 0.335 10 49 0.174 11 60 0.198 12 60 0.178

The average in vivo release rate is 0.224 g per day and the in vitro / in vivo ratio is about 4: 1.

31 75735

Example 4

Boluses were made of stainless steel tubes with the following dimensions: outer diameter 22.225 mm, inner diameter 21.336 (wall thickness 0.889 mm) and length 3 cm.

The ends of the tube were provided with threads (0.5 mm at each end) for positioning the collar to secure the hydrogel impregnated porous fabric sheet in place. Plates (outer diameter 22.225 mm and thickness 3.175 mm) of polypropylene filter cloth with an average pore size of 50 micrometers and impregnated with gelled cellulose satiracetate were treated by immersion in a 6% solution of cellulose triacetate in 25% formic acid in formic acid with formic acid vacuum. The flask and its contents were kept under vacuum for about 10 minutes, the plates were removed, and excess cellulose triacetate solution was removed by wiping. They were then immersed in distilled water and kept there overnight. The plates were then removed from the water, then dried by wiping and then equilibrated with polyethylene glycol 400 overnight. The plates were removed and wiped with a towel.

Impregnated plates were installed at both ends of the pipes by fixing them between two washers having a thickness of 0.254 mm and a diameter the same as that of a steel pipe. The washer closest to the steel tube was cellulose acetate butyrate and the other a dental rubber seal. The ends were then sealed with stainless steel plates with an opening of 21.336 mm in diameter. The tubes were then filled with a mixture of morantel tartrate (63.3%), polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%) and the other end of the tube was sealed as described above.

Boluses containing 21.4 g of morantel tartrate weighed 97 g and had an average density of 3.30 g / ml.

The bolus was administered to young bulls with a reticulum equipped with a fistula using a ball gun and removed through the fistula at 30, 45, 60, 75, and 90 days to determine the amount of drug remaining in the bolus from which the mean daily depletion rate of morantel tartrate was calculated.

32 75735

Bolus Day, In Taurus Release rate (mg / day) ΐ 30 67 2 30 108 3 45 82 4 45 58 5 60 336 6 60 91 7 '75 71 8 75 68 9 90 67 10 90 106

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

A significant decrease in the number of parasitic eggs in the feces was observed in each Taurus.

Example 5

According to Example 1, four boluses of sintered polyethylene (average pore size 10 μm) were prepared, the pores of which were filled with gelled cellulose triacetate and using a stainless steel sheath for only a portion of the total length of the boluses (so that part of the bolus had no mantle) and containers containing 63.3%) mixed with polyethylene glycol 400 (26.6%) and sodium hexamethaphosphate (10.1%). However, instead of the torn stainless steel sheaths used therein, non-perforated sheaths of 5.08 cm, 4.445 cm, 3.175 cm and 1.905 cm were used, respectively. The thickness of the diaper walls was 0.165 cm. The drug mixture was then placed in each bolus to provide drug bands above the sheaths with widths of 6.35, 12.70, 25.4, and 38.1 mm, respectively. A stainless steel plug 12.7 mm thick and 22.225 mm in diameter was inserted into each bolus above the drug mixture. The ends of the boluses containing the steel plug were treated so that a plate of cellulose acetate butyrate could be placed on top of the plug flush with the ends of the boluses. The individual bolus weights were 120.0, 115.4, 106.2, and 97.0 g, respectively. The weight of the drug mixture ranged from 25.5 to 27.4 g per 33,75735 bolus. The bolus densities were 3.1, 2.98, 2.75 and 2.51 g / ml, respectively.

Example 6

In the in vitro bolus release rate tests of the bolus of Example 5, each released the drug at a constant rate over 3-21 days. The lightest (envelope length 1.905 cm) of the four bolus of Example 5 had a mean release rate of 774.8 mg morantel citrate per day over a period of 3-21 days with a constant release rate.

Example 7

Fourteen boluses prepared according to Example 1, tested in vivo in cattle, gave a mean release rate of 238 mg of morantel tartrate per day over 60 days. The normal deviation was 67 mg (28%).

Example 8

Boluses were prepared according to Example 1 except that instead of the drug mixture of said example, the following chemicals were used in the container: pyrenterlitartrate (63.3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%); morantel tartrate (100%); pyrantel hydrochloride (100%); tetramisole hydrochloride (100%); levamisole hydrochloride (85.0%), glycerol (15.0%); diethylcarbamazine citrate (100%); hydromycin B (100%); doxycycline hemihydrate heme alcoholate (100%) and bacitracin methylene salicylic acid (66.0%), sorbitol (22.0%), sodium lauryl sulfate (12.0%), ampicillin, sodium salt (65.3%), polyethylene glycol (26.5%) ), sodium hexametaphosphate (10.0%) and sodium penicillin G (67.3%); N, N-dimethylformamide (22.2%), sodium glycerol monolauryl sulfate (10.5%); neomycin complex (68.5%), dimethyl sulfoxide (22.5%); sodium lauryl sulfate (10.0%); streptomycin trihydrochloride (100%); oleandomycin hydrochloride (80%); polyethylene glycol 400 (20%); tvlosin hydrochloride (100%); polymycin hydrochloride (79.5%), glycerol (15.0%), sodium lauryl sulfate (5.5%); lincomycin hydrochloride hemihydrate (100%); magnesium acetate tetrahydrate (77%), sorbitol (15%), dioctyl disodium sulfosuccinate (8%).

34 7 5 7 3 5

Example 9

According to Example 1, a bolus was prepared consisting of sintered polyethylene with pores (average size 100 μm) filled with cross-linked polyvinyl alcohol hydrogel and a container containing morantel citrate (63.3%), polyethylene glycol 400 (26.6%), and sodium hexate (10%). 1%) and with a perforated stainless steel jacket. However, instead of the cellulose triacetate-formic acid solution, the hydrogel solution consisted of a 10% aqueous solution of polyvinyl alcohol (88% hydrolyzed polyvinyl acetate) containing 3% resorcinol. The tubes, after vacuum treatment to fill the pores, were wiped clean and kept at 0-10 ° C for 5 hours to gel the polymer. Balancing the tube in water was not necessary. The tubes were then tested for leaks, equilibrated in polyethylene glycol 400, filled and sealed as in Example 1.

An in vitro test showed it to be suitable for the controlled release of morantel citrate.

Example 10

The procedure of Example 1 was repeated except that sintered polyethylene pipes having half the length and diameter of those used in Example 1 were used. The resulting boluses were designed for use in sheep and were suitable for the controlled release of an anthelmintic over a long period of time in vivo.

Example 11

The procedures of Examples 1 and 5 were repeated except that the following microporous materials were used instead of sintered polyethylene: porous ceramics, porous steel, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene (average) of each material.

Each bolus thus prepared provided controlled release of the chemical over a long period of time when studied in vitro.

li 35 75735

Example 12

Boluses were prepared from stainless steel tubes with the following dimensions: outer diameter 22.225 mm, inner diameter 21.336 mm (wall thickness 0.889 mm) and length 7.62 cm. The ends of the tubes were threaded (0.5 mm at both ends) to install a mounting flange holding a porous, hydrogel-impregnated plate in place. Sheets (outer diameter 22.225 mm and thickness 3.175 mm), impregnated with sintered polyethylene with gelled cellulose triacetate, were prepared by immersing them in a 6% solution of cellulose triacetate in acetic acid in a container capable of forming a vacuum of 25 mmHg or less. The flask and its contents were kept under vacuum for about 10 minutes, the plates were removed and the cellulose triacetate solution was removed by wiping. They were then immersed in distilled water and equilibrated by keeping there overnight. The plates were then removed from the water, wiped dried and then equilibrated with polyethylene glycol 400 overnight. The plates were then removed and wiped with a towel.

At one end of each tube, an impregnated plate was then mounted by attaching them between two washers having a thickness of 0.254 mm and a diameter the same as that of the steel tubes. The plate closest to the steel tube was cellulose acetate butyrate and the other a dental rubber sealant. The ends were then closed with stainless steel plates with an opening of 21.336 mm in diameter. The tubes were filled with the desired chemical and the other end of each tube was sealed as described above.

Tubes (boluses) were prepared containing containers of 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%); tetramizole hydrochloride (100%); poloxane (100%); erythromycin hydrochloride (100%); thiamine hydrochloride (100%).

Example 13

The procedure of Example 1 was repeated except that the bolus was filled with morantel tartrate instead of the morantel tartrate-polyethylene glycol 400-sodium hexametaphosphate mixture ___ - ττ 36 75735 in this example. The bolus weighed 84.0 g, of which 18.6 g was Moran batch tartrate.

The bolus prepared according to the procedure described herein provided a controlled and nearly constant release rate for morantel tartrate in an in vitro test over an 8-20 day test period with an average release rate of 1.36 g per day.

D. in the in vitro test> Accumulation amount in grams _morantel tartrate_ 1.7 0.04 5.7 1.03 8.7 2.74 12.7 7.63 15.7 12.3 19.7 17.5 23.7 18.3 26.7 18.6

Example 14

Low carbon steel tube with the following dimensions: length 8.77 cm, inner diameter 2.16 cm, outer diameter 2.54 and with a groove 0.3 cm deep and 0.6 cm wide 0.1 cm from it at both ends to attach an aluminum compression rim and completely surrounding the tube was sealed at one end with a sintered polyethylene sheet of very high molecular weight (average 2-4 million, sold by Glasrock, Porex Division, Fairburn, GA.) with an average pore size of 10 micrometers and a saturated pore size of with gelled cellulose triacetate as shown in Example 15. A plate with a diameter of 2.54 cm and a thickness of 0.16 cm was attached to the tube with an aluminum compression rim. The tubes were then inverted and filled with a homogeneous mixture of 54.4% morantel tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The plate / compression edge procedure was repeated to obtain a final bolus. The total weight of the bolus 37,75735 was 145.1 g, of which 41.4 g was a drug mixture. Its density was 2.3 g / ml.

The open central portion of the aluminum compression rim at both ends of the tube was 3.25 cm and the total area was 6.5 cm available for drug delivery. Bolus released controlled-release morantel tartrate in cattle over a period of approximately 90 days. Example 15

An aluminum cylinder 6 cm in length, 2.1 cm in outer diameter and 0.1 cm in wall thickness, provided with a groove at its open end for attaching an aluminum compression rim, was filled with a preparation containing 70% levamisole hydrochloride, 30% polyethylene glycol 400 and sealed with sintered, on a high density (0.95-0.97 g / ml) polyethylene sheet impregnated with gelled cellulose triacetate according to Example 15. The bolus density was 2.8 g / ml. The container contained 23.46 g of the drug mixture corresponding to 16.42 g of levamisole hydrochloride.

The aluminum compression rim used had an open circular area in the middle with a diameter of 1.1 cm and an area of the permeation area of 0.95 cm.

In in vitro tests at 37 ° C, the bolus released levamisole hydrochloride at a controlled rate.

Day in vitro Levamisole hydrochloride released, grams 3 0.815 5 1.572 6 1.805 7 2.33 8 2.64 10 2.79 11 2.83 14 2.87 15 4.66 18 5.10: 22 6, 67 _______ - H_ ____ 38 75735

Example 16 This example shows a field study performed on 40 experimental pigs of the same sex and species and uniform in weight (average 150 kg) and not previously grazed. The calves were divided into four groups of 10 calves based on body weight. Two of the groups were statistically mediated groups and two were statistical control groups. The worm-free control animal was included in each of the four groups of experimental calves at the beginning of the field study and every four weeks thereafter. Each control calf was kept in its pen for two weeks, then removed and placed indoors for three weeks before slaughter to identify worms.

The experimental and control calves were placed on a contaminated pasture where diseased animals had been grazed the previous summer and autumn. The pasture size was sufficient to graze 44 animals throughout the grazing period and was divided into four equal and separate enclosures.

Two medicated statistical groups were orally administered a 60-day bolus prepared according to the procedure of Example 1. The boluses continuously released morantel tartrate at a rate of 250 mg / animal (corresponding to 150 mg of morantel base) per day for 60 days. Medicated groups of animals received boluses two days before they were allowed to graze in the spring. The presence of a bolus in each treated animal was detected by a metal detector 24 hours after dosing. Bolus persistence was examined every two weeks thereafter. All animals, medicated, control and control calves, were weighed before and every 4 weeks before being allowed to graze.

Grass samples were taken according to the method proposed by Taylor (Parasitology, 31, 473, 1939) every two weeks starting four weeks before the start of the field study and continued until the end of the study.

Faecal samples for counting McMaster eggs and lungworm larvae were taken at baseline and every two weeks thereafter. For the first eight weeks, they were rectal specimens (one from each animal). After that, 7 7 7 7 7 5 samples were taken every four weeks together with the weighing of the animals. Intermediate samples, 10 from each group, were taken from the pasture (Gibson, Veterinary Bulletin No. 7, 403-410, 1965).

A decrease in the total number of worms was performed from the rumen of slaughtered animals including mucosal digestion, gastric port, and lung.

Group Treatment Pasture Number of animals 1 Morantel tartrate A 10 + one reference calf 250 mg / d every four weeks 2 Morantel tartrate B 10 + one reference calf 250 mg / d every four weeks 3 Reference group C 10 + one reference calf every four weeks 4 Reference group D 10 + one reference calf every four weeks

The values are shown graphically in Figures 6, 7 and 8. Figure 6 shows the weight gain during the grazing period for both the treated and control groups. In both groups, weight gain was found to be nearly the same over the first three months or so. Thereafter, the weight gain in the control groups slowed down and even decreased for a certain period of time simultaneously with the increase in the number of pasture parasites. The treated animals, on the other hand, continued to gain weight almost similar to that observed at the beginning of the season.

Figures 7 and 8 show the parasitic population during the grazing period in both medicated and control animals. The curves show the number of eggs per gram of faeces (right ordinate) and the number of larvae per kilogram of dry pasture grass (left ordinate). The calves were released into pasture in mid-May; medicated calves were orally administered 60-day boluses two days before being allowed to graze, giving the duration of treatment until mid-July.

When removed from the pasture, the number of eggs in the feces and the number of larvae in the pasture were small. In the control group, fig. 7, eggs began to appear in animal feces in early June, a peak of 40,757,35 was reached in late July and the number slowly decreased during August and September. These eggs caused an increase in grazing larvae observed in late July and peaked in August.

In the treated group, Fig. 8, egg formation during June and July was a strongly decreased factor, which was repeated with a sharp decrease in grazing larvae in July and September.

Example 17

Similar studies were performed using the device of Example 16, but using only one medicated group and one control group in each study. The values obtained are shown in the following table.

Research Animal Avg. weight- Cumulative Decrease% n number increase, number of medicated eggs in the group its advantage .......

1, doc. vert.

for comparison_ 1 12 17.0 kg. 0 79 100 2 13 9.0 33 146 77 3 12 32, 5 67 408 84 4 n 9, 5 145 436 67 5 17 18.2 135 886 85 6 18 13.4 23 62 63 7 24 17, 1 34 150 77 8 31 36, 5 14 28 50

Example 18

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

II

4i 75735

Porous fabric Average pore size (pm)

Polyethylene 75

Polytetrafluoroethylene 100

Glass 60

Stainless steel filter cloth 80

Copper screen 30

Modacrylic fiber ^ 10

/ M

Nickel-copper alloy screen 50 (a) copolymer of acrylonitrile (40%) and vinyl chloride (60%); sells under the trade name DYNEL Union Carbide Corp., N.Y.

(b) sells under the tradename Morel The International Nickel Co., Inc., N.Y.

Claims (7)

A device for the continuous delivery of a chemical, such as a drug, to an aqueous liquid environment over an extended period of time at a controlled rate, wherein the chemical is enclosed in a container surrounded by a shaped wall of at least partially porous material insoluble in the liquid medium, the porous material being at least partially in contact with the container, characterized in that the pores of the porous material are impregnated with a hydrogel medium which permeates the chemical and the aqueous liquid in the environment. Device according to Claim 1, characterized in that the container contains a chemical mixed with a water-soluble carrier. Device according to Claim 1, characterized in that the container contains a chemical mixed with a water-soluble liquid carrier and a surfactant. Device according to Claim 1 or 2, characterized in that the porous material is sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, sintered polystyrene or a porous woven material made of polyethylene, polyethylene, polypropylene, polytetethylene. Device according to claim 4, characterized in that it is intended to be placed in the rumen of a ruminant and the chemical is an anti-gut agent. Device according to Claim 4 or 5, characterized in that the hydrogel is gelled cellulose triacetate. Device according to Claim 6, characterized in that the porous material is sintered polypropylene or sintered polyethylene.