JPS6118525B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides an improved drug-containing chemical-permeable system for releasing drugs or chemicals from a drug-containing reservoir at a controlled rate into an aqueous liquid-containing environment, particularly the physical environment of animals, including humans. or to devices and drug or chemical evacuation devices including such systems. This in particular consists at least in part of a wall formed of a porous material, the pores of which contain a hydrogel, such as porous fibers, and the porous material is in contact with the drug or drug-containing storage source. More particularly, it relates to such systems and devices which provide a controlled release drug to a ruminant, and which contains a large ruminant, which is retained in the pouch of the animal's ruminant stomach. Regarding pills. controlled release of drugs, i.e. controlled release or sustained or extended release;
Drug delivery systems and devices for drug delivery are well known in the art. Various methods have been described in the literature, including physiological regulation of absorption and excretion, preparation of solvents, chemical preparation of drugs, adsorption of drugs on insoluble carriers, use of suspensions, and incorporation of pellets into the body. Includes installation (Edkins, J.Pharm.
Pharmacol., 11, 54T-66T, 1959). Another method involves mixing the drug with a carrier that is gradually degraded by the environment, such as body fluids, to release the drug. Waxes, oils, fats and soluble polymers have been used as carriers. It is also known to disperse the drug in a solid matrix material from which it is released by diffusion, or to encapsulate the drug in a capsule with a polymeric wall, through which the drug can pass by diffusion. US Pat. No. 3,975,350 describes a hydrogel carrier system composed of polyurethane polymers for use in pharmaceutical, fungicide, insecticide, algaecide, etc. applications. US Pat. No. 1,693,890 describes the production of porous semipermeable membranes of gelatinous cellulose acetate for use in dialysis. This method consists of precipitating cellulose acetate from its acetic acid solution by addition of a non-solvent such as water. If desired, this semipermeable membrane can be formed on the support. The semipermeable membrane thus produced is impregnated with water, but may be freed from water by washing with alcohol, acetone, or other water-miscible liquid. Cellulosic polymer-liquid composite (PLC) materials in the form of films, fibers or microspheres, such as cellulose esters such as cellulose triacetate, cellulose nitrate or molecular mixtures thereof, are used in the United States as vehicles for the controlled release of various materials. It is described in Patent No. 3985298. The substance to be released is the liquid phase (alcohol,
water or mixtures thereof). US Pat. No. 3,846,404 describes semipermeable membranes of gelled cellulose triacetate useful as carriers for other substances such as liquids with pharmaceutical properties. Impregnation of smooth-finished, non-woven polyethylene fabrics and plain woven cotton fabrics with gelled cellulose triacetate is described to provide supported cellulose triacetate hydrogel materials. The use of drug-impregnated gelled cellulose triacetate products as slow-release agents for placement within the body of animals is described, as is the casting of gelled cellulose triacetate onto woven or non-woven support sheet materials. has been done. A controlled release drug delivery device comprising a reservoir formed of a drug and a solid or liquid carrier and a diffusible material (e.g., solution, colloidal solution) in contact with or surrounding this source that is permeable to the drug by diffusion. Walls formed from any of a variety of materials are described in one or more of the following US patents, such as microporous materials with micropores containing microorganisms, suspensions, or sols. US Patent 3993072;
3993073; 3896819; 3948254; 3948262;
3828777; 3747494; 4060084 and 3995634. U.S. Pat. No. 3,993,073 also discloses hydrophilic hydrogels of esters of polyvinyl alcohol crosslinked with acrylic and methacrylic acids as suitable wall-forming materials. A key feature of the device of the present invention is that the pores are at least partially made of a microporous material containing a drug-permeable drug release rate controlling medium; The use of a reservoir consisting of a carrier that is permeable to the drug at a greater rate than the controlled release medium. Suitable for administering therapeutic or nutritive substances to ruminants, this substance can be partially incorporated into a permeable, water-insoluble material having capillaries or internal communicating pores throughout, and a water-insoluble polymer such as cellulose triacetate. A device consisting of an encapsulation of impregnated paper or cloth is described in British Patent No. 1318259. US Patent No. 3,594,469 discloses pellets containing these metals for administration to ruminants to provide them with magnesium and iron over an extended period of time. In one embodiment, the pellet consists of a magnesium alloy cylindrical tube filled with metal shots and some biologically active substance and padded at both ends with porous disks. U.S. Pat. No. 3,938,515 discloses a continuous drug delivery system for extended periods of time consisting of a storage source containing a drug and a drug-permeable solid or liquid carrier and a surrounding polymeric wall that is permeable to the drug but allows it to pass through at a rate less than that of the carrier. Known devices designed for administration are made. U.S. Pat. No. 3,946,734 was designed primarily for use in the body, essentially having one end sealed with an impermeable material and the other end and the remainder of the tube encapsulated with a porous neutral hydrogel. A diffusion cell consisting of a capillary tube is disclosed. The biologically active substance is placed in this capillary on the impermeable substance side;
The capillary is then filled with hydrogel (agarose, polyacrylamide), through which the biologically active agent diffuses. Many of the known controlled release devices are described as zero order release devices. However, although such devices are capable of maintaining zero-order release rates for a relatively short portion of their intended lifespan, they are impractical for long-term use, for example in ruminants. On the other hand, the device of the present invention achieves and maintains controlled and predictable zero-order release rates over long periods of time.
Additionally, known devices include, for example, a drug-containing reservoir and a molded wall surrounding it formed at least in part from a microporous material, the micropores of which have a drug-permeable drug release rate controlling medium (diffusive medium). are susceptible to physical obstruction or physical damage in certain environments of use, such as in the ruminal pouch of ruminants. This occlusion reduces or even stops the release of the drug, thus rendering the device incapable of operating for its intended purpose.
This problem is essentially non-existent in the device of the present invention because the pores of the porous material in contact with the drug-containing reservoir contain hydrogels and can be controlled in an aqueous medium-containing environment for extended periods of time. and can provide predictable release rates. When used for controlled release of highly water soluble drugs, known devices (U.S. Pat. No. 3,993,073,
3993072, 3967618, 3948262, 3948254 and
No. 3,896,819) in which the walls and/or reservoir are formed from a substantially water-impermeable material to prevent absorption of body fluids into the device, thereby diluting the drug and reducing the rate of drug release. likes to be treated. They are therefore unsuitable for the elimination of water-soluble drugs, especially at relatively high rates. Furthermore, the devices described in most of these patents require that the drug permeability of the drug release rate controlling medium in the pores of the porous wall surrounding the reservoir is less than the drug permeability of the carrier in the reservoir. I need. According to this measure, wall penetration of the drug is the rate-limiting step. The device of the present invention does not suffer from such limitations. Indeed, the difference of the device of the invention over known devices lies in the presence of a highly water-permeable hydrogel in the pores of the porous material in contact with the storage source. The device is based on the diffusion of water from the aqueous liquid environment in which it is placed through the liquid filling the micropores or channels in the hydrogel to the storage source and the outward diffusion of the drug from the storage source into the environment. Unexpectedly, the concentration of drug dissolved in the depot does not decrease, thus providing a substantially constant release rate over an extended period of time. However, the amount of drug dissolved in the reservoir varies continuously throughout the life of the device of the present invention. Downing uses a low content of the anthelmintic morantel tartrate in calf drinking water, allowing calves to drink the drug-containing water as a means of internal parasite control.
et al., Irish Vet. J. 221, November 1974 and British Patent No. 1530161. Continuous daily application of dewormer to calves from early April to mid-July reduced the shedding of insect eggs by the calves and prevented, or at least minimized, the spread of severe infection by grass larvae. It's been found. When calves were given low-concentration morantel tartrate in their feed every day from the time they were put out on the pasture until mid-July, the grass used by the grazing calves became highly contaminated, resulting in parasitic infections. Jones et al) have been successful in controlling gastroenteritis caused by insects and infections caused by lung nematodes. , Brit.Vet.J.134, 166
(1978). To release chemicals, such as veterinary drugs, from a chemical-containing storage source into an aqueous liquid-containing environment, particularly into the internal environment of an animal such as a human, at a controlled rate that is physiologically or pharmaceutically effective. The present invention relates to an improved chemical permeability system and device.
In particular, the present invention relates to such systems and devices comprising a container, at least a portion of which wall is comprised of a porous material, such as a porous fiber, the pores of which contain a hydrogel. The present invention relates to a device in which a chemical substance is in contact with at least a portion of a chemical substance or a chemical-containing storage source. More particularly, the present invention comprises a system for delivering a drug in a controlled release manner to a ruminant,
Concerning large pills held in the pouch of the honeycomb stomach. The improved chemical, e.g., drug (these terms are used interchangeably herein) permeable systems and devices of the present invention provide for the controlled introduction of drugs and other chemicals into an aqueous liquid-containing environment. It is particularly valuable for oral administration to animals, including humans, and can be used in a variety of pharmaceutical preparations. Furthermore, the device is particularly suitable for discharging highly water-soluble substances at high speeds, which cannot be easily achieved with known devices. The systems and devices of the present invention provide controlled release of chemicals over long periods of time, are easy to manufacture, and are reliable and easy to use. Moreover, the devices of the invention retain their physical and chemical integrity, do not become occluded in the environment of use, and are particularly valuable for oral use in ruminant bolus form. These provide for the first time a practical device for the controlled continuous release of chemicals, such as drugs, into an aqueous liquid environment, thus meeting a long-standing need, particularly in the storage industry. The controlled rate release systems and devices of the present invention contain a haze barrier layer or wall in contact with at least a portion of the chemical storage source, the wall being partially or entirely porous, such as a porous fibrous material. The hydrogel contains a material whose pores allow liquids to pass from the environment through the pores within the hydrogel itself by diffusion, and chemicals to pass from a storage source. When the device of the present invention is in use, the hydrogel contains liquid from the environment, which is provided by sections or passageways (pores) within the hydrogel itself for the diffusion of the environmental liquid and the delivery of the drug. Contained in micropores that serve as passageways. The systems and devices of the present invention may take on a variety of shapes and sizes depending on the purpose for which they are used. For example, they may be in capsule form for oral use in humans and animals, or in cylindrical form for use as inserts or bolus in ruminants. A preferred form of the device of the invention, in its broadest aspect, comprises a porous material, the pores of which contain a hydrogel, in particular gelled cellulose triacetate, and which are freed from the environment by diffusion through the pores within the hydrogel. permeable to liquids and drugs, the porous material being permeable to at least a portion of the chemical, e.g., drug, containing reservoir, consisting of a chemical and, if desired, a suitable aqueous liquid excipient and, if desired, a detergent. The device is made in the specific form of a pill used to provide controlled drug release over a long period of time to ruminants, especially cattle and sheep. Particular uses of such pills are parasitological, in particular the deworming of cattle and sheep, gastrointestinal and pulmonary nematode infections and pasture parasitic contamination;
control, prevention and treatment. As used herein, the term "bolus" includes devices that are generally cylindrical, spherical, round, oval, or otherwise shaped without sharp edges or protrusions. . Known devices require consideration or compromise of several factors for each application. These factors include the carrier used within the reservoir, the solubility and/or permeability of the carrier to the drug contained within the reservoir, the nature of the microporous wall surrounding the reservoir, and the pores contained within the microporous wall. the diffusible medium, the relative permeation rates of the diffusible medium and carrier for the drug, the relative solubility of the drug in the diffusible medium and carrier, and the need to maintain a substantially constant amount of drug dissolved in the reservoir source. . On the other hand, the device of the invention is significantly simpler in design and operation. In a given device,
The rate of chemical release can be varied widely by simple means of varying the area and thickness of the porous material, such as a porous fibrous material, whose pores are filled with hydrogel and in contact with the storage source. Therefore, it is possible to control the amount of chemical released by manipulating just two parameters. Figures 1 to 5 of the accompanying drawings illustrate various examples of the apparatus of the invention. The fact that only a few examples have been shown does not limit the invention in any way; many modifications and equivalents thereof are possible. FIG. 1 is a perspective cross-sectional view of one device of the invention, in which the evacuation device 10 consists of a cylindrical wall 11 in contact with a chemical-containing storage source 12. The wall 11 is comprised of a porous material, the pores 14 of which contain a hydrogel (not shown) through which liquid from the aqueous liquid-containing environment diffuses into the storage source 12. The chemicals from 12 diffuse into the environment through channels or pores within the hydrogel itself.
The reservoir 12 consists of a chemical 15, and in a preferred embodiment of the invention, a drug and a water-soluble excipient 16. End 17 is an impermeable cap or closure. FIG. 2 is a schematic diagram of one device of the present invention, which is a discharge device of the type shown in FIG.
However, a perforated sleeve 18, such as stainless steel, iron, or plastic, is inserted as a means to control the surface area of the hydrogel-impregnated porous wall 14 and, if metal, as a means to increase the weight of the device. FIG. 3 is an enlarged view of the porous wall 11 of the device 10 of the invention, the pores 14 of which are defined by the hydrogel 19.
The wall itself contains a chemical-containing storage source 1 consisting of a chemical 15 and an aqueous liquid excipient 16.
It is in contact with 2. FIG. 4 shows a discharge device shaped as a capsule and having only one enclosure 17. FIG. 5 depicts yet another device 10 of the invention in which the end wall of the device 10 comprises a porous material whose pores 14 contain a hydrogel (not shown). The cylindrical wall 18 is in this case made of impermeable, non-porous material stainless steel, which along with the hydrogel impregnated end wall 14 is impregnated with the chemical 1.
4 and excipient 16 is enclosed. As illustrated above, the improved evacuation device or system of the present invention includes a chemical agent and, in a preferred form, a chemical agent, e.g., a drug-containing reservoir, consisting of a chemical agent and an aqueous liquid vehicle. Water-soluble liquid excipients serve several important functions, such as allowing large loadings in the manufacture of this device by excluding air from the storage source (constant release of chemicals) speed) to increase convective mixing within the storage source. Additionally, the water-soluble liquid excipient serves the additional role that as the chemical dissolves, there is no change in volume as the chemical goes from a solid or crystalline state to a solution state. Typical water-soluble liquid excipients include mono- or polyhydric alcohols and their ethers, such as ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycol, sorbidol, di- and tri-ethylene glycols, di- and tri- Propylene glycol, 1.2
- Mono-C _1-4 alkyl ether of dimethoxyethane, ethylene and propylene glycol; N,N
-dimethylformamide, dimethylformamide, etc. Of course, the excipient must be compatible with the hydrogel. Of course, the device of the present invention can
When used in liquid-containing environments used by animals, such as aquariums, fishponds, animal and poultry water systems, hydroponic systems, the water-soluble liquid excipient should be a physiologically suitable substance. The amount of water-soluble liquid excipient used per unit weight of drug varies depending on the characteristics of the drug. Generally, enough excipient is used to form the drug-excipient combination into a compact mass, which can be readily determined by simple experimentation. For the total weight of storage sources (chemicals, e.g. drugs and, if used, excipients and detergents)
Up to 20% by weight of detergent may be used in the reservoir to minimize the possibility of clogging the equipment during use. Typical cleaning agents may be inorganic or organic in nature, such as sodium and potassium hexametaphosphoric acid and tripolyphosphate, sodium lauryl sulfate, sodium glyceryl monolaur sulfate, dioctyl sodium sulfosuccinate, sodium bis(1-methylamyl) sulfosuccinate, Included are polyoxyethylene sorbitan monooleate and other fatty acid esters and others known to those skilled in the art. The amount used when cleaning agents are used is not critical and in any case can be kept to a minimum so as not to compromise the chemical loading in the reservoir. The optimal amount is determined by the method described below. As used herein, "reservoir", "chemical-containing reservoir", "chemical-containing reservoir", "chemical-containing reservoir"
reservoir) and drug-containing reservoir (drug-
The term "containing reservoir" is used interchangeably. For convenience, the term "drug-containing depot" is the preferred form, since the preferred devices of the invention are for use in the controlled release of drugs. As used herein, "porous material"
materials)", "porous membranes (porous
"membranes" or "porous walls"
The term "walls" includes porous fibrous materials. Representative types of such materials will be described below. Even if the porous material used is isotropic, that is, it has a uniform pore structure over the entire cross-section of the material,
Alternatively, it may be anisotropic, that is, it may have a non-uniform porous structure. These must, of course, be insoluble and unreactive with the environment and the contents of the reservoir. Generally, porous materials having pore sizes of about 1 to 100 microns can be used in the controlled release devices of the present invention. A porous material is needed that has a porous structure containing continuous pores, ie pores that are effectively open on both sides of the porous walls that join them. The pores, or portions of the pores, of the porous material are filled with a hydrogel to facilitate the transfer of drug from a storage source to the environment when using the controlled release device of the present invention. The result of the combination of a porous material whose pores are partially filled with hydrogel is that the device resists occlusion and physical disruption under normal conditions of use, and by preserving its physical integrity, It can be used in environments and situations where previously known hydrogel devices would break down and be ineffective for providing controlled release of drugs over long periods of time. The device of the invention is of particular value for use in ruminants, particularly cattle and sheep. The hydrogel-containing pores allow liquid (water) to pass through the pores of the hydrogel itself by diffusion from the environment in which the controlled release device is provided to the reservoir containing the drug in use. The drug then passes through the liquid in the micropores of the hydrogel-containing pores of the porous material barrier to a concentration of the drug in solution in the storage source, barrier,
That is, it diffuses at different rates due to the resistance provided by the liquid in the micropores of the hydrogel and the effective surface area of the porous portion of the wall. As the drug exits the device, a depletion zone gradually forms, causing movement of the drug/solution boundary. Diffusion of water into the device from the environment through micropores in the hydrogel-containing pores of the walls to the storage source causes convective mixing of the incoming aqueous phase with the solution in the storage source of the device. The driving force for this mixing is the difference in density between the two solutions due to their large concentration difference. As mentioned above, the function of the water-soluble liquid excipient is to help maintain this large density difference and thus enhance this critical mixing. Convective mixing causes the reservoir to have a constant drug concentration while the reservoir provides a controlled release of drug over an extended period of time, thus resulting in zero-order release of drug as long as undissolved drug remains in the device. guaranteed. As the drug leaves the reservoir, aqueous liquid from the environment diffuses into the reservoir. The amount of drug dissolved in the reservoir varies continuously over the life of the device, ie, over a long drug release period. This drug release mechanism can employ any device configuration, and the size and shape of the reservoir is not limited. This is US Patent No.
This is in direct contrast to the known device described in No. 3993073. The latter relies on and is configured to achieve a substantially constant amount of dissolved drug in the reservoir and diffusion of the dissolved drug in the reservoir to deliver the drug to the wall. Products have strict restrictions regarding size and shape. The term "hydrogel" as used herein refers to a gel containing water, Hackh's Chemical Dictionary, Section 4.
ed. Grant, p. 332, 1969, it is defined as "a gel produced by the coagulation of a water-containing colloid." Representative hydrogels that can be used to fill the pores of porous materials include: Gelled cellulose triacetate (see US Pat. Nos. 1,693,890 and 3,846,404); acetyl content 20
Cellulose acetate hydrogel derived from ~40% cellulose acetate; polymerizable hydroxyethyl methacrylate; cross-linked
bonded) polyvinyl alcohol; agarose;
Polyacrylamide; crosslinked partially hydrolyzed polyvinyl acetate; hydroxyethyl acrylate; diethylene glycol monoacrylate; diethylene glycol monomethacrylate; 2-hydroxypropyl acrylate; 2-hydroxypropyl methacrylate; 3-hydroxypropyl acrylate; 3-hydroxypropyl methacrylate; Propylene glycol monomethyl acrylate; Vinylpyrrolidone; Acrylamide; Methacrylamide; N-propylacrylamide;
N-isopropylmethacrylamide; N-methylacrylamide; N-2-hydroxyethylmethacrylamide; poly(alkyleneoxy)polyol and organic diisocyanate or organic polyamine lightly crosslinked with water as described in U.S. Pat. No. 3,939,105 It is a reaction product with Polyurethane hydrogels consisting of lightly crosslinked polymers of isocyanate-terminated prepolymers; copolymer of ethylenically unsaturated monomers of hydroxyalkyl acrylates and methacrylates and alkoxyalkylene glycol acrylates and methacrylates as described in U.S. Pat. No. 4,038,264; Polymer; organic diisocyanate, the first diol is a water-soluble polyalkylene glycol with a molecular weight of 3,000 to 30,000, and the second diol is an oxyalkylenated diphenol having 2 to 20 oxyalkylene groups. and others known to those skilled in the art. Advantageous hydrogels used in the present invention are polyurethanes; polymerizable hydroxy lower alkyl acrylates or methacrylates, vinylpyrrolidone, acrylamide, N-lower alkyl acrylamides and methacrylamides, especially crosslinked or copolymerized with hydroxyalkyl acrylates or methacrylates. The resulting copolymer is made water-insoluble. Preferred hydrogels are gelled cellulose triacetate, polymerizable hydroxyethyl methacrylate and crosslinked polyvinyl alcohol. Particularly preferred are gelled cellulose triacetates which provide smooth and efficient operation of the controlled release device of the present invention. The water present in the micropores of the hydrogel can be easily replaced by a water-soluble liquid, such as the water-soluble liquid excipients disclosed above. Other water-soluble liquids, such as alcohols of 1 to 4 carbon atoms, can also be used to replace water. As a practical matter, to stabilize the device of the invention, particularly when the hydrogel is a gelled cellulose triacetate,
The water in the hydrogel is replaced with a suitable water-soluble liquid having a vapor pressure lower than that of water, and thus the device can be stored without loss of efficiency as a result of drying of the hydrogel. When using a water-soluble liquid excipient-drug combination in the reservoir, it is convenient to use the same liquid that displaces water from the hydrogel. Hydrogels themselves are porous in the sense that they contain portions or regions, channels or pores, filled with water or other liquids.
Therefore, throughout this specification with reference to the diffusion or transport of chemicals or agents through the walls, ``pores of which hydrogels'' are used.
``containing hydrogel'' and similar expressions are intended to mean that diffusion or transport of the chemical or drug occurs through these regions rather than through the hydrogel itself. The hydrogel itself has liquid-filled pores that provide channels for diffusion and are, in fact, permeable to environmental liquids and chemicals from storage sources. The porous wall in contact with the drug-containing reservoir may be any of a variety of materials. The porous material may completely surround the storage source or may form part of a wall surrounding the storage source. Suitable porous materials include porous metals, porous ceramics, sintered polyethylene, sintered polyvinyl chloride, sintered polypropylene, sintered polystyrene and sintered tetrafluoroethylene, Chem.Eng.News, December 11, 1978. These include porous polymers made from thermoplastic resins by phase separation techniques such as those described on page 23 of Japan, and others well known to those skilled in the art. Preferred porous fibers are polypropylene and polyethylene, especially each type is a "filter cloth".
These fibers are called glass, polytetrafluoroethylene, nylon, cotton; modacrylic fibers, i.e. acrylic fibers, consisting of long chain synthetic polymers containing 35-85% acrylonitrile units; acrylic fibers, i.e. Synthetic polymers with 85% by weight of acrylonitrile; polyesters, i.e. long-chain synthetic polymers consisting of at least 85% by weight of dihydric alcohols and esters of terectalic acid; polyvinyl acetate; polyvinyl chloride; vinyl acetate-vinyl chloride copolymers Polyvinyl alcohol, vinyl alcohol-vinyl acetate copolymer, polyvinyl alkyl ether; vinylidene cyanide, vinylidene chloride, vinylidene fluoride polymer,
Polyureas and others known to those skilled in the art [Encyclopedia of Polymex 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, 445
and 506 (1969); Vol.14, 305, 575 (1971),
(See Interscience Publishers, New York). Also suitable are metal meshes or filter cloths, such as those made from stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel-copper, and the like. Of course, the particular fiber selected must be compatible with the hydrogel in which it is impregnated and with the end use of the device. Thus, in the case of a device used as a bolus for administering drugs to ruminants over long periods of time, cotton cannot be used as a fiber as it would be degraded by the ruminants. Cotton can be used in devices used for controlled release of chemicals into aqueous environments, such as aquariums or reservoirs. When gelled cellulose acetate becomes a hydrogel, nylon is not used as the fiber. This is because nylon is degraded by the formic acid or acetic acid used during the impregnation process. The porous fibrous material impregnated with hydrogel is of course sufficiently strong, durable, and inert to the drug and the environment of use, so that the controlled release device made therefrom has physical and Must maintain chemical integrity. The porous material is impregnated with a suitable hydrogel in a manner known to those skilled in the art. An advantageous and relatively simple method of impregnating a porous material with the preferred hydrogel, gelled cellulose triacetate, is to add a formic or acetic acid solution of cellulose triacetate to the cellulose triacetate solution in a container that can be evacuated. It consists of forcibly penetrating into the pores of a porous material by immersing it in the material. After impregnation, the plastic "loaded" with cellulose triacetate is coagulated by contacting and equilibrating with a large amount of water, thus producing a hydrogel impregnated material. When the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate, acetic acid is more advantageous than formic acid as a solvent for cellulose triacetate. This is because it wets polyethylene better than formic acid and thus facilitates the production of hydrogel-impregnated porous materials. If the hydrogel is derived from 2-hydroxyethyl methacrylate crosslinked with ethylene glycol dimethacrylate as described in U.S. Pat. and ethylene glycol dimethacrylate, and then the mixture was filled with peroctanoic acid t-
This is achieved by polymerization within the pores by addition of a radical catalyst such as butyl. In a similar manner, other hydrogels are impregnated into porous wall materials by such "in situ" formation methods from appropriate reactants. When the hydrogel is cross-linked polyvinyl alcohol, the pores are prepared using polyvinyl alcohol (10% aqueous solution) and resorcinol (2-3
%) mixture, thus crosslinking is achieved in situ. Of course, other crosslinking agents can also be used, as is well known to those skilled in the art. When producing a storage-stable device prior to use, the hydrogel-impregnated pores are rendered water-free by equilibrating them in a suitable aqueous liquid, such as the aqueous liquid excipients listed above. When the storage source consists of a combination of chemicals and excipients, it is convenient to replace the water in the hydrogel-filled pores of the porous material with the same aqueous liquid used as the excipient in the storage source. You will find it good. If in the device of the invention the storage source consists of chemicals alone:
The choice of aqueous liquid used to displace water from the hydrogel in the porous-walled hydrogel-filled pores is determined solely by the end use of the device, i.e. whether a physiologically relevant aqueous liquid is required. be done. Such a liquid is conveniently introduced into the hydrogel when producing a porous wall whose pores are impregnated with the hydrogel, prior to filling the reservoir of the device as exemplified herein. The known devices most closely related to the device of the present invention, namely those described in U.S. Pat. It depends on the difference in the rate of permeation of the drug through the drug-carrier phase.
To actually achieve the zero-order release rates claimed to be achieved with the devices described in these patents, it is essential that the medium in the device walls be less permeable to the drug than the drug carrier in the reservoir source. be. The medium in the wall thus becomes the drug release rate controlling part of the device. Dissolved drug diffuses through the more permeable carrier to the inner wall quickly enough that the wall becomes the drug release rate controlling part. As a result, a zero-order release rate occurs for some time, but stops when the receding drug boundary within the device becomes large enough to compensate for the permeability difference between the carrier and wall media, thus reducing this zero-order rate. The next speed is no longer available. For this reason, these devices have had limited success in practice and are not suitable for the sub-dose delivery of large quantities of drugs in the form of practically useful dosage forms. In contrast to conventional devices, the device of the present invention has an aqueous environmental medium within the walls and within the storage source during use.
The drug permeability is the same in the wall and in the liquid within the reservoir, but a zero-order release rate is achieved over most of the lifetime of the device. Furthermore, maintenance of zero-order release is not dependent on diffusion in the depot carrier, so these devices have no geometric or dosage limitations and for the first time large quantities of drug can be accommodated in a practical size and shape. In this embodiment, it became possible to eject at zero-order velocity. For the most efficient operation of the controlled release systems and devices of the present invention, it is essential that the porous material be as completely impregnated with the hydrogel as possible. If the device has the same surface area, the properties of its membrane wall,
Different dosing rates and release periods can be provided for a given drug, especially by varying its thickness, pore size and porosity, and by varying the size of the reservoir fill. As mentioned above, the preferred form of the device is in the form of a bolus for use in the controlled release of drugs to ruminants, primarily cattle and sheep, over long periods of time. The pill is administered to ruminants, preferably by oral administration, in such a way that it remains in the ruminal pouch for an extended period of time, during which time the pill continuously delivers the drug at a controlled rate of release. released into animals.
The device thus allows for the control (preventive and therapeutic) of various pharmaceutical and physiological conditions to which the animal is exposed by simple oral administration of the device to the animal. In order for a large pill to be able to remain for a long time once placed in the gastric pouch of a cow's hump stomach, the large pill needs to have a density of at least 2.0 g/ml. In practice, the density can vary from as low as 2.0 to as high as 7 or higher. Of course, density is the most important factor influencing the retention of the pill in the hump-honey pouch. The overall size of the pill is a function of the required dosage 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 desirable to use the largest possible dimensions. The reason is that a larger bolus with a given density will retain better than one with a lower density. However, even if the average density of the bolus is increased to values above about 5.0, increasing the size of the bolus does not significantly improve the retention factor. The preferred average density for the bolus is about 2.5-5 g/ml. The size of the pill varies, of course, depending on the animal being 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 size of the pill used in any animal is determined by the practical difficulty of administering such a target to the animal. When administered to sheep, the minimum weight that a density 4 bolus can retain is approximately 1 g. The size of the large pill varies depending on the density of the large pill. When administered to cattle,
The minimum weight of a large pill with a density of about 4 is about 5 grams. Again, the upper size limit is determined by the practical convenience of dosing the subject animal and the minimum average density of the bolus. For example, length 7.5cm, diameter 2.5cm, density
A 2.2 large pill has a weight on the order of about 90g. The density of a pill containing only the above-mentioned elements is generally lower than the lower limit indicated above. Therefore, in order to increase the density to the desired value, it is possible to increase the density of large pills by incorporating suitable high-density substances such as metals (iron powder, iron granules, steel granules) or other densifying agents, minerals such as _CaSO4 . It is necessary to increase the average density. Alternatively, average density can be achieved by incorporating a dense porous material, such as a metal (e.g., stainless steel, steel, especially low carbon steel or iron), as an inner sleeve in the pill, surrounded by a hydrogel-impregnated porous membrane. It can be conveniently increased by providing . The pores in the sleeve must be large enough to allow free passage of drug and liquids from the environment through the hydrogel-impregnated porous membrane. The key factors in such sleeves are to increase the average density of the bolus to a value that will result in its retention in the ruminal pouch and to control the surface area of the hydrogel-impregnated porous material in contact with the drug-containing reservoir. There is a particular thing. Furthermore, such a sleeve improves the physical safety of the bolus, although it is not necessary, and ensures that it substantially retains its physical shape under conditions of use. Yet another preferred variant consists of a cylinder made of metal, for example steel or iron, which is capped at one or both ends with a porous membrane, the pores of which are impregnated with hydrogel. This type of large pill is preferred because it is simple and economical to manufacture, and its density can be easily adjusted. Low carbon steel is highly preferred as a material for making cylinders. Other variations can be easily deduced by those skilled in the art. The controlled release device of the present invention can be used for a variety of purposes and situations where controlled release of drugs or other chemicals is desired. These can administer drugs and deliver chemicals near or remote from the point of use of the device. They can be placed by suitable means in a suitable location in contact with body fluids within the animal body, for example in the stomach of domestic animals, in particular in the rumen of ruminants. Also included within the controlled release devices of the present invention are those for use as depot implants for the purpose of administering drugs to a host at a controlled rate. This installation differs from the device of the invention used for other purposes only in its shape, which is of course designed for installation inside the body. Other uses include sublingual or buccal tablets, petals, suppositories, bandages, and skin patches. Further applications of the controlled release system and device of the present invention are in agriculture for the administration of fertilizers and pesticides, in fish farming such as aquariums and fishponds, in drains, canals and aquaria for algae control and in particular for the administration of pesticides. It is found in the water supply systems of animals and poultry that require it for therapeutic or preventive treatment. The criteria for suitable substances, such as drugs or chemicals, for use in the device of the invention is that they have sufficient water solubility to achieve a rate of release of the drug or chemical that produces the desired results in the environment of use. That's true. For this reason, it is desirable to use drugs and chemicals that are acids or bases in the form of their physiologically or pharmaceutically appropriate salts. The rate of release of the drug or chemical from the device of the present invention depends on the wall thickness, available surface area, effective pore size, wall porosity, the nature of the hydrogel, the concentration of the material in the reservoir and its solubility in the environmental fluid. It depends on several factors. The suitability of a given material is determined by the methods described below. Representative examples of drugs that can be used in the device of the present invention are as follows. Anthelmintics such as morantel, pyrantel, oxantel, piperazine, diethylcarbamazine, levamisole, tetramisole and salts of hygromycin B; tetracyclines,
Antibacterial agents such as 5-oxytetracycline, chlorotetracycline, doxycycline and their Mannich bases; penicillins such as ampicillin, penicillin G; neomycin, streptomycin, apramycin, and bacitracin with its zinc or methylene Aminoglycosides as disalicylic acid derivatives; macrolides such as erythromycin, oleandomycin and tyrosine; antibacterial agents such as salts of avoparicin, polymyxin, lincomycin, bambermycin and ecrotomycin; growth promoters; diethylstilbe; hormonal growth promoters such as Stoll, Zealanol; anthelmintics such as Amprolium; nutritional supplements such as Yagnesium, Selenium, Copper soluble salts and vitamins such as Thiamine Hydrochloride; sulfur drugs such as Sulfamethazine, N- Molluscicides such as rutilemorphine and anti-edema agents such as alcohol ethoxylates and poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) polymers, such as poloxalene. As mentioned above, in a preferred form of the invention, the drug-containing depot consists of a drug and an aqueous liquid excipient. Devices manufactured in this way have the advantage of providing a higher volume per device and increasing the useful life of the device. However, the reservoir can contain only selected drugs. The device of the invention is particularly valuable as a slow-release pill for use in the control (therapeutic and prophylactic) of parasitic infections in ruminants, especially cattle. Conservation of pasture animals becomes relatively easy. In mild climates, low initial populations of grass larvae, left over from previous seasons' contamination, are propagated by circulation by animals grazing on them, and in summer,
This results in a significant increase in pasture infection. During the summer grazing season, this condition results in clinical parasitism and behavioral decline in animals grazing on this pasture. Continuous and controlled release of anthelmintics, such as morantel, into the rumen-nest pouch of animals grazed early in the season when pasture contamination is low reduces the production of parasite eggs and subsequent larvae; This breaks the cycle described above and keeps the parasite load on grass and animals at a low level. Infection by parasites of ruminants grazed on the same pasture throughout the summer is thus minimized. This method of parasite control is particularly attractive and valuable for calves. The reason is that these calves have very low resistance to parasites when they are first grazed. The consistent action of the pill reduces the reservoir of infectious parasite forms in a given location. When the anthelmintic pill of the present invention is used in this manner, the seasonal increase in grass larvae, which can cause gastroenteritis and behavioral impairment due to parasites in grazing animals at the end of the season, can be prevented or at least minimized. Make it. In this control method, the period of drug release is during the spring breeding season and not during the period of severe pasture contamination, larval attack and larval infection that results in clinical disease and behavioral impairment. This method of use is therefore called "indirect control." In other words, when grazing a ruminant that has one or more devices of the invention in its rumen pouch, the device is removed from the pasture at the beginning of the season, when larval contamination is at or near its lowest level. It allows for a controlled and continuous release of anthelmintics, such as morantel, into the sac at the ground, making it possible to minimize the normal seasonal increase in larval contamination of pastures, and allowing for the entire grazing season. It serves to protect the animals grazing on it. In the case of "indirect control" of parasites, the device of the invention, preferably in the form of a pill, is used to ensure that the contamination of pasture with the parasite, its eggs and/or larval stages is at the lowest level in the epidemiological cycle of the parasite. administered to ruminants when the substance is at or near the In temperate regions, this period marks the start of spring grazing, when calves are first put out on the pasture (beginning to graze). For maximum efficiency, feed calves approximately 2 to 7 days before starting grazing. In non-temperate parts of the world, such as in the subtropics and tropics, the lowest infection of grasses usually occurs before the rainy season. It is preferable to administer Oogan to ruminants in such regions 2 to 14 days before the start of the rainy season. However, because the rainy season is unpredictable, parasite control in non-temperate regions is best achieved by "direct control" methods. The pill of the present invention also eradicates already established parasitic infections in ruminants and prevents the establishment of adult infections during the summer period during the height of attack. This method of use is called "direct control." Direct control methods protect ruminants only during the period of anthelmintic release. Parasitic control methods protect animals grazing on a given pasture for an entire season. The reason is that this achieves a significant overall reduction in pasture contamination.
As mentioned above, the device of the present invention allows continuous release of agents, such as dewormers, at a controlled rate. Particularly useful for such purposes are (E)-1,
4,5,6-tetrahydro-1-methyl-2-
[2-(3-methyl-2-thienyl)ethenyl]pyrimidine (molantel), (E)-1,4,5,6
-tetrahydro-1-methyl-2-[2-(2-thienyl)ethenyl]pyrimidine (pyrantel) and (I)-2,3,4,5-tetrahydro-6-
It is a water-soluble salt of phenylimidazo[2.1-b]thiazole (tetramisole) and its L-(-)-form, levamisole. Representative examples of preferred water-soluble salts of pyrantel and morantel are the tartrate and citrate salts, and in the case of tetramisole and levamisole, the hydrochloride salt. The large pill of the present invention is orally administered to animals using, for example, a balling gun. When used in calves, the desired average release rate of morantel (calculated as base) for relevant control of parasites is on the order of 60 to 200 mg (morantel base) per day for approximately 60 days; encompasses the normal maximum survival period of the spring larval population. 60~ for direct control method
A longer release period of 120 days is desirable. This is because the period of exposure to intense pasture contamination typically spans from mid-summer to fall. Release rates of about 60 to 150 mg per day (calculated as morantel base) effectively control parasitic infections over such release periods. When administering to larger animals, more than one pill can be administered. In the case of indirect control of parasites using salts of pyrantel or lavamisole, the desired average release rates of each (calculated as free base) are 100-400 mg and 100-500 mg, respectively, per day for a period of about 60 days. It is of the order of. For direct control, a release rate of approximately 100 to 300 mg of pyrantene (as free base) and 100 to 400 mg of levamisole (as free base) per day effectively controls parasite infection for 60 to 120 days during the most severe attack. Prevent. Continuous low level administration of morantel using the device of the invention for parasite control results in
It provides a surprisingly different, more advantageous, and unpredictable effect profile than that observed in conventional therapeutic uses of morantel. For example, maintaining long-term resident amounts of morantel tartrate or citrate (or other salts) in the gastrointestinal tract of a ruminant is effective in preventing lung nematode infection in the animal during the period of drug release. Additionally, while cows or sheep grazing on contaminated pastures are exposed to immediate reinfection with intestinal nematodes after conventional therapeutic medications, animals receiving Opil are essentially You are free from infection and are protected from reinfection for at least 60 days. The use of omaru for the control of pasture contamination, the indirect control method, is a unique practical and current method of parasite control to protect ruminants, especially ruminants that are grazed and treated in this way during the whole grazing season. This method is unprecedented and offers performance advantages over prior art control methods. Throughout the grazing season,
The increase in daily weight gain compared to untreated control animals is substantially greater than that obtained after conventional therapy. The rate of release of a drug, or other chemical, from a drug-containing reservoir through its wall in a controlled release device of the invention and the rate of release of a given drug and/or water-soluble excipient and/or detergent in the device. The effectiveness of the combination can be easily determined by one skilled in the art by permeability methods or adsorption-desorption methods. Techniques that can be conveniently used to select suitable porous materials and hydrogels include those whose controlled release rapidly stirs a saturated aqueous solution of the desired drug or chemical, while a controlled release device is used to control the aqueous liquid in which the controlled release device is to be used. The temperature of each solution consists of rapidly stirring an environmentally simulated solvent bath, filling the pores with the selected hydrogel, using a selected porous material as a barrier between the two, with the temperature of each solution at a constant value; Samples are withdrawn from the solvent bath at regular intervals, preferably kept at a value close to the average temperature of the environment in which the device is used, and the drug concentration determined. Standard methods for determining the permeability of drugs or other chemicals through porous materials whose pores are filled with hydrogels also include
Encyclopendia of Polymer Science
andTechnology, Volumes 5 and 6, pp. 65-82 and No. 797-809, respectively, 1968 and McGraw-Hill,
Chemical Engineers published by Inc.
It can also be determined by standard methods such as those described in Handbook, pages 17-45, 1963. The relative merits of a given excipient or detergent in a method and a given device, particularly where the drug is morantel, are valuable in determining the release rate of the device of the present invention, and can be summarized as follows: be. This method, an in vitro method, is based on the release of a water-soluble salt of morantel, such as tartrate, as a function of time from a device manufactured according to the invention. The morantel tartrate-containing device of the present invention,
Due to the photosensitivity of morantel tartrate, it is placed in an Erlenmeyer flask protected from light, 500 ml of PPH7 phosphate buffer is added, and the temperature of the flask and contents is adjusted and maintained at 37°C. Shake the flask containing the apparatus with approximately 70 excursions per minute (7.62 cm) and periodically withdraw a 5 ml sample. Replace with buffer solution and continue shaking the flask. The concentration of morantel in the sample is determined by absorbance spectroscopy by measuring the absorbance of the sample against fresh PPH7 phosphate buffer at 318 nm. The sampling process is repeated until 5 g of morantel tartrate has been released, at which point 500 ml of new P
Transfer to another flask containing PH7 phosphate buffer and repeat the process as above. In vivo release of morantel tartrate from the device according to the invention can be achieved by administering the device to, for example, a normal castrated bull or a bull with a hump gastrostomy;
This is determined by determining the residual morantel in the device after a period of time, such as 30, 60, 90, or 120 days, by removing the device from the stoma or by sacrificing the animal and recovering the device. This type of test showed that the release rate of morantel tartrate in vitro was about four times the in vivo release rate. The following examples merely illustrate the invention. They should not be construed as limiting the scope of the invention. Many variations of this invention are possible, as will be recognized by those skilled in the art. Example 1 A reservoir consisting of sintered polyethylene whose pores are filled with gelled cellulose triacetate and a reservoir containing morantel tartrate mixed with polyethylene glycol 400 and sodium hexametaphosphate and has a perforated stainless steel sleeve. Daimaru was manufactured as follows. Average pore diameter 10μ, outer diameter 25.4mm (1 inch), inner diameter
22.225 mm (7/8 inch) and length 7.938 cm (3 1/8 inch)
One end (referred to as end 1) of the sintered polyethylene tube (referred to as end 1) is 4.763 mm (3/16 inch) deep in a 10% cellulose acetate butyrate solution in methylene chloride.
immersed until. It was then air dried and the other end of the tube (designated end 2) was dipped into the cellulose acetate butyrate solution to a depth of 3/8 inch and dried. This process was repeated. Edge 1
Soak again in this cellulose acetate butyrate solution for 30 seconds and air dry for 60 seconds, then attach the diameter to the end of the tube.
22.225mm (7/8") Cellulose Acetate Butyrate Disc (3.175mm Thick, 1/8")
was inserted so that it was at the same height as the end. The cellulose acetate butyrate disk was floated on methylene chloride for 60 seconds before being inserted into end 1 of the tube. The tube was then rolled on a workbench while pressing the end holding the disk with a finger to ensure complete bonding of the disk and tube. When the tube was placed in the bottom of the flask, a 1-hole #3 rubber stopper fitted with a glass tube of sufficient length to protrude through the 1-hole rubber stopper of the vacuum flask was inserted into the tube. The protruding end of the tube was then connected to a flask containing 6% cellulose triacetate in formic acid and a vacuum of approximately 150 mm Hg was applied. After the outer wall of the tube that was not immersed in cellulose acetate butyrate was coated with the cellulose triacetate solution, the tube was removed from the vacuum flask and most of the cellulose triacetate was wiped off. The tube was then inverted to drain the cellulose triacetate inside the tube. The inner and outer open ends of the tube were wiped clean with a towel. The tubes were then immersed in distilled water overnight to equilibrate. It was then removed from the water, dried with a towel on the outside, and the excess water inside the tube was shaken off. The process of equilibrating the pores of the tube with distilled water impregnated with cellulose triacetate was repeated. This was then allowed to equilibrate in running water for 4 hours. At this point the tube was connected to a nitrogen source and tested for leaks by submerging the tube in water and applying ⁴ psi nitrogen pressure for 10 seconds. If leaks are present, repeat the impregnation and equilibration in water steps. The tube was then soaked in polyethylene glycol 400
Equilibrated overnight, removed from polyethylene glycol 400, and drained in an inverted position for 4 hours. Wipe excess polyethylene glycol 400 from the outside of the tube with a towel and remove the tube with an outer diameter of 22.225 mm (7/8 inch), an inner diameter of 18.923 mm (0.745 inch), and a length of 6.985 cm (23/4 inch).
inch) and 16 equally spaced circular holes (diameter
A perforated stainless steel tube with a diameter of 7.114 mm (9/32 inch) was inserted until it was flush with the sealed end. Cellulose triacetate debris resulting from inserting the fitting sleeve into the tube was removed. A cellulose acetate butyrate disk (3.175 mm) was then inserted into the open end of the tube flush with the stainless steel, and the tube was truncated so that the end of the tube was flush with the disk. The disk was removed and the tube was filled to the level of the stainless steel sleeve with a homogeneous mixture consisting of 63.31% morantal tartrate, 26.61% polyethylene glycol 400, and 10.08% sodium hexametaphosphate. The open end of the tube was filled with a 10% cellulose acetate butyrate solution, which was immediately poured off, and the open end of the tube was immersed in this cellulose acetate butyrate solution to a depth of 6.35 mm (1/4 inch) and allowed to dry. . A cellulose acetate butyrate disk (floated in methylene chloride for 60 seconds immediately before use) was then pushed into the open end of the tube, applying sufficient pressure to force the disk against the stainless steel sleeve. The tube was then rolled on the bench with sufficient finger pressure to ensure complete disk-to-tube coupling. Let the tube dry for an hour, then close one end of the tube.
6.35 to 10% cellulose acetate butyrate solution
immersed to 1/4 inch (mm) and dried. The weight of the pill was approximately 90g, of which 24.8g was the dry mixture. Its density was 2.2 g/ml. This device is used in the body of a cow for about 60 days to produce approximately
Released 250 mg of morantel tartrate. Example 2 Three large pills manufactured according to Example 1 and tested in vitro according to the method described herein gave a nearly constant release rate over a period of 4 to 17 days;
All three pills gave an average release rate of 0.97 g of morantel tartrate per day.

[Table] In-vivo test of three other large pills prepared according to Example 1 and placed in the rumen-honey pouch of cows yielded 0.224 g per day when collected at the end of 30 days.
showed a morantel tartrate release rate of . This was an in vitro/in vivo ratio of 4:1. Example 3 In vitro testing of two other large pills prepared according to Example 1 and tested as described herein was conducted at 0.96 g per day over a constant rate period, i.e. from 0 to 14 days. gave an average release rate of morantel tartrate.

【table】

[Table] A 30 to 60 day in-vivo test using the same large pill placed in the hump stomach of a cow gave the following results.

Table: The overall average in vivo rate was 0.224 g per day, and the in vitro/in vivo ratio was approximately 4:1. Example 4 Dimensions: outer diameter 22.225 mm (7/8 inch), inner diameter 21.336
mm (wall thickness = 0.889mm = 0.035 inch) and length 3cm
A large pill was manufactured from stainless steel tubes. The ends of the tube were threaded (0.5 mm on each end) to receive a collar that served to hold the hydrogel-impregnated porous fiber disc in place. A disc (22.225 mm outside diameter and 3.175 mm thick, 1/8 inch) of polypropylene filter cloth impregnated with gelled cellulose triacetate and having pores with an average diameter of 50 microns.
were prepared by immersing them in a 6% cellulose triacetate solution in formic acid in a container (flask) that was subjected to a vacuum of 25 mmHg or less. The flask and contents were held under vacuum for approximately 10 minutes, then the disk was removed and excess cellulose triacetate solution was wiped off. These were then immersed in distilled water overnight to equilibrate. The discs were then removed from the water, towel dried, and then equilibrated in polyethylene glycol 400 overnight.
I took out the disk and wiped it with a towel. Place the impregnated disc at one end of each tube and
It was sandwiched between two washers having a thickness of 0.254 mm (0.01 inch) and the same diameter as the steel tube. The washer adjacent to the steel tube was comprised of cellulose acetate butyrate and the other was comprised of a dental moisture barrier rubber material. Then, cut both ends to the diameter
Capped with a stainless steel collar with a 21.336mm opening. The tube was then filled with morantel tartrate (63.3
%), filled with polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%),
The other end of each tube was sealed as described above. This large pill contained 21.4 g of morantel tartrate, weighed 97 g, and had an average density of 3.30 g/ml. Large pills were administered to castrated bulls with humped gastrostomy tubes using a bowling gun, and 30, 45, 60, 75
The drug was removed through the fistula every 90 days and the amount of drug remaining in the pill was determined, from which the average daily release rate of morantel tartrate was calculated.

[Table] The average release rate was 85 mg/day with a standard deviation of 25 mg. A significant reduction in the number of fecal parasite eggs was observed in each bull. Example 5 Sintered polyethylene whose pores were filled with gelled cellulose triacetate (average pore size 10
µ) with a stainless steel sleeve on only a portion of the total length of the pill (thus leaving a portion of the pill without a sleeve), morantel citrate (63.3%) in polyethylene glycol
400 (26.6%) and with a storage source containing mixed with sodium hexametaphosphate (10.1%)
Large pills were manufactured according to the method of Example 1.
However, instead of the perforated sleeves used there, non-perforated sleeves of 5.08 cm, 4.445 cm, 3.175 cm and 1.905 cm were used, respectively. Sleeve wall is 0.165cm
It was thick. The drug mixture is then filled into each pill, thus each 6.35 mm above the sleeve.
The drug band widths are 12.70, 25.4 and 38.1mm. A 12.7 mm thick, 22.225 mm diameter stainless steel stopper was inserted into each pill above the drug mix. The end of the bolus holding the steel stopper was cut off to allow insertion of a cellulose acetate butyrate disk over the stopper and at the same height as the bolus. The weights of each large pill are 120.0, 115.4, and 106.2, respectively.
and 97.0g. The weight of the drug mixture was 25.5 to 27.4 g per pill. The densities of the large pills were 3.1, 2.98, 2.75 and 2.51 g/ml, respectively. Example 6 An in vitro test of the release rate of morantel citrate by the large pills of Example 5 showed that each of these
It was shown to provide constant drug release over a period of 21 days. The lighter of the four large pills of Example 5 (with a 1.905 cm sleeve) had an average release rate of 774.8 mg morantel citrate per day over a constant release period of 3 to 21 days. Was. Example 7 When tested in vivo in cattle, 14 large pills prepared according to Example 1 exhibited an average release rate of 238 mg/day of morantel tartrate over a 60 day period. Example 8 A bolus was prepared according to the method of Example 1, but using the following drugs in the reservoir instead of the drug mixture in that example. Pyrantel tartrate (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%); diethylcarbamidine citrate (100%); hydro Mycin B (100%); Doxycycline hemihydrate hemialcoholate (100%)
%); Bacitracin methylenedisalicylate (66
%), sorbitol (22.0%), sodium lauryl sulfate (12.0%); ampicillin sodium salt (63.5%), polyethylene glycol (26.5%),
Sodium hexametaphosphate (10.0%); sodium penicillin G (67.3%), N,N-dimethylformamide (22.2%), sodium glycerylmunolauryl 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%);
%); Tyrosine hydrochloride (100%); Polymyxin hydrochloride (79.5%), glycerol (15.0%), sodium lauryl sulfate (5.5%); Lincomycin hydrochloride hemihydrate (100%); Magnesium acetate tetrahydrate (77%), sorbitol (15%), dioctyl sodium sulfosuccinate (8%). Example 9 Sintered polyethylene and morantel citrate (63.3
%), polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1%). A bolus consisting of a water reservoir containing a water source and having a perforated stainless steel sleeve was manufactured according to the method of Example 1. However, cellulose triacetate-
Instead of the formic acid solution, the hydrogel solution consisted of an aqueous solution of 10% polyvinyl alcohol (88% hydrolyzed polyvinyl acetate) containing 3% resorcinol. After vacuum treatment to fill the pores, the tube was wiped clean and the polymer was allowed to gel by holding at 0-10° C. for 5 hours. It was unnecessary to equilibrate the tube in water. The tubes were then wet tested as in Example 1, equilibrated in polyethylene glycol 400, filled, and then sealed. In vivo studies show that this provides controlled release of morantel citrate. Example 10 The method of Example 1 was repeated using a sintered polyethylene tube having half the length and half the radius of that used in Example 1. The resulting large pill was designed for use in sheep and provided a controlled release of anthelmintic agent over an extended period of time in vivo. Example 11 The method of Examples 1 and 5 was repeated using the following porous materials in place of sintered polyethylene. Sintered polyethylene, porous ceramic, porous steel,
Sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride, and sintered polystyrene (the average pore diameter of each material was 100 μm). Each of the Ooyu drugs produced in this way lasted for a long time when tested in vitro. , giving a controlled release of the drug. Example 12 Dimensions are outer diameter 22.225 mm (7/8 inch), inner diameter 21.336
mm (wall thickness 0.889mm≡0.035 inch) and length 7.62cm
Large pills were manufactured from (3 inch) stainless steel tubing. The ends of the tube were threaded (0.5 mm on each end) to receive a collar that served to hold the porous hydrogel-impregnated disc in place. Discs made of sintered polyethylene impregnated with gelled cellulose triacetate (outer diameter 22.225 mm, thickness
3.175 mm) were prepared by immersing them in a 6% cellulose triacetate solution in acetic acid in a container that was subjected to a vacuum of less than 25 mm Hg. The flask and contents were held under vacuum for approximately 10 minutes, the disk was removed, and excess cellulose triacetate solution was wiped off. They were then soaked in distilled water overnight to equilibrate. The discs were then removed from the water, towel dried, and then equilibrated with polyethylene glycol 400 overnight. I took out the disk and wiped it with a towel. These impregnated discs are 0.254mm thick
(0.01 inch) at one end of each tube by sandwiching it between two washers having the same radius as the steel tube. The washer adjacent to the steel tube was comprised of a cellulose triacetate butyrate solution and the other was comprised of a dental moisture barrier rubber material. The ends were then capped with a stainless steel collar with a 21.336 mm diameter opening. The tubes were then filled with the desired chemical and the other end of each tube was sealed as described above. A tube (large pill) was prepared with the following chemicals in the reservoir. Morantel Citrate (63.3
%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (10.1%); oxytetracycline hydrochloride (100%), pyrantel citrate (88%), glycerol (12%); pyrantel tartrate (63.3%) ); Polyethylene glycol 400 (26.6%) Sodium lauryl sulfate (10.1
%); Tetramisole hydrochloride (100%); Poloxalene (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 in place of the morantel tartrate-polyethylene glycol 400-sodium hexametaphosphate mixture of Example 1. Daimaru medicine is
84.0g, of which 18.6g was morantel tartrate. When tested in vitro according to the methods described herein, the large pill provides a controlled, nearly constant release of morantel tartrate with an average release rate of 1.36 g/day during the 8-20 day test period. gave speed.

[Table] Example 14 A cedar pipe has a length of 8.77 cm, an inner diameter of 2.16 cm, and an outer diameter of 2.54 cm, and a groove of 0.3 cm deep and 0.6 cm wide is made at a position 0.1 cm from each end to receive an aluminum crimp. , using a low carbon steel tube that has been wrapped around the entire circumference of the tube, one end of which is covered with an ultra-high molecular weight sintered polyethylene disk (average molecular weight 2-4 million,
(commercially available from Glasrock, Porex Division, Fairburn, Ga.), average pore size 10 microns, impregnated with gelled cellulose triacetate as described in Example 12. This disc has a diameter of 2.54
cm, 0.16 cm thick, and sealed in a tube with an aluminum crimp. Then invert the tube, 54.4%
It was filled with a homogeneous mixture consisting of morantel tartrate, 35.6% polyethylene glycol 400 and 10% sodium hexametaphosphate. The disc/crimp encapsulation process was repeated to give the final bolus.
The total weight of Daimaru is 145.1g, of which 41.4g
g was the drug mixture. Its density is 2.8g/ml
It was hot. At each end of the tube the aluminum crimp had an open center of 3.25 ^cm2 , giving a total area of 6.5 ^cm2 available for drug evacuation. Daimaru gave controlled release of morantel tartrate to cattle for approximately 90 days. Example 15 70% levamisole hydrochloride, 30% in an aluminum cylinder with a length of 6 cm, an outer diameter of 2.1 cm and a wall thickness of 0.1 cm and grooved at the open end to receive an aluminum crimp.
A formulation consisting of polyethylene glycol 400 was filled and sealed with sintered, high density (0.95-0.97 g/ml) polyethylene discs impregnated with gelled cellulose triacetate according to the method of Example 12. The large pill had a density of 2.8 g/ml.
The reservoir contained 23.46 g of drug mixture, which corresponded to 16.42 g of levamisole hydrochloride. The aluminum crimp used had a circular opening in its central part, which had a diameter of 1.1 cm, giving a carrying area of 0.95 ^cm2 . In vitro tests at 37℃ showed that the pill released levamisole hydrochloride at a constant rate.

Table: Example 16 This example describes a field trial carried out on 40 test calves of uniform breed, weight (average 150 Kg) and sex, never previously grazed. The calves were divided into four groups of 10 each based on body weight. Two of these groups were the repeated test drug administration group, and 2 groups were the repeated test control group. Parasite-free tracer calves were added to each of the four groups at the beginning of the field trial and every four weeks thereafter, kept in the small pasture for two weeks, then removed and kept indoors for three weeks. After raising them, they were killed to test for parasites. Test and follow-up calves were grazed on infected pastures in which infected calves had been grazed the previous summer and fall. The pasture was large enough to house 44 animals during the entire grazing season and was divided into four equally separate small pastures. In the second group of the repeated drug administration test, a large pill for 60 days manufactured according to the method of Example 1 was orally administered. Daimaru 250 morantel tartrate per day for 60 days
A continuous release of mg/animal (equivalent to 150 mg morantel base) was given. The drug-administered group of animals was orally administered a large pill two days before grazing in the spring pasture. The presence of Oogan in the body of each drug-administered animal indicates that the drug is administered at 24 days after administration.
After some time, it was confirmed with a metal detector. Thereafter, checks for retention of Daimaru were carried out at two-week intervals. All drug, control and follow-up calves were weighed prior to grazing and at 4 week intervals. Pasture samples were collected by Taylor (Parasitology, 31, 473,
Samples were collected at two-week intervals starting four weeks before the start of the field study and continued until the end of the study, according to the method described by (1939). Fecal samples for enumeration of McMaster eggs and lung worm larvae were collected at the beginning of the study and at two week intervals thereafter. For the first 8 weeks these were rectal samples (one sample from each animal). Thereafter, rectal samples were taken every 4 weeks at the time of animal weight measurement. At the intervention site, 10 samples per group were collected from pasture (Gibson, Veterinary Bulletin No. 7, 403-
410, 1965). Total parasite counts were performed on the abomasum (including mucosal digesta), small intestine, and lungs of sacrificed animals.

[Table] The data are shown graphically in Figures 6, 7 and 7.
Figure 6 shows the weight gain during the grazing season for both treated and control groups. It was found that both groups gained weight at about the same net rate for about the first three months. After this period, weight gain in the control group decreased and even decreased for a period of time.
This coincided with an increase in the number of parasites in the pasture. On the other hand, drug-treated animals continued to gain weight approximately equal to that observed earlier in the season. Figures 7 and 8 show parasite populations during the grazing season for drug-treated and control animals. The number of eggs per gram of feces (right axis) and the number of larvae per kilogram of dry grass (left axis) were plotted. The calves were put out to pasture in mid-May. Drug-treated calves were orally administered a 60-day pill two days before grazing.
These were left to be processed until mid-month. During grazing, the number of eggs in feces and larvae in pasture is low. In the control group shown in Figure 7, eggs began to appear in the animal feces in mid-June, reached a peak at the end of July, and gradually declined from August to September. These eggs are observed at the end of July and attach to grass larvae which reach their peak in August. In the drug-administered group shown in Figure 8, egg production from June to July was extremely reduced, and this fact was reflected in a marked decrease in the number of grass larvae from July to September. Example 17 A similar field study was conducted according to the design of Example 16, except that in each study there was one drug-treated and one control group. Related data is shown in the table below.

EXAMPLE 18 The method of Example 4 was repeated using the gelled cellulose triacetate impregnated porous fibers described below in place of the gelled cellulose triacetate impregnated polypropylene filter cloth. Porous fiber average pore size Polyethylene 75μ Polytetrafluoroethylene 100μ Glass 60μ Stainless steel filter cloth 80μ Copper wire mesh 30μ Modacrylic fiber (a) 10μ Nickel copper alloy wire mesh (b) 50μ (a) Acrylonitrile (40%) and vinyl chloride (60μ)
%) copolymer, Union Carbide Corp., NY
Commercially available under the Dynel trademark. (b) Commercially available under the trademark Morel from The International Nickel Co., Inc., NY.

[Brief explanation of the drawing]

FIG. 1 is a perspective sectional view showing one device of the present invention. FIG. 2 is a schematic diagram showing another apparatus of the present invention. FIG. 3 is an enlarged view of the porous wall 11 of the device 10 of the present invention. FIG. 4 is a sectional view showing a capsule-type device of the present invention. FIG. 5 is a schematic partial cross-sectional view showing still another apparatus of the present invention. 10...Emission device, 11...Wall, 12...Storage source, 1
4... Pore, 15... Chemical, 16... Excipient, 17
... end or enclosure, 18... perforated sleeve (Figure 2), cylindrical wall (Figure 5), 19... hydrogel. 6, 7 and 8 are graphs showing the test results in Example 16. FIG. 6 shows the weight gain during the grazing season of the drug-administered group (○×...○× in the figure) and the control group (×−× in the figure). Figure 7 (control group) and Figure 8 (medicine administration group) show the number of parasites during the grazing season for both, and the right axis shows the number of eggs per g of feces (△...△ in the figure). The left axis represents the number of larvae per kg of dry grass (●-● in the figure). The calves were released into pasture at the time marked ↓ in the figure, and were treated with chemicals between May and July, marked ←→.

Claims (1)

[Scope of Claims] 1. A device for the controlled and continuous administration of a chemical agent into an aqueous liquid-containing environment over an extended period of time, the device comprising: a storage source containing the chemical agent; a dense material in an amount such that the material has a density of , and has a shaped wall at least partially formed of a porous material, the pores of the porous material being impregnated with a hydrogel; A device in which the porous wall is at least partially in contact with the storage source and is insoluble and stable in the environment, and the chemical is a veterinary drug. 2. The porous material is selected from the first group consisting of sintered polyethylene, sintered polypropylene, sintered polytetrafluoroethylene, sintered polyvinyl chloride or sintered polystyrene, and polyethylene, polypropylene, polytetrafluoroethylene, glass or modacrylic. 2. The device of claim 1, wherein the device is selected from the second group of porous fibrous materials. 3. A claim in which the dense material is steel and the shaped wall consists of a cylinder of the steel, the ends of which are sealed with sintered polyethylene, the pores of which contain gelled cellulose triacetate. The device according to item 2 of the scope of the invention. 4. The device of claim 2, wherein the dense material is present as a perforated steel or iron sleeve between the storage source and the porous material in the device. 5. The device of claim 4, wherein the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate. 6. The device according to claim 3, wherein the aqueous liquid-containing environment is a ruminant gastric pouch of a ruminant. 7. The device according to claim 6, wherein the veterinary drug is a water-soluble salt of Moralten. 8. The device according to claim 7, wherein the water-soluble salt is citrate. 9. The device according to claim 7, wherein the water-soluble salt is tartrate.