JPS612850A - Long-lasting drug discharge apparatus - Google Patents

Abstract

(57) [Abstract] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention has application in the technical fields of animal husbandry and pharmaceuticals, and relates to an apparatus which is advantageous in terms of long-term, sustained efficacy of pharmaceuticals for ruminants. PRIOR ART The technical problem to be solved by the present invention is to prolong the release time of drugs into the gastrointestinal tract of ruminants. There is no problem when giving drugs to ruminants kept in stables or feeding areas. In other words, the drug can simply be mixed into the animal's feed in the appropriate proportions. However, ruminants are often grazed on pastures,
In this case, food is not given even after a long period of time. Needless to say, it is extremely difficult to administer effective doses of drugs to grazing animals. Traditionally, drugs have been given in the following ways: One method is to mix a drug with a salt block and have animals lick it. Another method is to feed the animal daily with a concentrated diet laced with a drug. However, the above method cannot reliably provide each animal with a daily dose of drug. Moreover, the latter method has the problem of placing a considerable burden on the operator, and is extremely difficult when the animals are spread over a wide range of pastures. Therefore, there is a need to develop better methods of delivering oral medications over a very long period of time. In most pastures, the maximum period during which animals can grow is approximately five months, for example. Therefore, this period of 5 months can be said to be approximately the maximum period for using the drug delivery device for humpbacks. A particularly preferred drug for release by the device is a ruminant feed efficiency enhancer. Regarding this enhancer, monensin is the most important. Raun U.S. Patent No. 3.839.557
According to the issue, if monenone is orally administered to ruminants,
The weight gain rate of ruminants per unit amount of feed consumed can be significantly improved. Another orally administered compound of particular importance is an anthelmintic, particularly a henzimidazole anthelmintic. Ruminants are unique animals whose digestive tracts include a large tube and a rumen (rumen) and a honeycomb (abomasum) (hereinafter collectively referred to as the rumen). I'm here. And in these organs feed is stored and fermented over a long period of time. Therefore, these organs are constantly sickened by the feed being digested. Therefore, it has long been recognized that it is better to allow the drug release device to remain in the rumen for a long period of time, and many countermeasures have been attempted. The basic problems are the design of a device that is mechanically retained within the rumen and the synthesis of a drug that ensures the release of only a given dosage form each day over an extended period of time. Attempts have been made to solve the problem of holding the device from the viewpoints of specific gravity and geometry. The newest and most excellent high-density device proposed in the past is the Simpson (S.
1 IIlpson). The device consists of a core of polymeric drug matrix filled within a steel cylinder. Both ends of the rim are open to the rumen. In addition, the specific gravity of the device as a whole is such that due to the weight of the steel Norinda, the device stays at the bottom of the rumen, and the device does not allow the movement of feed in the rumen or the movement of feed from the rumen. It is not affected by movement. A representative example of a device that is adapted to be retained in the rumen due to its shape is shown in US Pat. No. 4,251.506 to Laby. This patent shows a cylindrical device that includes:
It is open at one end and has expandable wings. The wings are closed when the animal swallows the device, and are expanded once the device is in the rumen. In both Tokinobuson's device and Raby's device, the end of the Norinck, a constant area, is exposed to gastric fluid to ensure uniform dissolution of the drug-containing matrix. I have to. When using this method, it is necessary to dissolve or suspend the drug in a substance that dissolves or disintegrates in a uniform ratio of 1:1 in the gastric juices. An excellent polymer suitable for this purpose is Nevin.
), U.S. Pat. No. 4,273,920. This polymer consists of lactic acid and glycolic acid and is produced by condensing a mixture of these acids in the presence of a strongly acidic ion exchange resin. The problems with the cylindrical drug release device are as follows. Zunawara,
The container of the device must have no contact with the seven-link walls of the gastric fluid or drug matrix. Therefore,
The only time it is possible to consistently direct the drug is to contact only one or more surfaces of the gastric fluid or Noring during the life of the device - to act on a fixed chain acid. However, a problem identified in the technology is that it is difficult to prevent gastric juice from leaking between the drug matrix and the tube surrounding it. SUMMARY OF THE INVENTION The present invention provides a method for use in the stomach (rumen) of ruminants.
The present invention aims to provide a drug release device with a sustained effect. The present invention relates to a sustained release drug release device for use in the rumen of a ruminant animal, having a hydrolyzable biodegradable polymer core. Dissolved or suspended within the core is a drug that is absorbed into the ruminant's gastrointestinal tract to exert its effect. The L core is housed within a tube that is compatible with the rumen and is open at one end, and is further provided with a relatively thick layer of narrow elastic material. The no-rat (the ring formed between the J core and the tube is filled with a sheet over the entire length, and both the core and the tube are bonded together, and water permeates through the tube). The present invention is characterized in that it is compatible with both tubes and 1a, and is also compatible with the rumen and is not affected by the rumen. Examples will be described in detail. First of all, it should be noted that in this text, unless otherwise indicated, temperatures are expressed in degrees Celsius, and percentages and ratios are expressed in weight % and weight ratio. The device according to the invention is housed in a tube 21 of high specific gravity, as shown in FIG. 1.2. tube 21
As such, it is preferable to use a cylindrical tube, but tubes of other shapes may be used if necessary. 10th
Is it possible to use square tubes as shown in the figure, or triangular tubes or oval shaped tubes? In this case, shaping and filling them will be more difficult than in the case of cylindrical tubes. . The key to designing the tube 21 is that the device is to be administered orally to the animal to be treated. Therefore, it is not good to make some of the corners of the tube sharp. if,
If square tubes or triangular tubes are used, they must be manufactured so that some of their corners are rounded. In one preferred embodiment, shown in Figure 1.2,
The tube 21 is a cylindrical tube, both ends 22.23 of which are open, and both ends of the polymer core 26 are connected to both ends 22.23 of the tube 21 and the road surface. Each end cap 3o has a hole 31 and has a round cross section. Each cap 30 is retained on the tube 21 by its lip 28 engaging a groove 20 formed in the end of the tube. The material constituting the tube 21 must have a high specific gravity and be compatible with the gastrointestinal tract. for example,
Lead is a material that is not suitable for administration to livestock due to its high density.The preferred tube wall thickness is ferroalloy,
Especially low grade carbon steel and stainless steel. Many iron alloys generally have a density or specific gravity in the range of 70-7.9 g/cc, which is a suitable specific gravity for the device. The device according to the invention is filled with at least two
It is preferable to have a specific gravity of Og/CG, and more preferably about 25 to 50. It is easy to understand that as the polymer core 26 shown in FIG. 2 is eroded, the specific gravity of the device increases (because the specific gravity of the polymer core 21 is greater than the specific gravity of the core 26). will be done. - The tube 21 may be made of many metals, such as nickel. From an economical and manufacturing point of view, the most preferred material is a ferrous alloy; in any case, the material of the tube is at least 6 g/c
c and a specific gravity of up to about IJ/cc. In addition, when administering the drug to an animal, make sure to remove it from the outside of the tube to avoid injuring the animal.
-9 Is it necessary to make it smooth? Therefore, handmade or extruded tubes are preferred over molded tubes. There is no need to coat the outer surface of the tube to give it a smooth finish. This is because sufficient smoothness can be obtained due to the surface roughness of ordinary metals,
This is because medication can be easily administered. The wall thickness of the L-cove need only be large enough to provide the required overall specific gravity, yet strong enough for handling and dosing. The wall thickness of the tube will vary depending on the diameter of the device to be fabricated, or will suitably range from about 1 mmhy to about 4+x. For devices for administering to cattle, it is preferable that the tube wall thickness is 2 to 3 μm, and for devices for administering to small animals. - It is preferable that the wall thickness is 1 to 2 um. Another preferred range of tube wall thickness for cattle devices is about 1 to 3 inches. The inner surface of the tube is as rough as F1 No. 40 in Figure 11.
Decide whether to make it easier for Norat 27c to adhere by subtracting the power 1114' or the pattern (=1).Select an appropriate metal or appropriate Nolat. Eliminating the need for pre-treatment -4 If it is possible or cost-effective, the above pre-treatments may be effective and may be taken into consideration. Other treatments also help the sealant adhere to the inner surface of the tube wall, such as sand blasting the inner surface of the tube to make it rougher, or creating deeper grooves or threads in the inner surface of the tube. A recess is formed and the tooling is allowed to flow into this recess. However, it is preferable to simply use it as manufactured without any treatment to roughen the inner surface of the tube. Seamed tube or seamless tube. Any of these tubes may be used, depending on the circumstances, as is convenient or economical.In the case of tubes with seams, it is necessary to avoid large protruding seams that could interfere with the Norland layer. In addition, in the case of a seamless tube, it is manufactured by, for example, forming a flat notebook into a seamless tube.Once the device is assembled, It becomes possible to fill the above sealant 4゛, and as a result,
The junction where the edges meet is knolled. The dimensions of the device according to the invention depend on the size of the animal to be administered, the amount of drug to be administered, and the period of administration. Although large livestock sometimes swallow very large objects themselves, the maximum tube length for the device described here is approximately 85jI11. If an end cap 3o is used, this cap 30 allows the overall length of the device to be increased somewhat. The maximum diameter is approximately 40"□jI waste. If the livestock to be treated is, for example, a 150&g calf, the maximum dimensions of the device are sufficiently small, such as length 50zz and diameter 25RR. In the case of sheep or goats, the device is of course even smaller, measuring 25-351131 mm in length and 10 mm in diameter.
The size is ~20jIJ+. The minimum dimensions of the device depend on the daily dose of the drug and the duration of administration. Generally speaking, the preferred dimensions of a device for dosing livestock are approximately 50 mm in tube and core length.
Approximately 75mvt, and the outer diameter is approximately 25zi to approximately 40
It is y. For smaller ruminants to be dosed, a preferred method is about 10 to 20 rump in diameter and about 20 to 35 RR in tube and core length. The tube 21 and core 26 are arranged as shown in FIG.
Preferably, the length dimensions are approximately the same. However, because
In certain cases, it may be preferable to protect the ends of the core by making the tube longer than the core so that the tube wall extends outwardly relative to the two sides, as shown in FIG. Also, sometimes the core is longer than the tube to allow drug release to occur immediately and more rapidly after dispensing. The tube is preferably open on its entire surface (full diameter eagle) at both ends 22, 23, so that the core is eroded at both ends. However, as shown in Fig. 4, there is no problem in using a tube with one end 25 closed, in other words, a cup-shaped tube. Otherwise, only the edges of the core will be exposed to erosion. In a tube that is occluded at one end in this manner, it may be more difficult to insert the core and fill with sealant 27b, or it may be entirely possible to construct such a device to achieve the desired dosing rate. This is particularly advantageous if the temperature is quite low. To make it easier to adhere to the inner surface of the toolant or tube,
It may be desirable or necessary to pretreat or coat the inner surface of the tube. If the tube is made of stainless steel, nickel, or other metal with a low iron content, no other pretreatment is necessary other than cleaning. This is because such metals have stable surfaces. However, if the tube is made of a metal that cannot be considered inert, such as steel or alloy steel that can be oxidized, pretreatment of the adhesive surface is required. Such metals may be surface-plated with an inert metal such as nickel, cadmium, chromium, or tin. Such metals may be coated with some kind of film. As a particularly economical and preferred method, this method eliminates corrosion of the metal and improves adhesion. Needless to say, he has developed properties that are compatible with Norat as well as ruminants (as is the case with CT vrum and IJ), and coachic and lacquers are composed of numerous types of polymeric materials. These coatings and lacquers are used in accordance with the requirements for the sealant used. For example, euboquino resins, polystyrenes, phenolic resins, eudylene hinyl acetate, borihinyl acetate, di-1-o cellulose, acrylics and other coating materials are often applicable. by Norland to be used)
Then, coating materials containing silicone rubber or styrene butanoene laher are used (heavily used). Preferred coating materials are polyethylene, hynylacetate, and polyethylene. cylinyl polymers, including silica and their copolymers, and acrylics.The coating material used is the ruminal environment--reducing, approximately neutral in pH, and hydrolyzable. It is necessary to select it by taking into consideration the fact that it is suitable for
The above-mentioned Kochiic is also used for animals as food.4
- It must be safe for people as well. Additionally, particularly useful bridging or coating materials for the metal tubes described above include nitrile rubber, mixtures of nitrile rubber and phenolic resins, polyurethane lacquers, and modified materials such as nylon, nitrile rubber or mixtures of phenolic resin and evoquino. Evokin resin, including quality Evokin, is included. Cobblinking agents, especially Noranocasobringing agents, are useful for producing moisture-impermeable bonds between Norat and metal. If a separate end cap 30, shown in Figure 1.2, is used with the device, the tube will need to fit over the end cap. For example, the most preferred method is to form a groove at both ends of the tube (or at one end if only one end or one end of the tube is open), and to form a groove on the inner lip 28 formed at the end of the cap. −
Make sure to hold it in the groove 29 with a blade stopper. Of course, it goes without saying that other suitable methods may be used instead of this method. For example, the end of the tube may be formed with a hole, while the end cap may be formed with an inwardly projecting slotted projection that engages within the hole.
You can do so. Similarly, as shown in Figure 13,
It is also possible to combine a tube with a groove 29b near the end and a deformable end camp. In this case, either the assembled assembly or a portion of the material in the end gap is deformed and pressed into the L groove. Furthermore, the outer diameter of the tube can be reduced by rotating or brazing the tube in a tie, or by attaching an end cap to the reduced diameter end using a coil 1. A smooth surface of the device provides a smooth outer surface of the device, thus facilitating drug administration. Figure 1.2 shows this configuration. In the embodiment shown in FIG. 4, one end 25 of the tube is occluded so that erosion and release of the drug occurs only at one end of the polymer core 26b. The figure shows an end cap 30a according to a modified example. In this example, the grooves 29a of the grooves 29a and 29a are formed by machining, and the end caps are made of an elastic material and are pressurized into the Doi fII 29a by a nanoprinter or a clap 35. It's stopped. Preferably, the end cap for one or both open ends of the device is provided with a hole. This end cap serves at least two 1-1 purposes - 4-0 one of which is to mechanically protect the core from erosion [r+1; = Fragment of Ia)
is held in the tube. Mechanical protection for the working surfaces of the core is of critical importance. This is because the stomach of an animal (especially if it has been grazed) contains a large amount of wire and debris. All of these have been swallowed by animals. Rashi,
Retaining the core securely within the tube is particularly important if too high a dose of the feed efficiency enhancer drug for the separated animals would be harmful. If the core, or large pieces of the core, were to leave the tube, the core would almost certainly flow back into the mouth and be chewed when the animal was cutting, thus losing all of the drug at once. will be released. If the core becomes loose within the tube, the drug release rate cannot be controlled to the specified amount, and as the core erodes from the sides, the dose may exceed the specified amount. In this case, if the loose core is retained within the tube, the drug will not be delivered in doses that would be harmful due to toxicity. It has been found that the open area of the open end camp of hole 31 is not a critical factor. For a device with a diameter of about 35xi, a preferred reasonable open area is about 35-45%. Such an end gap provides adequate circulation to the eroding surface and provides physical strength. In fact, even an end cap with an open area as small as 18% is satisfactory, and the open area can be made larger as long as the mechanical strength is sufficient. The shape of the end cap may be selected as appropriate. The most preferred shape of the end cap is rounded, particularly hemispherical, as shown in FIG. Such a shape allows the device to be miniaturized and facilitates administration. There are, of course, other convenient end cap shapes. For example, it can have a flat shape as shown in Figure 5.6.8, a pointed shape as shown in Figure 7, or a pyramid shape as shown in Figure 10. I can do 6 things. The cap shape itself is such that the size and shape of the hole 31 in the cap is such that it cannot be easily blocked by granulated feed, and as long as the cap itself is strong enough to maintain its shape and position. There are no decisive factors. Experimental results show that a certain amount of feed always collects near the eroded surface of the core, and the space within the end cap is almost completely filled with feed. This material, or feed, does not appear to alter the erosion rate of the core and therefore the rate of drug release to the animal. There are various variations of end caps. For example, the 12th
By surrounding the entire device with a screen or mesh 32 as shown in Figure 1, it is possible to provide the same function as the cap described in -j1. The most convenient covering material is a plasdec reticulated tube that shrinks when heated. The tube is placed over the device and fastened with fasteners at both ends, and then shrunk by heating. Shrinkable plastic products of this type are commonly used. The open area of the end cap may be secured by a force d as shown in FIG. 4-The noose is also attached 4' to each end of the tube by one or a few wires 30e or other strips of material. If the electrostatic adhesive on the core tube becomes detached, small pieces of the core will not be retained. However, the entire core is retained. - The end cap wire can be attached by inserting both ends into holes formed in the outer wall of the tube and bending the ends, or it can be attached as a circular nanoprinter by holding it in a groove formed on the outside of the tube. It is attached by configuring both ends of the wire. Similarly, instead of flat plastic end caps, filament shaped end caps can be used. The braided end gear knob includes a predetermined number of thin cross-over elements and is snap-fitted into position on the tube as described above. The material used for the end key/knob is a material that is compatible with the conditions of the human stomach and is relatively strong.7 The preferred material is a plus material that is easy to mold. Yes, for example polyethylene, linear or cross-linked polypropylene, polyurethane, -j. It is vinyl chloride. There is no need to use hard plastics, such as melamine, phenolic resins, polycarbonates, and the like, although they may be used if desired. Of course, the end camp may also be constructed of metal. These metals include aluminum, stainless steel, steel, plated steel with tin plating, nickel plating, etc.
Brass is an example, but in short, any metal that meets the conditions of the rumen can be used. Even pure M (brain steel) can be used as this end gear. This is because erosion in the rumen is not so strong. Steel (or other metals) may be coated with lacquer as described above to further protect the metal. As shown in FIG. 9, a metal net 30f may be used. There are many ways to attach the end gear knob to the tube. Some of the methods are illustrated in the drawings. For example, attach the portion of the end cap that overlaps the end of the tube to the tube load with a snap ring.
It can be attached by tightening the cap or by tightening the clamp 35 around the cap as shown in FIG. Of course, the end caps are configured to provide a snug friction fit. However, this method is not recommended. This is because the required diametrical precision cannot be manufactured at the low cost desired for the device. The end cap can be held in place by adhesive 36 as shown in FIG. This is especially because the tube must be able to hold the sealant in order for it to adhere well. Suitable adhesives for bonding plus deck to metal are well known. In particular, evoquino adhesives are compatible with metals suitable for tubing and with most plus decks. Metal end caps may be adhesively bonded as well. Therefore, evoquino adhesives are very useful. Additionally, the tube and end cap may be mated with threads to be screwed together. This structure is particularly useful for metal caps. In particular, it can be applied to Plus J Kukya Jpnira. However, the best method is as shown in Figure 2.
A groove 29 is formed by reducing the diameter of the end of the tube by the J-measure, and the protruding lip of the gear is fitted into the groove 29. Then, an end face camp is constructed with an elastomer material so as to form a lip 28 that fits into the groove 29. In this case, the end cap should be attached to the tube with the "-" mark on the tube, and if the tube and cap are not the same, then the iM'I method should be used. You can get the device with smooth surface. If a holed end cap is to be made at low = 1 stroke, this cap may be formed by extending the material forming the tube. 0° Figures 15-17 illustrate a device with such an end cap. A preferred method of manufacturing this device is to first form each end of a metal plate into a sawtooth shape to form claws 30 as shown in FIG. This is followed by forming the tube part of the device. However, the claws constituting the saw-integrated end canop 30k shown in FIG. 16 are constructed by cutting each end of a P-shaped metal tube. As shown in Figures 15-17, when the end cap is configured as an extension of the tube, one end of the device has a constant diameter, and one end is a four-way metal container section. This is the part of the metal container which forms an open area which brings the contents contained in the gastric juices into contact with the curvature of the core. In Figure 15, the tube is designated 21a and the end cap is 30] and their 1ilVl! sections are shown respectively in 11 and 21. Another method of making a holed end cap (J) is to place the entire tube in one outer nobo cutter (J). 3. Construct the end gear knob on the outside]-r itself.
This device is illustrated in Figure 23. It is preferable that the nonyl on the i-coordination side is made of a plastic material and molded by moon-shaped molding. This is due to the ease and economy of fabrication of the outer nonyl. The materials for the separate end cap are also useful for this outer nozzle;
Especially polyethylene is most suitable. FIG. 18 shows nonyl on the t-coordinating side. The outer nonyl is comprised of two flips, each with a molded end cap at one end thereof. 1-The registration shells 50,51 are provided with snap fittings that fit together. Especially the two outer nonyls are 50.5! If they are made of materials suitable for welding, they can be joined by welding. For example, the outer nonyl of polyethylene or polyurethane can be joined by rotary welding or heat welding by contacting heated rollers or open flames, by solvent welding, or by simple adhesive bonding. If the parts of the outer nonyl are connected by welding, the ends of each nonyl 50, 51 can be made into one piece and manufacturing costs are reduced. As shown in FIG. 3, a tube and core surrounded by an outer nonyl effacing integral end cap is the simplest embodiment of the invention. Also, as shown in Figures 18-23, the outer nonyl need not necessarily be adhered to the tube, but instead may simply surround and protect the tube. The outer nonyl end cap shown in Figures 18-23 has a generally hemispherical shape, which is the preferred shape as previously discussed. However, the end caps forming part of the outer nonyl may have other shapes, as described above with respect to FIGS. 5-10. The outer nonyl can be used to reduce the dosage rate delivered by the device. However, by opening only one end of the outer nonyl, the dosage rate returned to the device can be lowered. FIG. 20 shows a device having an outer shell with one end cap. The other end of the device is closed. In Figure 20,
The closed end of the outer nozzle 52 is connected to the end of the end cap of the nonyl 50a by a snap hook. However, this connection can be made by welding or gluing.
] Do something. The outer nozzle may be formed by integral molding, in which case it is closed in the axial direction around the tube. Such an outer shell is shown in Figures 21-23. If the form shown in the figure is adopted, it is necessary to select the material from the viewpoint of whether it is necessary to form the integral hinge 54 shown in FIG. 23 or not. Poly", tyrene (J) is a material that has a large amount of material on the outside.
A cross section of the integral outer shell is shown in Figure 23 and closed! Further, a cross section of the device is shown in FIG. FIG. 21 is a perspective view of the entire device. In Figures 21 to 23, the L symbol side) has a smaller snap connection system. First, the integral outer tube may be closed by welding or using an adhesive, and these methods are limited in terms of the length of the connection in the axial direction of the outer nonyl as shown in FIG. This is more preferable than the outer nonyl case shown in Figures 18-20. The axially connected outer nonyl may also consist of two separate halves, which are connected around the tip. Each half of this outer nonyl has the shape shown in FIG. 23, except that it is separated at the tip 54. -1° The respective halves are connected by means of a sander, or preferably, by the above-described welding method. The polymer constituting the matrix portion of the polymer core is described by Ncvin, US 81 No. 4, 27
It is the same as the polymer disclosed in No. 3.920. The content disclosed in the patent constitutes part of the content of the text. The above polymer is a =J copolymer of lactic acid and clinyl acid, with about 60% to 95% lactic acid and about 40% to 5% lactic acid.
% glycolic acid. Preferred copolymers contain about 70% to 90% lactic acid, and most preferred copolymers contain about 80% lactic acid and about 20% glycolic acid. According to Nepin's teachings, polymerization is carried out at elevated temperatures using strong acid ion exchange resins. The average molecular weight of the copolymer is relatively easily controlled by reaction time and reaction temperature. Mr. Nehino teaches the following: That is, the preferred average molecular weight is about 6,000 to 3
5,000, more preferably +5,000 to a
o, o o. It is. His molecular weight calculations were based on gel permeation chromatography, which gives the weight average molecular weight. It has been found that the average molecular weight is best calculated by a titration method that determines the number of unreacted acid end groups present to give the average molecular weight. This analytical method will be explained in Production Example 1 below. When the average molecular weight is determined by the above method, the preferred range is about 2,000 to 6.000, the more preferred range is about 2,000 to 4,500, and the most preferred range is about 2.500. ~4.500. The lower the molecular weight, the higher the rate of hydrolysis and therefore the higher the rate of drug release. For example, when assembling a device that is open at both ends, a higher molecular weight polymer is used to obtain a given dosage rate than for a device that is open at only one end. Furthermore, when the drug concentration within the polymer core is high, a higher molecular weight polymer is used to achieve a given dosage than when it is low. To obtain maximum duration of action from a core of a given size, a polymer of high molecular weight is required to release the drug slowly and increase the duration of action. The production of the above polymer will be described in further detail in Production Example 1, which illustrates a large-scale polymerization example described below. The drug used in the polymeric core of the device is one that is beneficial to ruminants when administered orally. The drug may also be a pharmaceutically acceptable salt or salt of the drug being administered. The most important and preferred agents are the two agents for improving feed efficiency of livestock animals. Such compounds are known in the industrial field. The most important and preferred group of compounds is the Hague (
Monensin and Narasin, which were disclosed in US Pat. The feed effects of the two last-mentioned compounds are taught in Raun, U.S. Pat. No. 3,794,732 and Berg et al., U.S. Pat. No. 4,085,224. . Particularly preferred compounds are monomonone and naratsuno. From other points of view, the most preferred compounds of A1 are Naratsuno and Zarinomai 7no. This is because the daily dosing rate of these compounds is significantly lower than that of other ruminant feed efficiency agents, and therefore it is difficult to obtain a given shelf life with smaller equipment. In most cases, the drug will need to be partially incorporated into the polymer and the rest suspended and entrapped within the polymer matrix. Even insoluble drugs with no solubility in the polymer can constitute very satisfactory devices. This is because, by hydrolysis of the polymer matrix, particles of the drug are released all at once or in small numbers, allowing for continuous administration of the drug in appropriate doses. Anthelmintics are another agent that is particularly useful with the present device. This compound must be administered into the gastrointestinal tract, since the purpose of the drug is to exterminate parasites residing within the gastrointestinal tract. It is a type of carbamate.
4.8'l No. 6 J. and No. 4,156.006, which patents are incorporated herein by reference. A particularly preferred class of henzimidazole carnomers is represented by the following chemical formula. In the above chemical formula, R' is hydrogen, lower alkyl, lower alkokino, lower alkyl (A, benozoyl, halohendiyl, phenylthio,) S-nylsulfinyl, cyclopropylmethylsulfinyl, and lower alkyl-C
o, NH. Particularly preferred henzimidazoles having the above chemical formula are medyl-5(6)-phenylthiohenzimidazole carhamate (commonly referred to as fenhendazole) and methyl 5-propylthio-11-
1-benzimidazole-2-ylbamate (commonly referred to as alhedazole). In the chemical formula that defines henzimidazole methyl carhamate, R7 is a lower alkyl group such as C, -C, alkyl, a lower alkyl group such as C, -C, alkokino, C
, -C, alkylthio, and lower alkyl-CO, Nl-1, such as C, -C, alkyl-CO, NH. Compounds that are closely related to benozimidazoles and are useful in this device include thiabendazole, which is 2-(4-deazolyl)-henzimidazole, and 6-benzimidazole.
-amylavonyl-(2,3°5.6)-tetrahydroimidazo(2,1-b) thiazole, Rehamisole, and N-(2-r2.3-bis(methquincarbonyl))
guanidino]-5-,-(phenylthio)phenyl)-
Includes febantel, 2-methquin acetamide. Other anthelmintic agents of particular value useful in this device are pyrantyl, trans-1,4,5,6-tetrahydro-1-medyru-2-[2-(2-chenyl)hinyl]-biriminone, and noamphenetide, his [β-(4=acetamidophenoquino)ethyl]ether. A more preferred anthelmintic is ivermectin, which has 2
Also called 2.23-nohydroavermethacdine 131 [U.S. Pat.
Noe Mesoto Ke 1.23.1134-3 published in 0
6 (J, Med, Chem, 23.1134-36)]. Zoologists will appreciate that other classes of compounds may be administered and beneficial by the present device. A drug which is beneficial to the ruminant when administered into the gastrointestinal tract of the ruminant, and whose dosage is relatively small over a long period of time, is to be filtered into the device. The compound is effective for about 1 to 6 months after taking such a dose. Efficacy towards [shaving and anthelmintic songs, especially effective drugs IL'
lir + horn, hatsu trough), upstream sloth mainono, ri (
7) Feed-infused insecticides like methoprene, U.S. Pat. No. 3,980,784. 2-Full 1 [l
3. Use ectoparasiticides such as argylhenzimitazole, and oestrus suppressants such as melenkestrol. In addition, this device contains trace amounts of marukiwayo, selenium, copper, sulfur, iodine, hitamine A, hitamino 1),
When administering vitamins (such as vitamins (D)), the device is capable of administering one drug or a mixture of several drugs.
1. Do not release the appropriate amount. = 17, the eroded surface area of the core, and the molecular weight of the polymer as J
By adjusting A1 and II, it is possible to easily obtain the desired dosage. For example, the release of monenone at 100 decompositions per day is - 250 R7 per day hydrolyzed, 40
% drug-containing core. The examples below illustrate experiments that are used as models. It is clear that a device that releases both a ruminant feed efficiency enhancer and another drug would be very useful, and the present invention includes such a combined drug delivery device. Narasin and salinomycin are highly preferred for application in this combination drug delivery device. If so, these are active at low j1 dosage rates. A combination drug combining narasin or salinomaino with ) J nohendazole, alhedazole or pyranodel is a particularly preferred drug combination. More preferred combinations U are the combination 0 of Mone 7 Nono and mesingestrol, the combination 0 of Mone 7 Nono and ivermectin, and furthermore the combination 0 of Mone 7 Nono and ivermectin, and also the combination of The combination is U. The concentration of the drug or combination of drugs within the polymer core depends on the rate of hydrolysis of the polymer in which the drug is dispersed and the desired period of activity. In any case, the maximum concentration of drug is approximately 50%. This is because the drug particles need to be completely covered by the polymer. It is preferred to use a maximum concentration within the range of about 40%. If the desired dosage rate is low, or if the required period of action is not particularly long, lower concentrations, for example 1%, may be used to accommodate core manufacturing considerations. Since the drug within the polymer must be completely dispersed,
The drug is made into fine particles and distributed uniformly throughout the polymer.
Is it necessary to mix it in? However, there is no problem with either particle size or mixing of the drug when the drug is incorporated into the polymer. However, if the drug is insoluble or only partially soluble, it may be powdered or less than about 50 metsutu.
It is necessary to correspond to the particle of θ. It is preferable that the drug be finely ground so that the largest particle is smaller than 015z* (100 mz), and by grinding it into a powder, the drug can be made even finer and more uniformly administered. rate is obtained. Mixing the polymer and drug can be accomplished in a variety of ways. Since the polymer softens at high temperatures, the drug can be mixed into the softened polymer using a roll mill, extrusion method, or other pressure device of this type. The most convenient method of manufacturing the drug is to grind the polymer and drug and mix the powders. This mixture is then heated to about 100°. At this heating temperature, the polymer softens and forms a mass that becomes an amorphous material that can be easily crushed upon cooling. The coarsely ground material is then passed through an extruder operated at high temperature, which mixes the L material and forces it through a die. When the material exits the gou, it forms a lot with the desired core cross-sectional shape. The lot is then automatically cut to a predetermined length A and cooled. A particularly preferred method of forming the core is to first mix the powdered drug with m powdered polymer and then pelletize the mixture using an extruder. The pellets produced in this way are cooled and fed to an injection molding machine or other extruder. According to injection molding, a predetermined core is directly molded. If a second extruder is used, it may be a molded extruder lined with Teflon, or it may be extruded into a long pipe lined with Teflon.
It is preferable to make a long throat-shaped core. The long throat-shaped core material is cut into cores of a certain length when cooled. The cutting speed is slow and the mixing speed is very fast. If a separate extrusion device is not used, the powdered drug and polymer can simply be mixed and fed into the extruder. This can also be done in other ways, such as by heating the polymer to soften it. Second, the powdered drug can be added and the mixture can be vigorously mixed in equipment capable of mixing heavy pastes.The mixed polymer mass can then be extruded to form a core or each The polymer is dissolved in some organic solvents, particularly methane. Once the drug is dissolved in the solvent, both polymer and drug are dissolved and mixed and then the solvent is removed. Upon evaporation, a very homogeneously mixed polymeric drug mixture is obtained which is then extruded or molded without heating as described above. Mixing is not critical if the drug is completely dissolved in the polymer.In such cases, the polymer should be kept in contact with the molten polymer for 1 minute to dissolve. The polymer may be mixed with the drug by heating 11-]. Certain drugs may be added to the polymerization reactor and mixed with the polymer produced therein. However, polymerization at high temperatures for long periods of time may The polymer core is secured within the tube by a relatively thick Norland layer.The function of the sealant is to keep moisture between the core and the tube. It is a tight (moisture-tight) bond that prevents the sides of the core from coming into contact with gastric fluids.This sealant layer is responsible for the very high reliability of the drug dosage dispensed by this device. .As with conventional devices, this sealant layer often fails because gastric fluids can penetrate the sides of the core and hydrolyze it, thus allowing drug to be released from uncontrolled areas. Some examples of conventional devices have been successfully implemented, and hydrolysis is carried out substantially only from the end face of the core.However, even if the devices are selected from the same Hanoji, other By way of example, hydrolysis could not be controlled as desired, and therefore sufficient reliability could not be obtained. If the dosage is not controlled, the animal treatment method is of little value. Therefore, the most important attribute of a sealant is its ability to reliably adhere to the polymer core. This adhesion must be made securely over the entire surface of the core and must be moisture-tight. Additionally, the sealant itself must be substantially moisture-free so that water in gastric fluids is not absorbed into the sealant and migrates through the sealant layer into the core. Although complete impermeability cannot be achieved, the sealant should be sufficiently impervious to water that no appreciable hydrolysis of the copolymer occurs at the core-sealant interface. is necessary. Similarly, the sealant must not be affected or altered by gastric fluids. Of course, it goes without saying that the above sealant must be able to adhere to the tube. This adhesion can be strengthened, for example, by forming a pattern (or grooves) on the inner surface of the tube to provide a mechanical holding effect in addition to adhesive adhesion.As mentioned above, The metal tubes may also be coated to enhance adhesion.It is also preferred, of course, that end caps are applied to the device. This is because the end cap will hold the core in place if the sealant-to-tube bond were to become dislodged.However, the sealant-to-tube bond must be strong and tight. The best results may be obtained in certain cases. It is also preferable to use a Norat that adheres not only to the core but also to the tube. The Norat must be compatible with both the tube and the core. Of course. However, since the device will remain in the stomach for several months, the sealant must not only be compatible with the stomach but also safe for the animal. Conventionally, many types of sealants have been proven to have physiological safety and are permitted to be used, for example, in food packaging, so the safety conditions described in 1-1 can be easily achieved. Depending on the design of the device, Norland is subject to certain requirements: the sealant must cure or solidify into a fairly thick film without coming into contact with air or other ambient influences. - Polymers that solidify under the action of air or moisture, such as silicone that hardens by hydrolysis of esters, cannot be used.Norland must be selected from the following materials:
B, which can be applied in a molten state and solidifies by cooling;
and materials that are applied at ambient temperature and solidify by a chemical reaction. Certain elasticity is a necessary property of a sealant. One important function of a sealant is to absorb the relative movement between the tube and the core caused by thermal expansion and contraction. Sealants are generally proprietary products and are made of polymers and adhesives. It has been manufactured and perfected by experts in the sealant technology.It is highly unlikely that the use of the device according to the invention in large numbers will justify the development of new sealant manufacturing formulations. We will be applying an already existing bleached product manufactured for use. Therefore, information on sealants from textbooks and other books is extremely important in this case. One is the "Adhesive Handbook" (
Van Nostranot Reinholt (2nd edition published in 1977) by Arching Skiest Nid. E
(Handbook of Adhesives. I rving 5keist, Ed,, 2nd ed.
ition, Van No5trand Re1nho
(1977)]. Preferably, the sealant is heat meltable. The outer layer of the polymer core, which has a relatively low melting point, forms an adhesive bond with some physical welding when contacted with hot melt Norland. Hot melt sealants are typically selected from ethylene-hinyl acetate copolymer, polyamide resins, or polyamide resins. Ethylene hinyl acetate (EVA) is most preferred;
This copolymer is described in the 30th book of Mr. Skeest's book mentioned above.
The chapters are carefully explained. Generally speaking, such sealants, or adhesives as they are commonly called, are based on copolymers containing about 15-50% vinyl acetate. This EVA copolymer must be modified with other components, which can amount to 50% of Norat. For example, waxes, particularly microcrystalline waxes, are added to reduce the viscosity of the melt sealant. Also, a tacky polymeric material such as polybutene may be added to provide good initial adhesion of the tube to more easily assemble the tube and core. To avoid high-temperature deterioration of the sealant, it is recommended to add an antioxidant. Butylated hydroquinotoluene and butylated hydroquinoanisole are useful as antioxidants. The EVA copolymer may be mixed with selected low molecular weight resins to improve adhesion, wetting, thickness and high temperature hardening. Among the suitable resins are medyl styrene copolymers, lonone esters and polyterpene resins. Generally, microcrystalline wax or wax, which accounts for the majority, is used up to about 20%. The plasticizer is also about 2
It can be used up to about 0%. Further, a modifying resin as described above is used in an amount of about 20 to 50%. Inert inorganic fillers may also be used in the two-land. However, this filler is preferably not used, and should not be used in an amount greater than about 20% of the sealant. Hot melt sealant (especially EVA sealant)
The melting temperature, more precisely the softening temperature, as well as its viscosity are generally controlled by changing the molecular type of the polymer and the composition of the modifying components. In the present invention, the following hot-melt sealant was found to be the best. That is, one having a moderate viscosity in the molten state, e.g., at the application temperature, about 800-
10,000cP, preferably about 800-3.000c
P hot melt toolant is good. Because the melting point of the polymer core is relatively low and the drug is sensitive to heat, application temperatures must be avoided to become too high. Generally, the application temperature is about 120-17
A range of 5° is appropriate. Hot melt sealants based on polyolefin resins, preferably J polyethylene resins, are widely used and available, such as those available from Eastman Chemical Products, Inc. These sealants are made from polyolefin resins and are coated with microcrystalline wax to improve viscosity and viscosity properties. A third type of hot melt sealant preferably used in this device is a polyamide, which contains a noamine, generally an ethylenenoamine or similar small alkylene compound, with a polymeric acid base. Typically, the acid is a "dimer" bound by two carboxyne groups or an average 34-carbon hydrocarbon group containing many unsaturated bonds. Polyamides have excellent properties for wetting relatively non-porous materials, such as the tubes of the device, and have particularly good storage stability, resulting in particularly good adhesion properties. Polyamide sealants require less formulation to achieve superior results when compared to the other chemical nolats discussed above. Another class of hot melt sealants useful in the present invention is based on polyamide sealants. It is a substance with 4 properties.Such a GoJ1 is a polymer (usually a block polymer consisting of styrene and butanoene or styrene and inobrene) having a goliath-like component and a plastic component. ).This polymer is prepared in such a way that the glassy endblocks of polystyrene are incompatible with the rubbery isoprene or butanoene midblocks, or the endgroups of the polymer. Borisjiren's end blocks tend to gather together in one place, and the rubber chains are held in place.

[There is a tendency to form J-noquoro domains. When the thermoplastic polymer 18 is heated above the transition temperature of the end block, the polymer becomes fluidized and capable of extrusion 1 J or into a small opening 18, such as a ring between the core and tube of the device. This allows it to be press-fitted into the Sujirenonoyu. The embronocco polymer is composed of a low molecular weight resin or a plasticizer. Aromatic resins, such as styrene homolog copolymers, tend to associate with hard styrene endogenous domains; whereas lower molecular weight olefin resins, lonone esters, and polyterpenes precipitate into the genome and become sticky. Among the liquid plasticizers, polybutenes are also compatible with the Mitblock phase. As such, they are preferred for non-heat-melting non-Norland applications by chemical methods. Of course, as a solution in a solvent or as a dispersion in a solvent.
Alternatively, do not apply a sealant in the form of an emulsion. This is because no solvent or water can escape from within the long, confined space in which the Norat must be placed. Therefore, hot-fusible sealants must be such that they do not release any water during curing or curing due to chemical action. Applied at about room temperature and cured by chemical action, the 1:Una sealant is for Jl-always i. For this purpose, Silicon Norland® is preferred. Norat is currently widely used, especially in the construction and electrical industries.
0 to 1.600) and a polyfunctional compound cross-linked by condensation using a catalyst. Catalysts for "White" are compounds of tin or titanium, in particular soaps with tin octoate, butyltin nolaurate, etc. Condensation and polymerization are carried out immediately before application in the condensation catalyst or Norland apparatus. This occurs in anaerobic locations, such as in this sealant layer, when the polysulfite is separate from the functional compound. These sealants are also used in
It has been used as a compound for the treatment of dental cavities and is therefore physiologically safe. This sealant solidifies by polymerizing thiol end units having a downward molecular weight of about 4.000 as represented by the following general formula % to form a flexible and resilient polymer. The catalyst for polymerizing polysulfite is an oxidizing agent. Although lead oxide is the most widely used, it is clearly inappropriate in this case. On the other hand, manganese dioxide and zinc peroxide are used as oxidizing agents and are used in the present invention. The polysulfide sealant is made by mixing the monomer with an oxidizing agent immediately after assembly of the device. The Norat is injected into the annulus between the core and the tube, and the combined device is cured by the polymer. Polysulfite is both water resistant and has a high resistance to thermal expansion and contraction, making it particularly suitable for the present invention. The chemistry is not very important to the success of the device as long as the Norat is compatible with the tube and the core.The physical properties of the Norat are extremely important and can be obtained from a large number of chemical entities. In short, the required physical properties are a property that allows the polymer core to bond moisture-tightly to the tube, and a high degree of water compatibility that prevents water from penetrating through the Norat layer to the sides of the core. It is also necessary for the sealant to have sufficient adhesion and elasticity so that it can withstand temperature changes in the range of about -20° to 50° when used in a stored state. It is capable of absorbing the relative motion between the core and the tube caused by thermal expansion and contraction.The sealant is constructed as a relatively thick layer and is filled over the entire length of the ring formed between the core and the tube. L thickening of Norat layer is at least 0,7 Ill
and preferably about 2 to 43131. Another preferred range for the thickness of the sealant layer is at least 1n. Of course, for smaller equipment used on sheep and goats, the sealant layer could be thinner;
The nolat must have a thickness of at least a few percent of the diameter of the core. For example, about 3-20%, preferably about 5-20%. The formulation and manufacture of the polymer core was previously described. This core is assembled with the tube as follows. That is,
The core is disposed approximately concentrically with the tube. Then, the ring is filled with Norat. Exact concentricity is not required. This is because the thickness of the Norat layer does not control the dosage rate. For example, a tolerance of about 0.5 RR is allowed for the concentricity between the core and the tube. Therefore, assembly of the device need not be done all at once. long (e.g. 1 cm long) [1 gutter-shaped: 1 abrasive material is manufactured by extrusion or molding, and then the core is held in a predetermined position in the tube 4 - installation is the same length within the prefecture Insert it into the tube. The sealant, which may be hot-melt or chemically curable, is then injected into the ring and the assembly is cooled or cured. and then cut to the appropriate length for the desired device. However, the tube and the extruded or molded core are cut to the appropriate length for each device, and a mounting 1 is required to hold the core in place while the sealant is injected into the annulus.
(It is preferable to place each core in a tube within the prefecture.The injection device is manufactured by the trademark [-Slaughterback (SIauti
erback) J's version is particularly suitable for this purpose. The assembled device is held in place while the sealant cools or cures. If a hot-melt sealant that hardens quickly is used, fewer tools may be needed for the above-mentioned installation, and in this case, the disadvantages of using a hot-melt nolat will be clearly seen. When using a tube with a body-shaped end cap, as is the case with the device shown in FIGS. 15-17, it is difficult to remove the tube from the end of the ring. Therefore, as shown in Figure 15.17, it is necessary to make a small hole 41 in the tube and inject the NORAT through the hole. After the sealant has cooled and hardened, the ends of the device should be inspected to ensure that the sealant has not flowed out of the annulus and spread over and covered the end faces of the core. Preferably. The open end of the device may be pressed against an abrasive belt or similar material to allow contact with the contents of the stomach over the entire diameter of the core. 'The trouble is,
If a separate end cap is used, this end gap may be fitted and the outside including the end cap may be fitted; The external metal claws that can be closed - there are 4 to 7 levers. It should be closed loosely. The tube or outer nonyl may be marked with ink or paint, or the rumen may be affixed with a label that is received, so that the marking of l:kl, e.g., can be reduced. The tube is made of plastic material and is then printed on and then contracted around the tube or outer nonyl for permanent attachment.The device is then administered orally to the animal using a polling can. In other words, guide this device into the throat of the fruit of the tongue using the Horikkan described above and administer it. Then,
The device remains in the passage, honeycomb or rumen. In order to further clarify the present invention, an example illustrating the structure and usage of a typical device according to the present invention is shown below. still,
This example is not intended to limit the invention. The first preparation example shows the large scale synthesis of the polymer. 1 - A 50 gallon capacity reactor with a drain pipe (condenser, condensate returned to the reactor or L) is equipped with a pumping device, a suction device and a pressure device).
o&g 88% aqueous lactic acid (80 mol%) and 30 to 9
Add 70% aqueous clifuric acid (20 mol%). Then, 1.3C of Towex (D
owex) acid exchange resin NCR-W 2-1-1 was added. This mixture was then heated at 130° for over 4 hours. The water coming out of the polymerization mixture was removed in the condenser and discharged. After the temperature reached 130°, the pressure in the reactor was gradually reduced over 15 hours or 13 hours while the temperature was allowed to rise. Finally, the temperature became 160° and the pressure became 70jIxl1g. [-F, care must be taken to avoid violent boiling in the reactor while the pressure is being reduced. In addition, the mixture must be frequently monitored and 1 part of night must be added to the reactor to suppress foaming. After 15 hours, the reactor is returned to atmospheric pressure and the collected water is drained. The fundeno was then connected to the steam to prevent clogging in the steam and was further circulated to the cooling brine or condenser nodule. The evaporation line was heated with sulphide in the column to prevent blockages in the line. The temperature in the reactor was then gradually increased from 160 DEG to 1708 DEG and the pressure was gradually reduced to 1 DEG at 20 mm/11 g. The polymerization mixture was held at I-temperature and N-force for 220 JI. The temperature was then raised to 185° over a period of 4 hours, and the force and pressure were lowered to 511ul1g, and the L rim was reduced to a small vacuum. The mixture is then 4011,'
The specimen was held at 185° for a period of time, and samples were taken periodically. The intrinsic viscosity of each sample was determined using an Unoherode viscometer by dissolving a portion of the polymer in chlorophor, 1%, 0%,
The intrinsic viscosity is calculated by dividing the natural logarithm of the ratio of the run-off time of the polymer solution to the run-off time of the pure solvent by 05.・Boitz)・ has an intrinsic viscosity of 0
．． The polymer was then sieved through a 60 metric stainless steel screen to remove any catalytic heath, poured into Swals steel trays for cooling, and finally,
It was crushed into islets for storage. The yield of process 1 was 65 & 9 polymers. Analytical Method The number average molecular weight of the polymer prepared in Preparation Example 1 is determined by titrating a sample of the polymer with base. This analytical method assumes that each molecule of the polymer carries one carfoquinol end group. exactly S1
Approximately 19 samples of the polymer weighed are approximately 2,501 and 0
0＠・Dissolved in Renault＼, 01% in methanol
-) Prepare 15 drops of a solution containing a J-Norlet indicator. 3. A titrant ("0.IN sodium hydroxide in methanol"), which dissolves 49% of sodium hydroxide for analysis in about 5IQ of water. IQ the solution with methanol
It is made by diluting it. The above titrant is
Standardize using the usual method against a standard acidic substance such as potassium tarrate. A sample of the polymer is titrated in a conventional manner, the weight of the polymer sample and the equivalent millimoles of base are measured, and the average molecular weight of the polymer is calculated from that value. The polymer hatches used to make the devices in the examples shown below were analyzed according to the method described above. Also,
The determined molecular weights are shown here. Examples 1-6 Six different types of devices were manufactured to perform livestock testing. The same drug-loaded polymer core was used in all six devices. The polymer was made according to the process of Preparation Example 1. Its number average molecular rarity was 3.000. The l-polymer has a particle size of 0. It was ground to a smaller size than 18RR and then mixed with 60% by weight of ground polymer or 40% by weight of powdered monenone, sodium salt. The mixture was heated at 95° for 2 hours, and the sintered body was cooled and ground to 3+u+ or less using a hammer mill. A second core was formed from this granular mixture. That is, the granular mixture was extruded into a Teflon mold through a 380zx long Killion extruder with barrel 191 to produce a core with a diameter of 25R1 and a length of 58zi. In the above extruder, in the addition zone, 50
°, 88° in the heating zone and 160° in the Gui
It was driven by. The pressure at the end of the die in the compression zone is 1.000~! , 500psi. The mold was also at room temperature. The tubing used to construct the device was rounded and unjointed, weighing 99 grams. - It was bu. Its outer diameter is 35gm, and its inner diameter is 3.
0+u, the length dimension was 503131. The tubing used in Examples 1.3 and 5 was 304 stainless steel and was cleaned with soapy water and degreased using a microwave with JCl methane. Example 2, 7I upper and 6 tubes are made of mild steel)
- The inner surface of the tube is sandblasted and
In order to assemble and sulfurize this device, which has been cleaned as described above, a 1-butter injection molding machine (S 1auLLerb
ack 1njector) was used. Seven, that is,
Place the melted thermofusible Norat into the ring between the tube and 71A. The tubes were preheated to 60-80° during assembly, and the cores were heated at room temperature. Additionally, 64 sealants were applied at 175-190 degrees. The device was left to cool. Then, the protruding end 5L of the core and the excess sealant are polished by a polishing belt, and the end of the core is polished as shown in 3. - coincide with and fasten the end of the tube. Three thermofusible Nolan] were used. The Norat used in Examples 1 and 2 was yeast hot (1=:a
STOBOND) using A-11OS. In Examples 3 and 4, Eastpond A 337S was used. Furthermore, in Examples 5 and 6, ary-l'' (A
lli+! d) CII 35 was used (heavily used.
S, Inc.) and is made of polyethylene that has been completely modified with microcrystalline wax. A-
The viscosity of 11O8 is 2.200 cP at 163°
It is. Also, the softening point according to the ring and ball softening point test method is 960.
It is. The viscosity of A-3378 is 2,3 at 163°
00 cP, and its softening point according to the ring and ball softening point test method is 95°. r REET CH-35 is Allied
Adhesive Corp., Inc., New York City, New York, U.S.A., manufactured by Adhesive Corp. Styreno resin supplied by Tanotoyer Chemical Company (oodycra C: hcmiclC)
Winktanok market mixed olefins produced by
1/2 quality polypropylene supplied by M.D. Muber (Fairfield, Conn.)
, a microcrystalline wax also supplied by More and Munger, as well as paraflint synthetic wax. Its viscosity is 900 cP at 175°. Test 1 The devices of Examples 1-6 were administered to livestock with fistulas to determine when the devices would release drug. The livestock was a mixed breed and weighed between 900 and 1.400 bonds. Each animal had a fistula surgically inserted into the rumen, so the device could be placed within the rumen and moved at will. The experiment began with two devices placed in the honeycomb stomach of each animal. Ten devices from each lot were tested. The research was conducted in late winter at a research institute in Texas, USA.
It was held during the second spring. There was natural grass in the meadows where the animals were fed. The animals were then rotated to new pastures as needed. Hay was given when the land was covered with snow. All devices were removed from the animals at approximately 2-week intervals;
After washing and drying with paper towels, the weight was measured. The weight lost from the core was measured and the amount of drug released was then calculated from the weight consumed as well as the known proportion of drug in the core. The device was not returned to the animal if the core showed significant uncontrolled erosion, for example if the erosion progressed to the end of the core or down the wall. Some devices were also removed from testing and made available for research. The results of the test are shown in Table 1 below. The average daily drug dosage for each measurement interval is shown along with the standard deviation. The number of devices tested is shown in parentheses for each measurement interval. Six devices in Study 3 and eight devices in Study 4 were removed from the study at the 69 day measurement. This is because these devices apparently interfered with the adhesion between the sealant and the core and did not control erosion. (F margin) Tests Other tests were conducted on the devices of Examples 1-6 during February and March in a pasture near the Gulf Coast of Texas, USA. The livestock at this time was a male calf with a fistula. The meadows were covered with lush oats and rye during the trial period. And it was determined that this pasture was more than the feed the animals needed. Thirty-nine male calves were used for the study. Two devices were then administered to each calf. Therefore, 13 devices from each of the 60 units were tested. The device was initially administered orally to the fistula-injected animal using a suitable poling gun. The location of the device within the gastrointestinal tract or honeycomb was noted each time the device was removed. In addition, the device is approximately the same after weighing.
returned to position. In most cases, the device was located within the honeycomb rather than within the rumen. The results are shown in Table ■. (Margin below) It will be observed that the dosing rate in Study I is consistently lower than the dosing rate in Study H. This difference is likely due to the different feeds of the livestock. The reason why the dosage rate was high in Test H, in which the livestock were fed lush, moist feed, is probably due to the large amount of water in the rumen of the livestock. The uncoated steel devices used in Examples 2.4 and 6 showed more variable and higher dosing rates than the stainless steel devices shown in Examples 1.3 and 5. ing. Examples 7-8 Twenty devices were made. And in this case, Examples 1-6
Substantially the same polymer as that used in was used. The drug in Example 7 was monene nonsodium of standard manufacture, using 904% pure compound or 40% to 60% polymer. Example 8 had 40% 95.2% pure recrystallized monosodium and was used with 60% polymer. Polymer-drug mixtures Examples 1-6
It was manufactured in the same way that it was bypassed. -1- The flicks in all of the examples above were made of 304 stainless steel, and grooves were formed on the inner surface to facilitate adhesion. The tube is cylindrical, Examples 1-6
The dimensions were the same as those used in - judicial. The polymer core was molded in the same extruder and Teflon mold used in Examples 1-6. The extruder was operated at 60 rpm with a feed zone of 80°, a heating zone of 138°, and a die of 120°. The melt left the die at 126-127°. The Nuranoto used was East Pond A-3378. Device combination U was made as described in Examples 1-6. Thirty-six Holstein-crossbred male calves or 7-8 calves implanted with a training fistula were used to test the device. These calves weighed between 700 and 1,000 bonds. The experiment was conducted on a rangeland in central California. The pastures were fed 80% improved feed and 20% natural feed. The pasture is irrigated;
Calves should also be moved around the pasture as necessary to maintain forage quality. The device was inserted into the honeycomb stomach of each calf through the fistula, and the test was started in this state. The device was then removed and inspected in substantially the same manner as described in Test 1 above, and its weight was determined. In some cases, heavy measurements were not taken because some of the devices were not found in the ruminal contents. Table III shows the amounts released in this test. (Left below) Test ■ The device of Examples 7-8 was tested on other groups of Holstein and crossbred male calves. These calves weigh 75
The weight ranged from 0 to 1,335 pounds. The study was conducted on improved pasture in a similar area in Central California. The diet was similar to that in trial 2, but this trial was carried out in winter and therefore the calves needed occasional supplementation with oats, hay and stored corn. The device was evaluated as described in the previous test. The observed dosage rates are as shown in the following table. (Left below) Examples 9 to 14 The six tests listed here were evaluated from four viewpoints. The polymer was the same as that described in Preparation Example 1. Then, 20 polymers with different molecular weights were used. The number average molecular weights are 2.800 and 4, respectively.
There were 400. In all cases, the drug was mixed with 60% polymer 9
It consisted of 40% monene nonosodium with a purity of 0.02%. The polymer and drug are mixed, and this mixture is
The cores were extruded and formed as described in the preparation of Examples 1-6. The tubing was 304 type stainless steel seamless tubing. The legal structure is the same as that of Example B described in Examples 1 to 6. However, in some instances, the tube 1 (and core) having a length of 76 RM was used. In some instances, the end of the device or the end of the polyurethane as shown in FIG. The end cap had an open area of 38%.The end cap was attached to the tube by snapping a molded lip into a groove configured in the tube, as shown in FIG. Two types of hot melt sealants were used in this example. In some examples, Allied CH
-35 was used, and in some other examples Eastbond A-3378 was used. In all cases, the sealant was injection molded at elevated temperature as described in Examples 1-6. The following table shows examples of changes used in the configuration of each side. Carp origin five spoons seventy one mu A sealant 9 50
Ilff2800 Unmanned-337S1
0 50 440G None
(Jl-351+ 50 4400 Yes
^-337312 50 2800
Yes Cl-3513764400 No
8-337S14 76 440On'
The devices of CH-35 Examples 9-14 were tested on male calves with inserted fissures in hot summer weather in Central Indiana. Some calves died from the heat. Animals were grazed on pastures with improved forage. However, hay and mixed feed needed to be supplemented to supplement their daily rations. This is because the grass (fodder) did not grow as normal due to the weather. Two devices were placed in the honeycomb stomach of each animal. Each device was then removed, evaluated, and then returned to the same location within the rumen or honeycomb stomach. When cleaning feed stuck in the cap of a capped device, care must be taken to avoid touching or damaging the surface of the core. The observed drug dosing rates from the device obtained during periodic measurements were as follows. It is clear that the gear knob does not have a significant effect on the dosing rate and that the molecular weight of the polymer has an appreciable effect on the dosing rate. EXAMPLES 15-16 An additional 20 devices were constructed according to the general scheme of Examples 9-14. The number average molecular weight of the polymer used in this device was 2.600. The tubing used in this device was a 304 type stainless steel cylindrical seamless tube with a 751 shoulder length. Further, its inner diameter and outer diameter were the same as those used in the above example. The sealant in Example 15 was Ari-)"CH-35, which was injection molded in the hot melt state, and the tube was uncapped. The sealant in Example 16 was Eastbond A-337.
8, and the tube was fitted with a hemispherical polyurethane cap as shown in FIG. The open area of this tube was 38%. The device is Example 1
It was assembled in a similar manner as described for ~6. Test ■ No fistula was inserted in the animals used in this study. Therefore, it was not possible to test the device periodically throughout the test period. Instead, the device was surgically removed at regular intervals throughout the study period. The data obtained in this study therefore represents only the average dose rate delivered by the device over the entire period from dosing to surgical removal. The animal was a male calf. When the exam begins,
These calves weighed between 675 and 840 pounds. The calves were grazed on pasture with improved forage during hot, dry summers in Central Indiana. To supplement the calves' daily diet, hay and mixed feed needed to be replenished from time to time. The study began by administering two devices to each calf via polling gun. Each calf was given free access to water and treated for any illnesses that developed during the study period. During the section period shown in the following table, some calves were subjected to anterior canalotomy, the device was removed, cleaned, dried, and weighed to determine the amount of medicated core eroded. It was decided that The results are shown in the following table ■. In the table, the daily amount of monene nonsodium released from the device is shown in places, as well as the average over the period from dosing to removal of the device. The number of devices removed and weighed during each section is indicated in parentheses. (Left below) The small standard deviation and consistency of release from one period to another indicate that the device is highly reliable in releasing drug. The release rate shows a tendency to increase as the experiment progresses. This rate of release should increase because the larger the animal, the higher the dose required. Also, devices with a low molecular weight polymer core are better than those with a high molecular weight polymer core. It can be seen that the drug is stably released at a greater dosage rate than in the case of the device. Example 17 A ten anthelmintic drug device was made. This device contains fenbendazole as the drug. This drug is 100%
It is pure and in the form of a fine powder, and its 20
% was mixed with 80% polymer and prepared according to Preparation Example 1 above. Its number average molecular weight is 5. It was too. The above fenbendazole and polymer are
The mixture was mixed and granulated as described in 6. The mixture was then extruded and formed into cores as described in Examples 7-8 above. However, in the molding machine, the feed zone was operated at 18-38 degrees, the heating zone was operated at 88 degrees, and the die was operated at 138 degrees. The core was cut to 58JIIF lengths, cooled, and assembled into a 5011 norinda made of 304 type stainless steel with an inside diameter of 30mm and an outside diameter of 35zi. The sealant is Allid Cl-1-35, which is injection molded in the hot melt state and after the sealant has cooled.
The protruding ends of the core as well as the excess Nolat were removed by polishing. The ends were then capped with polyurethane hemispherical end caps. This end gap had the shape shown in FIG. 1 and had an open area of 38%. Test■ The device of Example 17 was tested on a male calf with a fistula inserted and
Both normal calves were tested. Two devices were administered to each of the two fistulae calves via a Bowling gun and then removed at 14-day intervals, cleaned, dried, and weighed. Fenbendazole dosage was calculated based on weight loss;
The results are shown in the following table (■). Table ■ Release rate for each fixed period of time Phenobendazol Rg 1 day ±5 DO
-14th 14-28th 7 overflow 1.3□ha± 4
2-56 days 0 25+15 30+17 4
0±1056-70 mills 70-87 days 87-9
Day 8 42±9 41±1034±8 One device was dosed to each of 10 normal calves. Each calf was then placed on pasture for 90 days. The device is
It was then removed by rumenotomy. Five of the animals were removed after 62 days and the other five after 90 days, as described above.
Washed, dried and weighed. The cumulative release rate of fenbendazole is 25 ± 2 shoulder g/EJ for more than 62 days and 32 ± 1 for more than 90 days.
It was solved/day. Examples 18-2 ■ Forty dewormer devices were made. Fenbendazole was used as the drug. 25% of 100% pure powdered phenobendazole and 75% polymer were mixed and prepared as shown in Preparation Example 1. Twenty polymers with different molecular weights were used. Example 18
．． In No. 19, a polymer with a number average molecular weight of 2.730 was used. Also, in Example 20.21 a lot with a number average molecule of 14.275 was used. The drug and polymer were mixed, granulated, and extruded as described in Example 17, and the molded core was cut to 58 shoulder lengths. The tubing was 304 type stealth steel length F+Oxx unjointed tubing. The inner diameter l method and outer diameter dimensions are the same as the tube used in the above example. The core was assembled into a tube containing one of two thermofusible nolats. Example 18.20 used Alito Cl-1-35. Also, in Example 19.21, Eastbond A-3375 was used. After the edges of the device were sanded smooth, the device was capped with a polyurethane hemispherical cap. The open area of the cap was 38%. Whip! The devices of Examples 18-21 are for Indiana, USA, and were tested on male calves with inserted fistulas. Gorera's calves were kept on improved pasture. These r.cows had free access to water. And these calves were given the necessary medicines to keep them in good health. During the compartment periods detailed in Table 1 below, the device was removed from the animal and cleaned, dried, and weighed as shown in the previous example. The results of the test are shown in Table 1 below, in which the At amount and the period between measurements were counted as 1. - [released per 1] J nohentasol or q (hereinafter in the margin) Examples 22-23 The device used in this example was 501R long, uncapped, and 90.4% pure. The polymer had a core containing 40% sodium chloride.The polymer was the same as in Preparation Example 1, and had a number average molecular weight of 11.
It was 3,000. The polymer and powdered monenonone were mixed, granulated, and extruded to form cores as shown in Examples 7-8. The device was constructed by injection molding a hot melt sealant into the ring. In Example 22, the sealant is Eastbond A-11.
O8 and in Example 23, the sealant was American CI-
It was 1-35. The tube was a 304 type stainless steel cylinder with the dimensions used in the example above. The device was placed on an abrasive belt. Study IX The device of Example 22.23 was administered by poling gun to a male calf with a fistula inserted. Each calf received two devices. And five devices were used for each lot. The animals were housed on improved pasture in Central Indiana and were cared for and treated to maintain good health throughout the study period. At regular intervals, the device was removed and weighed as described in the example above. Then, the release rate was calculated for each period of observation days. The release rates are shown in Table IX below. In the table, the sodium monene released per day is indicated in places and the standard deviation is indicated plus or minus. Note that some equipment was not weighed during a certain period. This was because it was not possible to find all the devices in the rumen of a very large calf that had a fistula inserted. Table W ・Average release rate for each period Mone 7 Nonona Sodium Town/Stomach SD Treatment Observation l” Example 22 Example 2328
67:'4(11) 81±7(10)42
74±7(II) 78±II(II)569
6±16(11) 89±9(I 1)731
10±15(9) 84±8(10)84
146±60(1,0) 85±1
3(+2)100 --- 2
05±62 (10) Examples 24-26 One group of devices was fabricated from 304 type stainless steel seamless tubing with length dimension 50u+. The inner diameter of this tube was 3 (lu) and its outer diameter was 35311. However, the number average molecular weight was 3500. Monononono and the polymer were mixed, granulated, and
Extrusion molding 1k in the same manner as shown in 8. However, some cores were extruded to an outside diameter of 31+R and machined to a diameter of 254 shoulder. Example 26 used a machined core device. In other cases a molded core was used. The core is formed in the same manner as described on each side above.
The thermofusible Norat was injection molded into a tube. Norat is Example 24 and Allied CH-35
, and Eastpond A-11O8 in Examples 25.26. After assembly, the device was subjected to an abrasive belt. The core was processed to be the same length as the tube. Edge camps were not used. The devices of Kamiri Examples 24-26 were tested on livestock with fistulas inserted. The livestock was raised on improved pasture in Central Indiana. The calves were given good care and the necessary medications to maintain good health. Each animal received two devices via poling gun. Ten devices were tested for each loft. The devices were periodically removed and tested in the same manner as in the previous example. The results are shown in Table X below. ＼ Average release rate for each fixed period moneno/ton sodium 119/day SD 輯片” □ Example 24 ---- L-≦- Possible ----- A length - 1446 ± 25 (9) 27 ± 19(9) 4
0±16(10)28 105±27(10) 8
7±26(9) 93±19(9)4298±22(
10) 86±43(9) 65±25(9)63
94±34(8) 125±21(Q) 150±
32(9)70 129±76(8) 238±7
0(9) 305±96(9)84 122±19
(8) +23±27(8) 1.56±52(9
)9885±14(8) 192±28(8) 1
62±24(2) Examples 27-32 Six devices of different types were fabricated as two groups. The same core was used in each device. The polymer was the same as that used in Production Example 1, and its number average molecular weight was 3,700. The 60% polymer was mixed with 40% monenonone sodium of 873% purity. Cores were manufactured similar to those described in 1-Examples 1-6 and assembled into tubes with Allid co-35 Norat. The tubes used here are as follows. Example 27 Low carbonization 1 28 Zinc phosphate soaked low element steel 29 304 type stainless steel 30 Nickel plated low grade carbon steel 31 Low carbon steel coated with Evokino resin 32 Low carbon steel coated with polyhinyl chloride resin black plastisol All carbon steel tubes are 501 JI in length and have an inner diameter of 301
There was a ゛ζ, and the outer diameter was 35+z. Polyurethane end caps were applied as shown in Figure 1.2. The open area of this cap was 38%. Confined Prisoners - The devices of Examples 27-32 were tested during the winter in central Indiana, USA, on livestock with fistulas inserted. Two devices were administered orally to each animal. Livestock were fed hay and mixed feed. This is because they could not find anything to eat in the pastures. Care was taken as necessary to maintain the health of livestock. At regular intervals, the device was removed from the animal's honeycomb stomach, dried and weighed in the same manner as in the previous test. Table M below shows the release rates obtained in the above tests. Average release rate of monene nonsodium RfI 7-day iSD observation example 2781 ± 29 (9) * * 287]
Di12(9) * *2942±8(1
0) 5g±19(10) 77±8(10)30
44±3(10) 59':10(10) 89±
7 (10) 3142±4 (10) 53! :3(10
) 77-t5 (10) 3244-total 4 (8) 4
1 ± 12 (8) 91 18 (10) *Example 27, 28
All of the above were excluded from the study at 53 [th place]. This is because the hydrolysis of the polymer progressed below the wall surface of the core, resulting in failure. Mackerel 33 One batch of end-capped devices was manufactured. This device used cores made generally as described in Preparation Example 1 and Examples 1-6. The number average molecular weight of the polymer was 3,700. Also, 40% substantially pure monenosine sodium was added to the polymer. The tube was stainless steel as described in Examples 1-6. Sealant ALET CH-35 was also injected into the 2.5 mm annulus between the tube and the core. A groove was formed in the end of the core to hold a polyurethane end cap as shown in FIG. The device of Example 33 was tested on Puistula-inserted livestock fed three different types of food, as shown in the cutout below. At regular intervals, the device was removed from the animal's rumen or honeycomb stomach, dried, and weighed, similar to the tests described above. Table mowing represents release rate in a form similar to that used in the previous tests. Average release rate for each period of surface cutting Sodium monene ay 1 day ± SD Sunkantan feed 0-33 33=56 56-88 88-
112 Grass 34±769±1278±14 11
8±23(Silage) Grain 24±1068±1246±20 156±
22 (Grain) Hay 20±563±960±10 112±16
(llaycubes) Examples 34-36 A large number of devices were constructed according to the general plan of Example 33. However, the number average molecular weight of the polymer was changed as follows. That is, in Example 34 it was 4°000, in Example 35 it was 3.600, and in Example 36 it was 3.200. TEST I'm tired. The device was removed at regular intervals through an anterior canalotomy. The release of monenone was then measured by weight loss as described in the previous test. The information from devices recovered in each region was combined and fully processed to create the following table. The number of instruments combined to obtain each mean and standard deviation is shown in parentheses after the data. The number of days in each processing period is approximated to some extent. This is because not all devices were collected on the same processing day. For example, the period 0-150 actually includes data from devices collected between days 149 and 160. Table xm Average release rate for each fixed period Monensin sodium 0/day SD Miyabi observation day 34 35
360-56 70±6(2
0) 80±4(+4) 85±6(14)018
77±6(14) 87±11(17) 9
2±5(16)0-140 76±8(14) 9
0±8(+6) 90±7(18)Oi50
90±8(48)0-175
89±2 (72) Test XIV The tests presented herein were conducted by administering the devices of Examples 34-36 to normal livestock. In four regions, namely, Idaho, Nebraska, Nevada, and Missouri, these livestock are kept in pens and fed with many types of grains as well as low nutritional value and bulk that stimulates intestinal motility. were fed high-quality feed. The test was conducted in the same manner as described in Test X■, except for the feed. Also, data is presented in a similar manner. Table XIV Average release rate for each period of time Monene nonsodium Shoulder 9/day ± SD Observation B 34 35
360-56 63i4(8) 72±6
(8) 79 chest 3 (8) Q-9868±5 (8)
84±5(8) 88±2(8)0-140
72±6(8) 82±4(8) 87±6(8
)0-150 89±9(32) Test X
v The device of Example 35 was administered to a group of common domestic livestock in Central Indiana. Sixty devices were administered to livestock kept on pasture and 20 devices were administered to livestock kept in pens and fed grain. The devices were removed after approximately 150 days and the average amount of monenone released was determined by weight loss midges. The average amount of monenone released in pasture livestock was 94±4M.
9/day, and the average emission in grain-fed animals was 78±6 m9/day.

[Brief explanation of drawings]

The drawings show embodiments of the invention, with FIG. 1 being a perspective view of the device;
2 is a partial sectional view of FIG. 1; FIG. 3 is a perspective view of an apparatus identical to that shown in FIGS. 1.2 with the exception of the end cap; and FIG. 4 is a third embodiment. 5 to 12 are cross-sectional views of the device according to the example, and FIGS.
3.14 is an enlarged cross-sectional view according to still another embodiment, showing a tuple for holding an end cap, and FIGS. 15 to 17 are views showing a device according to still another embodiment (FIG. (shows a sectional view), FIG. 18 is an exploded perspective view of another embodiment,
19 is a perspective view showing the device of the combination method shown in FIG. 18, FIG. 20 is a cross-sectional view of the device according to yet another embodiment, FIG. 21 is a perspective view according to still another embodiment, and FIG. 22 is the second
1, and FIG. 23 is a sectional view showing the device shown in FIGS. 21 and 22 in a state where the outer nonyl is opened. 21.21a tube, 21e tube, 21
f boundary, 22.23 end, 25 end, 2
6b polymer core, 27c sealant, 28 lip, 29.29a, 29b groove, 30, 30a
End cap, 30e wire, 3tH metal mesh,
30 claws, 31 holes, 32 screens or mesh, 30k integral end caps, 35 snaps.
Link, clamp, 36 adhesive, 41 hole, 50
．． 51 outer nonyl, 54 hinge. Patent applicant: Eli Lilly & Company Agent: Patent attorney: 2 people 301
F1617 Ff6;, 16
1g η no 5

Claims (1)

[Scope of Claims] 1. A sustained release drug release device for use in the rumen of a ruminant, comprising a hydrolyzable biodegradable polymer core, in which the ruminant's digestive The core is housed within a tube in which the drug to be administered to the tube is dissolved or suspended, the tube is compatible with the rumen, is open at at least one end, and is relatively thick. A layer of resilient sealant is provided, the sealant filling the entire length within the annulus formed between the core and the tube to bond both the core and the tube, and which is impermeable to water and adheres to the tube. A sustained release drug release device characterized by being compatible with both the core and being compatible with and unaffected by the rumen. 2. The polymer of the polymer core is composed of about 60 to 95% lactic acid and about 40 to 5% glycolic acid, and has a number average molecular weight of about 2,000 to 6,000. The sustained release drug release device according to item 1. 3. The sustained-release drug release device according to item 1 or 2, wherein the tube is made of a material having a specific gravity of about 6 to 10 g/cc. 4. The sustained release drug release device according to any one of items 1 to 3, wherein the tube is made of stainless steel or low carbon steel coated with a film compatible with the rumen and sealant. 5. The tube has a length of about 25 to 85 mm, an outer diameter of about 10 to 40 mm, or a wall of the tube has a thickness of about 1 to 4 mm. A sustained release drug release device as described in Section 1. 6. The sustained release drug release device according to item 5, wherein the length of the polymer core is substantially the same as the length of the tube. 7. The sustained-release drug release device according to any one of items 4 to 6, wherein the polymer forming the polymer core has a molecular weight of about 2,000 to 4,500. 8. The sustained release drug release device of clause 7, wherein the polymer core contains about 1-50% drug. 9. The above drug is a feed efficiency improver for ruminants, an anthelmintic, an antibiotic, an anticoccidial agent, an ectoparasiticide, a feed insecticide, an estrus suppressant, a trace element, a nutrient, or a combination thereof. 9. The sustained-release drug release device according to item 8. 10. Item 9, wherein the drug is monensin, narasin, salinomycin, lasalocid, fenbendazole, melengestrol, ivermectin, or a pharmaceutically acceptable salt or ester thereof, or a composite agent thereof. long-acting drug release device. 11. The elastic sealant is a heat-melt sealant,
Or, the sustained-release drug release device according to any one of items 1 to 10, which is a sealant that is chemically cured or solidified. 12. The sustained-release drug release device according to item 11, wherein the sealant is made of ethyl-vinyl acetate copolymer, polyethylene resin, polyamide resin, thermoplastic rubber, silicone, or polysulfide. 13. The sustained-release drug release device according to item 12, wherein the sealant is made of ethylene-vinyl acetate copolymer or polyethylene resin. 14. The sustained release drug release device of claim 13, wherein the open end of the tube is covered by a molded, resilient, perforated hemispherical end cap. 15. The sustained release drug release device of claim 13, wherein the open end of the tube is covered with a perforated end cap made from an extension of the material of the tube. 16. The sustained release drug release device of claim 13, wherein the end of the tube is covered with a perforated end cap that is an integral part of an outer shell enclosing the tube. 17. A method for administering drugs to ruminants, which comprises placing the sustained-release drug release device according to any one of items 1 to 16 above into the rumen of the animal.