JPH0657222B2 - Dosing device for administering an active agent composition to ruminants - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to new and useful administration systems for administering active agent compositions to animals. In particular, the present invention comprises the following elements: (1) outer wall, (2) inner compartment, (3) active agent composition from insoluble to readily soluble in aqueous biological liquid in compartment, (4) absorption of liquid, An intra-compartmental hydrogel for swelling and releasing the active agent composition from the administration system;
(5) The present invention relates to a dosing system comprising a dense element in a compartment for increasing the density of the dosing system and holding the dosing system in an animal body for a long time.

BACKGROUND OF THE INVENTION It is well known that ruminants, including cattle, sheep, giraffes, deer, goats and wild cattle, especially cattle and sheep, are important groups of animals capable of digesting large amounts of feed. These feeds are swallowed with little chewing and are consumed in the largest compartment of the animal's four stomachs, the rumen. However, the rumen is not a real stomach because it has no digestive glands. The rumen has the properties of a storage compartment, a mixing organ, and a reservoir with a high bacterial concentration. Bacteria in the rumen destroy the ingredients of the feed,
Convert it into a simple substance that animals can easily digest. The feed is then exhaled by the animal, defused into finer particles and again swallowed by the animal. After the feed particles have reduced to a certain critical size, they exit the rumen and enter the rest of the animal's stomach for further digestion.

The livestock industry is a valuable therapeutic agent that remains in the rumen for a long time,
There has long been a long-felt need for a dosing system manufactured as a dosing device which is capable of a corresponding long-term release of a nutritional or additive composition. Cattle, cattle, growing calves and sheep feed on large pastures, and it is very difficult to administer single dose units or multiple dose units of the active agent composition to animals. There is a need for such an administration system. In addition, the rancher, farmer and feedlot operator do not have the time required to administer the single dose unit or multiple dose units to the animal. This administration system is required especially when connection administration is required for animal health management.

Therefore, from the viewpoint of the above description, it functions as a rumen controlled release device and remains in the rumen after a single administration to effectively release the active agent composition into the rumen for a long period of time. There is a long-felt need for a new livestock treatment system. That is, in the rumen, which is easily swallowed by a ruminant and remains in the rumen for a long period of time, and the active agent composition is connected and released into the rumen without being exhaled by the ruminant. The device is needed.

OBJECTS OF THE INVENTION It is therefore the main object of the present invention to provide a new and useful veterinary therapeutic administration system which meets the urgent needs well known in the prior art and can be used in ruminants.

Another object of the present invention is to provide a veterinary therapeutic administration system manufactured as a rumen device which releases the active agent composition at a controlled rate over a long period of time.

Yet another object of the present invention is to provide a veterinary therapeutic administration system which remains in the rumen-reticular sac for a long period of time and releases the active agent composition at a rate controlled by the administration system.

Yet another object of the present invention is to provide a dosing device in which the rate of release of the active agent is a rate controlled by the dosing device and is essentially time independent during the course of effective use of the dosing device. Is to provide.

Yet another object of the invention is a veterinary therapeutic administration for use in the administration of an active agent composition which is difficult to administer and which can be administered by the administration device at a meaningful rate over an extended period of time. Is to provide the device.

Yet another object of the present invention is a compartment containing an insoluble to readily soluble active agent composition in an aqueous or biological liquid, a hydrogel that acts to swell and reduce the space occupied by the active agent composition. An inflatable drive means and a dosing device comprising a dense means having a specific gravity greater than that of the liquid present in the rumen for long-term retention in the rumen. Is to provide.

Yet another object of the present invention is a dosing device comprising a combination of an active agent composition-containing compartment and an expandable means and a dense means having a specific gravity of greater than 1, wherein the combined means expands and is effective from the dosing device. An object of the present invention is to provide an administration device which extrudes a drug composition and holds the administration device in an environment of use for a long time.

Yet another object of the present invention is to be able to carry out a completely pharmacological, nutritional or anti-infective treatment method over a certain period of time, the use of which only intervenes for the initiation and termination of the treatment method. Is to provide a dosing device that only requires.

Other objects, features, aspects and advantages of the present invention will become more apparent to those skilled in the field of pharmacy from the detailed description and claims set forth below in connection with the accompanying drawings.

Detailed Description of the Drawings The drawings, which are examples of novel and useful administration systems for administering active agent compositions, will now be discussed in detail. These examples should not be construed as limiting the invention.

FIG. 1 illustrates one embodiment of the administration system (designated by numeral 10). In FIG. 1, the administration system 10 is manufactured as an administration device having a shape and size suitable for oral administration into the gastrointestinal tract of an animal. The dosing device 10 of FIG. 1 comprises a body 11 consisting of wall means 12 surrounding and forming an internal compartment (not shown in FIG. 1). The dosing device 10 includes a passageway 13 shown as a partial opening in the wall 12 for releasing the active agent composition from the dosing device 10.

FIG. 2 is a sectional view of the administration device 10. The dosing device 10 of FIG. 2 comprises a body 11, a wall 12 and a passage 13. The wall 12 surrounds an internal compartment 14 or lumen. In a preferred embodiment of the present invention, at least a portion of wall 12 is formed from a wall-forming composition that is permeable to the passage of external liquids. The wall 12 is composed entirely of a semipermeable composition that is permeable to the passage of liquid but substantially impermeable to the active agent and other components within the compartment 14. Compartment 14 contains active agent composition 15 (indicated by dots) that is insoluble to readily soluble in the liquids present in the environment of use. Effective agent composition 1
When 5 is soluble in the liquid, the active agent composition 15 exhibits an osmotic pressure gradient across the semipermeable composition-containing wall 12 with respect to the external body being absorbed in the compartment 14. If the active agent composition 15 exhibits limited solubility or is substantially insoluble in the external liquid, is there limited osmotic gradient activity across the semipermeable composition-containing wall 12 with respect to the external liquid? Or will not be shown at all. Effective agent composition 1
Permeation that is soluble in the external liquid and exhibits an osmotic pressure gradient across the semipermeable composition-containing wall 12 relative to the external liquid when 5 has a limited solubility or is substantially insoluble in the external liquid. Agent 16 (shown as a dash) can be mixed.

In another embodiment, the active agent composition 15 is a carrier means 1.
Present in compartment 14 with 7 (indicated by wavy lines). The active agent composition 15 can be dispersed homogeneously or heterogeneously with the carrier means 17. The carrier means 17 is a non-heat absorbing hydrophilic polymer composition and is a soluble polymer or a lightly crosslinked polymer. In the preferred embodiment, the carrier means 17 is a permeable polymer having a permeability capable of ingesting and absorbing liquids and exhibits an osmotic pressure gradient across the semipermeable wall 12 with respect to external liquids. The carrier means 17 forms a releasable composition comprising a liquid to be absorbed in the compartment 14 and the active agent 15, which composition is released from the administration device 10 through the passageway 13.

Compartment 14 further includes an inflatable element 18. This element, in one of the preferred embodiments of the present invention, is the interface 20 formed by the drive element 18 and the active agent composition 15.
And the penetrant or penetrating polymer 17 is blended in the active agent composition. Inflatable element 1
8 has a shape corresponding to the internal shape of the compartment 14. Compartment 14 also includes a compact element or compact 19 that contacts passageway 13 and active agent composition 15. The passageway 20 extends through the confluence element 19 for releasing the active agent composition from the conversion 14 and out of the administration device 10. The passageway 20 is aligned with the passageway 13 within the semipermeable outer wall 12 to provide complete communication between the compartment 14 and the exterior of the administration system 10.

Upon actuation of the administration device 10, the administration device 10 exerts a thermodynamically and kinetically coordinated series of activities, whereby the active agent composition is released into the liquid biological use environment. It That is, in any of the embodiments, the active agent or active agent-penetrating agent composition or active agent-penetrating polymer composition first absorbs the liquid through the semipermeable wall into the compartment and releases the active agent. A releasable, soft paste-like permeable polymer containing possible solutions or actives is formed. Upon formation of the releasable composition, at the same time external liquid is absorbed through the semipermeable outer wall by the expandable hydrophilic layer in a tendency to reach osmotic equilibrium, causing continuous expansion of layer 18. , Swell. In a preferred embodiment of the present invention, the layer 18 expands forming a completely immiscible boundary line at the interface 20 defined by the active agent composition and the expandable layer. As the layer 18 swells and swells continuously, the volume of the layer 18 increases and at the same time the layer 18 in the compartment 14 swells so that the active agent composition is extruded through the passageways 20 and 13. The combined action of liquid absorption by the active agent composition and elimination of the active agent composition by the expandable layer usually occurs at a controlled rate over a long period of time, from about 1 day to 6 months or more. Dense element 19
Is for retaining the administration device 10 in the rumen during this period.

FIG. 3 is a cross-sectional view of another dosing device according to the present invention.
The dosing device 10 of FIG. 3 has an outer wall 12, an inner compartment 14, an active agent 15, an osmotic agent 16 or an osmotic polymer 17, an expandable hydrogel 18 (in a preferred embodiment of the invention, different from the osmotic polymer 17 forming material). It is a substance) and a weight 19. Dosing device 1
The 0 also includes an inner wall 21 formed as a single capsule element or as a two-part element. Inner wall 21 is wall 1
Formed from a wall-forming composition different from the two-forming composition.
The dense element 19 of the administration device 10 of FIG. 3 is located away from the passage 13. In this latter embodiment, the expandable element 18 exerts a direct pressure on the active agent composition which forces it out of the passageway 13.

FIG. 4 illustrates another product according to the present invention. FIG. 4 is a cross-sectional view of the administration system of FIG. 1 showing another internal arrangement in which there is a compaction element 19 between the active agent composition and the expandable drive element. In this product, the dense element 19 is solid and its presence in the compartment 14 negates the presence of passageways in the dense element 19. In an optional embodiment, the surface of the dense element close to the outlet is geometrically compliant with the outlet device curvature so that the active agent is completely released from the passageway.

FIG. 5 illustrates another product according to the present invention. 5 is the same as the dispensing device described above, but with the dispensing device 10 of FIG.
A compaction element 22 (indicated by dots) comprises inflatable elements 18 dispersed therein. The compact element 22 present in the inflatable element 18 is an element of the administration device 10 for retaining the administration device 10 in the rumen of an animal during active agent administration. The dosing device 10 operates as described above.

FIG. 6 illustrates another product according to the present invention. The dosing device 10 of FIG. 6 is similar to the dosing device of Examples 1-5, except that the dosing device 10 of FIG.
(Indicated by circles) are dispersed uniformly or non-uniformly in the active agent composition. In this embodiment, when the active agent composition is released from the administration device 10 through the passageway 13, the active agent composition entrains the dense element 23. Furthermore, when the active agent composition is released from the dosing device 10 with the dense element 23, the dosing device 10 becomes lighter and drains from the environment of use at the end of the dosing period.

The administration device 10 can be manufactured in a variety of sizes and shapes suitable for administering the administration device 10 to warm-blooded animals, including ruminants. The preferred shape of the present invention is a cylinder-like or capsule-like shape. For example,
For use on sheep, the dosing system 10 may take a capsule-like shape and have a diameter of about 0.5 to 2.5 inches (1.3 cm to 6.6 cm). System 1 for use on cattle
0 is about 1 to 3.5 inches (2.5 to 7.8 cm) in diameter and 3.0 to 5.
It can take 0 inches (7.2 to 12.2 cm). 1 to 6
Although various dosing systems 10 that can be made in accordance with the present invention are described herein, these dosing devices can take other shapes, sizes and formats to administer the active agent to a biological environment. It should be clear that this system should not be construed as limiting the invention. The dosing system can be used in veterinary clinics, farms, zoos, laboratories, rangelands, feedlots and other environments of use. The dosing device can be used to release the active agent composition into a liquid use environment. The liquid environment in this case is an aqueous environment containing a biological aqueous liquid.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the practice of the invention, typical materials for forming the wall 12 are, in a preferred embodiment of the invention, semipermeable polymers and semipermeable homopolymers, for example: It is now known to include cellulose monoesters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, mixtures thereof and the like. These cellulosic polymers have a degree of substitution (DS) on their anhydroglucose units of greater than 0 and up to 3. By degree of substitution is meant the average number of hydroxyl groups normally present on the anhydroglucose unit that are either replaced by a substituent or converted to another group. Anhydroglucose units may be partially or completely attached by a semipermeable polymer-forming group such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate. Is replaced by. Semipermeable materials typically include cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tri-cellulose alkanylates, mono-, Di- and tri-alkenylates, mono-,
The element is selected from the group consisting of di- and tri-alloylates. Typical polymers include DS1.8-2.
3, cellulose acetate having an acetyl content of 32-39.9%; DS1-2, cellulose diacetate having an acetyl content of 21-35%; DS2-3, acetyl content 34-44.8
% Cellulose triacetate and the like. More specific cellulose polymers are DS1.8, cellulose propionate having a propionyl content of 38.5%; cellulose acetate propionate having an acetyl content of 1.5 to 7% and a propionyl content of 39 to 42%; and an acetyl content of 2.
5% to 3%, average propionyl content 39.2 to 45%, hydroxyl content 2.8 to 5.4% cellulose acetate propionate; DS1.8, acetyl content 13 to 15%, butyryl content 34 to 29% cellulose acetate butyrate; acetyl Content 2 to 29.5%, butyryl content 7 to 5
2%, cellulose acetate butyrate with a hydroxyl content of 0.5-4.7%; eg cellulose trivalerate,
Cellulose triacylates with a DS 2.9 to 3 such as cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate and cellulose tripropionate; eg cellulose disuccinate, cellulose dipalmitate, cellulose dioctae Note,
Cellulose diesters of DS2.2 to 2.6 such as cellulose dicarpyrate; Cellulose propionate morpholinobutyrate; Cellulose acetate butyrate; Cellulose acetate phthalate etc .; Cellulose acetate valerate, Cellulose acetate succinate, Cellulose propionate There are mixed cellulose esters such as onate succinate, cellulose acetate octanoate, cellulose valerate palmitate, cellulose acetate heptonate and the like. Semi-permeable polymers are known from U.S. Pat. No. 4,077,407 and are available from Interscience Publis.
hers, clnc.) (New York), Encyclopedia of Polymer Science and Technolo
gy) Vol. 3, pages 325-354 (1964).

Other polymers include cellulose acetaldehyde dimethyl cellulose acetate; cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylaminoacetate; cellulose compositions from cellulose acetate and cellulose hydroxypropylmethyl cellulose; cellulose acetate and cellulose acetate butyrate. Cellulose composition, cellulose composition from cellulose acetate butyrate and hydroxypropyl methylcellulose; semipermeable polyamide; semipermeable polyurethane; semipermeable polysulfone; semipermeable sulfonated polystyrene; US Pat. Nos. 3,173,876, 3,276,586, Third 3,541,
Crosslinked selectively semipermeable polymers formed by coprecipitation of polyanions and polycations as described in 005, 3,541,006, and 3,546,142; selectively permeable silicone rubbers. U.S. Pat. No. 3,133,132 to Loe
semipermeable polymers as disclosed in b) and Sourirayan; semipermeable polystyrene derivatives; semipermeable (sodium polystyrene sulfonate); semipermeable poly (vinylbenzyltrimethyl) ammonium chloride; semipermeable Expressed as a difference in hydrostatic pressure or osmotic pressure across the wall per atmospheric pressure, 10 ^-1 to 10 ^-7 (cc.mil/cm ² · hour ・ a
There are semipermeable polymers that exhibit liquid permeability of tm). These polymers are disclosed by J.A. R. Scott (J.R., published in U.S. Pat. Nos. 3,845,770, 3,916,899 and 4,160,020, and by CRC Press, Cleveland, Ohio). Scot
t) and Tabulieu Jei Roff (WJ Roff) by Hand-book of Comon Polymers (Hand-book of Co
mmon Polymers) (1971).

In products where the device 10 comprises an inner wall formed from encapsulation elements, the encapsulation elements are generally in the form of tubes and
The end has an opening, and the end apart from this opening is closed as a hemispherical or dome-shaped end. The capsule element has a wall that surrounds and defines the internal compartment,
It is used as a hollow body with an opening for establishing communication with the outside of the capsule and filling the capsule. In one embodiment, a mandrel, such as a stainless steel mandrel, is dipped into a bath containing a solution of capsule wall-forming material to form a capsule by coating the mandrel and severing the lumen. A capsule with is obtained.
The material used to form the capsule is gelatin, i.e. 15-30
Gelatin with Millipoise viscosity and Bloom strength up to 150 g; Gelatin with Bloom value of 160-250;
Composition of gelatin, glycerin, water and titanium dioxide; Composition of gelatin, erythrosine, iron oxide and titanium dioxide; Composition of gelatin, glycerin, sorbitol, potassium sorbate and titanium dioxide; Gelatin, acacia, glycerin A composition consisting of water; a commercially available material including a water-soluble polymer and the like which can be permeated with water and can be formed into a capsule.

The wall can also include a flux modifier. A flux modifier is a compound added to the wall-forming material that helps control the liquid permeability of the flux through the wall.
The flux modulator can be a flux enhancer or a flux reducer. Modulators can be preselected to enhance or decrease the liquid flux. Modulators that significantly enhance permeability to liquids such as water are often hydrophilic in nature, while modulators that significantly reduce permeability to liquids such as water are hydrophobic in nature. When incorporated into the wall, the amount of modifier is generally from about 0.02% to more than 20% by weight. The flux modifiers in embodiments that enhance the flux are polyhydric alcohols, polyalkylene alcohols, polyalkylene diols, alkylene glycol polyesters, and the like. Typical flux enhancers include polyethylene glycol 300, 400, 600, 1500, 4
000,6000, etc .; low molecular weight glycols such as polypropylene glycol, polybutylene glycol and polyamine glycol; poly (1,3-propanediol), poly (1,4-butanediol), poly (1,6-hexadiol) Polyalkylene diols such as;
Aliphatic diols such as butylene glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, etc .; glycerin, 1,2,3-butanetriol, 1,2,4-hexanetriol, 1,3,3. Alkylenetriols such as 6-hexanetriol; esters such as ethylene glycol dipropionate, ethylene glycol butyrate, butylene glycol dipropionate glycerol acetate ester and the like. Typical flux reducing agents are phthalates substituted with alkyl, alkoxy or both alkyl and alkoxy groups, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di (2-ethyl-hexyl) flate]; triphenyl. Aryl phthalates such as phthalate and butylbenzyl phthalate; Insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, etc .; Insoluble oxides such as titanium oxide; polystyrene, polymethylmethacrylate, etc.
Polymers in the form of powder, granules, etc., such as polycarbonates and polysulfones; esters such as citrates esterified with long-chain alkyl groups; inert, substantially water-impermeable fillers A resin or the like which is compatible with a wall forming material containing cellulose as a main component. Dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, and C 6-11 carbons are used as materials for imparting flexibility and stretchability to the wall to make the wall low-destructive to non-destructive and to increase tear strength. There are plasticizers represented by phthalate plasticizers such as linear letterate, diisononyl phthalate and diisodecyl phthalate. Plasticizers include triacetin, dioctyl azelate, epoxidized talate,
There are also non-phthalate plasticizers such as triisooctyl trimellitate, triisononyl tomellitate, sucrose acetate isobutyrate, epoxidized soybean oil and the like.
When mixed in the wall, the amount of the plasticizer is about 0.01% by weight to 2
It is 0% by weight or more.

The expandable means 18 has a shape that matches the internal shape of the compartment 14 and is preferably made from a hydrogel composition. The hydrogel composition is non-crosslinkable or optionally crosslinkable and has properties such as the ability to absorb an external liquid through the wall, and when the polymer is permeable, to the external liquid of the administration system 10. The semi-permeable gradient is shown. The substance used to form the expandable / swellable inner layer 18 is a neat polymeric material and a polymeric material mixed with a penetrant, which interacts with water or biological liquids, absorbs the liquids, and reaches an equilibrium state. Swells and swells up to. These polymers can retain a significant portion of the absorbed liquid within the polymer molecular structure. The polymer of the preferred embodiment swells and swells to a very high degree,
It is a gel polymer capable of exhibiting a volume increase of 2 to 50 times. The swellable hydrophilic polymer and the permeable polymer can be non-crosslinkable or low crosslinkable. The cross-linking of polymers that are capable of swelling in the presence of liquids is a covalent bond or an ionic bond, which when cross-linked, becomes insoluble in the presence of aqueous liquids. The polymer used for the expandable means 18 generally has a viscosity of 5,000 to 10,000,000 centipoise (25 ° C). Such polymers can be of plant, animal or synthetic origin. The polymer material used for this purpose has a molecular weight of 5,
000-5,000,000 poly (hydroxyalkylmethacrylate), molecular weight 10,000-360,000 poly (vinylpyrrolidone); anionic and cationic swellable hydrogels; polyelectrolyte complex; poly (vinyl alcohol) with few acetate residues ); Swellable mixture of agar and carboxymethylcellulose; Swellable composition consisting of methylcellulose mixed with low crosslinkable agar; Dispersing and reducing a finely divided copolymer of maleic anhydride and styrene, ethylene, propylene or isobutylene Water-swellable copolymers; N-vinyllactam water-swellable polymers and the like.

Used to form a hydrophilic inflatable propulsion element 18,
Absorption or ingestion of other hydrogels or gellable liquids
・ Retentive polymer has a molecular weight range of 30,000 to 300,000
Chin; agar, acacia, karaya, tragacanth, algi
Polysaccharides such as guar and guar; Carbopol Acidic carboxy
Sipolymer and its salt derivatives; polyacrylamide; in water
Swellable indene-maleic anhydride polymer; Goodri
te Polyacrylic acid with a molecular weight of 80,000 to 200,000; Polyox
Polyethylene oxide with a molecular weight of 10,000 to 5,000,000
Limmer; starch graft copolymer; Aqua-Keep Original weight
An acrylate polymer having a water absorption of about 400 times the amount;
Polyglucan diesters; cross-linked polyvinyl alco
And poly (N-vinyl-2-pyrrolidone) mixture;
Zein available as prolamin; molecular weight 4,000-10
It is 0,000 poly (ethylene glycol) or the like. Preferred
In another embodiment, the thermoformable, permeable polymer 17 is
Polymers and poly containing different molecular structures
An expandable element is formed from the mer composition. Has hydrophilicity
A representative polymer that can be used is U.S. Patent No. 3,865,108,
4,002,173, 4,207,893, 4,327,725 and chestnut
-Brand Rubber Company
Scott, published by (Cleveland, Ohio)
Handbook of Camon by (Scott) and Roff
Known from Polymers (Handbook of Commo Polymers)
is there.

The active agent carrier means 17 used to form a releasable composition with the active agent absorbs or ingests liquids.
A hydrophilic polymer that can be retained to form a viscous solution or semi-paste-like carrier. The carrier containing the absorbed liquid and the active agent is discharged from the administration device 10 through the passage 13. The liquids absorbed in compartment 14 are aqueous liquids and aqueous-biological liquids. In a preferred embodiment of the invention, the carrier means 17 is a non-crosslinkable hydrogel, preferably a hydrogel different from the expandable element 18. Generally, the carrier 17 hydrogel has a solution viscosity of from about 100 centipoise at 5% to about 1000 centipoise at 5% (measured at 25 ° C.). For purposes of the present invention, the viscosity of the inflatable means 18 is usually at least 4, more than that of the carrier means 17.
Only 000 centipoise is big. The solution viscosity of a polymer can be measured using a Brookfield Viscometer. The viscosity measurement method is
Reminton (Reminton, published by Mack Pubuishing Co., Easton, PA)
Pharmacological Science (Phar
maceutical Sciences) 14th edition, pp. 361-371 (1970)
Is disclosed in. The molecular weight measurement method was published by Van Nostrand Reinhold Co. (New York), Encyclopedia of Chemistry, 2nd edition, by Clerk. Handbook of Camon Polymers, 5 by Scott, pages 663-667 (1966) and Chemical Rubber, Inc. (Cleveland, Ohio).
Chapter 2, pages 487-497 (1971).

The osmotically active compound, which can be mixed with the active agent, is an osmotically effective solute that is soluble in the liquid absorbed in the compartment, and is capable of creating an osmotic pressure gradient across the semipermeable wall against the external liquid. Show. Osmotically effective compounds are also well known as penetrants in the pharmaceutical arts. The osmotically effective compounds useful for this invention include magnesium sulfate,
Magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sordol, isositol, sucrose, glucose and the like. Osmotic pressure of the penetrant suitable for the present invention (atmospheric pressure, atm)
Is greater than zero atmospheric pressure, and is generally from 8 atmospheric pressure to 500 atmospheric pressure or more. Generally 0.1% by weight in compartment
Optionally up to 40% by weight of penetrant. The penetrant forms an aqueous solution in which the active agent is dispersed, or a suspension is formed in situ if the active agent is insoluble in aqueous and biological liquids. One of ordinary skill in the art can readily select an osmotic agent and measure its osmotic pressure with a commercially available osmometer. For a detailed description of penetrants, see US Pat. No. 4,008,716.
Exists in the issue.

Mixing with the expandable polymer 18 or with the active agent, weight gaining or compaction means are used. This density enhancing means is used to initially hold the dosing device 10 within the rumen-reticular sac of the ruminant. The dense element designed as a compact 19 or uniformly or non-uniformly mixed with the expandable polymer 18 is used to initially hold the administration device 10 within the rumen-reticular sac of the ruminant. In the embodiment in which the compact element is mixed with the active agent, the administration device 10 remains in the rumen for the duration of the administration and then enters the digestive tract and is excreted there. Generally, the dense element 19 has a density of from about 1 to about 8 or more. When the dense element is compounded with the expandable polymer 18 or the active agent 15, the weight of the weight means is mixed with the expandable hydrogel or effective agent. In a preferred embodiment of the present invention, the density exhibits a specific gravity of 2.0 to 7.6, which should be sufficient to give the agent composition an initial density of 1-8.
For ruminant cattle and sheep, it is desirable to first exhibit a density such that the compact or complex thereof yields a dosage system density of about 3. Materials with densities from 1 to 8 are iron, iron oxide-coated iron shots, iron shots and magnesium alloys, steel, stainless steel, copper oxides, mixtures of cobalt oxides and iron powders, mixtures of iron and copper oxides. Etc.
The weight means may be in the form of powder, granules, pellets, etc. for the purpose of compacting or mixing with the active agent or with the expandable hydrogel. The weight means can be mixed with the hydrogel by solvent mixing, pouring and evaporation during polymerization, compression molding the mixture, and the like.
The weight increasing means can be mixed with the active agent by mixing in a commercially available V-blender and compression molding in a tablet machine. The amount of weight means admixed with the expandable hydrogel or active agent is about 0.5 to 50% by weight, i.e., an amount sufficient to produce the desired density. Density, specific gravity and specific customer measurements were made in 1970 by Remington's Pharmaceutical Sciences (Rem), edited by Osol, published by Matsuk Publicshwing (Easton, Ohio).
Clinton's Pharmaceutical Sciences), vol. 14, 95-10
It can be easily performed by a method known in the art as disclosed on page 0.

As used herein, the term "active agent" refers to drugs, drugs, nutrients, vitamins, anthelmintics, substances that kill organisms, parasiticides,
By feed supplements and other agents that benefit ruminants. The active agent can range from insoluble to readily soluble in the aqueous carrier means formed in situ within the administration system. The amount of active agent present in the administration system is from 10 ng to over 40 g. The administration system is, for example, 75 ng, 1 mg, 5 mg, 100 mg, 250 mg, 750 mg,
Various amounts of active agent can be contained, such as 1.5 mg, 2 g, 5 g, 10 g, 15 g, etc. It is possible to administer a single dosing system to the ruminant or more than one dosing system to the ruminant during the treatment program.

Representative representatives that can be administered using the administration system of the present invention
Examples of effective agents include mebendazole, levamisole, and
Rubendazole, Cambendazole, Fuenbendazo
Le, Parbendazole, Oxfuendazole, Oki
Cybendazole, thiabendazole, tichlorfon,
Like Praziquantel, Oxantel, Pirantel, etc.
Anthelmintic drugs; US Pat. Nos. 4,199,569 and 4,389,397 and
Opened in Science 221, 823-828 (1983)
Like avermectin and ivermectin shown
Parasiticide (The ivermectin is like roundworm, lungworm, etc.)
Effective for controlling the infestation that normally occurs in various animals
And the early avermectins are
For treatment of infections such as mi and scabies mites
Said to be effective); avermectin and phosphorus
Milbemycin acid; Chlortetracycline, Oxite
Tracycline, Tetracycline, Streptomyces
, Dihydrostreptomycin, bacitracin, eri
Thromycin, ampicillin, penicillin, cephalos
Fungicide such as porin; sulfamethazine, sulfa
A sulfa drug such as thiazole; Menesin Natriu
Mu, ephrotomycin and Elfazeprm Growth spines like
Drugs; anti-inflammatory such as dexamethasone and flumethasone
Drugs: lazaloside, salinomycin, buazinamycin
And rumen-like fermenting agents and ionofu
A; Copper oxide, cobalt sulfate, sodium selenite, acid
Inorganic substances including zinc oxide, magnesium sulfate, zinc sulfate, etc.
And inorganic salts; bloating prevention like organopolysiloxane
Agents; hormone growth aids such as stilbestrol;
Vitamins like thiamine hydrochloride; like furazolidone
Anti-inflammatory agents; lysine monohydrochloride, methionine, magnesium carbonate
Like soluble salts of um, magnesium, copper, selenium, etc.
There are nutritional supplements, etc.

The wall-forming composition can be applied to form a device, i.e., molding, air spraying, dipping, a semipermeable wall-forming material as the outer surface of the layered capsule.
It can be coated by casting or brushing. Other preferred methods for the present invention which can be used for wall coating are the air suspension method and the pan coating method. The air suspension method involves suspending and rotating a device-forming element in a stream of air and a semi-permeable wall-forming substance until the wall surrounds and coats the device-forming element, i.e. until it surrounds and coats the capsule element. Consists of. This method can be repeated for various semipermeable wall forming compositions to form semipermeable layered walls. Air suspension method is US Patent 2,799,241
No. Am. Farm. Asoku (J.Am.Pharm.Ass
oc.) 48, 451-459 (1979); ibid, 49, 82.
~ P. 84 (1960). Other standard manufacturing methods are by Remington, published by Modern Plastics Encyclopedia, Vol. 46, pages 62-70 (1969) and published by Matsuk Publicus Jewing (Easton, PA). Pharmaceutical Science 14th Edition, 1626-16
P. 78 (1970).

Typical solvents suitable for making semipermeable walls include materials, capsule walls, active agents, liquid reactive compositions, swellable elements,
Inert inorganic and organic solvents which do not adversely affect the compact element and the final administration device. Such solvents are widely used in aqueous solvents, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents,
Includes an element selected from the group consisting of alicyclic solvents, aromatic, heterocyclic solvents, and mixtures thereof. Typical solvents are acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptone. , Ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, carbon tetrachloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, cyclohexane, cyclooctane, benzene, toluene, naphtha, 1 , 4-dioxane, tetrahydrofuran, diglyme, water and acetone and water, acetone and methanol, acetone and ethyl alcohol, Renjikurorido and methanol, a mixture such as ethylene dichloride and methanol.

The expression "passage" or "orifuisu" used here is
By in-wall or laminar wall means or methods suitable for releasing the active agent from the administration device. The passageways can be formed by mechanical or laser perforation, or by erosion of corrosive elements in the wall, such as gelatin plugs. The passage can be opened through the wall only or through the wall-capsule, layered wall. In those embodiments where the passageway is opened only through the wall, the capsule wall passageway is formed by destroying, corroding or dissolving the capsule wall passageway in the environment of use. The passageway is a porous polymer composition having at least one pore, or a microporous polymer having at least one or more micropores that serves as one or more passageways suitably provided in a portion of the wall of the administration device. It can be a composition. The location of the passages is visually inspected, by optical density inspection when passing through the device laser equipment, and by optically positioning the device through the manufacturing process and by following it, the reflected wavelengths emitted by the device are optically detected. Detecting can be fixed in place on the wall by magnetic orientation and by similar standard manufacturing methods. A detailed description of the orifice and preferred maximum and minimum sizes for the orifice are set forth in US Pat. Nos. 3,845,770 and 3,916,899.

Description of Embodiments of the Invention The following examples are merely illustrative of the present invention, and these and their equivalents will be apparent to those of ordinary skill in the art having reference to the description of the invention, the drawings and the claims. In any case, these examples should not be construed as limiting the scope of the invention.

Example 1 Controlled-release ivermectin administration device for livestock treatment
Is prepared as follows; first sodium chloride 1.2
g and Carbopol Poly (acrylic) available as 934-P
Acid) sodium salt 4.6 g and inflatable drive element
The mass is compression molded into a solid mass shaped like a tablet. Manest
Tablets using y-press, 18mm tablet and 31/2 ton compression force
Form an agent. This tablet is compatible with the inner shape of the capsule opening.
It has a corresponding shape. Next, open the tablet element with the capsule
Insert into the end until it contacts the bottom of the capsule. Next
First, the capsule is filled with a layer of the active agent composition. Effective agent
The composition is 1.6 g of poly (vinylpyrrolidone), steari
1.2 g of magnesium acidate and 0.5 g of sodium chloride
It consists of 4 g of ivermectin mixed homogeneously. V-Bure
Mix these ingredients thoroughly using a
Compressed under a pressure head of 1 1/2 tons in the press to form tablets
Of layers and contacting it with the expandable hydrogel layer
And place it in the capsule. Then inside
It has a hole and has a dense fit that fits inside the capsule.
Contacting the Tensless Steel Element with the Active Agent Composition in a Capsule
And place and insert. Next, this capsule
Cellulose acetate butyrate 91% and po
Release of 1.8 g of polyethylene glycol 400 9%
Cover the speed control wall. Walls are methylene chloride / methano
Coating from a 5% wt / wt solution in a 90:10 v / v solvent system.
To do. The wall-coated dosage system is then dried at 30% for 24 hours.
Let it dry. Then visually position the device.
Using a high speed mechanical drill, semi-permeable walls and gelatin caps
Drill a 30 mil emission path through the cell wall and
Communicate with solid holes and internal compartments of equipment
It This passage allows the active agent composition to be dispensed from the device for extended periods
Ensure contact with the active agent composition for release over time.
It stands.

Example 2 A dosing device is manufactured according to the method described in Example 1 using the conditions described above, but in this example instead of the dense body, the dense element is added to the expandable polymer. The swellable-swellable composition consists of 70% by weight poly (ethylene oxide) with a molecular weight of 3,000,000, 10% by weight sodium chloride and 20% by weight a 50:50 mixture of cobalt and iron swatch.

Example 3 A dosing device is manufactured as follows: First, the body portion of the capsule is placed with the opening upright, and a layer of expandable-swellable dense composition is inserted into the hemispherical end of the capsule. To do. The shape of this layer matches the internal shape of the capsule. This composition has a sodium chloride content of 5% by weight and a molecular weight of 200,
It consists of 70% by weight of poly (ethylene oxide) of 000 and 25% by weight of stainless steel small particles. The swelling-swellable dense composition-forming component is heated in a commercially available blender while heating.
Mix for 0 minutes to obtain a homogeneous composition. The heated composition is inserted into a capsule to form a layer that occupies about 1/3 of the capsule. The active agent composition is then added to the capsule in such a way that it covers the expandable, dense composition. The active agent composition comprises levamisole 70% by weight, sorbitol 10% by weight,
An osmotically active water-absorbing composition comprising 15% by weight of poly (vinylpyrrolidone) and 5% by weight of calcium stearate.

Then a solution containing 15% by weight of cellulose acetate with an acetyl content of 39.8% is prepared in a methylene chloride / methanol solvent system and the capsules are coated with a semipermeable wall.
The walls are dipped by immersing the capsules in the coating solution for 15 minutes, ie first 5 seconds, then twice 10 seconds, then 30 seconds, then 1
The walls are applied by dipping with a 5 minute drying period in between. After dipping, the dosing device is dried at room temperature (72 ° F, about 22 ° C) for 5 days.
By this method, a semipermeable wall of about 2 mm thickness is applied. Next, in order to release the active agent composition into the liquid use environment over a long period of time, the semi-permeable wall is laser-perforated with a passageway positioned by an optical detection method so that the active agent composition and the outside of the administration device are exposed. Contact the composition.

Example 4 A dosing system for administering an active agent to a warm-blooded ruminant is manufactured as follows: First, ethylene glycol is placed in a mold having a shape and morphology corresponding to the hemispherical closed end and inner diameter of the capsule. Fill an expandable compact composition comprising 30 parts monomethacrylate (containing 0.12 parts ethylene glycol dimethacrylate), 10 parts 0.13% aqueous solution of sodium disulfate in aqueous ethanol, and 30 parts iron powder / magnesium.
The composition polymerizes at 30 ° C., equilibrated to room temperature 2
After 0 minutes, remove the solid layer from the mold. This solid expandable layer is then loaded into the hemispherical portion of the capsule through the opening of the capsule. The capsules are then filled with an active agent composition consisting essentially of 50% morantel tartrate, 20% polyethylene glycol, 6% sodium hexametaphosphate and 24% sodium chloride in a layered arrangement with inflatable dense elements. . The filled capsules are then coated with a peripheral wall of cellulose acetate containing 10% polyethylene glycol 400. The semi-permeable wall is applied in a pan-type high coater. The solvent used for wall formation consists essentially of methylene chloride and methanol (95 parts by weight: 5 parts by weight). The outer surface of this capsule is coated with a 12 mil thick (0.30 mm thick) cellulose acetate butyrate wall. Finally, the passage is laser drilled through the semipermeable wall and the capsule wall to communicate the active agent-containing composition to the environment of use for its release.

Example 5 The procedure of Example 1 is repeated, but in this example, instead of the active agent composition, the anthelmintic drug pyrantel tartrate, pyrantel pamoate or pyrantel embonate; the anthelmintic drug tetramisole; the anthelmintic drug diethylcarpamazine hydrochloride. Or diethylcarbamazine citrate; anthelmintic drug oxantel hydrochloride,
Oxantel embonate or oxantel pamoate; antibacterial agent avoparcin; bloating inhibitor poloxalen; antiparasitic drug avermectin A1a, avermectin A2
a, avermectin B1a or avermectin B2a
To use.

Example 6 A dosing device is manufactured according to the method described in Example 1 using the conditions and materials described above, but in this example a release rate controlling wall of varying thickness (comprising cellulose acetate butyrate polyethylene glycol 400). Is applied to the dosing device. The thickness of the release rate control wall varies uniformly from 30 mil (0.76 mm) at the distal end from the passageway to 15 mil (0.38 mm) adjacent to the dense element.

Example 7 A dosing device is manufactured according to the method described above. This dosing device comprises a first compression molding composition consisting of 36 g of poly (ethylene oxide) with a molecular weight of 500,000, 30 g of iron powder and 5 g of sodium chloride, 1.7 g of palbendazole, 38.5 g of polyvinylpyrrolidone and 9.7 of sodium chloride.
pressing into a second compression molding composition of g. This compression-molded laminate was used as cellulose acetate
Butyrate 50%, poly (sulfone) 45% and acetyltributyl citrate and acetyltri-2-ethyl-
It is surrounded by a semi-permeable wall consisting of 5% citroflex citrate selected from the group consisting of hexyl citrate. The device has a passageway through the semipermeable wall that communicates the active agent composition to the exterior of the device.

Example 8 A dosing system is prepared according to the method described in Example 7 using all of the above conditions, but in this case the semipermeable wall is 80% cellulose acetate butyrate and poly (sulfone) 2.
From 0% or cellulose acetate butyrate 20
% And poly (sulfone) 80%.

Example 9 A veterinary therapeutic dosing device is manufactured according to Example 7 using the conditions described above, but the dosing device of this example has a 1 for the inflatable hydrogel in contact to absorb liquid.
The end is closed with a cellulose acetate film having an acetyl content of 9.5% and the other end is closed with a microporous poly (tetrafluoroethylene) film to release the contacting active agent composition from the administration device. It consists of a high density polyethylene tubular wall surrounding the.

Embodiments of the present invention include (1) a method of enhancing the releasability of an active agent by formulating a releasable composition containing the active agent, and (2) a method of enhancing the releasability of an active agent of the invention. Related to the manufacture of the administration system. An embodiment of the present invention provides a method of administering an active agent to a rumen of a ruminant at a controlled rate, comprising: (A) the following elements: (1) An outer wall that is at least partially composed of a semipermeable polymer that is substantially impermeable to passage;
(2) Implement a treatment program in a pharmaceutically acceptable carrier sensitive to aqueous or biological fluids that provides a means for absorbing fluids at the body temperature of the animal and delivering the active agent from the administration device. A lumen containing an active agent composition layer comprising a unit dose of the drug for enclosing with an outer wall; (3) a density enhancing means for maintaining the dosing device in the pelvic stomach for a long period of time. An inflatable hydrogel layer in the lumen; or (4) a compact element in the lumen for maintaining the administration device in the rumen for a long period of time; or (5) a liquid-sensitive active agent. A dosing device consisting of an orifice in the wall coupled to the composition is placed in the rumen; (B) semipermeable at a rate determined by the permeability of the semipermeable wall and the osmotic gradient across the semipermeable wall. The liquid is absorbed through the flexible wall and the hydrogel To Zhang, swelling; (C)
A liquid is absorbed into the active agent composition to form a releasable, flowable aqueous solution or suspension composition in situ at the temperature of use; and (D) the swellable hydrogel is constantly swellable and releasable Release of the active agent composition from the compartment by pressing the composition, and a therapeutically effective amount of the composition from the orifice is placed at a controlled rate on the pelvic stomach for a prolonged period of time. Concerned.

It is to be understood that changes and modifications can be made in accordance with the principles of the invention disclosed herein without departing from the scope of the invention, as long as the preceding description is directed to preferred embodiments of the invention.

[Brief description of drawings]

In the accompanying drawings, which are not to scale and which illustrate embodiments of the present invention, the drawings are illustrated as follows: Figure 1 shows an active agent composition administered to an animal over an extended period of time. FIG. 2 is a view of a dosing system designed and manufactured as a dosing device for; FIG. 2 is a cross-sectional view of the dosing system of FIG. 1 taken along the vertical axis 2-2 of the dosing system, the outer wall, the compartment, the active agent. Figure 2 illustrates the structure of a dosing system for administering an active agent composition to an animal, and more particularly to a warm-blooded ruminant animal, comprising a composition, an expandable element and a dense element; 3 is a cross-sectional view through which FIG. 3 illustrates an embodiment of the administration system different from that of FIG. 2 including an inner wall forming element and a different arrangement of the elements within the compartment; FIG. 4 is a cross-sectional view of FIG. Of this administration system, which describes another embodiment according to Elements cooperate with each other to provide controlled release of the active agent composition over an extended period of 1 day to 6 months; FIG. 5 is a cross-sectional view of the administration system of FIG. And FIG. 6 is a cross-sectional view of the administration system of FIG. 1, wherein the compartment is a composite composition of the active agent composition and a dense element having a specific gravity greater than 1. Another embodiment of the present invention containing a product will be described. In the drawings and description, like parts in the related drawings are designated by the same numerals. Terms appearing in the description of the drawings and specific examples thereof will be described in detail in other portions of the specification. DESCRIPTION OF SYMBOLS 10 ... Dosing device, 11 ... Body 12 ... Outer wall, 13 ... Passage 14 ... Compartment, 15 ... Active agent composition 17 ... Carrier means, 18 ... Inflatable means 19 ...

Claims (7)

[Claims] 1. A dosing device for releasing an active agent composition into an environment of use, comprising: (a) a wall means surrounding and forming an internal compartment, at least a portion of which is permeable to a liquid present in the environment of use. (B) an active agent composition in the compartment that forms a releasable composition by a liquid that penetrates into the compartment through the wall means, (c) absorbs the liquid and occupies space in the compartment An intracompartmental means for increasing the amount, (d) an intracompartmental means for increasing the weight of a dosing device having a density of at least 1.0, (d)
The means of (c) forms a separate layer from the means of (c), and (e) communicates the exterior with the compartment of the device,
An intramural means for releasing the active agent composition into the environment of use over a period of time. 2. A dosing device for releasing the active agent composition according to claim 1 to the environment of use, wherein the intramural means for communicating the compartment with the exterior of the device comprises at least one intramural passage. 3. An active agent composition according to claim 1, wherein the active agent composition comprises at least one element selected from the group consisting of penetrants and osmopolymers. Dosing device. 4. A dosing device for releasing the active agent composition according to claim 1 to the environment of use, wherein the means for absorbing liquid is a swellable hydrogel. 5. An active agent composition comprising mebendazole, levamisole, albendazole, cambendazole, fuembendazole, parbendazole, oxfuendazole, thiabendazole, tichlorphane, braziquantel, morantel, pyrantel, avermectin, ivermectin, oxantel. A dosing device for releasing the active agent composition according to claim 1 to the environment of use, comprising an element selected from the group consisting of :, piperazine, diethylcarbamazine, tetramizole, poraxalene, selenium and geralanol. 6. A method according to claim 1 wherein at least a portion of the wall means comprises an element selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate. An administration device for releasing the active agent composition according to claim 1 into the environment of use. 7. The active agent composition according to claim 1, wherein the means for absorbing liquid and increasing the amount of space occupied in the compartment is a polymer having a viscosity of 5000 to 10000000 centipoise at 25 ° C. Dosing device to do.