JPS6244249A - Apparatus for dispensing effective drug composition to ruminant - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a new and useful administration system for administering active agent compositions to animals. In particular, the present invention provides the following elements = (1)
(2) an internal compartment; (3) an active agent composition that is insoluble to readily soluble in the biological aqueous fluid within the compartment; (4) absorbs liquid and expands to remove the active agent composition from the administration system. The present invention relates to a delivery system consisting of an intracompartmental hydrogel for release and (5) a dense element in the compartment for increasing the density of the delivery system for retention within the animal body for an extended period of time.

BACKGROUND OF THE INVENTION It is well known that brute animals, including cattle, sheep, giraffes, deer, goats, and cattle, and especially cattle and sheep, are an important group of animals that can digest large amounts of feed.

These feeds are swallowed with little chewing and are ingested into the rumen, the largest compartment of the animal's four stomachs.

However, the rumen has no digestive glands, so it is not a real stomach. The stomach is a storage compartment.

It has the properties of a mixing organ and a reservoir with a large bacterial concentration. Bacteria on the back of the hump destroy the ingredients in the feed and kill the animal.
Hishiichi? Convert it into a simple substance. The feed is then regurgitated by the animal, masticated into finer particles, and swallowed by the animal again.

After the feed particles have been reduced to a critical size, they exit the rumen and enter the rest of the animal's stomach for further digestion.

The livestock industry has long-term residual and beneficial therapeutic agents in the rumen,
A delivery system manufactured as a delivery device capable of releasing nutrients or additive compositions over a correspondingly long period of time? I've been craving it for a long time. Cattle, cows, growing herders, and sheep graze on large pastures, and it is very difficult to administer single-dose or multiple-dose units of the active agent composition to animals requiring multiple doses. this,
The livestock industry is looking for such a delivery system. Plus, ranchers.

Farmers and feed lot operators do not have the time necessary to administer single dose units or multiple dose rates to animals. This administration system is particularly sought after when continuous administration is required during animal health care.

Therefore, in view of the above explanation, it functions as an intraruminal controlled release device, remains in the rumen after one administration, and effectively releases the active agent composition into the rumen over a long period of time. There is a great need for a delivery system for treating livestock.

When swallowed by a ruminant, the active agent composition remains in the rumen for a long period of time and is not regurgitated by the ruminant, resulting in a sustained release of the active agent composition into the rumen.
An intraruminal device is needed.

OBJECTS OF THE INVENTION It is therefore a principal object of the present invention to meet the urgent need well known in the prior art and to provide a new and useful veterinary therapeutic administration system for use in ruminant animals. be.

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

Yet another object of the present invention is to provide a livestock administration system which remains in the rumen-reticular pallidum for an extended 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 active agent release is controlled by the dosing device and is essentially time-independent during the course of effective use of the dosing device. It is to be.

Yet another object of the present invention is a veterinary therapeutic dosing device for use in administering active agent compositions that are difficult to administer and cannot be administered at a meaningful rate over an extended period of time by the dosing device. The goal is to provide the following.

Yet another object of the present invention is to provide a compartment containing an active agent composition that is from insoluble to readily soluble in an aqueous or biological fluid, such that the compartment expands to reduce the space occupied by the active agent composition. Veterinary treatment comprising an inflatable drive means consisting of a working hydrogel and a dosing device having a specific gravity greater than the specific gravity of the liquid present in the rumen for retention in the rumen for an extended period of time. It is to provide a dosing device for use.

Still another object of the present invention is a delivery device comprising a combination of an active agent composition compartment, an inflatable means and a closed means (having a specific gravity less than 1), the combination means being inflatable and capable of administering the active agent composition. It is an object of the present invention to provide a dispensing device that extrudes an active agent composition from the device and retains it in the environment in which the dispensing device 2 is used for an extended period of time.

Yet another object of the invention is that a complete pharmaceutical, nutritional or anti-infective treatment can be carried out over a specified period of time, and that its use requires intervention only for the initiation and termination of the treatment. It is an object of the present invention to provide a dosing device that is suitable for use as a drug.

Other objects, features, aspects and advantages of the invention will become more apparent to those skilled in the art of pharmacy from the following detailed description and claims taken in conjunction with the accompanying drawings.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Next, we will discuss in detail some drawings which are examples of new and useful administration systems for administering active agent compositions.

These examples should not be construed as limiting the invention.

FIG. 1 illustrates one embodiment of a dosing system (indicated by the numeral 10). In FIG. 1, administration system 10 is constructed as an administration device of a single shape and size suitable for oral administration into the gastrointestinal tract of an animal. The dispensing device 10 of FIG. 1 includes a body 11 comprising wall means 12 surrounding and defining an internal compartment (not shown in FIG. 1). Dispensing device 10 includes a passageway 13, shown as a partial opening in wall 12, for expelling the active agent composition from dispensing device 10.

FIG. 2 is a cross-sectional view of the administration device 10. Dosing device 1 in Figure 2
0 is body 11. It consists of a wall 12 and a passage 16. wall 12
There are 14 internal compartments surrounding the lumen.

In a preferred embodiment of the invention, at least one of the walls 12
The portion is formed from a wall-forming composition that is permeable to the passage of external liquids. Wall 12 is comprised of a semi-permeable composition that is permeable to the passage of liquid but substantially impermeable to the active agent and other components within compartment 14. Compartment 14 contains an active agent composition 15 (indicated by dots) that is insoluble to readily soluble in the liquid present in the environment of use.

When the benefit agent composition 15 is soluble in the liquid, the benefit agent composition 15 is absorbed into the compartment 14 and exhibits an osmotic pressure gradient across the semipermeable composition-containing wall 12 relative to the external liquid. If the active agent composition 15 exhibits limited solubility or is substantially insoluble in the external liquid, osmotic pressure gradient activity across the semipermeable composition-containing wall 12 to the external liquid will be limited or All (will not be shown.

If the effective agent composition 15 has limited solubility and is substantially insoluble in the external liquid, the composition-containing wall 12 is soluble in the external liquid and semipermeable to the external liquid. Osmotic agent 16 showing an osmotic pressure gradient across it (indicated by a dash)
be able to mix.

In other embodiments, the active agent composition 15 is present in the carrier means 1.
7 (indicated by a wave) in compartment 14. The active agent composition 15 may be homogeneously or heterogeneously dispersed with the carrier means 17. The carrier means 17 is a non-heat absorbing, hydrophilic polymer composition, which may be a soluble polymer or a lightly cross-linked polymer. In a preferred embodiment, the carrier means 17 is an osmotic polymer having a permeability capable of absorbing and absorbing liquids, presenting an osmotic pressure gradient 2 across the semi-permeable wall 12 to the external body. Carrier means 17 forms a releasable composition containing liquid and active agent 15 which is absorbed into compartment 14 and which is discharged from dispensing device 10 through passageway 16 .

Compartment 14 further includes an inflatable element 18. This element, in one preferred embodiment of the invention, includes an interface 20 formed by drive element 18 and active agent composition 15.
A penetrating agent or penetrating polymer 17 is included in the effective agent composition. Expandable element 1
8 has a shape corresponding to the internal shape of the compartment 14. Compartment 14 also includes a canister 19 that contacts passageway 13 and active agent composition 15 . Passageway 20 includes aperture element 19 for discharging the active agent composition outside of compartment 14 and dispensing device 10.
It extends through the. Passage 20 is compartment 14
and is in line with a passageway 16 in the semi-permeable outer wall 12 for complete communication with the exterior of the administration system 10.

Upon operation of the dispensing device 10, the dispensing device 10 is thermodynamically and kinetically adjusted to release the active agent composition into the liquid biological use environment through a series of activities. be done. In any embodiment,
Active Agent or Effective Agent - Osmotic Agent Composition or Page Active Agent - An osmotic polymeric composition that first absorbs liquid into a compartment through a semi-permeable wall to contain a releasable solution or active agent containing the active agent. Forms a releasable soft paste-like osmotic polymer. Once the releasable composition is formed, external liquid is simultaneously absorbed through the semi-permeable outer wall by the expandable hydrophilic layer to reach osmotic equilibrium, causing layer 18 to expand continuously; swell. In a preferred embodiment of the invention, layer 18 expands forming a completely immiscible boundary at interface 20 defined by the benefit agent composition and the expandable layer. As layer 18 expands and continues to swell, the volume of layer 1B increases and at the same time layer 18 within compartment 14 expands so that the active agent composition fills passageway 2.
Pass through 0 and 13Y and be pushed out. The combined effects of liquid absorption by the active agent composition and expulsion of the active agent composition by the expandable layer occur at a controlled rate over an extended period of time, usually from about 1 day to over 6 months. ) The sound element 19 is for keeping the administration device 10χ in the rumen during this period.

FIG. 6 is a cross-sectional view of another administration device according to the invention. Figure 6
The dosing device 10 has an outer wall 12. Internal compartment 14
．． Effective agent 15. Penetrating agent 16 or penetrating polymer 17.
It consists of an expandable hydrogel 18 (which in a preferred embodiment of the invention is a different material than the material forming the permeable polymer 17) and a weight 19. The dispensing device 10 also includes an inner wall 21, which is formed as a two-part element. Inner wall 21 is formed from a wall forming composition different from the wall 12 forming composition. After the dispensing device 10 of FIG. 6, the acoustic element 19 is located remote from the passageway 16. In this latter embodiment, expandable element 18 exerts pressure directly on the active agent composition to force it out of passageway 16.

FIG. 4 illustrates another product according to the invention. FIG. 4 is a cross-sectional view of the administration system of FIG. 1, showing an alternative internal arrangement 2 in which an acoustic element 19 (between the active agent composition and the expandable drive element) is present. In this product) the lid element 19 is solid and its presence within the compartment 14 subsequently negates the existence of a passage within the acoustic element 19. In any embodiment,
In order to ensure that the active agent is completely released from the passageway, the surface of the acoustic element near the outlet is geometrically shaped to follow the curvature of the outlet of the dispensing device.

FIG. 5 illustrates another product χ according to the invention. 5 is the same as the dispensing device described above, except that the dispensing device 10 of FIG.
It consists of an expandable element 18 with dispersed elements 22 (indicated by dots) therein. The acoustic element 22 (present in the inflatable element 18) is an element of the administration device 10 for retaining the administration device 10 within the animal's rumen during the administration of the active agent. Administration device 10 operates as described above.

Figure 6 illustrates another product according to the invention. The dispensing device 10 of FIG. 6 is similar to the dispensing devices of Examples 1-5, except that in the dispensing device 10 of FIG. are distributed in In this embodiment, as the active agent composition is ejected from the dispensing device 10 through the passageway 13, the active agent composition is entrained by the audible element 26. Furthermore, when the active agent composition is ejected from the dispensing device iio, accompanied by the acoustic element 23,
The dosing device 10 becomes lighter and can be removed from the environment of use at the end of the dosing period.

Administration device 10 can be manufactured in a variety of sizes and shapes suitable for administering administration device 10 to warm-blooded animals, including breeders. A preferred shape of the present invention is a cylinder-like or capsule-like shape. For example, for use in sheep, the administration system 10 can be in the form of a capsule and approximately 0.5 to 2.5 inches (1,36 In to 6
．． 6 cm) in diameter. For use on cattle, system 10 has a diameter of approximately 1 to 6.5 inches (2.5 to 7.5 inches).
．． 8cIrL), length 5.0-5. C1 inch (7,2
~12.2cm). Although FIGS. 1-6 illustrate various delivery systems 10 that can be made in accordance with the present invention, the delivery devices may take other shapes, sizes, and formats for administering the active agent into a biological use environment. Therefore, it is clear that these systems should not be interpreted as limiting the present invention. Administration systems include veterinary clinics, farms, and zoos.

Can be used in laboratories, pastures, feed lots and other usage environments. The dispensing device can be used to deliver the active agent composition into a liquid use environment. The liquid environment in this case is an aqueous environment containing a biological aqueous liquid Z.

In accordance with the practice of the present invention, typical materials for forming the walls 12 are semipermeable polymers and semipermeable homopolymers, such as cellulose, in preferred embodiments of the invention. It has now been found that these include 7-esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ethers, mixtures thereof, and the like. These cellulose polymers have a degree of substitution (I), s, )2 on their anhydroglucose units of greater than 0 and up to 6. Degree of substitution refers to a group that is replaced by a substituent or converted into another group,
It refers to the average number of hydroxyl groups normally present on an anhydroglucose unit. Anhydroglucose units are partially capacitated by semipermeable polymer-forming groups such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, halogen, carboalkyl, alkyl carbamate, alkyl carbonate, alkyl sulfonate, alkyl sulfamate, etc. Completely replaced. The semi-permeable material is typically cellulose acylate.

Cellulose diacylate, cellulose triacylate,
Cellulose acetate, cellulose diacetate, cellulose triacetate, nanano, di- and hydry-cellulose alkanilates, mo/-.

The element selected from the group consisting of G- and tri-alkenylates, hexa-N, G- and tri-alloylates, and the like.

Typical polymers include D, S, 1.8-2.3, cellulose acetate with acetyl content of 32-399%; D, 3.1-2, cellulose diacetate with acetyl content of 21-65%; 3.2-6, acetyl content 54
~44.8% cellulose triacetate, etc.

More specific cellulose polymers include D, S
, 1.8, cellulose propionate with a nolopionyl content of 68.5%; cellulose acylate propionate with an acetyl content of 1.5-7% and a nolopionyl content of 39-42%; acetyl content i of 2.5%-3%, average Noropionyl content 692-45%, hydroxyl content iL 2.8-5
．． 4% cellulose acetate propionate; D
, S, 1.8, cellulose acetate butyrate with acetyl content 1L 13-15%, phthyryl content 1T 34-29%; acetyl content 2-295%, butyryl content 7
~52% hydroxyl-containing io, 5-4.7% cellulose acetate butyrate; such as cellulose trivalerate, cellulose trilaurate, cellulose tripalmitate, cellulose trioctanoate and cellulose trinolobionate, D , S, 2.9~
Cellulose triacylate; such as cellulose disuccinate, cellulose cibalmitate, cellulose dioctanoate, cellulose cicarbinote,
D, S, cellulose diester of 2.2 to 2.6;
Cellulose gropionate/morpholinobutyrate:′
Cellulose acetate/butyrate; cellulose acetate/phthalate, etc.; cellulose acetate valerate, cellulose acetate succinate, cellulose glopionate succinate.

There are mixed cellulose esters such as cellulose acetate octanoate, cellulose buffrate palmitate, cellulose acetate butonate, and the like. Semi-permeable polymers are known from US Pat. No. 4,077,407 and are available from Interscience, Publishers, Inc.
terseiencePubl 1she'rs, cl
Encyclopedia of Polymer Science and Technology (Encyclopedia of Polymer Science and Technology), published by
lymer 5science and Technology
3, pp. 625-654 (1964).

Other polymers include cellulose acetaldehyde dimethylcellulose acef-); cellulose acetate ethyl carbamate; cellulose acetate methyl carbamate; cellulose dimethylamine acetate; cellulose compositions from cellulose acetate and cellulose hydroxypropyl methyl cellulose; cellulose compositions from cellulose acetate butyrate and hydroxypropyl methylcellulose; semipermeable polyamide; semipermeable polyurethane; semipermeable polysulfone; semipermeable sulfone ratio polystyrene:
U.S. Patent Nos. 3,173,876 and 3,276,58
No. 6, No. 3,541,005, No. 3.541.006
No. 3,546.142, a crosslinked selectively semipermeable polymer formed by co-precipitation of a polyvalent anion and a polyvalent cation; selectively semipermeable silicone rubber; Patent No. 3,133,132, Loep (L
oeb) and Sourirayan; semipermeable polystyrene derivatives; semipermeable (sodium polystyrene sulfonate); semipermeable poly(vinylbenzyltrimethyl)
Ammonium chloride; expressed as a hydrostatic or osmotic pressure difference across a semi-permeable wall per atm.
There are semipermeable polymers that exhibit liquid permeability of 10-7 (cc, mil/ad temporary-atm). These polymers are described in U.S. Pat. Nos. 3,845,770 and 3,91
No. 6,899 and No. 4.160,020, and published by cRCPress, Creeplanton, Ohio.

R, 5cott) and W.J. Roff (W,
J.

Hand-book of Common Po
(1971).

In products where the device 10 includes an inner wall formed from a capsule element, the capsule element is generally in the shape of a tube and has an opening at one end, and the end remote from the opening has a hemispherical or dome-shaped end. It is blocked as a. The capsule element has a wall surrounding and delimiting the internal compartment, establishes communication with the exterior of the capsule, and is used as a hollow body with an opening for filling the capsule. In one embodiment, a mandrel, such as a stainless steel mandrel, is melted into the capsule wall forming material W1. A capsule with lumen 2 is obtained by immersing it in a hot bath and coating it with a mandrel to form a capsule and cutting it out. The material used to form the capsule is gelatin, 15 to 6
Gelatin with a viscosity of 0 millipoise and a bloom strength up to isog; gelatin with a noflume value of 160-250; a composition consisting of gelatin, glycerin, water and titanium; A composition consisting of; gelatin, glycerin.

Compositions of gelatin, acacia, glycerin and water; compositions of gelatin, acacia, glycerin and water; water-permeable, water-soluble polymers that can be made into capsules, etc. It is the material.

The wall can also include a flux modifier.

Flux modifiers are compounds added to wall-forming materials that help adjust the liquid permeability of flux through the wall. A flux modifier can be a flux enhancer or a flux reducer.

Modifiers can be preselected to enhance or reduce plate flux. For example, modifiers that significantly increase EML permeability to liquids such as water are often hydrophilic in nature, whereas modifiers that significantly decrease EML permeability to liquids such as water are hydrophobic in nature. be. Conditioner on the wall? The amount of modifier, if incorporated, is generally from about 0.02% to more than 20% by weight. Flux modifiers in flux enhancement embodiments include polyalcoholic realkylene diols, polyesters of alkynon glycols, and the like. Typical flux enhancers include polyethylene glycol 300, 400, 600.

1500, 4000, 6000, etc.; low molecular weight glycols such as polypropylene glycol, polyamine glycol and polyamine glycol; poly(1,3-propanediol), poly(1,,4-butanediol),
Polyalkylene diols such as poly(1,6-hexanediol); 1,6-butylene glycol, 1.4
-Pentamethylene glycol, 1.

Aliphatic diols such as 4-hexamethylene glycol; glycerin, 1,2,3-butanetriol,
1,2.4-hexanetriol, 1,3.6-
alkylenetriols such as hexanetriol;
These include esters such as ethylene glycol dipropionate, ethylene glycol butyrate, ethylene glycol dipropionate glycerol acetate ester, and the like. Typical flux reducers include phthalates substituted with alkyl, alkoxy or both alkyl and alkoxy groups, such as diethyl phthalate, dimethoxyethyl phthalate, dimethyl phthalate and [di(2-
ethyl-hexyl) phthalate]; aryl phthalates such as triphenyl phthalate and butylbenzyl phthalate; insoluble salts such as calcium sulfate, barium sulfate, calcium phosphate, etc.; insoluble oxides such as titanium; e.g. polystyrene, polymethyl methacrylate , polymeric materials, polymers in powder, granule, etc. form, such as esters and polysulfones; unaesters such as citric acid esters esterified by long-chain alkyl groups; Filler: A resin, etc. that is compatible with wall-forming materials whose main component is cellulose. Give the wall flexibility and elasticity 2 to make the wall less destructible to non-destructive.
Substances used to increase tear resistance include phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, linear retalates having 6 to 11 carbon atoms, diisononyl 77-late, and diisodecyl phthalate. There are 5 plasticizers. Plasticizers also include non-phthalate plasticizers such as triacetin, dioctyl azelate, epoxy tallate, triisooctyl trimellitate, triinnonyl trimellitate, sucrose acetate isobutinate, and epoxy soybean oil. . The amount of plasticizer when incorporated into the wall is from about 0.01% to more than 20% by weight.

The expandable means 18 has a shape Z that matches the internal shape of the compartment 14 and is manufactured from a hydrogel composition f
l. r: Preferably something. Are hydrogel compositions non-crosslinked or optionally crosslinked, with properties such as the ability to absorb external liquids through their walls? If it is an osmotic polymer, it exhibits a semi-permeability gradient with respect to the external liquid of the administration system 10. The material used to form the expandable and swellable inner layer 18 is a neat polymeric material and a polymeric material mixed with an osmotic agent that interacts with and absorbs water or biological fluids to reach an equilibrium state. Expands and swells until These polymers are capable of retaining a significant portion of the absorbed liquid within the polymer molecular structure. The polymer of a preferred embodiment is a gel polymer that can swell to a very high degree and exhibit a 2 to 50 fold increase in body weight. Swellable hydrophilic polymers and permeable polymers can be non-crosslinked or low crosslinked. The crosslinks of polymers that can swell in the presence of liquids are conjugated or ionic bonds, and when crosslinked, the polymers become insoluble in the presence of aqueous liquids. The polymer used in the expandable means 18 generally has a 5.000 to io, o o
o, o o o It has a viscosity of centipoise (25°C). Such polymers may be of vegetable, animal or synthetic origin. Polymer materials used for this purpose include poly(hydroxyalkyl methacrylate) with a molecular weight of 5,000 to 5,000,000;
,000 poly(vinylpyrrolidone); anionic and cationic swellable hydrogel; polyelectrolyte complex; poly(vinyl alcohol) with low acetate residues
swellable mixtures of agar and carboxymethylcellulose; swellable compositions consisting of methylcellulose mixed with low-crosslinking agar; reduced by dispersing finely divided copolymers of maleic anhydride and styrene, ethylene, propylene or imbutylene; water-swellable copolymers; water-swellable polymers of N-vinyl lactam; and the like.

For the formation of the hydrophilic expandable propulsion element 1B, other hydrogels or gels capable of absorbing or retaining liquids are polymers in the molecular weight range 30.000-30.
0.000 pectin: gravel, acacia.

Polysaccharides such as karaya, tragacanth, algin and guar; Carbopol [F] acidic carboxy polymer and its salt derivatives; polyacrylamide; water-swellable indene-maleic anhydride polymer; Goodrit
e■Polyac with a molecular weight of 80,000 to 200,000!
J Ruic acid; Polyoxo molecule R10,000~5,
000,000 polyethylene oxide polymer; starch graft copolymer; Aqua-Keepo acrylate polymer with a water absorption capacity of approximately 400 times its original weight; polyglucan nosiesester; pyrrolidone) mixture; zein available as prolamin; molecule i 4.0
00 to i o o, o o o poly(ethylene glycol), etc. In a preferred embodiment, the thermoformable, expandable element 17 is formed from a polymer and polymer composition that includes a different molecular structure than the structure underlying the permeable polymer 17. Representative polymers having hydrophilicity χ are U.S. Pat. No. 3,865,108, U.S. Pat. lan
Published by dRubber Company) (yF High, State, 1J-7-:177) and published by Scotto (
Handbook of Comeon Polymers by Scott Scott and Roff
ommon Polymers).

The active agent carrier means 17 used to form a releasable composition with an active agent absorbs and retains liquid to form a viscous solution or semi-paste-like carrier. The resulting hydrophilic polymer. The carrier containing the absorbed liquid and active agent is expelled from the dispensing device 10 through the passageway 16. The liquids absorbed into compartment 14 are aqueous liquids and aqueous-biological liquids. In a preferred embodiment of the invention, the carrier means 17 is a non-crosslinked hydrogel, preferably a different hydrogel than the expandable element 18. Generally, the hydrogel of carrier means 17 has a solution viscosity of from about 100 centipoise at a 5% concentration to about 1000 centipoise (measured at 25° C.) at a 5% concentration. For the purpose of the invention, inflatable means 18
The viscosity of the carrier means 17 is typically at least 4,000 centipoise greater than the viscosity of the carrier means 17. The dissolution viscosity of the polymer is measured using a Brookfield viscometer.
d Visc.

meter)'. The viscosity measurement method is used by Mack Publishing Company (MackP).
Remington Publishing Co., Ltd., Easton, Pennsylvania.
Pharmaceutical Sciences (Ph.n.)
14
Edition, pp. 661-671 (1970).

The molecular weight measurement method was performed by Van Nostrand Reinhold Co.
, ) (New E-ri), published by Encyclopedia of Chemistry (Ency-clopedia).
Dia of Chemistry).

C1ERK, 2nd edition, 666-667
(1966) and Chemical Rubber Co., Crepeland, Ohio, published by Scots, Chapter 52, 487-497.
(1971).

The osmotically active compound that can be mixed with the active agent is an osmotically active solute that is absorbed into the compartment and is soluble in the liquid, increasing the osmotic pressure across the semi-permeable wall to the external liquid. Gradient Z is shown. Osmotically effective compounds are also known in the pharmaceutical art as penetrants. Osmotically active compounds useful in this invention include magnesium sulfate, magnesium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, incitol asucrose.

There are glucose, etc. The osmotic pressure of the osmotic agent suitable for the present invention (
Atmospheric pressure (ATM) is much lower than zero atmospheric pressure, and generally ranges from 8 atm to over 500 atm. Generally, the compartments optionally contain from 0.1% to 40311% penetrant by weight. The penetrant forms a water bath liquid in which the active agent is dispersed,
If the active agent is insoluble in the aqueous and biological fluid, a suspension will form. One skilled in the art can readily select an osmotic agent and measure its osmotic pressure using a commercially available osmometer. A detailed description of penetrants is found in US Pat. No. 4,008,716.

The polymer mixed with the expandable polymer 18 is mixed with the active agent and the weight increasing means=! or) use secret means. This density enhancement means is used to initially hold the dosing device 10 in the rumen-reticulum complexion of the separated animal. ) Designed as a can body 19 with 1 dense element =! 1 is an expandable polymer 18
The dense element (mixed homogeneously or heterogeneously with the drug) should be applied to the rumen-reticulum of the ruminant animal in the administration device [10], which is initially held at one time.

) In one embodiment, the administration device 10 remains in the rumen during the administration period and then enters the gastrointestinal tract from which it is excreted. Generally, when the dense element 19 is formulated with an expandable polymer 18 or an active agent 15, the density element 19 has a density of from about 1 to about 8 or more, the amount of the weight means mixed is In a preferred embodiment of the present invention, the density should exhibit a specific gravity of 2.0 to 16, giving the possible hydrogel or benefit composition an initial density of 1 to 8. For separate animals such as cattle and sheep, it is desirable to first obtain a density such that the complex yields a dosage system density of about 600 kg. Substances with a density χ from 1 to 8 are coated with iron, 1 arsenate oxide and shot with 1 iron.

A mixture of iron shot and magnesium alloy, steel, stainless steel, copper oxide, cobalt oxide and iron powder.

It is a mixture of iron and copper acid. The weight means may be in the form of a powder, granules, pellets, etc., either in compact form or mixed with the active agent or mixed with the expandable hydrogel. The weight means can be mixed with the hydrogel during polymerization, such as by solvent mixing, injection, and evaporation, 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 mixed with the active agent in the swellable hydrogel is about 0.5 to 50% by weight, an amount sufficient to produce the desired density. Determination of Density, Specific Gravity, and Specific Volume, published in 1970 by McG Publishing Co., Easton, Ohio, and edited by T. Osol.
emington's Pharmaceutical
14, pp. 95-100.

As used herein, the term "active agent" refers to a drug.

It means nutrients, vitamins, anthelmintics, biocides, insecticidal agents, feed supplements, and other agents beneficial to fertile animals. The active agent may range from insoluble to readily soluble in the free aqueous carrier means formed within the administration system.

The amount of drug present in the administration system ranges from 10 ng to more than 40 g. For example, the administration system is 75n! 9.1mg,
5yng, 11]Omg, 250mg.

750mg, 1.5mg, 2g, 5y, 10y, 15g
It is possible to accommodate various amounts of effective agents such as, etc.

It is possible to administer a single administration system or more than one administration system to an animal during a treatment program.

Representative active agents that can be administered using the administration system of the present invention include, for example, mebendazole, levamisole, albendazole, cambendazole, fenbendazole, parpentasol, oxfendazole, oxibendazole, Thiabendazole, cyclolfon,
Anthelmintics such as praziquantel, oxantel, pyrantil, etc.; U.S. Pat. Nos. 4,199,569 and 4,3
No. 89,397 and Science
221, pp. 823-828 (1983), such as avermectin and ivermectin (said ivermectin is effective in controlling infestations that commonly occur in animals such as roundworms and lungworms). avermectin and milbemycin phosphate; chlortetracycline.

Oxytetracycline, tetracycline, streptomycin, dihydrostreptomycin.

bacitracin, erythromycin, amvicillin.

Bactericidal agents such as penicillin, cephalosporin etc.; Sulfa drugs such as sulfamethacin, sulfathiazole etc.; Growth stimulants such as Menes in @ Sodium 2 Ephrodomycin and Elfazepr; Anti-inflammatory agents such as dexamethacin and flumethacin Drugs; ruminal fermentation treatments and ionophores, such as lazaroside, salinomycin, vaginamycin, and lonnel; minerals, including copper, cobalt sulfate, sodium selenite, zinc chloride, magnesium sulfate, zinc sulfate, etc. and inorganic salts; antibloating agents such as organopolysiloxanes; hormonal growth supplements such as stilbestrol; vitamins such as thiamine hydrochloride; antienteritis agents such as flagiridone;
These include nutritional supplements such as soluble salts of lysine hydrochloride, methionine, magnesium carbonate, magnesium, copper, selenium, etc.

The wall-forming composition can be applied to the outer surface of the capsule by layering the semi-permeable wall-forming material on the outer surface of the capsule, such as by air spraying, dipping, etc.
It can be coated by casting or painting. Other methods preferred for the present invention that can be used for wall coating are air suspension methods and pan coating methods. The air suspension method involves suspending and rotating the device-forming element in a flow of air and a semi-permeable wall-forming material until the wall surrounds and covers the device-forming element. consists of things.

This method can be replicated on semi-permeable wall-forming compositions to form semi-permeable layered walls. The air suspension method is disclosed in U.S. Pat. No. 2,799,241; J.A., Am.

Pharm, As5oc (J, Am, Pharm, As5oc
, ) 48 volumes.

pp. 451-459 (1979); same magazine, vol. 49, 82-
84 (1960). Other standard manufacturing methods are described in the Modern Plastics Encyclopedia.
46, pp. 62-70 (1969) and published by Mag Publishing Co., Easton, Pennsylvania, 14th edition of Pharmaceutical Sciences by Nmington, 1626-16.
78 (1970).

Typical solvents suitable for the manufacture of semipermeable walls include those that do not adversely affect the material, the capsule wall, the active agent, the skin-responsive composition, the expandable element, the dense element and the final administration device. It is an inert, free and organic solvent. Such solvents include a wide range of aqueous solvents, alcohols, ketones, esters, and ethers.

Aliphatic carbon ratio hydrogen, halogen ratio solvent, alicyclic decomposition.

An element selected from the group consisting of aromatic, heterocyclic solvents, and mixtures thereof. Typical solvents are acetone, diacetone alcohol, and methanol.

Ethanol, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate.

Isopropyl acetate, n-butyl acetate.

Methyl isobutyl ketone, methyl globyl ketone.

n-hexane, n-heftone, ethyl glycol 7-ethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, ethylene dichloride, propylene dichloride, 4-carbon, nitroethane, nitropropane, tetrachloroethane, ethyl ether, cyclohexane , cyclooctane, benzene, toluene,
+ 7 Cy 1゜4-dioxane, tetrahydrofuran, diglyme.

These are various mixtures such as water and acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, methylene dichloride and methanol, etc.

As used herein, the expression "passageway" or "orifice" refers to any intramural or intralaminar wall means or method suitable for transporting the active agent composition from the dispensing device. The passageway can be formed by mechanical or laser drilling, or by erosion of corrosive elements within the wall, such as gelatin plugs. The passage can be opened by passing only through two walls, and by tearing through the wall and one capsule layer. In embodiments where the passageway is opened only through the wall, the passageway in the capsule wall is formed by disrupting, corroding or dissolving the passageway in the capsule wall in the environment of use. A porous polymeric composition having at least one pore, or a microporous polymeric composition having at least one pore, serving as one or more passages suitably provided in a portion of the wall of the dosing device. It can be a porous polymeric composition. The location of the passageway was determined by visual inspection, by optical density inspection when connecting the device to a laser device, and by tracking the location of the device throughout the manufacturing stages, and by optically detecting the length of reflections emitted by the device. By doing so, it can be positioned in the wall by magnetic orientation and by similar standard manufacturing methods. A detailed description of the orifice and the preferred maximum and minimum sizes of the orifice are set forth in US Pat. Nos. 3,845,770 and 3,916,899.

DETAILED DESCRIPTION OF THE INVENTION The following examples are merely illustrative of the invention; these examples and their equivalents will become clear to those skilled in the art upon reference to the description of the invention, the drawings, and the claims. In any event, these examples should not be construed as limiting the scope of the invention.

Example 1 A veterinary therapeutic administration device with controlled release of ivermectin is manufactured as follows: initially consisting of 1.21 g of sodium chloride and 4.6 g of poly(acrylic acid) sodium salt, available as Carbopolo 964-P. The expandable drive element is compressed into a solid mass shaped like a tablet. Manesty press, 18 tomo tablet machine and 6
% tons compression force is used to form tablets. The tablet has a shape that corresponds to the internal shape of the capsule opening. next,
Insert the tablet element into the open end of the capsule until it touches the bottom of the capsule. The capsule is then filled with the active agent composition. The active agent composition consists of 1.6 g of poly(vinylpyrrolidone), 1.2 I of magnesium stearate, and 0.5 I of sodium chloride! 7'a' consists of 4J of Tubermectin homogeneously mixed. - Thoroughly mix these ingredients using a blender and compress them under a 13A ton pressure head in a Manesty press to form tablets with Mw.
fabricated and placed in contact with the expandable hydrogel layer and inserted into the capsule. A dense stainless steel element (having an internal pore χ and shaped to fit inside the capsule) is then placed and inserted into the capsule in contact with the active agent composition. The capsules are then coated with a release rate controlling wall consisting of 1.8 g of 91% cellulose acetate butyrate and 4009% polyethylene glycol in a pan coater. The walls are coated from a 5% wt/wt solution in a methine cloth/methanol 90:10 v/v solvent system. Wall coating dosing system 2nd time at 60”C for 24
Let dry for an hour. The device was then visually located and a 30 ml discharge channel was drilled using a high speed mechanical drill through the semi-permeable wall and gelatin capsule wall (2) through the can body hole and the internal compartment of the device. I will contact you. This passageway establishes communication with the active agent composition such that the active agent composition is released from the dispensing device over an extended period of time.

Example 2 Following the method described in Example 1 and using the conditions described above, a dosing device is constructed, but in this example instead of a housing)
The element is added to the expandable polymer. Swelling - The swellable composition is made of poly(
70% by weight of ethylene oxide), 10% by weight of sodium chloride and 50:50 of cobalt and iron shot.
The mixture consisted of 2 Oi&it%.

Example 6 Dosing Device 2 Manufactured as follows: First, the body part of the capsule is placed with the opening upright and the inflatable-swellable dense composition layer is inserted into the hemispherical end of the capsule. do. The shape of this layer matches the internal shape of the capsule. This composition contains 5% by weight of sodium chloride and a molecular weight of 200.
,000 poly(ethylene oxide) and 25% by weight of stainless steel small particles. The swellable (swellable) dense composition-forming ingredients are steeped for 20 minutes with heating in a commercially available blender to obtain a homogeneous composition.

The heated composition is inserted into the capsule to form a layer that occupies about % of the capsule. The active agent composition is then added to the capsule, covering the expandable composition. The active agent composition includes 0% by weight of levamisol, 101% by weight of sorbitol, and 15% by weight of poly(vinylpyrrolidone).
and 5% by weight of calcium stearate.

Next, a solution containing cellulose acetate containing 39.8% acetyl and 15% χ was mixed with methylene chloride/
Produced in a methanol solvent system, the capsules are coated with a semi-permeable wall. The walls were coated by soaking in the capsule coating solution for 15 minutes, first for 5 seconds, then twice for 10 seconds, then for 60 seconds, then for 1 minute each, then for 5 minutes. The wall is applied by dipping with a drying period in between. After soaking,
Dry the dosing device at room temperature (72'F) for 5 days.

By this method, a semi-permeable wall approximately 2 mm thick is applied. The active agent composition is then positioned by optical detection methods to release the active agent composition into the liquid use environment over an extended period of time.
This passageway is perforated in the semi-permeable wall to communicate the active agent composition with the exterior of the administration device.

Example 4 Administering Active Agents to Warm-Blooded Animals 1 This administration system is manufactured as follows: first, in a mold having a shape and form corresponding to the hemispherical closed end and inner diameter of a capsule; A swellable dense composition containing 60 parts of ethylene glycol monomethacrylate (containing 0.12 parts of ethylene glycol dimethacrylate), 10 parts of a 0.13% aqueous solution of aqueous ethanolic sodium unisulphate, and 6° parts of iron powder/magnesium is charged. The composition was heated to 60° C., reached equilibrium with room temperature, and after 1 to 20 minutes was removed from the mold as a solid layer. 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% arsenic salt (expandable) in a layered arrangement with dense elements. Fill it. The filled capsules were then covered with a surrounding wall of cellulose acetate containing 10% polyethylene glycol 400. Apply in a semi-permeable wall pan type high coater. The filter solvent used for wall formation consisted essentially of methylene chloride and methanol (95 parts by weight: 5 parts by weight). A 12 ml (0.30 mm thick) cellulose acetate-butyrate wall is applied to the outer surface of the capsule. Finally, a passage χ laser is drilled through the semi-permeable wall and the capsule wall to communicate the active agent-containing composition to the environment of use upon release.

Example 5 The method of Example 1 was repeated, but in this example, the active agent composition was replaced with the anthelmintic pyrantel tartrate, pyrantyl pamoate, or virantyl embonate; the anthelmintic tetramisole hydrochloride; the anthelmintic diethyl hydrochloride. Carbamazine or diethylcarbamazine citrate; anthelmintic oxanthyl hydrochloride,
Oxanthyl embonatema Tζ, is a pamo-induced oxanthyl; the antibacterial agent avoparcin; the anti-bloating agent boroxalen;
Parasiticide avermectin A1a, avermectin A2
a.

Use avermectin B2a instead of avermectin B1a.

Example 6 A dosing device was manufactured according to the method described in Example 1 and using the conditions and materials described above, but in this example a release rate controlling wall of different thickness (cellulose acetate butyrate and polyethylene glycol) was manufactured. 400) to the dosing device. The thickness of the release rate control wall varies in a uniform taper from 3 [] mil (0.76 mm) at the end distal to the passageway to 15 ml (0.38 mm) adjacent to the compaction element.

Example 7 A dosing device is manufactured according to the method described above. This dosing device consists of a first compression molded composition consisting of 66 g of poly(ethylene oxide) with a molecular weight of 500.000, 30 g of iron powder and 5 g of sodium salt; 1.5 g of palpendazole; '7 g
, into a second compression molding composition consisting of 68.5 g of polyvinylpyrrolidone and 9.7 g of the salt monoarsenium. The compression molded laminate contained 50% cellulose acetate butyrate, 45% poly(sulfone), and 5% Citroflex citrate ester selected from the group consisting of acetyltributyl citrate and acetyl tri-2-ethyl-hexyl citrate. Surrounded by a semi-permeable wall consisting of %. The device has a passageway 2 through a semi-permeable wall that communicates the active agent composition Z with the outside of the device.

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

Example ? In accordance with Example 7, a veterinary treatment dosing device is manufactured using conditions 2 above, in which the contacting expandable hydrogel absorbs liquid and has an acetyl content of 695%. consisting of a high-density polyethylene tubular wall surrounding a lumen closed by a cellulose acetate film and the other end closed by a microporous poly(tetramolethylene) film for releasing the contacting active agent composition from the dispensing device. .

Embodiments of the present invention provide for the possibility of releasing an active agent by (1) formulating a releasable composition containing the active agent.
(2) the preparation of the administration system of the present invention that allows for the release of active agents; Embodiments of the present invention provide a method for administering an active agent composition at a controlled rate into the rumen of a ruminant, in which: (A) the following elements: (1) permeable to the passage of fluid but effective (2) an outer wall comprising at least a portion of a semi-permeable polymer that is substantially impermeable to passage of the agent; (2) a means for absorbing liquid at the body temperature of the animal and transporting the active agent from the administration device; An active agent composition layer consisting of a unit dose of drug for implementing a therapeutic program in a pharmaceutically acceptable carrier that is aqueous or sensitive to biological fluids. (3) a swellable hydrogel layer within the lumen, including means for increasing the density of the lumen, which retains the administration device within the stomach for an extended period of time; (4) an intraluminal dense element for maintaining the administration device in the rumen for an extended period of time; and (5) an orifice in the wall that communicates with the fluid-sensitive active agent composition. (B) the semipermeable wall χ at a rate determined by the osmotic pressure gradient between the permeability of the semipermeable wall and the semipermeable polymer;
Liquid is absorbed into the active agent composition, causing the hydrogel to swell and swell; liquid is absorbed into the active agent composition to form a releasable fluid aqueous solution or an aqueous suspension composition at the temperature of use. and (D) the expandable hydrogel continuously expands and compresses the releasable composition, thereby releasing the active agent composition from the compartment and releasing a therapeutically effective amount of the composition from the orifice. Beg for control t'L1
It also relates to a method comprising the step of administering the drug to the patient over a long period of time at this rate.

To the extent that the description in Section M relates to preferred embodiments of the invention, it will be understood that changes and modifications may be made in accordance with the principles of the invention disclosed herein without departing from the scope of the invention.

[Brief explanation of the drawing]

The accompanying drawings (c), which are not drawn to scale, illustrate embodiments of the invention. 2 is a cross-sectional view of the dosing system of FIG. 1 along the vertical axis 2-2 of the dosing system, with the outer wall, a compartment, consisting of an active agent composition, an inflatable element and an active agent element;
The structure of an administration system for administering an active agent composition to an animal, more specifically a warm-blooded animal; FIG. 6 is a cross-sectional view taken through 2-2 in FIG. Figure 4 is a cross-sectional view of Figure 1, illustrating another IM embodiment according to the invention; The main components of the administration system cooperate with each other to deliver the active agent composition over an extended period of time, from one day to six months.
FIG. 5 is a cross-sectional view of the administration system of FIG. 1, illustrating an embodiment in which the expandable means and the compact means are combined into one unitary composition; FIG. 6 is a cross-sectional view of the administration system of FIG. Figure 2 is a cross-sectional view of a delivery system illustrating another embodiment of the invention in which the compartment contains a composite composition of an active agent composition and a dense element (having a specific gravity greater than 1); In the drawings and description, like parts of related figures are designated by like numerals. Terms that appear in the description of the drawings and specific examples thereof are explained in detail elsewhere in the specification. 10...Administration device 11...Body 12...Outer wall 16...
... Passage 14 ... Compartment 15.
・Interactive agent composition 17゛°゛°°°Kigiya Means 1
8...Inflatable means 19...) Can body

Claims (7)

[Claims] (1) A dispensing device for discharging an active agent composition into an environment of use, comprising: (a) wall means surrounding and forming an internal compartment, at least a portion of which is permeable to liquids present in the environment of use; wall means; (b) an active agent within the compartment that forms a composition releasable by liquid entering the compartment through the wall means; (c) an active agent within the compartment that absorbs liquid to increase the amount of space occupied within the compartment. (d) intracompartment means for increasing the weight of the dispensing device, having a density of at least 1.0; and (e) communicating the compartment with the exterior of the device for dispensing the active agent composition into the environment of use over an extended period of time. an intramural means for ejection; (2) A dispensing device for delivering an active agent composition into an environment of use as claimed in claim 1, wherein the intramural means communicating the compartment with the exterior of the device comprises at least one intramural passageway. (3) A dispensing device for delivering the active agent composition of claim 1 into a use environment, wherein the active agent composition comprises at least one element selected from the group consisting of a penetrant and an osmotic polymer. . (4) A dispensing device for delivering the active agent composition according to claim 1 into an environment of use, wherein the means for absorbing liquid is a swellable hydrogel. (5) The active agent composition is mebendazole, levamisole,
Consisting of albendazole, cambendazole, fenbendazole, parbendazole, oxfendazole, thiabendazole, cychlorphan, praziquantel, morantel, pyrantel, avermectin, ivermectin, oxantel, piperazine, diethylcarbamazine, tetramisole, poraxalen, selenium and zeralanol A dispensing device for delivering into an environment of use an active composition as claimed in claim 1 comprising a member selected from the group. (6) At least a portion of the wall means comprises an element selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose trianlate, cellulose acetate, cellulose diacetate and cellulose triacetate. A dispensing device for delivering an active agent composition into a use environment. (7) The means for absorbing liquid and increasing the space occupied in the compartment is 5,000 to 1,000,000 at 25°C.
A dispensing device for delivering an active agent composition according to claim 1, which is a polymer having a viscosity of centipoise, into an environment of use.