Ruminant dispensing device with thermo-activated memory

A dispensing device is disclosed for delivering a beneficial agent. The device comprises (1) a housing defining an internal space, (2) an expandable composition comprising a dense member in the space, (3) a composition comprising a beneficial agent and a non-toxic heat responsive carrier in the space, and (4) a passageway in the housing for delivering the beneficial agent from the dispensing device.

FIELD OF THE INVENTION 
This invention pertains to both a novel and useful dispensing device. More 
particularly, the invention relates to a dispensing device comprising a 
wall surrounding an internal lumen containing (1) a thermo-responsive 
beneficial agent formulation and (2) an expandable delivery means 
containing weight means. The thermo-responsive formulation and the 
delivery means perform in concert for dispensing a beneficial agent 
through passageway means to an animal over a prolonged period of time. 
BACKGROUND OF THE INVENTION 
Ruminant animals, including cattle, sheep, giraffe, deer, goat, bison and 
camels, and more particularly cattle and sheep, comprise an important 
group of animals that require periodic administration of medicines and 
nutrients. The medicines and nutrients are administered for the treatment 
and alleviation of various medical and infectious related conditions and 
generally for better health. Ruminants have a complex three or four 
compartment stomach. The rumen, the largest of the stomach compartments, 
serves as an important location for receiving and passing medicines and 
nutrients into other compartments, including the abomasum and the 
intestine. Presently, ruminants are treated by repeated administrations of 
medicines and nutrients at frequent time intervals. This form of treatment 
is inconvenient and expensive, and it does not lend itself to good 
reliable therapy. Additionally, medicines and nutrients are administered 
orally in the form of a bolus to ruminants. However, bolus form of 
therapy, like the repeated dose mode of administration, does not lend 
itself to widely-practiced and acceptable therapy. That is, ruminants 
regurgitate what they swallow, they chew their cuds, and they spit out 
conventional boluses quickly after administration. 
There is, therefore, in view of the above presentation, a pressing need for 
a therapeutic delivery system for use in ruminant therapy that will, after 
a single administration, efficiently dispense medicines and nutrients over 
a prolonged period of time. There also is a pressing need for a 
therapeutic delivery system for prolonged releasing of a medicine or a 
nutrient at a controlled rate in the rumen, by a delivery system that is 
swallowed easily by the ruminant and remains in the rumen for a long 
period of time without being regurgitated or otherwise eliminated from the 
rumen. 
OBJECTS OF THE INVENTION 
It is a principle object of this invention to provide both a novel and 
useful therapeutic dispensing device for use in animal therapy that 
fulfills the pressing need known to the prior art. 
Another object of the invention is to provide a therapeutic dispensing 
device that delivers a medicine or a nutrient at a controlled rate over a 
prolonged period of time. 
Another object of the invention is to provide a therapeutic dispensing 
device that can remain in the rumen of a ruminant for a prolonged period 
of time. 
Another object of the invention is to provide a therapeutic dispensing 
device that is self-contained, self-starting and self-powered in a fluid 
environment, is easy to make, and can be used for dispensing beneficial 
agents to a warm-blooded animal including a ruminant. 
Another object of the invention is to provide a dispensing device 
comprising a wall surrounding an internal lumen containing a temperature 
sensitive beneficial agent composition and an expandable member containing 
a density producing member. 
Another object of the invention is to provide a dispensing device 
comprising an internal space formed by a capsule arrangement that is easy 
to manufacture at low cost thereby increasing the usefulness and making 
the dispensing device practical for treating domestic animals. 
Another object of the invention is to provide a dispensing device 
comprising a wall surrounding a capsule containing a temperature-sensitive 
beneficial agent composition, an expandable member comprising a hydrogel 
and a density increasing member, and a passageway useful for dispensing a 
beneficial agent to an animal. 
Another object of the invention is to provide a dispensing device 
comprising a wall that surrounds an internal lumen, and which dispensing 
device delivers a thermo-sensititve composition containing a beneficial 
agent by the combined physical-chemical operations of the composition 
melting and becoming fluid to semisolid or the like, with the composition 
being displaced from the device by an expanding member containing a 
density increasing member that swells and occupies space in the area 
initially occupied by the composition. 
Another object of the invention is to provide a dispensing device 
comprising a dense member dispersed throughout an expandable member, for 
keeping the dispensing device in the rumen over time, and wherein the 
dispensing device administers a composition that is a complete 
pharmaceutical dosage regimen for a medical or nutritional effect over a 
prolonged period of time, the use of which dispensing device requires 
intervention only for the initiation of the regimen. 
Another object of the invention is to provide a dispensing device that can 
deliver a beneficial drug contained in a thermo-responsive, lipophilic 
pharmaceutically acceptable carrier that melts in the rumen in the 
presence of thermal energy absorbed from environment of the rumen into a 
dispensable composition that is innocuous, thereby substantially avoiding 
mammalian tissue irritation and interaction with mammalian protein 
tissues. 
Another object of the invention is to provide a dispensing device 
containing an eutectic composition formed of at least two components and 
at least one drug, which eutectic composition has a melting point 
approximately the same as the temperature of a warm-blooded animal's 
rumen, and is dispensed from the dispensing device at the temperature of 
the animal. 
Another object of the invention is to provide a dispensing device 
comprising a dense member dispersed throughout an expandable member 
wherein, after the delivery period of the pharmaceutical composition, the 
expandable member is delivered causing a reduction in the density member 
thereby allowing the device to be passed from the environment of use. 
Another object of the invention is to provide a dispensing device 
comprising an inner capsule housing a thermo-responsive hydrophobic 
composition comprising insoluble to soluble drugs, and which 
thermo-responsive composition in response to energy input present in the 
gastrointestinal tract of a ruminant, changes its form and becomes 
dispensable for operative delivery from the dispensing device. 
Another object of the invention is to provide a dispensing device for 
dispensing a drug to a ruminant, which dispensing device comprises a 
walled body containing a thermoplastic composition that includes a 
beneficial agent that is poorly soluble in an aqueous environment and can 
be housed in the device in a nonaqueous dispensing carrier for delivery by 
an expendable component containing a density member to a ruminant. 
Other objects, features and advantages of the invention will be more 
apparent to those skilled in the dispensing art form the following 
detailed description of the specification, taken in conjunction with the 
drawings and the accompanying claims.

In the drawing figures and in the specifications, like parts in related 
drawing figures are identified by like parts. The terms appearing earlier 
in the specification and in the description of the drawing figures as well 
as embodiments thereof, are further detailed elsewhere in the disclosure. 
DETAILED DESCRIPTION OF THE DRAWINGS 
Turning now to the drawing figures in detail, which are examples of the 
novel and useful dispensing device of the invention, which examples are 
not to be construed as limiting, one example of a therapeutic dispensing 
device is seen in FIG. 1, identified by the numeral 10. In FIG. 1, 
dispensing device 10 comprises a body 11 formed of a wall that surrounds 
and forms an internal lumen, not seen in FIG. 1. Therapeutic dispensing 
device 10 comprises at least one passageway 13 preformed or formed during 
use in wall 12 for delivering a beneficial agent from dispensing device 
10. 
FIG. 2 is an opened, sectional view of dispensing device 10 of FIG. 1. 
Therapeutic dispensing device 10 of FIG. 2 comprises body 11, wall 12 and 
passageway 13. Wall 12 surrounds and defines an internal compartment 14, 
an internal lumen. In a presently preferred embodiment wall 12 is formed 
in at least a part, or totally, of a semipermeable wall-forming 
composition. The semipermeable composition is substantially permeable to 
the passage of an external fluid, and it is substantially impermeable to 
the passage of a beneficial agent and other ingredients contained in 
dispensing device 10. When wall 12 is formed in at least a part of a 
semipermeable composition, the rest of wall 12 is formed of a wall-forming 
composition that is substantially impermeable to the passage of fluid and 
substantially impermeable to the passage of a beneficial agent and other 
ingredients housed in device 10. Wall 12 is non-toxic, and it maintains 
its physical and chemical integrity. That is, it is inert, and it does not 
erode during the dispensing period. Lumen 14 contains a thermo-responsive 
heat sensitive composition 15, identified by wavy lines, containing a 
beneficial agent 16, represented by dots. Lumen 14 further contains an 
expandable driving member 17 that is in one embodiment in layer contact 
with at contacting surfaces 18 with thermo-responsive composition 15. 
Expandable driving member 17 contains a density member 19, identified by 
dots, dispersed therein. Density member 19, a densifier, is a component of 
dispensing device 10 for keeping device 10 in the rumen of an animal 
during the beneficial agent dispensing period. Thermo-responsive 
composition 15 and driving member 17 possess a shape that corresponds to 
the internal shape of lumen 14. A passageway 13 extends through 
semipermeable wall 12 for communicating lumen 14 and the exterior of 
device 10. 
FIG. 3 depicts another manufacture provided by the invention. FIG. 3 is an 
opened view of dispensing device of FIG. 1, and it comprises body 11, wall 
12, passageway 13, and internal compartment 14. Wall 12 in FIG. 3 is 
formed of a wall-forming composition that is impermeable to both fluid and 
agents, except for a part of wall 12 at wall 20 that is formed of a 
wall-forming material that is permeable to fluid and impermeable to 
agents. In FIG. 3, compartment 14 contains thermo-responsive composition 
15 comprising beneficial agent 16 in laminar arrangement with driving 
member 17 containing weight means 19. In FIG. 3, driving member 17 
contains an osmotically effective solute 21 that exhibits an osmotic 
pressure gradient across semipermeable wall 20 against an external fluid 
present in the environment of use. In operation, driving member 17 imbibes 
and absorbs fluid and osmotic solute 21 imbibes fluid, which combined 
operation causes driving member to expand and urge thermo-responsive 
composition 15 through passageway 13 to the environment of use. 
FIG. 4 is an opened view of another dispensing device 10 provided by the 
invention. Dispensing device 10 of FIG. 4 is similar to device 10 of FIGS. 
1 through 3, with the added embodiment that FIG. 4, wall 12 is an internal 
capsule which surrounds compartment 14. Wall 12 comprising the internal 
capsule is surrounded by an outer semipermeable wall 22 that is permeable 
to the passage of fluid and impermeable to the passage of an agent. The 
internal capsule used for forming inner wall 12 can comprise a single unit 
capsule body member, or it can be a dual capsule body member, not seen in 
FIG. 4. Passageway 13 extends through outer semipermeable wall 22 and 
inner wall 12 for delivering the thermo-responsive beneficial agent 
composition to the exterior of device 10. 
Therapeutic dispensing device 10 of FIGS. 1 through 4, in operation in a 
fluid biological environment of use, delivers beneficial agent 16 by a 
combination of thermodynamic and kinetic integrally performed activities. 
That is, in operation heat sensitive composition 15, in response to the 
temperature of the rumen, absorbs thermal energy, melts and forms a 
deliverable composition, for example, a fluidic, a semi-paste or like 
deliverable composition for dispensing beneficial agent 16 through 
passageway 13. As composition 15 softens, melts or becomes flowable, 
external fluid is concomitantly imbibed through semipermeable wall 12 by 
expandable hydrophilic composition 17. Expandable composition 17 imbibes 
fluid in a tendency towards osmotic equilibrium causing it to continuously 
expand or swell. As layer 17 expands and swells, it increases in size and 
volume simultaneously moving against composition 15 thereby urging 
composition 15 through passageway 13. In a presently preferred embodiment 
layer 17 expands while maintaining an intact immiscible boundary at 
interface 18 defined by heat sensitive composition 15 and expandable layer 
17. In the embodiment wherein expandable layer 17 contains an osmotically 
effective solute 21, solute 21 imbibes fluid through the semipermeable 
wall into dispenser 10. This fluid serves two purposes, it becomes 
available for expandable hydrogel 17 for it to swell to a maximum 
dimension, and it increases the fluidic volume in the area of expandable 
hydrogel 17 for it to apply pressure against composition 15. Device 10 is 
maintained in the rumen by the presence of dense member 19 contained in 
expandable member 17 throughout the dispensing operation of device 10. 
Initially the density or mass per unit volume of device 10 is such that 
device 10 remains in the rumen. As beneficial composition 15 is dispensed 
from device 10, density is maintained by imbibition of water into 
expandable member 17 balancing delivery of beneficial composition, and as 
expandable member 17 occupies compartment 14 and is dispensed fully 
through passageway 13, as seen in FIG. 5, the density of device 10 drops 
so that it will pass with the ruminal contents. In this operation, device 
10 goes from a rumen-retentive to a rumenexpellable device over time. 
The dispensing device 10 can be manufactured in a variety of sizes and 
shapes for administering device 10 to ruminant animals. One presently 
preferred shape is a cylinder-like or capsule-like shape. For example, for 
use with sheep, delivery system 10 can embrace a capsule-like shape and 
have a diameter of about 0.5 inches to 1 inch (1.3 cm to 2.5 cm) and a 
length of about 0.5 inches to 2.5 inches (1.3 cm to 6.6 cm). For use with 
cattle, system 10 has a diameter of about 0.5 inches to 1.5 inches (1.3 cm 
to 3.8 cm), and a length of about 1 inch to 3.5 inches (2.5 cm to 7.8 cm). 
While FIGS. 1 through 5 illustrate various delivery systems 10 that can be 
made according to the invention, it is to be understood these systems are 
not to be construed as limiting the invention, as the dispenser can take 
other shapes, sizes and forms for delivering beneficial agents to the 
biological environment of use. The delivery system can be used in medical 
devices, hospitals, veterinary clinics, farms, zoos, laboratories, 
physician's offices, on the range, in feed lots, and other environments of 
use. 
DETAILED DESCRIPTION OF THE INVENTION 
In accordance with the practice of this invention, it has now been found 
representative materials for forming a wall include semipermeable 
homopolymers, semipermeable copolymers, and the like. In one embodiment 
typical materials include cellulose esters, cellulose monoesters, 
cellulose diesters, cellulose triesters, cellulose ethers, and cellulose 
ester-ethers, mixtures thereof, and the like. These cellulosic polymers 
have a degree of substitution, D.S., on their anhydroglucose unit from 
greater than 0 up to 3 inclusive. By degree of substitution is meant the 
average number of hydroxyl groups originally present on the anhydroglucose 
unit that are replaced by a substituting group, or converted into another 
group. The anhydroglucose unit can be partially or completely substituted 
with groups such as acyl, alkanoyl, aroyl, alkyl, alkenyl, alkoxy, 
halogen, carboalkyl, alkylcarbamate, alkylcarbonate, alkylsulfonate, 
alkylsufamate, and like semipermeable polymer forming groups. The 
semipermeable materials typically include a member selected from the group 
consisting of cellulose acylate, cellulose diacylate, cellulose 
triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, 
nono-, di- and tri-cellulose alkanylates, mono-, di- and tri-alkenylates, 
mono-, di- and tri-aroylates, and the like. Exemplary polymers including 
cellulose acetate having a D.S. of 1.8 to 2.3 and an acetyl content of 32 
to 39.9%; cellulose diacetate having a D.S. of 1 to 2 and an acetyl 
content of 21 to 35%; cellulose triacetate having a D.S. of 2 to 3 and an 
acetyl content of 34 to 44.8% and the like. More specific cellulosic 
polymers include cellulose propionate having a D.S. of 1.8 and a propionyl 
content of 38.5%; cellulose acetate propionate having an acetyl content of 
1.5 to 7% and an acetyl content of 39 to 42%; cellulose acetate propionate 
having an acetyl content of 2.5 to 3%, an average propionyl content of 
39.2 to 45% and a hydroxyl content of 2.8 to 5.4%; cellulose acetate 
butyrate having a D.S. of 1.8, and acetyl content of 13 to 15%, and a 
butyryl content of 34 to 29%; cellulose acetate butyrate having an acetyl 
content of 2 to 29.5%, a butyryl content of 7 to 52%, and a hydroxyl 
content of 0.5 to 4.7%; cellulose triacylates having a D.S. of 2.9 to 3 
such as cellulose trivalerate, cellulose trilaurate, cellulose 
tripalmitate, cellulose trioctanoate, and cellulose tripropionate; 
cellulose diesters having a D.S. of 2.2 to 2.6 such as cellulose 
disuccinate, cellulose dipalmitate, cellulose dioctanoate, cellulose 
dicarpylate; cellulose propionate morpholinobutyrate; cellulose acetae 
butyrate; cellulose acetae phthalate, and the like; mixed cellulose esters 
such as cellulose acetate valerate, cellulose acetate succinate, cellulose 
propionate succinate, cellulose acetate octanoate, cellulose valerate 
palmitate, cellulose acetae heptonate, and the like. Semipermeable polymer 
are known in U.S. Pat. No. 4,077,407, and they can be made by procedures 
described in Encyclopedia of Polymer Science and Technology Vol. 3, pp 325 
to 354, 1964, published by Interscience Publishers, Inc., New York. 
Additional semipermeable polymers includes cellulose acetaldehyde dimethyl 
cellulose acetate; cellulose acetate ethylcarbamate; cellulose acetate 
methylcarbamate; cellulose dimethylaminoacetate; a cellulose composition 
comprising cellulose acetate and hydroxypropyl methylcellulose; a 
composition comprising cellulose acetate and cellulose acetate butyrate; a 
cellulose composition comprising cellulose acetate butyrate and 
hydroxypropyl methylcellulose; semi-permeable polyamides; semipermeable 
polyurethanes; semipermeable polyamides; semipermeable polyurethanes; 
semipermeable polysulfane; semipermeable sulfonated polystyrenes, 
cross-linked, selectively semipermeable polymers formed by the 
coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat. 
Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,142; selectively 
semi-permeable silicon rubbers; semipermeable polymer as disclosed by Loeb 
and Sourirajan in U.S. Pat. No. 3,133,132; semi-permeable polystyrene 
derivatives; semipermeable (polysodium-styrenesulfonate); semipermeable 
poly(vinylbenzyltrimethyl) ammonium chloride; semipermeable polymer 
exhibiting a fluid permeability of 10.sup.-1 to 10.sup.-7 (cc.mil/cm.sup.2 
hr.atm) expressed as per atmosphere of hydrostatic or osmotic pressure 
difference across a semipermeable wall. The polymers are known to the art 
in U.S. Pat. Nos. 3,845,770; 3,916,899 and 4,160,020, and in Handbook of 
Common Polymers by J. R. Scott and W. J. Roff, 1971, published by CRC 
Press, Cleveland, OH. 
In the manufacture wherein device 10 comprises a capsule member, the 
capsule member generally is tubular shaped and it has a mouth at one end, 
and at the end distant therefrom it is closed in a hemi-spherical or dome 
shaped end. The capsule member serves as a hollow body having a wall that 
surrounds and defines an interior compartment provided with an opening for 
establishing communication with the exterior of the capsule and for 
filling the capsule. In one embodiment, a capsule is made by dipping a 
mandrel, such as a stain-less steel mandrel, into a bath containing a 
solution of a capsule wall forming material to coat the mandrel with the 
material. Then, the mandrel is withdrawn, cooled and dried in a current of 
air. The capsule is stripped from the mandrel and trimmed to yield a 
capsule with an internal lumen. The materials used for forming the capsule 
are then commercially available materials including gelatin, gelatin 
having a viscosity of 15 to 30 millipoises and a bloom strength up to 150 
grams; gelatin having a bloom value of 160 to 250; a composition 
comprising gelatin, glycerine water and titanium dioxide; a composition 
comprising gelatin, erythrosin, iron oxide and titanium dioxide; a 
composition comprising gelatin, glycerine, sorbitol, potassium sorbate and 
titanium dioxide; a composition comprising gelatin, acacia, glycerin and 
water; water soluble polymers that permit the transport of water 
therethrough and can be made into capsules, and the like. 
The wall of device 10 also can comprise a flux regulating agent. The flux 
regulating agent is a compound added to a wall forming composition that 
assists in regulating the fluid permeability of flux through the wall. The 
flux regulating agent can be a flux enhancing agent or a flux decreasing 
agent. The agent can be preselected to increase or decrease the liquid 
flux. Agents that produce a marked increase in permeability to fluid such 
as water, are often essential hydrophilic, while those that produce a 
marked decrease to fluids such as water, are essentially hydrophobic. The 
amount of regulator in the wall when incorporated therein generally is 
from about 0.01% to 20% by weight or more. The flux regulator agents in 
one embodiment that increase flux include polyhydric alcohols, 
polyalkylene glycols, polyalkylenediols, polyesters of alkylene glycols 
and the like. Typical flux enhancers include polyethylene glycol 300, 400, 
600, 1500, 4000, 6000 and the like; low molecular weight glycols such as 
polypropylene glycol, polybutylene glycol and polyamylene glycol; the 
polyalkylenediols such as poly(1,3-propanediol), poly(1,4-butanediol), 
poly(1,6-hexanediol) and the like; aliphatic diols such as 1,3-butylene 
glycol, 1,4-pentamethylene glycol, 1,4-hexamethylene glycol, and the like; 
alkylene triols such as glycerine, 1,2,3-butanetriol, 1,2,4-hexanetriol, 
1,3,6-hexanetriol and the like; ester such as ethylene glycol 
diproprionate, ethylene glycol butyrate, butylene glycol dipropionate 
glycerol acetate esters, and the like. Representative flux decreasing 
agents include phthalates substituted with an alkyl, an alkoxy or with 
both an alkyl and alkoxy group such as diethyl phthalate, dimethoxyethyl 
phthalate, dimethyl phthalate, and [di(2-ethyl-hexyl)phthalate]; aryl 
phthalate such as triphenyl phthalate, and butyl benzyl phthalate; 
insoluble salts such as calcium sulphate, barium sulphate, calcium 
phosphate, and the like; insoluble oxides such as titanium oxide; polymers 
in powder, granule and like form such as polystyrene, 
polymethylmethacrylate, poly-carbonate, and polysulfone; esters such as 
citric acid esters esterified with long chain alkyl groups; inert and 
substantially water impermeable fillers; resins compatible with cellulose 
based wall forming materials, and the like. 
Other materials that can be used to impart flexibility and elongation 
properties to the wall, for making the wall less-to-nonbrittle, and for 
increasing tear strength include plasticizers, presently exemplified by 
phthalate plasticizers such as dibenzyl phthalate, dihexyl phthalate, 
butyl octyl phthalate, straight chain phthalates of six to eleven carbons, 
diisononyl phthalate, diisodecyl phthalate, and the like. The plasticizers 
include nonphthalates such as citric acid esters, triacetin, dioctyl 
azelate, epoxidized tallate, triisoctyl trimellitate, triisononyl 
trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil and the 
like. The plasticizers include non-phthalates such as triacetin, dioctyl 
azelate, epoxidized tallate, triisoctyl trimellitate, triisononyl 
trimellitate, sucrose acetate isobutyrate, epoxidized soybean oil, and the 
like. The amount of plasticizer in a wall when incorporated therein is 
about 0.01% to 20% by weight, or higher. 
Expandable means 17 preferably has a shape that corresponds to the internal 
shape of compartment 14 and it is made from a hydrogel composition. The 
hydrogel composition is noncross-linked or optionally crosslinked and it 
possesses properties, such as the ability to absorb and/or imbibe an 
exterior fluid through the wall, and when it is an osmotic-acting hydrogel 
it exhibits an osmotic pressure gradient across the wall against a fluid 
outside delivery system 10. The materials used for forming the swellable, 
expandable inner layer 17 are polymeric materials neat, and polymeric 
materials blended with osmotic agents that interact with water or a 
biological fluid, absorb the fluid and swell or expand to an equilibrium 
state. The polymer exhibits the ability to retain a significant fraction 
of imbibed fluid in the polymer molecular structure. The polymers in a 
preferred embodiment are gel polymers that can swell or expand to a very 
high degree, usually exhibiting a 2 to 50 fold volume increase. The 
swellable, hydrophilic polymers that function by osmotic properties, also 
known as osmopolymers which osmopolymers can be noncross-linked or lightly 
cross-linked. The cross-links can be covalent or ionic bonds with the 
polymer possessing the ability to swell in the presence of fluid, and when 
cross-linked it will not dissolve in the presence of aqueous fluid. The 
polymer can be of plant, animal or synthetic origin. Polymeric materials 
useful for the present purpose include poly(hydroxyalkyl methacrylate) 
having a molecular weight of from 5,000 to 5,000,000; 
poly(vinylpyrrolidone) having a molecular weight of from 10,000 to 
360,000; anionic and cationic expandable hydrogels; poly(electrolyte) 
complexes; poly(vinyl alcohol) having a low acetate residual; a swellable 
mixture of agar and carboxymethyl cellulose; a swellable composition 
comprising methyl cellulose mixed with a sparingly cross-linked agar; a 
water-swellable copolymer reduced by a dispersion of finely divided 
copolymer of maleic anhydride with styrene, ethylene, propylene, or 
isobutylene; water swellable polymer of N-vinyl lactams; and the like. 
Other hydrogel or gelable fluid absorbing or imbibing and retaining 
polymers useful for forming hydrophilic, expandable push member 17 include 
pectin having a molecular weight ranging from 30,000 to 300,000; 
polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar; 
Carbopol.RTM. acidic carboxy polymer and its salt derivatives; 
polyacrylamides; water-swellable indene maleic anhydride polymers; 
Good-rite.RTM. polyacrylic acid having a molecular weight of 80,000 to 
200,000; Polyox.RTM. polyethylene oxide polymers having a molecular weight 
of 100,000 to 5,000,000; starch graft copolymers; Aqua-Keep.RTM. acrylate 
polymers with water absorbability of about 400 times its original weight; 
diesters of polyglucan; a mixture of cross-linked polyvinyl alcohol and 
poly(N-vinyl-2-pyrrolidone); zein available as prolamine; poly(ethylene 
glycol) having a molecular weight of 4,000 to 100,000; and the like. In a 
preferred embodiment, the expandable member is formed from polymer and 
polymeric compositions that are thermoformable. Representative polymers 
possessing hydrophilic properties are known in U.S. Pat. Nos. 3,865,108; 
4,022,173; 4,207,893; 4,327,725, and in Handbook of Common Polymers, by 
Scott and Roff, published by Cleveland Rubber Company, Cleveland, OH. 
The osmotically effective compound that can be blended homogeneously or 
heterogeneously with the swellable polymer means 17, to form push member 
17, are the osmotically effective solutes that are soluble in fluid 
imbibed into the swellable polymer, and exhibit an osmotic pressure 
gradient across the semipermeable wall against an exterior fluid. 
Osmotically effective compounds are known in the dispensing art also as 
osmagents. Osmotically effective osmagents useful for the present purpose 
include magnesium sulfate, magnesium chloride, sodium chloride, lithium 
chloride, potassium sulfate, sodium sulfate, mannitol, urea, sorbitol, 
inositol, succrose, glucose, and the like. The osmotic pressure in 
atmospheres, atm, of the osmagents suitable for the invention will be 
greater than zero atm, generally from eight atm up to 500 atm, or higher. 
The swellable, expandable polymer, in addition to providing a driving 
source for delivering a beneficial agent formulation 15 from the dispenser 
10, further serves to function as a supporting matrix for an osmotically 
effective solute. The composition in a presently preferred embodiment 
comprises at least one expandable polymer and at least one osmotic solute. 
Generally an expandable composition will comprise about 20% to 90% by 
weight of polymer and 80% to 10% by weight of osmotic solute, with a 
presently preferred expandable composition comprising 35% to 75% by weight 
of expandable polymer and 65% to 25% by weight of osmotic solute. 
The weight means, or density increasing member, also referred to as 
densifier, that is homogeneously or heterogeneously dispersed throughout 
the expandable hydrogel is used for initially retaining device 10 in the 
rumen-reticular sac of a ruminant. The dense member lets device 10 remain 
in the rumen during the dispensing period before device 10 passes into the 
alimentary tract and is eliminated therefrom. During the period of time 
device 10 remains in the rumen, beneficial active agent is delivered by 
device 10 at a controlled rate to the ruminant over time. Generally the 
amount of weight means mixed with the expandable hydrogel will be an 
amount sufficient to impart an initial density to the expanding hydrogel 
of greater than 1 to 8, with the density in a presently preferred 
embodiment exhibiting a specific gravity of from 2.2 to 7.6. For ruminant 
cattle and sheep it is presently preferred the combination expandable 
hydrogel weight means initially exhibit a density such that there is a 
resulting system density of about 3. Materials that have a density of from 
1 to 8 that can be blended with the hydrogel include iron, iron shot, iron 
shot coated with iron oxide, iron shot magnesium alloy, steel, stainless 
steel, copper oxide, a mixture of cobalt oxide and iron powder, a mixture 
of iron and copper oxide, and the like. The weight means can be in powder, 
granule, pellet and like form for blending with the hydrogel. The weight 
means can be blended with the hydrogel during polymerization, by blending 
solvent casting and evaporating, by compressing a blend and the like. The 
amount of weight means blended with a hydrogel is about 0.5 to 50 volume 
percent, or an amount sufficient to produce the desired density. Density, 
specific gravity and specific volume determinations are easily performed 
by procedures known in the art as disclosed in Remington's Pharmaceutical 
Sciences, Vol. 14, pp 95 to 100, edited by Osol, 1970, by Mack Publishing 
Co., Easton, PA. 
The thermo-responsive composition containing a beneficial agent 
homogeneously or heterogeneously dispersed or dissolved therein, is formed 
in a presently preferred embodiment of a heat sensitive, hydrophilic or 
hydrophobic material that exhibits solid-like properties at room 
temperature of 24.degree. C., and within a few centigrade degrees thereof, 
and exhibits in a preferred embodiment a melting point of 24.degree. C. to 
45.degree. C. that, in a preferred embodiment, approximates mammalian body 
temperatures of 37.degree. C., and within a few centigrade degrees 
thereof. The present invention uses the phrases "melting point", 
"softening point", "pour point", or "liquifies" to indicate the 
temperature at which the thermo-responsive composition melts, undergoes 
dissolution, or forms a paste-like ribbon, dissolves to form a dispensable 
carrier so it can be used for dispensing the beneficial agent from 
dispenser 10. The term "thermo-responsive" as used for the purpose of this 
invention includes thermoplastic compositions capable of softening, 
melting, becoming extrudable, becoming fluid, or becoming dispensable in 
response to heat and hardening again when cooled. The term also includes 
thermo-tropic compositions capable of undergoing change and becoming 
dispensable in response to the application of energy in a gradient manner. 
These materials also are temperature sensitive in their response to the 
application, and to the withdrawal of energy. The term "thermo-responsive" 
as used for the purpose of this invention in a preferred embodiment 
denotes the physical-chemical property of a composition agent carrier to 
exhibit storage or solid, or solid-like properties at temperatures up to 
24.degree. C., and become fluid, semisolid, or viscous when disturbed by 
heat at, usually in the range of 24.degree. C. to 45.degree. C. The 
thermo-responsive carrier is heat-sensitive and preferably anhydrous and 
it has the property of melting, dissolving, undergoing dissolution, 
softening, or liquifying at the elevated temperatures, thereby making it 
possible for the dispenser 10 to deliver the thermo-responsive carrier 
with the beneficial agent homogeneously or heterogeneously blended 
therein. The thermo-responsive carrier can be lipophilic, hydrophilic or 
hydrophobic. Another important property of the carrier is its ability to 
maintain the stability of the agent contained therein during storage and 
during delivery of the agent. Representative thermo-responsive 
compositions and their melting points are as follows: cocoa butter, 
32.degree. to 34.degree. C.; cocoa butter plus 2% beeswax, 35.degree. to 
37.degree. C.; propylene glycol mono- stearate and distearate, 32.degree. 
to 35.degree. C.; hydrogenated oils such as hydrogenated vegetable oil, 
36.degree. to 37.5.degree. C.; 80% hydrogenated vegetable oil and 20% 
sorbitan monopalmitate, 39.degree. to 39.5.degree. C.; 80% hydrogenated 
vegetable oil and 20% polysorbate 60, 36.degree. to 37.degree. C.; 77.5% 
hydrogenated vegetable oil with 20% sorbitan trioleate and 2.5% beeswax, 
35.degree. to 36.degree. C.; 72.5% hydrogenated vegetable oil with 20% 
sorbitan trioleate, 2.5% beeswax and 5.0% distilled water, 37.degree. to 
38.degree. C.; mono-, di-, and triglycerides of acids having from 8-22 
carbon atoms including saturated and unsaturated acids such as palmitic, 
stearic, oleic, lineolic, linolenic and archidonic; glycerides of fatty 
acids having a melting point of at least 32.degree. C. such as 
monoglycerides, diglycerides and triglycerides of vegetable fatty acids 
having 10 to 18 carbon atoms obtained from coconut oil, olive oil and the 
like; partially hydrogenated cottonseed oil, 35.degree. to 39.degree. C.; 
hardened fatty alcohols and fats, 33.degree. to 36.degree. C.; hexadienol 
and hydrous lanolin triethanolamine glyceryl monostearate, 38.degree. C.; 
eutectic mixtures of mono-, di-, and triglycerides, 35.degree. to 
39.degree. C.; Witepsol.RTM. #15, triglyceride of saturated vegetable 
fatty acid with monoglycerides, 33.5.degree. to 35.5.degree. C.; 
Witepsol.RTM. H32 free of hydroxyl groups, 31.degree. to 33.degree. C.; 
Witepsol.RTM. W25 having a saponification value of 225-240 and a melting 
point of 33.5.degree. to 35.5.degree. C.; Witepsol.RTM. #75 having a 
saponification value of 220-230 and a melting point of 37 .degree. to 
39.degree. C.; a polyalkylene glycol such as polyethylene glycol 1000, a 
linear polymer of ethylene oxide, 38.degree. to 41.degree. C.; 
polyethylene glycol 1500, melting at 38.degree. to 41.degree. C.; 
polyethylene glycol monostearate, 39.degree. to 42.5.degree. C.; 33% 
polyethylene glycol 1500, 47% polyethylene glycol 6000 and 20% distilled 
water, 39.degree. to 41.degree. C.; 30% polyethylene glycol 1500, 40% 
polyethylene glycol 4000 and 30% polyethlene glycol 400, 33.degree. to 
38.degree. C.; mixture of mono-, di-, and triglycerides of saturated fatty 
acids having 11 to 17 carbon atoms, 33.degree. to 35.degree. C.; block 
polymer of 1,2-butylene oxide and ethylene oxide; block polymer of 
propylene oxide and ethylene oxide; block polymer of polyoxyalkylene and 
propylene glycol, and the like. The thermo-responsive composition is a 
means for storing a beneficial agent in a solid composition at a 
temperature up to 24.degree. C., maintaining an immiscible boundary at the 
swelling composition interface, and for dispensing the agent in a flowable 
composition at a temperature greater than 24.degree. C., and preferably in 
the range of 24.degree. C. to 45.degree. C. The thermo-responsive 
composition on being dispensed into a biological environment are easily 
excreted, metabolized, assimilated, or the like, for effective use of the 
beneficial agent. 
The term "beneficial agent" as used herein includes medicines or drugs, 
nutrients, vitamines, anthelminthic, biocide, larvicides, fluikicides, 
parasiticide, anti-infection agents, antibloat agents, food supplements 
including mineral supplements, growth promotants and permittants, growth 
efficiency factors, chemical markers, and other agents that benefit a 
ruminant animal. The beneficial agent can be insoluble to very soluble in 
the temperature sensitive material housed in the delivery system. The 
amount of agent present in a delivery system can be from 10 ng to 40 g or 
more. The delivery system can house various amounts of the beneficial 
agent, for example, 75 ng, 1 mg, 5 mg, 100 mg, 250 mg, 750 mg, 1.5 mg, 2 
g, 5 g, 10 g, 15 g, and the like. A single delivery system can be 
administered to a ruminant, or more than one delivery system can be 
administered to a ruminant during a therapeutic program. A delivery system 
can deliver from 0.1 mg/hr to 1500 mg/hr, or more, over a prolonged period 
of time. The delivery system can be used for one day to six months or 
longer. 
Representative of beneficial agent that can be dispensed using the delivery 
system of this invention include anthelminthics such as mebendabzole, 
levamisole, albendazole, cambendazole, fenbendazole, parbendazole, 
oxfendazole, oxybendazole, thiabendazole, tichlorfon, praziquantel, 
morantel and pyrantel, and the like. Antiparasitic agents such as 
avermectins and ivermectin, as disclosed in U.S. Pat. Nos. 4,199,569 and 
4,389,397, both assigned to Merck and Co., and in Science, Vol. 221, pp 
823-828, 1983, wherein said ivermectin antiparasitic drug is disclosed as 
useful for aiding in controlling commonly occurring infestations in 
animals, such as roundworms, lungworms, and the like, and said ivermectin 
also being useful for management of insect infestations such as grub, 
lice, mange mite, and the like; antimicrobial agents such as 
chlortetracycline, oxytetracycline, tetracycline, streptomycin, 
dihydrostreptomycin, bacitracins, erythromycin, ampicillins, penicillins, 
cephalosporins, and the like; sulfa drugs such as sulfamethazine, 
sulfathiazole, and the like; growth stimulants such as Monesin.RTM. sodium 
and Elfazepam.RTM.; defleaing agents such as dexamethazone and 
flumethazone; rumen fermentation manipulators and ionophores such as 
lasalocid, virginamycin and ronnel, salinomycin; minerals and mineral 
salts; anti-bloat agents such as organopoly siloxanes; hormone growth 
supplements such as stilbestrol; growth efficiency factors such as 
-agonists, clenbuterol; vitamins; antienteritis agents such as 
furazolidone; nutritional supplements such as lysine monohydrochloride, 
methionine, magnesium carbonate, and the like; chemical markers such as 
chromic oxide and salts of yitterbium and erbium. 
The wall forming composition can be applied to form the device and as the 
exterior surface of the capsule in laminar arrangement by molding, air 
spraying, dipping, casting, or brushing, with a wall forming composition. 
Other and presently preferred techniques that can be used for applying the 
wall are the air suspension procedure and the pan coating procedure. The 
air procedure consists in suspending and tumbling the compress arrangement 
of the device forming components in a current of air and a wall forming 
composition until the wall surrounds and coats the components or surrounds 
and coats the capsule member. The procedure can be repeated with a 
different semipermeable wall forming composition to form a laminated wall. 
The air suspension procedure is described in U.S. Pat. No. 2,799,241; J. 
Am. Pharm. Assoc., Vol. 48, pp 451-459, 1979; and ibid., Vol. 49, pp 
82-84, 1960. Other standard manufacturing procedures are described in 
Modern Plastics Encyclopedia, Vol. 46, pp 62-70, 1969; and in 
Pharmaceutical Sciences, by Remington 14th Ed., pp 1626-1678, 1970, 
published by Mack Publishing Co., Easton, PA. 
Exemplary solvents suitable for manufacturing the wall include inert 
inorganic and organic solvents that do not adversely harm the materials, 
the capsule wall, the beneficial agent, the thermo-responsive composition, 
the expandable member, the dense member, and the final dispenser. The 
solvents broadly include members selected from the group consisting of 
aqueous solvents, alcohols, ketones, esters, ethers, aliphatic 
hydrocarbons, halogenated solvents, cycloaliphatics, aromatics, 
heterocyclic solvents and mixtures thereof. Typical solvents include 
acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, butyl 
alcohol, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetae, 
methyl isobutyl ketone, methyl propyl ketone, n-hexane, n-heptane, 
ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, 
methylene dichloride, ethylene dichloride, propylene dichloride, carbon 
tetra-chloride, nitroethane, nitropropane, tetrachloroethane, ethyl ether, 
isopropyl ether, cyclohexane, cyclo-octane, benzene, toluene, naptha, 
1,4-dioxane, tetrahydrofuran, diglyme, water, and mixtures thereof such as 
acetone and water, acetone and methanol, acetone and ethyl alcohol, 
methylene dichloride and methanol, and ethylene dichloride and methanol. 
Generally for the present purpose the semipermeable wall is applied at a 
temperature a few degrees less then the melting point of the 
thermo-responsive composition. Or, the thermoplastic composition can be 
loaded into the dispenser after applying the semipermeable wall. 
The expression "passageway" or "orifice" as used herein comprises means and 
methods in the wall or in a laminated wall suitable for releasing a 
beneficial agent formulation from the dispenser. The passageway can be 
formed by mechanical or laser drilling, or by eroding an erodible element 
in the wall, such as gelatin plug. The passageway can be drilled through 
the semipermeable wall only, or through the semipermeable wall capsule 
laminated wall. In these embodiments when the passageway is drilled only 
through the semipermeable wall, the passageway in the capsule wall is 
formed in the environment of use by bursting, eroding or dissolving a 
passageway in the capsule wall. The passageway can be a porous polymer 
composition having at least one pore, or a microporous polymer composition 
having at least one micropore or more than one micropores that serve as 
more than one passageway suitable made a part of the wall of the delivery 
system. The microporous releasing means can be formed by learching a pore 
former from the wall. The passageway can be positioned in a preselected 
loci of the wall by visual inspection, by optical density scanning as the 
device travels through a laser machine, by orienting and following the 
device through the manufacturing steps, by photo detection and responding 
to the reflected wave length emanating from a device, by magnetic 
orientation, and like standard manufacturing procedures. A detailed 
description of some orifice and the preferred maximum and minimum 
dimensions for an orifice are disclosed in U.S. Pat. Nos. 3,845,770 and 
3,916,899. 
DESCRIPTION OF EXAMPLES OF THE INVENTION 
The following examples are merely illustrative of the present invention and 
they should not be construed as limiting the scope of the invention in any 
way, as these examples and other equivalents thereof will become more 
apparent to those skilled in the art in the light of the present 
disclosure, the drawings and the accompanying claims. 
EXAMPLE 1 
A dispensing system for the controlled delivery of ivermectin is made as 
follows: first, 193 g of Butronic.RTM. L-1 polyol, a block polymer formed 
by the polymerization of 1,2-butylene oxide to which ethylene oxide is 
added, as reported in Cosmetics and Toiletries, Vol. 97, pp 61-66, 1982, 
which polymer flows at a pour point of 39.degree. C., is melted at 
55.degree. C. and then 13.98 g of ivermectin is added thereto using a high 
sheer ultrasonic mixer. The resulting mixture is placed in a vacuum oven 
at 55.degree. C. and the pressure reduced to less than 10 mm of mercury. 
The ivermectin Butronic.RTM. composition is allowed to remain in the 
vacuum for a period of about 10 minutes for removing entrapped air. Next, 
4 g of the resulting thermoplastic drug formulation is poured through the 
open tail end into the lead end of a 1/2 oz. gelatin capsule. Then, an 
expandable driving member comprising 1.2 g of sodium chloride, 4.6 g of 
the sodium salt of polyacrylic acid available as Carbopol.RTM. 934-P and 
30 g or iron chip are compressed into a solid mass shaped like a tablet. 
The tablet is formed using a 18.2 mm tableting tool and a 31/2 ton 
compression force and has a final shape that corresponds to the internal 
shape of the opening of the capsule. The tablet member is inserted into 
the opened end of the capsule until contact is made with the drug polyol 
formation. Next, the capsule is coated in a pan coater with a rate 
controlling wall comprising 1.8 g of 91% cellulose acetate butyrate and 9% 
polyethylene glycol 400. The wall is coated from a 5% wt/wt solution in 
methylene chloride methanol 90:10 v/v solvent system. The wall coated 
delivery systems then are dried at 30.degree. C. for 24 hours. Next, the 
device is visually oriented and a 30 mil exit passageway is drilled 
through the semipermeable wall and the gelatin capsule using a high speed 
mechanical drill for communicating the passageway with the internal 
compartment of the device. The passageway establishes communication with 
the heat-responsive drug formulation for delivering it from the delivery 
system. The dispenser made according to this example has an average 
release rate of 0.5 mg per hour over a 480 hour period of time. 
EXAMPLE 2 
A delivery system is made according to the procedure set forth in Example 
1, with the conditions as set forth, except that in this example the 
heat-responsive composition comprises 46.6 g of ivermectin and 200 g of 
polyethylene glycol 400 distearate, and the expandable-swellable 
composition comprises 70% by weight of poly(ethylene oxide) having a 
molecular weight of 3,000,000, 10% by weight of sodium chloride, and 20% 
by weight of a 50:50 mixture of iron shot and cobalt oxide. Delivery 
systems prepared according to this example dispense from 0.100 to 0.750 
mg/hr of the ivermectin. 
EXAMPLE 3 
A dispenser system is prepared as follows: first, the body section of a 
capsule is positioned with its mouth in an upright position, and a layer 
of an expandable-swellable density composition is charged into the 
hemispherical end of the capsule. The layer's shape matches the internal 
shape of the capsule. The composition comprises 5% by weight of sodium 
chloride, 70% by weight of poly(ethylene oxide) having a molecular weight 
of 200,000 and 25% by weight of stainless steel tiny particles. The 
expandable-swellable density composition forming ingredients are blended 
in a commercial blender with heat for 20 minutes to yield a homogeneous 
composition. The heated composition is charged into the capsule forming a 
layer that occupies about 1/3 of the capsule. Next, a heat-sensitive drug 
formulation comprising an eutectic mixture of 77% neutral fat having a 
melting point of 35-37.degree. C. and 19.5% paraffin having a melting 
point of 52.degree. C. is heated and 3.5% levamisole is added thereto. 
Then, the heated mixture is cooled to about 40.degree. C. and injected 
into the capsule in contacting relation with the expandable layer, and the 
capsule allowed to cool to room temperature. 
Then a solution of cellulose acetate, 15 wt percent, with an acetyl content 
of 39.8%, is prepared in a methylene chloride methanol solvent system and 
the capsule coated with a semipermeable wall. The wall is applied by 
dipping it into the coating solution for 15 times, first for a 5 second 
dip, then for two 10 second dips, then for a 30 second dip and then for 1 
minute per dip, with an intervening 5 minute drying period. Following the 
dipping the delivery dispenser is dried at room temperature, 72.degree. 
F., about 22.degree. C., for 5 days. The procedure applies about a 2 mm 
thick semipermeable wall. A passageway positioned by photo detection is 
laser drilled through the semi-permeable wall connecting the exterior of 
the dispenser with the heat sensitive drug formulation for releasing it at 
a controlled rate over time. 
EXAMPLE 4 
A dispensing system for delivering beneficial nutrients to warm-blooded 
ruminants is prepared as follows: first, a mold having a shape and 
configuration corresponding to the internal diameter and the hemispherical 
closed end of a capsule, is filled with an expandable density forming 
composition comprising 30 parts of ethyleneglycol monomethacrylate 
containing 0.12 parts of ethyleneglycol dimeth-acrylate, 10 parts of a 
0.13% aqueous solution of sodium disulfate in aqueous ethanol, and 30 
parts of iron powder and magnesium. The composition polymerizes at 
30.degree. C., and after 20 minutes following equilibrium to room 
temperature, the solid layer is removed from the mold. The solid 
expandable layer then is inserted, through the mouth of the capsule into 
the hemispherical area of the capsule. Next, the capsule is filled with a 
melted composition comprising 2.5% 1-lysine HCl, 1.5% DL-methionine, 21% 
glycergelatin and 75% theobromo oil, a glyceride of stearic acid, palmitic 
acid and lauric acid, to form on cooling to room temperature the 
thermo-responsive composition in laminar position with the expandable 
dense member. Next, the filled capsule is coated with a surrounding wall 
comprising cellulose acetate containing 10% polyethylene glycol 400. The 
semipermeable wall is applied in a pan type Hi-coater. The solvent used 
for forming the wall consists essentially of methylene chloride and 
methanol 95 parts by weight to 5 parts by weight. A 12 mil, 0.30 mm, thick 
wall of cellulose acetate butyrate is applied to the exterior surface of 
the capsule. Finally, a passageway is laser drilled through the 
semipermeable wall and the capsule wall communicating with the 
heat-responsive nutrient containing composition for its delivery to the 
environment of use. 
EXAMPLE 5 
A delivery device is made according to the procedure set forth in Example 
1, with the conditions and materials as set forth, except that in this 
example, a varying rate controlling wall thickness comprising cellulose 
acetate butyrate and polyethylene glycol 400 is applied to the device. The 
thickness of the rate controlling wall varies from 30 mil (0.76 mm) at the 
end distant from the passageway in a uniform taper to 15 mil (0.38 mm) 
adjacent to the expandable density member. 
EXAMPLE 6 
A delivery device is prepared by following the procedures set forth above. 
The delivery device comprises a first compressed composition comprising 35 
g of poly(ethylene oxide) having a molecular weight of 500,000; 30 g of 
iron powder and 5 g of sodium chloride, pressed against a second 
compressed composition comprising 38.5 g of neutral fat, 9.7 g of paraffin 
and 1.7 g of parbendazole. The laminated compressed layer are surrounded 
with a semipermeable wall that comprises 50% cellulose acetate butyrate, 
45% poly(sulfone) and 5% citroflex citric acid ester selected from the 
group consisting of acetyl tributyl citrate and acetyl tri-2-ethylhexyl 
citrate. The device has a passageway through the semipermeable wall 
connecting the beneficial drug formulation with the exterior of the 
device. 
EXAMPLE 7 
A delivery system is made according to the procedure as set forth in 
Example 6, with all conditions as described except that the semipermeable 
wall comprises 80% cellulose acetate butyrate and 20% poly(sulfone), or 
20% cellulose acetate butyrate and 80% poly(sulfone). 
EXAMPLE 8 
A series of delivery systems are prepared according to the procedures as 
set forth in Examples 6 and 7, with all conditions as described, except 
that in one embodiment 35 g of iron shot is used with the hydrogel; in 
another embodiment 80 g of iron shot is used with the hydrogel, and in 
another embodiment 120 g of iron shot is blended with the hydrogel to 
yield the respective delivery systems. 
An embodiment of the invention pertains to (1) a method of increasing the 
deliverability of a beneficial agent by formulating a heat-sensitive 
composition containing a beneficial agent and (2) making the delivery 
system of the invention for increasing the deliverability of the 
beneficial agent. An embodiment of the invention pertains also to a method 
for administering a beneficial agent at a controlled rate to the rumen of 
a ruminant, which method comprises the steps of: (A) admitting into rumen 
a dispensing device comprising (1) an outer wall formed of a polymeric 
composition permeable to the passage of fluid and substantially 
impermeable to the passage of drug, the wall surrounding (2) an internal 
lumen containing a layer of a beneficial drug formulation comprising a 
dosage unit amount of drug for preforming a therapeutic program in a 
heat-sensitive pharmaceutically acceptable carrier that melts at body 
temperature and is a means for transporting the drug from the dispenser; 
(3) a layer of an expandable hydrogel in the lumen; said layer of an 
expandable hydrogel containing a density producing member for maintaining 
the dispenser in the rumen over a prolonged period of time, and, (4) an 
orifice through the communicating with the heat-sensitive drug 
formulation; (B) imbibing fluid through the wall at a rate determined by 
the permeability of the semipermeable wall and the osmotic pressure 
gradient across the semipermeable wall causing the layer of expandable 
hydrogel to expand and swell; (C) melting the drug formulation to form a 
flowable formulation; (D) delivering the beneficial drug formulation from 
the compartment by the expandable layer continually expanding against the 
melting formulation causing the formulation to be dispensed in a 
therapeutically effective amount through the orifice at a controlled rate 
to the rumen over a prolonged period of time; and (E) after the delivery 
period of the beneficial drug formulation the expandable hydrogel with 
density producing member 15 delivered causing a reduced system density 
thereby allowing the system to be passed from the immediate area and from 
the animal. 
Inasmuch as the foregoing specification comprises preferred embodiment of 
the invention, it is understood that variations and modifications may be 
made herein in accordance with the inventive principles disclosed, without 
departing from the scope of the invention.