CA1113395A - Delivery system - Google Patents

Abstract

Abstract of the Disclosure Delivery systems and devices for the controlled release of chemicals, including drugs, comprising a wall, formed in part at least, of a porous material, including a porous fabric material, pores of which contain a hydrogel, said porous wall in contact with at least a portion of a reservoir comprised of a chemical and, if desired, a water-soluble liquid excipient and/or a detergent; process for preparation thereof, and use for the controlled release of chemicals, including drugs, to an aqueous liquid-containing environment. Emphasis is given to said systems and devices in which the hydrogel is gelled cellulose triacetate, and to their use for controlled release of drugs to animal, especially to ruminants over prolonged periods of time.

Description

IMPROVED DELIVERY SYSTE~
This inven~ion relates to improved chemical, including drug, permeable systems and devices adapted to release a drug or other chemical at a controlled rate from a drug-containing reservoir to an aqueous liquid-containing environment, particularly to an animal r including human, body environment and to drug or chemical delivery devices including such a system.
~t particularly relates to such systems and devices which are comprised of a wall or walls, formed in part at least, of a porous material, including a porous fabric, pores of whieh contain a hydrogel, and wherein said porous material is in contact with a drug or drug-containing reservoir. More particularly, it relates to boluses comprising said systems for controlled release of drugs to ruminants and which are retained in the rumeno-reticular sac of the animals.
Drug delivery systems and devices for controlled release of drugs; i.e~, controlled release and sustained or prolonged release, are well known in the art~ A
variety of methods have been described in the litera-ture, including physiological modification of absorption or excretion, modi~ication of the solvent, chemical modification of the drug, adsorption of drug on an insoluble carrier, use of suspensions and implantation pellets (Edkins, J. Pharm. Pharmacol., 11, 54T-66T, ; 1959). Other methods include mixing the drug with a carrier which is gradually disintegrated by the environ-ment, e.g., body fluids resulting in release of the drug. Waxes, oils, fats and soluble polymers have served as carriers.
It is also known in the art to disperse the drug throughout a solid matrix material through which the drug is released by diffusion, or to enclose the drug ~;

~ ~.
. ~
''~

within a capsule having a polymeric wall or walls through which the drug can pass by diffusion (U~S.
3,279,996).
U.S. 3,975,350 describes hydrogel carrier systems comprised of polyurethane polymers for use in medicinal, pesticidal, insecticidal, algaecidal, etc. applications.
U.S. 1,693,890 describes preparation of porous membranes of ~ellulose acetate in the form of jellies for use in dialysis. The process comprises precipitating the cellulose acetate ~rom a solution thereof in acetic acid by addition o~ a non-solvent such as water. If desired, the membranes can be formed on a support. The membranes thus produced are impregnated with water hut can be freed of water by washing with alcohol, acetone or any water miscible liquid.
Cellulosic polymer-liquid composite (PLC) materials in film, fiber or microspherical form, including cellulose esters such as cellulose triacetate or cellulose nitrate, or molecular mixtures thereo~, as vehicles for the controlled release of various substances are described in U.S. patent 3,985,298. The substance to be released is impregnated into and within the cellulosic PLC material as a part of or as all of the liquid phase (alcohol or water or mixtures, therof) contained within the micropores of the cellulosic PLC.
~ .S. 3,846,404 describes semipermeable membranes o gel}ed cellulose triacetate useful as carriers for other materials such as liquids having medicinal propertles. The impregnation o~ smooth-finish, nonwoven polyethylene ~abric and plain cotton cloth with yelled cellulose triacetate to provide supported cellulose triacetate hydrogel materials is described. The use o~
medication-impregnated gelled cellulose triacetate products as animal implantable slow-release agents are described, as is the casting of gelled cellulose triacetate onto a woven or nonwoven supportiny sheet material.

.

: , -,::: - : ~ : .: :~: .. . .

3:~

Controlled release drug delivery devices comprising a reservoir formed of a drug and a solid or liquid drug carrier and, in contact with or surrounding the reservoir, a wall formed of any of a variety of materials, including a microporous material the micropores of which contain a diffusive medium (e.g., a liquid phase comprised of a solu~ion, a colloidal solution, a suspension, or a sol) permeable to passage of drug by diffusion, are described in one or more of the following U.S. patents: 3,993,072; 3,993,073; 3,896,819; 3,948,254;
3,948,262; 3,828,777; 3,797,494; 4,06~,084 and 3,995,634.
U.S. 3,993,073 also discloses hydrophilic hydrogels of es~ers of acrylic acid and methacrylic acid, and cross-linked polyvinyl alcohol as suitable wall forming materials. A key feature of the devices of these patents is the use of a wall, composed in part at least, of a microporous material, pores of which contain a drug release rate controlling medium permeahle to passage of drug, and a reservoir comprising drug plus a carrier which is permeable to passage of drug but at a higher rate than the permeability of th~ rate ; controlling medium housed in the pores of ~he microporous wall. De~ices suitable for administering therapeutic or nutrient substances to ruminants and which comprise encasing the substance in a permeable, water-insoluble ~ material having capillary or interconnecting pores ; extending through them and paper or cloth partially impregnated with water-insoluble polymers, e.g.
cellulose acetate, are described in British Patent l,318,259.
U.S. Patent 3,594,469 describes pellets containing magnesium and iron for administration to ruminants for supplying the ruminants with said metals over an extended period of time. In one embodiment, the .~ .

: , , .. , . ~ ~

,q~

pelle-t consists o~ a cylindrical tube of magnesium alloy filled with shot and some biologically active substance and plugged at both ends by porous discs.
U.S~ Patent 3,938,515 makes known devices designed S for continuous administration of a drug for a prolonged period compri~ing a reservoir co~taining the drug and a solid or liquid carrier permeable to the drug, and a polymeric wall surrounding the reservoir which is permea~le to the drug, but at a rate less than that of the carrier.
~ .S. Patent 3,946,734 discloses a diffusion cell, designed principally for use as an implant and which is essentially a capillary, one end of which is sealed with an impervious material and the rest of the tube and the other end thereof is sealed with a porous, neutral hydrogel. The biologically active substance is placed in the capillary against the impervious material and the capillary then filled with the hydrogel (agarose, polyacrylamide) through which the biologically active medicament will diffuse.
Many of the prior art controlled release devic~s are described as zero order release devices. t~owever, said devices are able to maintain zero order rates of release for relatively short fractions of their projected life span and are not practical for extended use as, for example, in ruminants. The devices of this invention, on the other hand, achieve and maintain controlled, predictable, zero order rates of release of a given drug for extended periods of time. Additionally, the prior art devices, including those comprising a drug-containing reservoir surrounded by a shaped wall formed at least in part of a microporous ma~erial, pores of which have a drug release rate controlling medium (diffusive medium) permeable to passage of 3s drug, are subject to physical clogging or physical . ~
.. .
.'`~ " ' damage in certain use environments such as the rumeno-reticular sac of ruminants. The clogging decreases and even stops release of the drug rendering the devices inopPrative for their intended purpose. The devices of this invention wherein pores of the porous material in contact with the drug~containing resevoir contain a hydrogel axe essentially free of this problem and able to provide controlled and predictable release rates of drug to an aqueous liquid-containing environment for extended periods of time.
When used for controlled release of highly water-soluble drugs, prior art devices (of the type described in U.S. patents 3,993,073, 3,993,072; 3,967,618;
3~948,262; 3,948,254 and 3,896,819) prefer that the wall and/or the reservoir be formed ~rom a material that is substantially impermeable to water in order to prevent dilution of the drug in the reservoir by a~sorption of bod~ fluids into the device and decrease in drug release rate. They are, therefore, not suited for delivery of water soluble drugs, especially at . .
relatively high rates. Further, the devices described in most of these patents require that the permeability ~;
to drug of the drug release rate controlling medium in the pores of the porous wall surrounding the reservoir be less than the permeability of the liquid carrier in the reservoir to the drug. By this means, passage of druy through the wall is the rate controlling step.
; The devices of the present invention are completely free from such restrictions. In fact, a significant difference of the herein-described devices over the prior art devices resides in the presence of highly water permea~le hydrogel in the pores of the porous material in contact with the reservoir. Said devices depend upon diffusion of water from an aqueous-liquid environment into which the device is placed through liquid filled pores or channels in the hydrogel and :' . . . : . ., .. . . . .: -33~

::
into the reservoir~ and the outward diffusion of drug from the reservoir to the environment. Unexpectedly, the concentration o~ dissolved drug in the reservoir does not diminish, resulting in a substantially constant rate of release for a prolonged time. However, the amount oE drug dissolved in the reservoir varies continuously throughout the life span of the devices of this invention.
The use of a low-level of the anthelmintic agent morantel tartrate in the drinking water of calves, the calves having continuous access to the medicated water, as a means of endoparasite control is reported by ~owning _. al., Irish Vet. J.~ 221, November, 1974 and in British Patent 1,530,161._ _ _ Continuous daily anthelmintic medication o~ calves from early April to mid-July was found to suppress worm-egg output by *he calves and to prevent, or at least minimize, development o~ heavy larval infection on herbage.
Daily low-level feed aclministration of morantel tartrate to calves from turning out to mid-July was found by Jones et. al., Brit. Vet. J., 13~, 166 (1978) to successfully control parasitic gastroenteritis and lungworm infections by reducing contamination of the pasture available to the grazing calf.
This invention relates to an impro~ed device for the controlled and :^ :
2Q continuous administration of chemical *o an aqueous liquid-containing envir-onment over a prolonged period of time, said device comprising a reservoir containing a chemical, a shaped wall formed in part at least of a porous material, said porous wall in contact with at least a part of said reservoir ~ -and characterized by being insoluble in saicl environment and maintaining its integrity during said prolonged period of time, the improvement which com-`l prises impregnating the pores of said porous material with a hydrogel medium ~;; permeable to passage ~$ said chemical and to said aqueous liquid so that said ,~~
' 6 : .

''' ' ' ' , '; . '' . ' : ~ , ,: :: '' .' '`" ~ :" '' '' ', ' ', . :, ' . ,, , ::

S~ ;i 3~

device ~hen placed in said environment continuously releases said chemical from said reservoir to said environment at a physiologically effective controlled rate through said medium, the dissolved chemical so released being replaced by the continuous dissolving of said chemical in said reservoir, the amount of dissolved chemical in said reservoir changing continuously through-out said prolonged time period, so as to maintain the rate o~ chemical release to said environment substanti.ally constant during a substantial portion of said prolonged time period.
The invention further relates to a method for the control of : 10 helminths on pasture land, the helminth larvae contamination of which is at or near a minimum level, which comprises grazing on said land ruminant animals having in their rumeno-reticular sacs, a device for the controlled and con-tinuous administration of a water soluble salt of morantel to the aqueous liquid-containing environment in said rumeno-reticular sac over a prolonged period of time, said device comprising a reservoir containing said morantel, : a shaped wall formed in part at least of a porous material, pores of which contain a hydrogel medium, said porous wall in contact with at least a part .::
of said reservoir and characteriæed by being insoluble in said environment and maintaining i~s integrity during said prolonged period of time, said ~ ;
hydrogel being permeable to passage of said morantel and to said aqueous .
liquid so that said device ~hen placed in said environment continuously re- r leases said morantel from said reservoir to said environment at a physiologi-cally effecti.ve controlled rate through said medium, the dissolved morantel so released being replaced by the continuous dissolving of said morantel in said reservoir, the amount of dissolved morantel in said reservoir changing continuously throughout said prol ged time period, so as to maintain the rate of morantel release to said en~ironment substantially constant during a - 6a -33~

substantial portion of said prolongcd time period.
The present invention relates to improved chemical~ including drug~ :
permeable systems and devices adapted to release said substances at a physiologically or pharmacologically effective controlled rate from a chem- -ical-containing reservoir to an aqueous liquid-containing environment, partic-ularly to an animal, including human, body environment. In particular, it relates to such systems and devices comprising a container, at least part of the wall or walls of which :~!
.j `.
. . .

'.

:
.
:: .

~ - 6b -comprise a porous material, including a porous fabric material, pores of which contain a hydrogell and to devices wherein said porous material is in contact with at least a portion of a chemical or a chemical-containing reservoir. More particularly, it relatesto boluses comprising said systems for controlled release of drugs to ruminants and which are retained in the rumeno-reticular sac of the animals.
The improved chemical, including drug (the terms are used interchangeably herein) permeable systems and devices of this invention are of value for controlled release of drugs and other chemicals to aqueous ~iquid--,~ containing environments and are of particular value for oral dosing of animals, including man, and can be used for a variety of drugs. In addition, the devices are particularly well suited for delivering highly water soluble substances at high rates, not readily achievable with prior art devices. The systems and de~ices of this invention provide for the controlled release of chemicals over a prolonged period of time, are easy to produce and a;^e reliable and easy to use.
Moreover, the devices described herein maintain their physical and chemical integrity, do not clog in the environment of use and are especially valuable for oral use in a bolus-shaped form for ruminant animals.
They provide, for the first time, a practical device for controlled and continuous release of chemicals, including drugs, to an aqueous liquid-containing environment and, therefore/ fill a long-existing need, ; 30 particularly in animal husbandry.
The controlled rate release systems and de~ices of this invention comprise a barrier or wall in contact with at least a portion of a chemical-containing reservoir and wherein the wall consists par~ly or entirely of a .

porous material, including a porous fabric material, pores of which contain a hydrogel permeable to passage of liquid from the environment through pores within the hydrogel itself and of chemical from the reservoir by diffusion.
When the devices of this invention are in usç, the hydrogel contains liquid from the environment, said llquid heing contained within areas or channels (pores~ within the hydrogel itself and which serve as pathways for dif~usion of environmental liquid and transport o~ drug.
The systems and devices of this invention can assume a wide variety of shapes and sizes subject to the purpose for which they will be used. They can, for example, be capsule-shaped for oral use in humans and animals or cylindrical for implant or for use as a bolus in ruminants.
A favored form of device of this invention, in its broadest aspect, comprises a porous material, pores of which contain a h~drogel, especially gelled cellu~ose triacetate, permeable to passage of liquid from the environment and of drug by diffusion through pores within the hydrogel, said porous material in contact with at least a portion of a chemical, including drug, containing reservoir comprising chemical and, if desired, a suitable water-soluble liquid excipient, and also, if desired, a detergentl said device being made in the form of a bolus for use in the controlled ` 25 release of drug to ruminant animals, especially cattle and sheep, for a prolonged time. Particular use of such boluses is for parasitological, especially helminthic, control, prophylactic and therapeutic, o~ gastroenteral and lungworm infections in cattle and sheep and of helminth contamination of pasture land. The term "bolus" as used herein includes devices which are generally cylindrical, spherical, sphero-idal, elliptical or other form, free of sharp edges and protuberances.

., :. :
....

. - . . ~ : ~ : .: : : .

, .. :., .: .:. :, .
:: , . , . ~ , w~
:
The prior art devices require consideration and compromise of several factors for each use; namely, the carrier used in the reservoir; the solubility and/or permeability of the carrier to the drug contained in the reservoir; the nature of the microporous wall surrounding the reservoir; the diffusive medium contained in the p~res of the microporous wall; the relative permeahility rates of the diffusive ~edium and carrier to the drug; the rela-tive solubilities of the drug in the diffusive medium and carrier; and the need for maintaining a substantially constant amount of dissolved drug in the reservoir.
The devices of the present invention, on the other hand, are far simpler in design and operation. For a given device, the release rate of chemical can be varied widely by the simple expedient of varying the area or thickness of porous material, including porous fabric material, pores of which are filled with hydrogel, in contact with the reservoir. Thus, manipu-lation of only two parameters permits control of the amount of chemical released.
In the drawings which illustrate certain embodiments of this inven-,~., tlon: .
1 Figure l is a perspective7 cross-sectional vie~ of a device accord-:
20 ; ing to this invention;
` i~ Figure 2 is a schematic dra~ing of a delivery device of the type , . shown m Figure 1 with a perforated sleeve;
Figure 3 is an enlarged view of a porous wall of a device of this ~; invention;
.~
Figure 4 1S a perspectiVe, cross-sectional vie~ of a delivery ~ device shaped as a capsUlei ; Figure S is a schematIc, cross-sectional view of a slice of a ..:

;33~ :

device of this invention;
Figures 6, 7 and 8 are graphic representations of test data present-ed; Figure 6 showing a chart of weight gain for both control and treated groups and Figures 7 and 8 showing the parasite population for control and treated groups.
Figures 1-5 illustrate various examples of devices according to this invention. The fact that few examples are illustrated is not to be construed QS lîmiting the invention~ many variations and equivalents of which are possible. In Pigure 1, a perspective, cross-sectional view oE a device of this invention9 delivery device 10 is comprised of a cylindrical wall 11 in contact with a chemical-containing reservoir 12. ~all 11 i5 formed of a porous material, pores 14 of which contain a hydrogel ~not indicated) through which liquid from an aqueous liquid-containing environment diffuses into reservoir 12 and chemical from the reservoir diffuses into the environment through channels or pores within the hydrogel itself. Reservoir 12 is com-prised of a chemical 15 and, in a preferred embodiment of this invention9 of ;, a drug and a water-soluble excipient 16.
~ ' , :

i` '~; ' . .

' : :
~ B - 9a -. - . :, . ,. , ; . , :::: .; :::::: : ~ :, :: : : . . . : :: :.:::
: ;: . :~.: : ::, : , : .. .;. - . .,.: ; :.:. . .: . . .,. . - .; ~ . : :

3~

Ends 17 are non-permeable caps or closures.
FIG. 2, a schematic drawing of a device according .
to this invention, is a delivery device of the type shown in FIG. 1 but in which a perforated sleeve, e.g~
stainless steel, iron, plastic, 18 is inserted as a means o~ co~ltrolling the surface area of the hydrogel impregnatad porous wall 14 and, if metal, of increasing the weight of the device.
FIG. 3 presents an enlarged view of a porous wall 1011 of a device 10 o~ this invention, pores 14 of which contain a hydrogel 19, in contact with a chemical-containing reservoir 12 comprised of a chemical 1$ and .
a water-soluble liquid excipient I6.
FIG. 4 illustrates a delivery device shaped as a :~
capsule and having only one closure 1`/`~
FIG. 5 represents a further device 10 according to this invention wherein the porous material, pores ~ 14 of which contain a hydrogel tnot illustrated), comprises the end walls o~ the device I0. The cylindrical 20 wall 18 is comprised of a non-permeable, non-porous -:
material, in this instance, stainless steel which, in combination with the hydrogel impregnated end walls 14 enclose a reservoir 12 comprising a chemical 15 and an ~ excipient 16.

;~

:' - . ~:: . . - . . : ... .. ~

As illustrated above, the improved delivery devices or systems of this invention have a chemical, ;
including drug, containing reservoir comprising a chemical and, in a pre~erred form, che.mical and a water-soluble liquid excipient. The water-soluble liquid excipient serves several important functions, such as elimination of air ~rom khe reservoir, thus permitting greater n loading" in the manufactura of the devices and enhancement of convective mixing within the reservoir (which assures constant rate of chemical release). Additionally, said water-soluble liquid excipient serves a still further role in that, as chemical dissolves, there is no apparent volume change as the chemical goes from the solid or cryctalline ; 15 state to the solution state.
` Typical water-soluble liquid excipient~ include mono-ols and polyols, and ethers thereof, such as ethanol, ethylene glycol, propylene glycol, glycerol, polyethylene glycols, sorbitol, di-and triethylene glycol, di- and tri-propylene glycol, 1,2-dimethoxy-ethane, mono-Cl 4 alkyl ethers of ethylene and propylene ; glycolsi N,N-dimethylformamide, dimethylsulfoxide, and the like. The excipients must, of course, be compatible ~ with t'ne hydrogel.
-~ 25 of course, when the herein-described devices are ~; to b~ used for animals, including humans, or in aqueous liquid-containing en~ironments used by animals, e.g.
;
aquariums, fish ponds, animal and poultry wa~er supplies, ;
hydroponic systems, the water~soluble liquid excipient should be a physiologically acceptable substance.
The amount of water-soluble liquid excipient used per unit weight of drug depends upon the characteristics of the drug. In qeneral, sufficient excipient is used to ~ ,v permit formation of the drug-excipient combination into a compact mass, and i5 readily determined by simple expeximent.
Detergents, up to 20% by weight, based on the total weight of the reservoir (chemical, including drug, plus, if used, excipient and detergent) can be used in the reservoir to minimize possible clogging of the devices when in use. Representative detergents can be inorganic or organic in nature and include sodium and potassium hexametaphosphates and tripoly-- phosphates, sodium lauryl sulfate, sodium glyceryl monolauxyl sulate, dioctyl sodium sulfosuccinate, bis(1-methylamyl)sodium sulfosuccinate, polyoxyethylene sorbitan mono-oleate and other fatty acid esters, and others known to those skilled in the art. The amount o~ detergent when one is used is not critical and, in any instance, is kept to a minimum in order not to sacrifice loading of chemical into the reservoir. The optimal amount is determined by procedures described below.
In this specification and accompanying claims, the terms "reservoir", "chemical-containing res~rvoir'7, and "drug-containing reservoir~ are used interchangeably.
For convenience, since the preferred devices of this invention are those used for con-trolled release of drugs, the term "drug-containing reservoir" is the favored term.
The terms "porous materials", "porous membranes"
or "porous walls" as used herein include porous fabric materials. Representative types of such materials are described below. The porous materials used can be isotropic, i.e., of homogeneous pore structure throughout the crosslsection of the material, or can be anisotropic, i.e. r of non-homogeneous pore structure. They should, of course, be insoluble and non-reactive with the .
. .- ~. . . : . ,. :

.. , . , ~ .

:: . . ~

3~?~

environment and with the contents of the reservoir.
In general, porous materials having pore sizes of from about one micron to about 100 microns can be used in the controlled release devices of this invention.
5 Porous materials having pore structures which include continuous pores; that is, pores that efectively have an opening on both faces of the porous wall connected thereto are necessary. In order to facilitate transfer of the drug from the reservoir to the environment when the controlled release devices of this invention are used, the pores, or a portion of the pores, of the -~
porous material are filled with a hydrogel. The net `~ result of the combination of the porous material, pores of which are filled to a greater or lesser extent with a hydrogel, is provision of a device able to withstand clogging and physical destruction under -, conditions of normal use and, by maintaining its physical integrity, one which can be used in environments and situations under which previously known hydrogel devices would be destroyed and ineffective for controlled release of drugs over prolonged periods of time. The `~
herein described devices are of particular value for use in ruminants, especially in cattle and sheep. The ~-hydrogel-containing pores permit passage of liquid (water) through pores within the hydrogel itself by diffusion from the environment into which the controlled release device is placed when in use into the reservoir dissolving the drug. The drug then diffuses through liquid in pores of the hydrogel-containing pores of the porous material barrier at a rate dependent on the drug concentration in the solution in the reservoir, upon the resistance offered by ~he barrier; i.e..
liquid in the pores of the hydrogel, and the effective surface area of the porous portion of the wall.
`-., ~ . . . , . .. , -,., ... , ~ .

3~r~

As drug lea~es the device, a zone of depletion gradually forms giving rise to a moving drug/solution boundary. The diffusion of water into the device from the environment through pores within the hydrogel-containing pores of the wall into the reservoir gives ; rise to ~onvective mixing of the incoming aqueous phasa with the solukiGn in the reservoir o~ the device. The motive force for this mixing is the differen~e in densities of the two solution~ caused by their large concentration differences. A function of ` the water-soluble liquid excipient, as noted above, is to help maintain this large density difference, hence enhancing this critical mixing. The convective mixing results in a constant drug concentration within the reservoir which in turn provides controlled release of ~ the drug over a prolonged period of time, thus insuring ;; zero order release of drug as long as undissolved drug remains in the device. As drug is removed from the reservoir~ and aqueous liquid rom the environment dif~uses into the reservoir, the amount o dissolved drug within the reservoir varies continuously throughout the life span of the device; that is, throughout the prolonged time period of drug release. This mechanism of drug release allows any device geometry to be adopted, the;size and shape of the reservoir is not limited. This is in direct contrast to the prior art devices of U.S. 3,993,073 which depend upon, and are so fabricated as to achieve, a substantially constant amount of dissolved drug within the reservoir, diffusion of dissolved drug within the reservoir to æupply drug to the wall, and, therefore, have severe product limitations in terms of size and shape.
The term "hydrogel" as used herein refers to a gel having water content and is defined in Hackh's Chemical Dictionary, Fourth Edition, Grant, page 332, .

~33~

1969, as "a gel produced by the coagulation of a colloid with the inclusion of water". Repxesentative hydrogels which can be used to fill the pores of the porous material are the following: gelled cellulose triacetate, see U.S. 1,693,890 and 3,846,404; cellulose acetate hydrogels derived from cellulose acetate having an acetyl content of from 20% to 40~; polymeric hydroxyethyl methacrylate; cross bonded polyvinyl alcohol; agarose; polyacrylamide; cross-linked partially : 10 hydrolyzed polyvinylacetate, hydroxyethyl acrylate, diethylene ylycol monoacrylate, diethyleneglycol monometihacrylate, 2-hydroxypropylacrylate, 2-hydroxy-propyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, dipropylene glycol mono-I5 methylacrylate, vinylpyrrolidone, acrylamide, methacrylamide, N-propylacrylamide, N isopropylmethacrylamide, N-methylacrylamide, N-2-hydroxyethylmethacrylamide;
i polyurethane hydrogels comprising lightly cross-linked '" ! polymers of isocyanate terminated prepolymers which are the reaction product of a poly(alkyleneoxy)polyol with an organic diisocyanate lightly cross-linked with water or an organic polyamine, as described in U.S.
3,939,105; copolymers of ethylenically unsaturated monomers of hydroxyalkyl acrylates and methacryla~es, and of alkoxy alkylene glycol acrylates and methacrylates, as described in U.S. 4,038j264; polyether polyurethane resins produced by reaction of an organic diisocyanate with a mixture of at least two diols, one af which is a water-soluble polyalkylene glycol with molecular 30 weight of from 3,000 to 30,000 and the second of which is an oxyalkylated diphenol having from 2 to 20 oxyalkylene groups, and others as are known to those skilled in the art.

:. .- ,' :-. '. ' .~'; ,' ' . :

3Y`'~

.
Favored hydrogels for use in this invention are polyurethanes; polymeric hydroxy lower alkyl acxyla-tes or methacrylates, vinyl pyrrolidone, acrylamide~ N-lower alkyl acrylamides and methacrylamides, especially 5 those cross linked or copolymerized with a hydroxyalkyl acrylate or methacrylate to render the resulting i~ copolymer water insoluble. The pre~erred hydrogels ` are gelled cellulose triaceta~e, polymeric hydro~yethyl ` methacrylate and crossbonded polyvinyl alcohol.
Especially preferred is gelled cellulose triacetata which affords smooth and efficient operation of the controlled release devices described herein.
The water present in the pores of the hydrogel can be readily replaced by water-soluble liquid~ such as the water-soluble liguid excipients disclosed above. Other water-soluble liquids can also be used to replace the water, including alcohols having one to four carbon atoms. As a practical matter, in order to stabilize the devices of this invention, particularly when the hydrogel is gelled cellulose triacetate, the water of the hydrogel is replaced with a suitable water-soluble liguid which has a vapor pressure lower than that of water so the devices can be stored without loss of efficiency as a result of drying out of the hydrogel. When a water-soluble liquid excipient-drug combination is used in the reservoir, it is convenient to use the same liquid to replace the water from the hydrogel.
The hydrogels themselves are porous in the sense they contain areas or regions; i.e., channels or pores, filled with water or other liquid. It is, therefore, intended throughout this specification when referring to diffusion or transport of chemicals or drugs through walls, "pores of which contain a hydrogel", , .. . . . . . . . , ., . , ., ~, . . . . . . . .

3~ ~

or similar expression to mean that diffusion or transport, of the chemical or drug occurs via these regions rather than through the hydrogel per se. The hydrogel itself has liquid filled pores which serve as the `~ 5 dif~usion pathways and, in e~fect, is considered as being permeable to passag~ of environmental liquid and of chemical from the reservoir.
The porous wall in contact with the drug-containing reservoir can be any of a variety o materials. The porous material can completely surround the reservoir or can comprise only a portion of the wall surrounding the reservoir. Suitable porous materials include porous metals, porous ceramics, sintered palyethylene, `~
`~; sintered poly~vinyl chloride), sintered polypropylene, sintered polystyrene and sintered poly(tetrafluoroethylene), porous polymers made ~rom thermoplastic resins by phase separation techniques as described in Chem. En~.
News, December 11, 1978, p.23, and others known to those skilled in the art.

-1~ ,., Suitable porous fabrics are polypropylene and polyethylene, especially those fabrics of each type commonly referred to as "filter cloth", glass, poly(tetra-fluoroethylene), nylon, cotton, modacrylic fibers;
i.e., acrylic fibers composed of a long chain synthetic polymer containing 35-85% of acrylonitrile units;
acrylic fibers; i.e. synthetic polymers having a minimum of 85% acrylonitrile by wei~ht; polyesters;
i.e., a long chain synthetic polymer composed of at least 85% by weight of an es~ier of a dihydric alcohol and terephthalic acid; poly(vinyl acetate), poly(vinyl chloride), poly(vinyl acetate-co-vinyl chloride), poly(vinyl alcohol), poly(vinyl alcohol-co-vinyl acetate), poly(vinyl alkyl ethers); polymers of lS vlnylidene cyanide, vinylidene chloride, vinylidene fluoride; polyureas and others known to those skilled in the art [see Encyclopedia of Polymer Science and Technoloqy, Vol. 1, 342 (1964); Vol. 8, 812 (1968);
Vol. 9, 403 (lg68); Vol. 10, 347, 206 (196~); Vol. 6, 275 (1967); Vol. 11, 62, 445, and 506 (1969)i Vol. 14, 305, 575 ~1971), Interscience Publishers, New York].
~dditionally, metal screen~ or filter cloths including ; those fabricated from stainless steel, carbon steel, brass, copper, aluminum, various alloys such as nickel-copper, e~c., are suitable.
The particular fabric chosen must, of course, be compatible~with the hydrogel with which it is to be imprsgnated and with the end use of the device. Thus, for a device to be used as a bolus for administaring a drug to ruminants over a prolonged period of time, cotton would not be used as the fabric since it would undergo degradation by the ruminant. In a device to be used for controlled release of a chamical to an aqueous environment such as an aquarium or a reservoir, cotton can be used.

~- . : ' ,, . '' :

~ ~ . r ' ~:
Nylon would not be used as the fabric when gelled cellulose triacetate is to serve as the hydrogel since it would be degraded by the formic or acetic acid used during the impregnation process.
The hydrogel impregnated porous fabric materials must, o~ course, be of sufficient strength, durability and inertness to drug and the use environment so that the controlled release device produced there~rom retains its physical and chemical integrity throughout its entire life.
The porous material is impregnated wi-th an appropriate hydrogeI by procedures known to those ~killed in the artO A favored and relatively simple procedure fvr impreg~ating the porous material with gelled cellulose triacetate, a preiferred hydrogel, comprises forcing a solution of cellulose triacetate in formic acid or ; acetic acid into the pores of t~e porous material by immersing the material in the cellulose triacetate solution contained in a vessel which can be subjected ; 20 to a vacuum. Following impregnation, the cellulose triacetate 'lloaded" plastic is then coagulated by contact with and equilibration with a large volume ;
of water to produce the hydrogel impregnated ~aterial.
When the porous material is sintered polyethylene and the hydrogel is gelled cellulose triacetate, acetic acid is favored as solvent for the cellulose triacetate over formic acid since it wets the polyethylene better i~
than ~oes formic acid thus ~acilitating preparation of the hydrogel impregnated porous material.
When the hydrogel is derived Erom 2-hydroxyethyl methacrylate cross-linked witll ethylene glycol dimetha-crylate as described in U.S. 3,520,949, impregnation of the porous material is accomplished by filling its pores with the 2~hydroxyethyl methacrylate--ethylene glycol dimethacrylate mixture and then polymerizing the mixture within the pores by addition of a free radical catalyst such as t-butyl peroctoate. In like :: ;

.:. . .

manner, other hydrogels are impregnated into the porous wall material by such "in situ'l procedures from appropriate reactants. When the hydrogel is cross-linked polyvinyl alcohol, the pores are filled with polyvinyl alcohol tlO~ aqueous solution)--resorcinol (2-3~) mixture by procedures described herein and the : cross-linking is accomplished in si~u. Other cross-linking agents can, of course, be used as is known to those skilled in the art.
10For production of devices stable to storage prior to use, the hydrogel filled pores are freed of water by allowing them to equilibrate in a suitable water-; soluble liquid such as, for example~ the water-soluble liquid excipients enumerated above. It is, as noted, convenient to exchange the water in the hydrogel-filled pores of the porous wall material with the same water-soluble liquid used as excipient in the reservoir when.the reservoir comprises a chemical-excipient combination. If chemical alone comprises the reservoir of the herein described devices, the choice of water-soluble liquid used to replace water from the hydrogel in the hydrogel-filled pores of the porous wall is determined only by the end use of the device; i.e., whether a physiologically acceptable water-soluble liquid is required. Such a liguid is conveniently placed in the hydrogel at the time of preparing the porous wall, pores of which contain a hydrogel, prior to filling the reservoir of the device as is illustrated herein.

3J~ ~

The prior art devices most closely related to the devices of this invention; i.e. those of U.S.
patents 3,993,073 and 3,993,072 depend upon different permeability rates of drug through a medium contained in the pores of the porous wall relative to that of drug in the drug-carrier phase in the reservoir. In order to achieve the zero order release rate alleged for the devices described in said patents it is essential that the madium in the walls of the devices have a lower permeability to drug than does the drug carrier within the reservoir. The medium in the wall thus becomes the drug rate of release controlling portion of khe device.
Dissolved drug diffuses through the more permeable lS carrier to the inner wall fast enough such that the wall becomes the drug rate of release controlling portion of the device. This results in zero order release rates for some time until the receding drug boundary in the device becomes large enough to offset the difference in permeabilities between carrier and wall medium, then zero order rates are no longer achieved. Because of this, successful practical use of these devices is limited and they are not suitable for zero order delivery of large amounts of drugs in practical, useful dosage form shapes.

.. :

.' ' .. '.'' . :, :., " ' ~ :

The devices of the present invention, contrary to the prior art devices, when in use, have aqueous environmental medium in the wall medium as well as in the reservoir. Although permeability to -the drug is the same in the liquid in the wall and reservoir, zero order release rates are attained for large ~ractions of the total device lifetime. In addition, maintenance of æero ordex release does not depend upon diffusion in the reservoir carrier, thus there are no geometric or dose restrictions on these devices and for the first time large amounts of drugs can be delivered at zero order rates in embodiments of practical sizes and shapes.
For most e~ icient operation of the controlled release systems and devices of this invention, to reduce leaking and clogging, it is important that the p~rous material be impregnated with hydrogel as completely as possible. Devices of the same surface area can, by varying the characteristics of the membrane wall, especially its thickness, pore size, and porosity and by ~arying the size of the load in the reservoir, provide different dosage rates and release periods for a given drug.
As noted above r a preferred form o} device of this invention is that of a bolus for use in controlled release of a drug to ruminant animals, principally to cattle and sheep, for a prolonged period. The bolus is administered to the ruminant in such a manner, preferably by oral administration, that it remains in the rumeno-reticular sac for an extended period o~
time, during which period it continuously releases drug to the animal at a controlled release rate.
Said devices thus permit control (prophylactic and therapeutic) of various pharmacological and physiological conditions to which the animals are subject by simple ~ oral administration to the animals of said devices.
', h --'' In order that the bolus, once introduced into the rumeno-reticular sac of cattle, remain there for an extended period, it is necessary that the bolus have a density of at least 2.0 g./ml. In practice, the density can range from as low as 2.0 to as high as 7, or even greater. Density, of course, is the most significant factor afecting retention of the bolus in the rumeno-reticular sac. Overall size of the bolus is a function of the needed dose to be given and size that can be practically administered.
Based on this, once the desired size is d~termined, additional weight can be added to achieve desired average density. If possible, it is desirable to use maximum allowable size since larger boluses of a given density are better retained than those of lower density. However, when the average density of the bolus increases to a value greater than about 5O0~ an increase in size of the bolus does not significantly improve the retention factor. The favored average density range for the bolus is from about 2.5 to about 5 g/ml.
The size of the bolus, of course, depends upon the animal to be treated therewith. For ruminants such as sheep and goats, the bolus size and weight

2~ will be less than that required for cattle. The maximum size of bolus for use in any animal is determined by the practical difficulties of administering such an object to the animal.
For administration to sheep, the minimum weight of bolus having a density of 4 which will be retained is about 1 gram. The size of a bolus will vary according to the density of the bolus. For administration to cattle, the minimum weight of bolus having an : ~ ,: - , - :: , .,, - " ~ - , . :
,. : :: . . - . .. - : .
, ~ .,: :, , . ; ,.-, , . :,;, : , .
-, ,, . ., ,: . :.:;: :: :: : .. :
: . . ~... : ,: . , ... : .

3;~

average density of 4 is about 5 grams. Again, as noted above, the upper limits of size are determined by the practical convenience of dosing the animal in question and by the minimum average density of the bolus. For example, a bolus of about 7.5 centimeters in length by 2.S centimeters in diameter and having a density of 2.2, will have a weight on the order of about 90 grams.
The density of boluses comprising only the elements enumerated above i5 generally below the lower level set ~orth above. It/ therefore, becomes necessary to increase the average density of the bolus b~ incorporation of a suitable high density material such as a metal (iron powder, iron shot, steel shot) or othex densifierst minerals such as CaSO4, to increase the density to the desired value.
Alternatively, the average density can be increased in convenient fashion by incorporating into the bolus, as an inner sleeve, a high density, perforated material, e.g. a metal (such as stainless steel, steel, especially low carbon steel, or iron~ which, in turn, is surrounded by the hydxogel impregnated porous membrane. The perforations in the sleeve should be sufficiently large so as to permit free passage of drug, and llquid from the environment, through the hydrogel impregnated porous membrane.
The principal functions of such a sleeve are to increase the average density of the bolus to a value such that the bolus is retained in the rumeno-reticular sac and to regulate the surface area of the hydrogel impregnated porous material in con~act with the drug-containing reservoir. In addition, such a sleeve, although not necessary, also improves the physical stability of the bolus, ensuring that its physical form is substantially retained under conditions of 3~
-25~

use. A still further, and preferred, alternative comprises a bolus comprising a metal, steel or iron, cylinder, one or both ends of which are capped with a porous membrane, pores of which are impregnated with a hydrogel. Boluses of this type are pre~erred because of their simplicity and economy of manufacture and the ease with which their density can be adjusted. A
low carbon st~el in highly favored as construction material for the cylinder~ Other alternatives will ;~
suggest themselves to the man skilled in the art.
The controlled release devices of this invention can be used for a variety of purposes and situations wherein controlled release of a drug or other chemical is desirable. They can be used for administering drugs and providing chemicals at sites near to or remote from the point of application of the device.
They can be positioned by appropriate means in suitable locations within the animal body where they are in contact with body fluids, e.g., the stomach of farm animals, especially the rumeno-reticular sac of ruminants. Also included within the controlled release devices of this invention are those for use as depot implants for the purpose of administering a drug at a controlled rate to the host. The implants differ from devices of this invention for other purposes only in their~shape which is, of course, adapted for implantation. Other uses include sublingual or buccal tablets, pessaries, suppositories, banda~es and skin patches. Still other uses for the con-trolled release systems and devices of this inventionoccur in agriculture for administration of fertilizers and pesticides, in pisciculture including aquariums and fish ponds; in drainage ditches, canals and tanks as for control of algae; and in water supplies especially . . , :- , ~ . , ; :, ;:.: ~; :,;, . ~' ':.: - : :

3~

for animals and poultry in need of drugs for thera- ~i peutic or prophylactic treatment.
The criterion for suitable substances, drugs or chemicals, for use in the devices of this invention is that they be sufficiently soluble in water to achieve a rate of release of said drug or chemical in the use environment which will produce the desired result. For this reason, drugs and chemicals which are acids or bases, are desirably u~ed in the form of their physiologically or pharmacologically acceptable salts. The rate of release of drug, or chemical, from the herein-described devices is dependent upon several factors such as the thickness of the wall, available surface area, effective pore diameter, porosity of the wall, the nature o~ the hydrogel, the concentration of the substance in the reservoir, and the solubility thereof in the environmental liquid.
The suitability of a given substance is determined as is described below.
~0 Representative of the drugs which can be used in the devices described herein are the following:
anthelmintics, including salts of morantel~ pyrantel, oxantel,~piperazine, diethylcarbamazine, levamisole, ~ tetramisole, and hygromycin B; antibacterials including ; ~ 25 salts of tetracyclines, such as 5-oxytetracycline, ~ chloro~etracycline, doxycycline and Mannich bases , thereof; penicillins such as ampicillin, penicillin G; aminoglycosides such as neomycin, streptomycin, apramycin, bacitracin as its zinc or methylene - 30 disalicylic acid derivative; macrolides such as erythromycin, oleandomycin and tylosin; antibacterial growth promotants such as salts of avoparicin, ; polymyxln,~lincomycin, bambermycin and efrotomycin;

3~

hormonal growth promotants including diethylstilbes~rol, zearalanol; antiparasitic agents such as amprolium;
nutritional agents such as soluble salts of magnesium, selenium, copper, and vitamins such as thiamine hydrochloride; sulfa drugs such as sulfametha2ine, molluscicides such as N-tritylmorphine; and bloat prevention agents s~ch as alcohol ethoxylates and poly(oxyethylene~-poly(oxypropylene)-poly(oxyethylene)-polymers, e.g. poloxalene.
As noted above, the drug~containing reservoir, in a preferred form of this invention, comprises a drug and a water-soluble excipient. Devices so constructed have the advantage of offering a greater amount of drug pex device and of extending the useful life of the device. However, the reservoir can contain only the chosen drug~
The devices of this invention are especially valuable as long-acting boluses for the control (therapeutic and prophylactic) of helminth infections in runimants, cattle in particular. Protection of range animals becomes relatively convenient. In temperate climates, the low, early spring population of pasture larvae, the residue of the previous season's contamination, is multiplied by cycling through animals grazing thereon to produce, in the summer~ a sharp increase in pasture infectivity. This condition gi~es rise, during the summer grazing season, to clinical parasitism and performance depression of ; animals grazing on said pasture.

: : '.; -, . ,. , : , : , ,. :, : . -: : : : .: ;, ,:: -- . : : .: .: :

:: , :: :: . ::: ~, :; -: ,., ,,: : . : .:: ::: ::

:, - : . .:::: : :. : , -::,: :. , ,. : , :; : . . ~ ~ . : . :

The continuous and controlled release of anthelmintic agent; e.g., morantel in the rumeno-reticular sac of grazing animals early in the season when pasture contamination is low, suppresses helminth egg and S subsequent larval output and thus breaks the above-mentioned cycle and keeps the pasture and animal worm burden at a low level. Parasitic infections of ruminants grazing on the same pasture land during the summer season is thus minimized. This method o~
helminth control is especially attractiYe and valuable for calves since they are highly susseptible to helminths when first placed on past~re. Consistent use of boluses reduces the reservoir of infective helminth forms at a given location. Utilization of anthelmintic-containing boluses of this invention in this manner prevents, ox at least minimizes, the seasonal increase in pasture larvae which causes parasitic gastroenteritis and performance depression in grazing animal 5 later in the season. In this mode of control, the period of drug release is that of the spring multiplication phase, not the period of heavy pasture contamination, larval challenge and worm infestation which produces clinical disease and performance depression. It is for this reason that this mode of u~age is called "indirect control". To put it another way, the grazing of ruminants having in theIr rumeno-reticular sac one or more of the herein-described devices, which device permits controlled and continuous release of anthelmintic agent, e.g.

.

:

3~;9 ~9 morantel, to said sac, on pasture land early in the season; i.e., when larval contamination is at or near a minimum level, permits minimization of the usual seasonal increase in larval contamination of the pasture land and serves to protect animals grazing thereon throughout the entire grazing season.
For "indirect control" of halminths, the devices of this invention, preferably in the form of a bolus, are administered ~o ruminants at a time in the epidemiological cycle of said helminths when pasture contamination by said helminths, their eggs and/or larval stages~ is at or near a minimum level~ In temperate zones, this time corresponds to spring turn `~
out, that is, the first placing (turning out) of the calves out to pasture. For maximum efficiency, the bolus is administered to the calves about two to seven days prior to turning out. In non-temperate zones of the world, e.gO semi-tropical and tropical areas, the period of lowest pasture infectivity normally occurs prior to the rainy season. Administration of the bolus to ruminants in such areas is desirably carried out within two to fourteen days before the start of the rainy season. ~owever, because of the unpredictability as regards the rainy season, helminth control in the non-temperate zones is best achieved by the "direct control" method.
The hereln-described ~oluses also eliminate established helminth infections Erom ruminants and prevent establishment of worm infections during the summer period of heavy challenge. This mode of use is called "direct control". The direct method of control pro~ects ruminants only during the period of release of the anthelmintic agent. The indirect method of helminth control protects ruminants grazing , ~ '`Q

: . : - . .-: , ;~ ........... , :. : , -, , " ' ' ' '' " ~' ` ' ; . i , ~ ~

on a given pas~ure for the entire season because it achieves an overall significant reduction in pasture contamination. ~s noted, the devices described herein provide continuous release, at a controlled rate, of drugs including anthelmintics. Particularly useful ~or such purposes are water-soluble salts of (E)-1,4~5,6-~etrahydro-1-methyl-2-[2-~3-methyl-2 thienyl~ethenyl]pyrimidine (morantel), (E)-1,4,5 t 6-tetrahydro~l-methyl-2-[2-(2-thienyl)ethenyl]pyrimidine (pyrant~l) and (+)-2,3,5,6-tetrahydro-6-phenyl-imidazo~2,1-b]thiazole (tetramisole) and levamisole, the L~ form thereofO Represantative of pre~erred water-soluble salts of pyrantel and morantel are the tartrate and citrate salts; and of tetramisole and levamisole, the hydrochloride salts.
The boluses of this invention are orally administered to animals by, for example, a balling gun. For use in calves, the desirable average release rate of morantel (calculated as base) for indirect control of helminths is on the order of 60-200 mg. (of morantel base) per day for a period of about 60 days, which covers the normal maximum survival time of the spring population of larvae. Longer release periods of from 60-120 days are desirable in the direc~ control mode of use since the period of exposure to heavy pasture contamination normally extents from mid-summer through autu~n. Release rates of about 60-150 mg. (calculated as morantel base) per day effectively control helminth infections over such release periods. For dosing larger animals, more than one bolus can be adminis~ered.
For indirect control of helminths using salts of pyrantel or levamisole, the desirable average release rates of each (calculated as frea base) are on the 3~

order of 100~400 mg. and 100-500 mg. per day, respectively for about a 60 day period. For direct control, release rates of about 100-300 mg. (as free base) of pyrantel and of about 100-400 mg. (as free base) of levamisole per day ef~ectively control helminth infections over the 60-120 day period of heaviest challenges.
Continuous, low-level administration of morantel by use of the herein described devices fox helmin~h control gives rise to an ef~icacy profile surprisingly different from and advantageous to that observed on conven~ional therapeutic use of morantel and which could not be predicted. For example, maintenance of a protracted level of ~orantel tartrate or citrate (or other salt) in the gastrointestinal tract of ruminants is effective in preventing lung worm infections in said animals during the period of drug releaseO
Further, while cat~le or sheep grazing on contaminated pasture are subject to immediate reinfection by intestinal nematodes after conventional therapeutic dosing, animals receiving the bolus are essentially freed of established infection and protected from reinfection over a period of 60 days or longer.
The use of the bolus for control of pasture con-tamination, i.e. the indirect control method, is aunique, practical and unprecedented method of helminth control which protects ruminants, and in particular grazing ruminants, treated via this mode for the entire grazing season and affords performance benefits superior to prior art control methods. The increase in daily weight gain over untreated controls over the grazing season is substantially greater than that obtained after conventional therapy.

.

The rate of release of drug, or other chemical, passing from the dxug-containing reservoir through the walls of controlled release devices of this invention, and the effectiveness of a given drug and/or water-soluble excipient and/or detergent combination in said devices, can readily be determined by those skilled in the art, for example, by transmission methods, or by sorption-desorption methods. A technique w~ich can conveniently be used to select suitable porous materials and hydrogels comprises using the chosen porous ~aterial, pores of which are filled with the selected hydrogel, as a barrier hetween a rapidly stirred saturated solution oE a drug or other chemical, the controlled release of which is desired, and a rapidly stirred solvent bath, the composition of which stimulates the aqueous liquid containlng environment in which the controlled release device is to be used. The temperature of each solution is maintained at a constant value, preferably at a value approximating the average temperature of the environment in which said device will be used. Samples are withdrawn at predetermined intervals from the solvent bath and analyzed for drug concentration. Standard procedures ~or determining the permeability of a drug, or o~her chemical substance, through the porous material~ pores of which are filled with hydrogel, can also be determined by standard procedures as are described in Encyclopedia of Pol~ Science and ~ , Vols, 5 and 9, pages 65-82 and 794-807 1968, respectively; and references cite~ therein; and in Chemical Enqineers andbook, pages 17-45, 1963, published by NcGraw-Hill, Inc.

- ~ :. .: .: : .:: : ~ ,:

3;~
-33~

A procedure of especial value in determining the release rate for devices of this invention and the relative merits of a given excipient or detergent for use in a given device, particularly wherein the drug is morantel, in summary, is as follows. The procedure~
an in vitro procedure, is based upon the release of a water-~oluble salt of morantel, for example the tartrate, rom a device made in accordance with this invention as a function of time. A morantel tartrate containing device of this invention is placed into a one-liter conical flask which is protected from light because of the photosensitivity of morantel tartrate, 500 ml. of p~ ~ phosphate buffer added, and the temperature of the flask and contents adjusted to and maintained at 37C~ The flask containing the device is shaken at about 70 excursions (7.62 cm.) per minute and 5 ml. samples are withdrawn periodically.
The volume of the withdrawn sample is replaced with an equivalent volume of fresh pH 7 phosphate buffer and shaking of the flask continued. The concentration of morantel in the samples is determined spactro-photometrically by measuring the absorbance of the sample at 31~ nm when read against fresh pH 7 phosphate buffer. The sampling process is repeated until 5 grams of morantel tartrate have been released at which point the device is transferred to another flask containing 500 ml. of fresh pH 7 phosphate buffer and the process continued as before.
_ vivo release of morantel tartrate ~rom devices according to this invention is determined by administering the devices to, for example, normal steers or steers with rumen fistula and, after a certain period of time such as 30, 60, 90 or 120 daysj removing the devices via the fistula or sacrificing the animals and recovering the devices to determine the residual ~, ,: . . . . . . .
: , ,: -,, ~ , - ~ , : . . : , ,,:- :: ,: . , , -morantel tartrate within the device. Tests of this sort have shown that the rate of release of morantel tartrate in vitro is approximately four times that of the in vlvo release rate.
The following e~amples are merely illustrative of the present invention. They are not to be conskrued as limiting the scope of this invention, many variations of which are possible as those skilled in the art will recognize.

3~

-3~-A bolus comprising sintered poly(ethylene), pores of which are filled with gelled cellulose triacetate, and a reservoir containing morantel kartrate admixed with polyethylene glycol 400 and sodium hexameta-phosphate, and having a perforated stainless steel sleeve was prepared as follows~
One end (referred to as End 1) of a sintered poly(ethylene) tube having an average pore size of 10 microns, an outside diameter of 25.4 mm. (1 inch), an inside diameter of 22.225 mm. (7/8 inch) and a length of 7.938 cm. (3 1~8 inches) was dipped into a 10 solution of cellulose acekate butyrate in methylene chloride to a depth of 4.763 mm. ~3/16 inch). It was then dried in air and the other end (rearred to as End 2) of the tube dipped into the cellulose acetate butyrate solution to a depth of 9.525 mm. (3/8 inch) and dried. This step was repeated. ~nd 1 was again dipped into the cellulose acetate butyrate solution for 30 seconds, allowed to dry in air for 60 seconds, and a 22~225 mm. diameter (7/8 inch) cellulose acetate butyrate disc (3.175 mm., 1/8 inch thick) inserted into the end of the tube so as to be flush with said end. The cellulose ace-tate butyrate disc was floated on methylene chloride for 60 seconds prior to its insertion into End 1 o the tube. The tube was then rolled along the bench, applying finger pressure to the end thereof containing the disc, so as to insure complete binding of disc and tube. A one-hole #3 rubber stopper fitted with a glass tube of sufficient length to protrude through the one~hole rubber stopper of a vacuum flask when the tube rests upon the bottom of the flask was inserted into the tube. The protruding end of khe tube was khen connected to a flask containing . .

a 6~ solution of cellulose triacetate in formic acid and a vacuum of about lS0 mm. of mercury applied.
When the cellulose triacetate solution covered the exterior walls of the tube which had not been dipped into cellulose acetate bu~yrate, the tube was removed from the vacuum flask and the bulk of the cellulose triacetate wiped off. The ~ube was then inverted in order to drain the cellulose triacetate from the interior of the tube. The exterior and interior open ends of the tube were wiped clean with a towel. The tube was then immersed in and allowed to equilibrate in distilled water overnight~ It was then removed from the water, the exterior dried with a towel and excess water shaken from the interior of the tub0.
lS The steps of impregnating the pores of the tube with cellulose triacetate and equilibrating it in distilled water were repeated. It was then equilibrated in running water for 4 hours~
The tube was tested at this point for leaks by connecting it to a nitrogen source, immersing the tube in water and applying a pressure of 0.28 kg. per square centimeter (4 psi) o~ ni rogen for 10 seconds.
If leaks exist, the steps of impregnation and equilibration in water are repeated.
The tube was then equilibrated in polyethylene glycol 400 overnight, removed from the polyethylene glycol 400 and allowed to drain in an inverted position - . : . . :: :, , 3~

for 4 hours. Excess polyethylene glycol 400 was wiped from the exterior of the tube with a towel and a per-forated stainless steel tube 22.225 mm (7/8 inch) outside diameter, 18.923 mm. (0.745 inch) inside dia-meter, 6.985 cm. (2 3/4 inches) in length and having 16 evenly spaced circular holes l7.114 mm., 9/32 inch in dia~eterl inserted into the tube until it was flush against the sealed end. The cellulose triacetate shavings which resulted from insertion of the snug-fitting sleeve into the tu~e were removed. A cellulose acetate butyrate disc (3.175 mm.) was then inserted into the open end of the tube flush with the stainless steel sleeve and the tube trimmed so that the end of the tube was flush with the disc. The disc was removed and the tube filled with a homogeneous mixture comprising 63.31% morantel tartrate, 26.61% poly-ethylene glycol 400 and 10.08~ sodium hexametaphos-phate flush with the end of the stainless steel sleeve. Th~ open end of the tube was filled with a 10% cellulose acetate butyrate solution which was then immediately poured off and the open end of the tube -~
dipped into the cellulose acetate butyrate solution to a depth of 6.35 mm. (1/4 inch) and allowed to dry. A
disc of cellulose acetate butyrate (floated on methylene chloride for 60 seconds immediately prior to use) was then forced into the open end of the tube, sufficient pressure being applied to force the disc against the stainlees ~teel sleeve. The tube was then rolled along the benchtop, applying sufficient finger pressure to insure complete binding between the disc and the tube.
The tube was allowed to dry for one hour after which each end of the tube was dipped into 10~ cellulose acetate butyrate to a depth of 6.35 mm. (1/4 inch) and allowed to dry. The weight of the bolus was approxi-mately 90 g., of which 24.8 g. was drug mixture. Its :
, '~

~- . ...

density was 2.2 g./ml. This device released about 250 mg. per day of morantel tartrate ln vivo in cattle for about 60 days. :

Three devices prepared according to Example 1 tested in vitro by the procedure described herein : provided an approxima~ely constant rate of release during the period of 4-17 days with a mean release ~; rate for all three boluses of 0.927 g. of morantel 10 tartrate per day.
A~cumulated ~. Morantel Tartrate Days _n VitroBolus 1 BQ1US 2 Bolu~ 3 1 0.357 0.295 0.2~4 ` 2 0.804 0.723 0.66 : 15 4 1.63 1.63 1.38 S 2.12 2.24 1.86 6 2.61 2.96 2.4 8 4.05 6.31 3.7 11 6.55 9.0 5.76 20 13 8.24 11.34 7.67 .11.38 13.4 9.74 19 14.52 16.2 13.2 : 25 17.99 17.4 15.4 ~ 29 17.13 17.3 15.9 :~ ~

~ ' .

~'~

.:

: .~
., :

~ 3 3--~ --In vivo tests of 3 other boluses prepared according to Example 1 and placed in the rumeno-reticular sac of ca~tle showed a release rate of 0.224 g. of morantel tartrate per day when recovered at the end of 30 days.
This is an ln vitro/in vivo ratio of 4~
.

In vitro tests of two other boluses prepared according to Example 1 and ~ested as described herein provided a mean release rate over the constant rate period, 0-14 days, of 0.96 g. morantel tartrate per day.
~- Accumulated g. Morantel Tartrate Bolus 4 Bolus 5 _. , ; 1 Q.51 O.S9 2 1.5 2.16 3 2~ 2.2

4.g 5.4 -: 6 5~1 5.9 7 6.5 6.1 20 10 9.7 9.7 12 11.0 11.7 14 13.5 12.6 17 I4.8 13.6 19 16.4 14.6 25 21 17.1 14.7 24 16.8 14.7 26 16.9 14~8 ., . . , - " .. , . . . ~ .

~3~
~40-In vivo tests with identical boluses placed in the rumeno-reticular sac of cattle for periods of 30-60 days provided the following results.
Days Mean g. Morantel Bolus No. In VivoTartrate Per Day 6 30 0.222 7 30 0.228 8 45 0.238 9 45 0.335 49 0.174 ll 60 0.198 ;
12 60 0.178 The overall mean in 5VlVO rate is 0.224 g. per day and the in vitro/in v~vo ratio is approximately 4 EXA~PI,E 4 ~ oluses were prepared from stainless steel tubes having the following dimensions: 22.225 mm.O.D. (7/8 inch), 21.336 mm. I.D. (wall thickness = 0.8B9 mm. -0.035 inch) and 3 cm. long. The ends of the tubes were threaded (0.5 mm. at each end) to receive a collar which serves to hold a hydrogel impregnated porous fabric disc in place. The discs (22~225 mm.
O~D. and 37175 mm., 118 inch thickj, polypropylene filter cloth having pores of 50 ~icron average size and impregnated with gelled cellulose triacetate~ were ~repared ~y immersing them in a 6% solution of cellulose triacetate in ~ormic acid contained in a vessel that could be subjected to a vacuum of 25 mm. mercury or less. The ~lask and contents were held under vacuum for about lO minutes, the discs removed, and wiped j free of excess cellulo~e triacetate solution. They wexe then immersed in and allowed to equilibrate in distilled water overnight. The discs were then removed from the water, dried with a towel and then equilibrated with polyethylene glycol 400 overnight. The discs 't were removed and wiped with a towel.
J

.''.-' '~

Impregnated discs were mounted on one end of each of the tubes by sandwiching them between two washers, 0.254 mm. (0.01 inch) thick and of the same diameters as the steel tube. The washer adjacent to the steel tube was of cellulose acetate butyrate and the other of dental dam gum rubber. The ends were then capped with stainless steel collars having an opening 21.336 mm. in diameter. The tubes were then ~illed with morantel tartrate ~63.3%), polyethylene glycol 400 10 (26.6%), sodium hexametaphosphate (10.1~) and the other end of each tube sealed as described above.
The boluses contained 21.4 g. of morantel tartra-te, weighed 97 g. and had a mean density of 3.30 g./ml.
The boluses were administered to steers with rumen fistula hy use of a balling gun and were removed via the fistule at in-tervals of 30, 45, 60, 75 and 90 days, to determine the amount of drug remaining in the bolus, from which the mean daily release rate of morantel tartrate was calculated.
20Bolus Day~s in Steer Release Rate (m~./d~) 3 ~5 82 9 9O 67 r The mean release rate was 85 mg./day with a standard devia-tion o~ 25 mg.
In each steer significant reduction in fecal parasite egg count was observed.
' ' `''' Foux boluses comprising sintered poly(ethylene), (mean pore size of 10 ~) pores of which are filled with gelled cellulose triacetate, and having stainless steel sleeves within only a portion of the overall length of the boluses ~so as to leave a segme.nt of bolus free of sleeve), and resPrvoirs containing morantel citrate (63.3~), admixed with polyethylene glycol 400 t26.6%) and sodium hexametaphosphate (10.1%) were prepared according to the procedure of Example l.
However, in place of the perforated stainless steel sleeve used therein, unperforated sleeves of 5.08 cm., 4.445 cm., 30175 cm. and 1.905 cm., respectively were used. The walls of the sleeves wexe 0.165 cm. thick.
Drug mix was then loaded into each bolus so as to provide a drug-band width of 6.35, 12.70, 25.4 and 38.1 mm., respectively above the sleeves. A stainless stsel plug, 12.7 mm. thick and 22.225 mm. diameter, was inserted into each of the boluses ahove the drug mixtuxe. The ends of the boluses bearing the steel plug were trimmed so as to permit insertion of a cellulose acetate butyrate disc on top of the plugs and 1ush with the ends of the boluses. The total weight of the individual holuses was 120.0, 115.4, 106.2 and 97.0 g., respectively. The weight of drug mixture rangas from about 25.5 g. to 27.4 g. per bolus. The densities of the boluses were 3.1, 2.98.
2.75 and 2.51 g./ml., respectively.
r ~J-' ' 3~

In vitro tests of the release rate of morantel citrate by the boluses of Example 5 showed each of them affords constant release of drug over a period of : 5 3-21 days. The lighter of the four boluses of Example

5 tthat having the l.905 cm. sleeve) had a mean release rate of 774.8 mgO morantel citrate per day over th~ 3-21 day period of constant release.

Fourteen boluses prepared according to Example l when tested ln vivo in cattle exhibited a mean release rate of morantel tartrate of 238 mg. per day over a 60 day period. The standard deviation was 67 mg. (2a%).

Boluses are prepared according to the procedure o~ Example l but using, in place of the drug mixture of said Example, the following chemicals in the reservoir:
pyrantel tartrate (63~3%), polyethylene glycol 400 (26.6%), sodium hexametaphosphate (lO.l~); morantel tartrate ~lO0%); pyrantel hydrochloride (100%); tetramisole hydrochloride (lO0~; levamisole hydrochloride (85.0%), - glycerol (15.0%); diethylcarbamazine citrate (lO0~);
hydromycin B (100%); doxycycline hemihydrate hemialcoholate (lO0~); bacitracin methylenedisalicyclic acid 166.0~), sorbitol (22.0%), sodium lauryl sulfate (12.0%);
ampicillin, sodium salt (63.5%), polyethylene glycol (26.5%), sodium hexametaphosphate (10.0%); sodium `
penicillin G (67.3~), N,N-dimethylformamide (22.2~), sodium glyceryl monolauryl sulfate (10.5%); neomycin - 30 complex (68.5%), dimethylsulfoxide ~22~5%~, sodium .' i . :, :: :

` , .. .. . .. .

lauryl sulfate (10.0%); streptomycin -trihydrochloride (100~); oleandomycin hydrochloride (80%)/ polyethylene glycol 400 (20~); tylosin hydrochloride (100%), polymyxin nydrochloride t79.5%), glycerol (15.0%), sodium lauryl sulfate (5.5%); lincomycin hydrochloride hemihydrate (100~)~ magnesium acetate tetrahydrate (77~), sorbitol ~15~, dioctyl disodium sulEosuccinate (8%).

A bolus comprising sintered poly(ethylene), pores (average siæe 100 ~ of which are filled with a cross-linked polyvinyl alcohol hydrogel, and a reservoir containing morantel citrate (63.3~-), polyethylene glycol 400 (26.6%) and sodium hexametaphosphate (10.1 and having a perfora~ed stainless steel sleeve is prepared accordiny to the procedure of Example 1. In place of cellulose triacetate-formic acid solution, - however, the hydrogel solution comprises an aqueous : solution of 10% polyvinyl alcohol (88~ hydrolyzed polyvinyl acetate) containing 3% resorcinol. The tube, following vacuum treatment to fill the pores, is :~ wiped clean and held at 0C. to -10C. for 5 hours to gel the polymer. Equilibration of the tube in water : is unnecessary. The tube is then tested for leaks, equilibrated in polyethylene glycol 400, filled and sealed as in Example 1.
: In vitro testing shows it affords controlled release of morantel citrate.
,'~

. ~
.~.,'~

~ , ,; ~, :

.. , , . . - :: : i:

33~3 The procedure of Example 1 is repeated but using sintered poly(ethylene) tubes one-half as long and one-hal~ the diameter o~ those used in Example 1. The resulting boluses are designed for use in sheep and afford controlled rel`ease of anthelmintic agent over an extended period of time in vivo~

The procedures o~ Examples 1 and 5 are repeated but using the following microporous materials in place of sintered poly~ethylene): ~orous ceramic, porous steel, sintered poly~pro~ylene); sintered poly(tetra-fluoroethylene); sintered poly(vinyl chloride)7 sintered poly~tyrene (avertge pore size of each material is 100 lS microns).
Each of the boluses thus produced provides controlled release of chemical over a prolonged period of time when tested in vitro.

Boluses are prepared from stainless steel tubes ~
having the following dimensions. 22.225 mm.O.D. (7/8 ,r . inch~, 21.336 mm~ I.D. (wall thickness = 0.889 mm. -~ 0.035 inch) and le.ngth 7.62 cm. ~3 inches). The ends ; of the tubes are threaded (0.5 mm. at each end) to receive a collar which serves to hold a porous, hydrogel ` impregnated disc in place. The discs (22.225 mm. O.D.
:;~ and 3.175 mm. thick), sintered polyethylene impregnated `: with gelled cellulose triacetate, are prepared by immersing them in a 6~ solution o~ cellulose triacetate ~:. 30 in acetic acid contained in a vessel that can be ~ subjected to a vacuum of 25 mm. mercury or less. The .: flask and contents are held under vacuum fo.r about 10 ~ minutes, the discs removed, and wiped free of excess ~3~

cellulose ~riacetate solu~ion. ~hey are ~hen immersed in and allowed to equilibrate in distilled water overnight. The discs are then removed from the water, dried with a towel and then equilibrated with polyethylene glycol 400 overnight, The discs are removed and wiped with a towel.
Impregnated discs are mounted on one end of each of the tubes by sandwiching them between two washers, 0.254 mmO (0.01 inch3 thick and of the same diameters as the steel tube. ~he washer adjacent to the steel tube is of cellulose acetate butyrate and the other of dental dam gum rubber. The ends are then capped with stainless steel collars having an opening 21.336 mm.
in diameter. The tubes are then filled with the desired chemicals and the o-ther end o each tube sealed as described aboveO
Tubes (boluses) having the following chemicals in the reservoir are thus prepared: morantel citrate ~63.3~), polyethylene glycol 400 (26.6%), sodium hexame-taphosphate (10.1~); oxyte-tracycline hydrochloride ` tlOO~); pyrantel citrate (88~), glycerol (12%); pyrantel ; tartrate (63.3%), polyethylene glycol 400 (26.6~), sodium lauryl sul~ate (iO.l~); tetramisole hydrochloride (100%); poloxalene (100%); erythromycin hydrochloride ~`, 25 (100~); thiamine hydrochloride (100~3.

:~ ' ;
.''~ ~' , ' `~

:, :

.,' . -,, ~

. . ! ., , ~ .

.~ . . 'i' ' `' 3:~ ~

-~7-EXAMPI,E 13 The procedure of Example 1 was repeated with the exception that the bolus was filled with morantel tartxate rather than with the morantel tartrate-polyethylene glycol 400-sodium hexametaphosphate mixture of said example. The bolus weighed 84.0 g., 18.6 g. of which was morantel tartrate.
The bolus, when tested in vitro according to the ; procedure describ~d herein, provided a controlled and nearly constant rate of release of morantel tartrate during the test period of 8-20 days with a mean release rate of 1.36 g. per day.
Accumulated g.
D~s in Vitro Morantel Tartra-te ` 15 1.7 -~
` 5-7 1.03 ; 8.7 2.74 .. ..
12.7 7.63 ;
15.7 12.3 20 19.7 17.5 ; 23.7 18.3 ; 26.7 1~.6 ~ .
;` A low carbon steel tube having the following dimensions:~ Length - 8.77 cm., ID - 2.16 cm., o . D . -2.54 cm., and a groove 0.3 cm. deep and 0.6 cm. wide `~ located O.l cm. from each end thereof to accept an , ~ , : - "
~ .
~` ;.

3~
~48-aluminum crimp, and which completely encircles the tube, was sealed at one end with an ultra high ~olecular weight ~average = 2 million to 4 million, available from Glasrock, Porex Division, Fairburn, GA.) sintered polyethylene disc, average pore size 10 microns, impregnated with gelled cellulose triaceta~e as described in Example 15. The disc, 2.54 cm. in diameter and 0.16 cm. thick, was sealed to the tube with an aluminum crimp. The tube was then inverted and filled with a homogenous mixture comprising 54.4% morantel tartrate, 35.6~ polyethylene glycol 400 and 10% sodium hexa-metaphosphate~ The disc/crimp sealing process was repeated to provide the final bolus. The total weight of the bolus was 145.1 ~., of which 41.4 g. was drug mixture. Its density was 2.8 g./ml.
The aluminum crimps at each end of the tube possessed an open center area of 3.25 cm.2 resulting in a total area of 6~5 cm.2 available for drug delivery.
The bolus affords controlled release of morantel ~;~ 20 tartrate to cattle over a period of approximately 90 ' days.

An aluminum cylinder, 6 cm. long with an outside diameter of 2.1 cm. and a wall thickness of 0.1 cm., and grooved at the open end to accept an aluminum crimp saal was filled with a formulation comprising 70% levamisole hydrochloride, 30~ polyethylene glycol 400 and sealed with a sintered, high density (0.95 -0~97 g./ml.) polyethylene disc impregnated with gelled -:~ 30 cellulose triacetate according to the process of ; Example 15. The bolus had a density of 2.8 g./ml.
The reservoir contained 23.46 g. of the drug mixture, equivalent to 16.42 g. of levamisole hydrochloride.
.

~:~
O~

- - : ~ : .: .; : . : : , . : . .
: . : , , . . : , . . : :
.:: . : - .: ~ .. ~.. :. : . , , . . : , . . ~ .
. . . , . , . ... .... .. , .... ... ,.. ., .: ., , ,', ' ' , ,` ; ' ` ! ' ~3 3~

The aluminum crimp used had a circular open area in its middle, said area having the diameter of 1.1 cm., affording a transport area of 0.95 cm.2.
In vitro tests at 37C. showed the bolus releases 5 levamisole hydrochloride at a controlled rate.
Levamisole Hydro-~y~ chloride Released 3 0.815 1.572

6 1.805

7 2-33

8 2.64 ~" 10 2~79 11 2.83 lS 14 2.~7 4.66 1~ 5.10 2~ 6.67 ~ EXAMPLE 16 -~ 20 This example describes a field trial conducted i with 40 trial calves of uniform, breed, weight (mean =
150 kg.) and sex which had not previously grazed. The calves were divided into four groups of 10 each on the ~ basis of body weight. Two of the groups were replicate - 25 medicate~ groups and two were replicate control groups.
A worm free tracer calf was added to each of the four groups of trial calves at the start of the field trial and every four weeks thereafter. Each tracer calf was held in its paddock for two weeks, then removed and housed three weeks before slaughter for worm counts.
The trial and tracer calves were turned out on infected pasture which had been grazed the previous summer and autumn by infected cattle. The pasture was - , . . , . ;
~:
.

- so -of sufficient si2e to hold 44 animals set-stocked for the entire grazing season and was divided into four equal and separate paddocks.
The two medicated replicate groups were orally administared a 60 day bolus prepared according to the procedure of Example 1. The boluses provided continuous release of morantel tartrate at 250 ml~./animal ~equiva~
lent to 150 mg. morantel base) per day for 60 days.
The medicated groups of animals received the boluses orally two days before ~urning out to pasture in the spring. The presence of the bolus in each medicated animal was confirmed with a metal detector 24 hours a~ter administration. Checks o~ bolus retention were conducted at two week intervals thereafter. All animals medicated, control and tracers were weighed .;
~`' before turning out and at 4 week intervals. -~
~erbage samples were collected according to the method described by Taylor (Parasitology, 31, 473, 1939) at two week intervals beginning four weeks before start of the field trial and continued until termination o~ the trial.
Faecal samples for McMaster egg counts and lungworm larval counts were collected at comméncement of the trial and at tiwo week intervals thereafter. For the ~; 25 first eight~weeks these were rectal samples (one from each animal). Thereafter, rectal samples were collected every four weeks to coincide with weighing of the animals. At intervening points samples~ 10 for each group, were collected from pasture (Gibson, Veterinary Bulletin No. 7, 403-410, 1965). ~;
Total worm counts were carried out on the abomasum, including mucosal digests, small intestine and lungs of slaughtered animals.

- : :.: - : ~ . ;: :. : ~ .. : ,-. : , -: :::

Group Trea~ment Paddock No. of Animals 1 Morantel tartrate A 10 & one tracer 250 mg./day. every four weeks~
2 Morantel tar~rate B 10 & one tracer 250 mg./day. every four weeks.
3 Control. C 10 & one tracer every four weeks~
~ 4 Control. D 10 & one tracer `~ every four weeks. ,r The data are presented gxaphically in Figures 6, 7 and 8. Figure 6 shows weight gains during the grazing season for both medicated and control groups. Both groups ~` were found to gain weight at nearly the same net rate for about the first 3 months. After this time, weight gains in tha control groups slowed, and even decreased for `~ a period of time, coincident with increase in the number of pasture parasites. Medicated animals, on the other hand, continued their growth at a weight nearly equal ~- to that observed early in the season.
~; 20 Figures 7 and 8 show the parasite population ~; throughout the gxazing season for medicated and control animals. The number of eggs per gram of feces (right ordinate) and the number of larvae per kg. of dry pasture herbage (}e~t ordinate) ara plotted. The calves were turned out to pasture in mid-May; the medicated calves being orally administered the 60 day boluses two days prior to turn out which afforded them treatment to mid-July.
At the time of turning out, the number of eggs in the feces and of larvae in the pasture was low. In the control group, Figure 7, eggs began to appear in the animals' feces in eaxly June, reached a peak in late July and slowly decreased through August and September. These eggs lead to the increase in pasture ~ : -,: . . .
, ~33~

larvae observed in lata July and which reached it~
pea]c in August.
In the medicated groups, Figure 8, the production of esgs during June and July was dramatically reduced, a fact which wa~ reflected in the significant reduction of pasture larvae during July and September.

. 5imilar ~ield trials were conducted according to the design of Example 16 but using only one medicated : 10 and one control group in each trial. Pertinent data are tabulated below:
Mean Wt Gain No. of Advantage of Cumulative Trial Animals Treated Over Egg Count % Reduc- . :
No. ~ Control Trtd Contrl tion , v : 1 12 17.0 kg. 0 79 100 . 2 13 g.0 33 146 77 ~ -. 3 12 32.5 67 408 84 ;~' 4 11 9.5 145436 67 -~ 20 S 17 18.2 135886 85 6 18 13.4 23 62 63 ~
7 24 17.1 3~ 150 77 ~`
8 31 36.5 14 28 S0 :~ .
~, ~133~
-53~

The procedure of Example 4 is repeated but using, in place of poly(propylene) filter cloth impregnated with gelled cellulose triacetate, the following gelled cellulose triacetate porous fabrics:
Porous Fabric Aver~ re .i~e ~ poly(ethylene) 75 :- poly(tetrafluoroethylene~ 100 ~
glass 60 u stainless steel filter 80 ~ ~:
clot~
copper screen 30 modacrylic fiber(a~10 nickel copper alloy50 ~ 15 screen(b) : (a) copolymer of acrylonitrile (40%) and vinyl chloride ~ (60%), sold under the trademark Dynel by Union Carbide :~ Corp., N. Y.
(b) sold under the trademark Morel by The International Nickel Co., Inc., ~. Y.

: ~
.

, , . .,. , ,., ., .,.. ::, . ,., . . -. - . .

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. In a device for the controlled and continuous administration of chemical to an aqueous liquid-containing environment over a prolonged period of time, said device comprising a reservoir containing a chemical, a shaped wall formed in part at least of a porous material, said porous wall in contact with at least a part of said reservoir and characterized by being insoluble in said environment and maintaining its integrity during said prolonged period of time, the improvement which comprises impregnating the pores of said porous material with a hydrogel medium permeable to passage of said chemical and to said aqueous liquid so that said device when placed in said environment continuously releases said chemical from said reservoir to said environment at a physiologically effective controlled rate through said medium, the dissolved chemical so released being replaced by the continuous dissolving of said chemical in said reservoir, the amount of dissolved chemical in said reservoir changing continuously throughout said prolonged time period, so as to maintain the rate of chemical release to said environment substantially constant during a substan-tial portion of said prolonged time period.

2. A device according to claim 1 wherein the reser-voir contains chemical in admixture with a water-soluble excipient.

3. A device according to claim 1 wherein the reser-voir contains chemical in admixture with a water-soluble liquid excipient and a detergent.

4. A device according to claims 1 or 2 wherein said porous material is selected from a first group consisting of sintered poly(ethylene), sintered poly(propylene), sintered poly(tetrafluoroethylene), sintered poly(vinyl chloride) or sintered polystyrene; and a second group consisting of a porous fabric material selected from poly(ethylene), poly(propylene), poly(tetra-fluoroethylene), glass or modacrylic.

5. A device according to claims 1 or 2 wherein the aqueous liquid containing environment is an animal body site.

6. A device according to claims 1 or 2 wherein the aqueous liquid containing environment is an animal body site being the rumeno-reticular sac of a ruminant.

7. A device according to claim 6 wherein the hydrogel medium is gelled cellulose triacetate.

8. A device according to claim 7 wherein the chemical is an anthel-mintic agent.

9. A device according to claim 8 wherein the chemical is a water-soluble acid addition salt of pyrantel, morantel or levamisole.

10. A device according to claim 9 wherein the water soluble acid addi-tion salt is selected from the group consisting of levamisole hydrochloride and the tartrate and citrate salts of morantel and pyrantel.

11. A device according to claim 10 wherein the chemical is a water-soluble acid addition salt of morantel.

12. A device according to claim 11 wherein the porous material is sintered poly(propylene) or sintered poly(ethylene) and the water soluble salt is the tartrate.

13. A device according to claims 1 or 2 wherein said device contains a high density material in such quantity that the device has a density of at least 2Ø

14. A device according to claims 1 and 2 wherein the porous material is selected from a first group consisting of sintered poly(ethylene), sin-tered poly(propylene), sintered poly(tetrafluoroethylene), sintered poly-(vinyl chloride) or sintered polystyrene; and a second group consisting of a porous fabric material selected from poly(ethylene), poly(propylene), poly-(tetrafluoroethylene), glass or modacrylic.

15. A device according to claim 14 wherein said high density mate-rial is steel and the shaped wall comprises a cylinder of said steel, the ends of which are sealed with sintered polyethylene, pores of which contain gelled cellulose triacetate.

16. A device according to claim 14 wherein said high density mate-rial is present as a perforated steel or iron sleeve within said device be-tween the reservoir and the porous material.

17. A device according to claim 16 wherein the porous material is sintered poly(ethylene) and the hydrogel is gelled cellulose triacetate.

18. A device according to claim 15 wherein the aqueous liquid-con-taining environment is the rumeno-reticular sac of a ruminant.

19. A device according to claim 18 wherein the chemical is a water soluble salt of morantel.

20. A device according to claim 19 wherein the water soluble salt is the citrate salt.

21. A device according to claim 19 wherein the water soluble salt is the tartrate salt.

22. A method for the control of helminths on pasture land, the helminth larvae contamination of which is at or near a minimum level, which comprises grazing on said land ruminant animals having in their rumeno-reticular sacs, a device for the controlled and con-tinuous administration of a water soluble salt of mor-antel to the aqueous liquid-containing environment in said rumeno-reticular sac over a prolonged period of time, said device comprising a reservoir containing said morantel, a shaped wall formed in part at least of a porous material, pores of which contain a hydrogel medium, said porous wall in contact with at least a part of said reservoir and characterized by being insoluble in said environment and maintaining its integrity during said prolonged period of time, said hydrogel being permeable to passage of said morantel and to said aqueous liquid so that said device when placed in said environ-ment continuously releases said morantel from said reservoir to said environment at a physiologically effective controlled rate through said medium, the dissolved morantel so released being replaced by the continuous dissolving of said morantel in said reser-voir, the amount of dissolved morantel in said reservoir changing continuously throughout said prolonged time period, so as to maintain the rate of morantel release to said environment substantially constant during a sub-stantial portion of said prolonged time period.

23. A method according to claim 22 wherein the wall of said device comprises a steel cylinder, the ends of which are sealed with sintered polyethylene, pores of which contain gelled cellulose triacetate.

24. Process for production of a device for the controlled and continuous administration of chemical to an aqueous liquid-containing environment over a prolonged period of time, characterized in that a chemical is enclosed in a reservoir surrounded by a shaped wall formed in part at least of a porous material, said porous material being in contact with at least a part of said reservoir and characterized by being insoluble in said environment and maintaining its integrity during said prolonged period of time, the pores of said porous material being impregnated with a hydrogel medium permeable to passage of said chemical and to said aqueous liquid so that said device when placed in said environment continuously releases said chemical from said reservoir to said environment at a physiologically effective controlled rate through said medium, the dissolved chemical so released being replaced by the continuous dissolving of said chemical in said reservoir, the amount of dissolved chemical in said reservoir changing continuously throughout said prolonged time period, so as to maintain the rate of chemical release to said environment substantially constant during a substantial portion of said prolonged time period.

25. Process in accordance with claim 24 wherein the reservoir contains chemical in admixture with a water-soluble excipient.

26. Process in accordance with claim 24 wherein the reservoir contains chemical in admixture with a water-soluble liquid excipient and a detergent.

27. Process in accordance with claim 24, characterized in that said porous material is selected from a first group consisting of sintered poly(ethylene), sintered poly(propylene), sintered poly(tetrafluoro-ethylene), sintered (vinyl chloride) or sintered poly-styrene; and a second group consisting of porous fabric material selected from poly(ethylene), poly(propylene), poly(tetrafluoroethylene), glass or modacrylic.

28. Process in accordance with claim 27, character-ized by production of a device to be placed in the rumeno-reticular sac of a ruminant animal, the chemical being an anthelmintic agent.

29. Process in accordance with any of claims 27 to 28, characterized in that the hydrogel medium is gelled cellulose triacetate.

30. Process in accordance with claim 29, character-ized in that the chemical is a water soluble salt of levamisole, pyrantel or morantel.

31. Process in accordance with claim 30, character-ized in that the porous material is sintered poly-(propylene) or sintered poly(ethylene).

32. Process in accordance with claim 31, character-ized in that the water soluble salt of morantel is the tartrate.