Ruminal drug delivery device

The present invention is concerned with improving the delivery of a drug from a ruminal delivery device to give a consistent delivery of drug to the ruminal environment. Thus, the invention is directed to an improved ruminal drug delivery device comprising a semipermeable membrane having an exit orifice and defining a compartment, the compartment containing a swellable osmotic agent expandable member, a drug to be dispensed, a density element and, optionally, a partition layer between the osmotic expandable member and the drug formulation, wherein the improvement comprises an essentially gas-impermeable barrier means that separates the density element from the other components within the delivery device for isolating gases evolved from the density element from the other components within the delivery device. The invention is also directed to methods and articles for providing a consistent delivery of drug from a ruminal drug delivery device.

FIELD OF THE INVENTION 
This invention relates to ruminal drug delivery devices. More particularly, 
this invention relates to a ruminal device having improved delivery 
activity. 
BACKGROUND OF THE INVENTION 
Ruminant animals, including cattle, sheep, giraffe, deer, goats, bison and 
camels, and more particularly cattle and sheep, comprise an important 
group of animals that require periodic administration of medicines, 
nutrients and other biologically active agents (which are hereinafter 
referred to in their broadest sense as "drugs") for the treatment and 
alleviation of various conditions and for better health. 
Ruminants have a complex three or four compartment stomach, with the rumen 
being the largest compartment. The rumen serves as an important location 
for receiving and absorbing medicines and nutrients into other 
compartments including the abomasum and the intestine. 
There are numerous ruminal delivery devices known in the art which are 
capable of prolongedly releasing drugs. These devices are easily swallowed 
by the ruminant or otherwise introduced into the rumen and remain within 
the rumen for a long period of time without being regurgitated or 
otherwise expelled. Typical devices having an osmotic portion which 
imbibes ruminal fluid and expands, forcing a liquid or paste drug portion 
of the device through an orifice into the rumen, are those disclosed in 
U.S. Pat. Nos. 4,595,583 and 4,612,186, the disclosures of which are 
incorporated herein by reference. 
In order to insure that these devices remain in the rumen for a prolonged 
period of time, a density element is often incorporated into the device. 
Typically, the density element is manufactured from a material such as 
iron or steel, iron shot, iron shot coated with iron oxide, magnesium 
alloy, copper oxide or mixtures of cobalt oxide and iron powder, and the 
like. Such density elements typically have sufficient density to bring the 
overall density of the delivery device to a level greater than the density 
of ruminal fluid (approximately 1 gm/mL) and preferably to an overall 
density of at least 2 gm/mL. 
The osmotic ruminal delivery device or bolus has encountered some 
difficulties, however; the daily output of the bolus has been seen to 
often be highly erratic. It has been found that density elements made from 
materials such as iron, magnesium or zinc are susceptible to corrosion in 
water or ruminal fluids. This corrosion causes production of gases, which 
gases enter into other portions of the device and accumulate as gas 
bubbles which can cause fissures within the drug formulation and/or the 
osmotic expandable member. The presence of such fissures can cause gaps in 
the flow of drug formulation or a rapid expulsion of a portion of the lo 
formulation. Typically, the formation of a fissure causes a rapid 
expulsion of a portion of the formulation (fissure/bubble formation) 
followed by gaps or a decrease in the flow of drug formulation (fissure 
closure or expulsion through orifice). Thus, erratic flow is observed with 
days of low output and days of high output. In one effort to decrease 
corrosion, density elements of sintered metal have been impregnated during 
manufacture with an inert hydrophobic material such as silicone oil, 
mineral oil or wax (see, U.S. Pat. No. 5,206,024 and PCT patent publn. WO 
90/11856). This method, while apparently successful, has the disadvantages 
of being a time-consuming process during, and adding considerable expense 
to, the manufacture of the ruminal delivery device. Additionally, this is 
not a practical solution when the density element is not of the 
fragmentable sintered type disclosed in the above publications. 
SUMMARY OF THE INVENTION 
The present invention is concerned with improving the delivery of a drug 
from a ruminal delivery device to give a consistent delivery of drug to 
the ruminal environment. Thus, the invention is directed to an improved 
ruminal drug delivery device comprising a semipermeable membrane defining 
a compartment, the compartment containing an osmotic expandable member, a 
drug to be dispensed, a density element, an exit orifice and, optionally, 
a moveable partition layer between the osmotic expandable member and the 
drug formulation, wherein the improvement comprises an essentially 
gas-impermeable barrier means that separates the density element from the 
other components within the delivery device for isolating gases evolved 
from the density element from the other components within the delivery 
device. 
This invention is also directed to an article which improves the 
performance of a ruminal drug delivery device. The article comprises an 
essentially gas-impermeable insert which is sized and shaped to be placed 
between the density element and the other components within the ruminal 
device. The insert acts as a barrier means to protect the drug formulation 
and other components from gas evolved during corrosion of the density 
element, thus providing a more constant and consistent delivery profile of 
drug from the device. 
The invention is further directed to a method for providing a consistent 
delivery of drug from a ruminal delivery device, the method comprising 
placing into the rumen of a ruminant animal an improved ruminal delivery 
device of the present invention, and allowing fluid from the ruminal 
environment to be taken up by the osmotic expandable member for delivering 
the drug from the device at a consistent rate.

DETAILED DESCRIPTION OF THE INVENTION 
It has been found that placing a barrier between the density element and 
the other components of a ruminal delivery device as generally disclosed 
herein substantially reduces erratic delivery of drug from the device, 
while at the same time being simple and inexpensive to incorporate into 
the manufacture of the device. 
The improved controlled release ruminal delivery device of this invention 
comprises a semipermeable membrane which defines a compartment, the 
compartment being divided into first and second portions by an interface 
or, in certain embodiments, by a moveable partition. The first compartment 
portion contains a swellable osmotic material and the second compartment 
portion contains a drug or medicament or other therapeutic agent to be 
dispensed, generally in a semiliquid, gel or paste form. A density element 
resides within the compartment and may be positioned either adjacent to 
the exit orifice or at the end opposite from the exit orifice or elsewhere 
in the device. An orifice having an inside cross-sectional shape and 
extending through the membrane and, when the density element is adjacent 
to the orifice, through the density element connects the second 
compartment portion with the exterior of the device. When the device is in 
contact with water such as is found in the ruminal fluid of a ruminant, 
the semipermeable membrane allows water to pass therethrough which is 
imbibed by the swellable osmotic material which forces the interface 
between the osmotic material and the medicament to move the medicament to 
be dispensed through the orifice. The improvement of this invention 
comprises a barrier means which is placed between the density element and 
the other components within the device to separate the density element 
from the other components. The barrier means is essentially impermeable to 
gases that are evolved as a result of corrosion of materials making up the 
density element and acts to keep the evolved gases from passing into the 
other components, and especially the drug formulation, within the device. 
This invention will be described with respect to ruminal delivery devices 
of the type shown in the Figures, but it is not limited to the specific 
devices disclosed. The ruminal delivery device designs illustrated herein 
are merely exemplary of devices known to the art, and the gas barrier 
means of this invention can be adapted to fit in a ruminal delivery device 
and with a density element of any configuration. In the following 
description of the Figures, the Figures are not necessarily drawn to scale 
and like elements in the different Figures will be referred to by the same 
number. 
FIG. 1 illustrates a ruminal device 10 having a semipermeable wall 12 which 
surrounds an optional internal capsule wall 14 and defines an internal 
compartment 16, which is partially shown in FIG. 1. The agent or drug to 
be delivered can be dispersed throughout a drug composition 18, which is 
delivered through an exit orifice 20 by pressure exerted upon said 
composition by an osmotically activated expandable member 22. A density 
element 24 is situated at the end of the device 10 opposite from the exit 
orifice 20. Present between density element 24 and expandable member 22 is 
a gas-impermeable barrier means 26 for keeping gas evolved as a result of 
corrosion of the density element from entering into the expandable member 
22 and the drug formulation 18. That portion of density element 24 facing 
to the lower or bottom end 28 of device 10 is not enclosed by wall 12 or 
barrier means 26, in part so that the evolved gases can vent to the 
exterior environment. 
FIG. 2 illustrates another embodiment of a ruminal delivery device 30, 
which has a semipermeable wall 12, an internal compartment 16 (partially 
shown), exit orifice 20, drug formulation 18, expandable member 22, 
density element 32, and impermeable barrier means 34. For purposes of 
illustration only, device 30 differs from device 10 by having only a 
single wall 12 and having a rounded bottom 40. In device 30, the density 
element 32 is positioned near the exit orifice 20 and includes a bore or 
passageway 36 extending through the density element to provide contact 
between drug formulation 18 and the exterior through exit orifice 20. 
Barrier means 34, also having a bore therethrough, is placed in the 
passageway 36 and otherwise between the density element and the drug 
formulation throughout the interface between the two so that there is no 
contact between them, to provide a barrier for keeping evolved gases from 
passing into and displacing the drug formulation. 
In a presently preferred embodiment, there is a space or vent 38 between 
the density element 32 and the barrier means 34 for providing a channel 
for the evolved gas to vent to the outside of the device. This vent 38 may 
be provided in any of a number of ways known to the art such as, for 
example, having the barrier means 34 being in contact with the density 
element 32 in only a portion of the interface between them, as illustrated 
in device 30 at point 33. This is also illustrated in FIG. 6, where the 
barrier means 26 is in contact with only a portion of the density element 
24 to provide vent 38. Vent 38 may alternatively be provided by, for 
example, one or more protrusions extending from either the density element 
or the barrier means, or both, to separate apart the density element and 
the barrier; or by one or more grooves present on the interface surface of 
either the density element or the barrier means, or both. The number of 
protrusions or grooves is not critical and may be from 1 to 300 or more. 
In a further alternative embodiment, vents, bores or channels are formed 
within the density element (by drilling, molding or other means known in 
the art) and extending through the density element to the exterior 
environment. This is illustrated in FIG. 6 where bore or vent 39 extends 
through density element 24 to allow evolved gases to escape to the 
environment at bottom end 28. Bore or vent 39 may extend completely 
through the density element, as shown, or it may extend only partially 
through the density element. The number of vents or bores is not critical 
and may be from 1 to 50 or more. Other ways of providing a venting means 
are known or can be determined without undue experimentation by those 
skilled in the art. 
In certain uses of a ruminal delivery device, it is desireable to have a 
screen across the exit orifice for keeping external matter out of the 
device or for providing a back-pressure for improved drug delivery from 
the device. Capscreens are disclosed in U.S. Pat. Nos. 4,872,873, 
5,122,128 and 5,213,809, the disclosures of which are incorporated herein 
by reference. In one contemplated embodiment of the present invention, 
shown in FIG. 3, an exit port screen 42 is incorporated into the barrier 
means 34 of the present invention. Exit port screen 42 is located at that 
end of barrier means 34 which is adjacent to the exit orifice 20 of the 
device and integral with the exit orifice. Exit port screen 42 may, 
optionally, extend within at least a portion of bore or passageway 36 
(shown). Exit port screen 42 covers the exit orifice and has a plurality 
of screen passageways 44 extending through it for allowing passage of the 
drug formulation 18 to the external environment. The number of screen 
passageways 44 is not critical and will depend on the use contemplated for 
the exit port screen 42, the drug formulation to be delivered, and other 
considerations pertinent to the particular contemplated use, as is taught 
in the above cited patents, previously incorporated by reference. 
In other contemplated uses of a ruminal delivery device, it may be 
desireable to include a loading dose for providing immediate delivery of a 
drug during the period of startup of the device itself. See, U.S. Pat. No. 
5,045,082, the disclosure of which is incorporated herein by reference. In 
one embodiment of the present invention, device 50 as shown in FIG. 4, a 
loading dose chamber 52 is incorporated into the barrier means 34 adjacent 
to and integral with the exit orifice 20 and the bore or passageway 
Loading dose chamber 52, together with retaining means 54, is designed to 
retain a loading dose 56 which contains a formulation for release of drug 
or other therapeutic agent. The retaining means 54 which covers the 
loading dose chamber 52 functions to keep the loading dose 56 as an 
integral part of the dispensing device 50 while allowing consistent 
dispersion of the loading dose to the external environment over time, as 
is taught in the above cited patent, previously incorporated by reference. 
Evolved gases which enter vent 38 are also released through the retaining 
means, which extends from the loading dose chamber to cover the vent 38 
where it opens to the external environment. 
In a presently preferred embodiment of the delivery device herein, a 
moveable partition layer 58 is present between the drug formulation 18 and 
the expandable member 22 to maintain the separate identity of the two 
components and to assist in the expulsion of the drug formulation from the 
device into the external environment. Partition layers are well known in 
the art and are further described in, for example, U.S. Pat. Nos. 
4,772,474 and 4,844,984, the disclosures of which are incorporated herein 
by reference. 
The barrier means of this invention are characterized by being essentially 
impermeable to any gases, and in particular to hydrogen gas, which are 
evolved as part of the corrosion process of metallic density elements. By 
"essentially impermeable" is meant that the barrier material is not 
permeable to such gases at all, or that the gases permeate the material in 
only a negligible amount, of no greater than about 20.times.10.sup.-10 
cm/sec-cmHg. The materials suitable for the barrier means are any 
materials that are essentially impermeable to gases and that are 
additionally inert to the drug formulation, the density element and the 
other components of the delivery device. Such characteristics are known in 
the art or can be determined without undue experimentation. Materials may 
be selected from, but are not limited to, polyvinyl alcohol; 
polypropylene; cellulose; cellulose esters; Delrin.RTM.; fluorocarbon 
polymers; polyamides; polyesters; polyolefins; noncorrosive metals such as 
stainless steel; nylon; and the like. 
The barrier means can be manufactured according to processes well known in 
the polymer and plastic arts, such as by injection molding, compression 
molding, casting, mechanical machining, and the like. Where venting means 
are not present between the density element and the barrier means, the 
barrier means may be a coating applied directly onto the surface of the 
density element by coating processes as are known in the art. When the 
barrier means is an insert, it is sized and shaped to be placed between 
the density element and the other components within a ruminal drug 
delivery device. 
A representative embodiment of an insert barrier article of the present 
invention is shown in FIG. 5. FIG. 5 illustrates an insert 34 (which is 
shown in FIG. 2 in cross-section positioned in a ruminal delivery device). 
Barrier insert 34 is funnel-shaped, having a circular cross-section along 
its longitudinal axis. It has the dimensions indicated in FIG. 5 and is 
sized and shaped to fit within a density element (32 in FIG. 2) with a 
clearance of about 7 mil (0.18 mm) to form a channel for escaping gases 
(vent 38 in FIG. 2). In a presently preferred embodiment, the barrier 
insert of the present invention is manufactured of Delrin.RTM. 
((polyoxymethylene) acetyl resin homopolymer; DuPont). 
The term "drug" is used broadly and generically herein to refer to any drug 
or other beneficial agent which it is desired to deliver to a ruminant 
animal from a ruminal delivery device, and the present invention is not 
limited to any particular drugs. Such beneficial agents are known to the 
art and representative agents are disclosed in the patents incorporated 
herein by reference. 
The following examples are illustrative of the present invention. They are 
not to be construed as limitations of the scope of the invention. 
Variations and equivalents of these examples will be apparent to one 
skilled in the art in light of the present disclosure, the drawings, and 
the claims herein. All percentages are weight-weight percent, and all 
temperatures are in degrees Celsius, unless otherwise noted. 
EXAMPLE 1 
An improved ruminal delivery device according to the present invention is 
prepared as follows. 
A semipermeable wall was prepared by sizing and then mixing together 50.5 g 
cellulose acetate butyrate having a butyryl content of 17% and an acetyl 
content of 29% (Eastman), 17.5 g cellulose acetate having an acetyl 
content of 39.8% (Eastman), 22.0 g triethyl citrate (Citroflex-4.RTM., 
Morflex, Inc.), 6.0 g tributyl citrate (Citroflex-2.RTM., Pfizer, Inc.), 
and 4.0 g polyethylene glycol having a molecular weight of 400 (PEG 400, 
Union Carbide). After mixing for 20 minutes, the material was transferred 
to the feed hopper of an injector molder equipped with a suitable mold to 
produce a cellulosic membrane cup weighting 10.1 g and having the 
following dimensions: 7.9 cm height, 2.5 cm width, and wall thickness of 
0.17 cm. 
An osmotic expandable member was prepared by blending together 60.3 g 
sodium salt of polyacrylic acid having a MW of 3,000,000 (Sodium 
Carbomer.RTM.934P, B. F. Goodrich Chemical), 0.9 g polyvinylpyrrolidone 
(PVP), 0.9 g magnesium stearate, 12.9 g water, and 25 g sodium chloride. 
8.41 Grams of the blend was compressed under 10 tons of force to form 
tablets which conform to the internal diameter of the membrane cups 
prepared above. One of the compressed osmotic tablets was inserted into 
the membrane cup. 
A placebo "drug" formulation was prepared by melting a microcrystalline wax 
(Multiwax.RTM. X145A; Witco Chemical Co.) and, with the temperature 
maintained at 68.degree. C., delivering 11.5 g (about 12.8 mL) of the wax 
to the membrane cup assembly over the osmotic tablet. 
A sintered iron density element was prepared, having a 5.1 mm diameter bore 
therethrough and shaped generally as illustrated in FIG. 2 and of a size 
for placement in the membrane cup. 
A barrier insert as illustrated in FIG. 5 was prepared by machining a 
funnel-shaped insert from Delrin.RTM. in the shape and dimensions set out 
in FIG. 5 to fit into the inside of the density element with about 7 mil 
(0.18 mm) clearance between the insert and most of the density element. 
The barrier insert was placed into the density element so that it is 
situated next to or against the interior portion of the element, after 
which the density element was inserted into the open end of the membrane 
cup assembly and seated against the "drug" formulation. The barrier insert 
separates the drug formulation from exposure to the density element. The 
protruding lip of the cup was heated until softened using a hot air gun, 
and the lip was crimped over the density element, leaving the exit orifice 
open. 
EXAMPLE 2 
A ruminal delivery device identical to the device in Example 1 was 
prepared, except that a barrier insert was not placed into the density 
element, resulting in a prior art ruminal bolus having an untreated 
density element placed in contact with drug formulation. 
In the same manner, a prior art delivery device was prepared having an 
impregnated density element and no barrier insert. The density element was 
impregnated during manufacture with microcrystalline wax Multiwax 180M, 
following the procedures of U.S. Pat. No. 5,206,024. 
EXAMPLE 3 
The delivery device of the present invention of Example 1 was compared, in 
vitro, with the prior art devices of Example 2 to compare delivery 
profiles and presence or absence of gas within the drug formulation, as 
follows. 
The devices (n=8) were placed in deionized water and maintained at ruminant 
body temperature. Material which extruded from the devices was removed 
periodically and weighed to determine the release rate from each of the 
devices. The comparative averaged release rates for the devices are 
presented in FIG. 7. 
At the end of the testing, each of the devices was cut open to determine 
the presence or absence of voids caused by gas bubbles. Out of the eight 
devices in each set, there were severe voids (15-25 mm) in three of the 
untreated devices, there were minor voids (2-5 mm) in three of the 
wax-impregnated devices, and there were no voids whatever in any of the 
devices of the invention having barrier inserts. 
EXAMPLE 4 
A delivery device for the delivery of ivermectin is prepared as described 
in Example 1, except as follows. 
After the osmotic expandable tablet is inserted into the membrane cup, two 
grades of microcrystalline wax (49 g Multiwax.RTM. 180M and 49 g 
Multiwax.RTM. X145A) and 2 g Cab-0-Sil.RTM. (colloidal silicone dioxide, 
Cabot Corp.) are mixed together, and the mixture is heated to 85.degree. 
in a hot-melt tank pump. 3.0 Grams (about 3.3 mL) of the wax mixture is 
poured into the membrane cup in laminated arrangement above the osmotic 
expandable tablet to form a partition layer. 
An ivermectin drug formulation is prepared as follows. 831 g Multiwax X145A 
and 20 g Cab-0-Sil are melted, after which the temperature is adjusted to 
80.degree. C. Ivermectin (149 g) is added, using a high sheer mixing 
apparatus. The temperature of the formulation is maintained at 68.degree. 
C. while 8.5 g (about 9.5 mL) of the formulation is delivered to the 
membrane cup assembly over the partition layer. 
The barrier insert and the density member are then added as in Example b 1 
to give an ivermectin ruminal bolus.