Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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1 64680-510
IMPROVED MEANS FOR CONSTRAINING A RUMEN DRUG
DELIVERY DEVICE IN A ROLLED CONFIGURATION
This invention relates to improved means for
constraining rumen drug delivery devices in a rolled
configuration. More particularly, it relates to laminates
comprising water permeable material having a low friction surface
in the presence of water, said material being bonded to a
repulpable tape having a water-dispersible adhesive on both
surfaces; to laminates comprising a flexible, water-permeable
polymeric material bonded between the low friction surface
material and the repulpable tape; and to devices so constrained.
U.S. Patents 4,228,149, 4,601,893 and 4,861,596 and
European Patent Publication No. 0334516 refer to rumen drug
delivery devices constrained in a rolled-up configuration by
appropriate constraining means.
In has been observed that the prior art devices
described above are sometimes expelled by the ruminant because of
untimely removal of the constraining means within the rumen.
Additionally, difficulty is often encountered upon oral
administration of the constrained devices to young ruminants.
Premature removal of the constraining means and subsequent
unrolling of the constrained device or slow transit of the
constrained device can lead to dosing problems. Thus, the need
for improved constraining means for rumen drug delivery devices
which will facilitate dosing of ruminants therewith and enable
timely change of configuration in the rumen and eliminate
expulsion of the device by the ruminant.
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The constraining means of the present invention
provide a low friction surface to facilitate dosing of
the device, afford timely change in geometry of the
rolled-up device within the rumen, avoid premature
unrolling of the devices on dosing, are stable and
non-toxic.
The improved constraining means of the present
invention is a laminate which comprises a water-
permeable material having a low friction surface in the
presence of water, said material being bonded by means
of a water-dispersible pressure sensitive adhesive to a
repulpable tape which is coated on both surfaces with
said adhesive. In one embodiment of the present
invention, the above-described laminate comprises a
flexible, water-permeable polymeric material bonded
between the low friction surface material and the
repulpable tape. A still further embodiment
comprises a laminate comprising a flexible,
water-permeable polymeric material sandwiched between
two sheets of a water-permeable material having a low
friction surface in the presence of water, one surface
of which is bonded by means of a water-dispersible
pressure sensitive adhesive to a repulpable tape which
is coated on both surfaces (doubly coated) with said
adhesive. Also included in this invention are
rolled-up rumen drug delivery devices constrained by
the herein-described improved constraining means.
Water-dispersible pressure sensitive tapes and
repulpable tapes coated with said water-dispersible
pressure sensitive adhesives are described in U.S.
patents 3,865,770; 3,441,430; 4,413,080; and 4,569,960.
Such tapes find extensive use in the paper-making
industry.
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The favored water-permeable material having a low
friction surface in the presence of water is nitro-
cellulose. As the outermost, or top layer, of the
laminates described herein, the nitrocellulose
facilitates oral administration of the constrained
devices in view of the low-friction surface which it
acquires in the presence of the saliva in the
ruminant's esophageal passage.
In one form of the herein described constraining
means, the nitrocellulose film is bonded directly to
one surface of the doubly adhesive coated repulpable
tape. The other adhesive coated surface, of the tape
is, of course, bonded to the rolled-up drug delivery
device so as to constrain it in said configuration.
This form of constraining means may, if increased flow
of environmental fluid to the water dispersible
adhesive is desired, be perforated, especially with
macroholes ranging from about 0.5-5 mm in diameter,
prior to its being applied to the rolled-up device.
The holes are normally circular but could be any shape
such as, for example, ovals, triangles, squares,
hexagons, etc. The perforations tend to accelerate
removal of the constraining means.
In a modified, and favored, form of the improved
constraining means of this invention, a flexible,
water-permeable polymeric material, preferably
cellophane, is bonded between the low friction surface
material and the repulpable tape. The cellophane
serves to enhance removal of the constraining means and
unrolling of the rolled-up device. In addition to
cellophane other water-permeable polymers, such as
polyvinyl acetate, polymethylmethacrylate, polyethyl-
methacrylate, polyvinylchloride, cellulose acetate and
polydimethylsiloxane, can be used.
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A preferred modification of the improved
constraining means of this invention comprises a
laminate comprising a flexible, water-permeable
polymeric material, such as is described above,
sandwiched between two sheets of a water-permeable
material (e.g. nitrocellulose) having a low friction
surface in the presence of water, one surface of which
is bonded to a repulpable tape doubly coated with a
water-dispersible pressure sensitive adhesive. The
thickness of~6~d coated/ee~13phanc can range from
about 0.3 to 3.0 mils (0.0076 to 0.076 mm.). Cellophane~
coated on both surfaces with nitrocellulose, i.e.,
sandwiched between nitrocellulose, is commercially
available from BCL America, Inc. of Malvern, PA. 19355,
product grade 345 PS-41. It has a thickness of about
0.9 mil (0.023 mm.).
Each of the forms of the constraining means
described herein may optionally have macroperforations
made in them, especially at that portion thereof where
the said means abut or overlap when placed about the
rolled-up delivery device to enhance unrolling of the
device in the use environment.
The laminates of this invention are conveniently
constructed by contacting the individual layers of the
lamina, e.g., nitrocellulose, or cellophane coated on
both sides with nitrocellulose, with the repulpable
tape doubly coated with a water-dispersible pressure
sensitive adhesive. Suitable water-dispersible
pressure sensitive adhesives are well known in the art.
Representa~ive water-dispersible pressure
sensitive adhesives are those comprising a copolymer of
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monomeric acrylic acid esters and vinyl carboxylic acid
monomer, said copolymer being partially neutralized
with a secondary or tertiary alkanolamine, or an alkali
metal hydroxide. Oily plasticizing compounds such as
water-soluble polyoxyethylenes; and tackifiers such as
reaction products of acid rosins and alkanolamines are
added thereto. Such adhesives and their use to make
repulpable tapes are described in U.S. patents
3,865,770; 4,413,080, 4,569,960.
Illustrative of such adhesives described in said
patents are those comprising:
(I) (a) a copolymer of monomers consisting
essentially of
(1) about 90-20 parts by weight
monomeric acrylic acid ester of non-tertiary alkyl
alcohol the molecules of which have 1 to 4 carbon
atoms; and
(2) about 10-80 parts by weight vinyl
carboxylic acid monomer copolymerizable with said
20 acrylic acid ester, at least a number of the carboxyl
groups in said acid monomers sufficient to constitute
about 3-22% the weight of said copolymer, having been
neutralized by reaction with a secondary or tertiary
alkanolamine containing at least 4 carbon atoms; and
(b) 0-400 parts by weight of at least one
water-dispersible tack-promoting material selected from
the class consisting of the oily plasticizing
water-soluble polyoxyethylene compounds and the
tackifying reaction products of acid rosins and
alkanolamines; or
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(II) the blended reaction product of
(a) 100 parts by weight of a copolymer of
monomers consisting essentially of
(1) about 75-85 weight percent of at least
one monomeric acrylic acid ester of nontertiary alkyl
alcohol, and correspondingly,
(2) about 25-15 weight percent of vinyl
carboxylic acid,
(b) about 35-100 parts by weight of acidic rosin
or rosin derivative,
(c) sufficient potassium hydroxide to neutralize
about 30-45~ of the combined carboxyl groups of the
copolymer and rosin or rosin derivative,
(d) sufficient sodium hydroxide, lithium
hydroxide, or a combination of sodium and lithium
hydroxide to neutralize about 20-45~ of said carboxyl
groups, and
(e) about 100-225 parts by weight of oily
plasticizing water-soluble polyoxyethylene compound; or
(III) the blended reaction product of
(a) 100 parts by weight of a copolymer of
monomers consisting essentially of
(1) about 60-85 weight percent of at least
one monomeric acrylic acid ester of nontertiary alkyl
alcohol having 4-14 carbon atoms, and correspondingly,
(2) about 40-15 weight percent of vinyl
carboxylic acid,
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(b) about 50 to 250 parts by weight of
ethoxylated plasticizing components, sufficient to
impart adhesion values such as to cause the adhesive to
delaminate kraft paper when tested as described herein,
consisting essentially of at least one of the
following:
(1) up to about 125 parts by weight, but not
so much as to cause adhesive separation, of one or more
OH-functional ethoxylated plasticizers and
(2) one or more electrolyte-tolerant complex
and acidic esters of phosphoric acid and an ethoxylated
nonionic surfactant, and
(c) alkaline hydroxide consisting essentially of
(1) sodium hydroxide, lithium hydroxide, or
both sodium hydroxide and lithium hydroxide, in an
amount sufficient to enhance shear strength and
minimize bleeding but insufficient to cause separation
of any OH-functional ethoxylated plasticizer present,
not exceeding about 0.07 hydroxyl equivalent if
OH-functional ethoxylated plasticizer is the only
plasticizing component present, and
(2) potassium hydroxide in an amount
sufficient to promote water solubility.
The constraining means of this invention should
not substantially increase the overall diameter of the
constrained device at the point of constrainment to a
thickness that would give rise to dosing problems when
the constrained device is administered to a rumen.
This relationship between the thickness (diameter) of
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the rolled-up device and that of the constraining means
will be recognized by those skilled in the art. Said
individuals will appreciate the need to maintain the
thickness of the constraining means to a minimum
thickness consistent with acceptable times of removal
- of the constraining means in the use environment. In
general, constraining means of this invention having a
thickness of from about 1.3 to 10.0 mils (0.0013 to
0.010 inch; or 0.033 to 0.254 ml.) afford acceptable
release times.
Using the improved constraining means of this
invention, it is easy to prepare a device for the
controlled and prolonged release of veterinary
medicaments, for example, anthelminthics, for the
treatment of animals. The device comprises a resilient
and flexible ethylene-vinyl acetate copolymer core
which is sandwiched between a pair of coextensive
resilient films of the copolymer. The core sheet can
contain from about 10~ to about 75~ by weight of a
water-soluble morantel salt (e.g., morantel tartrate)
which is dispersed within the core sheet. The device
can have one or a plurality of circular
macroperforations of about 0.5 to about 10 mm in
diameter. These macroperforations are distributed
symmetrically across the face of the device and extend
through the resilient films and the core sheet. The
diameter and arrangement of the macroperforations in
relation to the thickness of the core sheet are
selected to expose sufficient interior edge area of the
core sheet. Exposing sufficient edge area would
1 33853û
provide the desired morantel salt release rate. The
device is constrained in a rolled configuration by a
constraining means which is releasable in the rumen of
an animal. Suitable constraining means include the
laminate of the present invention.
The point of greatest tension in the constraining
means occurs at that segment of the roll where the
constraining means bridges the gap formed by its
contact with the terminal edge of the outer layer of
the rolled-up device and the surface of the layer upon
said outer layer ends. The effect of this tension can
be minimized by doubling the thickness of the overall
length of the constraining means used. Alternatively,
the effect can be minimized by placing a reinforcing
strip of said constraining means having the thickness
disclosed above over said segment.
As will be appreciated the constraining means used
can be of sufficient length as to completely wrap about
the rolled-up device, the ends thereof forming a butt
joint. Alternatively, the constraining means can be of
such a length that the ends thereof overlap to a lesser
or greater extent when said means is placed about a
rolled-up device. The extent of overlap should, for
economic reasons, be less than that which would result
in a double thickness of constraining means. Still
further, the constraining means need not entirely wrap
about the rolled-up device. It should, at the least,
be in contact with the terminal end of the outer layer
of the rolled-up device and the surface of the layer
upon which said outer layer ends. The favored length
of constraining means is that required to completely
wrap about the rolled-up device.
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The improved constraining means of this invention
are readily prepared by laminating the adhesive coated
repulpable tape to the water-permeable polymeric
material having a low friction surface in the presence
A 5 of water, e.g., nitrocellulose; or to the nitro-
C~ll o ~hq ~)~*cellulose coated/ccllophanc, by known methods, care
being taken to avoid formation of bubbles or wrinkles.
The laminated tape is then cut to desired size.
Perforations may be conveniently made either before or
after cutting of the laminated tape.
The removability of the constraining means of this
invention in the use environment, e.g., the rumen of a
ruminant, is determined by in vitro or in vivo methods.
The in vitro method comprises placing the constrained
device in water, or more appropriately a synthetic
rumen fluid, at 40C on an incubator shaker (ca.~0
excursions per minute~ and observing the time required
for unrolling of the constrained device. The in vivo
method comprises administering the constrained device
to a fistulated ruminant and observing the time
required for unrolling of the constrained device.
To further minimize dosing problems, the
constrained devices desirably have plugs, e.g.,
polyethylene plugs, inserted into their open ends to
convert the hollow tube to substantially a rod like
device.
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EXAMPLE 1
A morantel tartrate containing device prepared
according to Example 1 of U.S. patent 4,601,893 was
constrained in a rolled-up configuration with a
constraining means of this invention comprising a 8.9 x
A 7.6 cm wide laminate of 3M tape no. 900 and~c~ophan
coated on both surfaces with nitrocellulose (product
grade 345 PS-41). The ends of the tape when wrapped
around the device overlapped 0.635 cm.
When placed in water at 40C as described above,
the constraining means was removed in 40 minutes.
A similar device which had been stored at ambient
temperature for 6 months required 57 minutes for
removal of the constraining means when placed in 40C
water.
EXAMPLE 2
The constraining means of a constrained device
prepared according to Example 1, when administered to a
fistulated ruminant, was observed to be removed within
40 minutes, resulting in unrolling of the device.
EXAMPLE 3
The experiment of Example 1 was repeated but using
a tape in which 50 perforations, each 2 mm in diameter,
were made in the overlapping ends.
The constraining means was removed in 15 minutes
when the constrained device was placed in 40C. water.
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EXAMPLE 4
A device prepared according to Example 2 of U.S.
patent 4,228,149 is constrained in a rolled confi-
guration by a 8.9 x 7.6 cm wide laminate of 3M tape no.
405 and ~c~lPophanc~coated on both surfaces with
nitrocellulose. The laminate was sufficiently long so
that the ends overlapped 0.635 cm.
EXAMPLE 5
The procedure of Example 3 is repeated but using
doubly coated repulpable tapes prepared using the
adhesives of Example 29 of U.S. patent 4,569,960 and of
Example 7 of U.S. patent 4,413,080.
EXAMPLE 6
Ten devices are prepared according to the
procedure of Example 1 except that, prior to being
constrained, the devices are annealed at 50C for 24
hours. The devices are then tested at varying time
levels for their ability to unroll. All devices, even
those stored at ambient temperature for 6 months,
unrolled; i.e., the constraining means is removed, from
their original 2.5 cm cross-section diameter to a
cross-section diameter within one hour sufficient to
prevent their regurgitation by a ruminant.
EXAMPLE 7
Devices prepared according to Example l were
administered to 100 young ruminants (approximately
100 kg in weight). No difficulty was experienced in
dosing the animals and no devices were regurgitated by
any of the animals.
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EXAMPLE 8
Twenty devices prepared substantially according to
Example 1 were divided into two equal groups. Group A
devices were placed in 40C water as described above
and group B devices were administered to fistulated
cattle, one device per animal. The times required for
removal of the constraining means were recorded
Average Range of Standard
GroupRemoval Time Removal Time Deviation
A - in vitro31 minutes 20-46 minutes 8 minutes
B - in vivo51 minutes 30-63 minutes 9 minutes
EXAMPLE 9
Nitrocellulose coated/a~ phanc (BCL 345 PS 41)
was coated with (Fitchburg Coated Products Inc.,
Scranton, PA 18501) WASH-AWAY adhesive (a blend of
polyvinyl methyl ether, maleic anhydride and a
phosphate ester) to prepare a pressure sensitive
constraining means with water soluble adhesive. A
device from Example 1 of U.S. 4,601,893 was constrained
by the above-mentioned constraining means. The
constrained device when immersed in water at 40C
underwent removal of the constraining means in 23
minutes.
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