NZ750914B2 - Intra-ruminal device - Google Patents
Intra-ruminal device Download PDFInfo
- Publication number
- NZ750914B2 NZ750914B2 NZ750914A NZ75091419A NZ750914B2 NZ 750914 B2 NZ750914 B2 NZ 750914B2 NZ 750914 A NZ750914 A NZ 750914A NZ 75091419 A NZ75091419 A NZ 75091419A NZ 750914 B2 NZ750914 B2 NZ 750914B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- barrel
- cap
- intra
- ruminal
- protrusion
- Prior art date
Links
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Abstract
Intraruminal devices comprise a barrel and cap, wherein the cap may be separated from the barrel when in use. The present device provides an effective mechanism to attach the cap to the barrel of an intraruminal device using ultrasonic welding, wherein the device comprises a barrel with a first and second end, a cap having a sidewall and top and opening at the first and a variable geometry device connected to and extending from the body at the second end. The cap sidewalls overlap a portion of the barrel to define an attachment zone, and located within the attachment zone is at least one protrusion providing a localised point of contact between a wall of barrel and an internal portion of the sidewall of the cap to provide for an ultrasonic weld between the barrel and the cap. second end, a cap having a sidewall and top and opening at the first and a variable geometry device connected to and extending from the body at the second end. The cap sidewalls overlap a portion of the barrel to define an attachment zone, and located within the attachment zone is at least one protrusion providing a localised point of contact between a wall of barrel and an internal portion of the sidewall of the cap to provide for an ultrasonic weld between the barrel and the cap.
Description
INTRA-RUMINAL DEVICE
FIELD OF THE INVENTION
The present invention relates to an improved intra-ruminal
device and method of making the device. In particular, the invention
relates to an apparatus and method to improve the structural integrity
of an intra-ruminal device and prevent the separation of various
components of the device during and after use.
BACKGROUND TO THE INVENTION
An intra-ruminal controlled release device is a delivery
device designed to provide therapeutic agents to the rumen over
extended periods. To ensure the device performs as intended, certain
Critical Quality Attributes (CQAs) must be met.
CQAs include such requirements as (1) to keep the device
intact so that the therapeutic agent is only exposed at an orifice, (2) to
prevent damage to the rumen by individual components of the device
(e.g. spring), and (3) to ensure the device remains in situ for the entire
pay-out period.
In conventional devices, the separation of device
components within the rumen and/or after regurgitation remains a
problem. This is undesirable as internal separation of components may
result in internal dose dumps, leading to toxicity to the animal and/or
physical safety issues. Separation of the device following regurgitation,
such as if the device is crushed, could lead to other safety and
environmental issues.
The efficacy of some conventional devices also continues to
be limited due to pressure build-up inside the device leading to
uncontrolled and inconsistent dosing.
It is an object of the present invention to address one or
more of the abovementioned issues, and/or to provide an improved
intra-ruminal device and/or to at least provide the public with a useful
choice.
83212440.1
SUMMARY OF THE INVENTION
In a first aspect the present invention relates to an intra-
ruminal device comprising:
an elongate body or body assembly substantially impervious to
rumen fluids, the body defining a barrel having a first end and a second
end, and an opening at the first end,
at least one variable geometry device connected to and extending
from the body at the second end to assist rumen retention,
a dose of an active agent within the body to be accessible to
rumen fluid via the first end,
a biasing arrangement within the body adapted to bias the active
agent in the barrel towards the first end, and
a cap having a sidewall and top, the cap located over the opening
at the first end and comprising an outlet in the top, the sidewalls of the
cap overlap a portion of the barrel to define an attachment zone, and
located within the attachment zone is at least one protrusion providing a
localised point of contact between a wall of the barrel and an internal
portion of the sidewall of the cap to provide for an ultrasonic weld
between the barrel and the cap at the attachment zone.
In a further aspect the present invention relates to a
method of assembling an intra-ruminal device, the method
comprising:
providing an intra-ruminal device comprising:
o an elongate body or body assembly substantially
impervious to rumen fluids, the body defining a barrel
having a first end and a second end, and an opening
at the first end,
o at least one variable geometry device dependent from
the body to assist rumen retention,
o a dose of an active agent within the body to be
accessible to rumen fluid via the first end,
o a biasing arrangement within the body adapted to bias
the active agent in the barrel towards the first end,
loading the active agent into the barrel,
attaching a cap located over the opening at the first end,
the cap comprising an outlet in the top and having
sidewalls that overlap a portion of the barrel to define an
83212440.1
attachment zone, and located within the attachment zone
is at least one protrusion providing a localised point of
contact between the barrel wall and the internal sidewall of
the cap,
subjecting the attachment zone to ultrasonic vibrations to
produce frictional heat energy at the protrusion to form a
weld between the protrusion at its contact surface.
In a further aspect the present invention relates to the use
of an intra-ruminal device as described above in a ruminant.
The following embodiments may relate to any of the above
aspects.
Preferably the intra-ruminal device comprises a plurality of
protrusions.
Preferably the protrusions are in the same plane.
Alternately, the protrusions are in different, yet adjacent,
planes.
In one embodiment the protrusions are formed contiguously
about the perimeter.
In some embodiments the protrusions are
i) located on the outer surface of the barrel in the
attachment zone,
ii) on the inner surface of the cap side wall, or
iii) both (i) and (ii).
Preferably the at least one protrusion in cross section is
triangular or trapezoidal.
Preferably a portion of the inner surface of the cap sidewall
comprises a notch, into which extends a protrusion from the outer wall
of the barrel to contact the surface of the notch.
Preferably the thickness of the barrel wall adjacent the
attachment zone is thickened.
83212440.1
Preferably the thickening of the barrel side wall is to
substantially match the thickness of the cap sidewall.
Preferably at least one protrusion mates with a substantially
flat surface of the corresponding wall surface.
Preferably the primary direction of the ultrasonic vibrations
are substantially perpendicular to the cap sidewall.
Preferably the body and the cap are held together under
heat and pressure.
Preferably the intra-ruminal device is used in a group or
herd of ruminants, each ruminant being administered an intra-ruminal
device, and wherein the cap remains on the barrel of the intra-ruminal
device for the duration of the administration period.
The term “comprising” as used in this specification means
“consisting at least in part of”. When interpreting statements in this
specification which include that term, the features, prefaced by that
term in each statement, all need to be present but other features can
also be present. Related terms such as “comprise” and “comprised” are
to be interpreted in the same manner.
It is intended that reference to a range of numbers
disclosed herein (for example, 1 to 10) also incorporates reference to all
rational numbers within that range (for example, 1, 1.1, 2, 3, 3.9, 4, 5,
6, 6.5, 7, 8, 9 and 10) and also any range of rational numbers within
that range (for example, 2 to 8, 1.5 to 5.5 and 3.1 to 4.7).
This invention may also be said broadly to consist in the
parts, elements and features referred to or indicated in the specification
of the application, individually or collectively, and any or all
combinations of any two or more of said parts, elements or features,
and where specific integers are mentioned herein which have known
equivalents in the art to which this invention relates, such known
equivalents are deemed to be incorporated herein as if individually set
forth.)
To those skilled in the art to which the invention relates,
many changes in construction and widely differing embodiments and
83212440.1
applications of the invention will suggest themselves without departing
from the scope of the invention as defined in the appended claims. The
disclosures and the descriptions herein are purely illustrative and are not
intended to be in any sense limiting.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described by way of example only
and with reference to the drawings in which:
Figure 1 is a cross-sectional view of an intra-ruminal deice
of the present invention showing the attachment of a cap to the barrel.
Figure 2 is a partial cross-sectional view showing the
attachment of a cap to the barrel in a pre-weld condition.
Figure 3 is a perspective view of the cap.
Figure 4 is a cross-sectional view of the cap showing detail
Figure 5 is an enlargement of detail C from Figure 5.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an intra-ruminal device that
comprises an elongate body or body assembly substantially impervious
to rumen fluids. The body defines a barrel having a first end and a
second end, with an opening at the first end. The device includes at
least one variable geometry device connected to and extending from the
body to assist rumen retention. Within the body is a dose of an active
agent accessible to rumen fluid via the first end. Also within the body is
a biasing arrangement that is adapted to bias a plunger against the
active agent in the barrel towards the first end. When assembled, the
device includes a cap having a sidewall and top, the cap located over the
opening at the first end and comprising an outlet in the top. Preferably,
the barrel comprises a flared portion towards the first end of the device.
The device may additionally comprise a cap. Preferably, in an assembled
condition, the cap 4 is in contact with the flared portion. Preferably, the
cap 4 comprises sidewalls that contact at least a portion of the barrel to
define an attachment zone. Prior to assembly of the device, located
83212440.1
within the attachment zone is at least one protrusion providing a
localised point of contact between a wall of the barrel and an internal
portion of the sidewall of the cap to provide for an ultrasonic weld
between the barrel and the cap at the attachment zone.
The device may additional comprise a plunger located in the
barrel to define a first compartment holding the active agent between
the plunger and the first end, and a second compartment between the
plunger and the second end. The device may additionally comprise a
variable geometry device defined by at least one pair of resilient wings
extending outwardly from the end of the body distal to the first end.
A benefit of an intra-ruminal device of the present invention
include improved structural integrity.
The device of the invention may be used to deliver one or
more active ingredients to a non-human animal, preferably a ruminant
animal, such as for example cattle, goats, sheep, deer, yaks and
giraffes, preferably cattle or sheep.
1. Intra-ruminal device body
The body of the intra-ruminal device is formed of a material
that is substantially impervious to rumen fluids. So called “Laby devices”
(named after the inventor Ralph Laby), operate on the basis that the
medicament in the barrel is exposed to the ruminal fluid at the orifice, or
aperture end of the device only. As the medicaments typically swell
upon exposure to ruminal fluid, swelling of the medicament in the barrel
at locations other than at the orifice or aperture end may alter the
operation of the device.
As shown in Figure 1, the body of the intra-ruminal device 1
defines a barrel 2 having a first end and a second end, and an opening
at the first end. The second end is typically sealed. Preferably, the first
end of the barrel 2, comprises projections 5. Preferably, the projections
are located on an outer surface of the barrel.
A Laby device is typified by having a biasing mechanism
within the barrel that urges the plunger towards the first end,
83212440.1
maintaining the medicament in the barrel at the orifice or aperture at
the first end.
Preferably the intra-ruminal device is adapted for
continuous or sequential release of the active agent or agents via the
cap aperture, reliant on a column of matrices (i.e. tablets), at least
some of which contain the active agent or agents. The active agent or
agents are released in to the animal in a controlled manner by contact of
matrices with intra-ruminal fluid via the cap orifice or aperture thereby
allowing erosion or dissolution of the matrices into the animal.
The biasing arrangement is located within the body distal to
the active agents, and involves some form of biasing mechanism such
as a spring and plunger, to urge the active agent or agents to the outlet
end. Other mechanisms may be used such as the use of gas to create
pressure on the plunger or electrical mechanical means.
The intra-ruminal device includes a variable geometry
device 3 to ensure retention in the rumen. Ruminants typically
regurgitate their food as part of the digestive process, and without a
retention mechanism the device can be ejected from the animal.
The body of the intra-ruminal device may be formed into a
number of suitable shapes that are able to be administered via the
animal’s esophagus. Preferably the body of the intra-ruminal device is
cylindrically shaped, and preferably the cross section of the body is
circular.
In various embodiments, the at least one outlet may be
located at one end of the body. The outlet may be from about 1, 2, 3, 4,
4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5,
13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20,
.5, 21, 21.5, 22 mm or more in diameter, and useful ranges may be
selected in between any of these values (for example from about 3 to
about 20 mm, or from about 4 to about 18.5 mm in diameter). It will be
understood by a person skilled in the art that the size of the outlets will
depend on factors such as for example, the intended payout rate.
83212440.1
Preferably one or both ends of the body may taper in to a
reduced diameter to aid the passage of the intra-ruminal device down
the oesophagus to the rumen.
The diameter of the body of the intra-ruminal device 1 is
small enough to pass down the oesophagus of a ruminant animal with
ease and large enough to accommodate one or more matrices in the
barrel. The diameter of the barrel 2 depends on, for example the
thickness of the body of the intra-ruminal device. In some embodiments
the diameter of the intra-ruminal device 1 and the diameter of the barrel
2 may be very similar, the difference being the result of the thickness of
the body.
In some embodiments the diameter of the intra-ruminal
device may be less than about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,
1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4,
3.5, 3.6, 3.7, 3.8, 3.9 or 4 cm, and useful ranges may be selected from
any of these values (for example the diameter of the intra-ruminal
device may be from about 1 to about 4 cm, or from about 1.2 to about
3.5 cm).
The length of the body of the device can vary to, for
example, accommodate more or less matrices. The length of the body
may also vary depending on, for example, the animal to which the intra-
ruminal device will be administered the size of the animal, the dose and
pay-out period and may be from about 70, 75, 80, 85, 90, 95, 100, 105,
110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170 mm
or more, and useful ranges may be selected from any of these values
(for example from about 70mm to about 170 mm, or from about 75 mm
to about 165 mm). For example in some embodiments the length of the
body of an intra-ruminal device to be administered to sheep and other
small ruminants may be from about 76 mm to about 83 mm, and the
length of the body of the intra-ruminal device to be administered to
cattle and other similar-sized ruminants may be from about 97 to about
162 mm.
Biasing arrangement
The intra-ruminal device 1 comprises a biasing arrangement
located in the barrel 2 of the device 1 within the body, and is adapted to
83212440.1
bias the active agent or agents in the barrel to the outlet at the first end
of the barrel. In some embodiments, the biasing arrangement may
comprise a plunger 12 and biasing means, the plunger 12 defining a
space within the barrel between the plunger and the closed end of the
barrel. In various embodiments, the biasing means may comprise one or
more springs, gas inflation, or electrical mechanical means.
In some embodiments, the biasing means, such as a spring,
may be made of materials such as alloys of steel, for example stainless
steel, carbon steel, oil tempered wire, chrome silicon steel or chrome
vanadium steel. Other alloys may also be used, for example Inconel,
Monel, beryllium, copper or phosphor bronze. Other suitable materials
will be apparent to those skilled in the art.
In various embodiments the biasing arrangement may be
adapted to be extendible to at least about 45, 50, 55, 60, 65, 70, 75,
80, 85, 90, 95 or 100% of the length of the body, and suitable ranges
may be selected from any of these values (for example from about 45%
to about 100%, or from about 80% to about 100%).
In exemplary embodiments the biasing arrangement may
comprise a spring that is adapted to push a plunger to extend the
biasing arrangement to at least about 80, 85, 90, 95 or 100% of the
length of the body.
Without wishing to be bound by theory the inventors believe
the pressure exerted by the biasing arrangement, that is, the pressure
biasing the active agent or agents towards the at least one outlet
contributes to control of the payout period.
In various embodiments the pressure exerted by the
compression arrangement, for example the biasing means such as a
spring, may remain substantially constant for the entire payout period.
A number of factors can affect the function of the
compression arrangement, and these must be tightly controlled to
achieve constant, consistent and reliable payout of the one or more
active ingredients in the barrel. For example, in conventional devices the
permeability of gasses may be compromised, leading to the formation of
a partial vacuum in the space between part of the biasing arrangement,
83212440.1
for example the plunger of the biasing arrangement, and the closed end
of the barrel. This can then lead to inconsistent payout.
In some embodiments the intra-ruminal device 1 of the
invention may comprise a biasing arrangement in which part of the
biasing arrangement comprises at least one aperture 13.
Plunger
In various embodiments the biasing arrangement comprises
a plunger 12 and a biasing means, for example one or more springs.
The plunger 12 contacts the inner wall surface of the barrel
to substantially form a seal within the barrel.
Variable geometry retention means
In various embodiments, the retention means may comprise
a variable geometry device, preferably a retractable resilient wing or
wings, preferably on one end of the body. The retention mechanism
assists rumen retention by preventing regurgitation of the intra-ruminal
device 1.
Preferably, the resilient wing 3 comprises an extended
position and a retracted position.
Preferably the resilient wing 3 is in an extended position
when no force is applied to the wings 3 as shown in figure 1. In the
extended the position the wings extend outwardly from the end of the
body distal to the outlet (second end).
Preferably the resilient wing 3 transitions from an extended
position to a retracted position when a force is applied to a top surface
of the wings 3, such as when the intra-ruminal device 1 is being
administered into an internal cavity of an animal. As a force is applied to
the top surface of the wings 3, the variable geometry device, preferably
the wings 3 are pressed against the side of the body. The intra-ruminal
device 1 returns to an extended position after administration to prevent
regurgitation. In some embodiments the intra-ruminal device may
comprise more than one retention means, for example a variable
geometry device such as a wing or pair of wings and a weighted
component.
83212440.1
The variable geometry device, for example wings, may be
pressed against the side of the body using a number of means. For
example, water soluble tape or adhesive may be used to hold the wings
against the body.
In some embodiments the variable geometry device, for
example wings may be pressed against the side of the body using a
pharmaceutical grade polymer or co-polymer that is readily dissolved by
the contents of the rumen or using a polymer or co-polymer that melts
at the temperature of the rumen, for example a polymer that melts at a
temperature of from about 37.5, 38, 39, 39.5, 40, 40.5 or 41°C, and
useful ranges may be selected from any of these values (for example
from about 39 to about 40°C, or from about 38 to about 41°C).
Preferably the melting point of the polymer or co-polymer is from about
38.5 to about 40.5°C to avoid the polymer melting in the oesophagus of
the ruminant and releasing the wings from the side of the body before
the device enters the rumen.
In some embodiments the variable geometry device, for
example wings may be made from the same polymeric material as the
body, or they may be made from a different polymeric material. In
various embodiments the variable geometry device, for example wings
may be made of a polymeric material that is less rigid than the polymer
used to make the body, to allow the wings to be retained against the
side of the body during administration to an animal. Suitable polymeric
materials will be apparent to a person skilled in the art and may include
for example any pharmaceutical grade polymers that are sufficiently
pliable to be held against the side of the intra-ruminal device when
administered. In various embodiments the wings or part of the wings
may be made of polypropylene or a co-polymer thereof.
In some embodiments, the body, and the variable geometry
device, for example the wing(s) of the intra-ruminal device may be
manufactured from one or more parts moulded from plastic materials
(e.g. polypropylene) and may be fabricated together by adhesive and/or
welding, preferably ultrasonic welding.
83212440.1
Matrix
In various embodiments, the barrel of the intra-ruminal
device may comprise at least one active-containing matrix comprising at
least one active ingredient.
The at least one matrix may be any shape adapted to fit
inside the barrel of the device. In various embodiments, the barrel of
the intra-ruminal device may comprise more than one matrix. The form
of the matrix may be for example a tablet, a capsule, a caplet or a
wafer. In some embodiments, the one or more matrices may be shaped
to allow them to align axially with respect to one another along the
longitudinal axis of the body of the intra-ruminal device, such that they
are sequentially presentable to the rumen, as originally proposed in the
Laby device. Preferably the at least one matrix is a tablet, preferably
disc-shaped.
In some embodiments the diameter of the one or more
matrices may be less than about 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 mm,
and useful ranges may be selected from any of these values (for
example the diameter of the matrices may be from about 10 to about 35
mm, or from about 11 to about 32 mm). For example in some
embodiments one or more matrices for use in intra-ruminal devices to
be administered to sheep may be from about 11 to about 15 mm in
diameter and one or more matrices for use in intra-ruminal devices to
be administered to cows may be from about 15 to about 32 mm in
diameter.
The diameter of the one or more matrices comprising the
one or more active ingredients must be such that the diameter is small
enough to fit into the barrel of the device. For example if the diameter of
the barrel of the device is 20 mm, then the matrix may have a diameter
of for example around 18 mm.
In some embodiments the device may comprise a plurality
of matrices, for example a plurality of tablets, the number of matrices
depending on the length of the body of the device and the thickness of
the matrix. For example in some embodiments the thickness of the
matrices may be from at least about 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5,
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4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25,
8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10 mm or more, and useful ranges may
be selected between any of these values, for example from about 3 to
about 9 mm, or from about 7 to about 9 mm.
In some embodiments the barrel may comprise one matrix
only, for example one solid core comprising at least one active
ingredient and optionally one or more excipients. In such embodiments
the matrix may substantially span the length of the barrel from the
biasing arrangement to end of the body comprising the at least one
outlet.
In some embodiments, the active ingredient(s) may be
released in to the rumen in a controlled manner by contact of the
composition comprising the active ingredient(s) with the intra-ruminal
fluid allowing erosion or dissolution of the composition in to the rumen.
In some embodiments, a seal exists between the rumen-
facing end of the matrix comprising the active ingredient(s) and the
barrel of the intra-ruminal device. In various embodiments the part of
the compression arrangement, for example the plunger, contacts an
inner wall surface of the barrel to substantially form a seal within the
barrel. Without wishing to be bound by theory the inventors believe that
an ineffective seal between the barrel and rumen-facing end of the
matrix comprising the active ingredient(s) may allow other surfaces of
the matrix or other matrices in the stack to swell, adversely affecting, or
stopping reliable payout of the medication.’
Active ingredients
The one or more matrices of the present invention deliver a
therapeutic quantity of one or more active ingredients. The active
ingredient(s) are delivered from an intra-ruminal device and may be
absorbed in to the systematic circulation.
A wide range of active ingredients may be delivered from
the at least one matrix in the intra-ruminal devices of the present
invention.
In some embodiments the one or more matrices may
comprise one or more antibiotics, antifungals, antivirals, steroid
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hormones, antihistamines, metabolic regulators, productivity regulators,
corticosteroids, antiemetics, anti-thyroidal agents, parasiticidal agents,
such as for example anthelmintics, nutritional actives or a combination
thereof.
In some embodiments the one or more matrices may
comprise one or more vitamins, for example vitamin A, vitamin E,
vitamin B12, vitamin B3, d-pantothenic acid (vitamin B5), folic acid,
vitamin B6, vitamin B1, vitamin D3, vitamin C, vitamin B2. As another
example, the nutritional active could be a pro-vitamin, for example
beta-carotene or panthenol.
In some embodiments the nutritional active may be an
amino acid. Suitable amino acids include but are not limited to the 20
naturally occurring L-amino acids, for example arginine, isoleucine,
leucine, lysine, etc.
In some embodiments the nutritional active may be a co-
enzyme, for example co-enzyme Q.
In some embodiments the nutritional active may be a
mineral. Non-limiting examples of minerals include potassium, sodium,
manganese, zinc, iron, calcium, copper, cobalt, iodine, chlorine and
selenium. In some embodiments the mineral may be in the form of a
suitable salt.
In some embodiments the one or more matrices may
comprise one or more anti-microbial ingredients for example antibiotics,
antifungals, antivirals, anthelmintics, and the like.
Suitable antibiotic agents may be those that act as
inhibitors of cell wall synthesis (e.g. penicillins, cephalosporins,
bacitracin and vancomycin), inhibitors of protein synthesis
(aminoglycosides, macrolides, lincosamides, streptogramins,
chloramphenicol, tetracyclines), inhibitors of membrane function (e.g.
polymixin B and colistin), inhibitors of nucleic acid synthesis (e.g.
quinolones, metronidazole, and rifampin), or inhibitors of other
metabolic processes (e.g. anti-metabolites, sulfonamides, and
trimethoprim). Non-limiting examples of antibiotics include polyethers,
ionophores such as monensin and salinomycin, beta-lactams such as
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penicillins, aminopenicillins (e.g., amoxicillin, ampicillin, hetacillin, etc.),
penicillinase resistant antibiotics (e.g., cloxacillin, dicloxacillin,
methicillin, nafcillin, oxacillin, etc.), extended spectrum antibiotics (e.g.,
axlocillin, carbenicillin, mezlocillin, piperacillin, ticarcillin, etc.);
cephalosporins (e.g., cefadroxil, cefazolin, cephalixin, cephalothin,
cephapirin, cephradine, cefaclor, cefacmandole, cefmetazole, cefonicid,
ceforanide, cefotetan, cefoxitin, cefprozil, cefuroxime, loracarbef,
cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftiofur,
ceftizoxime, ceftriaxone, moxalactam, etc.); monobactams such as
aztreonam; carbapenems such as imipenem and eropenem; quinolones
(e.g., ciprofloxacin, enrofloxacin, difloxacin, orbifloxacin, marbofloxacin,
etc.); chloramphenicols (e.g., chloramphenicol, thiamphenicol,
florfenicol, etc.); tetracyclines (e.g., chlortetracycline, tetracycline,
oxytetracycline, doxycycline, minocycline, etc.); macrolides (e.g.,
erythromycin, tylosin, tlimicosin, clarithromycin, azithromycin, etc.);
lincosamides (e.g., lincomycin, clindamycin, etc.); aminoglycosides
(e.g., gentamicin, amikacin, kanamycin, apramycin, tobramycin,
neomycin, dihydrostreptomycin, paromomycin, etc.); sulfonamides
(e.g., sulfadmethoxine, sfulfamethazine, sulfaquinoxaline,
sulfamerazine, sulfathiazole, sulfasalazine, sulfadiazine,
sulfabromomethazine, suflaethoxypyridazine, etc.); glycopeptides (e.g.,
vancomycin, teicoplanin, ramoplanin, and decaplanin; and other
antibiotics (e.g., rifampin, nitrofuran, virginiamycin, polymyxins,
tobramycin, etc.).
In some embodiments the one or more matrices may
comprise one or more antifungal active ingredients for example one or
more polyenes, azoles, allylamines, morpholines, antimetabolites, and
combinations thereof. For example in some embodiments the matrices
of the invention may comprise one or more of fluconazole, itraconazole,
clotrimazole, ketoconazole, terbinafine, 5-fluorocytosine, and
amphotericin B, or combinations thereof.
Non-limiting examples of antivirals that may be present in
the one or more matrices of the invention may include didanosine,
lamivudine, stavudine, zidovudine, indinavir, and ritonavir.
In some embodiments the one or more matrices may
comprise one or more steroid hormone, for example steroid hormones
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such as growth promoters and production enhancers. In some
embodiments, the steroid hormone may be natural steroid hormone,
such as for example estradiol, progesterone, and testosterone, or a
synthetic steroid hormone, such as trenbolone acetate, estradiol
benzoate, estradiol 17β, and melengestrol acetate, and/or zeranol.
Steroid hormones that may be present in one or more
matrices of the invention may comprise for example natural and
synthetic steroid hormones, steroid hormone precursors, steroid
hormone metabolites, and derivatives thereof that are structurally
derived from cholesterol. Steroid hormones may be synthesized from
cholesterol via pathways that involve cytochrome P450 (cP450)
enzymes, which are heme-containing proteins.
In some embodiments the one or more matrices may
comprise one or more steroid hormones such as for example androgens,
estrogens, progestogens, mineral corticoids, and glucocorticoids.
Exemplary androgens include, but are not limited to, testosterone,
dehydroepiandrosterone, dehydroepiandrosterone sulphate,
dihydrotestosterone, androstenedione, androstenediol, androstanedione,
androstanediol, and any combination thereof. Exemplary estrogens
include, but are not limited to, estrone, estradiol, estriol, estetrol,
equilin, equilenin, and any combination thereof. Exemplary
progestogens include, but are not limited to, progesterone, 17-hydroxy-
progesterone, pregnenolone, dihydroprogesterone, allopregnanolone,
17-hydroxy- pregnenolone, 17-hydroxy-dihydroprogesterone, 17-
hydroxy-allopregnanolone, and any combination thereof. Exemplary
mineralcorticoids include, but are not limited to, aldosterone, 11-
deoxycorticosterone, fludrocortisones, 1 1-deoxy-cortisol,
pregnenedione, and any combination thereof. Exemplary glucocorticoids,
include, but are not limited to, cortisol (hydrocortisone), corticosterone,
18-hydroxy-corticosterone, cortisone, and any combination thereof.
In some embodiments the one or more matrices may
comprise one or more anti-histamines, such as for example clemastine,
clemastine fumarate (2(R)-[2-[1-(4-chlorophenyl)phenyl-
ethoxy]ethylmethylpyrrolidine), dexmedetomidine, doxylamine,
loratidine, desloratidine and promethazine, and diphenhydramine, or
pharmaceutically acceptable salts, solvates or esters thereof.
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In some embodiments one or more matrices may comprise
one or more anti-emetics, such as for example phenothiazines (e.g.,
prochloperazine, promethazine, thiethylperazine, perphenazine,
chlorpromazine, metopimazine, acepromazine, etc.); 5HT-3 receptor
antagonists such as ondansetron, granisetron, tropisetron, dolasetron,
hydrodolasetron, azasetron, ramosetron, lerisetron, indisetron and
palonosetron; and others such as dimenhydrinate, diphenhydramine
(which can also act as an antihistamine), cyclizine, meclizine,
promethazine, hyroxyzine, metoclopramide, domperidone, hyoscine,
hyoscine hydrobromide, hyoscine hydrochloride, scopolamine,
clebopride, alizapride, itopride, bromopride, droperidol, haloperidol,
benzquinamide, cerium oxalate, diphenidol, dronabinol, nabilone,
ginger, levosulpiride, butorphanol and aprepitant.
In some embodiments the one or more matrices may
comprise one or more metabolic regulators, such as for example one or
more methanogens or a hypothyroidism treatment.
In some embodiments the one or more matrices may
comprise one or more ingredients to treat hypothyroidism, such as for
example, thyroid hormones and derivatives thereof, such as thyroixines
such as T , T and T . “T ” refers to the thyroid hormone iodothyronine
2 3 4 2
or 3,5-diiodothyronine. “T ” refers to the art recognized thyroid
hormone, triiodothyronine (also known as (2S)amino[4-(4-
hydroxyiodo-phenoxy)-3,5-diiodo-phenyl]propanoic acid). “T4” refers
to the art recognized thyroid hormone, thyroxine, or 3,5,3′,5′-
tetraiodothyronine (also known as (2S)amino[4-(4-hydroxy-3,5-
diiododophenoxy)-3,5-diiodophenyl]propanoic acid).
In some embodiments the one or more matrices may
comprise one or more productivity regulators, for example polyethers
such as monensin. In some embodiments, the productivity regulator
may be a productivity enhancer.
In exemplary embodiments the one or more matrices may
comprise one or more anthelmintic agents, for example one or more
benzimidazoles, imidazothiazoles, tetrahydropyrimidines, macrocyclic
lactones, salicylanilides, substituted phenols, aromatic amides,
isoquinolines, amino acetonitriles, spiroindoles, or combinations thereof.
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Anthelmintic benzimidazoles comprise for example
mebendazole, flubendazole, fenbendazole, oxfendazole, oxibendazole,
albendazole, albendazole sulfoxide, thiabendazole, thiophanate,
febantel, netobimin, and triclabendazole. Further examples include
mebendazole, and ricobendazole.
Without wishing to be bound by theory, the inventors
believe that benzimidazole-based anthelmintics may interfere with the
worm's energy metabolism on a cellular level by binding to a specific
building block called beta tubulin and preventing its incorporation into
certain cellular structures called microtubules, which are essential for
energy metabolism.
Imidazothiazoles and tetrahydropyrimidines are both
nicotinic agonists. In some embodiments the one or more anthelmintic
agents in the one or more matrices may comprise imidathiazoles, for
example levamisole, tetramisole, and butamisole. Tetrahydropyrimidine
anthelmintics that may be used in the matrices of the invention include,
for example, morantel, oxantel, and pyrantel.
Without wishing to be bound by theory the inventors believe
that tetrahydropyrimidines may mimic the activity of acetylcholine, a
naturally occurring neurotransmitter that initiates muscular contraction.
This may lead to helminths that are unable to feed and starve.
Without wishing to be bound by theory the inventors believe
that imidazothiazoles may have a similar mode of action to
tetrahydropyrimidines and may cause spastic paralysis of helminths, For
example, levamisole is thought to have a broad spectrum of activity and
may therefore be effective against many larval stages of parasites.
In various embodiments the one or more matrices may
comprise one or more macrocyclic lactones, for example abamectin,
doramectin, eprinomectin, ivermectin, selamectin, milbemycin, for
example as milbemycin oxime, moxidectin or a combination thereof.
In some embodiments the one or more matrices may
comprise one or more salicylanilides for example brotianide, clioxanide,
closantel, niclosamide, oxyclozanide, rafoxanide, substituted phenols
including for example bithionol, disophenol, hexachlorophene, niclofolan,
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menichlopholan, nitroxynil, and aromatic amides, including for exmaple
diamfenetide (diamphenethide) or combinations thereof.
In some embodiments the one or more matrices may
comprise one or more isoquinoline anthelmintics, such as for example
praziquantel and epsiprantel. In some embodiments the matrices of the
invention and the intra-ruminal devices may comprise one or more
amino-acetonitrile derivatives, such as for example monepantel.
In some embodiments the one or more matrices may
comprise one or more active ingredients such as for example piperazine
and derivatives thereof such as piperazine and diethylcarbamazine
(DEC, a derivative of piperazine), benzenesulfonamides such as
clorsulon, amidines such as bunamidine, isothiocyantes such as
nitroscanate, and organophosphates such as dichlorvos, and spiroindoles
such as derquantel (2-deoxoparaherquamide).
In various embodiments, the one or more active
ingredient(s) in the at least one matrix of the intra-ruminal device,
is/are stable and does not react with other components in the reaction
mixture or degrade or decompose by other means.
In various embodiments, the payout rates of the active
ingredient(s) may be measured as a function of the width of a matrix
ejected into the rumen through the one or more outlets in the end cap.
In some embodiments the payout rate of the intra-ruminal device of the
invention may be from about 0.1, 0.125, 0.15, 0.175, 0.2, 0.225,
0.025, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.500,
0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775,
0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95, 0.975, 1, 1.1, 1.2, 1.3, 1.4,
1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9 to 3
mm or more per day in water., and suitable ranges may be selected
from any of these values, for example from about 0.3 mm to about 2.4
mm, or from about 0.5 mm to about 1.5 mm). Preferably, the payout of
the one or more active ingredients is linear and in various embodiments
the linearity may be greater than 0.95.
In various embodiments, the payout rates of the one or
more active ingredient(s) is/are minimally affected, preferably not
affected by the pH and ionic composition of the rumen.
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In some embodiments, the one or more matrices of the
intra-ruminal device, may comprise more than one active ingredient. For
example in some embodiments the matrices of the invention may
comprise from 2, 3, 4, 5, 7, 8, 9, or about 10, or more active
ingredients, and useful ranges may be selected from any of these values
(for example from 2 to about 10 or from 2 to about 5 active
ingredients).
In some embodiments the one or more matrices of the
intra-ruminal device, may comprise more than one active ingredient,
wherein some or all of the active ingredients belong to a different
therapeutic class, for example antibiotics, antifungals, antivirals, steroid
hormones, antihistamines, metabolic regulators, productivity regulators,
corticosteroids, antiemetics, anti-thyroidal agents, parasiticidal agents,
such as for example anthelmintics and/or nutritional actives. For
example the matrix may comprise 3 actives, one of which is an
anthelmintic, one of which is an antibiotic and the third one may be a
nutritional active, for example a vitamin.
In various embodiments the one or more matrices of the
intra-ruminal device may comprise more than one active ingredient,
each of which belongs in the same therapeutic class, preferably
anthelminitics. In some embodiments the matrix may comprise two or
more anthelmintic actives belonging to the same class of anthelmintics,
such as for example benzimidazoles, imidazothiazoles,
tetrahydropyrimidines, macrocyclic lactones, salicylanilides, substituted
phenols, aromatic amides, isoquinolines, amino acetonitriles and
spiroindoles. For example the matrices may comprise two or three
actives, each of which may be a macrocyclic lactone.
In various embodiments the one or more matrices of the
intra-ruminal device may comprise two or more active ingredients each
of which is an anthelmintic active and each belonging to a different
anthelmintic class, such as for example benzimidazoles,
imidazothiazoles, tetrahydropyrimidines, macrocyclic lactones,
salicylanilides, substituted phenols, aromatic amides, isoquinolines,
amino acetonitriles and spiroindoles. For example the matrices may
comprise two anthelmintics, one of which may be a macrocyclic lactone
and the other may be an imidazothiazole.
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In some embodiments the one or more matrices may
comprise at least about 5, 7.5, 10, 12.5, 15, 17.5, 20, 22.5, 25, 27.5,
, 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5 or 55% or more of one
or more active ingredients by weight of each matrix, and useful ranges
may be selected from any of these values (for example from about 8 to
about 50% or from about 10 to about 40% by weight of the matrix).
Other ingredients
The one or more matrices comprising the one or more
active ingredients and polymers may further comprise a number of
excipients. Examples of suitable excipient may include, but are not
limited to fillers, diluents, lubricants, surfactants, glidants, gel formers,
binders, and stabilisers, or combinations thereof.
In some embodiments, one or more matrices of the
invention may further comprise one or more fillers or diluents. Examples
of suitable fillers or diluents may include, but are not limited to, sugars
such as for example lactose, sucrose and mannitol, inorganic salts such
as calcium phosphate and calcium carbonate, cellulose, methyl cellulose,
ethyl cellulose, aluminium silicates such as kaolin or combinations
thereof.
In some embodiments the one or more matrices may
comprise one or more fillers and/or diluents at amounts of from about
0, 0.1, 0.25, 0.5, 0.75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12.5, 15, 17.5, 20,
22.5, 25, 27.5, 30 , 32.5, 35, 37.5, 40, 42.5, 45, 47.5, 50, 52.5, 55,
57.5, 60, 62.5, 65, 67.5, 70, 72.5, 75, 77.5, 80, 82.5, 85, 87.5, 90,
92.5, 95 % by weight of the matrix, and useful ranges may be selected
from any of these values (for example from about 0.1 to about 80 % by
weight or from about 0.1 to about 15 % by weight of the matrix).
In some embodiments, the one or more matrices may
comprise one or more surfactants or lubricants. Examples of surfactants
or lubricants may include, but are not limited to, metal stearates such as
for example metal or non-metal stearates such as magnesium stearate,
calcium stearate and stearyl fumarate, glyceryl stearates such as for
example glyceryl monostearate, glycerine derivatives, sodium lauryl
sulfate, sucrose fatty acid ester, mineral clays, and aluminium silicates
such as kaolin or combinations thereof.
83212440.1
In some embodiments the one or more surfactants and/or
lubricants may be present in the matrices of the invention in an amount
of from about 0, 0.01, 0.05, 0.075, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,
0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,
65, 70, 75, 80, 85, or 90% by weight of the matrix, and useful ranges
may be selected from any of these values (for example from about 0.5
to about 50 % or from about 5% to about 40 %).
In some embodiments, the one or more matrices may
further comprise one or more glidants. Examples of glidants include, but
are not limited to, colloidal silica dioxide, talc, metal stearates such as
magnesium stearate, calcium stearate and stearyl fumarate, and
glyceryl stearates such as glyceryl monostearate, or combinations
thereof
In some embodiments the glidant(s) may be present in the
one or more matrices in amounts of from about 0, 0.25, 0.5, 0.75, 1,
1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5,
4.75, or 5% by weight of the matrix, and useful ranges may be selected
from any of these values (for example from about 0.25 to about 4 % or
from about 0 to about 2 % by weight of the matrix).
In some embodiments, the one or more matrices may
comprise one or more additional gel formers. Examples of additional gel
formers that may be used include, but are not limited to, sucrose fatty
acid ester, cellulosic derivatives such as hydroxyethyl cellulose and
hydroxymethyl cellulose, and chitosan, or combinations thereof
The gel former(s) may be present in the one or more
matrices in amounts of from about 0, 0.1, 0.25, 0.5, 0.75, 1, 1.25, 1.5,
1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 10,
, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85 or 90% by
weight of the matrix, and useful ranges may be selected from any of
these values (for example from about 0.5 to about 80 % or from about
1% to about 50% by weight of the matrix ).
In some embodiments, the one or more matrices may
comprise one or more binders. Examples of binders include, but are not
limited to, cellulosic derivatives such as hydroxyethyl cellulose and
hydroxymethyl cellulose.
83212440.1
The binder(s) may be present in the one or more matrices
of the invention in amounts of from about 0, 0.1, 0.25, 0.5, 0.75, 1,
1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5,
4.75, 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50% by weight of the matrix,
and useful ranges may be selected from any of these values (for
example From about 0 to about 35 % by weight of the matrix.
In some embodiments, the one or more matrices may
comprise one or more stabilisers. Examples of stabilisers that may be
used in the matrices include, but are not limited to, antioxidants such as
for example butylated hydroxytoluene, butylated hydroxyanisol and
tocopherol, and buffers.
The stabilisers(s) may be present in the one or more
matrices in amounts of from about 0.01, 0.02, 0.03, 0.04, 0.05, 0.06,
0.07, 0.08, 0.09, 0.1, 0.15, 0.2, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2,
2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, or 5% by weight
of the matrix, and useful ranges may be selected from any of these
values (for example from about 0.1 to about 5% or from about 0.5 to
about 3.5% by weight of the matrix).
2. Intra-ruminal device cap
The intraluminal device 1 comprises a cap 4 that seals the
first end of the device to retain the matrix of active agents within the
barrel. The cap encapsulates the end of the barrel, and contains at least
one aperture.
In some embodiments, as shown in Figure 4, the cap 4
comprises sidewalls and a top, the top comprising one or more
apertures 11. The sidewalls of the cap 4 at least partially contacts the
first end of the barrel to define an attachment zone.
The inventors have found that intra-ruminal devices
comprising one or more ultrasonically welded caps show reduced
separation of device components within the rumen and after
regurgitation.
Without wishing to be bound by theory the inventors believe
that the inclusion of at least one protrusion 5 on the barrel and/or the
83212440.1
cap provides at least one point of contact between the barrel and cap
and provides a localised contact area for an ultrasonic weld between the
body and the cap.
The cap 4 may be formed such that it is contiguous to the
body 2 and comprises at least one protrusion.
In various embodiments the cap encapsulates the first end
outlet of the device, the cap comprising at least one aperture, and in
some embodiments at least one variable geometry device dependent
from the body to assist rumen retention, or both.
In some embodiments there may be at least one protrusion
6 located in the attachment zone and therefore at least one point of
contact between the barrel 2 and the cap 4. Preferably, at least
protrusion 6 is located on the inner surface of the cap 4.
Optionally, at least one protrusion 6 is located on the outer
surface of the first end of the barrel 2. Optionally, the projection 5 on
the outer surface of the first end of the barrel 2 is a protrusion providing
a localised contact area for an ultrasonic weld between the body and the
cap.
In some embodiments there may be more than one
protrusion 6 providing more than one point of contact between the body
and one or more external elements, for example 1, 2, 3, 4, 5, 6, 7, 8, 9,
, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more protrusions providing
1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or
more points of contact respectively and suitable ranges may be selected
from any of these values (for example from 1 to 20, 1 to 10, or 1 to 5
protrusions and points of contact).
In some embodiments the protrusion is continuous around
the perimeter of the barrel at the attachment zone, for example, around
the inside of the end cap and/or around the outside of the body or vice
versa.
In some embodiments the at least one protrusion may be
discontinuous around the perimeter of the body or of the external
element.
83212440.1
In some embodiments there may be a plurality of
protrusions on the body and/or one or more external elements, and the
plurality of protrusions may be provided in a spaced configuration or
adjacent to each other.
In some embodiments at least one protrusion may have a
triangular cross-section.
In some embodiments at least one protrusion may have a
trapezoid cross-section.
In various embodiments at least one protrusion on the
barrel mates with a substantially flat surface of the cap, or vice versa.
In various embodiments at least one protrusion on the body
mates with a surface of at least one external element comprising a
complementary indentation.
Optionally as shown in figure 2, the inner surface of the cap
4 in communication with the opening at the first end of the barrel 2,
comprises a barrier projection 17. The barrier projection 17 the inner
surface of the cap 4 preferably limits ruminal fluid and/or fluid of the
tablet from flowing along the under-surface of the cap. Limiting the flow
of liquids along the under-surface of the cap may be advantageous to
protect the bond between the cap 4 and the barrel 2. The barrier
projection 17 may reduce separation of the cap from the barrel within
the rumen and after regurgitation.
In some embodiments, the cap may be made of the same
material as the body or a different material. In various embodiments the
cap is made of a polymeric material that is stable under the conditions
present in the rumen of the animal. For example, the end cap may be
made of polypropylene or a co-polymer of polypropylene.
3. Weld attachment zone
As shown in figure 1, the intra-ruminal device 1 comprises
an attachment zone B towards the first end of the barrel 2, and the cap
4. At the attachment zone B, at least a portion of the inner surface of
the cap 4 sidewall is in contact with the outer wall surface of the barrel
83212440.1
Preferably, at the attachment zone, the barrel 2 comprises a
width less than the flared end of the barrel 2. Preferably, when the cap 4
is fixed onto the first end of the barrel, the outer surface of the barrel
and the cap is smooth and continuous, as shown in zone B of figure 1.
As best shown in figure 2, in the preferred configurations
prior to heat being applied to the attachment zone, in a pre-weld
condition, located within the attachment zone is at least one protrusion
6. Protrusions 6 provide a localised point of contact between the outer
barrel wall 2 and the internal sidewall of the cap 4.
In the preferred configuration as shown in figure 2, at least
one protrusion 6 comprises a triangular cross-section. Preferably, the
apex of at least one protrusion 6 contacts the outer barrel wall 2.
Preferably, the apex of at least one protrusion 6, points towards the
second end of the barrel. Optionally, the apex of at least one protrusion
6, points towards the first end of the barrel.
Preferably, in the pre-welded condition as shown in figure 2,
the height of the cap 4 in its pre-welded condition, including the
protrusions 6, is greater than the height of the attachment zone of the
barrel 2.
In the preferred configurations, the attachment zone
comprises at least one corresponding weld cavity 16 adjacent to each
protrusion 6. The weld cavities 16 are configured to capture melted
material from a corresponding protrusion 6. Preferably, the volume of
the weld cavities 16 is of the same or greater than the volume of the
corresponding protrusion 6. Preferably, the weld cavities 16 are at least
partially filled by plastic melted from the corresponding protrusion 6 in a
fixed condition.
4. Method of assembling intra-ruminal device
In one embodiment the method of assembling an intra-
ruminal device as described above includes first loading the active agent
into the barrel. The cap is then located over the opening at the first
end. The attachment zones are then subjected to ultrasonic vibrations
to produce frictional heat energy at the protrusions to form a weld
between the protrusion at its contact surface.
83212440.1
Preferably the cap is forced onto the barrel as the welding
takes place so that the cap forms a tight seal against the end of the
barrel.
Preferably, to assemble the intra-ruminal device 1, the
device transforms from a pre-weld condition as shown in Figure 2, to an
intermediate condition as the protrusions begin to melt, to a fixed
condition where the protrusions have melted and the base of the cap 19
is push up against the end of the barrel 20.
Preferably the cap and barrel include a snap fit protrusion
shown as item 5 (and the corresponding thickening of the terminal
portion of the cap 21) in Figure 2. That is, the cap is pushed onto the
end of the barrel until the terminal thickening of the cap 21 snaps over
the protrusion 5. This enables the cap to be held loosely on the end of
the barrel awaiting welding and fitting.
Pre-weld condition/ interference fit
As shown in Figure 2, preferably the pre-weld condition
provides an interference fit where the cap cannot be pushed against the
end of the barrel.
Preferably, the cap 4 is attached to the first end of the
barrel 4 by friction after the parts are pushed together. Preferably, to
attach the cap 4 onto the first end of the barrel 2, a force is applied to
the cap 2, to push it towards the second end of the barrel. Preferably, a
machine applies a force on the outer surface of the cap 2 towards the
second end of the barrel 2. Optionally, manual force using suitable
equipment known to the art can be used to apply the necessary force to
fit the cap 2 over the first end of the barrel 2.
To prevent the cap 4 from disconnecting, a projection 5 on
the barrel or cap is held against a corresponding surface or projection 21
by friction. Preferably, in an attached pre-weld condition, the cap 4 is
loosely fitted onto the first end of the barrel 2. Preferably, the cap 4 can
only be removed from the barrel 2 if sufficient force is applied onto the
cap in a direction towards first end of the barrel.
Preferably, in the pre-welded condition, the height of the
cap 4 in its pre-welded condition, including the protrusions 6, is greater
83212440.1
than the height of the attachment zone of the barrel 2. Preferably, in the
pre-weld condition, the inner surface of the top of the cap 4, is not on
the same plane as the opening at the first end of the barrel 2.
Intermediate condition/welding
Preferably, to transform the intra-ruminal device 1 from a
pre-weld condition, to a fixed condition, the cap 4 is ultrasonically
welded to the first end of the barrel 2. Ultrasonic welding as a method of
fixing the cap 4 to the barrel 2 is advantageous as the method may
improve efficiency, economy, and speed of adjoining the parts together.
To ultrasonically weld the cap 4 to the barrel 2, heat is
generated by a welder by friction via vibrations. In the preferred
configurations, to ultrasonically weld the cap 4 to the barrel 2, the
welder is applied onto the outer surface of the cap. Preferably, the
vibrational energy from the welder is applied substantially on the same
plane or area as the protrusion 6.
In one configuration, the weld is at the distal end of the cap
4. In another configuration, the weld is at the proximal end of the cap 4.
In the preferred configuration, the weld is at both the distal end and the
proximal end of the cap 4. Optionally, the weld is between the proximal
end and distal end of the cap 4.
Preferably sufficient heat is generated to substantially melt
the protrusions 6 in the attachment zone, between the barrel and the
sidewall of the cap 2. In the preferred configuration, pressure is applied
to compress the barrel and cap together to increase bonding.
The heat generated from vibrations is directed to localised
points of contact between the barrel and the cap. Preferably, the
localised points of contacts being the protrusions 6 that extend from one
surface to contact the other surface.
Preferably, the heat generated from the vibration and
friction between the protrusion 6 and a corresponding surface,
substantially melts the protrusion. The melted plastic from the
protrusion 6, preferably flows and at least partially fills the
corresponding welding cavity 16 in an intermediate condition.
Preferably, the distance between inner surface of the cap 4, and the
83212440.1
outer surface of the barrel 2 decreases from the pre-weld condition to
the intermediate condition. Preferably, as the protrusion 6 are melted,
the cap 4 displaces in a direction towards the second end of barrel.
Preferably the cylinder pressure of the ultrasonic welding is
3 bar.
Preferably the stroke of the ultrasonic welding is 1mm
proximal from the outlet.
Preferably the weld time of the ultrasonic welding is about
0.32 seconds.
Preferably the hold time of the ultrasonic welding is 1
second.
Preferably the delay time before the ultrasonic vibration
starts is about 0.5 seconds.
Preferably the amplitude of vibration of the ultrasonic
welding is 8.
The parameters used for ultrasonic welding may tailored to
effectively weld caps and device bodies comprising, for example,
protrusions of different sizes.
In some embodiments the cylinder pressure used for
ultrasonic welding may be from about 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,
1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6,
27, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1,
4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5 bar or more, and useful ranges
may be selected from any of these values (for example from about 0.5
to about 5, from about 1 to about 4, or from about 2 to about 3 bar).
In some embodiments the cylinder flow, the velocity of the
cylinder as it travels towards the components may be from about 5, 10,
, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or
100% and useful ranges may be selected from any of these values (for
example from about 5 to about 100%, from about 10 to about 60%, or
from about 40 to about 60%).
83212440.1
In some embodiments the distance that the cylinder travels
to press the components together (stroke) may be from about 0.5, 1, 2,
3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
90, 95 or 100mm or more, and useful ranges may be selected from any
of these values (for example from about 0.5 to about 100m, from about
1 to about 80mm, from about 1 to about 70mm).
In some embodiments the weld time, hold time - the
duration that the components are held together after the weld has been
completed – may be from about 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4,
0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0,9, 0.95, 1, 1.05, 1.1,
1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6, 1.65, 1.7, 1.75,
1.8, 1.85, 1.9, 1.95, 2.0, 2.05, 2.1, 2.15, 2.2, 2.25, 2.3, 2.35, 2.4,
2.45, 2.5, 2.55, 2.6, 2.65, 2.7, 2.75, 2.8, 2.85, 2.9, 2.95 or 3 seconds
or more and useful ranges may be selected from any of these values
(for example from about 0.1 to about 3, from about 0.1 to about 2, or
from about 0.1 to about 1 second).
In some embodiments the trigger – the delay time before
the ultrasonic vibration starts – may be from about 0.1, 0.15, 0.2, 0.25,
0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0,9,
0.95, 1, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.45, 1.5, 1.55, 1.6,
1.65, 1.7, 1.75, 1.8, 1.85, 1.9, 1.95, or 2.0 seconds or more and useful
ranges may be selected from any of these values (for example from
about 0.1 to about 2, from about 0.1 to about 2, or from about 0.1 to
about 0.75 seconds).
In some embodiments the amplitude of the vibration may
be from about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more
and useful ranges may be selected from any of these values (for
example from about 1 to about 15, from about 5 to about 15, or from
about 5 to about 10).
In the preferred embodiment, a rod forces the matrix of
active agents towards the second end of the barrel 2, away from the
welding zone, during the welding process. Preferably, the machine which
applies a force on the cap 4 towards the second end of the barrel,
simultaneously pushes the matrix of tablets in the same direction.
83212440.1
Optionally, a separate mechanism forces the matrix of active agents
towards the second end of the barrel 2.
An advantage of pushing the matrix of tablets towards the
second end of the barrel is to prevent heat damage to the internal
components of the intra-ruminal device 1, during the welding phase.
Fixed condition
Following, the ultrasonic welding phase, the intra-ruminal
device 1 undergoes a cooling phase wherein the barrel 2 and cap 4 are
cooled following ultrasonic welding to create a solid state weld.
Preferably, once the weld has cooled, the cap 4 and barrel 2 are fused
together in a fixed condition. Preferably, in the fixed condition, the
inner surface of the top of the cap 4, is on the same plane as the
opening at the first end of the barrel 2. The ultrasonically welded caps 4,
show reduced separation of device components within the rumen and
after regurgitation.
Although the invention has been described by way of
example and with reference to particular embodiments, it is to be
understood that modifications and/or improvements may be made
without departing from the scope or spirit of the invention.
The present invention will be further illustrated in the
following examples which are given for illustration purposes only and are
not intended to limit the invention in any way.
EXAMPLES
Example 1
This example demonstrates the effect of modifying the cap
protrusions.
Caps as shown in Figure 2 were prepared. These caps
comprise a thickened and blended wall section below the retention bead
compared to test caps 1.
Intra-ruminal device bodies were constructed out of Bormed
BE860MO resin and the intra-ruminal device bodies were ultrasonically
83212440.1
welded to either the cap of Figure 2 or test cap 1, both made of EP274P
resin.
When the weld parameters of Table 2 were used some
splitting was observed for test cap 1 but not the caps of Figure 2.
Increasing the weld time to 0.34s also resulted in
successfully welded devices comprising the caps of Figure 2 made of
EP274P resin.
Leak test
Five empty welded devices comprising the caps of Figure 2
formed using the weld parameters of Table 2 underwent leak tests by
submerging the welded devices in a dye solution contained in a pressure
vessel.
A 30 kPa vacuum was pulled for 30 seconds, after which
time the capsules were removed from the pressure vessel and examined
for signs of dye-incursion.
All devices passed the leak test.
Crush test
83212440.1
Ten empty welded devices comprising the caps of Figure 2
formed using the parameters of Table 2 were crushed in a vice to 5 mm.
No cracks were observed in any of the devices which all remained intact.
Appearance
All devices comprising the caps of Figure 2 (both empty and
full of tablets) welded using the settings described in Table 2 had an
acceptable weld appearance in that the weld joint was closed with no
splitting.
Example 2
This example provides an example of welding configuration
settings for ultrasonically welding a cap to the first end of the barrel of
an intraruminal device.
Optionally, an ADG20 generator is used for an Ultrasonic
Welder U149. The tables below provides an example of parameters
which can be used.
Welding Parameters
Welding Mode Energy mode
Throttle From 3.5 to 7.0
Amplitude (40-100% intern. From 95 to 100%
Gain 1.5 x 2.0 27.00um
Trigger (Pressure) 0.6
Welding Energy 310.0Ws
Hold Time 600ms
83212440.1
Claims (17)
1. An intra-ruminal device comprising an elongate body or body assembly substantially impervious to rumen fluids, the body defining a barrel having a first end and a second end, and an opening at the first end, at least one variable geometry device connected to and extending from the body second end to assist rumen retention, a dose of an active agent within the body to be accessible to rumen fluid via the first end, a biasing arrangement within the body adapted to bias a plunger against the active agent in the barrel towards the first end, and a cap having a sidewall and top, the cap located over the opening at the first end and comprising an outlet in the top, the sidewalls that overlap a portion of the barrel define an attachment zone, and located within the attachment zone is at least one protrusion providing a localised point of contact between a wall of barrel and an internal portion of the sidewall of the cap to provide for an ultrasonic weld between the barrel and the cap at the attachment zone.
2. A device of claim 1 wherein a plurality of protrusions are provided.
3. A device of claim 2 wherein the protrusions are in the same plane.
4. A device of claim 2 wherein the protrusions are in different, yet adjacent, planes.
5. A device of claim 1 or 4 wherein the protrusions form contiguously about the perimeter.
6. A device of any one of claims 1 to 5 wherein the protrusions are i) located on the outer surface of the barrel in the attachment zone, ii) on the inner surface of the cap side wall, or iii) both (i) and (ii).
7. A device of any one of claims 1 to 6 wherein at least one protrusion in cross section is triangular or trapezoidal. 83212440.1
8. A device of any of claims 1 to 7 wherein a portion of the inner surface of the cap sidewall comprises a notch, into which extends a protrusion from the outer wall of the barrel to contact the surface of the notch.
9. A device of any one of claims 1 to 8 wherein the thickness of the barrel wall adjacent the attachment zone is thickened.
10. A device of claim 9 wherein the thickening of the barrel side wall is to substantially match the thickness of the cap sidewall.
11. A device of any one of claims 1 to 10 wherein at least one protrusion mates with a substantially flat surface of the corresponding wall surface.
12. A method of assembling an intra-ruminal device, the method comprising: providing an intra-ruminal device comprising: o an elongate body or body assembly substantially impervious to rumen fluids, the body defining a barrel having a first end and a second end, and an opening at the first end, o at least one variable geometry device connected to and extending from the body at the second end to assist rumen retention, o a dose of an active agent within the body to be accessible to rumen fluid via the first end, o a biasing arrangement within the body adapted to bias a plunger against the active agent in the barrel towards the first end, loading the active agent into the barrel, attaching a cap located over the opening at the first end, the cap comprising an outlet in the top and having sidewalls that overlap a portion of the barrel to define an attachment zone, and located within the attachment zone is at least one protrusion providing a localised point of contact between a wall of the barrel and an internal portion of the sidewall of the cap, 83212440.1 subjecting the attachment zone to ultrasonic vibrations to produce frictional heat energy at the protrusion to form a weld between the protrusion at its contact surface.
13. A method of claim 12, wherein the primary direction of the ultrasonic vibrations are substantially perpendicular to the cap sidewall.
14. A method of claim 12 or 13 wherein the body and the cap are held together under heat and pressure.
15. A use of an intra-ruminal device of any one of claims 1 to 11 in a ruminant.
16. The use of claim 15 wherein the intra-ruminal device is used in a group or herd of ruminants, each ruminant being administered an intra- ruminal device, and wherein the cap remains on the barrel of the intra- ruminal device for the duration of the administration period.
17. The use of claim 15 or 16 wherein the intra-ruminal device is used in a group or herd of ruminants, each ruminant being administered an intra-ruminal device, and wherein the variable retention means remain attached to the body for the duration of the active agent payout period. 83212440.1 8 10
Publications (1)
Publication Number | Publication Date |
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NZ750914B2 true NZ750914B2 (en) | 2021-03-02 |
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