Note: Descriptions are shown in the official language in which they were submitted.
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IMPROVEMENTS IN DELIVERY TECHNOLOGY
TECHNICAL FIELD
The invention relates to an improved delivery technology.
More specifically, the invention relates to a delivery device for
administration to the
mammary gland of a subject.
BACKGROUND ART
For the purposes of this specification, the invention shall be disclosed in
terms of
administration to a cow however this is not linuting. It will be appreciated
by someone
to dulled in the art that the delivery device can be administered to other
animals besides
cows.
The question of delivering an active agent to a subject has been considered at
length in
prior art. Indeed, there are many different known methods of delivering an
active
agent to a subject including sprays, infusions, injections, suppositories,
pessaries,
tablets and capsules.
Where the active agent must be delivered directly to a body cavity, the mode
of
administration is usually a suppository type device that is physically
inserted into the
cavity. These devices are useful for providing a dose of an agent to a subject
as they
can reach parts of the subject's body that other methods of administration
cannot reach.
2o This method also has the disadvantage of not holding the deposit in place
other than by
normal bodily means. In worst cases the active agent leaks from the cavity
thus not
delivering the agent to the desired area for treatment.
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Physical teat plugs in particular have been considered in previous embodiments
to help
retain the agent in the mammary gland of cows. One problem with this is that
the
plugs must be physically removed once treatment is complete. Where a large
number
of animals are being treated, this is a time consuming and labour intensive
task.
In addition, the plugs are not always made of natural andlor biologically
acceptable
andlor physiologically acceptable materials. Furthermore, the plugs tend to
fall from
the teat thus wasting the active agent. A further problem is that plugs which
fall off
litter farm paddoclcs and can potentially become caught in and damage
machinery.
A further problem with such devices is that the viability of the active agent
can be
to reduced by a number of mechanisms prior to when the agent is delivered at
the site to
be treated. In worst cases the active agents brealcdown entirely before
insertion into
the subject. For example air exposure and/or heat exposure during storage can
lower
the activity of unstable agents. Finally, agent release can be haphazard and
not always
controlled due to device constraints as well as the already described problems
with
retaining the device (and active agent).
It is therefore desirable to have a device that overcomes the above problems
of
securing the device, physical waste (of agent and device) and 'bio-
friendliness' of the
device.
In intra-mammary treatments, traditional methods have tended to utilise
infusion
methods for administration of the agent rather than a suppository device. A
main
reason for this usage is that the suppositories available are not of the
appropriate shape
and/or size for intra-mammary applications. The infusion method has the
advantage of
relative ease of formulation and administration.
Infusion methods do however have several disadvantages. Hygiene requirements
mean
that each syringe and/or cannula must be replaced for each teat. This is both
time
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consuming and costly. Also, as the infusion formulation is typically viscous,
the
formulation may require warming to reduce the viscosity, thus allowing
administration
of the infusion. In worst case situations, active agent seeps out of the
infusion site.
A further problem with infusion formulations is that they often require
careful
treatment such as refrigeration before administration to ensure the active
remains
stable.
An alternative to intramamrnary infusions includes dilators coated with a
dextrin film
containing salicylic acid is described in U.S. Pat. No. 2,32,343 (Mosey.
However the
dilators must remain within the teat canal and be periodically replaced during
the
1o treatment period.
From the above discussion it can be seen that it is desirable to have an
alternative to
infusion methods for administering an active agent to a subject, particularly
for intra-
mammary applications.
All references, including any patents or patent applications cited in this
specification
are hereby incorporated by reference. No admission is made that any reference
constitutes prior art. The discussion of the references states what their
authors assert,
and the applicants reserve the right to challenge the accuracy and pertinency
of the
cited documents. It will be clearly understood that, although a number of
prior art
publications are referred to herein, this reference does not constitute an
admission that
any of these documents form part of the common general knowledge in the art,
in New
Zealand or in any other country.
It is acknowledged that the term 'comprise' may, under varying jurisdictions,
be
attributed with either an exclusive or an inclusive meaning. For the purpose
of this
specification, and unless otherwise noted, the term 'comprise' shall have an
inclusive
meaning - i.e. that it will be taken to mean an inclusion of not only the
listed
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components it directly references, but also other non-specified components or
elements. This rationale will also be used when the term 'comprised' or
'comprising' is
used in relation to one or more steps in a method or process.
It is an object of the present invention to address the foregoing problems or
at least to
provide the public with a useful choice.
Further aspects and advantages of the present invention will become apparent
from the
ensuing description which is given by way of example only.
DISCLOSURE OF THE INVENTION
l0 According to one aspect of the present invention there is provided a device
for
administration to the mammary gland of a subject including;
at least one active agent; and,
at least one carrier material; and,
characterised in that the environment into which the device is inserted into
triggers
dispersion of the active agent.
Preferably, the earner material is also characterised in that the environment
into which
the device is inserted into triggers dispersion of the carrier material.
The carrier material and active agent combination is preferably adapted to fit
the
cavity. Most preferably, the carrier material is in an elongated shape to aid
insertion
into the cavity.
The present invention describes a useful device that has been found by the
Applicant to
be effective in delivering a dose of active agent to the mammary gland of a
subject
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whereby the agent is lcept stable before application and, on application, the
device
breaks apart or disintegrates to release the active. The elongated shape in
particular,
enables simple administration of the device to the mammary gland cavity.
Depending on the carrier material used, it will be appreciated by those
spilled in the art
5 that the rate of release of the active agent can also be regulated. By way
of example,
the active agent is located wholly within the carrier material and the
dispersion of the
carrier material (and subsequently, the active agent) is controlled by choice
of carrier
material and trigger mechanism.
In preferred embodiments, administration is by physical means including
pushing the
device into the cavity by hand. An alternative embodiment is to apply the
device using
an applicator device.
Preferably, the device is in a solid form capable of retaining its shape in
order to allow
insertion. It will be appreciated however that liquid active agents (and even
gaseous
agents) can also be utilised provided that the agent can be entrapped within
the Garner
material, thus the invention has a wide degree of flexibility in state of the
active agent.
A further advantage of the device is that it is a single use complete device
as opposed
to an infusion method which requires replacement syringe, cannula and separate
assembly. Also use of an infusion method requires skill in placement of the
cannula
point - such shill is not required in the present invention where the device
need only be
physically inserted into the cavity.
Preferably the cavity is a mammary gland. Most preferably the device is
inserted into
the lumen of the teat of the mammary gland.
The device is particularly suited to intra-mammary applications where the
device is in
contact with the walls of the cavity. In particular the device retains the
active agent to
be delivered in the cavity.
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Preferably, the subject is an animal selected from species of the group
consisting of:
bovine; cervine; porcine; ovine; cervine; bovidae.
In preferred embodiments, the subject is a lactating animal.
It is the understanding of the Applicant that the formulation can be used with
any
active agent. The agent can have biological, chemical, and/or physical
activity but
preferably the agent is biologically active.
Typical agents include those selected from the group consisting of:
antibacterial agent;
antifungal agent; anti-inflammatory agent; antiparasitic agent; anti-
neoplastic agent;
analgesic agent; anaesthetic agent; antipsychotic agent; vaccine; central
nervous
to system agent; growth factor; hormone; antihistamine; osteoinductive agent;
cardiovascular agent; anti-ulcer agent; bronchodilating agent; vasodilating
agent; birth
control agent; antihypertensive agent; anticoagulant; antispasmodic agent;
fertility-
enhancing agent; and combinations thereof.
It will be appreciated by those slcilled in the art that, as the carrier
material is preferably
substantially inert with respect to the active agent, any type of active agent
can be
included.
In a further embodiment, a plurality of agents are used that act independently
or in
combination.
In preferred embodiments, the active agent is combined with the carrier
material in a
form selected from the group consisting of: a carrier material coating
enclosing the
active agent; an active agent coating on the outside of the carrier material;
active agent
randomly mixed through the carrier material; partial coating of carrier
material on the
active agent; and partial coating of active agent on the carrier material.
Most
preferably, the active agent is uniformly distributed throughout the carrier
material.
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Preferably, the carrier material or materials used are physiologically and
pharmaceutically acceptable and are also substantially inert with respect to
the active
agent or agents. Examples of preferred carrier materials are those selected
from the
group consisting of: lactose; celluloses; cyclodextrins; starch; gelatin;
dicalcium
phosphate; calcium sulfate; kaolin; mannitol; sodium chloride; thermoplastics;
stearates; and combinations thereof. Most preferably, the carrier material is
selected
from the group consisting of: lactose; magnesium stearate; and combinations
thereof.
In the preferred embodiment, the environment into which the device is inserted
triggers
dispersion of the agent. Preferably this trigger for dispersion is selected
from the group
consisting of: moisture; pH; temperature; enzyme activity; air contact; other
active
agent activity; and combinations thereof. Most preferably, the trigger for
dispersion is
moisture content.
In preferred embodiments, the dispersion method is selected from the group
consisting
of: effervescence; liquid formation; gas formation; solid erosion; other known
means
for dispersion; and combinations thereof. Most preferably, the mechanism is
dispersion in an effervescent manner like, for example a BeroccaTM tablet
placed in
water.
In preferred embodiments, the rate of dispersion is adjusted by use of
different carrier
materials. More preferably, the rate of dispersion is within a period of 1 to
10 minutes.
Optionally, a retainer material is used to provide a barrier to retain the
carrier material
and active agent within the cavity. Preferably the retainer material falls out
of the
cavity or erodes away after the agent has been dispersed. For example, the
retainer
material drops out of the teat and degrades away naturally thereafter on the
farm
paddock. Preferably, the retainer material is made of physiologically and
pharmaceutically acceptable materials. Most preferably the retainer material
is a
'muco-adhesive' material.
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For the purposes of this specification, 'muco-adhesive' refers to any polymer
or
material that when applied in a wet or dry form to a mucosal membrane, adheres
in
such a way as to slough off over a time period longer than that taken for
dispersion of
the active agent. Preferably muco-adhesive materials are selected from the
group
consisting of: polyethylene oxide; poly ethylene glycol; polyvinyl alcohol;
polyvinyl
pyrrolidine; poly acrylic acid; poly hydroxy ethyl methacrylate; hydroxypropyl
cellulose; hydroxypropyl methylcellulose; hydroxyethyl methylcellulose;
hydroxyethyl
ethyl cellulose; hydroxyethyl cellulose; chitosan; and combinations thereof.
Most
preferably, the muco-adhesive material is hydroxypropyl methylcellulose or
1o polyethylene oxide.
In preferred embodiments, the retainer material is applied to the carrier
material /
active agent mixture at a point selected from the group consisting of: at
least a portion
of the carrier material / active agent mixture; dispersed within the carrier
material /
active agent mixture; enclosing the carrier material / active agent mixture;
and
combinations thereof. Most preferably the retainer material for elongated
device
applications is applied to: an end of the Garner material / active agent
('layered'); as a
complete coating to the exterior of the carrier material / active agent ('a
coated core');
as a partial coating to the exterior of the carrier material / active agent
('a partially
coated core').
In further embodiments, the device can also contain further materials for
administration to the subject. These materials are preferably physiologically
and
pharmaceutically acceptable, such as thickening agents, emulsifiers,
stabilising agents,
glidants, lubricants and solubility enhancing agents.
According to a further aspect of the present invention there is provided a
method of
treatment of a subject by administration of a device substantially as
described above.
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According to a further aspect of the present invention there is provided the
use of a
device substantially as described above in the treatment of a subject.
It will be appreciated from the above description that there is provided a
device that
can be used quicldy and relatively cheaply compared to injection methods.
It will be also appreciated by those spilled in the art that the above
described device
provides several advantages over traditional suppository administration
devices
including the use of the device for mammary gland applications.
It will also be appreciated that, as the carrier material and active agent
mixture (and
retainer material if present) can be shaped, administration is made easier.
to In addition the device has a retainer material to hold the cancer material
/ active agent
in place. This retainer material degrades naturally and does not require
physical
removal unlike traditional methods that both fall out of the cavity and
pollute the
environment into which they are released or remain within the subject until
physical
removal.
BRIEF DESCRIPTION OF DRAWINGS
Further aspects of the present invention will become apparent from the ensuing
description which is given by way of example only and with reference to the
accompanying drawings in which:
2o Fi- ug re 1 is a cross section side view of the teat as described in the
preferred
embodiment; and,
Fi- ug re 2 is a further cross section side view of the teat as described in
the
preferred embodiment; and,
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Fi- ugLre 3 shows four preferred embodiments for the device.
BEST MODES FOR CARRYING OUT THE INVENTION
The invention will now be further described with reference to more detailed
examples.
With reference to the attached drawings, the methodology and process is
described
below.
For the purposes of this example, the subject is a lactating cow wherein the
device is
administered to the mammary gland (2) of the cow. It will be appreciated by
those
skilled in the art that this description is given by way of example only and
other
subjects are also encompassed within the invention.
Referring to Figure 1, an elongated shaped Garner material is used (3)
containing a
uniformly mixed biologically active agent (1) is inserted into the cow mammary
gland
(2). An end of the tablet is coated with a muco-adhesive material (the
'retainer
material')(4). This material acts to retain the device (3) in the gland (2).
In the embodiment shown, the device (3) shows an effervescence option. The
device
(3) is in an elongated shape and is inserted into the lumen (5) of the teat.
On contact
with moisture in the lumen (5), the device (3) rapidly breaks down to that
shown in
Figure 2 in an effervescent manner.
As shown in Figure 2, the active agent is dispersed (6) in the mammary gland.
The
muco-adhesive portion (4), entering last, acts to retain the device in the
lumen (5).
After a period of time following dispersion (6), the muco-adhesive portion (4)
drops
away from the lumen (5) of the teat.
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In the above example, one embodiment is shown for the device being a 'layered'
option. This is further described in Figure 3 and generally indicated by arrow
(9)
whereby the carrier material and active agent mixture (10) are evenly mixed
together
and a retainer material (11) is located at one end of the device. In this
embodiment, the
preferred carrier materials are a combination of lactose and magnesium
stearate (1%
wt). The retainer material is preferably polyethylene oxide.
Three other configurations are also shown, generally indicated by arrows (7),
(12) and
(15).
In the option indicated by arrow (7), a 'monolithic' example is shown whereby
the
to device is made up of a Garner material core and active agent only (8). An
example
carrier material in this embodiment is a mixture of lactose and magnesium
stearate
(1% wt).
In the option indicated by an ow (12), a 'coated core' example is shown
whereby the
device is made up of a carrier material and active agent (14) completely
enclosed
within a retainer material coating (13). An example carrier material in this
embodiment is a mixture of lactose and magnesium stearate (1% wt). The
retainer
material is preferably hydroxypropyl methylcellulose.
In the option indicated by arrow (15), a 'partial coated core' example is
shown
whereby the device is made up of a carrier material and active agent (16)
partially
enclosed within a retainer material coating (17). In this case, an opening
exists at one
end of the device however it will be appreciated that edges of the Garner
material /
active agent interior can be exposed on any edge or edges. An example carrier
material in this embodiment is a mixture of lactose and magnesium stearate (1%
wt).
The retainer material is preferably hydroxypropyl methylcellulose.
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It will be appreciated that a wide variety of different configurations are
possible and
only governed by the shape of the cavity and material characteristics.
Aspects of the present invention have been described by way of example only
and it
should be appreciated that modifications and additions may be made thereto
without
departing from the scope thereof as defined in the appended claims.
