U.S. patent application number 10/742497 was filed with the patent office on 2004-11-04 for ocular treatment device.
This patent application is currently assigned to Pharmacia Aktiebolag. Invention is credited to Embleton, Jonathan K., Houzego, Peter J., Jones, Stephen P., Malcolmsen, Richard J., Martini, Luigi G., Rocca, Sarah A., Stevens, Howard N..
Application Number | 20040220537 10/742497 |
Document ID | / |
Family ID | 10760545 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040220537 |
Kind Code |
A1 |
Embleton, Jonathan K. ; et
al. |
November 4, 2004 |
Ocular treatment device
Abstract
A unit container for a treatment fluid comprises a sealed
enclosure of which one wall section thereof is formed with at least
one opening. The enclosure is pressuriseable to discharge its
contents thorough the opening or openings, which is or are of
sufficient diameter to enable the generation of a jet and/or
discrete droplets of treatment fluid discharged therefrom. The one
wall section is typically a flat section of the enclosure wall, and
the enclosure is typically a blister pack, with the wall section at
a planar base of the blister. However the one wall section may be
dome-shaped and formed with at least one opening in the top region
of the dome. Containers of the invention may be provided in
packages, for example in strip form or in planar arrays. Dispensing
devices are described for discharging their content in
treatment.
Inventors: |
Embleton, Jonathan K.;
(Newbury, GB) ; Jones, Stephen P.; (Milngavie,
GB) ; Malcolmsen, Richard J.; (Freshbrook, GB)
; Martini, Luigi G.; (Oxton, GB) ; Houzego, Peter
J.; (Oakington, GB) ; Rocca, Sarah A.;
(Girton, GB) ; Stevens, Howard N.; (Drymen,
GB) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Pharmacia Aktiebolag
|
Family ID: |
10760545 |
Appl. No.: |
10/742497 |
Filed: |
December 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10742497 |
Dec 19, 2003 |
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09394591 |
Sep 13, 1999 |
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6726665 |
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09394591 |
Sep 13, 1999 |
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08793299 |
Aug 11, 1997 |
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6425888 |
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08793299 |
Aug 11, 1997 |
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PCT/GB95/02040 |
Aug 30, 1995 |
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Current U.S.
Class: |
604/290 |
Current CPC
Class: |
B65D 75/58 20130101;
B05B 9/0805 20130101; A61F 9/0008 20130101 |
Class at
Publication: |
604/290 |
International
Class: |
A61M 035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 30, 1994 |
GB |
GB 94 17399.4 |
Claims
1. A method of creating a directed jet and/or stream of droplets
forming a unit dose of treatment liquid comprising discharging such
liquid from a sealed enclosure through an opening in a wall section
thereof, the opening having a diameter in the range 20 to 200
.mu.m, by pressurising the enclosure at a rate sufficent to
generate a jet and/or stream of droplets with a minimum diameter of
20 .mu.m and sufficient momentum to sustain substantially linear
movement over a predetermined distance.
2. A method according to claim 1 wherein the enclosure is
pressurised by collapse of the wall thereof.
3. A method according to claim 2 wherein the wall includes a
reinforced region to orient its collapse.
4. A method according to any preceding claim wherein the enclosure
is pressurised by the relative movement of at least one wail
thereof.
5. A method according to any preceding claim wherein the enclosure
is a blister pack.
6. A method according to any preceding claim wherein the liquid is
discharged through the opening in a flat section of the enclosure
wall.
7. A method according to claim 5 and claim 6 wherein the wall
section is at a planar base of the blister.
8. A method according to any preceding claim including the step of
removing a cover overlaying said wall section and the opening
therein.
9. A method according to any of claims 1 to 7 wherein the opening
is closed by a membrane, which membrane ruptures upon
pressurisation of the enclosure.
10. A method according to any preceding claim wherein the treatment
liquid is an ophthalmic treatment fluid.
11. A method according to any preceding claim wherein the sealed
enclosure is one of a plurality thereof connected by a common
supporting substrate, and including the step of locating one of the
containers at a dosing station prior to discharging treatment
liquid therefrom.
12. A method according to claim 8 and claim 11 wherein the step of
locating a container at a dosing station is synchronised with the
removal of the cover.
13. A method according to any preceding claim wherein the enclosure
is pressurised by compressing the enclosure from the outside and
against the wall section thereof.
14. A method according to claim 13 wherein the enclosure is
pressurised by a piston or hammer mechanism for urging towards the
wall section of the enclosure an opposite section of the wall.
15. A method according to claim 13 wherein the enclosure is
pressurised by a piezoelectric element.
16. A method according to claim 15 wherein the piezoelectric
element is a ring transducer disposed around the enclosure.
17. A method of treatment comprising a method according to any
preceding claim wherein the generated jet and/or stream of droplets
is directed at a treatment site.
Description
[0001] This invention relates to ocular treatment devices, and
particularly to a device of the kind which is operable to deliver
to the eye treatment fluids in the form of a jet and/or small
droplets.
[0002] Ophthalmic treatment fluids are commonly administered to the
eye by means of eye drops or ointments. The use of eye drops has a
number of disadvantages, primarily as a consequence of the
difficulty with which drops are accepted by the patient. The drops
are relatively large, and the instinctive blink that is provoked by
the arrival of a drop on the eye severely limits the amount of or
proportion of fluid that actually contacts the target area on the
eye. Typically less than 10% of a 50.mu.l drop can be effective,
the remainder being lost by drainage, either externally or through
nasolacrimal drainage. Such use of expensive treatment fluids is
wasteful, as well as leading to substantial uncertainty regarding
the effectiveness of a treatment. Similar comments apply to the use
of ointments, although levels of wastage can be reduced by careful
delivery. The greater viscosity of ointments reduces their tendency
to drain or be washed away.
[0003] In our International Patent Application No. PCT/GB95/01482
there are proposed various techniques for delivering treatment
fluid to the eye. These employ systems in which treatment fluid is
drawn from a reservoir and discharged in a controlled manner to the
eye. While these techniques are useful, there are difficulties
arising from the repeated use of the multidose nozzle.
Specifically, it is difficult to maintain the sterility of the
treatment fluid in a system in which doses of fluid are
successively drawn from a reservoir, and passed through a re-usable
nozzle without the use of preservatives. The use of preservatives
has caused some concern as discussed on pages 8-11 of "Ophthalmic
Drug Delivery Systems" (Drugs in the Pharmaceutical Sciences,
Volume 58), published in 1993 by Marcel Dekker.
[0004] Reference is also directed to U.S. Pat. No. 3,934,585 which
discloses a variety of mechanisms for delivering unit doses of
treatment fluid to the human eye. The doses are held in dispensing
tubes which are fitted in the mechanisms when treatment is
required. The mechanisms are operative to apply compressed air to
one end of a tube resulting in the discharge of treatment fluid
from the other end.
[0005] It is an aim of the present invention to minimize or
eliminate the need to use preservatives in ophthalmic treatment
fluids without risking contamination. Thus, in a primary aspect,
the present invention provides a unit container for a treatment
fluid comprising a sealed enclosure of which one wall section
thereof is formed with at least one opening, the enclosure being
pressuriseable to discharge its contents through said at least one
opening, which opening is of sufficient diameter to enable the
generation of a jet and/or discrete droplets of treatment fluid
discharged therefrom.
[0006] The wall section of a container according to the invention
formed with the opening or openings is typically a flat section of
the enclosure wall, and the enclosure is typically a blister pack,
with the wall section at a planar base of the blister. However, we
have found that some particular benefits arise from the adoption of
a non-planar wall section in which the opening or openings are
formed. More particularly, we have found that the adoption of a
dome shape in the respective wall section can result in a more
reliable performance of the containers in use, and facilitate
certain other beneficial developments of the containers. Thus, in
preferred embodiments of the invention, a unit container for a
treatment fluid comprising an enclosure of which one wall section
is dome shaped and formed with at least one opening in the top
region of the dome shape, the enclosure being adapted to confine a
sealed volume of treatment fluid, and pressurisable to discharge
the contents of the sealed volume through said at least one
opening. One or more other wall sections may also define a dome
shape complementary to that with the opening, which is capable of
inversion into the one wall section in the discharge of the
container contents.
[0007] The enclosure of a unit container of the invention can be
pressurised by the application of an external force on the side of
the enclosure opposite the wall section formed with the opening or
openings. Where the respective wall section is substantially flat,
this method of pressurising the enclosure contents can create high
stresses in the wall section, and particularly around the opening
or openings. In some situations, this can result in the wall
section itself tearing around the opening or openings with the
consequence that the discharge of the enclosure contents becomes
less predictable. By locating the opening or openings at the top of
a dome shape, these stresses are reduced.
[0008] Either a single opening or an array of openings may be found
in the respective wall section of the container. Various arrays are
possible, and a particular choice will be influenced by a number of
factors. A larger number of openings will dispense treatment fluid
over a larger target area. Smaller openings produce narrower jets
and/or smaller drops which will be subject to greater deceleration
in their passage to the target area. This may allow the use of
higher pressures. A single opening can direct a jet or stream of
drops accurately to a specific target area, and minimize the time
taken to deliver the treatment fluid to beat the blink response.
The preferred minimum opening diameter is at least 10 .mu.m to
avoid creating a spray of droplets with insufficient linear
momentum to reach their target. The use of a single opening of 100
.mu.m diameter is particularly preferred. The intention is to
create droplets no smaller than say 20 .mu.m to avoid the creation
of an inhalable spray.
[0009] Another benefit arising from the adoption of a dome shaped
wall section in which the opening or openings are defined is that
discharge of substantially the entire contents of the enclosure is
facilitated. If the device used to pressurise the enclosure is a
piston or hammer, its operative end can be shaped to complement
that of the dome such that in operation the other wall sections of
the enclosure, which can similarly be shaped to complement that of
the dome, are inverted against the dome shaped wall section thus
substantially evacuating the entire enclosure.
[0010] The wall section of the enclosure in a container of the
invention may be provided with a removable cover overlaying the
opening or openings, which cover is only removed just prior to the
contents of the enclosure being discharged. In this way, the
contents are protected from the environment until required. In an
alternative arrangement the or each opening in the wall section of
the enclosure is closed by a membrane adapted to rupture upon
pressurisation of the enclosure. These means demonstrate how
treatment fluids can be kept sterile in containers of the
invention. As a consequence, the need for the use of preservatives
in the contents is minimised or eliminated.
[0011] The use of a dome wall section in preferred containers of
the present invention facilitates the creation of a separate sealed
volume within the enclosure. In these circumstances, the removable
cover overlaying the opening or openings can be dispensed with, or
at least the requirements for its sealing qualities can be reduced.
According to this aspect of the invention, which can of course also
be applied to a container without a dome shaped wall section with
the opening or openings, a dividing wall is included within the
enclosure, which dividing wall separates the wall section with the
opening or openings from a region within the enclosure which
defines the sealed volume. The dividing wall is adapted to rupture
prior to discharge of the contents from the enclosure.
Conveniently, the dividing wall can be adapted to rupture upon
pressurisation of the enclosure as part of the step of discharging
the contents of the sealed volume through the opening or openings
in the wall section. However, the dividing wall may be adapted to
rupture upon the application of an external force prior to
pressurisation of the enclosure. Particularly, when the container
is fitted, either as an individual unit or as part of a strip for
example, in a dispensing device, a mechanism can be included to
apply tensile force across the container to break the dividing wall
just prior to the enclosure being pressurised.
[0012] Where a container according to the invention defines a
sealed volume with a dividing wall, it will be understood that this
sealed volume can be formed as a individual component of the
container prior to attachment of the wall section formed with the
opening or openings. This feature also offers a number of
particular benefits, primarily in the manufacture of packages
containing a plurality of complete containers. Manufacturing these
components individually means they can be separately checked for
defects prior to incorporation in a package. It also facilitates
the creation of packages having containers with different dosages;
either different treatment fluids or different quantities of the
same fluid, and also enables a plurality of individual components
to be disposed under a common dome shaped wall section, whereby
different treatment fluids can be kept isolated, but mixed just
prior to discharge from the opening or openings.
[0013] Containers of the invention are designed to provide for the
successive or simultaneous delivery of a jet or small droplets,
sometimes in the form of a stream or spray, which may be diffuse or
collinear. A typical range for the size of opening in the wall
section of the enclosure to achieve is up to 1000 .mu.m, preferably
20 to 200 .mu.m. A particularly preferred size range is 100 to 150
.mu.m. A single opening or an array of openings can be used,
conveniently punched, drilled, electroformed or laser-drilled in a
plastics sheet or foil defining the wall section. A metal,
typically a nickel foil is preferred for electroforming.
[0014] The form of delivery that is appropriate for a particular
ophthalmic treatment; ie, single or multiple openings, and the
arrangement thereof, will be dictated by the need to achieve a
sufficient delivery rate to beat the "blink response", with minimal
adverse reaction or unpleasant sensation to the eye. Thus, if a
higher quantity of fluid must be delivered, in order to ensure
delivery prior to the patient blinking, and at a tolerable impact
speed, multiple openings will be used instead of a single opening
to achieve a sufficient overall delivery rate.
[0015] Unit containers according to the invention can be charged
such that each enclosure confines a prescribed unit dose for
discharge therefrom, typically no more than 10 .mu.l . However,
larger volumes such as 20, 50 or 100 .mu.l could be required, for
example for irrigation purposes. A plurality of containers may be
provided in the form of a package, conveniently on a common
substrate, and preferably in the form of a strip with the
containers arranged sequentially therealong.
[0016] The discharge of the contents of enclosures in containers
according to the invention can most simply be accomplished by
provoking the collapse of the enclosure wall, against the section
having the opening or openings, preferably by a mechanical system.
The wall may include a reinforced region to orient its collapse.
For example, the enclosure might be crushed from the side opposite
the wall section by a piston, hammer or cantilever mechanism, the
action of which may be dampened to control the speed of the
mechanism, with sufficient impact to discharge and project the
contents a predetermined minimum distance. In an alternative, the
enclosure might be formed as a cylindrical chamber, with an
opposite wall portion formed as a piston for movement towards the
wall section to force the enclosure contents through the opening or
openings.
[0017] The invention is also directed at devices for discharging a
treatment fluid from the sealed enclosures of containers of the
type described above. Such a device comprises a package of the
containers; a mechanism for feeding the containers seriatim to a
dosing station; and means for acting on the enclosure of a
container at the dosing station to discharge the contents thereof.
The invention also provides a manual feed device in which provision
is made for individual containers or packages thereof to be fed
manually to the dosing station as required. When the wall section
of the container enclosure has a cover, the device can include
means for its removal prior to discharge of the enclosure contents.
This means may be synchronised with the feeding mechanism.
[0018] The discharge of the contents of the enclosure at the dosing
station in the above device is preferably accomplished by pressure
such that it is forced through the opening or openings in the
respective wall section of the enclosure. However, in an
alternative, an electrostatic technique can be used, broadly of the
kind described in published European Patent Specification No. 0 224
352. For this alternative, the invention provides a modified unit
container in which the enclosure is not specifically pressurisable,
but has a wall which includes a conductive section for connection
to a source of electrical potential, whereby application of such
potential generates an electrical charge in the container contents,
and its discharge through said at least one opening.
[0019] In discharging devices of the invention in which the
discharge of the container contents is accomplished by pressurising
its enclosure, the preferred means is a physical mechanism such as
a crushing unit for acting directly on the outside of the enclosure
from the side opposite the wall section formed with the opening or
openings. This can take the form of a piston-cylinder mechanism,
and such a mechanism can also be used to move an opposite wall
portion in a cylindrical enclosure of the kind described above.
[0020] Another technique that can be used to pressurise the
enclosure in containers of the invention uses piezoelectric
elements. Such elements enable the degree of pressurisation
achieved to be accurately controlled, and can be disposed for
example, against a face of the enclosure opposite the wall
section,or in the form of a ring around the body of the enclosure.
In either arrangement such an element can be operated selectively
or repeatedly to discharge discrete droplets or a rapid sequence.
The element may take the form of an ultrasonic transducer, one
which is particularly suited to the generation of a spray through
an array of openings in the wall section of the enclosure.
[0021] Other features can also be employed in devices according to
the invention to indicate the successful delivery of a treatment
fluid to its target. A light can be provided to maintain the eye
open, and this could typically be white. Alternatively, a coloured
system may be employed in which a different colour indicates the
stage of treatment. For example, the device can be offered up to
the eye showing a red light, which will switch to green only after
the predetermined dose has been dispatched.
[0022] Devices according to the invention can also include a number
of safety features which are already well established in dosing
devices of various kinds. The number of containers in a device will
of course be finite, and a dose recorder may be included to provide
an indication of the number of doses remaining or delivered. A
delay mechanism can also be included to prevent the inadvertent
delivery of a multiple dose. In combination with the delivery
signal features referred to above, this can be of significant
benefit.
[0023] It will be recognised that devices according to the
invention can be for personal or hand held use, or for use on a
more regular basis in institutions. For whatever use, means can be
provided for ensuring a proper spacing between the device and the
eye to be targeted, and this can be made adjustable, particularly
in the devices adapted for institutional use. In this respect, it
will be noted that the mechanisms contemplated in the present
invention will be well capable of discharging a jet and/or droplets
substantially horizontally or vertically upwards over a minimum
distance, thereby not requiring a user to arrange for the device to
be operated from directly above an eye.
[0024] In addition to the containers and devices discussed above,
the present invention also provides methods of generating jets
and/or droplets and of treatment, using such containers and
devices. The methods of treatment additionally require the
targeting of generated jets and/or droplets at a respective
treatment site.
[0025] The invention will now be described by way of example and
with reference to the accompanying schematic drawings wherein:
[0026] FIG. 1 is a perspective view of a device in which the
enclosure of a unit is crushed to discharge its contents;
[0027] FIG. 2 is a detailed view of the crushing unit in the device
of FIG. 1;
[0028] FIG. 3 is a perspective view of a device in which a piston
mechanism is used to discharge the enclosure contents;
[0029] FIG. 4 is a detailed view of the piston unit of FIG. 3;
[0030] FIG. 5 is a perspective view of a device in which a
piezoelectric device is used to discharge the enclosure
contents;
[0031] FIG. 6 is a detailed view of the piezoelectric unit of FIG.
5;
[0032] FIG. 7 is a perspective view of a device similar to that of
FIGS. 5 and 6 but for use with individual containers;
[0033] FIG. 8 is a detailed view showing a container being
presented to the piezoelectric unit;
[0034] FIG. 9 is a perspective view of a device which uses an
electrostatic charging system to discharge the enclosure
contents;
[0035] FIG. 10 is a detailed view of the dosing station of the unit
of FIG. 9;
[0036] FIG. 11 is a cross-section through a preferred container
according to the invention;
[0037] FIGS. 12A, 12B and 12C illustrate cross-sections at
different stages in the manufacture of another preferred container
according to the invention;
[0038] FIG. 13 illustrates yet another preferred container
according to the invention;
[0039] FIG. 14 shows in plan view a length of strip or bandolier
formed with unit containers in the form of sachets embodying the
invention;
[0040] FIG. 15 illustrates a simple compression device for
discharging the contents of a sachet of the type illustrated in
FIG. 14; and
[0041] FIG. 16 shows the device of FIG. 15, having been activated
to discharge the sachets contents;
[0042] FIG. 17 shows in cross-section yet another unit dose
container embodying the invention;
[0043] FIG. 18 shows a device for discharging the contents from a
container as shown in FIG. 17; and
[0044] FIG. 19 is a graph showing the miotic response of rabbits
subjected to treatment using the device of FIG. 18.
[0045] The device shown in FIG. 1 comprises a housing 2 with an
open cowling 4 at one end with the dosing station 6 of the device
disposed at the base thereof. The device shown is for ophthalmic
treatment, and the cowling serves to ensure that the dosing station
is located correctly and spaced a proper distance from the eye for
a treatment to be effective. . Containers according to the
invention are mounted on a tape 8 which extends from a supply cord
10, around in front of the dosage station 6 and on to a take-up
reel 12. A capstan 14 is provided to wind the tape on to locate a
fresh container at the dosage station for discharge of its
contents. A button 16 is shown for initiating the activation of the
dosage station when it is properly charged. The enclosure of each
container on the tape 8 takes the form of a blister pack 18
depending from a continuous backing 20, as is better shown in FIG.
2. The open face of the blister pack 18 is closed by a continuous
metal foil 22, and over each blister the foil has ten 40 micron
openings electroformed therein. Overlaying the foil is a cover
layer 24, which is progressively removed from the foil as a blister
pack reaches the dosage station 6. It is removed by a spring loaded
take-up reel 26, which draws the cover layer around a guide bar 28
on the upstream side of the dosage station. A similar guide bar 28
is located on the downstream side of the dosage station, and the
tape 8 is held thereagainst by means, of spring loaded beams 30.
These beams 30 are spaced by a distance substantially equal to the
dimension of the blister 18 along the length of the tape 8 such
that they also serve to locate the blister centrally at the dosage
station 6.
[0046] The dosage station shown in FIG. 2 includes a piston 32 in a
block 34, which is itself mounted in a housing 36 and located
therein by means of a latch 38. To provoke the discharge of the
contents of the blister pack 18 through the openings in the foil
22, the button 16 is depressed to release a spring (not shown)
which charges the piston 32 against the blister 18, and crushes it
against the foil 22. The capstan 14 is then turned to bring the
next charged blister into alignment with the piston, and the
capstan 14 will also be coupled to the piston 32 to retract it to
its starting position prior to the fresh charged blister reaching
its discharge position.
[0047] In the device shown in FIG. 3 the container enclosures 40
are mounted on a bandolier 42 which, as with the embodiment of FIG.
1, extends from a supply reel 44 past a dosage station 46 and on to
a take-up reel 48 coupled to a capstan 50 for winding on. The
housing 52 has a cowling 54, but it will be noted that the
orientation of the housing relative to the cowling is
different.
[0048] At the dosage station which is better shown in FIG. 4 each
enclosure 40 is successively aligned with the piston 54 of the
cylinder mechanism 56. Each enclosure 40 is cylindrical, and has at
its forward end a nozzle 58 with one or a plurality of openings
therein. This end is closed by a foil seal 60. The other end of the
enclosure 40 is closed by a silicone piston 62, and when the dosage
station is activated the piston 54 engages the piston 62 and thus
compresses enclosure contents. This pressure forces the contents
through the opening or openings 58, simultaneously discarding the
foil seal 60, and the contents are then discharged in the form of a
spray as indicated at 64.
[0049] The device shown in FIGS. 5 and 6 is in some ways similar to
that of FIGS. 1 and 2, but in this embodiment discharge is effected
by means of a piezoelectric element. A tape 66 comprising discrete
containers is wound on by means of a capstan 68 to locate a
container at the dosage station 70. At the dosage station the
enclosure 72 of the container is aligned with a piezoelectric ring
transducer 74 while a cover layer 76 is removed in substantially
the same manner as it is in the embodiment of FIG. 1. Removal of
the cover again exposes a metal foil 78 overlaying the blister 72
and formed with ten 40 micron electroformed openings.
[0050] As with the dosage station illustrated in FIG. 2, in this
embodiment it comprises a piston 80 mounted in a cylinder 82 itself
located in a housing 84 by means of a latch 86. Depression of the
button 88 activates a spring to move the piston towards the blister
72, but only to locate the piezoelectric ring transducer 74 around
the body thereof. Means (not shown) then activate the transducer 74
to contract it around the blister 72 and thus discharge the
contents thereof through the openings in the metal foil. Again, and
as described above with reference to FIGS. 1 and 2, winding the
tape on with the capstan 68 also retracts the piston 80. However,
in this embodiment the capstan 68 also actuates a knife to detach
the used blister from the tape 66, which is then ejected through an
opening 88 in the device housing.
[0051] FIGS. 7 and 8 illustrate what can be regarded as a
simplified version of the embodiment of FIGS. 5 and 6. In this
embodiment, the containers are provided separately, and the housing
90 of the device is provided with a storage compartment 92 for the
container supply. When the device is to be used, a container 94
must be removed from the storage,compartment 92 and manually fitted
to the ring transducer 96 fixed at the base of the cowling 98 of
the housing. A battery 100 and the requisite electronics 102 are
disposed in a chamber 104 located between the storage compartment
92 and the transducer 96. To use the thus charged device, a cover
106 is removed from the visible face of the container 94 to expose
a wall section 108 of the enclosure formed with a 50 micron nozzle.
When the electronics 102 are activated by a button (not shown) the
ring transducer 96 contracts around the container 94 to discharge
its contents through the nozzle.
[0052] As can be seen, the enclosure of the container 94 is
reinforced around its inner perimeter by a section 110. This
inhibits rupture of the enclosure upon contraction of the ring
transducer, and its internal shape also serves to increase the
discharge velocity of fluid from the enclosure through the
nozzle.
[0053] FIGS. 9 and 10 illustrate an alternative embodiment of the
invention in which the contents of the enclosure are discharged by
means of an electrostatic charging system. A covered strip 112 of
containers 114 is provided in the housing 116, with a capstan 118
for advancing the strip 112 to locate a container 114 at the dosing
station 120, broadly in the manner described with reference to
FIGS. 1 and 2. In this embodiment however, the enclosures 122 of
the containers 114 are formed of an electrically conductive
material. A contact 124 is located at the dosing station 120 to
engage the enclosure wall, and a switch (not shown), activated by
the dispense button 126 is provided to apply an electrical
potential from a generator 128 to the enclosure wall to charge the
contents and force their discharge through the opening 130. Power
for the generator 128 is provided by a battery 132, also located in
the housing 116. Because the enclosure wall in each container is
conductive, they must be isolated from each other in the strip 112.
Thus, as shown in FIG. 10, the strip has an insulating section 134
between the containers 114.
[0054] Provision can be made for devices of the invention to
deliver different fluids to a target site in a composite treatment.
Thus, containers enclosing different fluids can be included for
feeding to the dosing station, and where the containers are mounted
on a strip or bandolier, then a chosen sequence can be
predetermined. For example, an anaesthetic or diagnostic aid such
as fluorescein might be enclosed in alternate containers mounted on
a strip.
[0055] FIGS. 11 to 13 illustrate preferred containers for use in
the devices described above, which are of "double-dome"
construction. The container shown in FIG. 11 defines an enclosure
202 in which is held a quantity of treatment fluid 204. The lower
part of the container as shown is created as a blister in a foil
laminate base sheet 206 which is overlaid with a foil laminate
upper sheet 208 which is formed into a dome where it defines the
upper part of the enclosure 202. The base and upper sheets 206, 208
are bonded where they contact one another to seal the enclosure at
the junction therebetween.
[0056] In the top section of the upper sheet 208 is formed an
opening 210, which is closed by a cover sheet 212 making sealing
engagement with the external surface of the upper sheet 208 around
the opening 210. The cover sheet 212 is typically a plastics sheet
or a metal foil.
[0057] In use, the container shown in FIG. 11 is fitted in a device
which properly locates the enclosure 202 relative to means such as
a piston or air pressure source, for forcing the base sheet 206
where it forms the lower part of the enclosure 202, towards the
opening 210 and against the upper sheet 208. The cover sheet 212 is
removed, and the system actuated. As a consequence, the treatment
fluid 204 in the enclosure 202 is discharged through the opening
210 towards its chosen target.
[0058] FIGS. 12 illustrate a container in which individual
components of the container can be prepared separately with
treatment fluid therein, and thereafter attached to an upper sheet
which completes the respective containers. Such a component is
shown in FIG. 12A, which consists of a base sheet 206 formed into a
blister to hold a quantity fluid 204. The blister is closed by an
intermediate layer 214 sealed around the periphery of the blister
to the base sheet, but including a weakened section 216 which
actually overlays the blister. Nevertheless, the component
illustrated is sealed, and the treatment fluid 204 in the blister
is properly protected from contact with the external atmosphere. It
also allows autoclave sterilisation of the sealed volume.
[0059] FIG. 12B shows a section of upper sheet 208 formed with an
opening 210 for disposal over the blister of the component shown in
FIG. 12. The assembled combination is shown in FIG. 12C.
[0060] Each component shown in FIG. 12A is manufactured as a
discrete element, and may be subject to quality control examination
to ensure that as a treatment fluid dosage component, it is sound
in every particular. To complete a container from which the
treatment fluid 204 may be discharged in accordance with the
invention, an upper sheet 208 is laid and sealed thereover with its
domed section including the opening 210 disposed directly opposite
the blister in which the treatment fluid 204 is held. If a strip of
containers is to be formed, then a continuous length of upper sheet
208 formed with a series of domed sections can be used to
simultaneously complete and interconnect a package of containers
according to the invention. Such a package is illustrated in FIG.
12C.
[0061] The use of a container of the type illustrated as part of
the package of FIG. 12C is generally similar to that of FIG. 11,
with two essential differences. Firstly, a cover sheet 212 is not
essential because the treatment fluid 204 is already sealed within
the volume defined within the container by the layer 214.
Nevertheless, some form of cover sheet might still be used,
although it will be understood that the bond between the cover
sheet 212 and the upper sheet 208 around the holes 210 does not
have to be effective to seal the enclosure to the same extent as it
does in the embodiment of FIG. 11. Secondly, when the enclosure is
pressurised, and particularly when the sealed volume containing the
treatment fluid 204 is compressed, the first effect is the
rupturing of the weakened section 216 of the layer 214, and the
weakened section 216 may be designed to rupture along a defined
axis. Thereafter, the discharge is essentially similar to that of
the embodiment of FIG. 11. The weakened section 216 may also absorb
some of the crushing force during the collapse of the blister,
resulting in lower pressures and a reduced tendency of the blister
or dome to burst or tear.
[0062] If because of the pressurising system used or for any other
reason, there is a need to rupture the weakened section 216 prior
to actual pressurisation of the enclosure, this can be
accomplished. The discharge device used can be adapted such that
the laminate of base and upper sheets 206, 208, and layer 214 is
gripped on either side of the blister, and stretched across the
blister to rupture the weakened section 216 before a piston for
example, engages the base sheet 206 to collapse the enclosure. The
direction of such stretching is indicated by the arrows shown
adjacent the container shown on the left-hand side of FIG. 12C.
[0063] FIG. 13 shows a container in which two treatment fluids can
be confined separately in the same enclosure, within respective
sealed volumes closed by weakened sections of an intermediate layer
214. The manufacture, assembly and use of the container is
essentially similar to those described with reference to FIGS. 12,
but FIG. 13 also illustrates a piston or hammer 218 for effecting
discharge of the treatment fluids through the opening 210.
[0064] It will be appreciated that the shapes of the blister in the
sheet 206 and the dome in the sheet 208 can be made complementary
such that when a piston such as 218 is applied to the blister, or
blisters as shown in FIG. 13, the entire section of sheet defining
the blister or blisters eventually engages the section of sheet
defining the dome to substantially completely evacuate the
enclosure of the treatment fluid or fluids previously contained
therein. This of course is particularly important in treatments
where dosages must be accurately defined.
[0065] The separate manufacture of individual components of
containers in accordance with the invention facilitates not only
quality control, but also sterilisation and other preparatory
procedures. In the embodiments described above, a foil laminate
upper sheet 208 can be used in which only a single opening 210 is
formed. However, particularly where a plurality of openings are
required, the preferred material for the upper sheet 208 is a metal
foil in which openings are made by photoresist electroforming. The
bonding of metal foils directly to laminated base sheets can have a
deleterious effect upon treatment fluid otherwise exposed in the
blister. These effects are much reduced where the treatment fluid
is already confined in its own sealed volume under the intermediate
layer 214, and where the upper sheet is bonded to the intermediate
layer 214.
[0066] In some instances it may be desirable to have a smooth
discharge of treatment fluid through the opening or openings in the
dome shaped wall section, or indeed the opening or openings through
which fluid is discharged from any of the containers described
herein. To this end preferred opening or openings should taper
towards the discharge end, with the inlet diameter typically of the
order of three times that of the outlet. The preferred axial length
of the opening or openings is 1 to 5 times the outlet diameter, and
at the outlet the opening may be made substantially
cylindrical.
[0067] The terms "dome" and "dome shaped" have been used in the
above description of FIGS. 11 to 13 in a very broad sense. They are
not intended to define a particular or necessarily symmetric form
of closure in containers of the invention. Others could be used to
equivalent effect. What is however important, is the disposition of
the opening or openings in the top region thereof whereby
discharging fluid is directed towards the opening or openings as
the enclosure is pressurised.
[0068] In the system illustrated in FIGS. 14, 15 and 16, individual
sachets 222 of treatment fluid are mounted on a strip 224. Each
sachet 222 is pear-shaped, and held in the backing or support sheet
226 for use as needed. Each sachet has a weakened wall section 228
located adjacent a cut out in the support sheet 226.
[0069] In use, the strip 224 is moved in a device (not shown) to
locate a sachet 224 at a discharge station. At the discharge
station two opposing pistons or hammers 230 are caused to
accelerate towards each other. This compresses the sachet 224 as
shown in FIG. 16 to force the contents of the sachet therefrom in
the direction shown. The pistons or hammers are then withdrawn,
releasing the emptied sachet which is then discarded.
[0070] The weakened wall section 228 can be very small, in order to
accurately focus the discharge on the chosen target. Further, it
can have a line of weakness across a diameter, or alternatively an
array of weak points which rupture in a pre-ordained manner.
[0071] The container shown in FIG. 17 comprises juxtaposed sheets
232 and 234 of for example, 30 .mu.m aluminium foil laminate and 40
.mu.m copper foil respectively, shaped and held around a continuous
path in a hot melt adhesive layer 236 to form a sealed bubble in
which is confined an 8 .mu.1 unit dose 238 of a treatment fluid.
Each sheet 232, 234 forms substantially half the bubble wall, and
at the apex of the dome formed by the copper foil layer 234 a
single 100 .mu.m opening is made, typically by punching, drilling,
electroforming or laser-drilling. The layer 236 forms flanges on
either side of the bubble, and a strip of containers may be made,
interconnected by a continuous length of the layer 236.
[0072] The device shown in FIG. 18 has a dosing station 240 with
two pairs of clamping plates 242 which define a path for a strip of
containers of the kind illustrated in FIG. 17 with continuous
flanges formed by the layer 236 disposed between respective plate
pairs. When the device is ready to operate, the plates 242 clamp
together to hold the flange and therefore the bubble in the
appropriate position in the dosing station. The plates may be
clamped by twisting the elements 244, or by an automatic mechanism
activated by triggering the device.
[0073] Location of a container at the dosing station aligns it with
an elongate piston 246 mounted for axial linear movement within a
main housing 248. The piston 242 is principally supported in a back
panel 250 mounted on the housing 248, and is guided at its forward
end by a guide screw 252, to which the piston is attached.
Compressed between the panel 250 and the guide screw 252 is a
spring 258, and it is held compressed by a catch 254 which engages
the forward face of the guide screw 252. Operating the trigger
mechanism 254 releases the guide screw 252 and piston 246 which is
then driven by the spring 258 to engage the nearer side of the
"bubble" and force the contents out of the container through the
100 .mu.m opening. To "re-cock" the device for further use, the
piston 246 is merely withdrawn to the left as shown against the
force of the spring 258 until the guide screw 252 latches behind
the catch 254. The guide screw 252 is balanced by a counterweight
256 at the other end of the piston 246, which can also be used to
pull the piston back against the force of the spring.
[0074] The device of FIG. 18 was used in a study of the ocular
response of rabbits to treatment according to the invention. The
rabbits selected for the study were allowed to acclimatise for 4-5
days prior to treatment. They were subjected to manual restraining
for 2 days prior to the study to condition them to the procedures
involved in dosing. A device of the kind illustrated in FIG. 18 was
then used to administer a single spray of isotonic 2% Pilocarpine
hydrochloride (Pilocarpine HCl) solution to the corneal surface of
the left eye of each of 5 rabbits, the right eyes remaining
undosed. The following settings were used:
[0075] 100 .mu.m nozzle diameter
[0076] 2.5 cm distance between nozzle tip and animal eye
[0077] Sprays targeted towards the center of the cornea of the
animal eye
[0078] The miotic response (reduction in pupil diameter) at various
intervals following the application of the pilocarpine HCl solution
was monitored under constant illumination using video photography.
The pupil diameter of the left eye was expressed in proportion to
the diameter of a fixed reference aperture situated at an equal
distance from the video camera. The actual diameter was then
calculated from the known diameter of the reference aperture.
[0079] Table 1 shows the pupil diameter of the left eye at
different intervals following application of the test dose, as is
represented graphically in FIG. 19.
1TABLE 1 Pupil Diameter (mm) Following Application of 2%
Pilocarpine HCl Using a Laboratory Model Blister Crushing Device
(Mean of 5 Rabbits) Measurement Timepoint Dose +15 +30 +45 +1 +1.5
+2 +2.5 +3 +3.5 +4 (0 min) min min min hr hr hr hr hr hr hr Mean
7.8 6.7 6.8 6.9 6.8 6.9 7.3 7.8 7.9 8.0 7.8
[0080] Devices according to the invention can typically generate
droplets with diameters of the order of 200 .mu.m, enabling the
delivery of multiple droplets in metered doses of very low volume,
5 .mu.l being typical. However, smaller droplets can be desirable
in some applications, as can larger droplets in others. A typical
delivery velocity is 10 m/s, but other velocities may be
appropriate in particular applications. Because of the manner in
which the dose is delivered, this provides a significant benefit
over traditional treatment techniques in which large doses of say
50 .mu.l are used. Using a device according to the invention in
ocular treatment a much greater proportion of treatment liquid will
actually make effective contact with the eye, leading to less
wastage, reduced risk of systemic absorption and less flooding of
the eye and risk of provoking blinking or watering which can result
in a treatment being wasted.
[0081] Ophthalmic treatment fluids that may be used with the
invention may be aqueous or non-aqueous liquids, optionally
containing a therapeutic compound or compounds such as:
[0082] 1) Anti-glaucoma/IOP (intra-ocular pressure) lowering
compounds
[0083] a) .beta.-adrenoceptor antagonists, e.g. carteolol,
cetamolol, betaxolol, levobunolol, metipranolol, timolol, etc.
[0084] b) Miotics, e.g. pilocarpine, carbachol, physostigmine,
etc.
[0085] c) Sympathomimetics, e.g. adrenaline, dipivefrine, etc.
[0086] d) Carbonic anhydrase inhibitors, e.g. acetazolamide,
dorzolamide, etc.
[0087] e) Prostaglandins, e.g. PGF-2 alpha.
[0088] 2) Anti-microbial compounds (including anti-bacterials and
anti-fungals), e.g. chloramphenicol, chlortetracycline,
ciprofloxacin, framycetin, fusidic acid, gentamicin, neomycin,
norfloxacin, ofloxacin, polymyxin, propamidine, tetracycline,
tobramycin, quinolines, etc.
[0089] 3) Anti-viral compounds, e.g. acyclovir, cidofovir,
idoxuridine, interferons, etc.
[0090] 4) Aldose reductase inhibitors, e.g. tolrestat, etc.
[0091] 5) Anti-inflammatory and/or anti-allergy compounds, e.g.
steroidal compounds such as betamethasone, clobetasone,
dexamethasone, fluorometholone, hydrocortisone, prednisolone etc.
and non-steroidal compounds such as antazoline, bromfenac,
diclofenac, indomethacin, lodoxamide, saprofen, sodium
cromoglycate, etc.
[0092] 6) Artificial tear/dry eye therapies, comfort drops,
irrigation fluids, etc., e.g. physiological saline, water, or oils;
all optionally containing polymeric compounds such as
acetylcysteine, hydroxyethylcellulose, hydroxymellose, hyaluronic
acid, polyvinyl alcohol, polyacrylic acid derivatives, etc.
[0093] 7) Diagnostics, e.g. fluorescein, rose bengal, etc.
[0094] 8) Local anaethetics, e.g. amethocaine, lignocaine,
oxbuprocaine, proxymetacaine., etc.
[0095] 9) Compounds which assist healing of corneal surface
defects, e.g. cyclosporine, diclofenac, urogastrone and growth
factors such as epidermal growth factor, etc.
[0096] 10) Mydriatics and cycloplegics e.g. atropine,
cyclopentolate, homatropine, hysocine, tropicamide, etc.
[0097] 11) Compounds for the treatment of pterygium, such as
mitomycin C, collagenase inhibitors (e.g. batimastat) etc.
[0098] 12) Compounds for the treatment of macular degeneration
and/or diabetic retinopathy and/or cataract prevention.
[0099] 13) Compounds for systemic effects following absorption into
the bloodstream after ocular administration, e.g. insulin. The
above compounds may be in the form of free acids or bases or
alternately as salts of these. Combinations of compounds e.g. an
anti-bacterial combined with an anti-flammatory may be desirable
for the optimization of therapy in some instances. The compounds
may be formulated as aqueous or non-aqueous (e.g. oil) solutions or
suspensions. Formulations may optionally contain other formulation
excipients, for example, thickening agents such as gels,
mucoadhesives and polymers, stabilisers, anti-oxidants,
preservatives, pH/tonicity adjusters etc.
[0100] It will be appreciated that devices of the invention might
comprise a single unit, as well as the modular systems illustrated
in which the delivery mechanism and the treatment liquid source are
provided separately, or at least independent of each other. Modular
systems do of course enable a fluid or treatment liquid to be
selected, and coupled to a delivery mechanism as desired. This
enables the same delivery mechanism to be used for different
treatments. Such a device of the invention for institutional use
can provide for such selection to be at least partially
automated.
* * * * *