U.S. patent application number 14/406171 was filed with the patent office on 2015-05-21 for syringe.
The applicant listed for this patent is CONSORT MEDICAL PLC. Invention is credited to Ian Anderson, Matt Ekman, Rachel Suzanne Koppelman.
Application Number | 20150141918 14/406171 |
Document ID | / |
Family ID | 46605576 |
Filed Date | 2015-05-21 |
United States Patent
Application |
20150141918 |
Kind Code |
A1 |
Anderson; Ian ; et
al. |
May 21, 2015 |
SYRINGE
Abstract
A syringe propellable by propellant that boils at a
predetermined temperature, the syringe including a barrel having an
outlet at a front end, and a stopper axially moveable in the
barrel. The stopper separates a first chamber and a second chamber,
the first chamber being axially forwards of the stopper and being
configured for containing a medicament, and the second chamber
being axially rearwards of the stopper and being configured to
receive propellant for acting on the stopper to move the stopper
axially forwardly in the barrel to expel medicament through the
outlet upon actuation of the syringe. The syringe further includes
a rupturing portion and a third chamber for containing propellant
where the third chamber is rupturable upon actuation of the syringe
to fluidly connect the third chamber to the second chamber. When
propellant is released into the second chamber the pressure in the
second chamber increases causing the stopper to move axially
forwardly to begin expulsion of medicament from the first chamber
through the outlet. The syringe is configured such that while the
medicament is expelled from the first chamber the pressure in the
second chamber changes to a second pressure.
Inventors: |
Anderson; Ian; (Burwell
Cambridgeshire, GB) ; Ekman; Matt; (Macclesfield,
GB) ; Koppelman; Rachel Suzanne; (Cambridge,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CONSORT MEDICAL PLC |
Hemel, Hempstead |
|
GB |
|
|
Family ID: |
46605576 |
Appl. No.: |
14/406171 |
Filed: |
June 7, 2013 |
PCT Filed: |
June 7, 2013 |
PCT NO: |
PCT/GB2013/051508 |
371 Date: |
December 5, 2014 |
Current U.S.
Class: |
604/113 ; 29/592;
604/141 |
Current CPC
Class: |
A61M 5/44 20130101; B65D
83/24 20130101; A61M 5/2053 20130101; A61M 5/142 20130101; A61M
39/22 20130101; B65B 31/045 20130101; A61M 5/14526 20130101; A61M
2207/10 20130101; B65B 51/30 20130101; A61M 2207/00 20130101; A61M
5/16881 20130101; A61M 5/155 20130101; A61M 5/16804 20130101; Y10T
29/49808 20150115; F04C 2270/0421 20130101; Y10T 29/49 20150115;
B65D 83/48 20130101; B65B 51/26 20130101; A61M 2039/2486 20130101;
A61M 2005/14513 20130101 |
Class at
Publication: |
604/113 ;
604/141; 29/592 |
International
Class: |
A61M 5/155 20060101
A61M005/155; A61M 5/168 20060101 A61M005/168; A61M 5/44 20060101
A61M005/44 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 7, 2012 |
GB |
1210082.2 |
Claims
1. A syringe propellable by propellant that boils at a
predetermined temperature, the syringe comprising: a barrel having
an outlet at a front end; and a stopper axially moveable in the
barrel; wherein the stopper separates a first chamber and a second
chamber, the first chamber being axially forwards of the stopper
and being configured for containing a medicament, and the second
chamber being axially rearwards of the stopper and being configured
to receive propellant for acting on the stopper to move the stopper
axially forwardly in the barrel to expel medicament through the
outlet upon actuation of the syringe; the syringe further
comprising a rupturing portion and a third chamber for containing
propellant where the third chamber is rupturable; wherein the
rupturing portion is configured to rupture the third chamber upon
actuation of the syringe to fluidly connect the third chamber to
the second chamber and release liquid propellant from the third
chamber so that the pressure in the second chamber increases at or
above the predetermined temperature causing the stopper to move
axially forwardly and begin to expel medicament from the first
chamber through the outlet; wherein when propellant is released
into the second chamber the pressure in the second chamber
increases over a first time period to a first pressure causing the
stopper to move axially forwardly to begin expulsion of medicament
from the first chamber through the outlet; the syringe being
configured such that while the medicament is expelled from the
first chamber the pressure in the second chamber changes over a
second time period from the first pressure to a second pressure,
and when substantially all the medicament has been expelled from
the first chamber the pressure in the second chamber increases over
a third time period towards a third pressure; wherein the magnitude
of the second pressure and the rate of increase of the pressure in
the second chamber during the third time period are controlled by
the thermal conductivity of the components of the syringe defining
the second chamber, the rate of delivery of propellant to the
second chamber, and the phase of the propellant during delivery
into the second chamber; and wherein the third pressure is
substantially equal to the vapor pressure of the propellant at
ambient temperature at the instantaneous volume of the vaporized
propellant, and at the third pressure the syringe contains liquid
propellant.
2. The syringe according to claim 1, wherein the third chamber has
a rupturable portion.
3. The syringe according to claim 2, wherein the rupturing portion
includes a tapered piercing element.
4-13. (canceled)
14. The syringe according to claim 1, wherein the syringe further
comprises a fourth chamber in fluid communication with said second
chamber, where the third chamber is fluidly connectable to said
fourth chamber upon rupturing.
15. The syringe according to claim 14, wherein said third chamber
is entirely within said fourth chamber.
16. The syringe according to claim 14, wherein said fourth chamber
is fluidly connected to said second chamber by a propellant conduit
that determines the flow rate of propellant from the fourth chamber
to the second chamber.
17-18. (canceled)
19. A syringe according to claim 1, wherein the third chamber
comprises a flexible rupturable container for containing
propellant.
20-33. (canceled)
34. The syringe according to claim 1, wherein the rupturing portion
comprises a valve having a valve body, a valve stem, and a locking
member, where the valve stem is slidably moveable relative to the
valve body between: i) a non-dispensing position in which an outlet
port of the valve stem is out of fluid communication with the third
chamber; and ii) a dispensing position in which the outlet port is
in fluid communication with the third chamber so as to permit
transfer of propellant form the third chamber through the valve
stem; wherein the locking member is configured to prevent return of
the valve stem into the non-dispensing position once the valve stem
slides beyond a locking position; and wherein the third chamber is
ruptured when the valve stem is in the dispensing position and
beyond the locking position.
35. The syringe according to claim 34, wherein the locking member
and the valve stem comprise inter-engaging members, wherein the
inter-engaging members: a) contact one another during movement of
the valve stem towards the dispensing position and permit movement
of the valve stem into the dispensing position; and b) contact one
another during attempted movement of the valve stem from beyond the
locking position back towards the dispensing position and prevent
movement of the valve stem back into the non-dispensing
position.
36-43. (canceled)
44. A syringe according claim 1, wherein the syringe further
comprises trigger means for triggering an action upon activation of
said trigger means, wherein the trigger means are activated when
the pressure in the second chamber satisfies a predetermined
condition.
45. (canceled)
46. The syringe according to claim 1, wherein said predetermined
temperature is between 15.degree. C. and 30.degree. C.
47-53. (canceled)
54. The syringe according to claim 1, wherein the first pressure is
substantially equal to the vapor pressure of the propellant at
ambient temperature at the instantaneous volume of the vaporized
propellant.
55-57. (canceled)
58. The syringe according to claim 1, further comprising cooling
means or heat means configured to remove or supply heat to
propellant in the second chamber, respectively.
59-65. (canceled)
66. The syringe according to claim 1, further comprising a fluid
propellant in the third chamber.
67. The syringe according to claim 66, wherein said fluid
propellant is configured to enter said second chamber primarily as
a liquid.
68. The syringe according to claim 66, wherein said fluid
propellant is configured to enter said second chamber primarily as
a gas.
69. The syringe according to claim 66, wherein said fluid
propellant includes a hydrofluoroalkane (HFA).
70. The syringe according to claim 69, wherein said HFA is selected
from a group consisting of: HFA 134a, HFA 422d, HFA 507c and HFA
123.
71. A method of designing a syringe, the syringe comprising: a
barrel for containing a medicament, the barrel having an outlet; a
stopper defining and separating a first chamber and a second
chamber where the first chamber is axially forwards of the stopper
and is configured for containing a medicament, and the second
chamber is axially rearwards of the stopper and is configured to
receive a propellant for acting on the stopper to move the stopper
axially forwardly in the barrel to expel medicament through the
outlet upon actuation of the syringe; the method comprising the one
or more of the steps of: i) selecting a thermal properties of the
syringe, ii) determining a rate of delivery of propellant into the
second chamber, or iii) determining a phase of propellant entering
the second chamber, to exhibit a desired pressure profile of fluid
acting on the stopper following actuation of the syringe.
72. (canceled)
73. A method according to claim 71, further comprising the step of
manufacturing a syringe having the determined thermal properties
required to exhibit the desired pressure profile of fluid acting on
the stopper following actuation of the syringe.
74-88. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a US national phase under 35 USC
.sctn.371 of International Application No. PCT/GB2013/051508, filed
Jun. 7, 2013, which claims priority to United Kingdom patent
application GB 1210082.2, filed Jun. 7, 2012. Priority application
GB 1210082.2 is hereby incorporated by reference.
FIELD OF THE DISCLOSURE
[0002] This invention relates to a medical device, and in
particular to a syringe for delivering a dose of medicament.
BACKGROUND
[0003] Automatically actuatable syringes are known and include a
power source, such as a spring or a compressed gas to deliver a
dose of medicament to a patient. Typically, a syringe has a barrel
defining a chamber for containing a dose of medicament and a
moveable stopper connected to a plunger rod for compressing the
medicament to force it out of an opening in the barrel. In more
complex devices, additional features are provided that are actuated
in a sequence determined by the axial position of the plunger rod
or the drive spring, for example. In such devices, the axial
position of the plunger rod or the like is indicative of the stage
of medicament delivery. Examples of such features include movement
of the needle out of or into the device, and movement of a needle
shroud between a needle-protecting and a needle-exposing
position.
[0004] A self-contained pressurized injection device used for
administering very viscous dermal filler material is described in
WO-A-2009/086250 (Aesthetic Sciences Corporation). The described
device includes an actuator assembly having a pressurized fluid
container, a regulator and a bias member. The pressurized fluid
container is configured to move between a first closed position and
a second open position to selectively activate the device. The bias
member biases the pressurized fluid container towards the first
closed position.
[0005] It is an object of the present invention to provide a
syringe device that is propellable by propellant that boils at a
predetermined temperature that provides improved reliability and
control in comparison to the prior art.
[0006] It is another object of the present invention to provide a
syringe device that is propellable by propellant that boils at a
predetermined temperature that may be used in a sequenced
autoinjector device.
BRIEF SUMMARY OF THE DISCLOSURE
[0007] In accordance with a first aspect of the present invention
there is provided a syringe propellable by propellant that boils at
a predetermined temperature, the syringe comprising: [0008] a
barrel having an outlet at a front end; and [0009] a stopper
axially moveable in the barrel;
[0010] wherein the stopper defines and separates a first chamber
and a second chamber, the first chamber being axially forwards of
the stopper and being configured for containing a medicament, and
the second chamber being axially rearwards of the stopper and being
configured to receive propellant for acting on the stopper to move
the stopper axially forwardly in the barrel to expel medicament
through the outlet upon actuation of the syringe;
[0011] the syringe further comprising a rupturing portion and a
third chamber for containing propellant where the third chamber is
rupturable;
[0012] wherein the rupturing portion is configured to rupture the
third chamber upon actuation of the syringe to fluidly connect the
third chamber to the second chamber so that propellant is released
into the second chamber and the pressure in the second chamber
increases at or above the predetermined temperature causing the
stopper to move axially forwardly and begin to expel medicament
from the first chamber through the outlet.
[0013] The third chamber may have a rupturable portion, and the
rupturable portion may form a propellant channel between the third
chamber and second chamber when the rupturable portion is ruptured.
Optionally, the propellant channel is defined by a propellant
conduit that determines the flow rate of propellant from the third
chamber to the second chamber. The propellant conduit may extend
into the third chamber so as to minimise the flow of liquid
propellant from the third chamber to the second chamber, in some
preferable embodiments by at least 0.3 mm.
[0014] Optionally, the syringe further comprises a fourth chamber
in fluid communication with the second chamber, where the third
chamber is fluidly connectable to the fourth chamber upon
rupturing. The third chamber may be entirely within the fourth
chamber. The fourth chamber may be fluidly connected to the second
chamber by a propellant conduit that determines the flow rate of
propellant from the fourth chamber to the second chamber. The
propellant conduit may extend into the fourth chamber so as to
substantially prevent the flow of liquid propellant from the fourth
chamber to the second chamber. Preferably, the propellant conduit
extends into the fourth chamber by at least 0.3 mm.
[0015] In some preferable embodiments, the third chamber comprises
a flexible rupturable container for containing propellant. The
flexible rupturable container may be sealed by one or more seals,
wherein the one or more seals are preferably formed between two
like materials. The one or more seals may be formed by heat
sealing, sonic welding, or adhesives. The flexible container is
preferably formed from a material that is substantially impermeable
to the propellant. The material preferably has a gas permeability
of less than 0.365 g/(m2.day) where the propellant used is HFA
134a. In some preferable embodiments, the material includes
polyethylene. Additionally or alternatively, the material includes
a polyamide, where preferably the material includes nylon. The
material may consist substantially of nylon. The material may
include a cyclic olefin copolymer (COC). The material may include a
cyclic olefin polymer (COP). The material may comprise a laminate
of polyethylene and a polyamide. The material may comprise a
laminate of polyethylene and a metal. The metal may be a metallic
foil.
[0016] Optionally, the syringe further comprises trigger means for
triggering an action upon activation of the trigger means, wherein
the trigger means are activated when the pressure in the second
chamber satisfies a predetermined condition.
[0017] The predetermined temperature may be ambient temperature.
Alternatively, the predetermined temperature may be any temperature
between 15.degree. C. and 30.degree. C. Specifically, the
temperature is between 20.degree. C. and 25.degree. C.
[0018] In some preferable embodiments, the predetermined
temperature is greater than ambient temperature.
[0019] In accordance with a second aspect of the present invention,
there is provided a syringe propellable by propellant that boils at
a predetermined temperature, the syringe comprising: [0020] a
barrel having an outlet at a front end; and [0021] a stopper
axially moveable in the barrel; [0022] wherein the stopper defines
and separates a first chamber and a second chamber, the first
chamber being axially forwards of the stopper and being configured
for containing a medicament, and the second chamber being axially
rearwards of the stopper and being configured to receive propellant
for acting on the stopper to move the stopper axially forwardly in
the barrel to expel medicament through the outlet upon actuation of
the syringe; [0023] wherein the syringe is configured such that, in
use, upon actuation of the syringe, propellant is released into the
second chamber and the pressure in the second chamber increases at
or above the predetermined temperature causing the stopper to move
axially forwardly and begin to expel medicament from the first
chamber through the outlet; [0024] the syringe further comprising a
trigger for triggering an action upon activation of the trigger,
wherein the trigger is activated in response to the pressure in the
second chamber satisfying a predetermined condition.
[0025] The syringe may further comprise a needle shield moveable
between a first position in which the needle is exposed and a
second position in which the needle is substantially covered by the
needle shield such that the needle shield is not exposed, wherein
the action includes the movement of the needle shield between the
first position and the second position.
[0026] The syringe may form part of an autoinjector device in which
the syringe is moveable relative to a housing of the autoinjector
device between a first position in which the needle is within the
housing and is not exposed and a second position in which the
needle extends out of the housing, and wherein the action includes
movement of the syringe between the first position and the second
position.
[0027] The syringe may have one or more indicators for signalling
to the user that an injection sequence is at a particular stage,
and wherein the action includes activating the one or more
indicators to produce the signal. The one or more indicators may
include a visual indicator, which may be an LED. The one or more
indicators may include an audible indicator, which may be a
speaker. The one or more indicators may signal the end of delivery
of medicament. The one or more indicators may signal that a
predetermined time period has elapsed since the end of delivery of
medicament. The predetermined condition may be exceeding a
predetermined pressure. The predetermined condition may be
exceeding the predetermined pressure after a predetermined time
period has elapsed or subsequent to a prior predetermined condition
being satisfied. The predetermined condition may be falling below a
predetermined pressure. The predetermined condition may be falling
below the predetermined pressure after a predetermined time period
has elapsed or subsequent to a prior predetermined condition being
satisfied. The predetermined temperature may be ambient
temperature. The predetermined temperature may be any temperature
between 15.degree. C. and 30.degree. C. More specifically, the
temperature may be between 20.degree. C. and 25.degree. C. The
predetermined temperature may be greater than ambient
temperature.
[0028] Optionally, the syringe further comprises a dispenser for
providing propellant to the second chamber, wherein the dispenser
is moveable from a closed position in which propellant cannot exit
the dispenser to an open position in which a predetermined volume
of propellant can exit the dispenser. The dispenser may have a
capacity for containing propellant, and the predetermined volume is
less than the capacity. The capacity may be defined by a first
internal volume of the dispenser, and the predetermined volume is
defined by a second internal volume of the dispenser, and wherein
in the closed position, the first internal volume is fluidly
connected to the second internal volume so as to allow propellant
to fill the second internal volume, and in the open position, the
first internal volume is not fluidly connected to the second
internal volume and the second internal volume is fluidly connected
to the second chamber so as to allow the predetermined volume of
propellant to be provided to the second chamber.
[0029] Optionally, when propellant is released into the second
chamber the pressure in the second chamber increases over a first
time period to a first pressure causing the stopper to move axially
forwardly to begin expulsion of medicament from the first chamber
through the outlet;
[0030] wherein the syringe is configured such that while the
medicament is expelled from the first chamber the pressure in the
second chamber changes over a second time period from the first
pressure to a second pressure, and
[0031] when substantially all the medicament has been expelled from
the first chamber the pressure in the second chamber increases over
a third time period towards a third pressure, and
[0032] wherein the magnitude of the second pressure and the rate of
increase of the pressure in the second chamber during the third
time period are controlled by the thermal conductivity of the
components of the syringe and defining the second chamber, the rate
of delivery of propellant to the second chamber, and the phase of
the propellant during delivery into the second chamber.
[0033] The first time period may be less than 1.0 second. The
second time period may be less than 15 seconds. The first pressure
may be more than 0.1 bar. The first pressure may be more than 2
bar. The first pressure may be less than 15 bar.
[0034] Optionally, one or both of the first pressure and the third
pressure is substantially equal to the vapor pressure of the
propellant at ambient temperature at the instantaneous volume of
the vaporised propellant.
[0035] The second pressure may be less than 99% of the first
pressure. The second pressure may be greater than 50% of the first
pressure. The difference between the first pressure and the second
pressure may be more than 0.1 bar.
[0036] Optionally, the syringe further comprises cooling means or
heating means configured to supply or remove heat to propellant in
the second chamber, respectively. The cooling means may comprise a
refrigerant channel for receiving refrigerant, the channel being
disposed proximate the barrel to permit the removal of heat from
the barrel by refrigerant. The refrigerant channel may be
configured to permit travel of refrigerant along the barrel from a
rear end of the barrel towards the front end of the barrel. The
refrigerant channel may be configured to permit application of
refrigerant to an injection site after travelling from the rear end
of the barrel towards the front end of the barrel along the
channel.
[0037] Optionally, the third chamber is arranged to supply
propellant to the refrigerant channel, where the supplied
propellant is the refrigerant.
[0038] The cooling or heating means may include a thermal transfer
component arranged in the second chamber and having a specific heat
capacity such that the thermal transfer component removes heat or
supplies heat to propellant in the second chamber, following
actuation of the syringe. The thermal transfer component may
comprise a metal.
[0039] The cooling means may include an insulation component
arranged to insulate the barrel from the environment, thereby
reducing heat transfer from the environment to the barrel.
[0040] Optionally, the syringe further comprises a fluid propellant
in the third chamber. The fluid propellant may be configured to
enter the second chamber primarily as a liquid. The fluid
propellant may be configured to enter the second chamber primarily
as a gas. The fluid propellant may include a hydrofluoroalkane
(HFA), wherein the HFA may be HFA 134a, HFA 422d, HFA 123, HFA
245fa, or HFA 507c.
[0041] The propellant source of the third aspect of the present
invention may be any suitable propellant source, including any
described in the present application, and particularly including
any described in relation to the first aspect of the present
invention (i.e. the third chamber and optional fourth chamber
arrangements).
[0042] In accordance with a third aspect of the present invention,
there is provided a container comprising a chamber containing a
propellant that boils at a predetermined temperature, and one or
more seals sealing the chamber, wherein the container is formed of
a flexible rupturable material substantially impermeable to the
propellant and the one or more seals are formed between two like
materials.
[0043] The one or more seals may be formed by heat sealing, sonic
welding, or adhesives. The material may have a gas permeability of
0.365 g/(m2.day). The material may include polyethylene. The
material may include a polyamide, and may include or consist
substantially of nylon. The material may comprise a laminate of
polyethylene and a polyamide. The material may comprise a laminate
of polyethylene and a metal, wherein the metal may be a metallic
foil.
[0044] The container may be formed from two sheets of the material,
wherein the chamber is defined by an area where the two sheets are
not bonded to one another and the one or more seals are defined by
one or more areas where the two sheets are bonded to one
another.
[0045] The container may be formed from a substantially cylindrical
piece of the material initially having two open ends, wherein the
two open ends are pinched closed to form two sealed ends.
[0046] The propellant may include a hydrofluoroalkane (HFA),
wherein the HFA may be HFA 134a, HFA 422d, HFA 123, HFA 245fa, or
HFA 507c.
[0047] Preferably, the container is a power source for actuating
the syringe.
[0048] In accordance with a fourth aspect of the present invention,
there is provided a method of manufacturing a container containing
propellant comprising the steps of: [0049] i) providing a tube of
rupturable material; [0050] ii) sealing a lower end of the tube to
form a lower seal; [0051] iii) sealing an upper end of the tube to
form a first upper seal and defining an internal volume between the
first upper seal and the lower seal; [0052] iv) forming an opening
in the tube; [0053] v) depositing propellant in the internal volume
through the opening; and [0054] vi) sealing the tube to form a
second upper seal that is between the first upper seal and the
lower seal, wherein the opening is between the first upper seal and
the second upper seal.
[0055] The method may further comprise the step of cutting the tube
through the second upper seal to form the container. The method may
further comprise the step of cutting the tube through the lower
seal to form the container. Step iv) may be performed prior to
performing step iii)
[0056] The step of depositing propellant in the internal volume
through the opening may comprise bringing a propellant dispenser
into fluid communication with the opening and where the propellant
dispenser forms a sealing arrangement around the opening.
[0057] The tube of rupturable material may be an extruded tube,
where optionally, at least steps i) to vi) are performed when the
extruded tube has not been cut from the extrusion line.
[0058] The first upper seal may become the lower seal of a tube
extending above thereof such that the method may be repeated for
the tube extending above thereof.
[0059] Any or each of the lower seal, the first upper seal and the
second upper seal may be a heat seal, a sonic weld, or an adhesive
seal.
[0060] The step of forming an opening in the tube preferably
produces substantially no loose material.
[0061] In accordance with a fifth aspect of the present invention,
there is provided a method of manufacturing a container containing
propellant comprising the steps of: [0062] i) sealing a first sheet
of rupturable material to a second sheet of rupturable material to
form a lower seal and two side seals; [0063] ii) placing a
propellant dispensing apparatus in fluid communication with a
central volume is defined by the lower seal, the two side seals and
a seal between the propellant dispensing apparatus and the first
and second sheets; [0064] iii) depositing propellant in the central
volume using the propellant dispensing apparatus; and [0065] iv)
sealing the first sheet to the second sheet to form an upper seal
to form a container where the propellant is contained between the
upper seal, the lower seal, and the two side seals.
[0066] Optionally, the first and second sheets move relative to the
propellant dispensing apparatus so that the upper seal of the
container becomes a lower seal of a subsequent container, where
steps i) to iv) are repeated to form the subsequent container.
[0067] Rollers may be provided to move the first and second sheets
relative to the propellant dispensing apparatus, the rollers
bringing the first sheet and the second sheet together along their
respective edges for formation of the two side seals. The rollers
may be configured to also form the two side seals. Two pairs of
separate rollers may be provided.
[0068] The lower seal and the upper seal may be severed to form a
discrete container. Any or each of the lower seal, the upper seal
and the two side seals is a heat seal, a sonic weld, or an adhesive
seal.
[0069] In accordance with a sixth aspect of the present invention,
there is provided a method of designing a syringe, the syringe
comprising: [0070] a barrel for containing a medicament, the barrel
having an outlet; [0071] a stopper defining and separating a first
chamber and a second chamber where the first chamber is axially
forwards of the stopper and is configured for containing a
medicament, and the second chamber is axially rearwards of the
stopper and is configured to receive propellant for acting on the
stopper to move the stopper axially forwardly in the barrel to
expel medicament through the outlet upon actuation of the syringe;
[0072] the method comprising the one or more of the steps of:
[0073] i) selecting the thermal properties of the syringe, [0074]
ii) determining the rate of delivery of propellant into the second
chamber, or [0075] iii) determining the phase of propellant
entering the second chamber, [0076] to exhibit a desired pressure
profile of fluid acting on the stopper following actuation of the
syringe.
[0077] The step of selecting the thermal properties of the syringe
to exhibit the desired pressure profile of fluid acting on the
stopper following actuation of the syringe may be performed by a
computer implemented calculation.
[0078] The method may further comprise the step of manufacturing a
syringe having the determined thermal properties required to
exhibit the desired pressure profile of fluid acting on the stopper
following actuation of the syringe.
[0079] The step of selecting the thermal properties of the syringe
to exhibit the desired pressure profile of fluid acting on the
stopper following actuation of the syringe may comprise the steps
of: [0080] a. determining a first pressure profile of fluid
propellant in a barrel of a syringe following actuation of the
syringe; [0081] b. comparing the first determined pressure profile
with the desired pressure profile; and if the first determined
pressure profile does not approximately equal the desired pressure
profile, then performing the steps: [0082] c. modifying the design
of the syringe to alter the heat transfer to fluid propellant in
the barrel following actuation of the syringe; [0083] d.
determining a second pressure profile of fluid propellant in the
barrel of the modified syringe following actuation of the modified
syringe; [0084] e. comparing the second determined pressure profile
with the desired pressure profile; and [0085] f. repeating steps b)
to e) until the second determined pressure profile approximately
equals the desired pressure profile.
[0086] The step of modifying the design of the syringe to alter the
heat transfer to fluid propellant in the barrel following actuation
of the syringe may comprise providing cooling means in the syringe
design, the cooling means being configured to reduce heat transfer
to the fluid propellant in the barrel following actuation of the
modified syringe.
[0087] The step of modifying the design of the syringe to alter the
heat transfer to fluid propellant in the barrel following actuation
of the syringe may comprise providing heating means in the syringe
design, the heating means being configured to increase heat
transfer to the fluid propellant in the barrel following actuation
of the modified syringe.
[0088] The step of modifying the design of the syringe to alter the
heat transfer to fluid propellant in the barrel following actuation
of the syringe may comprise providing thermal insulation means in
the syringe design, the thermal insulation means being configured
to reduce heat transfer to the fluid propellant in the barrel
following actuation of the modified syringe.
[0089] The step of modifying the design of the syringe to alter the
heat transfer to fluid propellant in the barrel following actuation
of the syringe may comprise providing thermal conductive means in
the syringe design, the thermal conductive means being configured
to increase heat transfer to the fluid propellant in the barrel
following actuation of the modified syringe.
[0090] The steps of determining a first pressure profile and a
second pressure profile may each comprise a measurement of
pressure. The step of determining a first pressure profile may
comprise a calculation. The step of determining a second pressure
profile may comprise a calculation. The or each calculation may be
a computer implemented calculation. The step of modifying the
design of the syringe may be a computer implemented step.
[0091] The method may further comprise the step of manufacturing a
syringe according to the design of the modified syringe that had a
second pressure profile approximately equal to the desired pressure
profile as determined by the method of any preceding claim.
[0092] The step of determining the rate of delivery of propellant
into the second chamber may comprise forming a restriction that
restrict the flow of propellant into the second chamber by a
desired amount.
[0093] The step of determining the phase of propellant entering the
second chamber may comprise providing a formation that limits or
prevents liquid propellant from entering the second chamber, but
permits gaseous propellant to enter the second chamber.
[0094] All non-mutually exclusive combinations of features
disclosed in the present application are within the scope of the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0095] Embodiments of the invention are further described
hereinafter with reference to the accompanying drawings, in
which:
[0096] FIG. 1A is a schematic cross sectional view of a syringe
according to an embodiment of the present invention comprising a
self-contained rupturable container of propellant;
[0097] FIG. 1B is a schematic cross sectional view of a syringe
according to an alternative embodiment of the present invention
comprising a rupturable propellant chamber;
[0098] FIG. 1C is a schematic cross sectional view of a syringe
according to an alternative embodiment of the present invention
comprising a propellant chamber with a partially rupturable
separating wall;
[0099] FIG. 1D is a schematic cross sectional view of a syringe
according to an alternative embodiment of the present invention
comprising a propellant chamber containing a self-contained
rupturable container of propellant;
[0100] FIG. 1E is a schematic cross sectional view of the syringe
of FIG. 1D additionally comprising a fluid conduit extending into
the propellant chamber;
[0101] FIG. 1F is a schematic cross sectional view of a syringe
according to an alternative embodiment of the present invention
comprising a propellant chamber with a partially rupturable
separating wall and a fluid conduit extending into the propellant
chamber;
[0102] FIG. 2 shows an embodiment of a container for containing
propellant in accordance with the present invention;
[0103] FIG. 3 shows an alternative embodiment of a container for
containing propellant in accordance with the present invention;
[0104] FIG. 4 shows a rupturing portion in accordance with an
embodiment of the present invention;
[0105] FIG. 5 shows an alternative rupturing portion in accordance
with an embodiment of the present invention;
[0106] FIG. 6A shows a time-dependent gas volume profile of a
compressed gas powered syringe in accordance with the prior art
where the compressed gas reservoir is large relative to the
internal volume of the system, and FIG. 6B shows the corresponding
time-dependent pressure profile;
[0107] FIG. 7A shows a time-dependent gas volume profile of a
compressed gas powered syringe in accordance with the prior art
where the compressed gas reservoir is small relative to the
internal volume of the system, and FIG. 7B shows the corresponding
time-dependent pressure profile;
[0108] FIG. 8A shows a time-dependent gas volume profile of a
propellant powered syringe in accordance with an embodiment of the
present invention, and FIG. 8B shows the corresponding
time-dependent pressure profile;
[0109] FIG. 9 shows a pressure profile of vapor pressure vs. time
for propellant in the second chamber of a syringe in accordance
with the present invention where liquid propellant is introduced
into the second chamber;
[0110] FIG. 10 shows a pressure profile of vapor pressure vs. time
for propellant in the second chamber of a syringe in accordance
with the present invention where gaseous and liquid propellant is
introduced into the second chamber;
[0111] FIG. 11 shows a pressure profile of vapor pressure vs. time
for propellant in the second chamber of a syringe in accordance
with the present invention where only gaseous propellant is
introduced into the second chamber;
[0112] FIG. 12 shows a pressure profile of vapor pressure vs. time
for propellant in the second chamber of a syringe in accordance
with the present invention where the propellant in the second
chamber has been actively cooled during delivery;
[0113] FIGS. 13A to 13D are schematic cross sectional views
representing a method of filling a propellant container in
accordance with an embodiment of the present invention;
[0114] FIGS. 14A and 14B are schematic cross sectional views
representing a method of filling a propellant container in
accordance with an alternative embodiment of the present invention,
and FIG. 14C is a schematic perspective view of a further step of
the method represented by FIGS. 14A and 14B; and
[0115] FIGS. 15A and 15B show cross-sectional views of a dispenser
for providing a predetermined volume of propellant to the second
chamber of the syringe in accordance with certain embodiments of
the present invention, where FIG. 15A shows the dispenser in a
closed position and FIG. 15B shows the dispenser in an open
position.
DETAILED DESCRIPTION
[0116] A syringe 10 according to an embodiment of the present
invention is shown in FIG. 1A. The syringe 10 has a barrel 12
having an outlet 14 at a forward end and a stopper 16 disposed in
the barrel 12. The stopper 16 is axially moveable within the barrel
12 when subjected to a sufficient axial force. The barrel 12 has a
finger flange 12a at a rear end, however some syringes within the
scope of the present invention may not comprises finger flanges.
The stopper 16 defines and separates a first chamber 18 and a
second chamber 20 where the first chamber 18 is axially forwards of
the stopper 16 and is configured for containing a substance such as
a medicament, and in particular, a liquid medicament. Hereinafter,
the first chamber 18 will be considered to be initially containing
medicament, although the skilled person will appreciate that other
alternative substances may be present. The second chamber 20 is
axially rearwards of the stopper 16 and is configured to receive
propellant from a propellant source. In the syringe of FIG. 1A, the
propellant source is a container 21 which comprises a rupturable
wall 24 defining a third chamber 22 containing propellant.
[0117] The syringe 10 additionally has a rupturing portion (not
shown) configured to rupture the rupturable wall 24 to irreversibly
fluidly connect the third chamber 22 and the second chamber 20 so
that propellant enters the second chamber 20. That is, the
rupturable wall 24 is frangible or breakable such that once it has
been broken or opened, it cannot be reclosed or resealed without
additional means for doing such. The rupturable wall 24 is
preferably flexible at least in part so that the shape of the
container 21 is changeable.
[0118] Within the scope of the present invention, once a fluid
connection is established between the third chamber 22 and the
second chamber 20, the fluid connection is maintained and not
closed or sealed. This is necessary for the desired thermodynamic
properties of the syringe 10 in accordance with the present
invention, as is described in more detail below. Depending on the
nature of the third chamber 22, the rupturing portion may be a
needle or other suitable element configured to slice, rupture,
break, pierce or otherwise create an opening in the rupturable wall
24 (or, in other embodiments, a similar rupturable element defining
at least a part of the third chamber 22) and establish a fluid
connection between the third chamber 22 and the second chamber 20.
In the case where the rupturing portion is a needle or similar
piercing element, it is preferable that it is either hooked, or
hollow in configuration or otherwise shaped so that upon rupturing,
breaking, or piercing the rupturable wall 24, the rupturing portion
itself does not entirely block the newly formed fluid passageway
between the third chamber 22 and the second chamber 20. In the case
where the rupturing portion has a hollow configuration, the
propellant may flow through the hollow portion from the third
chamber 22 to the second chamber 20. In other embodiments, the
rupturing portion may comprise apparatus for rupturing the
rupturable wall 24 by a bursting mechanism. That is, the rupturing
portion acts to exert a force on the container 21 so that that the
pressure in the third chamber 22 increases so that the rupturable
wall 24 is caused to rupture, thereby establishing a fluid
connection between the third chamber 22 and the second chamber 20.
In some embodiments, the rupturing portion may be moved towards the
third chamber 22 to rupture the third chamber 22. In other
embodiments, the third chamber 22 may be moved towards the
rupturing portion to cause rupturing of the third chamber 22. FIG.
4 shows an example of a rupturing portion 510 in accordance with an
embodiment of the present invention for establishing a permanent
fluid connection between the third chamber 22 and the second
chamber 20. The rupturing portion 510 includes a conical element
512 that has a cut-out portion 512a and a bore 512b running
therethrough. The conical element 512 projects from a base 514
through which the bore 512b passes. In use, the conical element 512
pierces a hole in a rupturable wall of the third chamber 22
requiring only a relatively low force to establish a fluid
connection between the third chamber 22 and the second chamber 20
via the bore 512b. The tapered profile of the conical element 512
means that as the rupturing portion 510 is advanced further towards
the rupturable wall, the conical element 512 will enlarge the hole
created and ensure that the fluid path between the third chamber 22
and second chamber 20 is not obstructed. The cut-out portion 512a
ensures that the hole is created effectively and minimizes the risk
of the rupturing portion 510 itself sealing the hole it creates.
Fluid egress from the third chamber 22 is therefore maximized. The
presence of the bore 512b facilitates direct and efficient passage
of both liquid and gaseous propellant between the third chamber 22
and second chamber 20.
[0119] The rupturing portion 510 may be shaped (e.g. the shape of
the base 514) so that multiple rupturing portions can be arranged
in close proximity to act on the same rupturable wall. As an
example, FIG. 5 shows two identical rupturing portions 510 in
suitably close arrangement for acting on a single rupturable wall.
The use of multiple rupturing portions (in general) will facilitate
greater transfer of fluid from the third chamber 22 to the second
chamber 20. The one or more rupturing portions may rupture the
third chamber 22 from any direction and in any orientation.
Depending on the specific syringe, it may be preferable to rupture
the third chamber 22 at a particular point or in a particular
direction to maximize or otherwise control the release of
propellant from the third chamber 22.
[0120] Other non-conical but tapered elements may be used to form
the rupturing portion of the present invention. In such cases, it
is still preferable for the tapered element to include a cut-out
portion to improve fluid flow and minimize the risk of the
rupturing element sealing newly created hole in the rupturable
wall. Additionally or alternatively, it is preferable for the
rupturing portion to include a through-bore for channeling fluid
from the third chamber 22 to the second chamber 20.
[0121] The propellant is one that boils at a predetermined
temperature which in all cases must be below the local operating
temperature of the system during use. A particularly preferable
propellant is or includes a hydrofluoroalkane (HFA) as this
provides a suitable pressure for use with aqueous solution in a
fine bore needle syringe. HFA 134a boils at -26.4.degree. C. which
is able to provide sufficient pressure even when the medicament
that is to be delivered is chilled. In other embodiments a
propellant may have a lower boiling point which provides an
increased pressure is use, which is especially useful for the
delivery of highly viscous drugs. For example HFA 422d has a
boiling point between -46.2.degree. C. and -41.5.degree. C.
Similarly, HFA 507c has a boiling point of -46.9.degree. C. In
alternative embodiments, the propellant may boil at a higher
temperature such that it cannot generate sufficient pressure to
drive the medicament without additional energy from an external
source such as the patient or another heat source. For example HFA
123 boils at +27.9.degree. C. Similarly, HFA 245fa has a boiling
point of +15.3.degree. C.
[0122] When the third chamber 22 is in fluid communication with the
second chamber 20, propellant is released into the second chamber
20. At the predetermined temperature, the propellant released into
the second chamber 20 is initially in its liquid phase.
Additionally or alternatively, some of the propellant may be
initially in its liquid phase due to the confines of the volume in
which it resides, even if the propellant is at a temperature above
the predetermined temperature.
[0123] Some of this liquid propellant will evaporate due to the
heat that the propellant is exposed to (e.g. ambient heat), thereby
providing gas phase propellant to the second chamber 20. Since the
vaporization of propellant requires the absorption of latent heat
from the liquid propellant, the process of evaporation cools the
remaining liquid propellant. This cooling results in the vapor
pressure immediately above the liquid propellant being lower than
it is at its initial starting (i.e. ambient) temperature.
Nevertheless, the pressure in the second chamber 20 begins to
increase enough so that the stopper 16 moves axially forwardly in
the barrel 12, thereby reducing the volume of the first chamber 18
and pressurizing the medicament held therein. The pressurized
medicament exits the barrel 12 through the outlet 14, which may be
fluidly connected to a needle or other applicator, for entry into
an injection site such as subcutaneous tissue.
[0124] In the case where a propellant is used that boils at a
temperature higher than ambient temperature, the ambient
temperature will not be sufficient to boil the propellant and thus
the stopper 16 will not move as a consequence. In these
embodiments, an additional heat source must be provided to boil the
propellant and begin movement of the stopper 16. For example, the
heat source could be the user's hand which will be at "body
temperature" (approximately 37.degree. C.). This arrangement may
reduce the risk of accidental delivery of medicament if the
propellant is inadvertently in fluid communication with the second
chamber 20.
[0125] As the stopper 16 moves axially forwards towards the outlet
14 to reduce the volume of the first chamber 18, the second chamber
20 is made larger. Thus, additional volume is continuously created
in the second chamber 20 into which the propellant can evaporate
into. This further vaporization causes further cooling of the
remaining liquid propellant and thus further reduces the observed
vapor pressure in the second chamber 20.
[0126] However, the system is not completely adiabatic (nor is it
isothermal) so thermal energy is absorbed by the liquid propellant
from its immediate environment (e.g. the barrel 12) to counter the
reduction in temperature of the liquid propellant and the reduction
in vapor pressure in the second chamber 20. Indeed, in the absence
of this heat absorption, the propellant would freeze as the
temperature of the liquid propellant continues to drop, and the
syringe 10 would cease to operate correctly. This drop in vapor
pressure in the second chamber 20 is exhibited throughout delivery
of the medicament from the first chamber 18. In particular, since
the stopper 16 is moving, the propellant in the second chamber 20
is continuously exposed to "new" sections of the inside of the
barrel 12. Since the "new" sections of the inside of the barrel
have not previously been in contact with the propellant, its
thermal energy will initially be substantially at or near to
ambient temperature or a higher temperature if additional heating
means are present (unlike the sections of the barrel 12 axially
rearward thereof which have already given up thermal energy to the
liquid propellant). The "new" sections of barrel that the
propellant is exposed to during delivery therefore act as a fresh
heat source which is able to provide thermal energy to the
propellant in the second chamber 20.
[0127] The stopper 16 continues to move axially forwardly in the
barrel 12 until it reaches the forwardmost end of the barrel 12
where further forward axial movement is not possible. At this
point, the full dose of medicament in the first chamber 18 has been
delivered and the first chamber 18 has been reduced to its smallest
volume (i.e. at or near substantially zero, depending on the
formation of the front end of the barrel 12). With no further
movement of the stopper 16, the temperature of the gas phase
propellant, and any remaining liquid propellant, begins to increase
as thermal energy is absorbed from the environment. Since, with the
stopper 16 stationary in the barrel 12, the second chamber 20 has a
constant volume, the increase in temperature of the propellant
results in an increase in vapor pressure in the second chamber 20.
This increase in vapor pressure tends towards the vapor pressure of
the propellant at the temperature of its immediate environment
(e.g. ambient temperature or a higher temperature if additional
heating means are still present at this point). Indeed, the vapor
pressure in the second chamber 20 will reach the vapor pressure of
the propellant at the temperature of its immediate environment
given long enough as equilibrium is reached.
[0128] The magnitude of the drop in vapor pressure in the second
chamber 20 during delivery from the initial vapor pressure maximum
when the propellant is released into the second chamber 20 to when
the stopper 16 has reached the front end of the barrel 12 depends
on any one or more of i) the thermal properties of the syringe 10,
ii) the rate of delivery of propellant into the second chamber 20,
and iii) the phase of the propellant entering the second chamber 20
(as will be described in more detail below). With regards to the
effects of the thermal properties of the syringe 10, such
properties determine the rate of heat transfer into the propellant
in the second chamber 20. Similarly, the rate and phase of
propellant entering the second chamber 20 affects the thermodynamic
processes occurring during delivery with regards to the propellant
in the second chamber 20.
[0129] As an example, a 0.5 bar drop in vapor pressure may be
exhibited when delivering 1 ml of aqueous solution through a 27
gauge needle attached to the outlet 14 measured from the initial
vapor pressure maximum when the propellant is released into the
second chamber 20 to when the stopper 16 has reached the front end
of the barrel 12.
[0130] The advantages of the present invention are best understood
by comparison with a syringe powered by a compressed gas. In known
prior art compressed gas syringes, compressed gas is released from
a reservoir into a volume behind a stopper in a syringe barrel
where the expanding volume of gas can act on the stopper and cause
it to move and expel medicament from the barrel. FIG. 6A shows a
time-dependent volume profile of a compressed gas syringe in
accordance with the prior art. 5 cc of compressed gas is initially
contained in a reservoir which is in selective fluid communication
with a volume of the syringe rearward of a stopper. As shown in
FIG. 6A, when the reservoir is opened the compressed gas expands
rapidly at 500 as the compressed gas fills the dead volume behind
the stopper.
[0131] There is a constant mass of gas which follows the ideal gas
law under adiabatic conditions and behaves as PV=nRT, where P is
the pressure of the gas, V is the volume of the gas, n is the
number of moles of gas, T is the temperature of the gas and R is
the universal gas constant. Once the dead volume is filled with
compressed gas, the expanding gas begins to gas the stopper to
move, as indicated at 502 on FIG. 6A, and medicament is expelled
from the barrel. Once the stopper reaches its forwardmost position
in the barrel, the compressed gas ceases to expand further, as
indicated at 504 of FIG. 6A.
[0132] Since the quantity nRT is constant for adiabatic expansion,
the pressure of the gas drops as the volume increases. This is
shown in FIG. 6B which shows a time-dependent pressure profile
corresponding to the volume profile of FIG. 6A. This drop in
pressure occurs both as the compressed gas enters the dead volume
(i.e. when the compressed gas reservoir is initially opened) and
during the time that the stopper is moving forwards and expelling
medicament. As shown in FIG. 6B, the result is an initially steep
drop in pressure, followed by a more gradual drop in pressure. The
final pressure of the compressed gas is determined by the volume in
which it resides at the end of the delivery, when the stopper is at
its forwardmost position in the barrel. FIGS. 6A and 6B relate to a
syringe where the reservoir of compressed gas is large relative to
the internal volume of the system. As a consequence of this, the
final pressure of compressed gas is maintained at a relatively high
level (.about.5 bar from an initial 10 bar).
[0133] FIGS. 7A and 7B relate to a syringe where the reservoir of
compressed gas is small (0.3 cc) relative to the internal volume of
the system. FIG. 7A shows the time-dependent volume profile of the
compressed gas, and FIG. 7B shows the corresponding time-dependent
pressure profile of the compressed gas. Again, FIG. 7A shows a
rapid increase in volume at 500 when the compressed gas reservoir
is initially opened and the compressed gas fills the dead volume.
This is followed by a more gradual increase in volume at 502 as the
stopper begins to move and the volume behind the stopper increases.
Finally, when the stopper is in its forwardmost position in the
barrel, the volume of the compressed gas ceases to increase as
shown at 504 of FIG. 7A. The corresponding pressure profile shown
in FIG. 7B shows that there is a large and initially rapid
reduction in pressure as the gas expands, and then a more gradual
decrease in pressure as the stopper begins to move.
[0134] In contrast, if the gas is initially a liquefied gas in
accordance with the present invention, the mass of the gas
increases as the gas expands as the liquid boils. It is this
increasing mass aligned with the increasing volume that provides a
more consistent pressure profile. FIG. 8A shows a time-dependent
volume profile of a syringe powered by 0.3 cc of a liquefied
propellant in accordance with an embodiment of the present
invention. In the reservoir (e.g. the third chamber) the propellant
will be a liquid in equilibrium with a saturated vapour. Once the
reservoir is opened and put into fluid communication with the
volume behind the stopper, the liquid propellant boils and volume
of the gas increases as shown at 500 of FIG. 8A. As with the
compressed gas, once the stopper begins to move, the volume behind
the stopper increases and permits the volume of the gas to increase
further as shown at 502. Once the stopper reaches its forwardmost
position, the volume of gas plateaus, as shown at 504. However,
since the mass of gas increases as the liquid boils, the propellant
generates more gas at the vapor pressure and therefore maintains a
more constant pressure as shown in FIG. 8B. Whilst there is an
initial variation in gas pressure as the reservoir is first put
into fluid communication with the volume behind the stopper, there
is no significant overall drop in gas pressure as there is with
compressed gases, as evidenced by FIGS. 6B and 7B. Consequently,
the present invention offers a much more consistent pressure
profile with a very small initial volume of propellant.
[0135] FIG. 9 shows an example of a pressure profile (i.e. vapor
pressure vs. time within the second chamber 20) exhibited by a
syringe such as the one described above in relation to FIG. 1A
during use. Point A indicates the start of propellant release into
the second chamber 20 and the subsequent boiling of the propellant
which results in a very fast increase in vapor pressure over a
first time period (typically of the order of 10-100 ms) up to point
B. At point B, the vapor pressure in the second chamber 20 is great
enough to cause the stopper 16 to move axially forwardly and begin
expulsion of medicament from the first chamber 18. In practice, the
stopper 16 may start to move just before point B is reached as the
pressure in the second chamber 20 is sufficient to overcome the
frictional resistance of the stopper 16 in the syringe 10. As
described above, the thermodynamics of the syringe 10 dictate that
the vapor pressure drops during delivery. This is shown in the
pressure profile of FIG. 9 as the negative gradient between points
B and C over a second time period, where point C is indicative of
the instant where axial movement of the stopper 16 ceases to
continue (i.e. the end of delivery). Consequently, the vapor
pressure at C is lower than the vapor pressure at B. A third time
period between point C and point D represents the vapor increase in
the second chamber 20 as the propellant therein absorbs heat from
the environment. This increase tends towards the vapor pressure of
the propellant at the temperature of its immediate environment
(e.g. ambient temperature). Indeed, point D represents
substantially this vapor pressure. For the pressure profile of FIG.
9, the vapor pressure at D is greater than both the vapor pressures
at B and C (and of course A). This may be because the stopper 16
began moving axially forwardly before the propellant could reach
its vapor pressure at the temperature of its immediate
environment.
[0136] The pressure profile of FIG. 9 reveals that there is not
necessarily a simple constant pressure acting on the stopper 16
(i.e. the vapor pressure in the second chamber 20) during delivery.
In accordance with the present invention, this pressure profile may
be manipulated so as to provide a more reliable and/or useful
device, and/or be more suitable for a particular medicament or
application. Indeed, as noted above, the form of the pressure
profile is dependent on any one or more of i) the thermal
properties of the syringe 10, ii) the rate of delivery of
propellant into the second chamber 20, and iii) the phase of the
propellant entering the second chamber.
[0137] Further embodiments of syringes 10 in accordance with the
present invention are described below with reference to FIGS. 2 to
6. Given the differences in configuration, the various embodiments
of syringes 10 will each exhibit a different pressure profile of
vapor pressure in the second chamber 20 during use.
[0138] In FIG. 1B, a syringe 10 is shown that is largely the same
as that shown in FIG. 1A, except that the third chamber 22 is no
longer defined by a rupturable wall 24 forming a self-contained
container 21. Instead, for the syringe 10 of FIG. 1B, the
rupturable wall 24 extends across the barrel 12 in a direction
substantially perpendicular to the longitudinal direction of the
syringe 10 (which is parallel the axial directions referred to
above). Therefore, for the syringe 10 of FIG. 1B, the third chamber
22 is defined by the rupturable wall 24 and the walls of the barrel
12. In alternative embodiments, the third chamber may be defined by
the rupturable wall 24 and possibly the walls of an additional
component (which may not be enveloped by or contained within the
barrel 12), but where the rupturable wall provides a boundary
between the third chamber 22 and the second chamber 20. The
rupturable wall may, for example, be a septum separating the third
chamber 22 and second chamber 20. Additionally, the rupturable wall
24 need not necessarily be perpendicular to the longitudinal axis
of the syringe 10, nor need it be disposed in a single plane. As
with the syringe 10 of FIG. 1A, the syringe 10 of FIG. 1B is
actuated when a rupturing portion (not shown) causes the rupturable
wall 24 to rupture so as to form a fluid connection between the
third chamber 22 and the second chamber 20 thereby permitting the
flow of propellant from the third chamber 22 into the second
chamber 20. As with the syringe of FIG. 1A, the stopper 16 of the
syringe 10 of FIG. 1B will then move axially forwardly under the
force of the vapor pressure in the second chamber 20 to expel
medicament from the first chamber 28 through the outlet 14.
[0139] A further embodiment of a syringe in accordance with the
present invention is shown in FIG. 1C. The syringe 10 of FIG. 1C
differs from the syringe of FIG. 1B in that the third chamber 22 is
not only defined by a rupturable wall 24, but also by a
non-rupturable wall (or walls) 26 extending between the walls of
the barrel 12 along an internal circumference of the barrel 12. In
the embodiment shown, the non-rupturable wall 26 extends from the
barrel 12 and has a central aperture across which the rupturable
wall 24 extends. In alternative embodiments, there may be a
plurality of rupturable walls 24 and non rupturable walls 26
extending across the barrel 12 in any configuration so as to define
the third chamber 22. Indeed, in some embodiments, any
configuration of rupturable walls 24, or rupturable walls 24 and
non-rupturable walls 26, may form a third chamber 22 that does not
bisect the longitudinal axis of the syringe 10.
[0140] In the embodiment of FIG. 1C, the extent of the rupturable
wall 24 (which is largely determined by the size of the aperture in
the non-rupturable wall 26) will largely determine the flow rate of
propellant from the third chamber 22 to the second chamber 20 upon
rupturing of the rupturable wall 24.
[0141] A further embodiment of a syringe in accordance with the
present invention is shown in FIG. 1D. The syringe 10 of FIG. 1D
comprises a non-rupturable wall 26 extending across the barrel 12
along an inner circumference of the barrel 12. The non-rupturable
wall 26 does not form a continuous disc and has an axial aperture
26a therethrough. The non-rupturable wall 26 defines a fourth
chamber 28 which is fluidly connected to the second chamber 20 via
aperture 26a which defines a propellant channel. The fourth chamber
28 contains a container 21 as described above in relation to FIG.
1A. In use, the rupturable wall 24 of the container ruptures to
fluidly connect the third chamber 22 to the fourth chamber 28, and
therefore also to the second chamber 20 via the aperture 26a. The
extent of the aperture 26a largely determines the flow rate of
propellant from the fourth chamber 28 to the second chamber 20 upon
rupturing of the rupturable wall 24. The aperture 26a may be a
simple hole, or may be any other fluid passageway that connects the
fourth chamber 28 to the second chamber 20. For example, in one
embodiment, the aperture 26a may be a labyrinth arrangement or a
valve arrangement that opens when the fluid pressure acting on it
exceeds a predetermined threshold. A baffle arrangement may prevent
or minimize the flow of droplets (e.g. a mist) of propellant
passing from the fourth chamber 28 to the second chamber 20.
[0142] Yet another embodiment of a syringe 10 in accordance with
the present invention is shown in FIG. 1E. The syringe 10 of FIG.
1E is largely the same as the syringe of FIG. 1D but the propellant
channel fluidly connecting the third chamber 22 and the fourth
chamber 28 is defined by a propellant conduit 30. The propellant
conduit 30 has a bore therethrough fluidly connecting the third
chamber 22 and the fourth chamber 28, and the bore largely
determines the flow rate of propellant from the third chamber 22 to
the fourth chamber 28. The propellant conduit 30 extends axially
rearwardly into the fourth chamber by distance L. The axially
rearwardly extending propellant conduit 30 acts to limit the
quantity of liquid propellant passing from the fourth chamber 28 to
the second chamber 20 during use of the syringe 10. In particular,
during use of the syringe 10, the syringe 10 will be orientated so
that the outlet 14 is proximate to an injection site. Usually, the
syringe 10 will be orientated so that the longitudinal axis of the
syringe is held vertically above the injection site (or at least be
inclined with respect to the horizontal). In this orientation,
liquid propellant exiting the third chamber 22 (i.e. after rupture
of rupturable wall 24) will move under the influence of gravity
towards the non-rupturable wall 26. The propellant conduit 30 will
then extend above some, if not all, of the liquid propellant,
depending on the magnitude of L and the quantity of propellant
present. The propellant conduit 30 acts to limit or prevent
entirely the flow of liquid propellant from the fourth chamber 28
to the second chamber 20. The syringe 10 may be used at
orientations other than vertical (e.g. horizontal, or indeed any
orientation between vertical and horizontal) and so it is
preferable for L to be sufficient so that the flow of liquid
propellant from the fourth chamber 28 to the second chamber 20 is
limited, or further preferably, substantially prevented.
[0143] Modeling the second chamber 20 as a cylinder having radius r
and height H, .pi.r.sup.2 L should be greater than the maximum
volume of liquid propellant in the second chamber 20 for the rear
(open) end of the propellant conduit 30 to rise above the
propellant liquid level when the syringe 10 is in a vertical
orientation. Additionally, (.pi.r.sup.2H/2) should be greater than
the maximum volume of liquid propellant in the second chamber 20
for the propellant conduit to remain above the propellant liquid
level when the syringe 10 is in a horizontal orientation. In one
example, for a 100 .mu.l volume of propellant in a second chamber
30 of diameter 6.35 mm, the magnitude of L should be 3.158 mm or
greater to be above the propellant liquid level. In another
example, for a 10 .mu.l volume of propellant in a second chamber 30
of diameter 6.35 mm, the magnitude of L should be 0.316 mm or
greater to be above the propellant liquid level.
[0144] A similar syringe 10 to that described above in relation to
FIG. 1E is shown in FIG. 1F. In the syringe 10 of FIG. 1F, the
third chamber 22 is not defined by a self-contained container 21,
but by a combination of a rupturable wall 24, non-rupturable wall
26 and the barrel 12 (similar to the embodiment shown in FIG. 1C).
Additionally, the syringe 10 of FIG. 1F comprises a propellant
conduit 30 that extends axially rearwardly into the third chamber
22 by a distance L and has a bore fluidly connecting the third
chamber 22 to the second chamber 20 (albeit for the presence of the
rupturable wall 24). The rupturable wall 24 may be located at any
position along the bore of the propellant conduit 30 to temporarily
fluidly isolate the third chamber 22 from the second chamber 20. As
with the embodiment of FIG. 1E, the propellant conduit 30 acts to
limit or prevent entirely the flow of liquid propellant into the
second chamber 20, this time from the third chamber 22. As
described above, a labyrinth or valved arrangement may be present
to prevent droplets of liquid propellant (e.g. a mist) passing
through into the second chamber 20.
[0145] The pressure profile of vapor pressure of propellant in the
second chamber 20 during use will be influenced by the phase of
propellant entering the second chamber. For example, if a constant
or near constant flow of gas-phase (or predominantly gas-phase)
propellant is being supplied to the second chamber 20 through the
propellant conduit 30, then the stopper 16 will experience a more
constant vapor pressure and move axially forwardly at a more
constant rate within the barrel 12 and expel medicament from the
first chamber 18 at a constant rate. This may be particularly
suitable for applications where it is important to deliver
medicament at a constant or near constant rate.
[0146] The passage of propellant through the propellant conduit 30
or aperture 26a does not constitute "regulated delivery". The
propellant passes through the propellant conduit 30 or aperture 26a
at a constant pressure that is lower than the pressure that would
be observed if the restriction (propellant conduit 30 or aperture
26a) were not present. Indeed, passage through the propellant
conduit 30 or aperture 26a constitutes bolus delivery of the
propellant into the second chamber 20.
[0147] Unless otherwise stated, all described features of the
syringe of FIG. 1A (excluding the form of the third chamber 22) may
be applicable to any one or more of the syringes of FIGS. 1B to 1F.
Indeed, any non-mutually exclusive features of any one or more of
the syringes of FIGS. 1A to 1F may be applicable to any other of
the syringes of FIGS. 1A to 1F.
[0148] FIG. 10 shows an example pressure profile of vapor pressure
in the second chamber 20 of a syringe 10 where mostly gas
propellant is supplied to the second chamber 20. The pressure
profile of FIG. 10 shows that propellant enters the second chamber
20 at point A and immediately results in an increase of vapor
pressure in the second chamber 20 to an initial maximum vapor
pressure and point B. The rate of increase of vapor pressure
decreases slightly immediately prior to reaching point B. The
change from point A to point B occurs over a first time period. The
vapor pressure then decreases slightly over a second time period as
the stopper 16 begins to move axially forwardly to deliver
medicament until point C is reached. During the second time period,
the little liquid that is present reduces in temperature as it
gives up heat of vaporization by the mechanism described above in
relation to the pressure profile of FIG. 9. However, the decrease
and the rate of decrease between points B and C in FIG. 10 are less
than the respective decrease and the rate of decrease in the
pressure profile of FIG. 9. In FIG. 10, point C represents the end
of delivery when the stopper 16 has reached the front of the barrel
12 and is no longer moving axially forwardly. Subsequent to point C
being reached, the propellant in the second chamber 20 absorbs heat
from the environment which increases the vapor pressure within the
second chamber 20. This increase tends towards the vapor pressure
of the propellant at the temperature of its immediate environment
(e.g. ambient temperature) which is indicated at point D, where the
time period between points C and D is a third time period.
[0149] FIG. 11 shows an example of a pressure profile of a syringe
10 in accordance with the present invention where substantially
only gas propellant is introduced into the second chamber 20. The
pressure profile of FIG. 11 is largely similar to that of FIG. 10,
however, in the pressure profile of FIG. 11, there is substantially
no change in the vapor pressure between points B and C. That is,
during delivery, there is a substantially constant vapor pressure
in the second chamber 20. As with the pressure profile of FIG. 10,
subsequent to the end of delivery (i.e. after point C), the vapor
pressure increases as the propellant in the second chamber absorbs
heat from the environment.
[0150] Comparing the pressure profiles of FIGS. 9, 10 and 11, it
can be seen that the drop in vapor pressure between points B and C
is reduced as the proportion of gas propellant relative to liquid
propellant introduced into the second chamber 20 is increased. It
is understood that this is predominantly due to the initial maximum
of vapor pressure (i.e. the vapor pressure at point B) being
reduced for more proportionally gaseous propellant introduced into
the second chamber 20. That is, the vapor pressure in the second
chamber 20 does not reach its vapor pressure at the temperature of
its immediate environment (e.g. ambient temperature) during
delivery when only gaseous or partially gaseous propellant is
introduced into the second chamber 20.
[0151] Indeed, it is anticipated that for some syringes in
accordance with the present invention, where only gaseous
propellant is introduced into the second chamber 20 that there will
be no initial maximum prior to the end of delivery. That is, the
initial increase in vapor pressure subsequent to point A will
result in the movement of the stopper 16 and the expulsion of
medicament, but at the end of delivery the vapor pressure will be
at a level not previously exceeded in the delivery process. To put
that another way, point C will represent the highest vapor pressure
of the first and second time periods. In this scenario, following
point C, the vapor pressure will increase as the propellant absorbs
heat energy from its environment and tends towards the vapor
pressure of the propellant at the temperature of its immediate
environment (e.g. ambient temperature).
[0152] As described above, the form of the pressure profile
produced by a propellant powered syringe 10 is determined by one of
three parameters, namely i) the thermal properties of the syringe
10, ii) the rate of delivery of propellant into the second chamber
20, and iii) the phase of the propellant entering the second
chamber 20. The embodiments described above demonstrate the effects
of parameters ii) and iii) on the form of the pressure profile.
[0153] FIG. 12, however, demonstrates the effects of parameter i)
on the form of the pressure profile. In particular, FIG. 12
represents the pressure profile of a syringe 10 in accordance with
the present invention, similar to the syringe that produced the
pressure profile of FIG. 9. However the syringe 10 associated with
the pressure profile of FIG. 12 additionally includes apparatus to
further cool the propellant in the second chamber 20 during use. By
"further cool" is meant reducing the temperature of the propellant
in the second chamber 20 by an amount that is more than if the
apparatus to further cool were not present, i.e. where the only
reduction in temperature in liquid propellant is due to loss of
latent heat of vaporization. The skilled person will appreciate
that the propellant in the second chamber 20 can be further cooled
by several methods within the scope of the present invention. For
example, a coolant or refrigerant (which may be an additional
supply of the propellant) may be applied to the outside of the
barrel 12 proximate the second chamber 20 so that the portion of
the barrel 12 proximate the second chamber 12 is cooled thereby
removing some of its thermal energy such that it has less thermal
energy to supply to the propellant in the second chamber 20. If the
part of the barrel 12 proximate the second chamber 20 has less
thermal energy to provide to the propellant in the second chamber
20, when the temperature of the liquid propellant falls as it loses
heat of vaporization as it boils, the liquid propellant has less
thermal energy available to it from the barrel 12 proximate the
second chamber 20 as it otherwise would. Therefore, there is less
thermal energy available to the liquid propellant in its immediate
environment that may be absorbed by the liquid propellant to offset
the reduction in temperature due to boiling. For this reason,
during operation of the syringe 10, the drop in vapor pressure in
the second chamber 20 is greater than it would otherwise be if no
means to cool the propellant therein were in place. Indeed, any
means or method that reduces the thermal energy available to the
liquid propellant in the second chamber 20 as it is boiling and
causing the stopper 16 to move axially forwardly in the barrel 12
will result in a greater drop in vapor pressure in the second
chamber 20 than would otherwise occur if no such means or method
were in place.
[0154] In the case where a coolant or refrigerant is applied to the
outside of the barrel 12 proximate the second chamber 20, the
coolant or refrigerant may be channeled or otherwise caused to
travel towards the injection site after cooling the barrel 12 (and
the liquid propellant in the second chamber 20) to additionally
provide cooling to the injection site. The cooling provided to the
injection site may provide the effect of reducing the level of pain
caused by the injection as perceived by the patient.
[0155] In other embodiments, thermally insulating material may be
present on or around the barrel 12 proximate the second chamber 12
so that the thermal transfer of heat from the environment to the
barrel 12 is reduced. In this embodiment, heat lost from the barrel
12 and absorbed by the liquid propellant in the second chamber 20
may not be replaced (or such replacement will at least be
restricted) by absorption of heat by the barrel 12 from the
external environment. Again, such measures will limit the heat
transfer to the second chamber 20 which contains the propellant so
that a greater vapor pressure drop will be exhibited.
[0156] Conversely, if more thermal energy is supplied to the second
chamber 20 such that the liquid propellant contained therein is
able to absorb more thermal energy during delivery than it
otherwise would be able to, the drop in vapor pressure exhibited in
the second chamber 20 during delivery may be reduced and even
reduced to substantially zero. Thermal energy may be supplied to
the second chamber 20 by active heating means, which for example
may be achieved by providing a heat source that has a temperature
above the ambient temperature so that thermal energy may be
transferred from the heat source to the second chamber 20, and in
particular to the propellant contained therein. Alternatively, the
thermal properties of the syringe 10, e.g. the barrel 12, may be
configured so as to increase the rate of heat transfer from the
environment to the second chamber 20. For example, the materials of
the syringe 10 may be chosen such that they have a high thermal
conductivity to maximize heat transfer into the second chamber 20
so that the liquid propellant is able to absorb sufficient heat to
offset (i.e. reduce or eliminate) the reduction in temperature due
to vaporization. Of course, if using materials having high thermal
conductivity to construct the syringe 10, the materials must also
provide other desired physical properties (e.g. strength and
durability) to a sufficient degree.
[0157] Thus, in accordance with the present invention a syringe 10
may be provided that has suitable properties such that upon
actuation of the syringe 10, a desired pressure profile of vapor
pressure in the second chamber is exhibited. The desired pressure
profile may be dictated by the desire to produce a delivery having
a particular pressure profile, to suit a particular medicament or
injection type, for example. Alternatively, the desired pressure
profile may be dictated by the requirement to have a pressure
feature of a particular type (e.g. magnitude, duration, gradient or
rate etc.). The pressure feature may be used to trigger a
subsequent action so that more complex modes of operation of the
syringe can be utilized (as is described in more detail below).
[0158] As described above, the "first time period" is the time
period between the initial release of propellant into the second
chamber 20 and the initial maximum vapor pressure. Typically
(although not always, as described above) the initial movement of
the stopper 16 will be coincident with an initial maximum vapor
pressure from which the vapor pressure decreases from over the
second time period. The "second time period" is the time period
between the initial forwardly axial movement of the stopper 16 and
the point where forward axial movement of the stopper 16 is
arrested (i.e. the end of the delivery phase when the stopper 16
reaches the front end of the barrel 12). The "third time period" is
defined as the time period between the end of the second time
period and the point where vapor pressure in the second chamber 20
reaches a predetermined level. In a preferable embodiment, the
predetermined level determining the third time period is the vapor
pressure of the propellant at the temperature of its immediate
environment (e.g. ambient temperature).
[0159] In preferable embodiments, the syringe 10 in accordance with
the present invention exhibits a pressure profile of vapor pressure
in the second chamber 20 wherein the first time period is less than
1.0 seconds. In further preferable embodiments, it is preferable
for the first time period to be shorter, such as less than 0.5
seconds, less than 0.2 seconds, or less than 0.1 seconds. In
preferable embodiments, it is preferable for the second time period
to be less than 15 seconds. However a second time period of around
15 seconds represents a relatively long delivery period, so in
practice it may be more preferable if the second time period is
less than 10 seconds and further preferably less than 5 seconds. In
particularly preferable embodiments, the second time period is less
than 3 seconds, less than 2 seconds, or less than 1 second. Where
an initial maximum vapor pressure (a "first pressure") is reached
that is substantially coincident with the initial movement of the
stopper 16 (i.e. coincident with the end of the first time period
and the beginning of the second time period) it is preferable that
this be less than 15 bar, or further preferably less than 10 bar,
less than 8 bar or less than 6 bar. In a preferable embodiment, the
first pressure is substantially equal to the vapor pressure of the
propellant at the temperature of its immediate environment (e.g.
ambient temperature). Defining the vapor pressure in the second
chamber 20 at the end of the second time period (i.e. the start of
the third time period) as a "second pressure", in preferable
embodiments the second pressure is preferably less than 99% of the
first pressure, or further preferably less than 95% or less than
90% of the first pressure. Similarly, in preferable embodiments the
second pressure is preferably greater than 50% of the first
pressure, or further preferably greater than 75% or greater than
85% of the first pressure. In preferable embodiments, the
difference between the first pressure and the second pressure is
more than 0.1 bar, and further preferably more than 0.5 bar or more
than 1.0 bar.
[0160] In accordance with a further or alternative aspect of the
present invention, there is provided a syringe propellable by a
propellant that boils at a predetermined temperature where the
syringe comprises a barrel having an outlet at a front end, and a
stopper axially moveable in the barrel, wherein the stopper defines
and separates a first chamber and a second chamber. The first
chamber is axially forwards of the stopper and is configured for
containing a substance such as a medicament, and the second chamber
is axially rearwards of the stopper and is configured to receive
propellant for acting on the stopper to move the stopper axially
forwardly in the barrel to expel medicament through the outlet upon
actuation of the syringe. Indeed, this syringe is much like the
syringes described above in accordance with other embodiments of
the invention, and, indeed, the syringe of this further aspect may
be identical to one of those earlier described syringes. However,
the syringe of this further aspect is not necessarily limited to
receiving propellant from a third chamber that includes a
rupturable container. Indeed, propellant may be supplied via a
valved container or otherwise to the syringe of this further aspect
of the invention.
[0161] The syringe is configured such that, in use, upon actuation
of the syringe, propellant is released into the second chamber (by
any suitable means) and the pressure in the second chamber
increases causing the stopper to move axially forwardly in the
barrel and begin to expel the substance contained in first chamber
therefrom through the outlet. The syringe additionally comprises a
trigger that is activated (or "triggered") in response to the
pressure in the second chamber satisfying a predetermined
condition. Upon activation of the trigger, an "action" is
triggered. The action may be the movement of a protecting needle
shield between a retracted exposing position and a forward
protecting position. Alternatively, the syringe may be part of a
larger autoinjector device where the syringe is axially moveable
between a first position where the needle is wholly within a
housing of the device and a second position where the needle
protrudes from the housing so as to be able to penetrate an
injection site. In this embodiment, the action triggered may be the
movement of the syringe in the device between the first and second
positions. Additionally or alternatively, the action triggered may
be the activation of one or more indicators to produce one or more
signals. The indicators may include a visual indicator, such as an
LED. Alternatively, the indicators may include an audible
indicator, such as a loud speaker. In any case, the one or more
indicators may signal the end of delivery of medicament or signal
that a predetermined time period has elapsed since the end of
delivery.
[0162] The predetermined condition that causes the activation of
the trigger may be a predetermined pressure being exceeded in the
second chamber. The trigger may be activated when the predetermined
pressure is exceeded in the second chamber after a predetermined
time period has elapsed or subsequent to a prior predetermined
condition being satisfied. The predetermined condition may be the
pressure falling below a predetermined pressure, and may be the
pressure falling below a predetermined pressure after a
predetermined time period has elapsed or subsequent to a prior
predetermined condition being satisfied. In further or alternative
embodiments, the predetermined pressure may be in respect of the
absolute pressure in the second chamber, a ratio of pressures in
the second chamber (with respect to time), or a difference in
pressures in the second chamber (with respect to time).
Alternatively, the predetermined condition could be a ratio or
difference between the pressure in the second chamber and the
pressure in a reference chamber, such as the third chamber.
[0163] The trigger may include a pressure sensor that is connected
to an actuator for causing the further action. Additionally or
alternatively, the trigger may include a mechanism whereby the
pressure in the second chamber directly causes the further action.
For example, the vapor pressure in the second chamber may be used
(once a predetermined condition is satisfied) to directly bias a
needle shield to its forward protecting position, or cause some
other physical mechanism to move. In the case of a moving needle
shield, the needle shield could be released so that under the
influence of a biasing member, the needle shield is biased against
the injection site (e.g. the patient's skin) so that when the
syringe is removed from the injection site there is no resistance
to the bias provided by the biasing member and the needle shield
moves fully to its protecting position.
[0164] If the syringe is configured to exhibit a pressure profile
in accordance with the present invention, the pressure profile can
be tailored (as part of the specification of the syringe) to have
pressure features that can be used as or for the predetermined
condition that activates the trigger.
[0165] As noted above, in certain embodiments, propellant may be
provided to the second chamber by means that do not have rupturable
walls (in accordance with certain aspects of the present
invention). For example, the syringe may comprise a dispenser for
providing propellant to the second chamber, wherein the dispenser
is moveable from a closed position in which propellant cannot exit
the dispenser to an open position in which a predetermined volume
of propellant can exit the dispenser. The dispenser may have a
capacity for containing propellant, where the predetermined volume
is less than the capacity. the capacity may be defined by a first
internal volume of the dispenser, and the predetermined volume is
defined by a second internal volume of the dispenser, and wherein
in the closed position, the first internal volume is fluidly
connected to the second internal volume so as to allow propellant
to fill the second internal volume, and in the open position, the
first internal volume is not fluidly connected to the second
internal volume and the second internal volume is fluidly connected
to the second chamber so as to allow the predetermined volume of
propellant to be provided to the second chamber.
[0166] FIGS. 15A and 15B show one specific embodiment of an
embodiment of a propellant dispenser 321 for supplying propellant
to the second chamber, where the propellant dispenser 321 does not
include a rupturable wall. The dispenser 321 comprises a reservoir
324 that defines a central volume 322 containing propellant. Inside
the central volume 322 is an internal frame 400 that has a series
of channels 400a,400b for allowing propellant to pass therethrough.
Within the internal frame 400 are a carriage 402 and a nozzle 406
that are connected to one another. The carriage 402 and nozzle 406
are connected to one another and are axially moveable within the
dispenser 321 between a closed position in which propellant cannot
exit the dispenser 321 (as shown in FIG. 15A) and an open position
in which propellant can exit the dispenser 321 (as shown in FIG.
15B). The carriage 402, and hence nozzle 406, are biased axially
forwardly from the frame 400 to the closed position by a biasing
member 404 in the form of a spring in the embodiment shown.
[0167] The carriage 402 and nozzle 406 are moveable through a rear
seal 408a and a forward seal 408b. The rear seal 408a and the
forward seal 408b together with the frame 400 define an annulus 410
around the carriage 402 and the nozzle 406. The nozzle 406 is
moveable so as to protrude through the forward seal 408b and an
opening 321a of the dispenser 321 in at least the open
position.
[0168] The carriage 402 has a pair of passageways 402a,402b that,
together with a hollow region 402b of the carriage 402, form a
fluidic bypass pathway (indicated as F1 in FIG. 15A) around the
rear seal 408a when the carriage 402 is in the closed position.
Therefore, in the closed position, propellant is able to flow from
the central volume 322 to the annulus 410 via the passageways
402a,402b.
[0169] Given that the carriage 402 and the nozzle 406 are biased by
the spring 404 towards the closed position, the central volume 322
will be fluidly connected to the annulus 410 in the natural state
of the dispenser 321 in the absence of external forces acting on
the carriage 402 and nozzle 406. In the closed position, there is
no fluid pathway from the annulus 410 to outside of the
dispenser.
[0170] If the nozzle 406 and carriage 402 are moved axially
rearwardly (as indicated by arrows M in FIG. 15B), they act against
the spring 404 and move towards their open position. In the open
position, the pair of passageways 402a,402b both move axially
rearwardly of the rear seal 408a so that they no longer form a
bypass pathway around the rear seal 408. Thus, in the open
position, the central volume 322 is no longer fluidly connected to
the annulus 410. However, in the open position the annulus 410 is
fluidly connected to the outside of the dispenser 321 via one or
more radial passageways 406a in the nozzle 406 that fluidly connect
the annulus 410 to a hollow channel 406b of the nozzle 406 that is
open to the external environment of the dispenser 321, bypassing
the forward seal 408b (indicated by F2 in FIG. 15B). Thus, in the
open position, the entire volume of propellant present in the
annulus 410 is dispensed from the dispenser 321. For completeness,
it is noted that in the closed position, the one or more radial
passageways 406a do not fluidly connect the annulus 410 to the
hollow channel 406b thus preventing fluid communication between the
annulus 410 and the external environment.
[0171] Therefore, unlike some prior art valve dispensers, the
dispenser 321 described above with reference to FIGS. 15A and 15B
only dispenses a predetermined volume of fluid (propellant) when in
the open position, where the predetermined volume is defined by the
volume of the annulus 410. This is contrast to some prior art
dispensers, where once in the open position, the dispenser will
continue to dispense fluid until moved to a closed position. The
presently described dispenser 321 is therefore advantageous for use
with the present invention in that a predetermined volume of
propellant can be provided to the second chamber, where the
predetermined volume can be tailored for a particular application,
such as for delivering a specified dose of medicament contained in
the first chamber.
[0172] Whilst the above described embodiment represents a
preferable arrangement of such as dispenser 321, alternative
embodiments may comprise any arrangement that is capable of
providing a predetermined volume of propellant to the second
chamber when moved to an open position, such that it is reusable to
then provide a further predetermined volume of propellant at a
later time. Crucially for these embodiments, once the dispenser is
in an open position, propellant is not delivered continuously such
that only the position of the dispenser determines when delivery of
propellant will cease.
[0173] In another example of a propellant dispenser, a container of
propellant has a valved outlet that is moveable between a closed
position where propellant cannot exit the container and an open
position where propellant can exit the container. The dispenser
additionally has a latching mechanism or other similar arrangement
that prevents the valved outlet moving back to the closed position
once moved to the open position. Therefore, once the valve has been
moved to the open position, the entire volume of propellant in the
container is discharged through the valved outlet. Preferably, the
container is configured to contain a predetermined volume of
propellant sufficient for the delivery of a dose of medicament. In
this example, the rupturing portion comprises the valved outlet and
the third chamber 22 is ruptured when the valved outlet is in the
open position and prevented from moving back to the closed
position. That is, the third chamber 22 is ruptured in the sense
that it is irreversibly opened and the entire contents of the third
chamber 22 discharge therefrom. In a specific example, the valved
outlet is a valve having a valve body, valve stem, and a locking
member, where the valve stem is slidably moveable relative to the
valve body between a non-dispensing ("closed") position in which an
outlet port of the valve stem is out of fluid communication with
the third chamber 22, and a dispensing ("open") position in which
the outlet port is in fluid communication with the third chamber 22
so as to permit transfer of propellant from the third chamber 22
through the valve stem.
[0174] The locking member is configured to prevent return of the
valve stem into the non-dispensing position once the valve stem
slides beyond a locking position.
[0175] In one embodiment, the locking member and the valve stem
comprise inter-engaging members, where the inter-engaging members
contact one another during movement of the valve stem towards the
dispensing position and permit movement of the valve stem into the
dispensing position, and contact one another during attempted
movement of the valve stem from beyond the locking position back
towards the dispensing position and prevent movement of the valve
stem back into the non-dispensing position.
[0176] The inter-engaging members, may contact one another during
movement of the valve stem towards the dispensing position and
permit movement of the valve stem into the dispensing position by
flexing or other distortion of at least one of the inter-engaging
members.
[0177] In a preferable embodiment, the inter-engaging member of the
valve stem comprises a flange. Wherein, further preferably, a
distal edge of the flange is angled to promote flexing of the
locking member during movement of the valve stem into the
dispensing position.
[0178] In a further or alternative preferable embodiment, the
inter-engaging member of the locking member comprises at least one
flexible latch, wherein the at least one flexible latch preferably
exhibits elastic behaviour.
[0179] The locking position of the valve stem may be defined as a
point where the inter-engaging member of the valve stem slides
beyond, and disengages from, the inter-engaging member of the
locking member.
[0180] In some embodiments, the valve may further comprise a
biasing member (a compression spring, for example) for biasing the
valve stem into the non-dispensing position.
[0181] In a further or alternative aspect of the present invention,
there is provided a method of designing a syringe where the syringe
comprises a barrel for containing a substance such as medicament,
where the barrel has an outlet. A stopper defines and separates a
first chamber and a second chamber where the first chamber is
axially forwards of the stopper and is configured for containing a
substance such as a medicament, and the second chamber is axially
rearwards of the stopper and is configured to receive propellant
for acting on the stopper to move the stopper axially forwardly in
the barrel to expel medicament through the outlet upon actuation of
the syringe. The method in accordance with the present invention
comprises one or more of the steps of i) selecting the thermal
properties of the syringe, ii) determining the rate of delivery of
propellant into the second chamber, or iii) determining the phase
of propellant entering the second chamber, in order to exhibit a
desired pressure profile of propellant acting on the stopper in the
second chamber following actuation of the syringe.
[0182] Selecting the thermal properties of the syringe means
configuring the syringe so that either additional heat or cooling
is provided to the propellant during use, or that a thermal pathway
of a desired thermal conductivity is present in the syringe. The
thermal pathway may be configured by selection of the materials of
the syringe, each material having a desired thermal conductivity.
Additionally or alternatively, additional components such as
thermally insulating or conducting elements such as jackets around
the barrel, may be included to alter the thermal pathway from the
external environment and the propellant in the second chamber.
Alternatively, an additional component such as a heat sink or heat
source may be provided in the second chamber. The heating or
cooling provided to the propellant may be by one of the methods
described above. As has been described above, the ability of the
propellant in the second chamber to absorb heat from its
surrounding (or not, as the case may be) impacts on the pressure
profile of the propellant acting on the stopper in the second
chamber.
[0183] The rate of delivery of propellant entering the second
chamber is determined, amongst other factors, by the configuration
of the source of propellant, the volume of propellant and the
configuration of any restriction that the propellant must pass
through in order to enter the second chamber. For example, a
pressurized jet of propellant from a propellant source will result
in a higher rate of delivery of propellant entering the second
chamber compared with propellant entering the second chamber solely
due to vaporization of the propellant by the temperature of its
immediate environment (e.g. ambient temperature). Additionally, a
narrow restriction will reduce the rate of propellant delivery
entering the second chamber compared with a wider restriction. The
rate of delivery of propellant into the second chamber affects the
vapor pressure (and therefore force) exerted on the stopper 16 and
therefore affects the rate of delivery of medicament and the
profile (i.e. force or vapor pressure profile) of the delivery.
[0184] As is described above, the phase of propellant that enters
the second chamber affects the pressure profile of the propellant
acting on the stopper in the second chamber. The phase of the
propellant entering the second chamber may be controlled by one of
the mechanisms described above (FIGS. 1E and 1F, for example) or by
any suitable alternative means, such as using a propellant source
that only supplies gaseous propellant, or supplies a desired ratio
of liquid and gaseous propellant to the second chamber.
[0185] The method of design may be an iterative physical redesign
sequence or may be assisted with computer implemented calculations,
for example in selecting the thermal properties of the syringe to
exhibit the desired pressure profile. In one embodiment, the step
of selecting the thermal properties of the syringe to exhibit the
desired pressure profile of fluid acting on the stopper following
actuation of the syringe comprises the steps of: [0186] i)
determining a first pressure profile of fluid propellant in a
barrel of a syringe following actuation of the syringe; [0187] ii)
comparing the first determined pressure profile with the desired
pressure profile; and if the first determined pressure profile does
not approximately equal the desired pressure profile, then
performing the steps: [0188] iii) modifying the design of the
syringe to alter the heat transfer to fluid propellant in the
barrel following actuation of the syringe; [0189] iv) determining a
second pressure profile of fluid propellant in the barrel of the
modified syringe following actuation of the modified syringe;
[0190] v) comparing the second determined pressure profile with the
desired pressure profile; and [0191] vi) repeating steps ii) to v)
until the second determined pressure profile approximately equals
the desired pressure profile.
[0192] Similar methods may be employed for obtaining a syringe
design through iterative modification of properties that affect the
rate of delivery of propellant into the second chamber and/or the
phase of propellant entering the second chamber. Indeed, an
iterative method in accordance with the present invention may
include the iterative step of modifying any one or combination of
properties that affect the thermal properties of the syringe, the
rate of delivery of propellant into the second chamber, and the
phase of propellant entering the second chamber.
[0193] The step of determining the pressure profile (at any point
during the iterative method) may be executed by measurement of
pressure or a calculation that may be a computer implemented
calculation.
[0194] Once a syringe design is reached that exhibits the desired
pressure profile, a syringe may be manufactured according to that
design.
[0195] In any of the described embodiments of syringes in
accordance with the present invention, the propellant containers
shown in FIGS. 2 and 3 may be used. The skilled person will
appreciate that other propellant containers may be used and that
syringes made in accordance with the present invention are not
necessarily limited to using the containers of FIG. 2 or 3. In FIG.
2, a container 121 is shown to be made of an upper sheet 124a and a
lower sheet 124b which together form a rupturable wall 124 of the
container 121. The sheets 124a,124b are generally square or
rectangular in shape in the embodiment shown in FIG. 2 and are
sealed to one another about their periphery forming seals 125. The
seals 125 circumvent a central volume 122 formed between the sheets
124a, 124b. This volume 122 is equivalent to the third chamber
described above in relation to container 22 and contains a volume
of propellant which is predominantly in its liquid phase at the
operating temperature of the syringe (e.g. ambient temperature) due
to being in the sealed volume 122. However, given that some of the
propellant will be in gaseous form due to vaporization, the
propellant will exert an outward pressure from within the volume
122. Therefore, the seals 125 must be sufficient to prevent
substantial loss of propellant from the volume 125. Indeed, an
ideal seal 125 will entirely prevent propellant escaping
therethrough from the volume 122, however in practice, the seals
125 may be such that a finite, albeit acceptable and not
substantial, amount of propellant may escape from the volume 122.
The magnitude of "acceptable" amount will depend upon the perceived
shelf life of the container (i.e. the length of time that the
container 125 may remain in storage following manufacture prior to
use), and the volume of propellant required to perform the desired
action.
[0196] The material that forms the sheets 124a,124b is flexible and
rupturable such that once ruptured (i.e. broken, torn or otherwise
penetrated) a fluid pathway is provided therethrough into the
volume 122 that is not resealable. The rupturable wall 124 is
preferably substantially impermeable to the propellant contained in
the volume 122. The actual gas permeability of the rupturable wall
124 may depend upon the chosen propellant contained in the volume
122. For example, for HFA 134a, it is preferable for the rupturable
wall to have a gas permeability such that the volume of propellant
remaining in the container 121 is sufficient to reliably deliver a
dose of medicament. Therefore, the limitations on the gas
permeability of the rupturable wall 124 are determined by the
intended volume of medicament to be delivered and the initial
volume of propellant contained in the container 121. To deliver a 1
ml dose of medicament, it is particularly preferable to ensure that
there is at least 20 .mu.l of propellant in the container 121.
Therefore, over a two year storage period, a container 121
initially containing 100 .mu.l of HFA propellant may lose up to 80
.mu.l as gas through the rupturable wall 124 for there to be at
least 20 IA remaining to deliver the 1 ml dose of medicament. In
this example, the maximum gas permeability of the container 121
would be 0.365 g/(m.sup.2.day). Whilst it would be preferable to
have at least 20 .mu.l of HFA propellant remaining after two years
for delivering a 1 ml dose of medicament, a container 121 having a
gas permeability that ensures that there is 5 .mu.l or more of HFA
propellant may be sufficient to ensure that enough propellant will
remain after two years to deliver a 1 ml dose of medicament.
[0197] The rupturable wall 124 may include polyethylene and/or may
include a polyamide and/or may include nylon and/or may include a
cyclic olefin copolymer (COC) and/or may include a cyclic olefin
polymer (COP). In some preferable embodiments, the rupturable wall
may be composed substantially of nylon. In alternative embodiments,
one or each sheet 124a,124b may be formed of a laminate of two or
more different materials selected from polyethylene, polyamide, and
metals (e.g. a metallic foil). The selection of the two or more
materials may be based upon one of the layers providing a
substantially impermeable gas barrier to prevent the propellant
from escaping from the volume 122, and another of the layers
providing mechanical strength to resist the outward pressure
exerted by gaseous propellant in the volume 122. The rupturable
wall 124 may be formed by co-extruding two or more materials.
[0198] Regardless of the type of material selected to form the
rupturable wall 124, the seals 125 are formed between two like
materials. So, in the case where one or both of the sheets
124a,124b comprise laminates of two or more materials, the sheets
124a,124b are arranged such that the interface between them
comprises two adjacent like materials which may form the seals 125.
The seals 125 may be formed by any of heat sealing, sonic welding
or by use of an adhesive.
[0199] The shape of the container 121 may differ from that shown in
FIG. 2. Indeed, any suitable shape that is able to contain the
propellant in the volume 122 sealed by the seals 125 may be used in
accordance with the present invention. However, the shape of the
container should be such that the outward pressure exerted by the
propellant is resisted to ensure that such pressure does not
inadvertently rupture the container 121.
[0200] FIG. 3 shows a container 221 in accordance with an
alternative embodiment of the present invention. The container 221
has a generally cylindrical rupturable wall 224 that is pinched at
either end to form seals 225 that are sealed by one of the above
described sealing methods. The rupturable wall 224 defines a
central volume 222 for containing fluid propellant that, again, is
equivalent to the third chamber 22 of embodiments described above.
The rupturable wall may be formed from the materials described
above in connection with rupturable wall 124 of the embodiment of
FIG. 2. The container 221 has the advantage that fewer seals 125
are required since a single cylindrical piece of material is used
to form the rupturable wall 224. Therefore, there are fewer
potential leak paths that the propellant may escape the volume 222
through.
[0201] Either of the containers 121 and 221 may be used in any of
the syringes described above in accordance with the present
invention. Alternatively, the containers 121,221 may be used in
other applications, including other medical devices. In particular,
the containers 121,221 may be used as a power source in
inhaler-type devices (e.g. nasal inhalers).
[0202] The containers 121,221 provide a small, convenient,
portable, cost effective power source that may be used in a
plethora of devices. For a re-usable syringe, for example, the
containers 121,221 offer a simple and effective means to power the
syringe over multiple uses, where the user removes a ruptured
container 121,221 following an injection and replaces it with a new
unruptured container 121,221 prior to the next use.
[0203] The propellant used in the containers 121,221 and indeed in
any of the syringes described above may be any propellant that
boils at a predetermined temperature. In preferable embodiments,
the propellant is or contains HFA and further preferable is or
contains HFA 134a. Indeed, mixtures of several propellant
substances or propellant substances and additives may provide a
propellant for use in accordance with the present invention. As
described above, the propellant may be chosen to be one that boils
at ambient temperature or one that boils at a temperature higher
than ambient temperature, in which case a further heat source is
required to cause the propellant to boil and move the stopper
16.
[0204] A schematic representation of a method of manufacturing a
container, such as the container 221 shown in FIG. 3, is shown in
FIGS. 13A to 13D. FIG. 13A shows an extruded tube 224 formed of a
rupturable material that has been sealed at a lower end by a lower
seal 225a. There are first sealing elements 306 and second sealing
elements 308 positioned around the tube 224. The tube 224 defines a
central volume 222 therein. A piercing element 302 is provided that
is adapted to form an opening 304 through the material of the tube
224 so as to provide a fluidic channel between the central volume
222 and the outside of the tube 224.
[0205] The method includes the steps of using the piercing element
302 to form the opening 304. The tube 224 may be pressurized (i.e.
a gaseous pressure may be applied in the central volume 222) to
increase its rigidity so as to permit effective use of the piercing
element 302. The opening 304 may be formed so that a complete hole
is not created. This is not essential, but forming an opening 304
that does not result in the formation of loose material (a
so-called "chad") minimizes the risk of loose material entering the
central volume 222 and/or interfering with the manufacturing
process. A horse-shoe shaped (i.e. U-shaped) opening 304 is one
suitable opening that does result in chad formation. In one
example, the piercing element 302 is a hypodermic needle.
[0206] The first sealing elements 304 may then be used to form a
first upper seal 225b above (i.e. upstream) of the opening 304 as
shown in FIG. 13B. Substantially simultaneously, a propellant
dispensing head 310 (which is connected to a source of
propellant--not shown) is inserted into the opening 304 and seals
the opening 304. The propellant dispensing head 310 may comprise
seal rings to aid the sealing of the opening 304. In alternative
embodiments, the propellant dispensing head 310 may additionally
have the feature of being the piercing element 302 and may form the
opening 304 at this stage (i.e. subsequent to the formation of the
first upper seal 225b.
[0207] As shown in FIG. 13C, a predetermined dose of propellant 300
is then introduced into the central volume 222 to fill the tube 224
to the desired level. A second upper seal 225c is then formed by
second sealing element 308 below (i.e. downstream) each of the
first upper seal 225b and the opening 304. After formation of the
second upper seal 225c, the central volume 222 containing the
propellant 300 is sealed at an upper end by second upper seal 225c
and at a lower end by the lower seal 225a thus forming a propellant
container 221. The container 221 may be cut along lower seal 225a
and second upper seal 225c to separate the container 221.
[0208] The tube 224 is oriented with its longitudinal axis
substantially parallel to the (gravitational) vertical so that the
propellant 300 condenses at a lower end of the tube 224. With this
arrangement, the second upper seal 225c can be formed above the
level of liquid propellant and therefore reduces the risk of liquid
propellant leaking from the tube 224 during formation of the
container 221.
[0209] The extruded tube may be moved relative to the first sealing
elements 306, second sealing elements 308, piercing element 302
and/or propellant dispensing head 310 so that the first upper seal
225b of the tube 224 becomes the lower seal 225a' of a subsequent
tube 224' and the process can begin again to fill the subsequent
tube 224'. The container 221 (and subsequent containers) can be
cut/removed from the production line following their filling and
sealing and prior to the filling and sealing of a subsequent
container. Alternatively, several containers may be filled and
sealed before being separated by cutting or otherwise separating
along the seals. Thus, a continuous string of containers can be
formed that are each easily handled and cut as required. The pitch
of the containers (e.g. the distance between lower seal 225a and
second upper seal 225c for container 221) may be altered to change
the magnitude of the central volume 222 in accordance with the
desired dose of propellant 300.
[0210] The first and second sealing elements 306, 308 may be any
suitable sealing apparatus that are capable of forming heat seals,
sonic welds or other seals, such as adhesive seals. The first and
second sealing elements 306,308 need not necessarily be capable of
forming the same type of seal as one another.
[0211] A schematic representation of an alternative method of
manufacturing a container, such as the container 121 shown in FIG.
2, is shown in FIGS. 14A to 14C. FIG. 14A shows two sheets
124a,124b of like material being brought together by a set of
rollers 412 rotating in direction R. Although the cross-sectional
views shown in FIGS. 14A and 14B show only two rollers 412, the set
actually comprises four rollers 412 as shown in the perspective
view of FIG. 14C. The rollers 412 are arranged in pairs such that
the two sheets 124a,124b of material come together between the
pairs, where the two rollers of each pair are spaced and arranged
along edges of the sheets 124a,124b. The rotation of the rollers
412 along direction R causes the sheets 124a,124b to come together
with one another along their edges (which are coincident with the
position of the rollers 412) and move downwards along direction D.
The edges of the sheets 124a,124b seal to one another to form side
seals 125b,125c. The rollers 412 may comprise means to form the
side seals 125b,125c or additional sealing apparatus may be
employed to form the side seals 125b,125c.
[0212] Sealing elements 408 seal the sheets 124a,124b together
across their entire width to form a lower seal 125a. A propellant
dispensing head 410 is arranged between the sheets 124a,124b and
between the four rollers 412 and is arranged relative to the sheets
124a,124b and the rollers 412 so that the sheets 124a,124b form a
seal with one another or the propellant dispensing head 410. The
result is that a sealed central volume 122 is formed that is
initially defined by the seals 125a,125b,125c and the seals between
the sheets 124a,124b and the propellant dispensing head 410.
[0213] In this position, the propellant dispensing head 410 is able
to deposit a desired dose of propellant 300 into the central volume
122. Once the desired dose of propellant 300 has been deposited,
the propellant dispensing head 410 may be switched off preventing
further deposition of propellant 300 and the sealing elements 408
may then seal the sheets 124a,124b above the deposited propellant
300 to form an upper seal 125d. This forms a container 121 that has
a central volume 122 containing propellant 300 where the central
volume 122 is defined by seals 125a,125b,125c,125d. Any or all of
the seals 125a,125b,125c,125d may be heat seals, sonic welds or
other seals, such as adhesive seals.
[0214] The upper seal 125d may then form the lower seal 125a' of a
subsequent container 121' (see FIG. 14C) so that the process may be
repeated to produce a series of connected containers 121,121', . .
. , etc. Lower and upper seals 125a,125d may be cut or otherwise
severed to separate each container 121. This separation may be done
when a series of containers has been produced or after the
formation of each container 121.
[0215] The pitch of the containers (e.g. the distance between lower
seal 125a and upper seal 125c) may be altered to change the
magnitude of the central volume 122 in accordance with the desired
dose of propellant 300.
[0216] Throughout the description, claims and figures of this
specification, 0 bar is considered to be defined as atmospheric
pressure, so that all values of pressure given in bar are relative
to atmospheric pressure (0 bar).
[0217] Throughout the present specification, the term "syringe"
relates to and includes any medicament delivery device having a
medicament container with an outlet and a moveable stopper for
expelling medicament therefrom. As examples, the syringe may
include a needle, a nozzle or a conduit attached to the outlet. In
other embodiments, the syringe may not include any further
components downstream of the outlet. The syringe of the present
invention may be or form part of a subcutaneous delivery device, a
nasal delivery device, an otic delivery device, an oral delivery
device, an ocular delivery device, an infusion device or any other
suitable medicament delivery device.
[0218] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of them mean
"including but not limited to", and they are not intended to (and
do not) exclude other moieties, additives, components, integers or
steps. Throughout the description and claims of this specification,
the singular encompasses the plural unless the context otherwise
requires. In particular, where the indefinite article is used, the
specification is to be understood as contemplating plurality as
well as singularity, unless the context requires otherwise.
[0219] Features, integers, characteristics, compounds, chemical
moieties or groups described in conjunction with a particular
aspect, embodiment or example of the invention are to be understood
to be applicable to any other aspect, embodiment or example
described herein unless incompatible therewith. All of the features
disclosed in this specification (including any accompanying claims,
abstract and drawings), and/or all of the steps of any method or
process so disclosed, may be combined in any combination, except
combinations where at least some of such features and/or steps are
mutually exclusive. The invention is not restricted to the details
of any foregoing embodiments. The invention extends to any novel
one, or any novel combination, of the features disclosed in this
specification (including any accompanying claims, abstract and
drawings), or to any novel one, or any novel combination, of the
steps of any method or process so disclosed.
[0220] The reader's attention is directed to all papers and
documents which are filed concurrently with or previous to this
specification in connection with this application and which are
open to public inspection with this specification, and the contents
of all such papers and documents are incorporated herein by
reference.
* * * * *