U.S. patent application number 16/942654 was filed with the patent office on 2021-06-17 for wearable automatic injection device for controlled delivery of therapeutic agents.
The applicant listed for this patent is AbbVie Biotechnology Ltd. Invention is credited to Philip D. Anderson, Sean Corrigan, William Fienup, Samuel M. Jang, Joseph F. Julian, Linas P. Laurusonis, Tomas Matusaitis, Timothy Parmer, Chris Strahm, Travis Yoch.
Application Number | 20210178074 16/942654 |
Document ID | / |
Family ID | 1000005432842 |
Filed Date | 2021-06-17 |
United States Patent
Application |
20210178074 |
Kind Code |
A1 |
Anderson; Philip D. ; et
al. |
June 17, 2021 |
WEARABLE AUTOMATIC INJECTION DEVICE FOR CONTROLLED DELIVERY OF
THERAPEUTIC AGENTS
Abstract
Exemplary embodiments provide wearable automatic injection
devices for subcutaneously injecting a therapeutic agent into a
patient's body at controlled rates, for example, in a single bolus.
Exemplary embodiments provide methods for assembling wearable
automatic injection devices for subcutaneously injecting a
therapeutic agent into a patient's body at controlled rates.
Exemplary embodiments provide methods for using wearable automatic
injection devices for subcutaneously injecting a therapeutic agent
into a patient's body at controlled rates.
Inventors: |
Anderson; Philip D.;
(Libertyville, IL) ; Julian; Joseph F.;
(Libertyville, IL) ; Laurusonis; Linas P.;
(Gurnee, IL) ; Parmer; Timothy; (Brooklyn Park,
MN) ; Yoch; Travis; (Woodbury, MN) ; Jang;
Samuel M.; (Woodbury, MN) ; Corrigan; Sean;
(Chicago, IL) ; Matusaitis; Tomas; (Chicago,
IL) ; Fienup; William; (St. Louis, MO) ;
Strahm; Chris; (Deforest, WI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Biotechnology Ltd |
Hamilton |
|
BM |
|
|
Family ID: |
1000005432842 |
Appl. No.: |
16/942654 |
Filed: |
July 29, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15818576 |
Nov 20, 2017 |
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16942654 |
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14872949 |
Oct 1, 2015 |
9821117 |
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15818576 |
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13092102 |
Apr 21, 2011 |
9180244 |
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14872949 |
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61326637 |
Apr 21, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61M 2205/13 20130101;
A61M 5/484 20130101; A61M 2005/14252 20130101; A61M 2005/1581
20130101; A61M 5/2033 20130101; A61M 2207/00 20130101; A61M 5/14526
20130101; A61M 5/1454 20130101; A61M 5/14566 20130101; A61M
2005/1583 20130101; A61M 5/326 20130101; A61M 2005/14513 20130101;
A61M 5/14248 20130101; A61M 2005/341 20130101; A61M 5/141 20130101;
A61M 2005/31518 20130101; A61M 5/50 20130101; A61M 2005/3143
20130101; A61M 5/1413 20130101; A61M 2005/2013 20130101; A61M 5/488
20130101; A61M 2005/206 20130101; A61M 2005/14506 20130101 |
International
Class: |
A61M 5/20 20060101
A61M005/20; A61M 5/142 20060101 A61M005/142 |
Claims
1. A wearable automatic injection device for providing a
subcutaneous injection of a therapeutic agent into a patient, the
wearable automatic injection device comprising: a housing
comprising a patient contact portion securable to the patient; an
injection assembly moveably disposed in the housing holding a
hypodermic injection needle for insertion into the patient, the
injection assembly moveable between a retracted position in which
the injection needle does not protrude outside the housing and an
extended position in which the injection needle protrudes outside
the housing; a vessel provided in the housing for holding the
therapeutic agent; a plunger moveably disposed in the vessel for
ejecting the therapeutic agent from the vessel into the injection
assembly; a plunger actuation mechanism for actuating the plunger
within the vessel; a retraction trigger responsive to a change of
state of the wearable automatic injection device from an injection
state to a post-injection state; and a retraction mechanism for
automatically retracting the injection assembly from the extended
position in the injection state to the retracted position in the
post-injection state upon triggering by the retraction trigger.
2.-7. (canceled)
8. The wearable automatic injection device of claim 1, wherein the
vessel comprises a syringe.
9. The wearable automatic injection device of claim 8, wherein the
syringe comprises: a barrel portion for holding the therapeutic
agent; and a syringe needle coupled to a distal end of the barrel
portion for establishing fluid communication between the barrel
portion of the syringe and the injection needle.
10.-11. (canceled)
12. The wearable automatic injection device of claim 1, wherein the
vessel comprises a cartridge.
13. The wearable automatic injection device of claim 12, wherein
the cartridge comprises: a barrel portion for holding the
therapeutic agent; and a septum that is pierceable by a piercing
needle.
14.-16. (canceled)
17. The wearable automatic injection device of claim 1, wherein the
vessel is moveably disposed within the housing.
18. The wearable automatic injection device of claim 17, wherein
the vessel is moveable between a first position in a pre-injection
state and a second position in the injection state.
19.-21. (canceled)
22. The wearable automatic injection device of claim 1, wherein the
plunger actuation mechanism comprises a biasing mechanism.
23. The wearable automatic injection device of claim 22, wherein
the plunger actuation mechanism further comprises: a fusee; and a
tether coupling the biasing mechanism to the fusee and the
plunger.
24.-31. (canceled)
32. The wearable automatic injection device of claim 1, wherein the
plunger actuation mechanism further comprises: a source of a
working fluid for providing a hydraulic pressure to eject the
therapeutic agent from the vessel; and a fluid conduit provided
between the source of the working fluid and the plunger.
33. The wearable automatic injection device of claim 32, wherein
the plunger actuation mechanism further comprises: a damping
mechanism coupled to the vessel and the source of the working fluid
to regulate the ejection of the therapeutic agent from the
vessel.
34.-42. (canceled)
43. A method for subcutaneously injecting a therapeutic agent into
a patient, the method comprising: providing a wearable automatic
injection device, comprising: a housing comprising a patient
contact portion securable to the patient, an injection assembly
moveably disposed in the housing holding a hypodermic injection
needle for insertion into the patient, the injection assembly
moveable between a retracted position in which the injection needle
does not protrude outside the housing and an extended position in
which the injection needle protrudes outside the housing, a vessel
provided in the housing for holding the therapeutic agent, a
plunger moveably disposed in the vessel for ejecting the
therapeutic agent from the vessel into the injection assembly, a
plunger actuation mechanism for actuating the plunger within the
vessel, a retraction trigger responsive to a change of state of the
wearable automatic injection device from an injection state to a
post-injection state, and a retraction mechanism for automatically
retracting the injection assembly from the extended position in the
injection state to the retracted position in the post-injection
state upon triggering by the retraction trigger; securing the
wearable automatic injection device to the skin of the patient or
an article of clothing on the patient using the patient contact of
the housing; and administering the therapeutic agent into the skin
of the patient using the wearable automatic injection device.
44.-47. (canceled)
48. The method of claim 43, wherein the vessel comprises a
cartridge.
49. The method of claim 48, wherein the cartridge comprises: a
barrel portion for holding the therapeutic agent; and a septum that
is pierceable by a piercing needle.
50.-52. (canceled)
53. The method of claim 43, wherein the vessel is moveably disposed
within the housing.
54. The method of claim 53, wherein the vessel is moveable between
a first position in a pre-injection state and a second position in
the injection state.
55.-56. (canceled)
57. The method of claim 43, wherein the plunger actuation mechanism
ejects the therapeutic agent into the patient at a controlled
rate.
58. The method of claim 43, wherein the plunger actuation mechanism
comprises a biasing mechanism.
59. The method of claim 58, wherein the plunger actuation mechanism
further comprises: a fusee; and a tether coupling the biasing
mechanism to the fusee and the plunger.
60. The method of claim 59, wherein the plunger actuation mechanism
further comprises: a damping mechanism coupled to the fusee for
regulating the movement of the fusee; and a gear train including
one or more gears for coupling the fusee to the damping
mechanism.
61.-78. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is related to and claims priority to U.S.
Provisional Application Ser. No. 61/326,637, filed Apr. 21, 2010,
the entire contents of which are expressly incorporated herein by
reference in their entirety.
BACKGROUND
[0002] Automatic injection devices offer an alternative to
manually-operated syringes for delivering therapeutic agents into
patients' bodies and allowing patients to self-administer
injections. Automatic injection devices have been used to deliver
medications under emergency conditions, for example, to administer
epinephrine to counteract the effects of a severe allergic
reaction. Automatic injection devices have also been described for
use in administering anti-arrhythmic medications and selective
thrombolytic agents during a heart attack (See, e.g., U.S. Pat Nos.
3,910,260; 4,004,577; 4,689,042; 4,755,169; and 4,795,433). Various
types of automatic injection devices are also described in, for
example, U.S. Pat. Nos. 3,941,130; 4,261,358; 5,085,642; 5,092,843;
5,102,393; 5,267,963; 6,149,626; 6,270,479; and 6,371,939; and
International Patent Publication No. WO/2008/005315.
[0003] Conventionally, an automatic injection device houses a
syringe and, when operated, causes the syringe to move forwardly
and a needle to project from the housing so that a therapeutic
agent contained in the syringe is ejected into a patient's skin. An
automatic injection device typically includes a bung disposed
within the syringe that, when actuated, moves within the syringe to
expel the therapeutic agent from the syringe and into the patient's
skin.
SUMMARY
[0004] Exemplary embodiments provide wearable automatic injection
devices that may adhere to the skin or clothing of a patient and
deliver a therapeutic agent into the patient's body by subcutaneous
injection at slow, controlled injection rates, e.g., in a single
slow bolus. Exemplary embodiments provide methods of assembling
exemplary wearable automatic injection devices. Exemplary
embodiments also provide methods of using wearable automatic
injection devices worn by a patient for slow, controlled
therapeutic agent delivery. Exemplary wearable automatic injection
devices reduce or eliminate a burning sensation often felt or
perceived by patients who use a conventional automatic injection
device. Exemplary wearable automatic injection devices maintain the
sterility of the therapeutic agent container (e.g., syringe), are
easy to use, pre-fill capable, easy to manufacture, and/or do not
require aseptic assembly. The wearable automatic injection devices
provided by exemplary embodiments may adhere to the skin or
clothing of the patient to deliver any therapeutic agent
subcutaneously including, but not limited to, a biologic drug, such
as, for example, an antibody, insulin, etc.
[0005] In accordance with an exemplary embodiment, a wearable
automatic injection device is provided for providing a subcutaneous
injection of a therapeutic agent into a patient. The device
includes a housing comprising a patient contact portion securable
to the patient. The device also includes an injection assembly
moveably disposed in the housing holding a hypodermic injection
needle for insertion into the patient, the injection assembly
moveable between a retracted position in which the injection needle
does not protrude outside the housing and an extended position in
which the injection needle protrudes outside the housing. The
device also includes a vessel provided in the housing for holding
the therapeutic agent, a plunger moveably disposed in the vessel
for ejecting the therapeutic agent from the vessel into the
injection assembly, and a plunger actuation mechanism for actuating
the plunger within the vessel. The device also includes a
retraction trigger responsive to a change of state of the wearable
automatic injection device from an injection state to a
post-injection state, and a retraction mechanism for automatically
retracting the injection assembly from the extended position in the
injection state to the retracted position in the post-injection
state upon triggering by the retraction trigger.
[0006] In accordance with another exemplary embodiment, a method is
provided for subcutaneously injecting a therapeutic agent into a
patient. The method includes providing a wearable automatic
injection device including a housing comprising a patient contact
portion securable to the patient. The device also includes an
injection assembly moveably disposed in the housing holding a
hypodermic injection needle for insertion into the patient, the
injection assembly moveable between a retracted position in which
the injection needle does not protrude outside the housing and an
extended position in which the injection needle protrudes outside
the housing. The device also includes a vessel provided in the
housing for holding the therapeutic agent, a plunger moveably
disposed in the vessel for ejecting the therapeutic agent from the
vessel into the injection assembly, and a plunger actuation
mechanism for actuating the plunger within the vessel. The device
also includes a retraction trigger responsive to a change of state
of the wearable automatic injection device from an injection state
to a post-injection state, and a retraction mechanism for
automatically retracting the injection assembly from the extended
position in the injection state to the retracted position in the
post-injection state upon triggering by the retraction trigger. The
method includes securing the wearable automatic injection device to
the skin of the patient or an article of clothing on the patient
using the patient contact of the housing. The method also includes
administering the therapeutic agent into the skin of the patient
using the wearable automatic injection device.
[0007] In accordance with another exemplary embodiment, a wearable
automatic injection device is provided for subcutaneously injecting
a therapeutic agent into a patient. The device includes a housing
and a cartridge assembly movably disposed within the housing. The
cartridge includes a barrel portion for holding the therapeutic
agent, and a hollow needle in fluid communication with the barrel
portion for ejecting the therapeutic agent from the barrel portion.
The cartridge also includes a bung for sealing the barrel portion
and selectively applying pressure to the therapeutic agent to force
the therapeutic agent through the hollow needle. The cartridge
further includes a plunger actuator for applying pressure to the
bung, and a trigger mechanism that actuates the plunger actuator to
apply pressure to the bung when the cartridge is depressed from a
ready position (in a pre-injection state) to a depressed position
(in an injection state) inside the housing. The trigger mechanism
actuates the plunger actuator such that the therapeutic agent is
ejected from the barrel portion and into the patient at a
controlled, slow rate with little or no burning sensation felt or
perceived by the patient. The device also includes a fastener layer
disposed on a patient contact surface to fasten the device to the
skin or clothing of the patient or to an article of clothing of the
patient. The fastener layer may include an adhesive for temporarily
securing the wearable automatic injection device to the patient at
least during the controlled injection of the therapeutic agent.
[0008] The wearable automatic injection device includes a
retraction mechanism that retracts the cartridge from the depressed
position to a retracted position (in a post-injection state). The
wearable automatic injection device also includes a retraction
trigger that activates the retraction mechanism, the retraction
trigger trips when delivery of the therapeutic agent completes, or
times out due an elapsed period of time, or when the wearable
automatic injection device is removed from the patient, for
example, before delivery of the therapeutic agent is completed. The
wearable automatic injection device operates and functions entirely
on mechanical principles or in combination with a controlled
reaction to transition from any state (i.e., a pre-injection state,
an injection state, a post-injection state), and controls the
injection rate of the therapeutic agent over a time period that is
selected for patient comfort, convenience or preference, or exceeds
a time period for injection by a conventional automatic handheld
device. In an exemplary embodiment, the time period of the
injection by an exemplary wearable automatic injection device may
range between about ten seconds and about twelve hours. In a
preferred embodiment, the time period may range between about five
minutes and about thirty minutes.
[0009] In another exemplary embodiment, a method is provided for
subcutaneously injecting a therapeutic agent into a patient. The
method includes providing a wearable automatic injection device
comprising a housing and a cartridge assembly movably disposed
within the housing. The cartridge includes a barrel portion for
holding a therapeutic agent, and a hollow needle in fluid
communication with the barrel portion for ejecting the therapeutic
agent from the barrel portion. The cartridge also includes a bung
for sealing the barrel portion and selectively applying pressure to
the therapeutic agent to force the therapeutic agent through the
hollow needle. The cartridge further includes a plunger actuator
for applying pressure to the bung, and a trigger mechanism that
actuates the plunger actuator to apply pressure to the bung when
the cartridge is depressed from a ready position (in a
pre-injection state) to a depressed position (in an injection
state) inside the housing. The trigger mechanism actuates the
plunger actuator such that the therapeutic agent is ejected from
the barrel portion and into the patient at a controlled, slow rate
and substantially free of any burning sensation.
[0010] The method also includes depressing the cartridge from the
ready position to a depressed position within the housing.
Depressing the cartridge automatically causes the injection needle
that is used to pierce the patient's skin to project from an
opening in the housing to penetrate the skin of the patient, and
actuates the plunger actuator to apply pressure to the bung such
that the therapeutic agent is delivered into the patient at a
controlled, slow rate and substantially free of any burning
sensation.
[0011] The method further includes automatically retracting the
cartridge from the depressed to a retracted position (in a
post-injection state) in the housing when delivery of the
therapeutic agent is completed, or times out due to an elapsed
period of time, or when the wearable automatic injection device is
removed from the skin or clothing of the patient, for example,
before delivery of the therapeutic agent is completed.
[0012] In an exemplary embodiment, a wearable automatic injection
device is provided. The wearable automatic injection device
provides a subcutaneous injection of a therapeutic agent into a
patient. The wearable automatic injection device includes a housing
having a patient contact portion securable to the patient and an
interior portion defined by a plurality of walls and defining at
least one open end opposing the patient contact portion. The
wearable automatic injection device also includes a cartridge
assembly movably disposed within the interior portion of the
housing and movable from any of a ready position, an injection
position, and a retraction position. The wearable automatic
injection device further includes a trigger mechanism responsive to
a change in state of the wearable automatic injection device from a
pre-injection state to an injection state to actuate a plunger
actuator disposed in the cartridge assembly to begin ejection of a
therapeutic agent from the cartridge assembly, and a retraction
trigger responsive to a change of state of the wearable automatic
injection device from the injection state to a post-injection
state. The wearable automatic injection device also includes a
retraction mechanism responsive to the retraction trigger to
automatically retract the cartridge assembly from the patient when
the automatic injection device enters the post-injection state.
[0013] In another exemplary embodiment, a method of subcutaneously
injecting a therapeutic agent into a patient is provided. The
method includes securing to a patient a wearable automatic
injection device comprising a housing having a patient contact
portion securable to the patient and an interior portion defined by
a plurality of walls and defining at least one open end opposing
the patient contact portion and a cartridge assembly movably
disposed within the interior portion of the housing and movable
from any of a ready position, an injection position, and a
retraction position, the cartridge assembly holding the therapeutic
agent in a pre-fillable and/or pre-filled sterile manner The method
also includes depressing the cartridge assembly downwardly towards
the patient contact portion to cause the wearable automatic
injection device to enter an injection state from a pre-injection
state to automatically project a needle from a needle aperture in
the housing and penetrate the skin of the patient and expel the
therapeutic agent into the patient at a controlled rate.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The foregoing and other objects, aspects, features, and
advantages of exemplary embodiments will become more apparent and
may be better understood by referring to the following description
taken in conjunction with the accompanying drawings, in which:
[0015] FIG. 1A illustrates a first end view and a first side view
of an exemplary wearable device including a cartridge assembly in a
packaged pre-injection state.
[0016] FIG. 1B illustrates the first end view and the first side
view of the exemplary device of FIG. 1A before an injection in a
pre-injection state in which a needle cover covering the injection
needle is removed in preparation for an injection.
[0017] FIG. 1C illustrates the first end view and the first side
view of the exemplary device of FIG. 1A during an injection in an
injection state in which the patient's skin is pierced by the
injection needle.
[0018] FIG. 1D illustrates the first end view and the first side
view of the exemplary device of FIG. 1A during an injection in an
injection state in which a barrel portion of the device containing
a dose of the therapeutic agent is deployed forwardly within the
housing of the device.
[0019] FIG. 1E illustrates the first end view and the first side
view of the exemplary device of FIG. 1A during an injection in an
injection state in which a bung of the device is actuated by a
plunger actuator to expel the dose of the therapeutic agent from
the barrel portion.
[0020] FIG. 1F illustrates the first end view and the first side
view of the exemplary device of FIG. 1A after an injection in a
post-injection state in which the injection needle is retracted
within the housing of the device.
[0021] FIG. 2A illustrates a first end view and a first side view
of an exemplary wearable device including a syringe assembly in a
packaged pre-injection state.
[0022] FIG. 2B illustrates the first end view and the first side
view of the exemplary device of FIG. 2A before an injection in a
pre-injection state in which a needle cover covering the injection
needle is removed in preparation for an injection.
[0023] FIG. 2C illustrates the first end view and the first side
view of the exemplary device of FIG. 2A during an injection in an
injection state in which the patient's skin is pierced by the
injection needle.
[0024] FIG. 2D illustrates the first end view and the first side
view of the exemplary device of FIG. 2A during an injection in an
injection state in which a barrel portion of the device containing
a dose of the therapeutic agent is deployed forwardly within the
housing of the device.
[0025] FIG. 2E illustrates the first end view and the first side
view of the exemplary device of FIG. 2A during an injection in an
injection state in which a bung of the device is actuated by a
plunger actuator to expel the dose of the therapeutic agent from
the barrel portion.
[0026] FIG. 2F illustrates the first end view and the first side
view of the exemplary device of FIG. 2A after an injection in a
post-injection state in which the injection needle is retracted
within the housing of the device.
[0027] FIG. 3 is a flow chart of an exemplary method of assembling
an exemplary wearable automatic injection device.
[0028] FIG. 4 is a flow chart of an exemplary method of using an
exemplary automatic wearable injection device.
[0029] FIG. 5 is a flow chart of an exemplary method of using an
exemplary wearable automatic injection device to inject a
therapeutic agent into a patient.
[0030] FIG. 6A illustrates an exemplary wearable automatic
injection device suitable for linear insertion into a patient in a
pre-injection state.
[0031] FIG. 6B illustrates the exemplary device of FIG. 6A in an
injection state ready to inject or injecting a dose of a
therapeutic agent into a patient.
[0032] FIG. 6C illustrates the exemplary device of FIGS. 6A and 6B
in a post injection state after it has completed injecting the
therapeutic agent into the patient or removed from the patient
prior to completion of the injecting of the therapeutic agent.
[0033] FIG. 7A illustrates an exemplary wearable automatic
injection device suitable for rotary insertion in a pre-injection
state ready for use by a patient.
[0034] FIG. 7B illustrates the exemplary device of FIG. 7A in an
injection state ready to inject or injecting a dose of a
therapeutic agent into a patient.
[0035] FIG. 7C illustrates the exemplary device of FIGS. 7A and 7B
in a post-injection state after it has completed injecting the
therapeutic agent into the patient or removed from the patient
prior to completion of the injecting of the therapeutic agent.
[0036] FIG. 8 is a flow chart of an exemplary method of assembling
an exemplary wearable automatic injection device.
[0037] FIG. 9 is a flow chart of an exemplary method of using an
exemplary wearable automatic injection device.
[0038] FIG. 10 is a flow chart of an exemplary method of using an
exemplary wearable automatic injection device to inject a
therapeutic agent into a patient.
[0039] FIG. 11 illustrates an exemplary barrel portion in which a
distal end of the barrel portion bears an injection needle that
extends substantially along the longitudinal axis of the barrel
portion.
[0040] FIG. 12 illustrates an exemplary barrel portion in which a
distal end of the barrel portion bears an injection needle that
extends at about 90 degrees relative to the longitudinal axis of
the barrel portion.
[0041] FIG. 13 illustrates an exemplary needle assembly in which an
exemplary adapter couples a syringe needle to an injection
needle.
[0042] FIG. 14 illustrates an exemplary needle assembly in which a
fluid conduit couples a syringe needle to an injection needle.
[0043] FIG. 15 illustrates an exemplary transfer mechanism for
providing a fluid conduit between a syringe needle and an injection
needle.
[0044] FIG. 16 illustrates an exemplary transfer mechanism for
providing a fluid conduit between a syringe needle and an injection
needle.
[0045] FIG. 17 illustrates an exemplary transfer mechanism for
providing a fluid conduit between a syringe needle and an injection
needle.
[0046] FIG. 18A illustrates a perspective view of an exemplary
wearable automatic injection device.
[0047] FIG. 18B illustrates a disassembled view showing the
components of the exemplary device of FIG. 18A.
[0048] FIG. 19A illustrates a side view of an exemplary wearable
automatic injection device.
[0049] FIG. 19B illustrates a perspective view showing the
components of the device of FIG. 19A.
[0050] FIG. 20A illustrates a perspective view of an exemplary
wearable automatic injection device.
[0051] FIG. 20B illustrates a top view of the device of FIG.
20A.
[0052] FIG. 20C illustrates a side view of the transfer mechanism
of the device of FIG. 20A.
[0053] FIG. 21A illustrates a perspective view of an exemplary
wearable automatic injection device including an exemplary
cartridge assembly.
[0054] FIG. 21B illustrates a sectional view of the exemplary
cartridge assembly of
[0055] FIG. 21A taken along a longitudinal axis.
[0056] FIG. 21C illustrates a transparent top view of the exemplary
device of FIG. 21A.
[0057] FIG. 22 illustrates an exemplary syringe or cartridge
actuator that may be used to advance a barrel portion and/or the
cartridge assembly from a retraction position to an extended
position within the housing of a wearable automatic injection
device.
[0058] FIG. 23 illustrates an exemplary syringe or cartridge
actuator including a first portion, a second portion and a hinge
portion provided between the first and second portions.
[0059] FIG. 24 illustrates a schematic of a portion of an exemplary
automatic injection device including a plunger actuation mechanism
that employs a fusee and a viscous damping mechanism.
[0060] FIG. 25 illustrates a wearable automatic injection device
may include a platform, a slideable carriage coupled to the
platform, and a cartridge assembly mounted on the slideable
carriage.
[0061] FIG. 26 illustrates a wearable automatic injection device
may include a platform, a slideable carriage coupled to the
platform, and a cartridge assembly mounted on the slideable
carriage.
[0062] FIG. 27 is a top view through a cover of an exemplary
automatic injection device including a plunger actuation mechanism
for automatically actuating a bung in a barrel portion.
[0063] FIG. 28 is a side view of the exemplary automatic injection
device of FIG. 27 showing a fusee and a damping mechanism.
[0064] FIG. 29 is a perspective view through a cover of the
exemplary automatic injection device of FIG. 27.
[0065] FIG. 30 illustrates x and y coordinates (in inches) of cam
profiles for: (i) the combination of spring 1 and a viscous damper,
(ii) the combination of spring 1 and an escapement, (iii) the
combination of spring 2 and a viscous damper, and (iv) the
combination of spring 2 and an escapement.
[0066] FIG. 31 illustrates a graph of therapeutic agent flow rates
(in milliliters per minute) versus time (in seconds) delivered by:
(i) the combination of spring 1 and a viscous damper, (ii) the
combination of spring 1, a viscous damper and a cam spool, (iii)
the combination of spring 1 and an escapement, (iv) the combination
of spring 1, an escapement and a cam spool, (v) the combination of
spring 2 and a viscous damper, (vi) the combination of spring 2, a
viscous damper and a cam spool, (vii) the combination of spring 2
and an escapement, (viii) the combination of spring 2, an
escapement and a cam spool, and (ix) and an ideal flow rate in
which the therapeutic agent is delivered at a substantially
constant rate.
[0067] FIG. 32 illustrates a graph of the volume of therapeutic
agent (in milliliters) versus time (in seconds) delivered by the
combinations of components of FIG. 31.
[0068] FIG. 33 illustrates a graph of the volume of therapeutic
agent (in milliliters) against time (in seconds) delivered using:
(i) a G damping mechanism having a damping coefficient of about
10.3 lbf*s/in with a gear ratio of 4:1, (ii) a B damping mechanism
having a damping coefficient of about 15.1 lbf*s/in with a gear
ratio of 4:1, (iii) a K damping mechanism having a damping
coefficient of about 18.9 lbf*s/in with a gear ratio of 4:1, (iv) a
V damping mechanism having a damping coefficient of about 24.9
lbf*s/in with a gear ratio of 4:1, (v) a G damping mechanism having
a damping coefficient of about 25.1 lbf*s/in with a gear ratio of
6.25:1, (vi) a B damping mechanism having a damping coefficient of
about 37.0 lbf*s/in with a gear ratio of 6.25:1, (vii) a K damping
mechanism having a damping coefficient of about 46.2 lbf*s/in with
a gear ratio of 6.25:1, (viii) a V damping mechanism having a
damping coefficient of about 60.7 lbf*s/in with a gear ratio of
6.25:1, (ix) a G damping mechanism having a damping coefficient of
about 164 lbf*s/in with a gear ratio of 16:1, (x) a B damping
mechanism having a damping coefficient of about 242 lbf*s/in with a
gear ratio of 16:1, (xi) a K damping mechanism having a damping
coefficient of about 303 lbf*s/in with a gear ratio of 16:1, (xii)
a V damping mechanism having a damping coefficient of about 398
lbf*s/in with a gear ratio of 16:1, and (xiii) an ideal flow rate
in which the therapeutic agent is delivered at a substantially
constant rate.
[0069] FIG. 34 illustrates a graph of exemplary damper torques
(that may be back-calculated from the displacement of the plunger
actuator) against damper speeds (in rpm) for G, B, K and V model
dampers having increasing damping coefficients.
[0070] FIG. 35 illustrates a graph of the volume of therapeutic
agent (in milliliters) against time (in seconds) delivered by
different exemplary syringes using a V model damper having a
damping coefficient of about 24.9 lbf*s/in and an exemplary gear
ratio of 4:1.
[0071] FIG. 36 illustrates a graph of the volume of therapeutic
agent (in milliliters) delivered and the diameter of the fusee or
cam spool (in inches) versus the time (in seconds).
[0072] FIG. 37 illustrates a graph of the volume of therapeutic
agent (in milliliters) delivered versus time (in seconds) achieved
by: (i) a first damper at room temperature, (ii) the first damper
at about 40 degrees Fahrenheit (in a refrigerator), (iii) a second
damper, (iv) the second damper at about 0 degree Fahrenheit (in a
freezer), (v) a third damper having manufacturing variability
relative to the first and second dampers, and (vi) a fourth damper
having manufacturing variability relative to the first and second
dampers.
[0073] FIG. 38 illustrates a schematic of a portion of an exemplary
automatic injection device including a plunger actuation mechanism
that employs a fusee and an escapement mechanism.
[0074] FIG. 39 illustrates an exemplary plunger actuation mechanism
that employs one or more linear biasing mechanism to provide a
force for expressing a therapeutic agent from the barrel portion of
a wearable automatic injection device.
[0075] FIG. 40 illustrates an exemplary plunger actuation mechanism
that employs one or more clock springs to provide a force for
expressing a therapeutic agent from the barrel portion of a
wearable automatic injection device.
[0076] FIG. 41 is a schematic of an exemplary automatic injection
device including a plunger actuation mechanism that employs one or
more fluid circuits.
[0077] FIG. 42 is an exemplary automatic injection device that
employs one or more fluid circuits to perspective view a force to a
bung for expressing a dose of a therapeutic agent from a barrel
portion.
[0078] FIG. 43 illustrates a graph of the cumulative amount of
therapeutic agent (in grams) against time (in seconds) as delivered
by an exemplary delivery system at an exemplary delivery pressure
of about 16.5 psi.
[0079] FIG. 44 illustrates a graph of the cumulative volume of
therapeutic agent (in milliliters) against time (in seconds) as
delivered by an exemplary delivery system including a first flow
restrictor.
[0080] FIG. 45 illustrates a graph of the cumulative volume of
therapeutic agent (in milliliters) against time (in seconds) as
delivered by an exemplary delivery system including a second flow
restrictor.
[0081] FIG. 46 is a schematic drawing of an exemplary automatic
injection device that employs one or more fluid circuits to provide
a force for expressing a therapeutic agent from a cartridge
assembly.
[0082] FIG. 47 is a top view of the exemplary device of FIG.
46.
[0083] FIG. 48 illustrates a top view of an exemplary automatic
injection device which shows a conduit coupling the master cylinder
to a flow restrictor, a conduit coupling the flow restrictor to the
bung, and a conduit coupling the master cylinder to a retraction
mechanism via a valve.
[0084] FIG. 49 illustrates a schematic diagram of the device of
FIG. 48.
[0085] FIG. 50 illustrates a graph of the pressure after a check
valve and behind a bung (in psi) versus time (in seconds) in an
exemplary embodiment.
[0086] FIG. 51 illustrates a side view of an exemplary automatic
injection device in which the housing of the wearable automatic
injection device includes a skin sensor foot.
[0087] FIGS. 52A and 52B illustrate an exemplary needle protection
system that maintains an injection needle in a retracted position
within a housing of an exemplary automatic injection system.
[0088] FIGS. 53A and 53B illustrate another exemplary needle
protection system provided in an exemplary automatic injection
system.
[0089] FIG. 54 illustrates another exemplary needle protection
system provided in of an exemplary automatic injection system.
[0090] FIG. 55 illustrates another exemplary needle protection
system provided in an exemplary automatic injection system.
DETAILED DESCRIPTION
[0091] Subcutaneous injection is a primary mode of therapeutic
agent delivery and involves administering a bolus of a therapeutic
agent into a patient. Subcutaneous injections are highly effective
in administering various therapeutic agents including insulin,
vaccines, and drugs such as morphine. Automatic injection devices
offer an alternative to a syringe for delivering a therapeutic
agent and allow patients to self-administer subcutaneous injections
of therapeutic agents. Conventional automatic injection devices
include hand held automatic injection devices and patch pumps,
which are self-adhesive, patient-mounted auto-injectors. In use, a
patch pump containing a therapeutic agent is mounted onto the skin
or clothing of a patient and triggered to inject the therapeutic
agent into the patient. Conventional patch pumps are typically
filled by a patient prior to use. In addition, certain conventional
patch pumps have an exposed needle inside the pump, and thus
require secondary sterile packaging to maintain sterility.
[0092] Studies have shown that there is a direct correlation
between the injection rate of certain therapeutic agents and the
pain perceived by a patient upon injection of the therapeutic
agents or agents. Some therapeutic agents cause pain, e.g., a
burning or stinging sensation when injected rapidly into the
patient. The pain sensation may be the result of a physiological
response of the patient's skin to the subcutaneous injection of a
therapeutic agent. Large volumes of any therapeutic agent, greater
than one milliliter, may also cause pain when injected into the
skin. Antibodies, and portions thereof, are exemplary therapeutic
agents that are least painful when delivered at slow injection
rates. Currently, there are no commercially viable conventional
patch pumps that effectively address the discomfort associated with
fast injection rates of hand held automatic injection devices.
[0093] Exemplary embodiments are described below with reference to
certain illustrative embodiments. While exemplary embodiments are
described with respect to using a wearable automatic injection
device to provide an injection of a dose of a liquid medication,
one of ordinary skill in the art will recognize that exemplary
embodiments are not limited to the illustrative embodiments and
that exemplary automatic injection devices may be used to inject
any suitable substance into a patient. In addition, components of
exemplary automatic injection devices and methods of making and
using exemplary automatic injection devices are not limited to the
illustrative embodiments described below.
[0094] A syringe assembly of exemplary automatic injections devices
may contain a dose of a TNFa inhibitor. In an exemplary embodiment,
the TNFa inhibitor may be a human TNFa antibody or antigen-biding
portion thereof. In an exemplary embodiment, the human TNFa
antibody or antigen-binding portion thereof may be adalimumab or
golimumab.
[0095] Exemplary embodiments provide wearable automatic injection
devices that may adhere to the skin or clothing of the patient and
deliver a therapeutic agent into patient by subcutaneous injection
at slow, controlled injection rates, e.g., in a single slow bolus.
The slow, controlled injection rates achieved by exemplary devices
minimize the pain sensation associated with a volume of a
therapeutic agent entering into the patent's tissue. Exemplary time
durations for slow delivery achieved by exemplary devices may range
from about 5 minutes to about 30 minutes, but are not limited to
this exemplary range. Exemplary volumes of therapeutic agent
deliverable by exemplary devices may range from about 0.8
milliliters to about 1 milliliter, but are not limited to this
exemplary range. In addition, exemplary devices may advantageously
minimize inflections in the delivery profile against time of the
therapeutic agent.
[0096] Exemplary embodiments minimize the size envelope of
exemplary automatic injection devices, and provide scalable
solutions with configurable delivery times and delivery profiles
that may be used for a range of therapeutic agent viscosities.
[0097] Exemplary embodiments provide wearable automatic injection
devices that deliver a therapeutic agent into a patient by
subcutaneous injection at slow, controlled injection rates, e.g.,
in a single slow bolus without battery power or other components
requiring electrical current or charge to operate. Exemplary
embodiments also provide methods of using the wearable automatic
injection devices for slow, controlled therapeutic agent delivery.
The wearable automatic injection devices provided by exemplary
embodiments are pre fillable prior to delivery to the patient,
maintain sterility of the therapeutic agent and all subcutaneous
contact surfaces (i.e., a hypodermic needle and one or more
septums) to avoid the need for aseptic assembly and address the
perceived patient discomfort due to injection by conventional hand
held automatic injection devices. Exemplary wearable automatic
injection devices include a primary therapeutic barrel portion that
maintains sterility and therefore requires no aseptic assembly.
Exemplary wearable automatic injection devices are disposable, easy
to use, pre-fill capable, and may substantially or completely
eliminate the burning sensation often experienced by a patient that
uses a wearable automatic injection device. The wearable automatic
injection devices provided by exemplary embodiments can be used to
deliver any therapeutic agent that may be delivered subcutaneously
including, but not limited to, an antibody or insulin, etc.
I. Definitions
[0098] Certain terms are defined in this section to facilitate
understanding of exemplary embodiments.
[0099] The wearable automatic injection device of exemplary
embodiments may include a "therapeutically effective amount" or a
"prophylactically effective amount" of an antibody or antibody
portion of the invention. A "therapeutically effective amount"
refers to an amount effective, at dosages and for periods of time
necessary, to achieve the desired therapeutic result. A
therapeutically effective amount of the antibody, antibody portion,
or other TNF.alpha. inhibitor may vary according to factors such as
the disease state, age, sex, and weight of the patient, and the
ability of the antibody, antibody portion, or other TNF.alpha.
inhibitor to elicit a desired response in the patient. A
therapeutically effective amount is also one in which any toxic or
detrimental effects of the antibody, antibody portion, or other
TNF.alpha. inhibitor are outweighed by the therapeutically
beneficial effects. A "prophylactically effective amount" refers to
an amount effective, at dosages and for periods of time necessary,
to achieve the desired prophylactic result. Typically, since a
prophylactic dose is used in patients prior to or at an earlier
stage of disease, the prophylactically effective amount will be
less than the therapeutically effective amount.
[0100] The terms "substance" and "therapeutic agent" refer to any
type of drug, biologically active agent, biological substance,
chemical substance or biochemical substance that is capable of
being administered in a therapeutically effective amount to a
patient employing exemplary automatic injection devices. Exemplary
substances include, but are not limited to, agents in a liquid
state. Such agents may include, but are not limited to, adalimumab
(HUMIRA.RTM.) and proteins that are in a liquid solution, e.g.,
fusion proteins and enzymes. Examples of proteins in solution
include, but are not limited to, Pulmozyme (Dornase alfa), Regranex
(Becaplermin), Activase (Alteplase), Aldurazyme (Laronidase),
Amevive (Alefacept), Aranesp (Darbepoetin alfa), Becaplermin
Concentrate, Betaseron (Interferon beta-1b), BOTOX (Botulinum Toxin
Type A), Elitek (Rasburicase), Elspar (Asparaginase), Epogen
(Epoetin alfa), Enbrel (Etanercept), Fabrazyme (Agalsidase beta),
Infergen (Interferon alfacon-1), Intron A (Interferon alfa-2a),
Kineret (Anakinra), MYOBLOC (Botulinum Toxin Type B), Neulasta
(Pegfilgrastim), Neumega (Oprelvekin), Neupogen (Filgrastim), Ontak
(Denileukin diftitox), PEGASYS (Peginterferon alfa-2a), Proleukin
(Aldesleukin), Pulmozyme (Dornase alfa), Rebif (Interferon
beta-1a), Regranex (Becaplermin), Retavase (Reteplase), Roferon-A
(Interferon alfa-2), TNKase (Tenecteplase), and Xigris (Drotrecogin
alfa), Arcalyst (Rilonacept), NPlate (Romiplostim), Mircera
(methoxypolyethylene glycol-epoetin beta), Cinryze (C1 esterase
inhibitor), Elaprase (idursulfase), Myozyme (alglucosidase alfa),
Orencia (abatacept), Naglazyme (galsulfase), Kepivance (palifermin)
and Actimmune (interferon gamma-1b).
[0101] A protein in solution may also be an immunoglobulin or
antigen-binding fragment thereof, such as an antibody or
antigen-binding portion thereof. Examples of antibodies that may be
used in an exemplary automatic injection device include, but are
not limited to, chimeric antibodies, non-human antibodies, human
antibodies, humanized antibodies, and domain antibodies (dAbs). In
an exemplary embodiment, the immunoglobulin or antigen-binding
fragment thereof, is an anti-TNFa and/or an anti-IL-12 antibody
(e.g., it may be a dual variable domain immunoglobulin (DVD) IgTM).
Other examples of immunoglobulins or antigen-binding fragments
thereof that may be used in the methods and compositions of
exemplary embodiments include, but are not limited to, 1D4.7
(anti-IL-12/IL-23 antibody; Abbott Laboratories); 2.5(E)mg1
(anti-IL-18; Abbott Laboratories); 13C5.5 (anti-IL-13 antibody;
Abbott Laboratories); J695 (anti-IL-12; Abbott Laboratories);
Afelimomab (Fab 2 anti-TNF; Abbott Laboratories); HUMIRA
(adalimumab) Abbott Laboratories); Campath (Alemtuzumab); CEA-Scan
Arcitumomab (fab fragment); Erbitux (Cetuximab); Herceptin
(Trastuzumab); Myoscint (Imciromab Pentetate); ProstaScint
(Capromab Pendetide); Remicade (Infliximab); ReoPro (Abciximab);
Rituxan (Rituximab); Simulect (Basiliximab); Synagis (Palivizumab);
Verluma (Nofetumomab); Xolair (Omalizumab); Zenapax (Daclizumab);
Zevalin (Ibritumomab Tiuxetan); Orthoclone OKT3 (Muromonab-CD3);
Panorex (Edrecolomab); Mylotarg (Gemtuzumab ozogamicin); golimumab
(Centocor); Cimzia (Certolizumab pegol); Soliris (Eculizumab); CNTO
1275 (ustekinumab); Vectibix (panitumumab); Bexxar (tositumomab and
I131 tositumomab); and Avastin (bevacizumab).
[0102] Additional examples of immunoglobulins, or antigen-binding
fragments thereof, that may be used in the methods and compositions
of exemplary embodiments include, but are not limited to, proteins
comprising one or more of the following: the D2E7 light chain
variable region (SEQ ID NO: 1), the D2E7 heavy chain variable
region (SEQ ID NO: 2), the D2E7 light chain variable region CDR3
(SEQ ID NO: 3), the D2E7 heavy chain variable region CDR3 (SEQ ID
NO:4), the D2E7 light chain variable region CDR2 (SEQ ID NO: 5),
the D2E7 heavy chain variable region CDR2 (SEQ ID NO: 6), the D2E7
light chain variable region CDR1 (SEQ ID NO: 7), the D2E7 heavy
chain variable region CDR1 (SEQ ID NO: 8), the 2SD4 light chain
variable region (SEQ ID NO: 9), the 2SD4 heavy chain variable
region (SEQ ID NO: 10), the 2SD4 light chain variable CDR3 (SEQ ID
NO: 11), the EP B12 light chain variable CDR3 (SEQ ID NO: 12), the
VL10E4 light chain variable CDR3 (SEQ ID NO: 13), the VL100A9 light
chain variable CDR3 (SEQ ID NO: 14), the VLL100D2 light chain
variable CDR3 (SEQ ID NO: 15), the VLL0F4 light chain variable CDR3
(SEQ ID NO: 16), the LOES light chain variable CDR3 (SEQ ID NO:
17), the VLLOG7 light chain variable CDR3 (SEQ ID NO: 18), the
VLLOG9 light chain variable CDR3 (SEQ ID NO: 19), the VLLOH1 light
chain variable CDR3 (SEQ ID NO: 20), the VLLOH10 light chain
variable CDR3 (SEQ ID NO: 21), the VL1B7 light chain variable CDR3
(SEQ ID NO: 22), the VL1C1 light chain variable CDR3 (SEQ ID NO:
23), the VL0.1F4 light chain variable CDR3 (SEQ ID NO: 24), the
VL0.1H8 light chain variable CDR3 (SEQ ID NO: 25), the LOE7. A
light chain variable CDR3 (SEQ ID NO: 26), the 2SD4 heavy chain
variable region CDR (SEQ ID NO: 27), the VH1B11 heavy chain
variable region CDR (SEQ ID NO: 28), the VH1D8 heavy chain variable
region CDR (SEQ ID NO: 29), the VH1A11 heavy chain variable region
CDR (SEQ ID NO: 30), the VH1B12 heavy chain variable region CDR
(SEQ ID NO: 31), the VH1E4 heavy chain variable region CDR (SEQ ID
NO: 32), the VH1F6 heavy chain variable region CDR (SEQ ID NO: 33),
the 3C-H2 heavy chain variable region CDR (SEQ ID NO: 34), and the
VH1-D2.N heavy chain variable region CDR (SEQ ID NO: 35).
[0103] The term "human TNF.alpha." (abbreviated herein as
hTNF.alpha., or simply hTNF) refers to a human cytokine that exists
as a 17 kD secreted form and a 26 kD membrane associated form, the
biologically active form of which is composed of a trimer of
noncovalently bound 17 kD molecules. The structure of hTNF.alpha.
is described further in, for example, Pennica, D., et al. (1984)
Nature 312:724-729; Davis, J. M., et al. (1987)
Biochem.26:1322-1326; and Jones, E. Y., et al. (1989) Nature
338:225-228. The term human TNF.alpha. is intended to include
recombinant human TNF.alpha. (rhTNF.alpha.), which can be prepared
by standard recombinant expression methods or purchased
commercially (R & D Systems, Catalog No. 210-TA, Minneapolis,
Minn.). TNF.alpha. is also referred to as TNF.
[0104] The term "TNF.alpha. inhibitor" refers to an agent that
interferes with TNF.alpha. activity. The term also includes each of
the anti-TNF.alpha. human antibodies (used interchangeably herein
with TNF.alpha. antibodies) and antibody portions described herein
as well as those described in U.S. Pat. Nos. 6,090,382; 6,258,562;
6,509,015; 7,223,394; and 6,509,015. In one embodiment, the
TNF.alpha. inhibitor used in the invention is an anti-TNF.alpha.
antibody, or a fragment thereof, including infliximab
(Remicade.RTM., Johnson and Johnson; described in U.S. Pat. No.
5,656,272); CDP571 (a humanized monoclonal anti-TNF-alpha IgG4
antibody); CDP 870 (a humanized monoclonal anti-TNF-alpha antibody
fragment); an anti-TNF dAb (Peptech); CNTO 148 (golimumab;
Centocor, See WO 02/12502 and U.S. Pat. Nos. 7,521,206 and
7,250,165); and adalimumab (HUMIRA.RTM. Abbott Laboratories, a
human anti-TNF mAb, described in U.S. Pat. No. 6,090,382 as D2E7).
Additional TNF antibodies that may be used in the invention are
described in U.S. Pat. Nos. 6,593,458; 6,498,237; 6,451,983; and
6,448,380. In another embodiment, the TNF.alpha. inhibitor is a TNF
fusion protein, e.g., etanercept (Enbrel.RTM., Amgen; described in
WO 91/03553 and WO 09/406476). In another embodiment, the
TNF.alpha. inhibitor is a recombinant TNF binding protein (r-TBP-I)
(Serono).
[0105] In one embodiment, the term "TNF.alpha. inhibitor" excludes
infliximab. In one embodiment, the term "TNF.alpha. inhibitor"
excludes adalimumab. In another embodiment, the term "TNF.alpha.
inhibitor" excludes adalimumab and infliximab.
[0106] In one embodiment, the term "TNF.alpha. inhibitor" excludes
etanercept, and, optionally, adalimumab, infliximab, and adalimumab
and infliximab.
[0107] In one embodiment, the term "TNF.alpha. antibody" excludes
infliximab. In one embodiment, the term "TNF.alpha. antibody"
excludes adalimumab. In another embodiment, the term "TNF.alpha.
antibody" excludes adalimumab and infliximab.
[0108] The term "antibody" refers to immunoglobulin molecules
generally comprised of four polypeptide chains, two heavy (H)
chains and two light (L) chains inter-connected by disulfide bonds.
Each heavy chain is comprised of a heavy chain variable region
(abbreviated herein as HCVR or VH) and a heavy chain constant
region. The heavy chain constant region is comprised of three
domains, CH1, CH2 and CH3. Each light chain is comprised of a light
chain variable region (abbreviated herein as LCVR or VL) and a
light chain constant region. The light chain constant region is
comprised of one domain, CL. The VH and VL regions can be further
subdivided into regions of hypervariability, termed complementarity
determining regions (CDR), interspersed with regions that are more
conserved, termed framework regions (FR). Each VH and VL is
composed of three CDRs and four FRs, arranged from amino-terminus
to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2,
FR3, CDR3, FR4. The antibodies of the invention are described in
further detail in U.S. Pat. Nos. 6,090,382; 6,258,562; and
6,509,015.
[0109] The term "antigen-binding portion" of an antibody (or simply
"antibody portion") refers to one or more fragments of an antibody
that retain the ability to specifically bind to an antigen (e.g.,
hTNF.alpha.). Fragments of a full-length antibody can perform the
antigen-binding function of an antibody. Examples of binding
fragments encompassed within the term "antigen-binding portion" of
an antibody include (i) a Fab fragment, a monovalent fragment
consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2
fragment, a bivalent fragment comprising two Fab fragments linked
by a disulfide bridge at the hinge region; (iii) a Fd fragment
consisting of the VH and CH1 domains; (iv) a Fv fragment consisting
of the VL and VH domains of a single arm of an antibody, (v) a dAb
fragment (Ward et al. (1989) Nature 341:544-546), which consists of
a VH or VL domain; (vi) an isolated complementarity determining
region (CDR); and (vii) a dual variable domain immunoglobulin
(DVD-Ig). Furthermore, although the two domains of the Fv fragment,
VL and VH, are coded for by separate genes, they can be joined,
using recombinant methods, by a synthetic linker that enables them
to be made as a single protein chain in which the VL and VH regions
pair to form monovalent molecules (known as single chain Fv (scFv);
See e.g., Bird et al. (1988) Science 242:423-426; and Huston et al.
(1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain
antibodies are also encompassed within the term "antigen-binding
portion" of an antibody. Other forms of single chain antibodies,
such as diabodies are also encompassed. Diabodies are bivalent,
bispecific antibodies in which VH and VL domains are expressed on a
single polypeptide chain, but using a linker that is too short to
allow for pairing between the two domains on the same chain,
thereby forcing the domains to pair with complementary domains of
another chain and creating two antigen binding sites (See e.g.,
Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448;
Poljak et al. (1994) Structure 2:1121-1123). The antibody portions
of the invention are described in further detail in U.S. Pat. Nos.
6,090,382; 6,258,562; and 6,509,015.
[0110] The term "recombinant human antibody" refers to all human
antibodies that are prepared, expressed, created or isolated by
recombinant means, such as antibodies expressed using a recombinant
expression vector transfected into a host cell (described further
below), antibodies isolated from a recombinant, combinatorial human
antibody library (described further below), antibodies isolated
from an animal (e.g., a mouse) that is transgenic for human
immunoglobulin genes (See e.g., Taylor et al. (1992) Nucl. Acids
Res. 20:6287) or antibodies prepared, expressed, created or
isolated by any other means that involves splicing of human
immunoglobulin gene sequences to other DNA sequences. Such
recombinant human antibodies have variable and constant regions
derived from human germ line immunoglobulin sequences. In certain
embodiments, however, such recombinant human antibodies are
subjected to in vitro mutagenesis (or, when an animal transgenic
for human Ig sequences is used, in vivo somatic mutagenesis) and
thus the amino acid sequences of the VH and VL regions of the
recombinant antibodies are sequences that, while derived from and
related to human germ line VH and VL sequences, may not naturally
exist within the human antibody germ line repertoire in vivo.
[0111] Such chimeric, humanized, human, and dual specific
antibodies can be produced by recombinant DNA techniques known in
the art, for example using methods described in PCT International
Application No. PCT/US86/02269; European Patent Application No.
184,187; European Patent Application No. 171,496; European Patent
Application No. 173,494; PCT International Publication No. WO
86/01533; U.S. Pat. No. 4,816,567; European Patent Application No.
125,023; Better et al. (1988) Science 240:1041-1043; Liu et al.
(1987) Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al. (1987)
J. Immunol. 139:3521-3526; Sun et al. (1987) Proc. Natl. Acad. Sci.
USA 84:214-218; Nishimura et al. (1987) Cancer Res. 47:999-1005;
Wood et al. (1985) Nature 314:446-449; Shaw et al. (1988) J. Natl.
Cancer Inst. 80:1553-1559; Morrison (1985) Science 229:1202-1207;
Oi et al. (1986) BioTechniques 4:214; U.S. Pat. No. 5,225,539;
Jones et al. (1986) Nature 321:552-525; Verhoeyan et al. (1988)
Science 239:1534; and Beidler et al. (1988) J. Immunol.
141:4053-4060, Queen et al. (1989) Proc. Natl. Acad. Sci. USA
86:10029-10033 (1989); U.S. Pat. Nos. 5,530,101; 5,585,089;
5,693,761; 5,693,762; WO 90/07861; and U.S. Pat. No. 5,225,539.
[0112] The term "isolated antibody" refers to an antibody that is
substantially free of other antibodies having different antigenic
specificities (e.g., an isolated antibody that specifically binds
hTNF.alpha. and is substantially free of antibodies that
specifically bind antigens other than hTNF.alpha.). An isolated
antibody that specifically binds hTNF.alpha. may have
cross-reactivity to other antigens, such as TNF.alpha. molecules
from other species. Moreover, an isolated antibody may be
substantially free of other cellular material and/or chemicals.
[0113] The term "neutralizing antibody" (or an "antibody that
neutralized hTNF.alpha. activity") refers to an antibody whose
binding to hTNF.alpha. results in inhibition of the biological
activity of hTNF.alpha.. This inhibition of the biological activity
of hTNF.alpha. can be assessed by measuring one or more indicators
of hTNF.alpha. biological activity, such as hTNF.alpha.-induced
cytotoxicity (either in vitro or in vivo), hTNF.alpha.-induced
cellular activation and hTNF.alpha. binding to hTNF.alpha.
receptors. These indicators of hTNF.alpha. biological activity can
be assessed by one or more of several standard in vitro or in vivo
assays known in the art (See U.S. Pat. No. 6,090,382). Preferably,
the ability of an antibody to neutralize hTNF.alpha. activity is
assessed by inhibition of hTNF.alpha.-induced cytotoxicity of L929
cells. As an additional or alternative parameter of hTNF.alpha.
activity, the ability of an antibody to inhibit hTNF.alpha.-induced
expression of ELAM-1 on HUVEC, as a measure of hTNF.alpha.-induced
cellular activation, can be assessed.
[0114] The term "surface plasmon resonance" refers to an optical
phenomenon that allows for the analysis of real-time biospecific
interactions by detection of alterations in protein concentrations
within a biosensor matrix, for example using the BIAcore system
(Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For
further descriptions, see Example 1 of U.S. Pat. 6,258,562 and
Jonsson et al. (1993) Ann. Biol. Clin. 51:19; Jonsson et al. (1991)
Biotechniques 11:620-627; Johnsson et al. (1995) J. Mol. Recognit.
8:125; and Johnnson et al. (1991) Anal.Biochem.198:268.
[0115] The term "Koff" refers to the off rate constant for
dissociation of an antibody from the antibody/antigen complex.
[0116] The term "Kd" refers to the dissociation constant of a
particular antibody-antigen interaction.
[0117] The term "IC50" refers to the concentration of the inhibitor
required to inhibit the biological endpoint of interest, e.g.,
neutralize cytotoxicity activity.
[0118] The term "dose" or "dosage" refers to an amount of a
substance, such as a TNF.alpha. inhibitor, which is administered to
a patient preferably using the wearable automatic injection device
of the invention. In one embodiment, the dose comprises an
effective amount, for example, including, but not limited to, 20
mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110
mg, 120 mg, 130 mg, 140 mg, 150 mg, and 160 mg, of the TNF.alpha.
inhibitor adalimumab.
[0119] The term "dosing" refers to the administration of a
substance (e.g., an anti-TNF.alpha. antibody) to achieve a
therapeutic objective (e.g., treatment of rheumatoid
arthritis).
[0120] The term "dosing regimen" describes a treatment schedule for
a substance, such as a TNF.alpha. inhibitor, e.g., a treatment
schedule over a prolonged period of time and/or throughout the
course of treatment, e.g. administering a first dose of a
TNF.alpha. inhibitor at week 0 followed by a second dose of a
TNF.alpha. inhibitor on a biweekly dosing regimen.
[0121] The term "biweekly dosing regimen", "biweekly dosing", and
"biweekly administration" refer to the time course of administering
a substance (e.g., an anti-TNF.alpha. antibody) to a patient to
achieve a therapeutic objective, e.g., throughout the course of
treatment. The biweekly dosing regimen is not intended to include a
weekly dosing regimen. Preferably, the substance is administered
every 9 to 19 days, more preferably, every 11 to 17 days, even more
preferably, every 13 to 15 days, and most preferably, every 14
days. In one embodiment, the biweekly dosing regimen is initiated
in a patient at week 0 of treatment. In another embodiment, a
maintenance dose is administered on a biweekly dosing regimen. In
one embodiment, both the loading and maintenance doses are
administered according to a biweekly dosing regimen. In one
embodiment, biweekly dosing includes a dosing regimen wherein doses
of a TNF.alpha. inhibitor are administered to a patient every other
week beginning at week 0. In one embodiment, biweekly dosing
includes a dosing regimen where doses of a TNF.alpha. inhibitor are
administered to a patient every other week consecutively for a
given time period, e.g., 4 weeks, 8 weeks, 16, weeks, 24 weeks, 26
weeks, 32 weeks, 36 weeks, 42 weeks, 48 weeks, 52 weeks, 56 weeks,
etc. Biweekly dosing methods are also described in U.S.
2003/0235585.
[0122] The term "combination" as in the phrase "a first agent in
combination with a second agent" includes co-administration of a
first agent and a second agent, which for example may be dissolved
or intermixed in the same pharmaceutically acceptable carrier, or
administration of a first agent, followed by the second agent, or
administration of the second agent, followed by the first
agent.
[0123] The term "concomitant" as in the phrase "concomitant
therapeutic treatment" includes administering an agent in the
presence of a second agent. A concomitant therapeutic treatment
method includes methods in which the first, second, third, or
additional substances are co-administered. A concomitant
therapeutic treatment method also includes methods in which the
first or additional agents are administered in the presence of a
second substance or additional substances, wherein the second or
additional agents, for example, may have been previously
administered. A concomitant therapeutic treatment method may be
executed step-wise by different patients. For example, one subject
may administer to a patient a first agent and a second subject may
to administered to the patient a second substance, and the
administering steps may be executed at the same time, or nearly the
same time, or at distant times, so long as the first substance (and
additional substances) are after administration in the presence of
the second substance (and additional substances). The actor and the
patient may be the same entity (e.g., human).
[0124] The term "combination therapy" refers to the administration
of two or more therapeutic substances, e.g., an anti-TNF.alpha.
antibody and another drug. The other drug(s) may be administered
concomitant with, prior to, or following the administration of an
anti-TNF.alpha. antibody.
[0125] The term "treatment" refers to therapeutic treatment, as
well as prophylactic or suppressive measures, for the treatment of
a disorder, such as a disorder in which TNF.alpha. is detrimental,
e.g., rheumatoid arthritis.
[0126] The term "patient" or "user" refers to any type of animal,
human or non-human, that may be injected a substance using
exemplary automatic injection devices.
[0127] The terms "wearable automatic injection device" and
"wearable autoinjector" refer to a device worn by a patient that
enables the patient to self-administer a therapeutically effective
dose of a therapeutic agent by either fastening the wearable device
directly to his or her skin or fastening the wearable device to an
article of clothing that allows penetration of a hypodermic needle,
wherein the wearable device differs from a conventional syringe by
the inclusion of a mechanism for automatically delivering the
therapeutic agent to the patient by injection when the mechanism is
engaged.
[0128] The terms "syringe" and "cartridge" encompass a sterile
barrel portion that is filled with a dose of a therapeutic agent
prior to distribution or sale to a patient or other non-medical
professional for administration of the therapeutic agent to a
patient. In an exemplary embodiment, a distal end of the barrel
portion of a syringe may be coupled to a sterile hypodermic needle.
In an exemplary embodiment, a distal end of the barrel portion of a
cartridge may not be coupled to a needle. That is, in exemplary
embodiments, a syringe may be a cartridge with a pre-attached
hollow needle coupled to its barrel portion.
[0129] Exemplary embodiments described herein with reference to a
syringe assembly may also be implemented using a cartridge
assembly. Similarly, exemplary embodiments described herein with
reference to a cartridge assembly may also be implemented using a
syringe assembly.
[0130] The term "vessel" refers to either a syringe or cartridge
that may be used in an exemplary wearable automatic injection
device for holding a dose of a therapeutic agent.
[0131] The term "injection needle" refers to a needle in a wearable
automatic injection device that is inserted into a patient's body
to deliver a dose of a therapeutic agent into the patient's body.
In an exemplary embodiment, the injection needle may be directly
coupled to or in contact with a syringe or a cartridge assembly
that holds the dose of the therapeutic agent. In another exemplary
embodiment, the injection needle may be indirectly coupled to the
syringe or cartridge assembly, for example, via a syringe needle
and/or a transfer mechanism that provides fluid communication
between the syringe or cartridge and the injection needle.
[0132] The term "syringe needle" refers to a needle in a wearable
automatic injection device that is coupled to or in contact with a
syringe or a cartridge assembly for conveying a dose of a
therapeutic agent from the syringe or cartridge assembly to an
injection needle which, in turn, delivers the therapeutic agent
into a patient's body. In an exemplary embodiment, the syringe
needle is not inserted into the patient's body. In another
exemplary embodiment, the syringe needle may be inserted into the
patient's body.
[0133] In an exemplary wearable automatic injection device
including a syringe assembly, the syringe needle may be coupled
directly to the barrel portion of the syringe and may be in fluid
communication with the barrel portion. In an exemplary wearable
automatic injection device including a cartridge assembly, the
syringe needle may be provided separately from the barrel portion
of the cartridge, for example, within an injection button or a
transfer mechanism. During an injection stage, the syringe needle
may be inserted into a distal end of the barrel portion of the
cartridge to establish fluid communication between the syringe
needle and the barrel portion.
[0134] The term "pre-injection state" refers to a state of a
wearable automatic injection device prior to the start of delivery
of a therapeutic agent contained in the device.
[0135] The term "injection state" refers to one or more states of a
wearable automatic injection device during the delivery of a
therapeutic agent contained in the device.
[0136] The term "post-injection state" refers to completion of
delivery of a therapeutically effective dose of a therapeutic agent
contained in the device and to removal of the device from the
patient prior to completion of delivery of a therapeutically
effective dose of the therapeutic agent.
[0137] The term "slow" refers to a delivery rate of a volume of a
therapeutic agent. In an exemplary embodiment, a volume of about
0.1 milliliters to about 1 milliliter or more may be delivered in a
delivery time period of about ten seconds to about twelve hours. In
a preferred embodiment, the delivery time period may range from
about five minutes to about thirty minutes.
[0138] The term "clothing" refers to any suitable covering on a
patient's body to which an exemplary wearable automatic injection
device may be coupled or attached. The article of clothing may thus
form an intermediate layer between the device and the patient's
skin and may be used to indirectly couple the device to the
patient's skin. In an exemplary embodiment, the article of clothing
may be snug clothing on the patient's body, for example, nylon
stockings. In another exemplary embodiment, the article of clothing
may be a covering on the patient's skin including, but not limited
to, a medical tape, a bandage, and the like. In another exemplary
embodiment, the article of clothing may be a coupling mechanism
that adheres the device in the proximity of the patient's skin
including, but not limited to, a sleeve that may fit round a
portion of the patient's body, a belt, a strap (e.g., a Velcro
strap), and the like.
II. Exemplary Embodiments
[0139] Certain exemplary wearable automatic injection devices are
described with reference to FIGS. 1-10. Certain exemplary needle
systems that may be used in exemplary wearable automatic injection
devices to convey a therapeutic agent are described with reference
to FIGS. 11-23. Certain exemplary plunger actuation systems that
may be used in exemplary wearable automatic injection devices to
expel a therapeutic agent from a syringe or cartridge are described
with reference to FIGS. 24-51. Certain exemplary needle protection
systems that may be used in exemplary wearable automatic injection
devices to maintain an injection needle in a retracted position in
a post-injection state are described with reference to FIGS.
52-55.
[0140] Exemplary wearable automatic injection devices may employ a
syringe assembly (as illustrated in FIGS. 1A-1F) or a cartridge
assembly (as illustrated in FIGS. 2A-2F) for holding a dose of a
therapeutic agent that may be delivered into a patient's body
through an injection needle.
[0141] FIGS. 1A-1F illustrate an exemplary embodiment of a wearable
automatic injection device 100 including a syringe assembly that
may be used to inject a dose of a therapeutic agent into the body
of a patient. FIG. 1A illustrates a first end view and a first side
view of the exemplary wearable device 100 in a packaged
pre-injection state. FIG. 1B illustrates the first end view and the
first side view of the exemplary device 100 in a pre-injection
state in which a needle shield covering the injection needle is
removed in preparation for an injection. FIG. 1C illustrates the
first end view and the first side view of the exemplary device 100
during an injection in an injection state in which the patient's
skin is pierced by the injection needle. FIG. 1D illustrates the
first end view and the first side view of the exemplary device 100
during an injection in an injection state in which the barrel
portion containing the dose of the therapeutic agent is deployed
forwardly within the housing of the device 100. FIG. 1E illustrates
the first end view and the first side view of the exemplary device
100 during an injection in an injection state in which the bung is
actuated by a plunger actuator to expel the dose of the therapeutic
agent from the barrel portion. FIG. 1F illustrates the first end
view and the first side view of the exemplary device 100 after an
injection in a post-injection state in which the injection needle
is retracted within the housing of the device 100.
[0142] The wearable automatic injection device 100 may include a
housing 102. In an exemplary embodiment, the housing 102 may have
an elongated configuration, although one of ordinary skill in the
art will recognize that the housing 102 may have any suitable size,
shape and configuration for housing a barrel portion containing a
dose of a therapeutic agent to be injected. In an exemplary
embodiment, the housing 102 may be formed of any suitable material
including, but not limited to, plastic and other known
materials.
[0143] The housing 102 of the wearable automatic injection device
100 may include an adhesive layer 124 disposed along a patient
contact portion at the bottom of the housing 102 that is placed
proximal to the skin of the patient or an article of clothing of
the patient. In some exemplary embodiments, the adhesive layer 124
may be configured to be placed on the skin of the patient in order
to attach the housing 102 to the patient to deliver the dose of the
therapeutic agent. The adhesive layer 124 may include a
non-adhesive tab 126 that is not adhesive. The non-adhesive tab 126
may be gripped by the patient and pulled to remove the wearable
automatic injection device 100 from the skin or clothing of the
patient.
[0144] Before the wearable automatic injection device 100 is put to
use, e.g., in the package state illustrated in FIG. 1A, the
adhesive layer 124 may be covered by a protective film 128 which
preserves the adhesive nature of the adhesive layer 124. The
protective film 128 may include a tab 130 which may be gripped by
the patient and pulled to remove the protective film 128 from the
adhesive layer 124. This exposes the adhesive layer 124, allowing
the patient to attach the housing 102 to his or her skin or article
of clothing by placing the side with the adhesive layer 124 on the
skin or the article of clothing.
[0145] The housing 102 may house a syringe assembly extending
substantially along a longitudinal axis L between a proximal end
(farthest from the injection needle) and a distal end (nearest to
the injection needle). The syringe assembly may include a barrel
portion 106 for holding a dose 108 of a therapeutic agent to be
injected into a patient's skin. The barrel portion 106 may extend
substantially along the longitudinal axis between a proximal end
(farthest from the injection needle) and a distal end (nearest to
the injection needle). In an exemplary embodiment, the barrel
portion 106 may be a substantially cylindrical member having a
circular cross-section, although one of ordinary skill in the art
will recognize that the barrel portion 106 may have any suitable
shape or configuration.
[0146] In an exemplary embodiment, the barrel portion 106 may be
stationary within the housing 102 so that the injection process
does not result in the movement of the barrel portion 106 within
and relative to the housing 102. In another exemplary embodiment,
the barrel portion 106 may initially, i.e., before an injection in
a pre-injection state, be in a retracted position toward the
proximal end of the device 100 (as illustrated in FIGS. 1A-1C), and
may be actuated during an injection in an injection state to an
extended position toward the distal end of the device 100.
[0147] A bung 110 may be provided at the proximal end of the barrel
portion 106 to seal the dose of the therapeutic agent within the
barrel portion 106 and to apply a force to the dose to expel the
dose from the barrel portion 106. The bung 110 may be moveable
within the barrel portion 106 toward the distal end of the barrel
portion 106 in order to expel the dose from the barrel portion 106
during an injection in an injection state. In an exemplary
embodiment, the bung 110 may be configured to perform both
functions of sealing the dose and squeezing the dose out of the
barrel portion 106. In another exemplary embodiment, a bung may be
provided to seal the dose within the barrel portion 106 and a
separate piston or plunger rod may be provided to impart a force to
the bung in order to squeeze the dose out of the barrel portion
106.
[0148] The syringe assembly may include, at or near its distal end,
a syringe stopper or a distal portion of the syringe 114 that may
include a syringe needle 120 and a needle cover 134 for covering
the syringe needle 120. The needle cover 134 may include a soft
needle shield, a rigid needle shield, or both. In an exemplary
embodiment, the syringe needle 120 may be aligned parallel to the
longitudinal axis L of the device 100. The syringe needle 120 may
have any suitable size, shape and configuration suitable for
piercing a septum, and is not limited to the illustrative
embodiment.
[0149] The syringe assembly may include, at or near its proximal
end, a plunger actuator 112 for selectively actuating the bung 110
forwardly within the barrel portion 106 toward the distal end in
order to inject the therapeutically effective dose contained in the
barrel portion 106 into a patient's skin. The plunger actuator 112
may employ an energy storage and controlled energy release
mechanism to actuate the bung 110. In exemplary embodiments, the
plunger actuator 112 may be located outside the barrel portion 106
or partly or fully within the barrel portion 106. In an exemplary
embodiments, the plunger actuator 112 may drive the bung 110
directly or indirectly though the use of a plunger disposed between
the bung 110 and the plunger actuator 112.
[0150] In an exemplary embodiment, the plunger actuator 112 may
include a biasing mechanism, e.g., a spring, that is retracted
before injection and that is released during injection to actuate
the bung 110 forwardly within the barrel portion 106. In another
exemplary embodiment, the plunger actuator 112 may include a
chemical gas generator, e.g., an expanding foam, that is in a
non-expanded phase before injection and that expands during
injection to actuate the bung 110 forwardly within the barrel
portion 106. In other exemplary embodiments, the plunger actuator
112 may employ hydraulic pressure of working fluids, gas pressure
of compressed gases, osmotic pressure, hydrogel expansion, and the
like.
[0151] In an exemplary embodiment, the plunger actuator 112 may be
moved forwardly within the barrel portion 106 in a substantially
linear manner, i.e., substantially constant speed. This may allow
the dose to be delivered to the patient at a substantially constant
delivery rate. The plunger actuator 112 may include or may be
coupled to a damping mechanism that may be used to absorb energy,
for example, an initial release of energy, and to provide a more
controlled release of energy during energy release by the plunger
actuator 112. The controlled release of energy may result in a
substantially linear delivery profile, i.e., a substantially
constant rate of delivery of the dose over time, and may prevent
abrupt changes in the speed of the delivery. In an exemplary
embodiment, a plunger actuator 112 may employ the hydraulic
pressure of a working fluid and a damping mechanism may employ a
flow restrictor placed in a fluid pathway between the working fluid
and the bung 110. In another exemplary embodiment, a plunger
actuator 112 may employ a biasing mechanism and a damping mechanism
may employ a viscous damper, a swiss lever escapement, a runaway
escapement, and the like. In another exemplary embodiment, a
plunger actuator 112 may employ a stepper motor connected to a gear
drive system to provide a constant linear delivery profile.
[0152] The housing 102 of the wearable automatic injection device
100 may also house an injection button 116 bearing a hollow
hypodermic injection needle 118 that is configured to pierce the
patient's skin. In an exemplary embodiment, the injection needle
118 may be aligned orthogonally to the longitudinal axis L of the
device 100. In an exemplary embodiment, the injection needle 118
may be held in place by an injection needle carrier (not pictured)
provided in the injection button 116 or separately from the
injection button 116. The injection needle 118 may have any
suitable size, shape and configuration suitable for piercing the
skin of the patient to deliver the therapeutic agent, and is not
limited to the illustrative embodiment. Suitable needles may have a
length configured or selected to provide an injection depth
suitable for the desired therapy. Subcutaneous injections typically
penetrate about six to ten millimeters into the skin. In an
exemplary embodiment, the injection needle 118 may have a length of
about twelve mm and may be injected to a depth of about seven mm
into the skin. In other exemplary embodiments, the injection needle
118 may have lengths suitable for intradermal, other subcutaneous,
or intramuscular therapies. Suitable injection needles may have a
wall thickness suitable to provide sufficient mechanism strength, a
diameter suitable to allow a desired flow rate of the injected
substance while minimizing patient sensation, and a tip geometry
suitable for the desired therapy while minimizing patient
sensation. Suitable injection needles may be coated as needed to
minimize patient sensation as allowed by therapy. The injection
needle 118 may be covered and maintained in aseptic condition,
i.e., sterile condition, by a needle cover 122, for example, a
rigid needle shield, a soft needle shield, or both.
[0153] The injection button 116 may also include a pierceable
septum disposed in the vicinity of the syringe needle 120. In a
pre-injection state, the syringe needle 120 does not pierce the
septum, thus prevent fluid communication between the barrel portion
106 and the syringe needle 120. In an injection state, when pierced
by a needle, for example, the syringe needle 120, the septum may
allow the dose to leave the barrel portion 106 and enter the
syringe needle 120. In an exemplary embodiment, one or more covers
115 may enclose the septum in a sterility barrier. The covers 115
may be pierced when the syringe needle 120 pierces the septum.
[0154] In an exemplary embodiment, the injection needle 118 and the
syringe needle 120 may be coupled to and in fluid communication
with each other via the body of the injection button 116. In
another exemplary embodiment, the injection needle 118 and the
syringe needle 120 may be coupled to and in fluid communication
with each other via one or more fluid conduits (not pictured). In
another exemplary embodiment, the injection needle 118 and the
syringe needle 120 may be directly coupled to and in fluid
communication with each other.
[0155] In an exemplary embodiment, before an injection in a
pre-injection state, the injection button 116 may be in a
vertically raised position relative to the housing 102 such that
the injection button 116 protrudes from the top of the housing 102,
as illustrated in FIGS. 1A and 1B. In this position, the injection
needle 118 may be retracted within the housing 102 and may not be
inserted into the patient's skin. In this position, the syringe
needle 120 may be aligned vertically below the septum in the
syringe stopper 114 and may not pierce the septum. At the beginning
of the injection process, the injection button 116 may be pressed
downward, for example, by a user of the device or automatically.
This may push the injection button 116 to a vertically depressed
position relative to the housing 102 closer to the patient's skin
such that the injection button 116 no longer protrudes from the top
of the housing 102, as illustrated in FIGS. 1C-1E. In this
position, the injection needle 118 may protrude from the bottom of
the housing 102 and may be inserted into the patient's skin. In
this position, the syringe needle 120 may be aligned with the
septum in the syringe stopper 114 and may pierce the septum.
[0156] In an exemplary embodiment, the septum may initially be
spaced from the injection button 116. In this embodiment, the
syringe needle 120 may pierce the septum when the syringe stopper
114 bearing the syringe needle 120 is advanced within the housing
102 toward the septum. That is, before an injection in a
pre-injection state, the syringe needle 120 may be spaced from the
septum such that there is no fluid communication between the barrel
portion 106 and the injection needle 118 coupled to the injection
button 116. In an injection state, the barrel portion 106 may
advance within the housing 102 toward the distal end of the device
100 such that that the syringe needle 120 may pierce the septum and
establish fluid communication between the barrel portion 106 and
the injection needle 118 coupled to the injection button 116. This
fluid communication may allow the dose of the therapeutic agent to
flow from the barrel portion 106 into the patient's skin through
the syringe needle 120 and the injection needle 118 when pressure
is applied to the dose by the bung 110 during an injection in an
injection state.
[0157] Referring now to FIG. 1F, in an exemplary embodiment, the
housing 102 of the wearable automatic injection device 100 may
include a skin sensor foot 132, which is a structure housed under
or in the portion of the housing 102 proximal to the injection
site. Prior to injection of the therapeutic agent and during
injection, the skin sensor foot 132 is retained within or forms a
portion of the underside of the housing 102. When the wearable
automatic injection device 100 is attached to the injection site
and activated, the skin sensor foot 132 may be free to move but may
be constrained by the injection site. When the wearable automatic
injection device 100 is removed from the injection site, regardless
of whether the drug delivery was completed, the skin sensor foot
132 is no longer constrained, and extends and projects outside the
periphery of the housing 102. This, in turn, trips a retraction
trigger. When the retraction trigger is activated, a retraction
mechanism retracts the injection needle 120 which may also raise
the injection button 116 from the vertically lowered position to
the vertically raised position, so that the injection button 116
protrudes from the top of the housing 102 and the injection needle
118 is retracted within the housing 102.
[0158] FIG. 1A illustrates the wearable automatic injection device
100 in a pre-injection state, for example, as packaged, in which
the barrel portion 106 may be pre-fillable and/or pre-filled with
the dose 108 of the therapeutic agent and in a retracted position
ready for use. The barrel portion 106 may contain the dose 108 of
the therapeutic agent in the interior space defined between the
wall or walls of the barrel portion 106 and the bung 110. In an
embodiment, the plunger actuator 112 may store energy that, when
released, may actuate the bung 110. The injection button 116 may be
partially disposed within the housing 102 at the vertically raised
position above the injection site, and the injection needle 118 may
be retracted within the housing 102. The protrusion of the
injection button 116 out of the top of the housing 102 may provide
a visual indication to the patient that the wearable automatic
injection device 100 is not in operation.
[0159] FIG. 1B illustrates the wearable automatic injection device
100 in a pre-injection state in which the needle cover 122 and the
septum cover are removed. In exemplary embodiments, the protective
film 128 may include a linking member that is connected to the
needle cover 122, the septum and syringe needle covers in the
syringe stopper 114. The linking member may include a tether or
other linkage mechanism. When the protective film 128 is removed,
the linking member of the protective film 128 may remove the needle
cover 122 and the septum and syringe needle covers in the syringe
stopper 114.
[0160] FIG. 1C illustrates the wearable automatic injection device
100 during an injection in an injection state in which the
injection button 116 is in the vertically lowered position within
the housing 102. In the vertically lowered position, the injection
button 116 may be disposed within the housing 102 at a depressed or
vertically lowered location above the injection site, and the
injection needle 118 may project from the bottom of the housing 102
through an aperture in the housing 102 so that it can penetrate the
skin at the injection site. In the vertically lowered state, the
injection button 116 may not protrude from the top of the housing
102, which may provide a visual indication to the patient that the
wearable automatic injection device 100 is in operation.
[0161] FIG. 1D illustrates the wearable automatic injection device
100 during an injection in an injection state in which the barrel
portion 106 containing the dose 108 of the therapeutic agent is
deployed forwardly from a retracted position to an extended
position within the housing of the device 100. The advancement of
the barrel portion 106 may bring the distal end of the barrel
portion 106 or the syringe stopper 114 in the vicinity of or in
contact with the injection button 116. In an exemplary embodiment,
the syringe needle 120 may pierce the septum held in the syringe
stopper 114 in order to establish fluid communication between the
barrel portion 106 and the injection needle 118.
[0162] FIG. 1E illustrates the wearable automatic injection device
100 during an injection in an injection state in which the plunger
actuator 112 is triggered to move the bung 110. Triggering of the
plunger actuator 112 may release stored energy in the plunger
actuator 112 in order to move the bung 110 within the barrel
portion 106 toward the distal end of the device 100. The movement
of the bung 110 may eject the dose of the therapeutic agent from
the barrel portion 106 through the distal end of the barrel portion
106. Any suitable mechanism may be used to trigger the plunger
actuator 112 including, but not limited to, a linking member that
is coupled to and activated by the depression of the injection
button 116 or by the removal of the needle cover 122, a trigger
button that may be used by the user, and the like.
[0163] FIG. 1F illustrates the wearable automatic injection device
100 after an injection in a post-injection state, for example,
after injecting a therapeutically effective dose of the therapeutic
agent or removal of the wearable automatic injection device 100
from the patient before delivery of a therapeutically effective
dose of the therapeutic agent, in which the injection button 116 is
in the vertically raised position. In the vertically raised
position, the injection button 116 may be disposed partly within
the housing 102 at an elevated or vertically raised location above
the injection site, and the injection needle 118 may be retracted
within the housing 102. A portion of the injection button 116 may
project from the top of the housing 102 to provide a visual
indication to the patient that the wearable automatic injection
device assembly 100 is not in operation (i.e., in a post-injection
state). The barrel portion 106 may be empty of the therapeutic
agent and the plunger actuator 112 may no longer store energy. A
skin sensor foot 132 may extend from the bottom of the housing 102
upon removal of the device 100 from the injection site.
[0164] The housing 102 may include a retraction mechanism that
automatically raises the injection button 116 from the vertically
lowered injection state (shown in FIGS. 1C-1E) to the vertically
raised post-injection state (shown in FIG. 1F). In an exemplary
embodiment, the retraction mechanism may include a biasing
mechanism, e.g., a spring, that biases the syringe assembly away
from the injection site when the retraction mechanism is
triggered.
[0165] A retraction trigger, when activated, may trigger the
retraction mechanism in order to raise the injection button 116
from the vertically lowered state to the vertically raised state.
In an exemplary embodiment, the bung 110 and/or the plunger
actuator 112 may include a linking member connected to the
retraction trigger. The linking member may include a tether or
other linkage mechanism. The linking member may be of a suitable
length such that, when the bung 110 has been moved to the end of
the barrel portion 106 (delivering a complete dose), the linking
member triggers a latch that in turn trips the retraction trigger.
In another exemplary embodiment, the extension of the skin sensor
foot 132 from the bottom of the housing 102 may trip the retraction
trigger.
[0166] In an exemplary embodiment, the retraction mechanism may
include an end-of-dose retraction trigger that, when tripped,
triggers the retraction mechanism. The end-of-dose retraction
trigger may be tripped when the therapeutically effective dose of
therapeutic agent in the wearable automatic injection device is
delivered. In an exemplary embodiment, the end-of-dose retraction
trigger may include a latch, e.g., a flexible plastic hook, that is
released upon completed drug delivery. The retraction mechanism may
also include an early-removal retraction trigger that, when
tripped, triggers the retraction mechanism. The early-removal
retraction trigger may be tripped when the wearable automatic
injection device is removed from the injection site before the
therapeutically effective dose of therapeutic agent is completely
delivered. In an exemplary embodiment, the early-removal retraction
trigger may include a latch, e.g., a flexible plastic hook, that is
released upon removal of the wearable automatic injection device
100 from the injection site. The retraction mechanism is responsive
to the end-of-dose retraction trigger and responsive to the
early-removal retraction trigger to automatically retract the
syringe assembly from the injection site.
[0167] In an exemplary embodiment, raising of the injection button
116 to the vertically raised position may cause the syringe needle
120 to bend upward, thus preventing undesirable reuse of the
syringe needle and the wearable automatic injection device.
[0168] FIGS. 2A-2F illustrate an exemplary embodiment of a wearable
automatic injection device 200 including a cartridge assembly that
may be used to inject a dose of a therapeutic agent into the body
of a patient. FIG. 2A illustrates a first end view and a first side
view of the exemplary wearable device 200 in a packaged
pre-injection state. FIG. 2B illustrates the first end view and the
first side view of the exemplary device 200 in a pre-injection
state in which a needle shield covering the injection needle is
removed in preparation for an injection. FIG. 2C illustrates the
first end view and the first side view of the exemplary device 200
during an injection in an injection state in which the patient's
skin is pierced by the injection needle. FIG. 2D illustrates the
first end view and the first side view of the exemplary device 200
during an injection in an injection state in which the barrel
portion containing the dose of the therapeutic agent is deployed
forwardly within the housing of the device 200. FIG. 2E illustrates
the first end view and the first side view of the exemplary device
200 during an injection in an injection state in which the bung is
actuated by a plunger actuator to expel the dose of the therapeutic
agent from the barrel portion. FIG. 2F illustrates the first end
view and the first side view of the exemplary device 200 after an
injection in a post-injection state in which the injection needle
is retracted within the housing of the device 200.
[0169] The wearable automatic injection device 200 may include a
housing 202. In an exemplary embodiment, the housing 202 may have
an elongated configuration, although one of ordinary skill in the
art will recognize that the housing 202 may have any suitable size,
shape and configuration for housing a barrel portion containing a
dose of a therapeutic agent to be injected. In an exemplary
embodiment, the housing 202 may be formed of any suitable material
including, but not limited to, plastic and other known
materials.
[0170] The housing 202 of the wearable automatic injection device
200 may include an adhesive layer 224 disposed along a patient
contact portion at the bottom of the housing 202 that is placed
proximal to the skin of the patient or an article of clothing of
the patient. In some exemplary embodiments, the adhesive layer 224
may be configured to be placed on the skin of the patient in order
to attach the housing 202 to the patient to deliver the dose of the
therapeutic agent. The adhesive layer 224 may include a
non-adhesive tab 226 that is not adhesive. The non-adhesive tab 226
may be gripped by the patient and pulled to remove the wearable
automatic injection device 200 from the skin or clothing of the
patient.
[0171] Before the wearable automatic injection device 200 is put to
use, e.g., in the package state illustrated in FIG. 2A, the
adhesive layer 224 may be covered by a protective film 228 which
preserves the adhesive nature of the adhesive layer 124. The
protective film 228 may include a tab 230 which may be gripped by
the patient and pulled to remove the protective film 228 from the
adhesive layer 224. This exposes the adhesive layer 224, allowing
the patient to attach the housing 202 to his or her skin or article
of clothing by placing the side with the adhesive layer 224 on the
skin or the article of clothing.
[0172] The housing 202 may house a therapeutic agent cartridge
assembly extending substantially along a longitudinal axis L
between a proximal end (farthest from the injection needle) and a
distal end (nearest to the injection needle). The cartridge
assembly may include a barrel portion 206 for holding a dose 208 of
a therapeutic agent to be injected into a patient's skin. The
barrel portion 206 may extend substantially along the longitudinal
axis between a proximal end (farthest from the injection needle)
and a distal end (nearest to the injection needle). In an exemplary
embodiment, the barrel portion 206 may be a substantially
cylindrical member having a circular cross-section, although one of
ordinary skill in the art will recognize that the barrel portion
206 may have any suitable shape or configuration.
[0173] In an exemplary embodiment, the barrel portion 206 may be
stationary within the housing 202 so that the injection process
does not result in the movement of the barrel portion 206 within
and relative to the housing 202. In another exemplary embodiment,
the barrel portion 206 may initially, i.e., before an injection in
a pre-injection state, be in a retracted position toward the
proximal end of the device 200 (as illustrated in FIGS. 2A-2C), and
may be actuated during an injection in an injection state to an
extended position toward the distal end of the device 200.
[0174] A bung 210 may be provided at the proximal end of the barrel
portion 206 to seal the dose of the therapeutic agent within the
barrel portion 206 and to apply a force to the dose to expel the
dose from the barrel portion 206. The bung 210 may be moveable
within the barrel portion 206 toward the distal end of the barrel
portion 206 in order to expel the dose from the barrel portion 206
during an injection in an injection state. In an exemplary
embodiment, the bung 210 may be configured to perform both
functions of sealing the dose and squeezing the dose out of the
barrel portion 206. In another exemplary embodiment, a bung may be
provided to seal the dose within the barrel portion 206 and a
separate piston may be provided to impart a force to the bung in
order to squeeze the dose out of the barrel portion 206.
[0175] The cartridge assembly may include, at or near its proximal
end, a plunger actuator 212 for selectively actuating the bung 210
forwardly within the barrel portion 206 toward the distal end in
order to inject the therapeutically effective dose contained in the
barrel portion 206 into a patient's skin. The plunger actuator 212
may employ an energy storage and controlled energy release
mechanism to actuate the bung 210. In exemplary embodiments, the
plunger actuator 212 may be located outside the barrel portion 206
or partly or fully within the barrel portion 206. In an exemplary
embodiment, the plunger actuator 212 may drive the bung 210
directly or indirectly though the use of a plunger disposed between
the bung 210 and the plunger actuator 212.
[0176] In an exemplary embodiment, the plunger actuator 212 may
include a biasing mechanism, e.g., a spring, that is retracted
before injection and that is released during injection to actuate
the bung 210 forwardly within the barrel portion 206. In another
exemplary embodiment, the plunger actuator 212 may include a
chemical gas generator, e.g., an expanding foam, that is in a
non-expanded phase before injection and that expands during
injection to actuate the bung 210 forwardly within the barrel
portion 206. In other exemplary embodiments, the plunger actuator
212 may employ hydraulic pressure of working fluids, gas pressure
of compressed gases, osmotic pressure, hydrogel expansion, and the
like.
[0177] In an exemplary embodiment, the plunger actuator 212 may be
moved forwardly within the barrel portion 206 in a substantially
linear manner, i.e., substantially constant speed. This may allow
the dose to be delivered to the patient at a substantially constant
delivery rate. The plunger actuator 212 may include or may be
coupled to a damping mechanism that may be used to absorb energy,
for example, an initial release of energy, and to provide a more
controlled release of energy during energy release by the plunger
actuator 212. The controlled release of energy may result in a
substantially linear delivery profile, i.e., a substantially
constant rate of delivery of the dose over time, and may prevent
abrupt changes in the speed of the delivery.
[0178] In an exemplary embodiment, a plunger actuator 212 may
employ one or more fluid circuits containing a working fluid in
which the hydraulic pressure of the working fluid applies a force
to the bung to move the bung within the barrel portion of the
cartridge. A damping mechanism may employ a flow restrictor placed
in the fluid circuit between a source of the working fluid and the
bung.
[0179] In another exemplary embodiment, a plunger actuator 212 may
employ a biasing mechanism, for example, a spiral spring or a
helical compression spring. A damping mechanism may employ a
viscous damper, a swiss lever escapement, a runaway escapement, and
the like.
[0180] In another exemplary embodiment, a plunger actuator 212 may
employ a stepper motor connected to a gear drive system to provide
a constant linear delivery profile.
[0181] The cartridge assembly may include, at or near its distal
end, a cartridge stopper 214 that may include a septum and a cover
215 for the septum. The septum may be a pierceable layer of
material that is disposed adjacent to the distal end of the barrel
portion 206 in order to seal the dose in the barrel portion 206.
When intact, the septum may seal the dose within the barrel portion
206. When pierced by a needle, for example, a syringe needle, the
septum may allow the dose to leave the barrel portion 206 and enter
the syringe needle. The septum may be formed of a material that may
be pierced by a syringe needle. A cover may be provided to
protectively cover the septum from accidental piercing by the
syringe needle when the device 200 is in the packaged pre-injection
state as illustrated in FIG. 2A. In an exemplary embodiment, the
cartridge stopper 214 may also include a cover to protectively
cover a syringe needle provided in the vicinity of the cartridge
stopper 214, thereby preventing accidental piercing of the septum
by the syringe needle when the device 200 is in the packaged
pre-injection state as illustrated in FIG. 2A.
[0182] The housing 202 of the wearable automatic injection device
200 may also house an injection button 216 bearing a hollow
hypodermic injection needle 218 that is configured to pierce the
patient's skin. In an exemplary embodiment, the injection needle
218 may be aligned orthogonally to the longitudinal axis L of the
device 200. In an exemplary embodiment, the injection needle 218
may be held in place by an injection needle carrier (not pictured)
provided in the injection button 216 or separately from the
injection button 216. The injection needle 218 may have any
suitable size, shape and configuration suitable for piercing the
skin of the patient to deliver the therapeutic agent, and is not
limited to the illustrative embodiment. Suitable needles may have a
length configured or selected to provide an injection depth
suitable for the desired therapy. Subcutaneous injections typically
penetrate about six to ten millimeters into the skin. In an
exemplary embodiment, the injection needle 218 may have a length of
about twelve mm and may be injected to a depth of about seven mm
into the skin. In other exemplary embodiments, the injection needle
218 may have lengths suitable for intradermal, other subcutaneous,
or intramuscular therapies. Suitable injection needles may have a
wall thickness suitable to provide sufficient mechanism strength, a
diameter suitable to allow a desired flow rate of the injected
substance while minimizing patient sensation, and a tip geometry
suitable for the desired therapy while minimizing patient
sensation. Suitable injection needles may be coated as needed to
minimize patient sensation as allowed by therapy. The injection
needle 218 may be covered and maintained in a septic condition by a
needle cover 222, for example, a rigid needle shield, a soft needle
shield, or both.
[0183] The injection button 216 may also bear a hollow syringe
needle 220 configured to pierce the septum and establish fluid
communication with the barrel portion 206. In an exemplary
embodiment, the syringe needle 220 may be aligned parallel to the
longitudinal axis L of the device 200. The syringe needle 220 may
have any suitable size, shape and configuration suitable for
piercing the septum and is not limited to the illustrative
embodiment.
[0184] In an exemplary embodiment, the injection needle 218 and the
syringe needle 220 may be coupled to and in fluid communication
with each other via the body of the injection button 216. In
another exemplary embodiment, the injection needle 218 and the
syringe needle 220 may be coupled to and in fluid communication
with each other via one or more fluid conduits (not pictured). In
another exemplary embodiment, the injection needle 218 and the
syringe needle 220 may be directly coupled to and in fluid
communication with each other.
[0185] In an exemplary embodiment, before an injection in a
pre-injection state, the injection button 216 may be in a
vertically raised position relative to the housing 202 such that
the injection button 216 protrudes from the top of the housing 202,
as illustrated in FIGS. 2A and 2B. In this position, the injection
needle 218 may be retracted within the housing 202 and may not be
inserted into the patient's skin. In this position, the syringe
needle 220 may be aligned vertically above the septum in the
cartridge stopper 214 and may not pierce the septum. At the
beginning of the injection process, the injection button 216 may be
pressed downward, for example, by a user of the device or
automatically. This may push the injection button 216 to a
vertically depressed position relative to the housing 202 closer to
the patient's skin such that the injection button 216 no longer
protrudes from the top of the housing 202, as illustrated in FIGS.
2C-2E. In this position, the injection needle 218 may protrude from
the bottom of the housing 202 and may be inserted into the
patient's skin. In this position, the syringe needle 220 may be
aligned with the septum in the cartridge stopper 214 and may pierce
the septum.
[0186] In an exemplary embodiment, the septum may initially be
spaced from the injection button 216. In this embodiment, the
syringe needle 220 may pierce the septum when the cartridge stopper
214 bearing the septum is advanced within the housing 202 toward
the injection button 216. That is, before an injection in a
pre-injection state, the syringe needle 220 may be spaced from the
septum such that there is no fluid communication between the barrel
portion 206 and the injection needle 218 coupled to the injection
button 216. In an injection state, the barrel portion 206 may
advance within the housing 202 toward the distal end of the device
200 so that the syringe needle 220 may pierce the septum and
establish fluid communication between the barrel portion 206 and
the injection needle 218 coupled to the injection button 216. This
fluid communication may allow the dose of the therapeutic agent to
flow from the barrel portion 206 into the patient's skin through
the syringe needle 220 and the injection needle 218 when pressure
is applied to the dose by the bung 210 during an injection in an
injection state.
[0187] Referring now to FIG. 2F, in an exemplary embodiment, the
housing 202 of the wearable automatic injection device 200 may
include a skin sensor foot 232, which is a structure housed under
or in the portion of the housing 202 proximal to the injection
site. Prior to injection of the therapeutic agent and during
injection, the skin sensor foot 232 is retained within or forms a
portion of the underside of the housing 202. When the wearable
automatic injection device 200 is attached to the injection site
and activated, the skin sensor foot 232 may be free to move but may
be constrained by the injection site. When the wearable automatic
injection device 200 is removed from the injection site, regardless
of whether the drug delivery was completed, the skin sensor foot
232 is no longer constrained, and extends and projects outside the
periphery of the housing 202. This, in turn, trips a retraction
trigger. When the retraction trigger is activated, a retraction
mechanism retracts the injection needle 220 which may also raise
the injection button 216 from the vertically lowered position to
the vertically raised position, so that the injection button 216
protrudes from the top of the housing 202 and the injection needle
218 is retracted within the housing 202.
[0188] FIG. 2A illustrates the wearable automatic injection device
200 in a pre-injection state, for example, as packaged, in which
the barrel portion 206 may be pre-fillable and/or pre-filled with
the dose 208 of the therapeutic agent and in a retracted position
ready for use. The barrel portion 206 may contain the dose 208 of
the therapeutic agent in the interior space defined between the
wall or walls of the barrel portion 206 and the bung 210. In an
embodiment, the plunger actuator 212 may store energy that, when
released, may actuate the bung 210. The injection button 216 may be
partially disposed within the housing 202 at the vertically raised
position above the injection site, and the injection needle 218 may
be retracted within the housing 202. The protrusion of the
injection button 216 out of the top of the housing 202 may provide
a visual indication to the patient that the wearable automatic
injection device 200 is not in operation.
[0189] FIG. 2B illustrates the wearable automatic injection device
200 in a pre-injection state in which the needle cover 222 and the
septum cover are removed. In exemplary embodiments, the protective
film 228 may include a linking member that is connected to the
needle cover 222 and the septum and syringe needle covers in the
cartridge stopper 214. The linking member may include a tether or
other linkage mechanism. When the protective film 228 is removed,
the linking member of the protective film 228 may remove the needle
cover 222 and the septum and syringe needle covers in the cartridge
stopper 214.
[0190] FIG. 2C illustrates the wearable automatic injection device
200 during an injection in an injection state in which the
injection button 216 is in the vertically lowered position within
the housing 202. In the vertically lowered position, the injection
button 216 may be disposed within the housing 202 at a depressed or
vertically lowered location above the injection site, and the
injection needle 218 may project from the bottom of the housing 202
through an aperture in the housing 202 so that it can penetrate the
skin at the injection site. In the vertically lowered state, the
injection button 216 may not protrude from the top of the housing
202, which may provide a visual indication to the patient that the
wearable automatic injection device 200 is in operation.
[0191] FIG. 2D illustrates the wearable automatic injection device
200 during an injection in an injection state in which the barrel
portion 206 containing the dose 208 of the therapeutic agent is
deployed forwardly from a retracted position to an extended
position within the housing of the device 200. The advancement of
the barrel portion 206 may bring the distal end of the barrel
portion 206 or the cartridge stopper 214 in the vicinity of or in
contact with the injection button 216. In an exemplary embodiment,
the syringe needle 220 may pierce the septum held in the cartridge
stopper 214 in order to establish fluid communication between the
barrel portion 206 and the injection needle 218.
[0192] FIG. 2E illustrates the wearable automatic injection device
200 during an injection in an injection state in which the plunger
actuator 212 is triggered to move the bung 210. Triggering of the
plunger actuator 212 may release stored energy in the plunger
actuator 212 in order to move the bung 210 within the barrel
portion 206 toward the distal end of the device 200. The movement
of the bung 210 may eject the dose of the therapeutic agent from
the barrel portion 206 through the distal end of the barrel portion
206. Any suitable mechanism may be used to trigger the plunger
actuator 212 including, but not limited to, a linking member that
is coupled to and activated by the depression of the injection
button 216 or by the removal of the needle cover 222, a trigger
button that may be used by the user, and the like.
[0193] FIG. 2F illustrates the wearable automatic injection device
200 after an injection in a post-injection state, for example,
after injecting a therapeutically effective dose of the therapeutic
agent or removal of the wearable automatic injection device 200
from the patient before delivery of a therapeutically effective
dose of the therapeutic agent, in which the injection button 216 is
in the vertically raised position. In the vertically raised
position, the injection button 216 may be disposed partly within
the housing 202 at an elevated or vertically raised location above
the injection site, and the injection needle 218 may be retracted
within the housing 202. A portion of the injection button 216 may
project from the top of the housing 202 to provide a visual
indication to the patient that the wearable automatic injection
device assembly 200 is not in operation (i.e., in a post-injection
state). The barrel portion 206 may be empty of the therapeutic
agent and the plunger actuator 212 may no longer store energy. A
skin sensor foot 232 may extend from the bottom of the housing 202
upon removal of the device 200 from the injection site.
[0194] The housing 202 may include a retraction mechanism that
automatically raises the injection button 216 from the vertically
lowered injection state (shown in FIGS. 2C-2E) to the vertically
raised post-injection state (shown in FIG. 2F). In an exemplary
embodiment, the retraction mechanism may include a biasing
mechanism, e.g., a spring, that biases the cartridge assembly away
from the injection site when the retraction mechanism is
triggered.
[0195] A retraction trigger, when activated, may trigger the
retraction mechanism in order to raise the injection button 216
from the vertically lowered state to the vertically raised state.
In an exemplary embodiment, the bung 210 and/or the plunger
actuator 212 may include a linking member connected to the
retraction trigger. The linking member may include a tether or
other linkage mechanism. The linking member may be of a suitable
length such that, when the bung 210 has been moved to the end of
the barrel portion 206 (delivering a complete dose), the linking
member triggers a latch that in turn trips the retraction trigger.
In another exemplary embodiment, the extension of the skin sensor
foot 232 from the bottom of the housing 202 may trip the retraction
trigger.
[0196] In an exemplary embodiment, the retraction mechanism may
include an end-of-dose retraction trigger that, when tripped,
triggers the retraction mechanism. The end-of-dose retraction
trigger may be tripped when the therapeutically effective dose of
therapeutic agent in the wearable automatic injection device is
delivered. In an exemplary embodiment, the end-of-dose retraction
trigger may include a latch, e.g., a flexible plastic hook, that is
released upon completed drug delivery. The retraction mechanism may
also include an early-removal retraction trigger that, when
tripped, triggers the retraction mechanism. The early-removal
retraction trigger may be tripped when the wearable automatic
injection device is removed from the injection site before the
therapeutically effective dose of therapeutic agent is completely
delivered. In an exemplary embodiment, the early-removal retraction
trigger may include a latch, e.g., a flexible plastic hook, that is
released upon removal of the wearable automatic injection device
200 from the injection site. The retraction mechanism is responsive
to the end-of-dose retraction trigger and responsive to the
early-removal retraction trigger to automatically retract the
cartridge assembly from the injection site.
[0197] In exemplary embodiments, the barrel portion of the wearable
automatic injection device 100 (in FIG. 1)/200 (in FIG. 2) may be
pre-fillable and/or pre-filled with any volume of a therapeutic
agent, e.g., a therapeutic antibody, desired for intradermal,
subcutaneous, or intramuscular injections. In an exemplary
embodiment, the barrel portion 106 may be pre-fillable and/or
pre-filled with a volume of between about 0.1 milliliters and about
1.0 milliliters, although exemplary devices are not limited to this
exemplary range of therapeutic agent volumes.
[0198] In exemplary embodiments, the wearable automatic injection
device 100 (in FIG. 1)/200 (in FIG. 2) may be used to inject a
therapeutically effective amount of therapeutic agent over a period
of time ranging from about ten seconds to about twelve hours.
Certain other exemplary embodiments provide actuation devices and
systems that cause actuation of the syringe plunger at a slow rate
in order to deliver the therapeutic agent to a patient at a slow
rate. Exemplary slow embodiments may deliver therapeutic agent
volumes of about 0.1 milliliters to about 1 milliliter or more in
about five minutes to about thirty minutes, although exemplary
delivery rates are not limited to this exemplary range.
[0199] Exemplary embodiments may provide a linear delivery profile
for the therapeutic agent so that the delivery rate is
substantially constant over time. In some cases, a linear delivery
profile may reduce discomfort experienced by the patient. In an
exemplary embodiment, the therapeutic agent may be delivered in a
single slow bolus.
[0200] The rate of delivery of the therapeutic agent may be
dependent on the ambient temperature. At room temperature, i.e.,
about 72.degree. F., the accuracy of the delivery time may range
between about three percent and about ten percent.
[0201] Exemplary dimensions of exemplary devices are described with
reference to Tables 1-6. However, one of ordinary skill in the art
will recognize that the exemplary dimensions are provided for
illustrative purposes, and that exemplary automatic injection
devices are not limited to the illustrative dimensions.
[0202] In an exemplary embodiment, a wearable automatic injection
device may have an exemplary length of about 4.37 inches, an
exemplary width of about 2.12 inches, and an exemplary height of
about 1.25 inches. In an exemplary embodiment, the diameter of the
barrel portion is about 1.470 inches and the length of the barrel
portion is about 2.520 inches. Tables 1-3 summarize the components
of the length, width and height, respectively, for two exemplary
types of the exemplary device.
TABLE-US-00001 TABLE 1 Summary of components of the length of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.185
0.120 Septum 0.397 0.272 Needle 0.500 0.500 Barrel portion 2.520
2.520 Advance spring 0.470 0.322 Hydraulic connection 0.113 0.113
Wall thickness 0.185 0.120 Total 4.370 3.968
TABLE-US-00002 TABLE 2 Summary of components of the width of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.185
0.120 Needle lock 1.045 0.935 Barrel portion width 0.470 0.470
Syringe lock 0.235 0.235 Wall thickness 0.185 0.120 Total 2.120
1.880
TABLE-US-00003 TABLE 3 Summary of components of the height of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.100
0.120 Needle cover 0.431 0.431 Septum 0.400 0.350 Spring solid
height 0.200 0.000 Wall thickness 0.185 0.125 Total 1.316 1.026
[0203] In an exemplary embodiment, the diameter of the barrel
portion in production may be increased from about 1.470 inches by
about 0.125 inches, and the length of the barrel portion may be
decreased in production from about 2.520 inches by about 0.732
inches. Tables 4-6 summarize the components of the length, width
and height, respectively, for two exemplary types of the exemplary
device.
TABLE-US-00004 TABLE 4 Summary of components of the length of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.185
0.120 Septum 0.397 0.272 Needle 0.500 0.250 Barrel portion 2.520
1.788 Advance spring 0.470 0.322 Hydraulic connection 0.113 0.113
Wall thickness 0.185 0.120 Total 4.370 2.986
TABLE-US-00005 TABLE 5 Summary of components of the width of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.185
0.120 Needle lock 1.045 0.935 Barrel portion width 0.470 0.595
Syringe lock 0.235 0.235 Wall thickness 0.185 0.120 Total 2.120
2.005
TABLE-US-00006 TABLE 6 Summary of components of the height of an
exemplary device (inch) Element Type 1 Type 2 Wall thickness 0.100
0.120 Needle cover 0.431 0.493 Septum 0.400 0.350 Spring solid
height 0.200 0.000 Wall thickness 0.185 0.125 Total 1.316 1.088
[0204] FIG. 3 is a flow chart of an exemplary method 300 of
assembling an exemplary automatic injection device 100. In step
302, a syringe or a cartridge assembly may be sterilized and
assembled. In step 304, an injection button may be sterilized and
assembled. In step 306, the barrel portion of the syringe or
cartridge assembly may be filled with a dose of a therapeutic agent
that is to be administered to a patient. In step 308, a sterile
bung may be placed in the barrel portion of the syringe or
cartridge assembly to seal the therapeutic agent inside the barrel
portion. The containment of the therapeutic agent inside the
wearable automatic injection device by the sterile barrel portion
and the sterile bung maintains sterility of the therapeutic agent.
As such, in an exemplary embodiment, the remaining components of
the wearable automatic injection device may be assembled in a
non-sterile environment after the barrel portion is pre-fillable
and/or pre-filled with the therapeutic agent. For example, in step
310, a non-sterile plunger actuator, for example, a biasing
mechanism may be inserted behind the bung.
[0205] In step 312, the syringe or cartridge assembly may be
inserted into a non-sterile housing. The housing may be
pre-assembled with other non-sterile components, e.g., an adhesive
layer, a protective film, a skin sensor foot, and the like. In step
314, the injection button (with an enclosed sterile fluid path and
one or more needles) may be inserted into the non-sterile housing.
In exemplary embodiments, the barrel portion, the enclosed
hypodermic injection needle, the syringe needle, the needle cover,
and the bung may provide the sterility barrier for the therapeutic
agent and the fluid path. Thus, once the barrel portion is filled
with the therapeutic agent and the bung is inserted into the barrel
portion, assembly of the remaining portions of the device does not
require aseptic conditions. No therapeutic agent transfer steps
need to be performed by the user. In step 316, the assembled
automatic injection device may be placed in an over-wrap, if
necessary, and may then be commercially packaged for sale. FIG. 1A
illustrates an exemplary embodiment of the assembled automatic
injection device in the packaged pre-injection state.
[0206] FIG. 4 is a flow chart of an exemplary method 400 of using
an exemplary automatic injection device. The wearable automatic
injection device packaged and pre-fillable and/or pre-filled with a
therapeutic agent may be generally stored in refrigerated storage
before use. In step 402, the packaged automatic injection device
may be removed from storage. In step 404, the wearable automatic
injection device may be removed from its packaging and any
over-wrap, and warmed to room temperature, e.g., by leaving the
wearable device outside the packaging at room temperature or by
warming the wearable device. In step 406, the patient may confirm
that the barrel portion contains a volume of the therapeutic agent
through an therapeutic agent inspection window disposed in the
device housing, and may also confirm the clarity of the therapeutic
agent if necessary.
[0207] In step 408, the injection site on the skin of the patient
may be selected and prepared for the delivery of the therapeutic
agent. In step 410, the patient uses the wearable automatic
injection device to inject the therapeutic agent into the injection
site. The steps generally involved within step 410 are described
below in connection with FIG. 5. In step 412, after performing the
injection, the wearable automatic injection device may be removed
from the patient and discarded in an appropriate manner.
[0208] FIG. 5 is a flow chart of an exemplary method 500 of using
an exemplary automatic injection device to inject a therapeutically
effective amount of a therapeutic agent into a patient. Exemplary
method 500 is a detailed outline of step 410 in FIG. 4. In step
502, the patient removes the protective film that covers and
protects the adhesive layer of the wearable automatic injection
device. In some exemplary embodiments, removal of the protective
film also removes the needle cover and the septum cover in the
syringe or cartridge stopper.
[0209] In step 504, the patient applies the patient contact portion
of the wearable automatic injection device with the adhesive layer
to the injection site (or an article of clothing around the
injections site) so that the device is reliably retained on the
injection site during the injection of the therapeutically
effective dose of therapeutic agent.
[0210] In step 506, once the wearable automatic injection device is
attached to the injection site, the patient may depress the
injection button from a vertically raised position in the
pre-injection state to a vertically lowered position in the
injection state within the housing. In the vertically raised
position, the end of the injection button bearing the injection
needle is retracted within the housing and is not exposed to the
outside of the housing. When depressed, the end of the injection
button bearing the injection needle is moved downward either
linearly or rotationally within the housing so that the injection
needle emerges from an aperture in the housing and is exposed. This
allows the injection needle to penetrate the skin of the patient to
an appropriate depth for injection of the therapeutic agent. The
downward movement of the injection button in the housing may be
linear (i.e., a vertical downward movement) or rotary (i.e., in a
circular movement about a pivot point).
[0211] In an exemplary embodiment, the injection button is
depressed into the housing by the patient manually pushing down the
injection button. In another exemplary embodiment, the patient may
activate an injection trigger, e.g., a trigger button located in a
conveniently accessible location such as the top of the housing,
which causes the injection trigger to automatically depress the
injection button into the housing and in turn, cause the injection
needle to pierce the skin of the patient. In an exemplary
embodiment, pressing the injection trigger button may release a
latch in the injection trigger that allows a spring to bias the
injection button downwardly in the housing. The same motion of the
injection button may cause the injection needle to be inserted into
the injection site to an appropriate depth.
[0212] In step 508, depressing the injection button may trigger a
syringe or cartridge actuator that moves the syringe or cartridge
assembly, more specifically, the barrel portion, forwardly within
and relative to the housing from a retracted position (in which the
distal end of the syringe or cartridge assembly is spaced from the
injection button) to an extended position (in which the distal end
of the syringe or cartridge assembly is adjacent to and/or in
contact with the injection button). In another exemplary
embodiment, the syringe or cartridge actuator is triggered not by
depressing the injection button, but by the user activating a
trigger, e.g., in the form of a trigger button. In an exemplary
embodiment, movement of the syringe or cartridge assembly toward
the injection button may cause the syringe needle to pierce the
septum.
[0213] In step 510, when the distal end of the barrel portion makes
contact with the injection button, the plunger actuator may break
the static friction (i.e., stiction) between the bung and the
inside wall or walls of the barrel portion and cause the bung to
move forwardly toward the syringe needle in the injection button to
deliver the therapeutic agent via the injection needle. The plunger
actuator may overcome the bung stiction in one step and actuate the
bung in a subsequent step, or the plunger actuator may overcome the
bung stiction and actuate the bung concurrently. Movement of the
bung may cause the dose to be released through the syringe needle
into the injection needle and thereby into the patient's skin.
[0214] In an exemplary embodiment, the forward advancement of the
syringe or cartridge assembly within the housing and the forward
advancement of the bung within the barrel portion may take place in
separate steps. In another exemplary embodiment, the forward
advancement of the syringe or cartridge assembly within the housing
and the forward advancement of the bung within the barrel portion
may take place in the same step, for example, simultaneously.
[0215] The rate of therapeutic agent delivery may depend on the
characteristics of the plunger actuator. The plunger actuator may
take the form of several exemplary embodiments. In some exemplary
embodiments, the plunger actuator may employ means of energy
storage and release, e.g., biasing mechanisms (including, but not
limited to, one or more springs, for example, spiral springs or
helical compression springs), compressed gases, chemical gas
generators (such as expanding foams), osmotic pressure, hydrogel
expansion, etc. A damping or control mechanism (including, but not
limited to, a viscous damper or an escapement) may be used to
absorb energy, for example, an initial release of energy, and to
provide a more controlled release of energy during energy release
by the plunger actuator. A flow restrictor placed in a fluid
pathway between the needle and the bung may be used to further
regulate the rate of therapeutic agent delivery, e.g., where the
plunger actuator delivers an unconstrained spring force via a
working fluid. Thus, an appropriate plunger actuator and an
appropriate control mechanism may be selected to deliver the dose
at a controlled rate, e.g., in a single slow bolus free of or
substantially free of any burning sensation to the patient.
[0216] In an exemplary embodiment, depressing the injection button
may arm the retraction mechanism which, when triggered, retracts
the injection button into the housing 102 after an injection in a
post-injection state.
[0217] In step 512, upon delivery of the therapeutically effective
dose, the bung and/or the plunger actuator may trip the end-of-dose
retraction trigger of the retraction mechanism. The bung and/or the
plunger actuator may include a linking member connected to the
end-of-dose retraction trigger. The linking member may include a
tether or other linkage mechanism. The linking member may be of a
suitable length such that, when the bung has been moved to the end
of the syringe or cartridge assembly (delivering a complete dose),
the linking member triggers a latch that in turn trips the
retraction trigger.
[0218] In step 514, once the end-of-dose retraction trigger is
tripped, the retraction mechanism may retract the injection button
upward inside the housing and away from the patient contact portion
so that the syringe or cartridge assembly enters a post-injection
state. In an exemplary embodiment, the movement of the injection
button from the injection state to the post-injection state creates
an audible sound, e.g., a "click," which provides an aural
indication of the completion of therapeutic agent delivery. Once
retracted, the injection button protrudes outside the housing,
which provides a visual indication of the state of the wearable
automatic injection device, for example, completion of therapeutic
agent delivery or a visual indication of the device in the
post-injection state.
[0219] However, if the wearable device is removed from the skin of
the patient before the completion of therapeutically effective dose
of the therapeutic agent, the skin sensor foot may extend to the
outside of the housing and trip the early-removal retraction
trigger of the retraction mechanism. Once the early-removal
retraction trigger is tripped, the retraction mechanism deploys the
injection button upward in the housing away from the patient
contact portion so that the syringe or cartridge assembly enters a
post-injection state. In an exemplary embodiment, the plunger
actuator may continue to move forwardly in the barrel portion
toward the syringe needle when the device is removed from the
patient before completion of delivery of a therapeutically
effective dose of the therapeutic agent.
[0220] In step 516, upon retraction, a needle lock engages with the
injection needle to prevent redeployment of the injection needle to
provide needle-stick protection. The needle lock may be a member
that prevents the injection needle from exiting the housing once
engaged, and may be located in the housing near the injection
needle. Exemplary needle locks may include, but are not limited to,
a plastic plate, a metal plate, a clip, etc.
[0221] FIGS. 6A-6C illustrate an exemplary embodiment of a wearable
automatic injection device 600 suitable for linear insertion of a
needle into the skin of a patient. By linear insertion, the end of
a cartridge assembly bearing a needle descends linearly within a
housing of the wearable automatic injection device so that the
needle is inserted into the patient. More specifically, FIG. 6A
illustrates the exemplary wearable device in a Pre-Injection State,
for example, as packaged; FIG. 6B illustrates the exemplary
wearable device in an Injection State just before, while or just
after it injects a therapeutic agent into a patient; and FIG. 6C
illustrates the exemplary wearable device in a Post Injection State
after it has completed delivery of the therapeutic agent into the
patient or removed from the patient prior to completion of delivery
of the therapeutic agent.
[0222] The wearable automatic injection device 600 includes a
housing 635 for housing a therapeutic agent cartridge assembly 610,
containing a dose of a therapeutic agent to be injected
subcutaneously into a patient. In an exemplary embodiment, the
outside of the therapeutic agent cartridge assembly 610 may be
provided with one or more ridges, and the inside of the housing 635
may be provided with one or more grooves or channels that provide a
smooth pathway for the ridges of the cartridge assembly 610 as the
cartridge assembly moves within the housing 635. The one or more
ridges on the outside of the cartridge assembly 610 may take the
form of raised lines on the cartridge assembly 610. The one or more
grooves or channels on the inside of the housing 635 may take the
formed of U-shaped depressed or trough-like lines. The top portion
of the grooves or channels may be open so that the ridges may slide
in and out of the top portion of the grooves or channels. In the
linear insertion embodiment illustrated in FIGS. 6A-6C, the ridges
and grooves/channels may be straight lines. In the rotary insertion
embodiment illustrated in FIGS. 7A-7C, the ridges and
grooves/channels may be lines that are curved about the center of
rotation, i.e., the pivot point of the cartridge assembly 610.
[0223] In another exemplary embodiment, the outside of the
cartridge assembly 610 may not have any ridges, and the inside of
the housing 635 may not have any grooves or channels.
[0224] The housing 635 preferably has an elongated configuration,
though one of ordinary skill in the art will recognize that the
housing 635 may have any suitable size, shape and configuration for
housing a hypodermic needle couplable to a barrel portion of a
therapeutic agent to be injected. The housing 635 may be formed of
any suitable material including, but not limited to, plastic and
other known materials. In another embodiment, the therapeutic agent
cartridge 610 may be formed of any compatible material suitable for
sterilization including, but not limited to, glass and other known
materials.
[0225] The housing 635 includes an adhesive layer 640 disposed
along a patient contact portion of the housing 635 that is placed
proximal to the skin of the patient or an article of clothing of
the patient. In some embodiments, the adhesive layer 640 is
configured to be placed on the skin of the patient to attach the
housing 635 to the patient to deliver a therapeutic agent. The
adhesive layer 640 includes a non-adhesive tab 645 which is not
adhesive. The non-adhesive tab 645 may be gripped by the patient
and pulled to remove the adhesive layer 640 and thus the wearable
automatic injection device 600 from the skin or clothing of the
patient.
[0226] Before the wearable automatic injection device 600 is put to
use, e.g., in the Pre-Injection state, the adhesive layer 640 is
covered by a protective film 650 which preserves the adhesive
nature of the adhesive layer 640. The protective film 650 may
include a tab 655 which may be gripped by the patient and pulled to
remove the protective film 650 from the adhesive layer 640. This
exposes the adhesive layer 640, allowing the patient to attach the
housing 635 to his or her skin or article of clothing by placing
the side with the adhesive layer 640 on the skin or the article of
clothing.
[0227] In exemplary embodiments, the protective film 650 (in FIG.
6A)/750 (in FIG. 7A) may include a linking member that is connected
to the plunger actuator 630 (in FIG. 6A)/730 (in FIG. 7A). The
linking member may include a tether or other linkage mechanism.
When the protective film 650 (in FIG. 6A)/750 (in FIG. 7A) is
removed, the linking member of the protective film 650 (in FIG.
6A)/750 (in FIG. 7A) relieves static friction between the bung 615
(in FIG. 6A)/715 (in FIG. 7A) and the interior wall of the barrel
605 (in FIG. 6A)/705 (in FIG. 7A), and triggers the plunger
actuator 630 (in FIG. 6A)/730 (in FIG. 7A).
[0228] The therapeutic agent cartridge assembly 610 may include a
hollow barrel portion 605 for holding a therapeutically effective
dose of the therapeutic agent to be injected. The illustrative
barrel portion 605 is substantially cylindrical in shape, although
one of ordinary skill in the art will recognize that the barrel
portion 605 may have any suitable shape or configuration. A bung
615 seals the dose of the therapeutic agent within the barrel
portion 605.
[0229] The therapeutic agent cartridge assembly 610 may also
include a hollow hypodermic needle 625 connectable to or connected
to, and in fluid communication with, the barrel portion 605,
through which the dose can be ejected by applying pressure to the
bung 615. The needle 625 may have any suitable size, shape and
configuration suitable for piercing the skin of the patient to
deliver the therapeutic agent subcutaneously, and is not limited to
the illustrative embodiment. Suitable needles may have a length
configured or selected to provide an injection depth suitable for
the desired therapy. Subcutaneous injections typically penetrate
about six to ten millimeters into the skin. In an exemplary
embodiment, needle 625 may have a length of about twelve mm and may
be injected to a depth of about seven mm into the skin. In other
exemplary embodiments, needle 625 may have lengths suitable for
intradermal, other subcutaneous, or intramuscular therapies.
Suitable needles may have a wall thickness suitable to provide
sufficient mechanism strength, a diameter suitable to allow a
desired flow rate of the injected substance while minimizing
patient sensation, and a tip geometry suitable for the desired
therapy while minimizing patient sensation. Suitable needles may be
coated as needed to minimize patient sensation as allowed by
therapy. Needle 625 may be covered and maintained in a septic
condition by a soft and rigid needle shield assembly 620.
[0230] In the exemplary embodiment illustrated in FIGS. 6A-6C, the
needle 625 projects substantially at a right angle to the
longitudinal axis of the wearable device 600. In this exemplary
embodiment, the barrel portion 605 includes an elbow 607 that
extends substantially at a right angle to the longitudinal axis of
the device 600. In this embodiment, the needle 625 is connected to
the elbow 607.
[0231] The wearable automatic injection device 600 may include a
plunger actuator 630 for selectively actuating the bung 615
forwardly toward the distal end of the therapeutic agent cartridge
assembly 610 to inject the therapeutically effective dose contained
in the barrel portion 605 into the patient. The plunger actuator
630 may employ an energy storage and controlled energy release
mechanism to actuate the bung 615. In an exemplary embodiment, the
plunger actuator 630 may include a biasing mechanism, e.g., a
spring, that is retracted before injection and that is released
during injection to actuate the bung 615 forwardly in the barrel
portion 605. In another exemplary embodiment, the plunger actuator
630 may include a chemical gas generator, e.g., an expanding foam,
that is in a non-expanded phase before injection and that expands
during injection to actuate the bung 615 forwardly in the barrel
portion 605 toward the distal end of the therapeutic agent
cartridge assembly 610. In other exemplary embodiments, the plunger
actuator 630 may employ compressed gases, osmotic pressure,
hydrogel expansion, etc. A damping mechanism may be used to absorb
energy, for example, an initial release of energy, and to provide a
controlled release of energy during energy release by the plunger
actuator 630 (in FIG. 6A)/730 (in FIG. 7A). A flow restrictor
placed in a fluid pathway between the needle and the bung 615 (in
FIG. 6A)/715 (in FIG. 7A) may be used to further regulate the rate
of therapeutic agent delivery, e.g., where the plunger actuator 630
(in FIG. 6A)/730 (in FIG. 7A) delivers an unconstrained spring
force.
[0232] In an exemplary embodiment, the plunger actuator 630 may be
advanced forwardly inside the barrel portion 605 in a constant
linear motion. Any number of mechanisms, internal or external to
the wearable automatic injection device 600, may be used to provide
a constant linear motion including, but not limited to, a stepper
motor connected to a gear drive system. Other exemplary mechanisms
for providing a substantially constant linear motion in a
controlled fashion are described with reference to FIGS. 24-45.
[0233] The bung 615 (in FIG. 6A)/715 (in FIG. 7A) and/or the
plunger actuator 630 (in FIG. 6A)/730 (in FIG. 7A) may include a
linking member connected to the retraction trigger. The linking
member may include a tether or other linkage mechanism. The linking
member may be of a suitable length such that, when the bung 615 (in
FIG. 6A)/715 (in FIG. 7A) has been moved to the end of the
cartridge assembly 610 (in FIG. 6A)/710 (in FIG. 7A) (delivering a
complete dose), the linking member triggers a latch that in turn
trips the retraction trigger.
[0234] Referring now to FIG. 6C, in an exemplary embodiment, the
housing 635 includes a skin sensor foot 660, which is a structure
housed under or in the portion of the housing 635 proximal to the
injection site. Prior to injection of the therapeutic agent and
during injection, the skin sensor foot 660 is retained within or
forms a portion of the underside of the housing 635. When the
wearable automatic injection device 600 is attached to the
injection site and activated, the skin sensor foot 660 may be free
to move but may be constrained by the injection site. When the
wearable automatic injection device 600 is removed from the
injection site, regardless of whether the drug delivery was
completed, the skin sensor foot 660 is no longer constrained, and
extends and projects outside the periphery of the housing 635.
This, in turn, trips the removal retraction trigger.
[0235] FIG. 6A illustrates the wearable automatic injection device
600 in a Pre-Injection State, for example, as packaged and ready
for use or as ready for packaging. The device 600 may include a
pre-fillable and/or pre-filled syringe or cartridge assembly. In an
exemplary embodiment, in a pre-injection state, the syringe or
cartridge assembly may be in a retracted position ready for use. In
the Pre-Injection State, the therapeutic agent cartridge assembly
610 is partially disposed within the housing 635 at an elevated
location distal from the injection site, and the needle 625 is
retracted within the housing 635. Visual indications to the patient
that the wearable automatic injection device 600 is not in
operation may include a portion of the therapeutic agent cartridge
assembly 610 projecting outside the housing 635 in the
pre-injection state. The barrel portion 605 contains a dose of a
therapeutic agent which is contained by the interior space defined
between the wall or walls of the barrel portion 605 and the bung
615. In an embodiment, the plunger actuator 630 stores energy.
[0236] FIG. 6B illustrates the wearable automatic injection device
600 in an Injection State ready to inject, injecting or just after
injecting a therapeutically effective dose of a therapeutic agent,
in which the therapeutic agent cartridge assembly 610 is in a
depressed position. In the depressed position, the therapeutic
agent cartridge assembly 610 is disposed within the housing 635 at
a depressed location proximal to the injection site, and the needle
625 projects outside the housing 635 through an aperture in the
housing 635 so that it can penetrate the skin at the injection
site. In the Injection State, the therapeutic agent cartridge
assembly 610 does not project outside the housing 635 to provide a
visual indication to the patient that the wearable automatic
injection device 600 is in operation. The plunger actuator 630
releases its stored energy to actuate the bung 615. This
cooperative movement of the plunger actuator 630 and the bung 615
ejects the therapeutic agent in the barrel portion 605 out through
the needle 625.
[0237] FIG. 6C illustrates the wearable automatic injection device
600 in a Post Injection State, for example, after injecting a
therapeutically effective dose of the therapeutic agent or removal
of the wearable automatic injection device 600 from the patient
before delivery of a therapeutically effective dose of the
therapeutic agent, in which the therapeutic agent cartridge
assembly 610 is in a retracted position. In the retracted position,
the therapeutic agent cartridge assembly 610 is disposed within the
housing 635 at an elevated location distal from the injection site,
and the needle 625 is retracted within the housing 635. A portion
of the therapeutic agent cartridge assembly 610 projects outside
the housing 635 to provide a visual indication to the patient that
the wearable automatic injection device assembly 600 is not in
operation (i.e., in a Post-Injection state). The barrel portion 605
may be empty of the therapeutic agent, and the plunger actuator 630
may no longer store energy.
[0238] The housing 635 includes a retraction mechanism that
automatically raises the therapeutic agent cartridge assembly 610
from the Injection State (depressed position shown in FIG. 6B) to
the Post-Injection state (retracted position shown in FIG. 6C). In
an exemplary embodiment, the retraction mechanism may include a
biasing mechanism, e.g., a spring, that biases the cartridge
assembly away from the injection site when the retraction mechanism
is triggered.
[0239] The retraction mechanism includes an end-of-dose retraction
trigger that, when tripped, triggers the retraction mechanism. The
end-of-dose retraction trigger is tripped when the therapeutically
effective dose of therapeutic agent in the wearable automatic
injection device is delivered. In an exemplary embodiment, the
end-of-dose retraction trigger may include a latch, e.g., a
flexible plastic hook, that is released upon completed drug
delivery. The retraction mechanism also includes an early-removal
retraction trigger that, when tripped, triggers the retraction
mechanism. The early-removal retraction trigger is tripped when the
wearable automatic injection device is removed from the injection
site before the therapeutically effective dose of therapeutic agent
is completely delivered. In an exemplary embodiment, the
early-removal retraction trigger may include a latch, e.g., a
flexible plastic hook, that is released upon removal of the
wearable automatic injection device 600 from the injection site.
The retraction mechanism is responsive to the end-of-dose
retraction trigger and responsive to the early-removal retraction
trigger to automatically retract the cartridge assembly from the
injection site.
[0240] FIGS. 7A-7C illustrate an exemplary embodiment of a wearable
automatic injection device 700 suitable for rotary insertion of the
needle into the skin of a patient. In rotary insertion, the end of
a therapeutic agent cartridge assembly 710 bearing the needle 725
descends in a rotary fashion about a pivot point to insert the
needle 725 into the skin of the patient. More specifically, FIG. 7A
illustrates the exemplary wearable device in a Pre-Injection State,
for example, as packaged with a pre-filled and curved sterile
hypodermic needle and barrel portion holding a therapeutic agent;
FIG. 7B illustrates the exemplary wearable device while in an
Injection State just before, while or just after injecting a
therapeutic agent into a patient; and FIG. 7C illustrates the
exemplary wearable device in a Post Injection State after delivery
of the therapeutic agent into the patient or removal of the
wearable device from the patient prior to completing delivery of
the therapeutic agent to the patient.
[0241] The therapeutic agent cartridge assembly 710 is rotatably
movable within the housing 735 about a pivot point 765 in the
housing. In an exemplary embodiment, the outside of the therapeutic
agent cartridge assembly 710 may be provided with one or more
ridges, and the inside of the housing 735 may be provided with one
or more grooves or channels that provide a pathway for the ridges
of the cartridge 710 as the cartridge moves within the housing 735
amongst the various states. In another exemplary embodiment, the
outside of the cartridge assembly 710 is free of ridges, and the
inside of the housing 735 is free of grooves or channels.
[0242] When the therapeutic agent cartridge assembly 710 is
depressed into the housing 735, the therapeutic agent cartridge
assembly 710 moves rotatably downward about the pivot point 765
such that the needle 725 becomes exposed and penetrates the skin of
the patient. In this exemplary embodiment, the needle 725
penetrates the skin of the patient at an angle offset from
90.degree.. Similarly, when the therapeutic agent cartridge
assembly 710 is retracted, the therapeutic agent cartridge assembly
710 moves rotatably upward about the pivot point 765 such that the
needle 725 retracts within the housing 735. The mechanism to
implement this rotational motion of the therapeutic agent cartridge
assembly 710 may be simpler and more robust than the mechanism
required for the linear insertion of FIGS. 6A-6C.
[0243] The needle 725 is curved, with a radius defined by the pivot
point 765 and the distance from the needle 715 to the pivot point
765 along the longitudinal axis of the housing 735. The curvature
of the needle 725 increases the comfort of the patient during
insertion of the needle. The needle 725 may be preferentially
oriented with the sharp needle tip closest to the pivot point
765.
[0244] Features in FIGS. 7A-7C similar to those illustrated in
FIGS. 6A-6C are described above in connection with FIGS. 6A-6C.
[0245] In exemplary embodiments, the therapeutic agent cartridge
assembly 610 and 720 of FIGS. 6A-6C and 7A-7C, respectively, may be
pre-fillable and/or pre-filled with any volume of a therapeutic
agent, e.g., a therapeutic antibody, desired for intradermal,
subcutaneous, or intramuscular injections. In an exemplary
embodiment, the cartridge assembly 610 and 720 may be pre-fillable
and/or pre-filled with a volume of about 0.8-0.85 milliliters,
although exemplary cartridge assemblies are not limited to these
exemplary volumes. In another exemplary embodiment, the cartridge
assembly 610 and 720 may be pre-fillable and/or pre-filled with a
volume of about 1 milliliter or more.
[0246] In exemplary embodiments, the wearable automatic injection
device 600 (in FIG. 6A)/700 (in FIG. 7A) may be used to inject the
therapeutically effective amount of therapeutic agent over a period
of time ranging from about ten seconds to about twelve hours. In an
exemplary embodiment, the therapeutic agent may be delivered at a
fixed rate for a delivery time of between about five minutes and
about thirty minutes. The wearable automatic injection device 600
(in FIG. 6A)/700 (in FIG. 7A) may be used to inject a volume of
therapeutic agent in a single slow bolus.
[0247] The rate of delivery of the therapeutic agent may be
dependent on the ambient temperature. At room temperature, i.e.,
about 72.degree. F., the accuracy of the delivery time may range
between about three percent and about ten percent.
[0248] FIG. 8 is a flow chart of an exemplary method 800 of
assembling an exemplary wearable automatic injection device 600 or
700. In step 805, the barrel portion 605/705, needle 625/725 and
needle shield 620/720 are sterilized. In step 810, the barrel
portion 605/705 is filled with a dose of the therapeutic agent that
is to be administered to the patient. In step 815, a sterile bung
615/715 is placed in the barrel portion 605/705 to seal the
therapeutic agent inside the barrel portion 605/705. The
containment of the therapeutic agent inside the wearable automatic
injection device 600 or 700 by the sterile barrel portion 605/705,
the sterile bung 615/715 and the needle shroud 620/720 maintains
sterility of the therapeutic agent and the needle 625/725. As such,
the remaining components of the wearable automatic injection device
may be assembled in a non-sterile environment after the barrel
portion 605/705 is pre-filled with a therapeutic agent. For
example, in step 820, a non-sterile plunger actuator 630/730 is
inserted behind the bung 615/715 in the therapeutic agent cartridge
assembly 610/710.
[0249] In step 825, the therapeutic agent cartridge assembly
610/710 is inserted into a non-sterile housing 635/735. The housing
635/735 may be pre-assembled with other non-sterile components,
e.g., the adhesive layer 640/740, the protective film 650/750, the
skin sensor foot 660/760. In exemplary embodiments, the barrel
portion 605/705, the needle 625/725, the needle shield 620/720 and
the bung 615/715 of the therapeutic agent cartridge assembly
610/710 provide the sterility barrier for the therapeutic agent and
the subcutaneous contact surfaces. Thus, once the barrel portion
605/705 is filled with the therapeutic agent, the plunger 615/715
is inserted into the barrel portion 605/705 and the needle shroud
620/720 is in place: assembly of the remaining portions of the
therapeutic agent cartridge assembly 610/710 and assembly of the
housing 635/735 do not require aseptic conditions. No therapeutic
agent transfer steps need to be performed by the user. FIGS. 6A and
7A illustrate exemplary embodiments of the wearable assembled
automatic injection device 600/700 in a Pre-Injection state.
[0250] In step 830, the assembled wearable automatic injection
device 600/700 may be placed in an over-wrap, if necessary, and is
then commercially packaged for sale.
[0251] FIG. 9 is a flow chart of an exemplary method 900 of using
an exemplary wearable automatic injection device 600 or 700. The
wearable automatic injection device 600/700 packaged and pre-filled
with a therapeutic agent is generally stored in refrigerated
storage before use. In step 905, the packaged wearable automatic
injection device 600/700 is removed from storage. In step 910, the
wearable automatic injection device 600/700 is removed from its
packaging and any over-wrap and warmed to room temperature, e.g.,
by leaving the wearable device outside the packaging at room
temperature or by warming the wearable device. In step 915, the
patient confirms the therapeutic agent cartridge assembly 610/710
includes a volume of the therapeutic agent in the wearable device
600/700 through an therapeutic agent inspection window disposed in
the wearable device housing and may also confirm the clarity of the
therapeutic agent, if necessary. In step 920, the injection site on
the skin of the patient is selected and prepared for the delivery
of the therapeutic agent. In step 925, the patient uses the
wearable automatic injection device 600/700 to inject the
therapeutic agent into the injection site. The steps generally
involved within step 920 are described below in connection with
FIG. 10. In step 930, after the wearable automatic injection device
600/700 is removed from the patient, the removed wearable automatic
injection device 600/700 is discarded in an appropriate manner
[0252] FIG. 10 is a flow chart of an exemplary method 1000 of using
an exemplary wearable automatic injection device 600 or 700 to
inject a therapeutically effective amount of a therapeutic agent
into a patient. Exemplary method 1000 is a detailed outline of step
920 in FIG. 9. In step 1005, the patient removes the protective
film 650/750 that covers and protects the adhesive layer 640/740 of
the wearable automatic injection device 600/700. In some exemplary
embodiments, removal of the protective film 650/750 also removes
the needle shield 620/720 and exposes the needle 625/725 for
injection. In some exemplary embodiments, removal of the protective
film 650/750 also breaks static friction (i.e., stiction) between
the bung 615/715 and the interior wall of the barrel 605/705 and
triggers the plunger actuator 630/730. In exemplary embodiments,
the protective film 650/750 may include a linking member that is
connected to the plunger actuator 630/730. The linking member may
include a tether or other linkage mechanism. When the protective
film 650/750 is removed, the linking member of the protective film
650/750 relieves static friction between the bung 615/715 and the
interior wall of the barrel 605/705, and triggers the plunger
actuator 630/730.
[0253] In step 1010, the patient applies the patient contact
portion of the wearable automatic injection device 600/700 with the
adhesive layer 640/740 to the injection site (or an article of
clothing around the injections site) so that the wearable device is
reliably retained on the injection site during the injection of the
therapeutically effective dose of therapeutic agent.
[0254] In step 1015, once the wearable automatic injection device
600/700 is attached to the injection site, the therapeutic agent
cartridge assembly 610/710 is depressed from a ready position in
the Pre-Injection State to a depressed position in the Injection
State within the housing 635/735. In the ready position, the end of
the therapeutic agent cartridge assembly 610/710 bearing the needle
625/725 is retracted within the housing 635/735 and is not exposed
to the outside of the housing. When depressed, the end of the
therapeutic agent cartridge assembly 610/710 bearing the needle
625/725 is moved downward either linearly or rotationally within
the housing 635/735 so that the needle 625/725 emerges from an
aperture in the housing 635/735 and is exposed. This allows the
needle 625/725 to penetrate the skin of the patient to an
appropriate depth for injection of the therapeutic agent. The
downward movement of the therapeutic agent cartridge assembly
610/710 in the housing 635/735 may be linear (i.e., a vertical
downward movement) or rotary (i.e., in a circular movement about a
pivot point). FIGS. 6B and 7B illustrate exemplary embodiments of
the wearable automatic injection device 600 and 700 in an Injection
state with the therapeutic agent cartridge 610/710 depressed into
the housing 635/735 after step 1015 is performed.
[0255] In an exemplary embodiment, the therapeutic agent cartridge
assembly 610/710 is depressed into the housing 635/735 by the
patient manually pushing down the therapeutic agent cartridge
assembly 610/710. In another exemplary embodiment, the patient may
activate an insertion trigger, e.g., an insertion trigger button
located in a conveniently accessible location such as the top of
the housing 635/735, which causes an insertion trigger to
automatically depress the therapeutic agent cartridge assembly
610/710 into the housing 635/735 and in turn, cause the needle
625/725 to pierce the skin of the patient. In an exemplary
embodiment, pressing the insertion trigger button may release a
latch in the insertion trigger that allows a spring to bias the
cartridge assembly 610/710 downwardly in the housing 635/735. The
same motion of the cartridge assembly 610/710 may cause the needle
625/725 to be inserted into the injection site to an appropriate
depth.
[0256] In an exemplary embodiment, depressing the therapeutic agent
cartridge assembly 610/710 triggers the plunger actuator 630/730 to
begin movement of the bung 615/715 to cooperatively inject the
therapeutically effective dose into the patient. Depression of the
therapeutic agent cartridge assembly 610/710 causes the plunger
actuator 630/730 to break the static friction (i.e., stiction)
between the bung 615/715 and the inside wall or walls of the barrel
portion 605/705 and cause the bung 615/715 to move forwardly toward
the needle 625/725 in the therapeutic agent cartridge assembly
610/710 to deliver the therapeutic agent via the needle 625/725.
The plunger actuator 630/730 may overcome the bung stiction in one
step and actuate the bung in a subsequent step, or the plunger
actuator 630/730 may overcome the bung stiction and actuate the
bung concurrently. In another exemplary embodiment, the plunger
actuator 630/730 is triggered not by depressing the therapeutic
agent cartridge, but by the user activating an injection trigger,
e.g., in the form of an injection trigger button.
[0257] The rate of therapeutic agent delivery may depend on the
characteristics of the plunger actuator 630/730. The plunger
actuator 630/730 may take the form of several exemplary
embodiments. In some exemplary embodiments, the plunger actuator
630/730 may employ means of energy storage and release, e.g.,
biasing mechanisms (such as springs), compressed gases, chemical
gas generators (such as expanding foams), osmotic pressure,
hydrogel expansion, etc. A damping mechanism may be used to absorb
energy, for example, an initial release of energy, and to provide a
more controlled release of energy during energy release by the
plunger actuator 630/730. A flow restrictor placed in a fluid
pathway between the needle and the bung 615/715 may be used to
further regulate the rate of therapeutic agent delivery, e.g.,
where the plunger actuator 630/730 delivers an unconstrained spring
force. Thus, an appropriate plunger actuator 630/730 and an
appropriate flow restrictor may be selected to deliver the dose at
a controlled rate, e.g., in a single slow bolus free of or
substantially free of any burning sensation to the patient.
[0258] In an exemplary embodiment, depressing the therapeutic agent
cartridge assembly 610/710 also arms the retraction mechanism
which, when triggered, retracts the therapeutic agent cartridge
assembly 610/710 into the housing 635/735.
[0259] In step 1020, the therapeutic agent cartridge assembly
610/710 is retracted from the depressed position to a retracted
position in a Post-Injection State so that it protrudes outside the
housing 635/735 and the needle 625/725 is retracted within the
housing 635/735 or protected by the skin sensor foot 660/760 or
both. FIGS. 6C and 7C illustrate exemplary embodiments of automatic
injection device 600 and 700, respectively, in a retracted position
after step 1020. Step 1020 is performed either when the
therapeutically effective dose of therapeutic agent is delivered or
when the wearable automatic injection device 600/700 is removed
from the injection site before the therapeutically effective dose
is completely delivered.
[0260] Upon delivery of the therapeutically effective dose, the
bung 615/715 and/or the plunger actuator 630/730 trips the
end-of-dose retraction trigger of the retraction mechanism. The
bung 615/715 and/or the plunger actuator 630/730 may include a
linking member connected to the retraction trigger. The linking
member may include a tether or other linkage mechanism. The linking
member may be of a suitable length such that, when the bung 615/715
has been moved to the end of the cartridge assembly 610/710
(delivering a complete dose), the linking member triggers a latch
that in turn trips the retraction trigger.
[0261] Once the end-of-dose retraction trigger is tripped, the
retraction mechanism deploys the therapeutic agent cartridge
assembly 610/710 upward inside the housing 635/735 and away from
the patient contact portion so that the therapeutic agent cartridge
assembly 610/710 enters a Post-Injection State. In an exemplary
embodiment, the movement of the therapeutic agent cartridge
assembly 610/710 from the injection state to the post-injection
state creates an audible sound, e.g., a "click," which provides an
aural indication of the completion of therapeutic agent delivery.
Once retracted, the therapeutic agent cartridge assembly 610/710
protrudes outside the housing 635/735 (as shown in FIGS. 6C and
7C), which provides a visual indication of the state of the
wearable automatic injection device 600/700, for example,
completion of therapeutic agent delivery or a visual indication of
the device in the Post-Injection State.
[0262] However, if the wearable device 600/700 is removed from the
skin of the patient before the completion of therapeutically
effective dose of the therapeutic agent, the skin sensor foot
660/760 extends to the outside of the housing 635/735 and trips the
early-removal retraction trigger of the retraction mechanism. Once
the early-removal retraction trigger is tripped, the retraction
mechanism deploys the therapeutic agent cartridge assembly 610/710
upward in the housing 635/735 away from the patient contact portion
so that the therapeutic agent cartridge assembly 610/710 is
returned to a retracted position. In an exemplary embodiment, the
plunger actuator 630/730 may continue to move forwardly in the
therapeutic agent cartridge 610/720 toward the needle 625/725 when
the wearable device 600/700 is removed from the patient before
completion of delivery of a therapeutically effective dose of the
therapeutic agent.
[0263] In step 1025, upon retraction, an automatic needle lock
engages with the injection needle 625/725 to prevent redeployment
of the needle 625/725 to provide needle-stick protection. The
needle lock may be a member that prevents the needle 625/725 from
exiting the housing 635/735 once engaged, and may be located in the
housing 635/735 near the needle 625/725. Exemplary needle locks may
include, but are not limited to, a plastic plate, a metal plate, a
clip, etc.
III. Exemplary Needle Systems
[0264] Exemplary embodiments provide different exemplary needle
assemblies for injecting a dose of a therapeutic agent into a
patient's skin. In some exemplary embodiments, an injection needle,
coupled to a barrel portion of an exemplary automatic injection
device containing the dose, may be inserted into the patient's skin
to inject the dose into the patient's skin. In other exemplary
embodiments, a syringe needle may be coupled to a barrel portion
containing the dose to conduct the dose out of the barrel portion,
and an injection needle coupled to the syringe needle may be
inserted into the patient's skin to inject the dose into the
patient's skin.
[0265] In some exemplary embodiments, as illustrated in FIGS. 11
and 12, a syringe may include a barrel portion and an injection
needle coupled to a distal end of the barrel portion. The injection
needle may be inserted into the patient's skin to deliver a
therapeutic agent contained in the barrel portion of the syringe.
The injection needle may be aligned at any suitable angle relative
to the longitudinal axis of the barrel portion ranging from about 0
degrees to about 180 degrees.
[0266] FIG. 11 illustrates an exemplary syringe 1100 suitable for
use in an exemplary automatic injection device. The syringe 1100
includes a barrel portion 1102 configured to hold a dose of a
therapeutic agent and extending between a proximal end and a distal
end along a longitudinal axis L. A distal end of the barrel portion
1102 is coupled to an injection needle 1104 that extends along the
longitudinal axis L.
[0267] FIG. 12 illustrates an exemplary syringe 1200 suitable for
use in an exemplary automatic injection device. The syringe 1200
includes a barrel portion 1202 configured to hold a dose of a
therapeutic agent and extending between a proximal end and a distal
end along a longitudinal axis L. A distal end of the barrel portion
1202 may include an elbow portion 1204 that extends substantially
at 90 degrees from the longitudinal axis L. A distal end of the
elbow portion 1204 is coupled to an injection needle 1206 that
extends substantially at 90 degrees from the longitudinal axis L.
One of ordinary skill in the art will recognize that exemplary
automatic injection devices may include injection needles that
extend along the longitudinal axis L of the syringe or that extend
at any suitable angle relative to the longitudinal axis L of the
syringe. Exemplary angles may include, but are not limited to,
about 70 degrees to about 110 degrees.
[0268] In some exemplary embodiments, as illustrated in FIGS. 13
and 14, a syringe may include a barrel portion and an injection
needle coupled to a distal end of the barrel portion. The injection
needle may be inserted into a patient's skin to deliver a
therapeutic agent contained in the barrel portion of the syringe.
The injection needle may be aligned at any suitable angle relative
to the longitudinal axis of the barrel portion ranging from about 0
degrees to about 180 degrees.
[0269] In some exemplary embodiments, as illustrated in FIGS. 13
and 14, a syringe may include a barrel portion and an injection
needle coupled directly or indirectly to a distal end of the barrel
portion. The syringe needle may convey a therapeutic agent
contained in the barrel portion of the syringe to the injection
needle, and the injection needle may deliver the therapeutic agent
into a patient's skin. A coupling between the syringe needle and
the injection needle may be provided by one or more intermediate
components. An exemplary coupling component may include, for
example, an adapter, provided between the distal end of the barrel
portion and the injection needle.
[0270] FIG. 13 illustrates an exemplary syringe 1300 suitable for
use in an exemplary automatic injection device. The syringe 1300
includes a barrel portion 1302 configured to extend from a proximal
end to a distal end along a longitudinal axis L and configured to
hold a dose of a therapeutic agent. A distal end of the barrel
portion 1302 is coupled to a hollow syringe needle 1304. The
syringe needle 1304 is, in turn, coupled to a hypodermic injection
needle 1306 through an exemplary intermediate adapter 1308. More
specifically, a proximal portion of the adapter 1308 is coupled to
the syringe needle 1304 and a distal portion of the adapter 1308 is
coupled to the injection needle 1306. The adapter 1308 may
establish a substantially .pi.degree alignment between the
longitudinal axis L of the barrel portion 1302 and the hypodermic
injection needle 1306.
[0271] The exemplary adapter 1308 is a component that includes a
first portion 1310 that extends from the barrel portion 1302
substantially parallel to the longitudinal axis L, and a second
portion 1312 that extends from the first portion 1310 substantially
perpendicular to the longitudinal axis L. More specifically, a
proximal end of the first portion 1310 is coupled to a distal end
of the barrel portion 1302. In an exemplary embodiment, the
proximal end of the first portion 1310 may envelope the distal end
of the barrel portion 1302. A distal end of the first portion 1310
is coupled to a proximal end of the second portion 1312. A distal
end of the second portion 1312 is coupled to a proximal end of the
injection needle 1306. In an exemplary embodiment, the first
portion 1310 and the second portion 1312 of the adapter 1308 may be
formed integrally.
[0272] Exemplary adapters may be formed of a rigid material
including, but not limited to, plastic materials, steel, and the
like. Exemplary adapters may alternatively be formed of a flexible
material including, but not limited to, rubber and the like.
[0273] The configuration of the adapter 1308 coupled to the
injection needle 1306 allows the injection needle 1306 to extend at
about .pi.degrees relative to the longitudinal axis L of the
syringe. This configuration simplifies the manufacturing of the
wearable automatic injection device as it eliminates the need for a
bent injection needle. The exemplary injection needle 1306
maintains a low profile against the patient while allowing for
proper insertion into the patient's skin during an injection in an
injection state. One of ordinary skill in the art will recognize
that exemplary injection needles may be bent from the longitudinal
axis of the syringe to any suitable angle not limited to about
.pi.degrees, e.g., about 70 degrees to about 110 degrees.
[0274] In some exemplary embodiments, one or more fluid conduits
may be disposed between the syringe needle and the injection needle
to allow a flow of the therapeutic agent from the barrel portion to
the injection needle through the syringe needle. Any suitable fluid
conduit or fluid transfer mechanism may be used to establish the
one or more fluid conduits between the syringe needle and the
injection needle. In an exemplary embodiment, a pierceable septum
in its intact state may separate the syringe needle from fluid
communication from the injection needle. When the syringe needle
pierces the septum during an injection in an injection state, fluid
communication may be established between the syringe needle and the
injection needle through the fluid conduit.
[0275] FIG. 14 illustrates a portion of an exemplary automatic
injection device in which a fluid conduit couples a syringe needle
and an injection needle. The device includes a syringe or cartridge
assembly having a barrel portion 1400 holding a dose of a
therapeutic agent. A distal end of the barrel portion 1400 is
coupled to a syringe needle 1402. A transfer mechanism 1404 is
provided in contact with or in the vicinity of the syringe needle
1402, and also in contact with or in the vicinity of an injection
needle (not pictured). The transfer mechanism 1404 includes a fluid
conduit or passageway 1406 that establishes fluid communication
between the syringe needle 1402 and the injection needle.
[0276] In an exemplary embodiment, the transfer mechanism 1404
includes a pierceable septum 1408 that separates the syringe needle
1402 from the fluid conduit 1406 in the transfer mechanism 1404
before an injection in a pre-injection state. In an exemplary
embodiment, during an injection in an injection state, the syringe
or cartridge may be moved toward the transfer mechanism 1404 so
that the syringe needle 1402 pierces the septum 1408 to create a
fluid communication path among the barrel portion 1400, the fluid
conduit 1406 of the transfer mechanism 1404, and the injection
needle. The therapeutic agent may thereby flow out of the barrel
portion 1400 through the syringe needle 1402 into the fluid conduit
1406. The therapeutic agent may then be transmitted through the
fluid conduit 1406 into the injection needle for delivery of the
therapeutic agent to a patient.
[0277] FIG. 15 illustrates an exemplary transfer mechanism 1500 for
providing a fluid conduit 1502 between a syringe needle (not
pictured) and an injection needle (not pictured). The fluid conduit
1502 may include a centrally extending channel 1504 through which
the therapeutic agent flows from the syringe needle to the
injection needle, and raised wall portions 1506 extending along the
edges of the channel 1504 in order to constrain the fluid to the
channel 1504. The fluid conduit 1502 may take any suitable form and
dimension. In the illustrative embodiment, the fluid conduit 1502
has a first substantially straight portion 1508 aligned at about
.pi.degrees from a second substantially straight portion 1510.
[0278] The fluid conduit 1502 may include a fluid inlet 1512 for
entry of the therapeutic agent from the syringe needle, and a fluid
outlet 1514 for exit of the therapeutic agent into the injection
needle. The fluid inlet 1512 may be coupled directly or indirectly
to the proximal end of a syringe needle. In an exemplary
embodiment, a pierceable septum (not pictured) may be provided at
the fluid inlet 1512 to prevent fluid flow from the syringe needle
when the septum is intact, and to allow fluid flow from the syringe
needle when the septum is pierced by the syringe needle. The fluid
outlet 1514 may be coupled directly or indirectly to the distal end
of the injection needle in order to establish a fluid flow path
between the fluid conduit 1502 and the injection needle.
[0279] Alternatively, 1512 may be used as the fluid outlet and 1514
may be used as the fluid inlet. In this exemplary embodiment, fluid
inlet 1514 may be coupled directly or indirectly to a syringe
needle, and fluid outlet 1512 may be coupled directly or indirectly
to an injection needle.
[0280] The transfer mechanism 1500 may be formed of two housing
portions 1516 and 1518 stacked together. In an exemplary
embodiment, the fluid conduit 1502 may be formed on the surface of
portion 1516, and portion 1518 may be stacked over the fluid
conduit 1502 so as to seal the edges of the fluid conduit 1502 in
order to prevent fluid leakage from the fluid conduit. Compression
between the two housing portions 1516 and 1518 may be provided by
one or more mechanical interlocking mechanism, for example, one or
more fasteners, snaps, chemical bonding, ultrasonic welding, and
others.
[0281] The fluid conduit 1502 may be formed on the surface of the
housing portion 1516 using any suitable technology. In an exemplary
embodiment, the raised wall portions 1506 of the fluid conduit 1502
may be formed of a low durometer material molded as a gasket to
seal the flow path of the therapeutic agent. In another exemplary
embodiment, laser welding may be used to trace a path around the
perimeter of the channel 1504 in order to simultaneously create a
seal around the channel 1504 and bond the two housing portions 1516
and 1518 together.
[0282] FIG. 16 illustrates an exemplary transfer mechanism 1600 for
providing a fluid conduit 1602 between a syringe with a syringe
needle 1604 coupled to a barrel portion 1606 and an injection
needle (not pictured). The transfer mechanism 1600 may include a
first portion 1608 having a septum 1610 provided in the vicinity of
the syringe needle 1604.
[0283] The first portion 1608 of the transfer mechanism 1600 may
include an internal hollow space for accommodating the therapeutic
agent and an inlet port 1612 coupled to one end of a hollow tube
1614. Another end of the hollow tube 1614 is coupled directly or
indirectly (for example, through a second portion similar to first
portion 1608) to the injection needle. The hollow tube 1614
provides a fluid path from the syringe needle 1604 to the injection
needle. The hollow tube 1614 may take any suitable form, alignment
and dimension. In the illustrative embodiment, the hollow tube 1614
extends substantially at right angles to the longitudinal axis of
the barrel portion 1606.
[0284] In an exemplary embodiment, the transfer mechanism 1600 may
be moveable upward and/or downward along the vertical axis. In this
embodiment, before an injection in a pre-injection state (for
example, when the syringe needle is covered by a needle cover), the
transfer mechanism 1600 may be in a vertically raised position
above the syringe needle 1604 such that the syringe needle 1604 is
not aligned with the septum 1610 in the transfer mechanism 1600,
thereby preventing fluid communication between the syringe needle
1604 and the transfer mechanism 1600. At the beginning of an
injection (for example, upon removal of the syringe cover from the
syringe needle 1604), the transfer mechanism 1600 may be
automatically lowered to a vertically lowered position such that
the syringe needle 1604 becomes aligned with the septum 1610 in the
transfer mechanism 1600, thus allowing the syringe needle 1604 to
pierce the septum 1610. Exemplary embodiments may provide any
suitable actuation mechanism for lowering the transfer mechanism
1600 from the vertically raised position to the vertically lowered
position at the beginning of an injection.
[0285] In an exemplary embodiment, the syringe needle 1604 may be
initially coupled to or provided immediately adjacent to the first
portion 1608. In another embodiment, the syringe may be in a
retraction position within the wearable automatic injection device
and the syringe needle 1604 may be initially separated from the
first portion 1608 of the transfer mechanism 1600. In this
embodiment, before an injection in a pre-injection state, the
syringe needle 1604 may be separated from the septum 1610 in the
first portion 1608 and may not be in fluid communication with the
transfer mechanism 1600. At the beginning of an injection, the
syringe may be moved forwardly by a cartridge or syringe actuator
to an extended position within the device, and the syringe needle
1604 may pierce the septum 1610, allowing the therapeutic agent to
flow from the barrel portion 1606 to the transfer mechanism 1600.
Exemplary embodiments may provide any suitable syringe or cartridge
actuation mechanism for advancing the barrel portion and/or the
cartridge assembly within the housing between the retracted
position and the extended position in order to pierce the septum
and convey the therapeutic agent to the patient's skin through the
injection needle.
[0286] An advantage of the exemplary transfer mechanism 1600 is
that the motions of the syringe needle 1604 and the injection
needle are decoupled and independent from each other. For example,
the mechanism coupling the syringe needle 1604 to the inlet port
1612 need not take into consideration how this coupling would
affect the outlet of the transfer mechanism 1600 coupled to the
injection needle.
[0287] FIG. 17 illustrates an exemplary transfer mechanism 1700 for
providing a fluid conduit between a syringe having a syringe needle
1704 coupled to a barrel portion 1706 and an injection needle (not
pictured). The transfer mechanism 1700 may include an inlet portion
(not pictured) couplable to the syringe needle 1704 and an outlet
portion (not pictured) couplable to the injection needle. A hollow
tube 1708, for example, a jumper tube, may be used to couple the
inlet portion of the transfer mechanism to the outlet portion of
the transfer mechanism. The hollow tube 1708 provides a fluid path
from the syringe needle 1704 to the injection needle. The hollow
tube 1708 may take any suitable form, alignment and dimension. In
the illustrative embodiment, the hollow tube 1708 extends
substantially at right angles to the longitudinal axis of the
barrel portion 1706.
[0288] In an exemplary embodiment, the inlet portion of the
transfer mechanism 1700 may include a septum (not pictured)
provided in the vicinity of the syringe needle 1704. Piercing of
the septum by the syringe needle 1704 may establish fluid
communication between the barrel portion 1706 and the transfer
mechanism 1700. In an exemplary embodiment, the outlet portion of
the transfer mechanism may include a septum (not pictured) provided
in the vicinity of the injection needle. Piercing of the septum by
the injection needle may establish fluid communication between the
transfer mechanism 1700 and the patient's skin.
[0289] In an exemplary embodiment, the transfer mechanism 1700 may
be moveable upward and/or downward along the vertical axis. In this
embodiment, before an injection in a pre-injection state (for
example, when the syringe needle is covered by a needle cover), the
transfer mechanism 1700 may be in a vertically raised position
above the syringe needle 1704 such that the syringe needle 1704 is
not aligned with the septum in the transfer mechanism 1700, thereby
preventing fluid communication between the syringe needle 1704 and
the transfer mechanism 1700. At the beginning of an injection (for
example, upon removal of the syringe cover from the syringe needle
1704), the transfer mechanism 1700 may be automatically lowered to
a vertically lowered position such that the syringe needle 1704
becomes aligned with the septum in the transfer mechanism 1700,
thus allowing the syringe needle 1704 to pierce the septum.
Exemplary embodiments may provide any suitable actuation mechanism
for lowering the transfer mechanism 1700 from the vertically raised
position to the vertically lowered position at the beginning of an
injection.
[0290] In an exemplary embodiment, the syringe needle 1704 may be
initially coupled to or provided immediately adjacent to the first
portion 1708. In another embodiment, the syringe may be in a
retraction position within the wearable automatic injection device
and the syringe needle 1704 may be initially separated from the
transfer mechanism 1700. In this embodiment, before an injection in
a pre-injection state, the syringe needle 1704 may be separated
from the septum and may not be in fluid communication with the
transfer mechanism 1700. At the beginning of an injection, the
syringe may be moved forwardly by a cartridge or syringe actuator
to an extended position within the device, and the syringe needle
1704 may pierce the septum, allowing the therapeutic agent to flow
from the barrel portion 1706 to the transfer mechanism 1700.
Exemplary embodiments may provide any suitable syringe or cartridge
actuation mechanism for advancing the barrel portion and/or the
cartridge assembly within the housing between the retracted
position and the extended position in order to pierce the septum
and convey the therapeutic agent to the patient's skin through the
injection needle.
[0291] In the exemplary embodiments illustrated in 15-17, a tight
and reliable fluid path conveys the therapeutic agent from the
barrel portion of a syringe or cartridge through a pierced septum
and a tube or channel in a transfer mechanism and eventually into
an injection needle. This configuration allows the syringe needle
assembly and the injection needle assembly to move independently of
each other, which facilitates retraction of the injection needle
into the housing in a post-injection state after an injection has
been performed, while leaving the syringe needle in a position in
which it pierces the septum.
[0292] FIGS. 18A and 18B illustrate an exemplary wearable automatic
injection device including a syringe and an exemplary transfer
mechanism. FIG. 18A illustrates a perspective view of the device.
FIG. 18B illustrates a disassembled view showing the components of
the device. The automatic injection device 1800 includes a housing
portion 1802 that includes an adhesive layer 1804 at a patient
contact region that may be removed to attach the device to a
patient's body or clothing.
[0293] The housing portion 1802 holds a syringe 1806 in a
stationary or moveable manner in the device 1800. The syringe 1806
holds a dose of a therapeutic agent and that is coupled to a
syringe needle 1808 at its distal end. The syringe needle 1808 may
extend substantially along the longitudinal axis of the syringe
1806. In a packaged pre-injection state, the syringe needle 1808
may be covered by a syringe needle cover 1805, which may be removed
by a patient before an injection. In an injection state, the
syringe needle 1808 may be uncovered. In an exemplary embodiment,
removal of the adhesive layer 1804 may also remove the syringe
needle cover 1805.
[0294] An injection button 1810 is provided in the vicinity of the
syringe needle 1808. The injection button 1810 includes holds an
injection needle 1812 at substantially 90 degrees relative to the
syringe needle 1808, and includes a transfer mechanism that
provides a fluid conduit between the syringe needle 1808 and the
injection needle 1812. In a packaged pre-injection state, the
injection needle 1812 may be covered by an injection needle cover
1813, which may be removed by a patient before an injection. In an
injection state, the injection needle 1812 may be uncovered. In an
exemplary embodiment, removal of the adhesive layer 1804 may also
remove the injection needle cover 1813.
[0295] The injection button 1810 also includes a septum 1811 that
prevents the syringe needle 1808 from establishing fluid
communication with the fluid conduit in the injection button 1810.
A cover 1813 may be provided to cover the septum 1811 in a
pre-injection state, which may be removed by a patient before an
injection. In an exemplary embodiment, the septum cover 1813 and
the syringe needle cover 1805 may be coupled so that removal of one
also removes the other.
[0296] In an exemplary embodiment, in a pre and post-injection
state, the syringe needle cover 1805 may cover the syringe needle
1808, and the injection button 1810 may be in a vertically raised
position as displaced by the syringe needle cover 1805 such that
the injection needle 1812 is retracted within the housing 1802. In
this state, the septum 1811 of the injection button 1810 may be
vertically above the syringe needle 1808. In addition, the syringe
1806 may be in a retracted position along the longitudinal axis of
the assembly 1806 spaced from the septum 1811 of the injection
button 1810.
[0297] When the syringe needle cover 1805 is removed from the
syringe needle 1808, the injection button 1810 is lowered to a
vertically lowered position such that the injection needle 1812
protrudes outside the housing 1802 into the patient contact region.
In an exemplary embodiment, the injection button 1810 may be
automatically lowered by the removal of the syringe needle cover
1805. In another exemplary embodiment, the injection button 1810 is
lowered by the patient pushing downward on the injection button
1810.
[0298] In an exemplary embodiment, the lowering of the injection
button 1810 aligns the syringe needle 1808 with the septum 1811 of
the injection button 1810. The lowering of the injection button
1810 also triggers a syringe actuator that advances the syringe
1806 along its longitudinal axis toward the septum 1811 of the
injection button 1810. This causes the syringe needle 1808 to
pierce the septum 1811 and establish fluid communication with the
injection needle 1812.
[0299] FIGS. 19A and 19B illustrate an exemplary wearable automatic
injection device including a syringe and an exemplary transfer
mechanism. FIG. 19A illustrates a side view of the device. FIG. 19B
illustrates a perspective view showing the components of the
device. The automatic injection device 1900 includes a housing 1902
holding a syringe 1904 in a stationary of moveable manner relative
to the housing 1902. An injection button 1906 is provided in the
housing 1902 in the vicinity of the syringe 1904 and holds an
injection needle (not pictured). The housing 1902 includes an
adhesive layer 1908 for attachment at a patient contact region.
[0300] Other components in the device 1900 similar to the
components in the device 1800 are described with reference to FIGS.
18A and 18B.
[0301] FIGS. 20A-20C illustrate an exemplary wearable automatic
injection device including a cartridge assembly and an exemplary
transfer mechanism. FIG. 20A illustrates a perspective view of the
device. FIG. 20B illustrates a top view of the device. FIG. 20C
illustrates a side view of the transfer mechanism of the device.
The automatic injection device 2000 includes a housing 2002 having
an adhesive layer 2003 for attachment at a patient contact region.
The housing 2002 holds a cartridge 2004 in a stationary or moveable
manner relative to the housing 2002. The cartridge 2004 is
configured to hold a dose of a therapeutic agent.
[0302] An injection button 2006 is provided in the housing 2002 in
the vicinity of the cartridge 2004. The injection button 2006 may
hold or be coupled to an injection needle 2008 extending
substantially at .pi.degrees relative to the longitudinal axis of
the cartridge 2004 and a syringe needle 2010 extending
substantially parallel to the longitudinal axis of the cartridge
2004. The injection button 2006 may form or include a transfer
mechanism that establishes fluid communication between the
cartridge 2004 to the injection needle 2008 through the syringe
needle 2010.
[0303] The injection button 2006 may include a housing engagement
portion 2012 that engages with a housing portion 2014 when the
injection button 2006 is pressed down during an injection in an
injection state. In an exemplary embodiment illustrated in FIG.
20C, the engagement between the housing engagement portion 2012 and
the housing portion 2014 causes the housing portion 2014 to move
parallel to the longitudinal axis of the cartridge 2004 toward the
distal end of the cartridge 2004, thus allowing the syringe needle
2010 to establish fluid communication with the barrel portion of
the cartridge 2004. In another exemplary embodiment, the engagement
between the housing engagement portion 2012 and the housing portion
2014 causes the cartridge 2004 to move parallel to the longitudinal
axis of the cartridge 2004 toward the syringe needle 2010, thus
allowing the syringe needle 2010 to establish fluid communication
with the barrel portion of the cartridge 2004.
[0304] Other components in the device 2000 similar to the
components in the device 1800 are described with reference to FIGS.
18A and 18B.
[0305] FIGS. 21A-21C illustrate an exemplary wearable automatic
injection device including an exemplary cartridge assembly. FIG.
21A illustrates a perspective view of the exemplary wearable
automatic injection device. FIG. 21B illustrates a sectional view
of the cartridge assembly taken along a longitudinal axis. FIG. 21C
illustrates a transparent top view of the transfer mechanism of the
device. The automatic injection device 2100 includes a housing 2102
having an adhesive layer 2103 for attachment at a patient contact
region. The housing 2102 holds a cartridge 2104 in a stationary or
moveable manner relative to the housing 2102. The cartridge 2104 is
configured to hold a dose of a therapeutic agent. A proximal end of
the cartridge 2104 includes a bung 2106 and a distal end of the
cartridge 2104 includes a septum 2108 that cooperatively seal the
dose within the cartridge 2104.
[0306] An injection button 2110 is provided in the housing 2102 in
the vicinity of the cartridge 2104. The injection button 2110 holds
an injection needle at a proximal end that extends substantially at
.pi.degrees relative to the longitudinal axis of the cartridge
2104. The injection button 2110 is coupled to a transfer mechanism
2111 that holds a syringe needle 2112 in the vicinity of the
cartridge 2104. The syringe needle 2112 extends substantially
parallel to the longitudinal axis of the cartridge 2104. The
transfer mechanism 2111 includes a fluid conduit to establish fluid
communication between the cartridge 2104 to the injection needle
2108 through the syringe needle 2110. In a pre-injection state, the
syringe needle 2112 may extend partly into a distal end of the
cartridge 2104 but may be spaced from the septum 2108. In an
injection state, the bung 2106 may be moved within the cartridge
2104 such that the fluid pressure in the cartridge 2104 moves the
septum 2108 forward toward the syringe needle 2112. This causes the
syringe needle 2112 to pierce the septum 2108 and establishes fluid
communication between the cartridge 2104 and the injection needle
through the syringe needle 2112.
[0307] Other components in the device 2100 similar to the
components in the device 1800 are described with reference to FIGS.
18A and 18B.
[0308] FIG. 22 illustrates an exemplary syringe or cartridge
actuator 2200 that may be used to advance a syringe 2202 or a
cartridge assembly from a retraction position to an extended
position within the housing of a wearable automatic injection
device. A proximal end of the barrel portion and/or the cartridge
assembly may be coupled to a biasing member 2204, for example, a
drive spring, that applies a force on the barrel portion of the
syringe and/or the cartridge assembly to move the barrel portion
and/or the cartridge assembly toward a septum in a transfer
mechanism (not pictured). The syringe or cartridge actuator 2200
may counter the biasing force of the biasing member, and may hold
and lock the barrel portion and/or the cartridge assembly in a
retracted position in a stable and reliable manner.
[0309] When triggered, the syringe or cartridge actuator 2200 may
allow the barrel portion and/or the cartridge assembly to move
forward toward the septum under the force of the biasing member. In
an exemplary embodiment, the syringe or cartridge actuator 2200 may
be configured and/or set to a certain distance to control the level
of triggering force required to advance the barrel portion and/or
the cartridge assembly from the retracted position to the extended
position.
[0310] Any suitable trigger mechanism may be used to trigger the
syringe or cartridge actuation systems. In an exemplary embodiment,
the trigger mechanism may automatically trigger the syringe or
cartridge actuation system when the wearable automatic injection
device moves from a pre-injection state to an injection state. In
an exemplary embodiment, the downward vertical movement of an
injection button within the housing to provide a fluid path between
the syringe or cartridge assembly and the injection needle may
provide a trigger force to trigger the plunger actuation system. In
another exemplary embodiment, the forward movement of the syringe
or cartridge assembly within the housing to establish a fluid path
between the syringe or cartridge assembly and the injection needle
may provide a trigger force to trigger the syringe or cartridge
system. In another exemplary embodiment, the syringe or cartridge
system may be manually triggered by a user.
[0311] Before an injection in a pre-injection state, a needle
cover, for example, a soft and rigid needle shield assembly (not
pictured), provided at the distal end of the syringe may
protectively cover the syringe needle. At this stage, since the
syringe needle is covered with the needle cover, the distal end of
the syringe has a first greater diameter. As such, the transfer
mechanism including the septum is maintained in a vertically raised
position above the needle cover, and the septum is not aligned with
the syringe needle. When the needle cover is removed from the
syringe in preparation for an injection (for example, manually by a
user or by an automatic mechanism), the transfer mechanism is
allowed to lower to a vertically lowered position since it is not
longer kept displaced by the rigid needle shield, and the septum in
the transfer mechanism is aligned with the syringe needle. The
removal of the needle cover thus lowers the transfer mechanism from
its raised position to its lowered position. The lowering of the
transfer mechanism, in turn, applies a trigger force to the syringe
or cartridge actuator 2200 and operates as the trigger mechanism
for the syringe or cartridge actuator 2200.
[0312] FIG. 23 illustrates an exemplary syringe or cartridge
actuator 2300 including a first portion 2302, a second portion 2304
and a hinge portion 2306 provided between the first and second
portions. The hinge portion 2306 allows the first and second
portions to rotate about the hinge relative to each other. In
different rotational configurations, the first and second portions
may have exemplary angles of between about 0 degrees and about 180
degrees between each other. The actuator 2300 may be coupled to the
syringe and to the septum and/or the transfer mechanism. When the
septum and/or transfer mechanism is in its first raised position,
the actuator 2300 may hold the syringe in place in its retracted
position. When the septum and/or transfer mechanism is in its
second lowered position, the actuator 2300 may release the syringe
so that the biasing member may push the syringe forward to its
extended position in order to pierce the septum.
IV. Exemplary Plunger Actuation Systems and Needle Retraction
Systems
[0313] Exemplary embodiments provide plunger actuation systems for
actuating a bung in a barrel portion of a wearable automatic
injection device so that the bung moves forwardly within the barrel
portion and expels a dose of a therapeutic agent contained in the
barrel portion. Any suitable trigger mechanism may be used to
trigger the plunger actuation systems. In an exemplary embodiment,
the trigger mechanism may automatically trigger the plunger
actuation system when the wearable automatic injection device moves
from a pre-injection state to an injection state. In an exemplary
embodiment, the downward vertical movement of an injection button
within the housing to provide a fluid path between the syringe or
cartridge assembly and the injection needle may provide a trigger
force to trigger the plunger actuation system. In another exemplary
embodiment, the forward movement of the syringe or cartridge
assembly within the housing to establish a fluid path between the
syringe or cartridge assembly and the injection needle may provide
a trigger force to trigger the plunger actuation system. In another
exemplary embodiment, the plunger actuation system may be manually
triggered by a user.
[0314] Certain other exemplary embodiments provide plunger
actuation devices and systems that cause actuation of the syringe
plunger at a slow rate in order to deliver the therapeutic agent to
a patient at a slow rate. Exemplary slow embodiments may deliver
therapeutic agent volumes of about 0.1 milliliters to about 1
milliliter or more in about five minutes to about thirty minutes,
although exemplary delivery rates are not limited to this exemplary
range.
[0315] Exemplary embodiments may provide a linear delivery profile
for the therapeutic agent so that the delivery rate is
substantially constant over time. In some cases, a linear delivery
profile may reduce discomfort experienced by the patient.
[0316] FIG. 24 illustrates a schematic of a portion of an exemplary
automatic injection device 2400 including a plunger actuation
mechanism that employs a fusee and a viscous damping mechanism. The
wearable automatic injection device 2400 includes a housing 2402
having a platform 2410 that is a mechanical structure for holding a
syringe or cartridge assembly 2404 in place within the wearable
automatic injection device 2400. The syringe or cartridge 2404
includes a barrel portion for holding a dose of a therapeutic agent
and a bung 2408 for sealing the dose within the barrel portion. A
plunger actuation mechanism 2406 is provided for moving the bung
2408 within the barrel portion for expelling the dose from the
barrel portion. A damping mechanism 2422, for example, a viscous
damper, is provided to regulate the motion of the bung 2408 so that
the therapeutic agent is delivered in a linear fashion, i.e., at a
substantially constant flow rate. A gear train 2420 including one
or more gears may be provided to couple the plunger actuation
mechanism 2406 to the damping mechanism 2422. The gear train 2420
may include any number of suitable gears to provide any suitable
gearing ratio.
[0317] The platform 2410 of the wearable automatic injection device
2400 may be stationary or moveable. In an exemplary embodiment, the
platform 2410 may be a substantially box-shaped or cylindrical
structure with an internal space for accommodating the syringe or
cartridge 2404. The peripheral walls surrounding the internal space
may be configured to hold a syringe or a cartridge assembly 2404 in
place. The platform 2410 may include one or more clamping mechanism
2412 for holding the syringe or cartridge 2404 in place. The
platform 2410 may also include a flange bearing 2414 provided at
the proximal end of the syringe or cartridge 2404. A flange
provided at the proximal end of the syringe or cartridge 2404 may
slide backward against the flange bearing 2414.
[0318] In an exemplary embodiment, the platform 2410 may hold the
syringe or cartridge 2404 stationary within and relative to the
platform 2410. In another exemplary embodiment, the platform 2410
may allow the syringe or cartridge 2404 to move relative to the
platform 2410, for example, toward or away from a fluid transfer
mechanism (not pictured). In this exemplary embodiment, the
internal space of the platform 2410 may include one or more
grooves, tracks or channels for facilitating the movement of the
syringe or cartridge 2404 within the platform 2410. In an exemplary
embodiment, the platform 2410 may include a window 2416, for
example, a cutout or a transparent portion, in order to allow the
patient to view the syringe or cartridge 2404.
[0319] One or more plunger actuators 2406 may be provided in the
vicinity of the syringe or cartridge 2404 for storing energy and
providing a force for driving a bung 2408 within the syringe or
cartridge 2404 toward the distal end of the syringe or cartridge
2404. In an exemplary embodiment, a plunger actuator 2406, for
example, a helical compression spring, may be used to drive the
bung 2408. The plunger actuator 2406 may be provided at least
partly within the syringe or cartridge 2404. Before an injection in
a pre-injection state, the plunger actuator 2406 may be maintained
in a compressed state. At the beginning of an injection or during
an injection in an injection state, the plunger actuator 2406 may
be allowed to expand from the compressed state to a released state.
The expansion of the plunger actuator 2406 may push the bung 2408
toward the distal end of the syringe or cartridge 2404, thus
expressing the therapeutic agent from the syringe or cartridge
2404. Advantageously, the configuration of the plunger actuator
2406 within the syringe or cartridge 2404 does not add to the
length of the housing required to hold the syringe or cartridge
2404. However, in some exemplary embodiments, the plunger actuator
2406 may not provide a constant force to drive the bung 2408.
[0320] In another exemplary embodiment, a spiral spring may be used
to drive the bung 2408. The spiral spring may be provided outside
but alongside the syringe or cartridge 2404 of within the platform
2410, which may add to the space requirement of the housing 2402.
Before an injection in a pre-injection state, the spring may be
maintained in a compressed state. At the beginning of an injection
or during an injection in an injection state, the spring may be
allowed to expand from the compressed state to a released state.
The expansion of the spring may push the bung 2408 toward the
distal end of the syringe or cartridge 2404, thus expressing the
therapeutic agent from the syringe or cartridge 2404.
Advantageously, the spiral spring may provide a substantially
constant force to drive the bung 2408.
[0321] One or more damping mechanisms may be provided for
regulating the release of energy in the plunger actuator 2406 in
order to control the delivery rate and/or the delivery time for
delivering the therapeutic agent. In an exemplary embodiment, to
achieve a slow and/or controlled delivery, the plunger actuator
2406 is prevented from accelerating without resistance from its
compressed state to a released state. The movement of the plunger
actuator 2406 may be maintained at a constant speed, for example,
by providing linear damping values. Any suitable mechanism may be
used to provide resistance against the acceleration of the plunger
actuator 2406. In an exemplary embodiment, a rotary viscous damper
2422 may be used to resist the acceleration of the plunger actuator
2406. The viscous damper 2422 may use one or more viscous fluids,
for example, silicon grease, to provide resistance. The viscous
damper 2422 may include a stationary housing holding a solid
rotating element called a "rotor." The outer circumference of the
rotor may include a plurality of teeth configured to be engaged by
the teeth of a gear in the gear train 2420. The rotor may be
surrounded by a thin film of a viscous fluid that is sealed inside
the housing. The rotation of the rotor may provide resistance
against the acceleration of the plunger actuator 2406 by shearing
the viscous fluid. In an exemplary embodiment, the viscous damper
2422 may be replaced with a different viscous damper providing a
different level of damping.
[0322] The force required to turn the rotary viscous damper 2422 is
described with reference to a coordinate system x where x=0 is at
the free length of a spring. If m is the inertia of the system, c
is the damping coefficient, and k is the spring constant, then:
m x + c x . + kx = 0 x = 1 m [ - c x . - kx ] ( 1 ) x + 2 .zeta.
.omega. 0 x . + .omega. 0 2 x = 0 ( 2 ) ##EQU00001##
where natural frequency:
.omega. 0 = k m ( 3 ) ##EQU00002##
and where damping ratio:
.zeta. = c 2 mk ( 4 ) ##EQU00003##
[0323] If the damping is driven by a rotary damper, the torque T
required to turn the dampener may be assumed to be linearly
proportional to the angular velocity by some constant C:
T=C.sub..theta.{dot over (.theta.)} (5)
[0324] If the rotary damper is coupled to the plunger actuator by a
gear train of reduction N and a spool of diameter D, then:
x . = D 2 N .theta. . .thrfore. .theta. . = 2 N x . D and ( 6 ) T
spool = F x D 2 = NT = NC .theta. .theta. . = 2 N 2 C .theta. D x .
.thrfore. F x = 4 N 2 C .theta. D 2 x . .thrfore. c x = 4 N 2 C
.theta. D 2 ##EQU00004##
[0325] In another exemplary embodiment, an escapement may be used
to resist the acceleration of the plunger actuator 2406. The
escapement may use a known period of oscillation of a balance wheel
and a spiral hairspring to incrementally release the energy of a
main spring. An escapement may provide a dependable design and
linearity in the release of the energy. In another exemplary
embodiment, a runaway escapement may be used to resist the
acceleration of the plunger actuator 2406. In another exemplary
embodiment, a swiss lever escapement may be used to resist the
acceleration of the plunger actuator 2406.
[0326] A gear train 2420 may be provided for coupling the plunger
actuator 2406 to the regulating device 2422, i.e., the viscous
damper or the escapement. The gear train 2420 may include a shaft
2424 may be coupled to the housing 2402 of the wearable automatic
injection device 2400 with a close slip fit. In an exemplary
embodiment, the shaft 2424 may support a cylindrical structure
2426, for example, a spool or a shaft, and a gear 2428 that is
provided below the spool 2426. In an exemplary embodiment, the
spool 2426 may be a cam spool or a fusee. One or more snap rings
2430 may be used to retain the spool 2426 and the gear 2428 on the
shaft 2424. The spool 2426 and the gear 2428 may be provided around
the shaft 2424 such that the centers of rotation of the spool 2426
and the gear 2428 are aligned with each other and with the shaft
2424. The spool 2426 and the gear 2428 may be cooperatively coupled
to each other and to the shaft 2424 such that the gear 2428 and the
spool 2426 may rotate together on the shaft 2424. In an exemplary
embodiment, the spool 2426 and the gear 2428 may be taken off from
the shaft 2424 and replaced with a different set of spools and
gears. The plunger actuator 2406 may be coupled to the gear train,
for example, the spool 2426, using one or more tethers or cables
2442.
[0327] In an exemplary embodiment, the spool 2426 may be any
suitable rotating mechanism including, but not limited to, a
constant diameter spool, a cam spool or fusee. If a cam or fusee is
used, the outer diameter of the cam or fusee may vary with linear
displacement D. Taking the equation for the linear damping
coefficient and holding the gear reduction N and the rotary damping
coefficient constant yields:
c x = 4 N 2 C .theta. D 2 = a D x 2 ( 7 ) ##EQU00005##
where a is constant. Substituting the above into the equation of
motion and assuming that the first derivative of .chi. is constant,
yields:
D x = - a x . k x - 1 2 - C 1 x - b + C 2 ( 8 ) ##EQU00006##
where C.sub.1, C.sub.2 and b are constants that may be varied in
order to make the velocity approximately constant. Plugging this
variable into the equation of motion and solving for x as a
function of time, x may be substituted into equation (8) to
determine D as a function of time, D.sub.t. The instantaneous
velocity may be represented as:
x . = D t 2 .phi. . .phi. . = 2 x . D t .phi. t = .intg. 0 t 2 x .
D t dt ( 9 ) ##EQU00007##
where .PHI. is the angular position of the cam or fusee. D.sub.t
and .PHI..sub.t are the polar coordinates of the cam profile.
[0328] Exemplary embodiments may couple the plunger actuator 2406
to a bung in the barrel portion of a syringe or cartridge using any
suitable mechanism. If a compression spring is used as the plunger
actuator 2406, one or more tethers or cables may be used to couple
the plunger actuator 2406 to the bung. If a spiral spring is used
as the plunger actuator 2406, spur gearing may be used to couple
the plunger actuator 2406 to the bung. The torque generated the
spiral spring by may be coupled to the bung using a pinion to push
a flexible rack around the corner of the syringe or cartridge.
[0329] In an exemplary embodiment, the spool 2426 may be in contact
with and/or coupled to a ratchet 2434 and pawl 2436. A torsion
spring (not pictured) may be provided below the pawl 2436 to
preload the pawl 2436 against the ratchet 2434. When the spool 2426
is being wound during assembly of the wearable automatic injection
device 2400, the torsion spring may be held in place. After the
spool 2426 is wound and before an injection in a pre-injection
state, the ratchet 2434 and pawl 2436 may hold the spool 2426 in
place and prevent rotational movement of the spool 2426. This holds
the tether 2442 in place which, in turn, maintains the plunger
actuator 2406 in its compressed state, preventing movement of the
plunger. At the beginning of an injection or during an injection in
an injection state, the pawl 2436 may be rotated to disengage the
ratchet 2434, for example, by a user or automatically upon the
pressing of an injection button. This allows the spool 2426 to
rotate under the pulling force of the tether 2442 caused by the
spring force of the plunger actuator 2406. The spring force of the
plunger actuator 2406 pulls the tether 2442 toward the distal end
of the syringe or cartridge 2404.
[0330] One or more additional gears may be provided in contact with
and/or coupled to the gear coupled to the spool 2426, thus forming
a gear train 2438. Each gear in the gear train 2438 may be provided
on a corresponding shaft coupled to the housing 2402 of the
wearable automatic injection device 2400. In an exemplary
embodiment, the gears in the gear train 2438 may be taken off from
their corresponding shafts and replaced with a different set of
gears. One of ordinary skill in the art will recognize that other
exemplary devices may include fewer or more gears.
[0331] The gear train 2438 may be coupled to the viscous damper
2422 or an escapement that resists acceleration of the bung 2408.
That is, the gear train may couple the viscous damper 2422 or an
escapement to the tether 2442 holding the bung 2408 so that, when
the bung 2408 is moved under the force of the plunger actuator
2406, acceleration of the plunger actuator 2406 is resisted by the
viscous damper 2422 or the escapement.
[0332] In an exemplary embodiment, the gear train 2438 may be
coupled to an encoding device 2440, for example, a rotary encoder,
that detects and logs the angular displacement or position of the
gear train and the corresponding time. A computing device may be
associated with the wearable automatic injection device to
determine the position of the syringe plunger based on the data
obtained by the encoding device 2440. The computing device may also
determine the flow rate of the therapeutic agent from the syringe
or cartridge 2404 and the corresponding time based on the data
obtained by the encoding device 2440. The computing device may be
provided integrally with the encoding device 2440 or separately
from the encoding device 2440. During assembly and testing of the
wearable automatic injection device, the encoding device 2440 may
be used to evaluate different gear trains, viscous dampers and
biasing elements, validate mathematical models and account for
variables not addressed in the mathematical models. During use of
the wearable automatic injection device to perform an injection,
the encoding device 2440 may be used to indicate one or more
conditions to the user, for example, the flow rate of the
therapeutic agent, malfunction of the device (for example, if the
flow rate is too high or too low), and the like.
[0333] In an exemplary embodiment illustrated in FIGS. 25 and 26, a
wearable automatic injection device may include a syringe assembly
moveable relative to a platform in the device. The wearable
automatic injection device includes a platform 2500, a slideable
carriage 2502 coupled to the platform 2500, and a syringe 2504
mounted on the slideable carriage 2502. A distal end of the syringe
2504 may be coupled to a syringe needle 2512. The syringe 2504 may
include a barrel portion 2506 containing a dose of a therapeutic
agent sealed by a bung 2508. A plunger actuator 2510 may be
provided in the vicinity or in contact with the bung 2508 for
moving the bung 2508 forwardly within the barrel portion 2506. In
an exemplary embodiment, the plunger actuator 2510 may include a
biasing mechanism coupled by a tether to a gear train and thereby
to a damping mechanism.
[0334] The device may also include an injection button bearing an
injection needle (not pictured) and including a pierceable septum
that may be pierced by the syringe needle 2512. The septum may be
coupled directly or through a conduit to the injection needle such
that, when pierced by the syringe needle 2512, the septum
establishes fluid communication between the barrel portion 2506 and
the injection needle.
[0335] In an exemplary embodiment, in a pre-injection state, the
syringe needle 2512 may already pierce the septum and be in fluid
communication with the injection needle. During an injection in an
injection state, the dose of the therapeutic agent may be expelled
from the barrel portion 2506 when the plunger actuator 2510 is
activated to move the bung 2508 forwardly within the barrel portion
2506. In this embodiment, the carriage 2502 may be stationary on
the platform 2500.
[0336] In another exemplary embodiment, in a pre-injection state,
the syringe needle 2512 may be spaced from the septum and may not
be in fluid communication with the injection needle. During an
injection in an injection state, the syringe 2504 may be moved
forwardly within and relative to the platform 2500 toward the
septum in order to pierce the septum with the syringe needle 2512.
In this exemplary embodiment, the carriage 2502 may be moveable and
may move relative to the platform 2500 toward the septum.
[0337] In an exemplary embodiment, a tether 2516 may be used to
couple the plunger actuator 2510 to a gear train 2518. The gear
train 2518 may in turn be coupled to a damping mechanism 2520 for
providing a linear delivery profile of the therapeutic agent. In a
pre-injection state, a lockout mechanism 2522 may hold the gear
train 2518 in place and prevent rotation of the gears. This causes
the tether 2516 to hold the plunger actuator 2510 in place and
prevents release of the plunger actuator 2510, thereby preventing
movement of the bung 2508. During an injection in an injection
state, the lockout mechanism 2522 may be released, for example,
manually by a user or automatically, thereby allowing the gears
2518 to rotate under the biasing force of the plunger actuator
2510. This may allow the moveable carriage 2502 to automatically
move toward the septum, which results in the syringe needle 2512
piercing the septum. The bung 2508 may also move within the barrel
portion 2506 toward the septum under the biasing force of the
plunger actuator 2510 to expel the dose through the syringe needle
2512.
[0338] FIGS. 27-29 illustrate a schematic of a portion of an
exemplary automatic injection device that may include a syringe
assembly that is stationary relative to the housing of the device.
The wearable automatic injection device 2800 includes a plunger
actuation mechanism for automatically actuating a bung 2802 in a
barrel portion 2804. FIG. 27 is a top view through a cover of the
device 2800. FIG. 28 is a side view of the device 2800. FIG. 29 is
a perspective view through a cover of the device 2800.
[0339] The plunger actuation mechanism may include a biasing
mechanism 2806 that operates as the plunger actuator. In an
exemplary embodiment, one or more tethers or cables 2812 may be
used to couple the biasing mechanism 2806 to a stage 3 gear 2810,
for example a fusee, that unwinds to allow the biasing mechanism
2806 to expand. A stage 1 damper 2808, for example, a viscous
damper or an escapement, regulates the movement of the bung 2802
during an injection in an injection state in order to achieve a
linear flow rate of the therapeutic agent. One or more stage 2
gears and pinions 2814 may be used to couple the stage 3 gear 2810
and the stage 1 damper 2808.
[0340] Table 7 summarizes exemplary features of an exemplary stage
1 damper, an exemplary stage 2 gear, an exemplary stage 2 pinion
and an exemplary stage 3 gear that may be used in exemplary
automatic injection devices.
TABLE-US-00007 TABLE 7 Exemplary features of exemplary plunger
actuation components Stage 3 Stage 2 Stage 2 Stage 1 Gear Pinion
Gear Damper Diametral 72 72 31.75 31.75 pitch teeth/in teeth/in
teeth/in teeth/in Number 50 teeth 18 teeth 16 teeth 11 teeth of
teeth Face width 0.100 in 0.100 in 0.050 in 0.118 in Tooth 14.5 deg
14.5 deg 14.5 deg 14.5 deg profile Material Nylon Nylon Nylon
Acetal Pitch 0.694 in 0.250 in 0.504 in 0.346 in diameter Circular
0.044 0.044 0.099 0.099 pitch in/tooth in/tooth in/tooth in/tooth
Yield 11.8 ksi 11.8 ksi 11.8 ksi 10.2 ksi strength Lewis form 0.346
0.270 0.255 0.192 factor Torque 8.5 oz-in 3.1 oz-in 3.1 oz-in 2.1
oz-in Tangential 1.53 lbf 1.53 lbf 0.76 lbf 0.76 lbf force Radial
0.39 lbf 0.39 lbf 0.20 lbf 0.20 lbf force Safety 3.71 2.90 6.25
9.62 factor Total 4.04 gearing
[0341] Failure analysis was performed on the exemplary plunger
actuation mechanism. In an exemplary embodiment, the gear train
(including the stage 2 gear) is designed assuming a Lewis bending
failure mode which assumes that the gear tooth is a simple
cantilever with tooth contact occurring at the tip. The results of
the failure analysis summarized in Table 7 indicate that the
minimum factor of safety for the gear train is 3 and that the total
gear ratio is 4.04.
[0342] Different combinations of different types of plunger
actuators (spring 1 and spring 2), spools (constant-diameter spool
or cam spool), and damping mechanisms (viscous damper or
escapement) were tested to determine their effect on the delivery
rate of the therapeutic agent. FIG. 30 illustrates x and y
coordinates (in inches) of cam profiles for: (i) the combination of
spring 1 and a viscous damper, (ii) the combination of spring 1 and
an escapement, (iii) the combination of spring 2 and a viscous
damper, and (iv) the combination of spring 2 and an escapement.
[0343] FIG. 31 illustrates a graph of therapeutic agent flow rates
(in milliliters per minute) versus time (in seconds) delivered by:
(i) the combination of spring 1 and a viscous damper, (ii) the
combination of spring 1, a viscous damper and a cam spool, (iii)
the combination of spring 1 and an escapement, (iv) the combination
of spring 1, an escapement and a cam spool, (v) the combination of
spring 2 and a viscous damper, (vi) the combination of spring 2, a
viscous damper and a cam spool, (vii) the combination of spring 2
and an escapement, (viii) the combination of spring 2, an
escapement and a cam spool, and (ix) and an ideal flow rate in
which the therapeutic agent is delivered at a substantially
constant rate. FIG. 32 illustrates a graph of the volume of
therapeutic agent (in milliliters) versus time (in seconds)
delivered by the combinations of components of FIG. 31.
[0344] FIGS. 31 and 32 show that a substantially linear flow rate
of the therapeutic agent may be achieved by the use of a cam spool
or a fusee. The use of an escapement, versus a viscous damper, may
be used to improve the linearity of the flow rate. The total
delivery time of the therapeutic agent may be controlled by
configuring the gearing ratio.
[0345] Different combinations of exemplary dampers and exemplary
gear ratios in exemplary plunger actuation mechanisms were tested.
The exemplary dampers included: (i) damping mechanism G, (ii)
damping mechanism B, (iii) damping mechanism K, and (iv) damping
mechanism V. The exemplary gear ratios included: (i) 4:1, (ii)
6.25:1, and (iii) 16:1. FIG. 33 illustrates a graph of the volume
of therapeutic agent (in milliliters) against time (in seconds)
delivered using: (i) a G damping mechanism having a damping
coefficient of about 10.3 lbf*s/in with a gear ratio of 4:1, (ii) a
B damping mechanism having a damping coefficient of about 15.1
lbf*s/in with a gear ratio of 4:1, (iii) a K damping mechanism
having a damping coefficient of about 18.9 lbf*s/in with a gear
ratio of 4:1, (iv) a V damping mechanism having a damping
coefficient of about 24.9 lbf*s/in with a gear ratio of 4:1, (v) a
G damping mechanism having a damping coefficient of about 25.1
lbf*s/in with a gear ratio of 6.25:1, (vi) a B damping mechanism
having a damping coefficient of about 37.0 lbf*s/in with a gear
ratio of 6.25:1, (vii) a K damping mechanism having a damping
coefficient of about 46.2 lbf*s/in with a gear ratio of 6.25:1,
(viii) a V damping mechanism having a damping coefficient of about
60.7 lbf*s/in with a gear ratio of 6.25:1, (ix) a G damping
mechanism having a damping coefficient of about 164 lbf*s/in with a
gear ratio of 16:1, (x) a B damping mechanism having a damping
coefficient of about 242 lbf*s/in with a gear ratio of 16:1, (xi) a
K damping mechanism having a damping coefficient of about 303
lbf*s/in with a gear ratio of 16:1, (xii) a V damping mechanism
having a damping coefficient of about 398 lbf*s/in with a gear
ratio of 16:1, and (xiii) an ideal flow rate in which the
therapeutic agent is delivered at a substantially constant
rate.
[0346] FIG. 33 shows that increasing the damping coefficient for
the same gear ratio increases the delivery time of the same volume
of therapeutic agent. In some cases, increasing the damping
coefficient makes the delivery rate more linear. For example, for
the 6:25:1 gear ratio, the highest damping coefficient of about
60.7 lbf*s/in yields linear delivery rate than the lower damping
coefficients.
[0347] FIG. 34 illustrates a graph of exemplary damper torques
(that may be back-calculated from the displacement of the plunger
actuator) against damper speeds (in rpm) for G, B, K and V model
dampers having increasing damping coefficients. The dots indicate
the actual torque values and the dotted lines indicate the assumed
manufacturer damping torque values, which indicates that the
manufacturer values were underestimated. The data indicate that the
torque values were substantially linear in the range of between 0
and about 20 rpm. This is evidenced by the high correlation
coefficient for the linear fit equations shown in the graph. Using
the new linear fit equations for the damper torque provided by the
linear fit adjusts the damping coefficient and includes a static
torque value. Substituting these new values into a computer model
allows for a close approximation of the system response.
[0348] Since the static torque is multiplied by the gear ratio and
subtracts directly from the spring force, it may be desirable to
choose the highest rate damper and the lowest gearing ratio in an
exemplary embodiment, for example, the V model damper and a 4:1
gearing ratio. FIG. 35 illustrates a graph of the volume of
therapeutic agent (in milliliters) against time (in seconds)
delivered by different exemplary syringes using a V model damper
having a damping coefficient of about 24.9 lbf*s/in and an
exemplary gear ratio of 4:1.
[0349] After adjusting the computer models to reflect the measured
damper torque, a fusee was designed to linearize the delivery rate
of therapeutic agent. FIG. 36 illustrates a graph of the volume of
therapeutic agent (in milliliters) delivered and the diameter of
the fusee or cam spool (in inches) versus the time (in seconds).
Since the diameter of the fusee changes over the delivery, the
angular position data was numerically integrated along the fusee
curve to yield the linear position data of the plunger actuator at
each data point.
[0350] FIG. 36 shows that the actual measured delivery rate is
about 10% slower than that predicted by the model but is nearly
constant as evidenced by the high correlation coefficient (0.9995).
The discrepancy between the measured and predicted data may be
explained by inefficiencies in the gearing, for example, areas
where the gearing binds may be seen as sharp changes in slope in
the graph. The discrepancy may also be explained by the tether
coupling the fusee to the plunger actuator not being perfectly in
line with the plunger actuator, or the spring rate of the plunger
actuator being lower in reality than calculated. Regardless of the
source of error, reducing the spring rate of the plunger actuator
by about 5% may produce a near perfect correlation (1.0).
[0351] Different exemplary damping mechanisms were tested at
different temperatures to determine the effect of temperature on
the damping effect, i.e., the linearity of the delivery of the
therapeutic agent. The viscous rotary damping torque is dependent
on the viscosity of the silicon grease inside the rotary damper.
The viscosity of the silicon grease depends in part on the
temperature of the surrounding environment. Different exemplary
damping mechanisms were also tested to determine the effect of
manufacturing variability in the damping mechanisms on the damping
effect, i.e., the linearity of the delivery of the therapeutic
agent. Variations in damper manufacturing may affect the resisting
torque provided by the damper.
[0352] FIG. 37 illustrates a graph of the volume of therapeutic
agent (in milliliters) delivered versus time (in seconds) achieved
by: (i) a first damper at room temperature, (ii) the first damper
at about 40 degrees Fahrenheit (in a refrigerator), (iii) a second
damper, (iv) the second damper at about 0 degree Fahrenheit (in a
freezer), (v) a third damper having manufacturing variability
relative to the first and second dampers, and (vi) a fourth damper
having manufacturing variability relative to the first and second
dampers.
[0353] FIG. 37 shows that changes in temperature did not
substantially affect the damping effect, i.e., the linearity of the
delivery of the therapeutic agent. However, the delivery rate was
affected in some cases by decreasing the temperature, for example,
for the first damper. Similarly, manufacturing variability in the
damping mechanisms did not substantially affect the damping effect,
i.e., the linearity of the delivery of the therapeutic agent.
However, the delivery rate was affected in some cases by
manufacturing variability. The damper torque values varied by about
5% in the sample group tested.
[0354] Thus, one or more factors may be configured to control the
linearity and/or the delivery rate of the therapeutic agent
including, but not limited to, the gear ratio, the damping
coefficient, manufacturing deviations in the damper, manufacturing
deviations in the plunger actuator, and the like. In addition,
other characteristics of the plunger actuator may be varied in
order to control the linearity and/or the rate of the flow of the
therapeutic agent.
[0355] FIG. 38 illustrates a schematic of a portion of an exemplary
automatic injection device 2600 that employs a fusee and an
escapement mechanism. The device 2600 includes a plunger actuation
mechanism for automatically actuating a bung 2408 contained in a
syringe or cartridge 2404. In the exemplary plunger actuation
mechanism, a runaway escapement 2602 may be used to resist the
acceleration of the plunger actuator 2406 by providing linear
damping. In the exemplary runaway escapement 2602, an escape wheel
is provided having a plurality of teeth on its circumferential
periphery and a pallet is provided in the vicinity of the escape
wheel. In an exemplary embodiment, the escape wheel may have 30
teeth, although exemplary escape wheels are not limited to 30
teeth. The escape wheel may be coupled to the spool 2426 via one or
more gears forming a gear train. In an exemplary embodiment, a
gearing ratio of 50:1 may couple the spool 2426 to the escape
wheel, but other exemplary gearing ratios may be used. The pallet
may have an adjustable mass moment of inertia by way of pin holes
that may be filed with one or more pins, for example, steel dowel
pins.
[0356] In operation, when torque is applied to the escape wheel,
the escape wheel rotates and a tooth of the escape wheel imparts an
impulse torque on the pallet such that the kinetic energy of the
pallet is reversed. The tooth pushes aside an arm of the pallet.
This causes the pallet to oscillate which frees the tooth of the
escape wheel, simultaneously bringing the alternate arm of the
pallet into interference with a second tooth of the escape wheel.
As such, as the escape wheel rotates, its movement is arrested by
periodic impact with the pallet, thus allowing the escape wheel to
rotate only when the pallet is free to oscillate. As the torque
applied to the escape wheel increases, the escape wheel imparts a
stronger impulse to the pallet, thus increasing the oscillation
speed pallet and therefore allowing the escape wheel to move more
rapidly.
[0357] Assuming that the collisions between the teeth of the escape
wheel and the pallet are perfectly elastic, the pallet absorbs, for
each impact:
T=J{dot over (.phi.)}.sup.2
[0358] The power dissipation of the pallet is directly proportion
to the frequency of oscillation of the pallet w because two
collisions occur between the escape wheel and the pallet for every
oscillation of the pallet. Thus:
P=2.omega.J{dot over (.phi.)}.sup.2
[0359] Assuming an impulse time of zero, since the collisions are
perfectly elastic, the magnitude of the angular velocity {dot over
(.phi.)} may be assumed to be constant and related to
.phi..sub.max, the angular distance between collisions (in radians)
may be represented by:
{dot over (.phi.)}=2.omega..phi..sub.max
[0360] Thus,
P=8J.omega..sup.3.phi..sub.max.sup.2
[0361] The rotational speed of the escape wheel {dot over
(.theta.)} is related to the number of teeth n and the oscillation
frequency .omega. and may be represented as:
.theta. . = 2 .pi. .omega. n .omega. = n .theta. . 2 .pi.
##EQU00008## Thus , P = J .PHI. max 2 n 3 .theta. . 3 .pi. 3
##EQU00008.2##
[0362] Since P=C.sub..theta.{dot over (.theta.)}.sup.2 for a
viscous rotary damper:
C .theta. = J .PHI. max 2 n 3 .theta. . .pi. 3 F x = ( 2 nN .pi. D
) 3 J .PHI. max 2 x . * x . = C x x . * x . ##EQU00009##
which creates a non-linear differential equation.
[0363] In another exemplary plunger actuation mechanism, a swiss
lever escapement may be used to resist the acceleration of the
plunger actuator. Assuming a coordinate system in which 0=0 is at
the equilibrium of a coil spring attached to a balance wheel. If
damping is negligible in this system, then:
J{umlaut over (.theta.)}+k.theta.=0
[0364] Where k is the torsional spring constant of the coil spring
and J is the mass moment of inertia:
J=.intg.r.sup.2dm
[0365] Where r is the distance from the center of rotation and m is
mass, the natural frequency of the system is:
.omega. 0 = k J ##EQU00010##
[0366] If the escapement wheel has n teeth and a spur gear train of
speed reduction N couples the escapement to a spool of diameter D,
then the spool rotates at angular velocity:
.phi. . = 2 .pi. .omega. 0 nN ##EQU00011##
[0367] Taking the derivative of the equation relating .theta. to
x:
d dt ( .phi. = 2 ( x - x 0 ) D ) ##EQU00012##
which yields:
.phi. . = 2 x . D ##EQU00013## Thus , x . = .pi. D .omega. 0 nN =
.pi. D nN k J ##EQU00013.2##
[0368] The components illustrated in FIG. 38 that are common to
FIG. 24 are described with reference to FIG. 24.
[0369] FIG. 39 illustrates an exemplary plunger actuation mechanism
3900 that employs one or more linear biasing mechanisms to provide
a force for expressing a therapeutic agent from the barrel portion
3902 of a wearable automatic injection device. The barrel portion
3902 extends longitudinally between a proximal end and a distal
end, and is configured to hold a dose of a therapeutic agent. A
distal end of the barrel portion 3902 is coupled to a syringe
needle 3904. A bung 3906 is provided moveably within the barrel
portion 3902 to seal the dose of the therapeutic agent.
[0370] One or more linear springs 3908 are provided for providing a
biasing force upon the bung 3906 in order to move the bung 3906
within the barrel portion 3902 toward the syringe needle 3904
during an injection in an injection state. A distal end of the
linear spring 3908 is in the vicinity of and/or in contact with a
plunger 3916 having a plurality of teeth configured for engagement
with a damping mechanism. The plunger 3916 may be provided in the
vicinity of and/or in contact with a distal end of a force
transmission mechanism, for example, one or more ball bearings
3910.
[0371] A distal end of the ball bearings 3910 may also be in the
vicinity of and/or in contact with the bung 3906 such that the
biasing force of the spring 3908 is transmitted to the bung 3906
through the ball bearings 3910. The ball bearings 3910 may be
enclosed in an enclosed track 3912 that restricts the lateral or
sideway movement of the ball bearings 3910. That is, the biasing
force of the spring 3908 causes the plunger 3916 and, in turn, ball
bearings 3910 to move substantially in a back or forth manner,
i.e., toward or away from the bung 3906. The use of the ball
bearings 3910 allows redirection of the biasing force to the bung
3906 and allows minimization of the size of the device. When
actuated, the spring 3908 exerts a biasing force in the direction
of the bung 3906. The biasing force is transmitted by the plunger
3916 and the ball bearings 3910 to the bung 3906 and causes the
bung 3906 to move toward the syringe needle 3904 within the barrel
portion 3902. This causes the therapeutic agent to be expressed
through the syringe needle 3904 to the exterior of the barrel
portion 3902.
[0372] A damping mechanism 3914, for example, a rotary viscous
damper, may be provided and associated with the spring 3908 and/or
the plunger 3916 to regulate the rate of delivery of the
therapeutic agent. The damper 3914 may include a hub and a
plurality of teeth that extend in a radial manner about the hub.
The teeth of the damper 3914 may be configured for engagement with
the teeth of the plunger 3916. The damper 3914 may provide a force
proportional to the speed of movement of the plunger 3916 in order
to regulate the delivery rate. As such, the exemplary system 3900
may be used to provide slow controlled delivery of the therapeutic
agent by configuring the force provided by the spring 3908 and/or
the properties of the damper 3914.
[0373] FIG. 40 illustrates an exemplary plunger actuation mechanism
4000 that employs one or more clock springs to provide a force to a
bung in a barrel portion in order to expel a therapeutic agent from
the barrel portion. A biasing means 4002 is provided by a
compression helical coil spring characterized by spring coils of
progressively increasing diameter, such that when the spring is
compressed, the coils nest one within the other in the manner of a
clock spring, thereby taking up the minimum of space. A portion of
the spring 4002 is in the vicinity of and/or in contact with a
mechanical escapement mechanism 4004 so that the rotary biasing
force of the spring 4002 is converted into a linear displacement of
the mechanical escapement mechanism 4004. The mechanical escapement
mechanism 4004 may be in the vicinity of and/or in contact with the
bung such that the biasing force of the spring 4002 is transmitted
as a linear displacement to the bung through the motion of the
mechanical escapement mechanism 4004. That is, the biasing force of
the spring 4002 causes the mechanical escapement mechanism 4004 to
move substantially in a back or forth manner, i.e., toward or away
from the bung. The use of the mechanical escapement mechanism 4004
allows redirection of the biasing force to the bung and allows
minimization of the size of the device.
[0374] When actuated, the spring 4002 exerts a biasing force that
is converted to a back and forth force by the mechanical escapement
mechanism 4004 in the direction of the bung. The biasing force is
transmitted directly or indirectly to the bung and causes the bung
to move toward the needle within the barrel portion. This causes
the therapeutic agent to be expressed through the needle to the
exterior of the barrel portion. As such, the exemplary system 4000
may be used to provide slow controlled delivery of the therapeutic
agent by configuring the force provided by the spring 4002 and/or
the linear displacement provided by the mechanical escapement
mechanism 4004. The mechanical escapement mechanism 4004 may be
configured to control, for example, the amount of advance per
cycle. The spring 4002 may be sized to predominate over stick-slip
forces.
[0375] FIGS. 41 and 42 illustrate an exemplary automatic injection
device 4100 that employs a fluid-based plunger actuation mechanism
in which the fluid pressure and/or movement of a working fluid is
used to move a bung within the barrel portion of a syringe or
cartridge. The plunger actuation mechanism includes one or more
fluid circuits to provide a force to a bung for expressing a dose
of a therapeutic agent from a barrel portion 4104 of a syringe or
cartridge. FIG. 41 is a schematic of the exemplary automatic
injection device 4100 and FIG. 40 is a perspective view of the
exemplary automatic injection device 4100. The wearable automatic
injection device 4100 may include a pressure element 4106 that
stores an incompressible working fluid that provides a fluid
pressure. Exemplary working fluids may include, but are not limited
to, water, air, oil, and the like. Exemplary pressure elements 4106
may include, but are not limited to, an elastic bladder, a master
cylinder, a spring-loaded syringe, and the like.
[0376] The pressure element 4106 may be coupled to a flow
restrictor 4108 via a tubing 4110. The flow restrictor 4108 may
restrict the flow of the working fluid so that the fluid pressure
upstream of the flow restrictor is greater than the fluid pressure
downstream of the flow restrictor. The flow restrictor 4108 may
include an orifice of diameter ranging from about 0.001 inch to
about 0.01 inch, but the diameters of exemplary flow restrictor
orifices are not limited to this exemplary range. The orifice of
the flow restrictor 4108 may have lengths ranging from about 10 mm
to about 50 mm, but the lengths of exemplary flow restrictor
orifices are not limited this exemplary range.
[0377] Exemplary embodiments may configure a number of
characteristics of the delivery system to control the total
delivery time of the therapeutic agent. Exemplary embodiments may
also configure a number of characteristics of the delivery system
based on the viscosity of the working fluid and/or the therapeutic
agent. Exemplary characteristics may include, but are not limited
to, the diameter of the orifice, the length of the orifice, the
viscosity of the working fluid, and the like. For example, the
diameter of the orifice of the flow restrictor may be decreased to
increase the total delivery time.
[0378] The flow restrictor 4108 may also be coupled to the bung via
a tubing 4112. When the working fluid is released from the pressure
element 4106 via the flow restrictor 4108, the fluid pressure of
the working fluid drives the bung forwardly within the barrel
portion 4104 in order to expel the dose of the therapeutic agent
from the barrel portion 4104.
[0379] In an exemplary embodiment, before an injection in a
pre-injection state, the working fluid may not be released from the
pressure element 4106. In this exemplary embodiment, a delivery
trigger (not pictured) may be coupled to the pressure element 4106
so that, upon activation of the delivery trigger, the working fluid
is released from the pressure element 4106 into the tubings 4110
and 4112. The fluid pressure of the working fluid advances the bung
within the barrel portion 4104, thus injecting the dose into the
patient's skin. Thus, the fluid circuit established by the flow of
the working fluid and the flow restrictor may provide a regulated
force to the bung.
[0380] In an exemplary embodiment, the dose is delivered in a
linear delivery profile, i.e., at a substantially constant delivery
rate. Linearity of the delivery profile may be achieved by the high
pressure of the working fluid provided by the pressure element 4106
upstream of the flow restrictor 4108 and the damping effect
provided by the flow restrictor 4108. The pressure upstream of the
flow restrictor 4108 may be maintained at a high level relative to
projected stick-slip forces such that a highly damped system is
achieved. For the bung to be moved forward within the barrel
portion 4104, the bung would need to pull a vacuum on the working
fluid between the flow restrictor 4108 and the barrel portion 4104,
which is difficult to achieve to an appreciable extent because the
working fluid is essentially incompressible.
[0381] Exemplary damped hydraulic delivery circuits allow movement
of the bung via volumetric metering, rather than by a direct
application of force, thereby minimizing stick-slip phenomena in
the delivery profile of the therapeutic agent.
[0382] In an exemplary embodiment, an exemplary volume of 0.8
milliliters of therapeutic agent may be delivered at an exemplary
delivery pressure of about 16.5 psi within an exemplary duration of
about 12 minutes. In another exemplary embodiment, an exemplary
volume of 0.8 milliliters of therapeutic agent may be delivered at
an exemplary delivery pressure of about 5 psi within an exemplary
duration of about 17 minutes.
[0383] FIG. 43 illustrates a graph of the cumulative amount of
therapeutic agent (in grams) against time (in seconds) as delivered
by an exemplary delivery system at an exemplary delivery pressure
of about 16.5 psi. FIG. 44 illustrates a graph of the cumulative
volume of therapeutic agent (in milliliters) against time (in
seconds) as delivered by an exemplary delivery system including a
first exemplary flow restrictor having an exemplary diameter of
about 0.008 inches and an exemplary length of about 34.3 mm The
total delivery time for delivering about 1 milliliters of a
therapeutic agent was about twenty seconds. FIG. 45 illustrates a
graph of the cumulative volume of therapeutic agent (in
milliliters) against time (in seconds) as delivered by an exemplary
delivery system including a second exemplary flow restrictor having
an exemplary diameter of about 0.002 inches and an exemplary length
of about 34.3 mm The total delivery time for delivering about 1
milliliters of a therapeutic agent was about 15 minutes. In the
illustrative graphs, the delivery profile is substantially linear,
i.e., substantially constant over time, and does not display an
initial bolus or abrupt changes or inflections representative of
inconsistent delivery rates.
[0384] FIG. 46 is a schematic drawing of an exemplary automatic
injection device 4600 that employs one or more fluid circuits to
provide a force for expressing a therapeutic agent from a cartridge
assembly. FIG. 47 is a top view of the exemplary device 4600. The
exemplary automatic injection device 4600 includes a barrel portion
4602 containing a dose of a therapeutic agent. A distal end of the
barrel portion 4602 is provided in the vicinity of or coupled to a
syringe needle (hidden by a needle cover 4604) that is protectively
covered by a needle cover 4604. The device 4600 includes an
injection button that includes a septum and bears an injection
needle (not pictured). In an exemplary embodiment, the device 4600
may include an injection needle carrier 4606 for holding the
injection needle. In an exemplary embodiment, the injection needle
may be extend substantially orthogonally to the plane of the device
as illustrated, and may be held in place by the needle carrier
4606. A needle lock 4608 may be provided for preventing the
injection needle from exiting the housing once engaged and may be
located in the housing near the injection needle.
[0385] In an exemplary embodiment, a syringe or cartridge actuator
4610 may be provided for advancing the barrel portion 4602 within
the housing toward the septum. A trigger may be provided for
triggering the syringe or cartridge actuator 4610, for example,
when the injection button is pressed down or when the needle cover
4604 is removed.
[0386] In this exemplary embodiment, a master cylinder 4612
containing a working fluid is provided for providing a fluid
pressure to actuate a bung 4614 within the barrel portion 4602. The
master cylinder 4612 may be coupled to a delivery trigger 4616
that, when activated, releases the working fluid into fluid
communication with the bung 4614 and allows the fluid pressure to
advance the bung 4614 within the barrel portion 4602.
[0387] Exemplary embodiments also provide needle retraction systems
for retracting an injection needle from a vertically lowered
position (or an extended or deployed position) outside the housing
of the device at the patient contact region to a vertically raised
position (or a retracted position) within the housing of the
device. The wearable automatic injection device 4600 includes a
retraction mechanism that automatically raises the injection button
from a vertically depressed position within the housing during an
injection in an injection state to a vertically raised position
within the housing in a post-injection state after an injection. In
an exemplary embodiment, the retraction mechanism may be a
telescoping element. The master cylinder 4612 may be coupled to a
retraction trigger that, when activated, releases the working fluid
into fluid communication with the retraction trigger and allows the
fluid pressure to activate the retraction mechanism.
[0388] FIG. 48 illustrates a top view of the device 4600 which
shows a conduit 4802 coupling the master cylinder 4612 to a flow
restrictor 4804, a conduit 4806 coupling the flow restrictor 4804
to the bung in the barrel portion of the device, and a conduit 4808
coupling the master cylinder 4612 to a retraction mechanism 4810
via a valve 4812, for example, a check valve. FIG. 49 illustrates a
schematic diagram of the device 4600.
[0389] The check valve 4812 may have a suitable cracking pressure
at or above which the check valve 4812 allows fluid into the
conduit 4808 coupled to the retraction mechanism 4810. In an
exemplary embodiment, the cracking pressure is higher than the
maximum fluid pressure in the conduit 4806 required to drive the
bung during an injection in an injection state. Otherwise,
undesirably, the needle retraction process may begin during or even
before the injection. In an exemplary embodiment, the pressure in
the conduit 4806 at the end of the movement of the bung during an
injection in an injection state is higher than the cracking
pressure. Otherwise, at the end of the movement of the bung, the
pressure in the conduit 4808 may be insufficient to activate the
retraction mechanism 4810. The volume of the working fluid in the
master cylinder 4612 is sufficient to deliver the entire dose of
the therapeutic agent and to activate the retraction mechanism
4810.
[0390] In an exemplary embodiment, the retraction mechanism 4810
and the check valve 4812 may be provided separately. In another
exemplary embodiment, the retraction mechanism 4810 and the check
valve 4812 may be provided as a single element, for example, as an
inverting diaphragm.
[0391] FIG. 50 illustrates a graph of the pressure after the check
valve and behind the bung (in psi) versus time (in seconds) in an
exemplary embodiment. In an exemplary embodiment, the cracking
pressure of the check valve may be about 7.5 psi and the diameter
of the flow restrictor orifice may be about 0.008 inches.
[0392] During an injection in an injection state, the flow
restrictor 4804 may cause the pressure in the conduit 4802 to be
about 10 to about 15 psi, while the pressure in the conduit 4806
may be about 5 to about 6 psi. The check valve 4812 thus prevents
any flow of the working fluid from entering the conduit 4808 while
the bung is moving during the injection. Once the bung stops moving
at the end of the injection, i.e., when the dose has been
completely expelled from the barrel portion, the pressure in the
conduit 4806 increases beyond 7.5 psi. This causes the check valve
4812 to open, allowing the working fluid to flow into the conduit
4808 which activates the retraction mechanism 4810. The retraction
mechanism 4810 in turn unlocks the needle lock and retracts the
injection button/carrier 4606 bearing the injection needle. Because
it is based on pressure equalization in the hydraulic circuit, the
needle retraction process ensures that the entire dose is delivered
before the injection needle is retracted, maximizes utilization of
the therapeutic agent, and minimizes the overfill required in the
barrel portion 4602.
[0393] Any suitable trigger mechanism may be used to trigger the
needle retraction systems. In an exemplary embodiment, the trigger
mechanism may automatically trigger the needle retraction system
when the wearable automatic injection device moves from an
injection state to a post-injection state. In an exemplary
embodiment, completion of the delivery of a therapeutically
effective dose of the therapeutic agent may trigger the needle
retraction system. In another exemplary embodiment, the removal of
the device from the patient before completion of the delivery of a
therapeutically effective dose of the therapeutic agent may trigger
the needle retraction system. In another exemplary embodiment, the
needle retraction system may be manually triggered by a user.
[0394] FIG. 51 illustrates a side view of an exemplary automatic
injection device 5100 in which the housing 5102 of the wearable
automatic injection device 5100 includes a skin sensor foot 5104,
which is a structure in an exemplary embodiment housed under or in
the portion of the housing 5102 proximal to the injection site. In
an exemplary embodiment, prior to injection of the therapeutic
agent and during injection, the skin sensor foot 5104 is retained
within or forms a portion of the underside of the housing 5102.
When the wearable automatic injection device 5100 is attached to
the injection site and activated, the skin sensor foot 5104 may be
free to move but may be constrained by the injection site. In an
exemplary embodiment, when the wearable automatic injection device
5100 is removed from the injection site, regardless of whether the
drug delivery was completed, the skin sensor foot 5104 is no longer
constrained, and extends and projects outside the periphery of the
housing 5102. This, in turn, trips a retraction trigger. When the
retraction trigger is activated, a retraction mechanism retracts
the injection needle which may also raise the injection button from
the vertically lowered position to the vertically raised position,
so that the injection button protrudes from the top of the housing
5102 and the injection needle is retracted within the housing
5102.
V. Exemplary Needle Protection Systems
[0395] Exemplary embodiments provide different exemplary needle
protection systems for maintaining the injection needle within the
wearable automatic injection device in a post-injection state after
an injection. Protection of the needle prevents accidental needle
sticks from injuring the patient or any other humans in the
vicinity of the wearable automatic injection device.
[0396] FIGS. 52A and 52B illustrate an exemplary needle protection
system 5200 that maintains an injection needle 5202 in a retracted
position within a housing 5204 of an automatic injection system.
The injection needle 5202 is movable relative to the housing 5204
away from or toward the patient's skin. When the needle 5202 is in
a position within the housing 5204 farther from the patient's skin,
the needle 5202 is in a retracted position and does not protrude
outside the housing 5204. When the needle 5202 is in a position
within the housing 5204 closer to the patient's skin, the needle
5202 is in an inserted or deployed position and protrudes fully or
partly from the housing 5204. The housing 5204 may be provided with
an aperture 5206 through which the needle 5202 may protrude outside
the housing 5204.
[0397] The needle protection system 5200 employs a barrier
mechanism 5208 which prevents the needle 5202 from protruding from
the housing 5204 in a pre-injection state before an injection and
in a post-injection state after an injection when the needle 5202
is in the retracted position. FIG. 52A illustrates the system 5200
in which the needle 5202 is in an inserted or deployed position and
protrudes fully or partly through the aperture 5206 outside the
housing 5204, for example, during an injection in an injection
state. In this case, the barrier mechanism 5208 is displaced away
from the aperture 5206 so that the aperture 5206 is open to the
outside of the housing 5204, and the needle 5202 is free to
protrude through the aperture 5206 to the outside of the housing
5204. FIG. 52B illustrates the system 5200 in which the needle 5202
is in a retracted position and does not protrude from the housing
5204, for example, in a pre-injection state and a post-injection
state. In this case, the barrier mechanism 5208 is aligned with and
covers the aperture 5206 so that the aperture 5206 is no longer
open to the outside of the housing 5204, and the needle 5202 is not
free to protrude through the aperture 5206 to the outside of the
housing 5204. In an exemplary embodiment, the barrier mechanism
5208 may be moved rotatably above a point of rotation between a
first position in which it exposes the aperture 5206 (in FIG. 52A)
to a second position in which it covers the aperture 5206 (in FIG.
52B).
[0398] FIGS. 53A and 53B illustrate another exemplary needle
protection system 5300 provided in the housing 5302 of an automatic
injection system. The automatic injection system includes an
injection needle 5304 that is movable relative to the housing 5302
away from or toward the patient's skin. When the needle 5304 is in
a position within the housing 5302 farther from the patient's skin,
the needle 5304 is in a retracted position and does not protrude
outside the housing 5302. When the needle 5304 is in a position
within the housing 5302 closer to the patient's skin, the needle
5304 is in an inserted or deployed position and protrudes fully or
partly from the housing 5302.
[0399] The needle protection system 5300 includes a needle lockout
sleeve 5306 provided in the vicinity of the injection needle 5304
for locking the injection needle in the retracted position in a
pre-injection state and a post-injection state. The needle lockout
sleeve 5306 may be coupled to a pin 5308 disposed in a slot 5310.
The pin 5308 may be in a first position (illustrated in FIG. 53A)
relative to the slot 5310 in which the needle lockout sleeve 5306
locks the injection needle 5304 in the retracted position within
the housing 5302. The pin 5308 may be in a second position
(illustrated in FIG. 53B) relative to the slot 5310 in which the
needle lockout sleeve 5306 allows the injection needle 5304 to
protrude outside the housing 5302.
[0400] In an exemplary embodiment, an early-removal retraction
trigger 5312 that, then tripped, triggers a retraction mechanism
that retracts the injection needle 5304 into the housing 5302. The
early-removal retraction trigger 5312 may be tripped when the
wearable automatic injection device 5300 is removed from the
injection site before the therapeutically effective dose of
therapeutic agent is completely delivered. In an exemplary
embodiment, the early-removal retraction trigger 5312 may include a
latch 5314, e.g., a flexible plastic hook, that is released upon
removal of the wearable automatic injection device 5300 from the
injection site. FIG. 53A shows the early-removal retraction trigger
5312 in which the latch 5314 is engaged to a portion of the lockout
sleeve 5306 when the wearable injection device is coupled to the
injection site. FIG. 53B shows the early-removal retraction trigger
5312 in which the latch 5314 is released from the portion of the
lockout sleeve 5306 when the wearable injection device is removed
from the injection device. Release of the latch 5314 from the
portion of the lockout sleeve 5306 triggers the retraction
mechanism. An exemplary retraction mechanism may be responsive to
an end-of-dose retraction trigger and responsive to the
early-removal retraction trigger 5310 to automatically retract the
injection needle 5304 from the injection site.
[0401] FIG. 54 illustrates an exemplary needle protection system
5400 that maintains an injection needle held by an injection
carrier 5402 in a retracted position within a housing 5404 of an
automatic injection system. The injection needle is movable
relative to the housing 5404 away from or toward the patient's
skin. When the injection needle is in a position within the housing
5404 farther from the patient's skin, the needle is in a retracted
position and does not protrude outside the housing 5404. When the
needle is in a position within the housing 5404 closer to the
patient's skin, the needle is in an inserted or deployed position
and protrudes fully or partly from the housing 5404. The housing
5404 may be provided with an aperture through which the needle may
protrude outside the housing 5404.
[0402] The needle protection system 5400 includes a needle lock
5408 provided in the vicinity of or in contact with the needle
carrier 5402. In an exemplary embodiment, the needle lock 5408 may
be a pivoting or rotating member that may pivot or rotate about a
pivoting point or interface. A needle lock release mechanism 5410
may be provided in the vicinity of or in contact with the needle
lock 5408. The needle lock release mechanism 5410 may be in a first
position when the injection needle is in a vertically lowered
position and protrudes outside the housing 5404 (in an injection
state), and in a second position when the injection needle is in a
vertically raised or retracted position within the housing 5404 (in
a pre-injection state or a post-injection state)
[0403] When the needle lock release mechanism 5410 is in the first
position (that is, when the injection needle is in a vertically
lowered injection position), the needle lock 5408 may be in an
unlocked position in which it does not lock the injection needle in
the vertically raised position in the housing 5404. Alternatively,
the needle lock 5408 may in a locked position in which it locks the
injection needle 5408 in the vertically lowered position in the
housing 5404. In an exemplary embodiment (that is, when the
injection needle is in a vertically lowered injection position),
retraction of the injection needle and/or the needle carrier 5402
to the vertically raised position within the housing 5404 may
trigger the needle lock release mechanism 5410, i.e., move the
release mechanism from the first position to the second position.
When the needle lock release mechanism 5410 is moved to the second
position, the needle lock 5408 may pivot or rotate, thereby locking
the injection needle and/or the needle carrier 5402 in the
vertically raised position in the housing 5404.
[0404] FIG. 55 illustrates an exemplary needle protection system
5500 that maintains an injection needle held by an injection
carrier 5502 in a retracted position within a housing 5504 of an
automatic injection system. The injection needle is movable
relative to the housing 5504 away from or toward the patient's
skin. When the injection needle is in a position within the housing
5504 farther from the patient's skin, the needle is in a retracted
position and does not protrude outside the housing 5504. When the
needle is in a position within the housing 5504 closer to the
patient's skin, the needle is in an inserted or deployed position
and protrudes fully or partly from the housing 5504. The housing
5504 may be provided with an aperture through which the needle may
protrude outside the housing 5504.
[0405] The needle protection system 5500 includes a needle lock
5508 provided in the vicinity of or in contact with the needle
carrier 5502. In an exemplary embodiment, the needle lock 5508 may
be a pivoting or rotating member that may pivot or rotate about a
pivoting point or interface. The needle lock 5508 may include a
biasing mechanism 5506 that applies a rotational spring force to
the needle carrier 5502 about a longitudinal axis of the biasing
mechanism. In an exemplary embodiment, the needle lock 5508 may be
provided in a symmetrical manner about the needle carrier 5502 such
that the rotational force is applied by the biasing mechanism 5506
substantially symmetrically about the needle carrier 5502.
[0406] A needle lock release mechanism 5510 may be provided in the
vicinity of or in contact with the needle lock 5508. The needle
lock release mechanism 5510 may be in a first position when the
injection needle is in a vertically lowered position and protrudes
outside the housing 5504 (in an injection state), and in a second
position when the injection needle is in a vertically raised or
retracted position within the housing 5504 (in a pre-injection
state or a post-injection state)
[0407] When the needle lock release mechanism 5510 is in the first
position (that is, when the injection needle is in a vertically
lowered injection position), the biasing mechanism 5506 may apply a
spring force to the needle carrier 5502 in the clockwise direction
toward the patient's body such that the needle carrier 5502 is held
in the vertically lowered position. When the needle lock release
mechanism 5510 is in the second position (that is, when the
injection needle is in a vertically raised pre or post-injection
state), the biasing mechanism 5506 may apply a spring force to the
needle carrier 5502 in the counter-clockwise direction away from
the patient's body such that the needle carrier 5502 is raised to
and held in the vertically raised position.
[0408] In an exemplary embodiment, retraction of the injection
needle and/or the needle carrier 5502 to the vertically raised
position within the housing 5504 may trigger the needle lock
release mechanism 5510, i.e., move the release mechanism from the
first position to the second position. When the needle lock release
mechanism 5510 is moved to the second position, the needle lock
5508 may pivot or rotate under the force of the biasing member 5506
in the counter-clockwise direction away from the patient's body,
thereby locking the injection needle and/or the needle carrier 5502
in the vertically raised position in the housing 5504.
VI. Therapeutic Agents for Use in Exemplary Automatic Injection
Devices
[0409] Exemplary automatic injection devices may be used to
administer essentially any substance or therapeutic agent that is
suitable for administration by injection. Typically, the substance
or therapeutic agent will be in a fluid, e.g., liquid form,
although medications in other forms such as gels or semi-solids,
slurries, particulate solutions, etc. also may suitable for use if
the wearable automatic injection device is designed to permit the
administration of such forms of the medication.
[0410] Preferred medications are biological agents, such as
antibodies, cytokines, vaccines, fusion proteins and growth
factors. Methods of making antibodies are described above.
[0411] Non-limiting examples of other biological agents that can be
used as the medication in the automatic injection device include
but are not limited to antibodies to or antagonists of human
cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,
IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, IL-21,
IL-23, interferons, EMAP-II, GM-CSF, FGF, and PDGF; antibodies to
cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28,
CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA or
their ligands including CD154 (gp39 or CD40L); TNF.alpha.
converting enzyme (TACE) inhibitors; IL-1 inhibitors
(Interleukin-1-converting enzyme inhibitors, IL-1RA etc.);
Interleukin 11; IL-18 antagonists including IL-18 antibodies or
soluble IL-18 receptors, or IL-18 binding proteins; non-depleting
anti-CD4 inhibitors; antagonists of the co-stimulatory pathway CD80
(B7.1) or CD86 (B7.2) including antibodies, soluble receptors or
antagonistic ligands; agents which interfere with signaling by
proinflammatory cytokines such as TNF.alpha. or IL-1 (e.g. IRAK,
NIK, IKK , p38 or MAP kinase inhibitors); IL-1.quadrature.
converting enzyme (ICE) inhibitors; T-cell signaling inhibitors
such as kinase inhibitors; metalloproteinase inhibitors;
angiotensin converting enzyme inhibitors; soluble cytokine
receptors and derivatives thereof (e.g. soluble p55 or p75 TNF
receptors and the derivatives p75TNFRIgG (Enbrel.TM. and p55TNFRIgG
(Lenercept)), sIL-1RI, sIL-1RII, sIL-6R); antiinflammatory
cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGF-beta); Rituximab;
IL-1 TRAP; MRA; CTLA4-Ig; IL-18 BP; anti-IL-18; anti-IL15;
IDEC-CE9.1/SB 210396 (non-depleting primatized anti-CD4 antibody;
IDEC/SmithKline; see e.g., Arthritis & Rheumatism (1995) Vol.
38; S185); DAB 486-IL-2 and/or DAB 389-IL-2 (IL-2 fusion proteins;
Seragen; see e.g., Arthritis & Rheumatism (1993) Vol. 36;
1223); Anti-Tac (humanized anti-IL-2Ra; Protein Design Labs/Roche);
IL-4 (anti-inflammatory cytokine; DNAX/Schering); IL-10 (SCH 52000;
recombinant IL-10, anti-inflammatory cytokine; DNAX/Schering);
IL-10 and/or IL-4 agonists (e.g., agonist antibodies); IL-1RA (IL-1
receptor antagonist; Synergen/Amgen); anakinra
(Kineret.RTM./Amgen); TNF-bp/s-TNF (soluble TNF binding protein;
see e.g., Arthritis & Rheumatism (1996) 39(9, supplement);
5284; Amer. J. Physiol.--Heart and Circulatory Physiology (1995)
268:37-42); R973401 (phosphodiesterase Type IV inhibitor; see e.g.,
Arthritis & Rheumatism (1996) 39(9, supplement); S282); MK-966
(COX-2 Inhibitor; see e.g., Arthritis & Rheumatism (1996) 39(9,
supplement); S81); Iloprost (see e.g., Arthritis & Rheumatism
(1996) 39(9, supplement); S82); zap-70 and/or lck inhibitor
(inhibitor of the tyrosine kinase zap-70 or lck); VEGF inhibitor
and/or VEGF-R inhibitor (inhibitors of vascular endothelial cell
growth factor or vascular endothelial cell growth factor receptor;
inhibitors of angiogenesis); TNF-convertase inhibitors; anti-IL-12
antibodies; anti-IL-18 antibodies; interleukin-11 (see e.g.,
Arthritis & Rheumatism (1996) 39(9, supplement), S296);
interleukin-13 (see e.g., Arthritis & Rheumatism (1996) 39(9,
supplement), S308); interleukin -17 inhibitors (see e.g., Arthritis
& Rheumatism (1996) 39(9, supplement), S120); anti-thymocyte
globulin; anti-CD4 antibodies; CD5-toxins; ICAM-1 antisense
phosphorothioate oligo-deoxynucleotides (ISIS 2302; Isis
Pharmaceuticals, Inc.); soluble complement receptor 1 (TP10; T Cell
Sciences, Inc.); and anti-IL2R antibodies.
VII. TNF.alpha. Inhibitors for Use in Exemplary Automatic Injection
Devices
[0412] According to one embodiment of the invention, the
illustrative automatic injection device may be used to deliver a
dose of a TNF inhibitor used to treat arthritis and other diseases.
In one embodiment, the solution contained in the syringe contains
40 or 80 milligrams of drug product (TNF.alpha. blocker or
inhibitor)/1 mL, for example, 40 or 80 mg adalimumab, 4.93 mg
sodium chloride, 0.69 mg monobasic sodium phosphate dehydrate, 1.22
mg dibasic sodium phosphate dehydrate, 0.24 mg sodium citrate, 1.04
mg citric acid monohydrate, 9.6 mg mannitol, 0.8 mg polysorbate 50
and water for injection, with USP sodium hydroxide added as
necessary to adjust pH to be about 5.2.
[0413] The present invention can be used to administer a dose of a
substance, such as a liquid drug, e.g., a TNF.alpha. inhibitor, to
a patient. In one embodiment, the dose delivered by the automatic
injection device of the invention comprises a human TNF.alpha.
antibody, or antigen-binding portion thereof.
[0414] In one embodiment, the TNF inhibitor used in the methods and
compositions of the invention includes isolated human antibodies,
or antigen-binding portions thereof, that bind to human TNF.alpha.
with high affinity and a low off rate, and have a high neutralizing
capacity. Preferably, the human antibodies of the invention are
recombinant, neutralizing human anti-hTNF.alpha. antibodies, such
as, e.g., the recombinant, neutralizing antibody referred to as
D2E7, also referred to as HUMIRA.sup..quadrature. or adalimumab
(Abbott Laboratories; the amino acid sequence of the D2E7 VL region
is shown in SEQ ID NO: 1 of U.S. Pat. No. 6,090,382 the amino acid
sequence of the D2E7 VH region is shown in SEQ ID NO: 2 of U.S.
Pat. No. 6,090,382). Properties of D2E7 have been described in
Salfeld et al., U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015.
Other examples of TNF.alpha. inhibitors include chimeric and
humanized murine anti-hTNF.alpha. antibodies that have undergone
clinical testing for treatment of rheumatoid arthritis (see e.g.,
Elliott et al. (1994) Lancet 344:1125-1127; Elliot et al. (1994)
Lancet 344:1105-1110; and Rankin et al. (1995) Br. J. Rheumatol.
34:334-342).
[0415] An anti-TNF.alpha. antibody (also referred to herein as a
TNF.alpha. antibody), or an antigen-binding fragment thereof,
includes chimeric, humanized, and human antibodies. Examples of
TNF.alpha. antibodies that may be used in the invention include,
but not limited to, infliximab (Remicade.RTM., Johnson and Johnson;
described in U.S. Pat. No. 5,656,272, incorporated by reference
herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4
antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody
fragment), an anti-TNF dAb (Peptech), and CNTO 148 (golimumab;
Medarex and Centocor, see WO 02/12502). Additional TNF antibodies
that may be used in the invention are described in U.S. Pat. Nos.
6,593,458; 6,498,237; 6,451,983; and 6,448,380.
[0416] Other examples of TNF.alpha. inhibitors which may be used in
the methods and compositions of the invention include etanercept
(Enbrel, described in WO 91/03553 and WO 09/406476), soluble TNF
receptor Type I, a pegylated soluble TNF receptor Type I (PEGs
TNF-R1), p55TNFR1 gG (Lenercept), and recombinant TNF binding
protein (r-TBP-I) (Serono).
[0417] In one embodiment, exemplary embodiments provide improved
uses and compositions for treating a disorder in which TNF.alpha.
is detrimental, e.g., rheumatoid arthritis, with a TNF.alpha.
inhibitor, e.g., a human TNF.alpha. antibody, or an antigen-binding
portion thereof, through a wearable automatic injection device.
[0418] A TNF.alpha. inhibitor includes any agent (or substance)
that interferes with TNF.alpha. activity. In a preferred
embodiment, the TNF.alpha. inhibitor can neutralize TNF.alpha.
activity, particularly detrimental TNF.alpha. activity which is
associated with disorders in which TNF.alpha. activity is
detrimental, including, but not limited to, rheumatoid arthritis,
juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's
disease, psoriasis, and psoriatic arthritis.
VIII. Pharmaceutical Compositions for Use in Exemplary Automatic
Injection Devices
[0419] Pharmaceutical compositions may be loaded into the automatic
injection device of the invention for delivery to a patient. In one
embodiment, antibodies, antibody-portions, as well as other
TNF.alpha. inhibitors, can be incorporated into pharmaceutical
compositions suitable for administration to a patient using the
device of the invention. Typically, the pharmaceutical composition
comprises an antibody, antibody portion, or other TNF.alpha.
inhibitor, and a pharmaceutically acceptable carrier.
"Pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents, and the like that
are physiologically compatible. Examples of pharmaceutically
acceptable carriers include one or more of water, saline, phosphate
buffered saline, dextrose, glycerol, ethanol and the like, as well
as combinations thereof. In many cases, it is preferable to include
isotonic agents, for example, sugars, polyalcohols such as
mannitol, sorbitol, or sodium chloride in the composition.
Pharmaceutically acceptable carriers may further comprise minor
amounts of auxiliary substances such as wetting or emulsifying
agents, preservatives or buffers, which enhance the shelf life or
effectiveness of the antibody, antibody portion, or other
TNF.alpha. inhibitor.
[0420] The compositions for use in the methods and compositions of
the invention may be in a variety of forms in accordance with
administration via the device of the invention, including, for
example, liquid solutions (e.g., injectable and infusible
solutions), dispersions or suspensions. In a preferred embodiment,
the antibody or other TNF.alpha. inhibitor is administered by
subcutaneous injection using the device of the invention. In one
embodiment, the patient administers the TNF.alpha. inhibitor,
including, but not limited to, TNF.alpha. antibody, or
antigen-binding portion thereof, to himself/herself using the
device of the invention
[0421] Therapeutic compositions typically must be sterile and
stable under the conditions of manufacture and storage. The
composition can be formulated as a solution, microemulsion,
dispersion, liposome, or other ordered structure suitable to high
drug concentration. Sterile injectable solutions can be prepared by
incorporating the active compound (i.e., antibody, antibody
portion, or other TNF.alpha. inhibitor) in the required amount in
an appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
are vacuum drying and freeze-drying that yields a powder of the
active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof. The proper fluidity
of a solution can be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required
particle size in the case of dispersion and by the use of
surfactants. Prolonged absorption of injectable compositions can be
brought about by including in the composition an agent that delays
absorption, for example, monostearate salts and gelatin.
[0422] In one embodiment, exemplary embodiments provide a wearable
automatic injection device, e.g., autoinjector pen, comprising an
effective TNF.alpha. inhibitor and a pharmaceutically acceptable
carrier. Thus, the invention provides a pre-fillable and/or
pre-filled automatic injection device comprising a TNF.alpha.
inhibitor.
[0423] In one embodiment, the antibody or antibody portion for use
in the methods of the invention is incorporated into a
pharmaceutical formulation as described in PCT/IB03/04502 and U.S.
Patent Publication No. 2004/0033228. This formulation includes a
concentration 50 mg/ml of the antibody D2E7 (adalimumab), wherein a
wearable automatic injection device contains 40 mg of antibody for
subcutaneous injection. In one embodiment, the automatic injection
device of the invention (or more specifically the syringe of the
device) comprises a formulation of adalimumab having the following
formula: adalimumab, sodium chloride, monobasic sodium phosphate
dihydrate, dibasic sodium phosphate dihydrate, sodium citrate,
citric acid monohydrate, mannitol, polysorbate 80 and water, e.g.,
water for injection. In another embodiment, the automatic injection
device comprises a volume of adalimumab including 40 mg adalimumab,
4.93 mg sodium chloride, 0.69 mg monobasic sodium phosphate
dihydrate, 1.22 mg dibasic sodium phosphate dihydrate, 0.24 mg
sodium citrate, 1.04 mg citric acid monohydrate, 9.6 mg mannitol,
0.8 mg polysorbate 80 and water, e.g., water for injection. In one
embodiment, sodium hydroxide is added as necessary to adjust
pH.
[0424] The dose amount of TNF.alpha. inhibitor in the automatic
injection device may vary according to the disorder for which the
TNF.alpha. inhibitor is being used to treat. In one embodiment, the
invention includes a wearable automatic injection device comprising
a dose of adalimumab of about 20 mg of adalimumab; 40 mg of
adalimumab; 80 mg of adalimumab; and 160 mg of adalimumab. It
should be noted that for all ranges described herein, including the
dose ranges, all numbers intermediary to the recited values are
included in the invention, e.g., 36 mg of adalimumab, 48 mg of
adalimumab, etc. In addition ranges recited using said numbers are
also included, e.g. 40 to 80 mg of adalimumab. The numbers recited
herein are not intended to limit the scope of the invention.
[0425] The TNF.alpha. antibodies and inhibitors used in the
invention may also be administered in the form of protein crystal
formulations that include a combination of protein crystals
encapsulated within a polymeric carrier to form coated particles.
The coated particles of the protein crystal formulation may have a
spherical morphology and be microspheres of up to 500 micro meters
in diameter or they may have some other morphology and be
microparticulates. The enhanced concentration of protein crystals
allows the antibody of the invention to be delivered
subcutaneously. In one embodiment, the TNF.alpha. antibodies of the
invention are delivered via a protein delivery system, wherein one
or more of a protein crystal formulation or composition, is
administered to a patient with a TNF.alpha.-related disorder.
Compositions and methods of preparing stabilized formulations of
whole antibody crystals or antibody fragment crystals are also
described in WO 02/072636, which is incorporated by reference
herein. In one embodiment, a formulation comprising the
crystallized antibody fragments described in International Patent
Application No. PCT/IB03/04502 and U.S. Patent Publication No.
2004/0033228 is used to treat rheumatoid arthritis using the
methods of the invention.
[0426] Supplementary active compounds can also be incorporated into
the compositions. In certain embodiments, an antibody or antibody
portion for use in the methods of the invention is co-formulated
with and/or co-administered with one or more additional therapeutic
agents, including a rheumatoid arthritis inhibitor or antagonist.
For example, an anti-hTNF.alpha. antibody or antibody portion may
be co-formulated and/or co-administered with one or more additional
antibodies that bind other targets associated with TNF.alpha.
related disorders (e.g., antibodies that bind other cytokines or
that bind cell surface molecules), one or more cytokines, soluble
TNF.alpha. receptor (see e.g., PCT Publication No. WO 94/06476)
and/or one or more chemical agents that inhibit hTNF.alpha.
production or activity (such as cyclohexane-ylidene derivatives as
described in PCT Publication No. WO 93/19751) or any combination
thereof. Furthermore, one or more antibodies of the invention may
be used in combination with two or more of the foregoing
therapeutic agents. Such combination therapies may advantageously
utilize lower dosages of the administered therapeutic agents, thus
avoiding possible side effects, complications or low level of
response by the patient associated with the various monotherapies.
Additional agents that may be used in combination with a TNF.alpha.
antibody or antibody portion are described in U.S. patent
application Ser. No. 11/800531, which is expressly incorporated
herein by reference in its entirety.
IX. Incorporation by Reference
[0427] The contents of all references, including patents and patent
applications, cited throughout this application are hereby
incorporated herein by reference in their entirety. The appropriate
components and methods of those references may be selected for the
invention and embodiments thereof. Still further, the components
and methods identified in the Background section are integral to
this disclosure and can be used in conjunction with or substituted
for components and methods described elsewhere in the disclosure
within the scope of the invention.
X. Equivalents
[0428] In describing exemplary embodiments, specific terminology is
used for the sake of clarity. For purposes of description, each
specific term is intended to at least include all technical and
functional equivalents that operate in a similar manner to
accomplish a similar purpose. Additionally, in some instances where
a particular exemplary embodiment includes a plurality of system
elements or method steps, those elements or steps may be replaced
with a single element or step. Likewise, a single element or step
may be replaced with a plurality of elements or steps that serve
the same purpose. Further, where parameters for various properties
are specified herein for exemplary embodiments, those parameters
may be adjusted up or down by 1/20th, 1/10th, 1/5th, 1/3rd, 1/2,
etc., or by rounded-off approximations thereof, unless otherwise
specified. Moreover, while exemplary embodiments have been shown
and described with references to particular embodiments thereof,
those of ordinary skill in the art will understand that various
substitutions and alterations in form and details may be made
therein without departing from the scope of the invention. Further
still, other aspects, functions and advantages are also within the
scope of the invention.
[0429] Exemplary flowcharts are provided herein for illustrative
purposes and are non-limiting examples of methods. One of ordinary
skill in the art will recognize that exemplary methods may include
more or fewer steps than those illustrated in the exemplary
flowcharts, and that the steps in the exemplary flowcharts may be
performed in a different order than shown.
Sequence CWU 1
1
371107PRTArtificialD2E7 light chain variable region 1Asp Ile Gln
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25 30Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40
45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg
Ala Pro Tyr 85 90 95Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
1052121PRTArtificialD2E7 heavy chain variable region 2Glu Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10 15Ser Leu
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30Ala
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val
50 55 60Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu
Asp Tyr Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser Ser 115
12039PRTArtificialD2E7 light chain variable region CDR3 3Gln Arg
Tyr Asn Arg Ala Pro Tyr Xaa1 5412PRTArtificialD2E7 heavy chain
variable region CDR3 4Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp
Xaa1 5 1057PRTArtificialD2E7 light chain variable region CDR2 5Ala
Ala Ser Thr Leu Gln Ser1 5617PRTArtificialD2E7 heavy chain variable
region CDR2 6Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp
Ser Val Glu1 5 10 15Gly711PRTArtificialD2E7 light chain variable
region CDR1 7Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala1 5
1085PRTArtificialD2E7 heavy chain variable region CDR1 8Asp Tyr Ala
Met His1 59107PRTArtificial2SD4 light chain variable region 9Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly1 5 10
15Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr
20 25 30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro65 70 75 80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Lys Tyr
Asn Ser Ala Pro Tyr 85 90 95Ala Phe Gly Gln Gly Thr Lys Val Glu Ile
Lys 100 10510121PRTArtificial2SD4 heavy chain variable region 10Gln
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Asp Trp
Val 35 40 45Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp
Ser Val 50 55 60Glu Gly Arg Phe Ala Val Ser Arg Asp Asn Ala Lys Asn
Ala Leu Tyr65 70 75 80Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95Thr Lys Ala Ser Tyr Leu Ser Thr Ser Ser
Ser Leu Asp Asn Trp Gly 100 105 110Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120119PRTArtificial2SD4 light chain variable region CDR3
11Gln Lys Tyr Asn Ser Ala Pro Tyr Ala1 5129PRTArtificialEP B12
light chain variable region CDR3 12Gln Lys Tyr Asn Arg Ala Pro Tyr
Ala1 5139PRTArtificialVL10E4 light chain variable region CDR3 13Gln
Lys Tyr Gln Arg Ala Pro Tyr Thr1 5149PRTArtificialVL100A9 light
chain variable region CDR3 14Gln Lys Tyr Ser Ser Ala Pro Tyr Thr1
5159PRTArtificialVLL100D2 light chain variable region CDR3 15Gln
Lys Tyr Asn Ser Ala Pro Tyr Thr1 5169PRTArtificialVLL0F4 light
chain variable region CDR3 16Gln Lys Tyr Asn Arg Ala Pro Tyr Thr1
5179PRTArtificialLOE5 light chain variable region CDR3 17Gln Lys
Tyr Asn Ser Ala Pro Tyr Tyr1 5189PRTArtificialVLLOG7 light chain
variable region CDR3 18Gln Lys Tyr Asn Ser Ala Pro Tyr Asn1
5199PRTArtificialVLLOG9 light chain variable region CDR3 19Gln Lys
Tyr Thr Ser Ala Pro Tyr Thr1 5209PRTArtificialVLLOH1 light chain
variable region CDR3 20Gln Lys Tyr Asn Arg Ala Pro Tyr Asn1
5219PRTArtificialVLLOH10 light chain variable region CDR3 21Gln Lys
Tyr Asn Ser Ala Ala Tyr Ser1 5229PRTArtificialVL1B7 light chain
variable region CDR3 22Gln Gln Tyr Asn Ser Ala Pro Asp Thr1
5239PRTArtificialVL1C1 light chain variable region CDR3 23Gln Lys
Tyr Asn Ser Asp Pro Tyr Thr1 5249PRTArtificialVL0.1F4 light chain
variable region CDR3 24Gln Lys Tyr Ile Ser Ala Pro Tyr Thr1
5259PRTArtificialVL0.1H8 light chain variable region CDR3 25Gln Lys
Tyr Asn Arg Pro Pro Tyr Thr1 5269PRTArtificialLOE7.A light chain
variable region CDR3 26Gln Arg Tyr Asn Arg Ala Pro Tyr Ala1
52712PRTArtificial2SD4 heavy chain variable region CDR3 27Ala Ser
Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asn1 5
102812PRTArtificialVH1B11 heavy chain variable region CDR3 28Ala
Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Lys1 5
102912PRTArtificialVH1D8 heavy chain variable region CDR3 29Ala Ser
Tyr Leu Ser Thr Ser Ser Ser Leu Asp Tyr1 5
103012PRTArtificialVH1A11 heavy chain variable region CDR3 30Ala
Ser Tyr Leu Ser Thr Ser Ser Ser Leu Asp Asp1 5
103112PRTArtificialVH1B12 heavy chain variable region CDR3 31Ala
Ser Tyr Leu Ser Thr Ser Phe Ser Leu Asp Tyr1 5
103212PRTArtificialVH1E4 heavy chain variable region CDR3 32Ala Ser
Tyr Leu Ser Thr Ser Ser Ser Leu His Tyr1 5 103312PRTArtificialVH1F6
heavy chain variable region CDR3 33Ala Ser Phe Leu Ser Thr Ser Ser
Ser Leu Glu Tyr1 5 103412PRTArtificial3C-H2 heavy chain variable
region CDR3 34Ala Ser Tyr Leu Ser Thr Ala Ser Ser Leu Glu Tyr1 5
103512PRTArtificialVH1-D2.N heavy chain variable region CDR3 35Val
Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Asn1 5
1036321DNAArtificialD2E7 light chain variable region 36gacatccaga
tgacccagtc tccatcctcc ctgtctgcat ctgtagggga cagagtcacc 60atcacttgtc
gggcaagtca gggcatcaga aattacttag cctggtatca gcaaaaacca
120gggaaagccc ctaagctcct gatctatgct gcatccactt tgcaatcagg
ggtcccatct 180cggttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag cctacagcct 240gaagatgttg caacttatta ctgtcaaagg
tataaccgtg caccgtatac ttttggccag 300gggaccaagg tggaaatcaa a
32137363DNAArtificialD2E7 heavy chain variable region 37gaggtgcagc
tggtggagtc tgggggaggc ttggtacagc ccggcaggtc cctgagactc 60tcctgtgcgg
cctctggatt cacctttgat gattatgcca tgcactgggt ccggcaagct
120ccagggaagg gcctggaatg ggtctcagct atcacttgga atagtggtca
catagactat 180gcggactctg tggagggccg attcaccatc tccagagaca
acgccaagaa ctccctgtat 240ctgcaaatga acagtctgag agctgaggat
acggccgtat attactgtgc gaaagtctcg 300taccttagca ccgcgtcctc
ccttgactat tggggccaag gtaccctggt caccgtctcg 360agt 363
* * * * *